High X-ray Dose Research Articles

Genotoxic effects of high dose rate X-ray and low dose rate gamma radiation in ApcMin/+ mice.

Risk estimates for radiation‐induced cancer in humans are based on epidemiological data largely drawn from the Japanese atomic bomb survivor studies, which received an acute high dose rate (HDR) ionising radiation. Limited knowledge exists about the effects of chronic low dose rate (LDR) exposure, particularly with respect to the application of the dose and dose rate effectiveness factor. As part of a study to investigate the development of colon cancer following chronic LDR vs. acute HDR radiation, this study presents the results of genotoxic effects in blood of exposed mice. CBAB6 F1 Apc+/+ (wild type) and ApcMin/+ mice were chronically exposed to estimated whole body absorbed doses of 1.7 or 3.2 Gy 60Co‐γ‐rays at a LDR (2.2 mGy h−1) or acutely exposed to 2.6 Gy HDR X‐rays (1.3 Gy min−1). Genotoxic endpoints assessed in blood included chromosomal damage (flow cytometry based micronuclei (MN) assay), mutation analyses (Pig‐a gene mutation assay), and levels of DNA lesions (Comet assay, single‐strand breaks (ssb), alkali labile sites (als), oxidized DNA bases). Ionising radiation (ca. 3 Gy) induced genotoxic effects dependent on the dose rate. Chromosomal aberrations (MN assay) increased 3‐ and 10‐fold after chronic LDR and acute HDR, respectively. Phenotypic mutation frequencies as well as DNA lesions (ssb/als) were modulated after acute HDR but not after chronic LDR. The ApcMin/+ genotype did not influence the outcome in any of the investigated endpoints. The results herein will add to the scant data available on genotoxic effects following chronic LDR of ionising radiation. Environ. Mol. Mutagen. 58:560–569, 2017. © 2017 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society

The CD44 standard isoform contributes to radioresistance of pancreatic cancer cells.

Resistance to chemoradiotherapy is one reason for the increased recurrence rate of pancreatic cancer after these therapies. These cells change the expression levels of several proteins, such as epithelial–mesenchymal transition (EMT), while acquiring the chemo- or radio-resistance. In this study, we focused on CD44, a pancreatic cancer stem cell marker. CD44 has isoforms with different functions: standard isoform (CD44s) and several variant isoforms (CD44v). However, little is known about the roles of these isoforms after ionizing irradiation. The purpose of this study was to investigate the role of CD44 isoforms in radioresistance of pancreatic cancer cells. AsPC-1 (a human pancreatic cancer cell line) was irradiated with 4 MV X-rays. The mRNA and protein levels of CD44s were strongly upregulated, dose dependently, compared with CD44v after irradiation. Thus, we further investigated CD44s at the point of cell proliferation. We evaluated cell proliferation and survival, using CD44s knockdown cells. CD44s knockdown did not change the proliferation rate for up to 72 h after the irradiation, but decreased cell viability in the colony formation assay. As one of the reasons for these effects, we found downregulation of phosphorylated extracellular signal–regulated kinase (Erk; which is involved with cell proliferation) by CD44s knockdown, time dependently. Moreover, radiation-induced EMT-like expression changes were detected and suppressed by CD44s knockdown. In conclusion, our work demonstrated that CD44 standard isoform was especially upregulated after high-dose X-ray irradiation in several isoforms of CD44 and contributed to longer-term cell survival after the irradiation through the maintenance of Erk phosphorylation and radiation-induced EMT.

Irradiation of Mesenchymal Stromal Cells With Low and High Doses of Alpha Particles Induces Senescence and/or Apoptosis.

The use of high-linear energy transfer charged particles is gaining attention as a medical tool because of the emission of radiations with an efficient cell-killing ability. Considerable interest has developed in the use of targeted alpha-particle therapy for the treatment of micrometastases. Moreover, the use of helium beams is gaining momentum, especially for treating pediatric tumors. We analyzed the effects of alpha particles on bone marrow mesenchymal stromal cells (MSCs), which have a subpopulation of stem cells capable of generating adipocytes, chondrocytes, and osteocytes. Further, these cells contribute toward maintenance of homeostasis in the body. MSCs were irradiated with low and high doses of alpha particles or X-rays and a comparative biological analysis was performed. At a low dose (40 mGy), alpha particles exhibited a limited negative effect on the biology of MSCs compared with X-rays. No significant perturbation of cell cycle was observed, and a minimal increase in apoptosis or senescence was detected. Self-renewal was preserved as revealed by the CFU assay. On the contrary, with 2000 mGy alpha particles, we observed adverse effects on the vitality, functionality, and stemness of MSCs. These results are the consequence of different proportion of cells targeted by alpha particles or X-rays and the quality of induced DNA damage. The present study suggests that radiotherapy with alpha particles may spare healthy stem cells more efficaciously than X-ray treatments, an observation that should be taken into consideration by physicians while planning irradiation of tumor areas close to stem cell niches, such as bone marrow. J. Cell. Biochem. 118: 2993-3002, 2017. © 2017 Wiley Periodicals, Inc.

Fluorescent nuclear track images of Ag-activated phosphate glass irradiated with photons and heavy charged particles

In this paper we report about the demonstration of the nuclear track imaging capabilities of Ag-activated phosphate glass. A 375nm laser and confocal laser scanning microscopy (CLSM) were respectively used for track excitation and detection. Specifically, the blue and orange radiophotoluminescent (RPL) tracks and dose distributions observed after irradiation with soft X-rays, gamma rays and heavy charged particles (HCPs) are examined. In addition, the origins of the reductions in RPL efficiency for high-dose X-ray irradiation and for irradiation with HCPs with high linear energy transfer (LET) values are investigated via a CLSM and a conventional fluorescent reader and discussed.

Assessment of the occupational eye lens dose for clinical staff in interventional radiology, cardiology and neuroradiology

In accordance with recommendations by the International Commission on Radiological Protection, the current European Basic Safety Standards has adopted a reduced occupational eye lens dose limit of 20 mSv yr–1. The radiation safety implications of this dose limit is of concern for clinical staff that work with relatively high dose x-ray angiography and interventional radiology. Presented in this work is a thorough assessment of the occupational eye lens dose based on clinical measurements with active personal dosimeters worn by staff during various types of procedures in interventional radiology, cardiology and neuroradiology. Results are presented in terms of the estimated equivalent eye lens dose for various medical professions. In order to compare the risk of exceeding the regulatory annual eye lens dose limit for the widely different clinical situations investigated in this work, the different medical professions were separated into categories based on their distinct work pattern: staff that work (a) regularly beside the patient, (b) in proximity to the patient and (c) typically at a distance from the patient. The results demonstrate that the risk of exceeding the annual eye lens dose limit is of concern for staff category (a), i.e. mainly the primary radiologist/cardiologist. However, the results also demonstrate that the risk can be greatly mitigated if radiation protection shields are used in the clinical routine. The results presented in this work cover a wide range of clinical situations, and can be used as a first indication of the risk of exceeding the annual eye lens dose limit for staff at other medical centres.

Combining Grid Computing and Docker Containers for the Study and Parametrization of CT Image Reconstruction Methods

Computed tomography (CT) is one of the most widely used methods in Medical Imaging. Despite of its relevance in the diagnosis of diseases with a high impact in our society (such as cancer), it is one of the most potentially harmful modalities. CT requires a high X-ray dose to be induced to the patients. Solving the CT Image Reconstruction problem iteratively in order to approximate the solution allows working with only a subset of the input data required by direct methods. This directly implies a reduction of the radiation received by the patient and a strong reduction on the potential morbidity. Therefore, we aim to study the feasibility of such methods for their actual application, with the purpose of concluding if they are accurate and can obtain good quality images with a lower dose of X rays. This paper discusses the use of containers within a Grid Computing platform to perform a thorough study of all the possible configurations and parameters of various methods being developed to reconstruct CT images iteratively, which could lead to find the optimal configuration of the parameters. The work compares two approaches for managing the software dependencies of the code: store the software libraries on a Storage Element and using containers for executing the job.

Anatomy, photochemical activity, and DNA polymorphism in leaves of dwarf tomato irradiated with X-rays

The response of higher plants to ionising radiation depends on factors related to both radiation properties and plant features including species, cultivar, age, and structural complexity of the target organ. Adult plants of dwarf tomato were irradiated with different doses of X-rays to investigate possible variations in leaf morpho-anatomical traits, photosynthetic efficiency, and genomic DNA. In order to assess if and how responses depend on leaf developmental stage, we analysed two types of leaves; nearly mature leaves (L1) and actively developing leaves (L2), whose lamina size corresponded to 70 and 25 %, respectively, of the lamina size of the fully expanded leaves. The results show that the X-rays prevented full lamina expansion of the L2 leaves at all doses and induced early death of tissue of plants irradiated with doses higher than 20 Gy. Most anatomical modifications were not clearly dose-dependent and the radiation-induced increase in phenolic compounds was irrespective of dose. At high doses of X-rays (50 and 100 Gy), photochemical efficiency decreased significantly in both leaf types, whereas total chlorophyll content significantly decreased only in the L2 leaves. The random amplification of polymorphic DNA data show that the X-rays induced mutagenic effects in the L2 leaves even at low doses despite the absence of severe phenotypic alterations. Genetic structure found in the population of samples corroborates the results of anatomical and eco-physiological analyses: the 20 Gy dose seems to mark the threshold dose above which genetic alterations, structural anomalies, and perturbations in the photosynthetic apparatus become significant, especially in the actively expanding leaves.

Evaluation of the MVAD pump: stability under high dose x-ray and proton radiation

Ventricular assist devices (VAD) continue to be miniaturized to decrease surgical trauma, allow for alternative implant techniques, and to provide support to a broader patient population. The MVAD pump (HeartWare Inc., Miami Lakes, FL) is the newest in this trend with a smaller displacement compared to current generation VADs. Two MVAD pumps (n = 2) were evaluated for operation stability during irradiation of high dose x-ray and proton therapeutic beams used for cancer treatment. An x-ray beam having energy of 18 MV was generated from a linear accelerator and delivered to the pump at a rate of 6 Gy min−1 to a maximum dose of 75 Gy. A Proton beam having energy of 208 MeV was generated from a cyclotron. The energy was adjusted by an energy degrader down to 175 MeV, which is equivalent to a depth of 16 cm in water, then modulated longitudinally along the beam-line by 10 cm generating the spread-out-Bragg-peak. The beam was delivered at a rate of 4 Gy min−1 to a dose of 70 Gy. Pump parameter data including power consumption, estimated flow rate, and impeller speed were recorded and analyzed for changes in pump operation between baseline, irradiation, and post-irradiation. Modeling of x-ray radiation attenuation and scattering were additionally quantified through a treatment planning computer and compared to radiation measurements. Pump operation was consistent for all tests with no fluctuations during radiation. X-ray attenuation was measured to be 27%, corresponding to a three-fold reduction over the previously evaluated HVAD pump (84%). The smaller MVAD pump can withstand therapeutic radiation levels from x-ray and proton particle accelerators and is less of an obstacle for physicians who care for patients requiring both mechanical circulatory support and radiation therapy regimens.

Investigation of relative metabolic changes in the organs and plasma of rats exposed to X-ray radiation using HR-MAS (1)H NMR and solution (1)H NMR.

Excess exposure to ionizing radiation generates reactive oxygen species and increases the cellular inflammatory response by modifying various metabolic pathways. However, an investigation of metabolic perturbations and organ-specific responses based on the amount of radiation during the acute phase has not been conducted. In this study, high-resolution magic-angle-spinning (HR-MAS) NMR and solution NMR-based metabolic profiling were used to investigate dose-dependent metabolic changes in multiple organs and tissues--including the jejunum, spleen, liver, and plasma--of rats exposed to X-ray radiation. The organs, tissues, and blood samples were obtained 24, 48, and 72 h after exposure to low-dose (2 Gy) and high-dose (6 Gy) X-ray radiation and subjected to metabolite profiling and multivariate analyses. The results showed the time course of the metabolic responses, and many significant changes were detected in the high-dose compared with the low-dose group. Metabolites with antioxidant properties showed acute responses in the jejunum and spleen after radiation exposure. The levels of metabolites related to lipid and protein metabolism were decreased in the jejunum. In addition, amino acid levels increased consistently at all post-irradiation time points as a consequence of activated protein breakdown. Consistent with these changes, plasma levels of tricarboxylic acid cycle intermediate metabolites decreased. The liver did not appear to undergo remarkable metabolic changes after radiation exposure. These results may provide insight into the major metabolic perturbations and mechanisms of the biological systems in response to pathophysiological damage caused by X-ray radiation.

Towards single particle imaging of human chromosomes at SACLA

Single particle imaging (SPI) is one of the front-page opportunities which were used to motivate the construction of the first x-ray free electron lasers (XFELs). SPI’s big advantage is that it avoids radiation damage to biological samples because the diffraction takes place in femtosecond single shots before any atomic motion can take place in the sample, hence before the onset of radiation damage. This is the ‘diffract before destruction’ theme, destruction being assured from the high x-ray doses used. This article reports our collaboration’s first attempt at SPI using the SACLA XFEL facility in June 2015. The report is limited to experience with the instrumentation and examples of data because we have not yet had time to invert them to images.

Growth Arrest and Cancer Stem Cell Marker Expression Following High Dose X-ray or Carbon Ion Beam Irradiation

Growth Arrest and Cancer Stem Cell Marker Expression Following High Dose X-ray or Carbon Ion Beam Irradiation

Involvement of UTR-dependent gene expression in the maintenance of cancer stem cell like phenotypes.

The present study demonstrated the acquisition of additional malignant characteristics in irradiated mouse fibrosarcoma cells compared with the parent cells. Several reporter assays indicated that hypoxia-inducible factor (HIF)-1α, activator protein-1 and Ets-dependent transcription were activated in irradiated cells. The cis-elements in the 5'-untranslated region (UTR) of these transcription factors plays a major role in their expression in surviving irradiated cancer cells. By contrast, there were no evident differences between the 3'-UTR-dependent repression demonstrated by parent cells and irradiated cells. A small population of parental fibrosarcoma cells was also found to exhibit the same enhanced 5'-UTR-dependent HIF-1α expression as that demonstrated by irradiated cells. These observations may indicate that high-dose X-ray irradiation affects the majority of proliferating cancer cells, but not the cancer stem cells (CSCs), and an increased CSC population may explain the progressive phenotypes of the irradiated cells. It appears likely that the transcription factors that maintain stemness are regulated by the same 5'-UTR-dependent mechanism.

X-ray doses to safely release the parasitoid Diachasmimorpha longicaudata (Hymenoptera: Braconidae) reared on Anastrepha fraterculus larvae (Diptera: Tephritidae)

Diachasmimorpha longicaudata is a koinobiont larval parasitoid that is currently used to control fruit flies of the genera Anastrepha, Ceratitis and Bactrocera. In the rearing process, a fraction of the host larvae that are exposed to parasitoids escape from parasitism and develop into viable and fertile flies. This creates the need to eliminate emerging flies before the parasitoids are shipped for release, increasing costs due to additional handling steps. Exposure of fly eggs or larvae to gamma-irradiation before they are parasitised has been used to reproductively sterilise hosts, or even inhibit their emergence. Our aim was to determine whether X-ray radiation applied to Anastrepha fraterculus third instar larvae before they are exposed to parasitoids, inhibits fly emergence in non-parasitised larvae without affecting the performance of the parasitoids that emerge from parasitised larvae. Three X-ray doses: 6250.2 R, 8333.6 R and 10417 R (equivalent to 60, 80 and 100 Gy, respectively) and one γ-ray dose (100 Gy) were tested. Fly emergence decreased with increasing doses of radiation, showing null values for the higher X-ray dose and the dose of 100 Gy. Irradiation showed either no impact or a positive effect on parasitism rate and fecundity. Sex rate was biased towards females in almost every dose. We conclude that the two types of radiation evaluated here were equally effective in suppressing fly emergence with no detrimental effects on the biological quality of the produced parasitoids. X-rays offer an alternative method of irradiation than the conventional radiation source, i.e. γ-rays. These results represent a significant improvement in the development of a biological control programme against A. fraterculus.

Enhanced radiation therapy with multilayer microdisks containing radiosensitizing gold nanoparticles.

A challenge of X-ray radiation therapy is that high dose X-rays at therapeutic conditions damage normal cells. This paper describes the use of gold nanoparticle-loaded multilayer microdisks to enhance X-ray radiation therapy, where each microdisk contains over 10(5) radiosensitizing nanoparticles. The microdisks are attached on cell membranes through electrostatic interaction. Upon X-ray irradiation, more photoelectrons and Auger electrons are generated in the vicinity of the nanoparticles, which cause water ionization and lead to the formation of free radicals that damage the DNA of adjacent cancer cells. By attaching a large amount of gold nanoparticles on cancer cells, the total X-ray dose required for DNA damage and cell killing can be reduced. Due to their controllable structure and composition, multilayer microdisks can be a viable choice for enhanced radiation therapy with nanoparticles.

Research on new high-dose X-ray tube

Research on new high-dose X-ray tube

Interventional digital tomosynthesis from a standard fluoroscopy system using 2D-3D registration.

Interventional fluoroscopy provides guidance in a variety of minimally invasive procedures. However, three-dimensional (3D) clinically relevant information is projected onto a two-dimensional (2D) image which can make image interpretation difficult. Moreover, vasculature visualisation requires the use of iodinated contrast media which is nephrotoxic and is the primary cause of renal complications. In this article, we demonstrate how digital tomosynthesis slices can be produced on standard fluoroscopy equipment by registering the preoperative CT volume and the intraoperative fluoroscopy images using 2D-3D image registration. The proposed method automatically reconstructs patient-anatomy-specific slices and removes clutter resulting from bony anatomy. Such slices could provide additional intraoperative information which cannot be provided by the preoperative CT volume alone, such as the deformed aorta position offering improved guidance precision. Image acquisition would fit with interventional clinical work-flow and would not require a high X-ray dose. Experiments are carried out using one phantom and four clinical datasets. Phantom results showed a 3351% contrast-to-noise improvement compared to standard fluoroscopy. Patient results showed our method enabled visualization of clinically relevant features: outline of the aorta, the aortic bifurcation and some aortic calcifications.

Low-dose X-ray irradiation promotes osteoblast proliferation, differentiation and fracture healing.

Great controversy exists regarding the biologic responses of osteoblasts to X-ray irradiation, and the mechanisms are poorly understood. In this study, the biological effects of low-dose radiation on stimulating osteoblast proliferation, differentiation and fracture healing were identified using in vitro cell culture and in vivo animal studies. First, low-dose (0.5 Gy) X-ray irradiation induced the cell viability and proliferation of MC3T3-E1 cells. However, high-dose (5 Gy) X-ray irradiation inhibited the viability and proliferation of osteoblasts. In addition, dynamic variations in osteoblast differentiation markers, including type I collagen, alkaline phosphatase, Runx2, Osterix and osteocalcin, were observed after both low-dose and high-dose irradiation by Western blot analysis. Second, fracture healing was evaluated via histology and gene expression after single-dose X-ray irradiation, and low-dose X-ray irradiation accelerates fracture healing of closed femoral fractures in rats. In low-dose X-ray irradiated fractures, an increase in proliferating cell nuclear antigen (PCNA)-positive cells, cartilage formation and fracture calluses was observed. In addition, we observed more rapid completion of endochondral and intramembranous ossification, which was accompanied by altered expression of genes involved in bone remodeling and fracture callus mineralization. Although the expression level of several osteoblast differentiation genes was increased in the fracture calluses of high-dose irradiated rats, the callus formation and fracture union were delayed compared with the control and low-dose irradiated fractures. These results reveal beneficial effects of low-dose irradiation, including the stimulation of osteoblast proliferation, differentiation and fracture healing, and highlight its potential translational application in novel therapies against bone-related diseases.

Design and First Tests of a Radiation-Hard Pixel Sensor for the European X-Ray Free-Electron Laser

The high intensity and high repetition rate of the European X-ray Free-Electron Laser, presently under construction in Hamburg, requires silicon sensors which can stand X-ray doses of up to 1 GGy for 3 years of operation at high bias voltage. Within the AGIPD Collaboration the X-ray-radiation damage in MOS Capacitors and Gate-Controlled Diodes fabricated by four vendors on high-ohmic n-type silicon with two crystal orientations and dif- ferent technological parameters, has been studied for doses between 1 kGy and 1 GGy. The extracted values of oxide-charge and surface-current densi- ties have been used in TCAD simulations, and the layout and technological parameters of the AGIPD pixel sensor optimized. It is found that the op- timized layout for high X-ray doses is significantly different from the one for non-irradiated sensors. First sensors and test structures have been de-livered in early 2013. Measurement results for X-ray doses of 0 to 10 MGy and their comparison to simulations are presented. They demonstrate that the optimization has been successful and that the sensors fulfill the required specifications.

Mutation Research and Human Welfare

From an address to the Society in November 1968.GENETICAL RADIATION DAMAGEKnowledge gained from mutation research can be put to various uses for the benefit of mankind. One of them is assessment of genetical hazards from ionizing radiations. Before the war, this meant almost exclusively X-rays used in diagnosis and therapy. H. J. Muller, who in 1927 discovered the mutagenic action of X-rays, almost at once entered upon a campaign against the reckless use of radiation in medical practice. Especially in the USA , it was fashionable for the G.P. to have in his surgery a fluoroscope with, usually, an unknown and, often, a very high output of radiation and to use it indiscriminately even where less dangerous methods of diagnosis were available. There was also a practice of temporarily sterilizing men by radiation; when these men later on became fertile again they produced children from sperm that had been heavily irradiated as spermatogonia. In women, similarly high X-ray doses were used to produce fertility by follicle rupture. Until the war, the medical profession took very little notice of Muller. This careless attitude changed when fall-out and nuclear accidents became a major concern. Nowadays many national and international organisations, in all of which geneticists play an important role, are engaged in monitoring the amount of radiation to which we are exposed, in assessing its genetical consequences and in fixing “permissible” levels of radiation.

Use of the DBD-FISH technique for detecting DNA breakage in response to high doses of X-rays.

The aim of this study was to generate a dose-response curve using the DNA breakage detection-fluorescent in situ hybridization (DBD-FISH) test as a biomarker of initial genetic effects induced by high doses of X-rays. A dose-response curve was obtained by measuring the ex vivo responses to increasing doses (0-50 Gy) of X-rays in the peripheral blood lymphocytes of ten healthy donors. The overall dose-response curve was constructed using integrated density (ID; area × fluorescence intensity) as a measure of genetic damage induced by irradiation. The correlation coefficient was high (r = 0.934, b(0) = 10.408, and b(1) = 0.094). One-way ANOVA with the Student-Newman-Keuls test for multiple comparisons showed significant differences among the average ln ID values according to dose. Our results suggest the usefulness of the DBD-FISH technique for measuring intrinsic individual cellular radio sensitivity ex vivo.