Efficacy of Single and Fractionated Neutron Irradiation of Normal and Tumor Cells In Vitro.

Expression of dose in neutron therapy

Radiation damage induced by neutron irradiation was studied by optical absorption measurements in undoped MgO crystals and in MgO crystals intentionally doped with either hydrogen or lithium impurities. The oxygen-vacancy concentration incurred by the neutron irradiation increases with neutron dose. Suppression of radiation damage as characterized by oxygen vacancies is observed in MgO:H crystals and attributed to migration of oxygen vacancies to microcavities filled with hydrogen gas. In MgO:Li crystals irradiated with neutron doses below ${10}^{18}$ ${\mathrm{n}\mathrm{e}\mathrm{u}\mathrm{t}\mathrm{r}\mathrm{o}\mathrm{n}\mathrm{s}/\mathrm{c}\mathrm{m}}^{2},$ most of the oxygen vacancies are camouflaged as hydride ions formed by the capture of protons by the oxygen vacancies. Substitutional lithium ions are also displaced. We postulate that they aggregate at ${\mathrm{Li}}_{2}\mathrm{O}$ precipitates. Thermal annealing experiments demonstrate that protons are mobile at 700 K and lithium ions at 1100 K.

Purpose: Preclinical studies have demonstrated that cancer cells may produce innate immune signals such as type-I interferons following radiation damage, which derives from activation of the cGAS-STING pathway following detection of cytosolic dsDNA. Limited studies have explored how these mechanisms vary from the conditions of the radiation exposure. High- linear energy transfer (LET) radiation induces more DNA double-strand breaks (DSB) per dose than low-LET radiation, thus is expected to be more immunogenic. However, DNA damage in hypoxic cells is more probable to undergo chemical repair due to limitations in oxygen fixation, thus is expected to be more immunosuppressive. Our goal is to study and model the dose response characteristics of IFNβ and Trex1 in vitro following exposure of radiations with varying LET and to develop techniques for further study in vivo. Methods: Reference data from Vanpouille-Box (2017) on STING dose response was applied to develop empirical models of cytosolic dsDNA and Trex1 regulation as a function of dose and quantity of DNA DSB, the latter of which is dependent on particle LET and oxygenation and is calculated using Monte Carlo Damage Simulation (MCDS) software. These models were used as preliminary data to guide in vitro experiments using Merkel cell carcinoma cells. The dose response of pro-inflammatory IFNβ and exonuclease Trex1, an anti-inflammatory suppressor of cGAS-STING, was measured post-irradiation. MCDS was again used to model fast neutron relative biological effectiveness for DSB induction (RBEDSB) and compared to laboratory measurements of the RBE for IFNβ production (RBEIFNβ). RBEIFNβ models were applied to radiation transport simulations to quantify the potential secretion of IFNβ in representative clinical beams. To enable intra-tumor radiation targeting of tumor hypoxia, mice were seeded with syngeneic tumors and imaged longitudinally with PCT- spectroscopy to determine local variations hemoglobin concentration (Hb) and oxygen saturation (SaO2) over time. Hypoxia classification was based on SaO2 levels in voxels containing hemoglobin relative to a “hypoxia threshold” of SaO2 < 0.2. Results: Based on analysis of published data, our preliminary models of cytosolic DNA and Trex1 dose responses demonstrate dose enhancements from high-LET radiation, such as that at the distal edge of a Bragg peak, and suppression from cellular hypoxia. This manifests as an RBE-dependent ‘shift’ in STING response. Laboratory measurements in MCC13 cells show peak IFNβ production at 6.1 Gy following fast neutron irradiation and 14.5 Gy following x-rays (RBEIFNβ = 2.4). However, IFNβ signal amplitudes were not significantly different between these radiation types. Trex1 signal increased linearly with dose, with fourfold higher upregulation per dose for fast neutrons. Modeling of RBE in clinical beams suggests that ion sources may induce spatially localized IFNβ near their end of range, which is potentially advantageous for initiation of tumor-specific immune activity. Uncharged sources stimulate IFNβ more uniformly with depth. Longitudinal PCT-S scanning is able to localize and distinguish chronic and acute hypoxia in vivo. Changes in the hypoxic classification from tumor growth and following anti-angiogenic therapy are distinguishable. Conclusion: Radiation-induced immunogenicity can be induced differentially based on radiation quality and is expected to be affected by cellular oxygenation. High-LET radiation, such as fast neutrons, drives greater IFNβ innate immune response per dose than low-LET radiation, such as x-rays, which may enhance abscopal effects when used in combination with immune-stimulating agents. However, anti-inflammatory signaling is greater per dose for fast neutrons, and it remains unclear if high-LET radiations are therapeutically advantageous over low-LET radiation for pro-inflammatory tumor signaling. High resolution in vivo imaging of tumor hypoxia is feasible with photoacoustic techniques, which can potentially be leveraged to study selective immunogenicity enhancement of the hypoxic niche following radiation therapy.

A comparison of gamma and neutron irradiation on Raji cells: effects on DNA damage, repair, cell cycle distribution and lethality

Effect of neutron and gamma irradiation on some properties of borate glasses

The bakelite for the RPCs of the experiment CMS

Objective Levels and distribution of radiation dose in a cyclotron room were investigated to guide protection of personnel against radiation onsite and provide technical basis for the shielding design of workplaces with radioactive drugs. Methods A cyclotron HM-20S and the room in a hospital where it was installed were investigated.Several LiF (Mg, Cu, and P) thermoluminescence dosimeters, CR39 neutron dosimeters, a neutron dose equivalent rate meter NH-1B, and a dose survey meter 451 B were used to measure the neutron and gamma radiation dose rates in the cyclotron room. Radiation dose levels outside the room were also validated. Results When irradiation conditions were 20 MeV of proton energy and 100 μA of beam current, the maximum neutron dose rate from the southern surface of the self-shielding body of the equipment was 63 times higher than that from northern surface of the self-shielding body. Additionally, the maximum gamma-ray dose rate of the southern surface was 6.0 times higher than that of the northern surface. Neutron and gamma-ray dose rates measured on the inner surface of the southern wall were 11 and 5.3 times higher than those measured on the inner surface of the northern wall, respectively. In addition, mean values of neutron and gamma-ray radiation dose rates from the inner surface of the eastern wall were 21 and 45 μSv/h, correspondingly, whereas those from the western side were 34 and 69 μSv/h, respectively. Conclusion Levels and distribution of radiation dose in a cyclotron room are closely related to several factors, such as beam direction and target position. Radiation dose values measured onsite can be used to facilitate the shielding design of workplaces and provide radiation safety for personnel. Key words: Cyclotron; Cyclotron room; Radiation dose; Radiation protection

Silicon carbide (SiC) is a promising structural and cladding material for accident tolerant fuel cladding of nuclear reactor due to its excellent properties. However, when exposed to severe environments (e.g., during neutron irradiation), lattice defects are created in amounts significantly greater than normal concentrations. Then, a series of radiation damage behaviors (e.g., radiation swelling) appear. Accurate understanding of radiation damage of nuclear materials is the key to the design of new fuel cladding materials. Multi-scale computational simulations are often required to understand the physical mechanism of radiation damage. In this work, the effect of neutron irradiation on the volume swelling of cubic-SiC film with 0.3 mm was studied by using the combination of molecular dynamics (MD) and rate theory (RT). It was found that for C-vacancy (CV), C-interstitial (CI), Si-vacancy (SiV), Si-interstitial (SiI), and Si-antisite (SiC), the volume of supercell increases linearly with the increase of concentration of these defects, while the volume of supercell decreases linearly with the increase of defect concentration for C-antisite (CSi). Furthermore, according to the neutron spectrum of a certain reactor, one RT model was constructed to simulate the evolution of point defect under neutron irradiation. Then, the relationship between the volume swelling and the dose of neutrons can be obtained through the results of MD and RT. It was found that swelling typically increases logarithmically with radiation dose and saturates at relatively low doses, and that the critical dose for abrupt transition of volume is consistent with the available experimental data, which indicates that the rate theory model can effectively describe the radiation damage evolution process of SiC. This work not only presents a systematic study on the relationship between various point defect and excess volume, but also gives a good example of multi-scale modelling through coupling the results of binary collision, MD and RT methods, etc., regardless of the multi-scale modelling only focus on the evolution of primary point defects.

The supporting role of proteases in tumor progression and invasion is well known; however, the use of proteases as therapeutic agents has also been demonstrated. In this article, the authors report on the differential effects of exogenous serine proteases on the motility of tumor and normal cells. The treatment of normal and tumor cells with a single dose of pancreatic serine proteases, trypsin (TR) and chymotrypsin (CH), leads to a concentration-dependent response by cells, first accelerating and then slowing mobility. Tumor cells are 10 to 20 times more sensitive to exogenous TR/CH, suggesting that a single dose of proteases may cause discordant movements of normal and tumor cells within the tumor environment. The inhibitory effects of TR on cell motility are contradicted by thrombin (TH), particularly in the regulation of normal cells' migration. The purpose of this investigation was to ascertain the role of protease-activated receptors (PARs) in terms of normal and tumor cell motility. Duplicate treatments with proteases resulted in diminished mobility of both normal and tumor cells. Repeated application of TR and TH in 1-hour treatment intervals initially desensitizes cell surface PARs. However, cell surface PARs reappear regardless of subsequent protease treatments in both normal and tumor cells. The resensitization process is retarded in tumor cells when compared with normal cells. This is evidenced by lower expression of PARs as well as by their relocalization at the tumor cell surfaces. Under these conditions, normal cells remain responsive to exogenous proteases in terms of cell motility. Exogenous proteases do not modulate motility of repeatedly stimulated tumor cells, and consequently, the migration of tumor cells appears disconnected from the PAR signaling pathways. The use of activating peptides in lieu of the cognate proteases for a given PAR system indicated that proteases may act through additional targets not regulated by PAR signaling. We hypothesize that the divergent migration patterns of normal and tumor cells due to exposure to proteases is in part mediated by PARs. Thus, treatment with exogenous proteases may cause rearrangement of the tumor and stromal cells within the tumor microenvironment. Such topographical effects may lead to the inhibition of tumor progression and metastasis development.

Low-dose neutron irradiation damage in FCC and BCC metals

Data from many laboratories are summarized that indicate that for mice the RBE of large single doses of gamma rays or neutrons is about the same for shortening of the life span as it is for acute lethality. However, for chronic irradiation the RBE is quite high for shortening of the life span, due to the fact that very small doses of neutrons are proportionately just as effective as large doses, while for gamma rays, small doses are proportionately only about 1/ 4 as effective as large doses. The reason for this difference was investigated by scoring the chromosome abberations in regenerating liver cells in mice subjected to both chronic and acute neutron and gamma irradiations. The results show that for gamma rays, very small doses are proportionately only about 25% as effective in producing chromosome aberrations as are large doses. However, for neutrons, large and small doses are proportionately equally effective. This result adequately explains the differences in RBE for life shortening and at the same time gives strong support for the somatic mutation theory of aging. Results indicate that for relatively large doses, equal rad doses of neutrons produce about twice the chromosome damage as do gamma rays. This would indicate that the RBE for acute effects can also be explained on the basis of chromosome damage. Following single doses of gamma rays, the percentages of abnormal chromosomes falls slowly over a period of many months, but following a single dose of neutrons the aberration frequency may be as high as 90% and stay this high for at least a year. There is no ready explanation for this difference in reaction to these two radiations. (auth)

The influence of dose and dose rate on tumorigenicity after neutron irradiation was investigated in female RFM mice exposed to various doses of neutrons at dose rates of 5 and 25 rad/min or 1 rad/day. Comparison of neutron irradiation with acute gamma irradiation showed that tumors were induced more effectively with neutrons than with gamma rays, particularly at low doses. Linear relationships were obtained at both dose rates for thymic lymphoma induction after neutron irradiation, while a dose-squared relationship was obtained for gamma rays. At low doses little dose-rate dependence was seen with neutrons, while at the highest doses the low dose rate was more effective. An increased incidence of lung adenomas was seen after neutron irradiation with doses as low as 20 rad, while the incidence after gamma-ray irradiation decreased with increased dose except at approximately 300 rad. In spite of the apparent sensitivity, the neutron dose--response curve for lung tumors was not linear. Neutron irradiation at low dose rates appeared to induce thymic lymphomas and possibly lung adenomas more efficiently than irradiation at high dose rates, but was less effective than high dose rates in inducing ovarian and pituitary tumors. Both the importance of a more complete understandingmore » of dose and dose-rate relationships (particularly in the low dose range) and the need for examination of the basis of such relationships are discussed.« less

Lubricants and O-rings are necessarily used for the construction of many accelerator-driven facilities as spallation sources or facilities for the production of radioactive isotopes. During operation, such component will absorb high doses of mixed neutron and gamma radiation, that can degrade their mechanical and structural properties. Experimental radiation damage tests of these components are mandatory for the construction of the facility. Methodologies for irradiation in nuclear reactor mixed fields and post-irradiation examination of lubricating oils, greases and O-rings were developed and are here presented. Samples were characterized with standard mechanical and physical-chemical tests. Parametric studies on the dose rate effects have been performed on O-rings. A case studies for a specific O-ring application in a gate valve has been developed. Some of the tested samples showed a dramatic change of their properties with dose, while others remain stable. Results were collected on nine commercial greases, on one oil and on four commercial elastomeric O-rings. The most radiation resistant among the selected products are now considered for application in facilities under construction. The main mechanisms of neutron and gamma radiation damage on these polymers were investigated at the mechanical and structural level.

Helium effect on temperature-displacement rate equivalence in radiation-induced swelling of iron: A study by improved stochastic cluster dynamics

Objective The difference of radiosensitivity of 4 human tumor cell lines to p(35)Be fast neutron and gamma ray was studied in order to provide basis for clinical therapy of tumors. MethodsThe radiosensitivity of these cell lines after p(35)Be neutron or gamma ray irradiation was assayed with cell colonogenic survival assay.And the gamma ray-and p(35)Be neutron-induced DNA damage and its repair in human melanoma cell line WM9839 was studied by using the method of comet-electrophoresis assay. Results The difference of D0(or SF2) after p(35)Be neutron irradiation between these 4 human tumor cell lines was smaller than that after gamma ray irradiation.The repair rate of DNA damage in WM9839 cells after 2 Gy fast-neutron irradiation was lower than that after 2 Gy γ-ray irradiation.The residual DNA damage at 180 min after neutron-irradiation was obviously severer than that after 2 Gy γ-ray irradiation. Conclusion The fast neutron therapy may make up the defect of the low LET ray therapy,especially to those radioresistant tumor cells to low LET rays.