Highest Proton Dose Research Articles

Efficacy of High Doses of Protons on the Induction of Solid Tumors in Mice by <i>Ex vivo</i> Irradiation of Ehrlich Ascitic Carcinoma Cells

We study the induction patterns of the solid form of Ehrlich ascitic carcinoma (EAC) in mice in the short(1 month) and long-term (18 months) periods after inoculation of ascitic cells irradiated ex vivo with a proton beam at doses of 30, 60, 90, 120, and 150 Gr. The growth rate of solid tumors after inoculation of irradiated cells ex vivo coincided with the growth of tumors in the control group. The frequency of tumor induction in mice transplanted with EAC cells was dose-dependent and decreased from 80% to 0% along with an increase in radiation dose. Thus, using the ex vivo model of tumor cell irradiation followed by in vivo grafting allowed us to determine the parameters of the antitumor effect of new proton therapy regimens.

Investigation of DNA Damage and Cell-Cycle Distribution in Human Peripheral Blood Lymphocytes under Exposure to High Doses of Proton Radiotherapy.

Simple SummaryRadiotherapy is a cornerstone care therapy for many tumors. Despite permanent advances in ra-diation dose delivery, there are unmet needs for further improvement. In principle, proton therapy offers a substantial clinical advantage over conventional modalities using photons in uniform-dose delivery of radiation to tumors, along with significant reductions in the harmful effects on normal tissue. However, the effect and mechanisms of a single high-dose delivery remain unclear. The study aimed to systematically observe and compare the biological effects of DNA damage and cell-cycle phase distribution in the human peripheral blood lymphocytes ex vivo irradiation model of normal tissue after proton versus conventional radiotherapy (X-rays). The effects induced at a single high-dose radiation exposure at a dose range of 8.00–20.00 Gy were studied. The results in-dicate a different distribution of DNA damage following high doses of irradiation with protons versus photons between donors, types of radiation, and doses. The results illuminate the cellular and molecular mechanisms that underlie differences in the distribution of DNA damage and cell-cycle phases. An understanding of the mechanisms in the distinct pathways induced by radiation can facilitate the development of more efficient radiotherapies with beneficial immunological conse-quences.This study systematically investigates how a single high-dose therapeutic proton beam versus X-rays influences cell-cycle phase distribution and DNA damage in human peripheral blood lymphocytes (HPBLs). Blood samples from ten volunteers (both male and female) were irradiated with doses of 8.00, 13.64, 15.00, and 20.00 Gy of 250 kV X-rays or 60 MeV protons. The dose–effect relations were calculated and distributed by plotting the frequencies of DNA damage of excess Premature Chromosome Condensation (PCC) fragments and rings in the G2/M phase, obtained via chemical induction with calyculin A. The Papworth’s u test was used to evaluate the distribution of DNA damage. The study shows that high doses of protons induce HPBL DNA damage in the G2/M phase differently than X-rays do. The results indicate a different distribution of DNA damage following high doses of irradiation with protons versus photons between donors, types of radiation, and doses. The proliferation index confirms the impact of high doses of mitosis and the influence of radiotherapy type on the different HPBL response. The results illuminate the cellular and molecular mechanisms that underlie differences in the distribution of DNA damage and cell-cycle phases; these findings may yield an improvement in the efficacy of the radiotherapies used.

Apoptosis and expression of apoptosis-related genes in mouse intestinal tissue after whole-body proton exposure.

Energetic protons are the most abundant particle type in space and can pose serious health risks to astronauts during long-duration missions. The health effects of proton exposure are also a concern for cancer patients undergoing radiation treatment with accelerated protons. To investigate the damage induced by energetic protons in vivo to radiosensitive organs, 6-week-old BALB/c male mice were subjected to 250MeV proton radiation at whole-body doses of 0.1, 1, and 2Gy. The gastrointestinal (GI) tract of each exposed animal was dissected 4h post-irradiation, and the isolated small intestinal tissue was analyzed for histopathological and gene expression changes. Histopathologic observation of the tissue using standard hematoxylin and eosin (H&E) staining methods to screen for morphologic changes showed a marked increase in apoptotic lesions for even the lowest dose of 0.1Gy, similar to X- or γrays. The percentage of apoptotic cells increased dose-dependently, but the dose response appeared supralinear, indicating hypersensitivity at low doses. A significant decrease in surviving crypts and mucosal surface area, as well as in cell proliferation, was also observed in irradiated mice. Gene expression analysis of 84 genes involved in the apoptotic process showed that most of the genes affected by protons were common between the low (0.1Gy) and high (1 and 2Gy) doses. However, the genes that were distinctively responsive to the low or high doses suggest that high doses of protons may cause apoptosis in the small intestine by direct damage to theDNA, whereas low doses of protons may trigger apoptosis through a different stress response mechanism.

Investigations of HAVAR<sup>®</sup> Alloy Using Positrons

A study of irradiation-induced damage in HAVAR® foils was initiated in order to extract the highest proton dose the foils can sustain. The lattice structure of HAVAR® foils in different metallurgic conditions is presented, as well as visible internal structure, measured by Transmission Electron Microscopy (TEM). Positron Annihilation Spectroscopy (PAS) techniques were used to investigate these foils, and another foil that had been irradiated to the maximal proton dose limit, set by the manufacturer to a total charge of 1 mAh (= 3.6 C). PAS techniques included Doppler broadening (DB) measurement in the SPONSOR beam and lifetime (LT) measurements, both carried at Helmholtz-Zentrum Dresden-Rossendorf (HZDR). Both positron spectroscopy methods show clear differences between the investigated foils, with distinguished characteristics for annealed, cold-rolled and irradiated foils. The advantages of using a slow positron beam to study thin foils and defect profiles, over a table-top LT spectrometer, are discussed and demonstrated by the HAVAR® measurements.

Protons sensitize epithelial cells to mesenchymal transition.

Proton radiotherapy has gained more favor among oncologists as a treatment option for localized and deep-seated tumors. In addition, protons are a major constituent of the space radiation astronauts receive during space flights. The potential for these exposures to lead to, or enhance cancer risk has not been well studied. Our objective is to study the biological effects of low energy protons on epithelial cells and its propensity to enhance transforming growth factor beta 1 (TGFβ1)-mediated epithelial-mesenchymal transition (EMT), a process occurring during tumor progression and critical for invasion and metastasis. Non-transformed mink lung epithelial cells (Mv1Lu) and hTERT- immortalized human esophageal epithelial cells (EPC) were used in this study. EMT was identified by alterations in cell morphology, EMT-related gene expression changes determined using real-time PCR, and EMT changes in specific cellular markers detected by immunostaining and western blotting. Although TGFβ1 treatment alone is able to induce EMT in both Mv1Lu and EPC cells, low energy protons (5 MeV) at doses as low as 0.1 Gy can enhance TGFβ1 induced EMT. Protons alone can also induce a mild induction of EMT. SD208, a potent TGFβ Receptor 1 (TGFβR1) kinase inhibitor, can efficiently block TGFβ1/Smad signaling and attenuate EMT induction. We suggest a model for EMT after proton irradiation in normal and cancerous tissue based on our results that showed that low and high doses of protons can sensitize normal human epithelial cells to mesenchymal transition, more prominently in the presence of TGFβ1, but also in the absence of TGFβ1.

Global Gene Expression Responses to Low- or High-Dose Radiation in a Human Three-Dimensional Tissue Model

Accumulating data suggest that the biological responses to high and low doses of radiation are qualitatively different, necessitating the direct study of low-dose responses to better understand potential risks. Most such studies have used two-dimensional culture systems, which may not fully represent responses in three-dimensional tissues. To gain insight into low-dose responses in tissue, we have profiled global gene expression in EPI-200, a three-dimensional tissue model that imitates the structure and function of human epidermis, at 4, 16 and 24 h after exposure to high (2.5 Gy) and low (0.1 Gy) doses of low-LET protons. The most significant gene ontology groups among genes altered in expression were consistent with effects observed at the tissue level, where the low dose was associated with recovery and tissue repair, while the high dose resulted in loss of structural integrity and terminal differentiation. Network analysis of the significantly responding genes suggested that TP53 dominated the response to 2.5 Gy, while HNF4A, a novel transcription factor not previously associated with radiation response, was most prominent in the low-dose response. HNF4A protein levels and phosphorylation were found to increase in tissues and cells after low- but not high-dose irradiation.

Influence of adjacent low-dose fields on tolerance to high doses of protons in rat cervical spinal cord

The dose-response relationship for a relatively short length (4 mm) of rat spinal cord has been shown to be significantly modified by adjacent low-dose fields. In an additional series of experiments, we have now established the dose-volume dependence of this effect. Wistar rats were irradiated on the cervical spinal cord with single doses of unmodulated protons (150 MeV) to obtain sharp lateral penumbras, by use of the shoot-through technique, which employs the plateau of the depth-dose profile rather than the Bragg peak. Three types of inhomogeneous dose distributions were administered: Twenty millimeters of cervical spinal cord were irradiated with variable subthreshold (= bath) doses (4 and 18 Gy). At the center of the 20-mm segment, a short segment of 2 mm or 8 mm (= shower) was irradiated with variable single doses. These inhomogeneous dose distributions are referred to as symmetrical bath-and-shower experiments. An asymmetrical dose distribution was arranged by irradiation of 12 mm (= bath) of spinal cord with a dose of 4 Gy. The caudal 2 mm (= shower) of the 12-mm bath was additionally irradiated with variable single doses. This arrangement of inhomogeneous dose distribution is referred to as asymmetrical bath-and-shower experiment. The endpoint for estimation of the dose-response relationships was paralysis of the fore limbs or hind limbs and confirmation by histology. The 2-mm bath-and-shower experiments with a 4-Gy bath dose showed a large shift of the dose-response curves compared with the 2-mm single field, which give lower ED50 values of 61.2 Gy and 68.6 Gy for the symmetrical and asymmetrical arrangement, respectively, compared with an ED50 of 87.8 Gy after irradiation of a 2-mm field only. If the bath dose is increased to 18 Gy, the ED50 value is decreased further to 30.9 Gy. For an 8-mm field, addition of a 4-Gy bath dose did not modify the ED50 obtained for an 8-mm field only (23.2 and 23.1 Gy). The spinal cord tolerance of relatively small volumes (shower) is strongly affected by low-dose irradiation (= bath) of adjacent tissue. The results of all bath-and-shower experiments show the effect of a low bath dose to be highest for a field of 2 mm, less for 4 mm, and absent for 8 mm. Adding a 4-Gy bath to only 1 side of a 2-mm field still showed a large effect. Because glial progenitor cells are known to migrate over at least 2 to 3 mm, this observation indicates that interference with stem cell migration is not the most likely mechanism of a bath effect.

Proton irradiation of ZnO schottky diodes

Zinc oxide is generally considered to be radiation hard, although there are few experimental reports supporting this assertion. In this paper, we present results on the changes in electrical performance of bulk Pt/ZnO Schottky rectifiers exposed to 40-MeV protons at fluences from 5×109 cm−2 to 5×1010 cm−2. These doses correspond to more than 10 years or 100 years, respectively, in low-earth satellite orbit. The reverse breakdown voltage of the ZnO diodes increased from ∼3.6V in unirradiated devices to ∼4 V after the highest proton dose. The effective barrier height decreased with proton dose, while the diode ideality factor increased from 1.8 to 1.9 for the highest dose. These devices appear promising for both aerospace and terrestrial applications where irradiation hardness is a prerequisite. The main degradation mechanism appears to be creation of recombination centers and traps.

Effects of high dose proton irradiation on the electrical performance of ZnO Schottky diodes

Bulk ZnO Schottky rectifiers with Pt rectifying contacts were exposed to 40 MeV protons at fluences from 5 × 109 to 5 × 1010 cm–2. These doses correspond to that received in more than 10 or 100 years, respectively, in low earth satellite orbit. The reverse breakdown voltage of the ZnO diodes increased from ∼3.2 V (taken at a current density of 0.1 A/cm2) in unirradiated devices to ∼3.9 V after the highest proton dose. The effective barrier height decreased with proton dose from 0.37 eV to 0.35 eV while the diode ideality factor increased from 1.8 to 1.9 for the 5 × 1010 dose. The very high tolerance of the ZnO diodes to high doses of energetic protons suggests that this material is well-suited to applications requiring high radiation tolerance. (© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Proton dose-dependent modification in track etching response in some polymers

In the present work, the effect of four different doses of 62 MeV protons, on the fission fragment track etching characteristics of two polymers, viz. polycarbonate (Makrofol-N (MFN)) and polyimide (PI) are studied by nuclear track technique. The bulk etch-rate of PI increased by around 30% at the highest proton dose, whereas the activation energy of etching remained almost constant for the same. A considerable increase in the bulk etch-rate of MFN was observed (75%) at the highest proton dose. The activation energy of etching of the fission fragment tracks in MFN was also found to be an inverse function of dose.

High energy proton irradiation effects on SiC Schottky rectifiers

4H-SiC Schottky rectifiers with dielectric overlap edge termination were exposed to 40 MeV protons at fluences from 5×107–5×109 cm−2. The reverse breakdown voltage decreased from ∼500 V in unirradiated devices to ∼−450 V after the highest proton dose. The reverse leakage current at −250 V was approximately doubled under these conditions. The forward current at −2 V decreased by ∼1% (fluence of 5×107 cm−2) to ∼42% (fluence of 5×109 cm−2), while the current at lower biases was increased due to the introduction of defect centers. The ideality factor, on-state resistance, and forward turn-on voltage showed modest increases for fluences of ⩽5×108 cm−2, but were more strongly affected (increase of 40%–75%) at the highest dose employed.

Changes in carrier dynamics induced by proton irradiation in quantum dots

The effects of proton irradiation on carrier dynamics were investigated by time-resolved photoluminescence on different InGaAs/GaAs quantum-dot (QD) structures varying in QD surface density and substrate orientation, as well as thin InGaAs quantum wells. The carrier lifetimes in the dots are much less affected by proton irradiation than in the wells. Decrease in lifetimes of only 40 percent at the highest proton dose are observed in some of the QDs, whereas an ∼20 to ∼40-fold decrease is observed in the wells. Similar trends were observed for all quantum dot samples.

Irradiation of tin doped indium oxide thin films using 1 MeV protons

Tin doped indium oxide thin films on float glass substrates have been irradiated with 1 MeV protons using fluences between 1 × 1015 and 25 × 1016 ions/cm2. The variation of the optical absorption coefficient with dose is presented for irradiation at room temperature and 373 K and shows a three-stage growth curve. A lower level of absorption is attained at the higher temperature for similar doses. In the range of proton doses corresponding to stages 1 and 2, X-ray diffraction studies show no effect on the diffraction peaks. However at the highest proton dose corresponding to stage 3, broadened peaks with a reduced intensity were observed. Recovery of these X-ray peaks was observed after a period of a month at ambient temperature. No recovery of the optical absorbance is observed in any of the samples at this point. There is, however, some reduction in the optical absorption coefficient of all the samples after a longer period.

CVD diamond particle detectors

Abstract CVD diamond's advantage as a particle detector over other materials is its radiation-hardness, its low atomic number, its high atom density and its robustness in hostile environments. It is possible to impose a very high electric field across a diamond, under which the electrons and holes created by an incident particle separate and are collected by electrodes on the surface of the film. The radiation-hardness is one of the supreme advantages of diamond over more conventional detector materials. We have investigated the radiation effects of high doses of neutrons, electrons, protons and alpha particles in diamond and compared the results to those in silicon, which is used for most conventional detectors of this type. The computer simulation packages GEANT and TRIM were used to plot the interactions of the incident particles with the diamond and the damage that they and the displaced carbon atoms cause within the solid. However, most of this damage anneals away while the irradiation continues, so we take into account the processes whereby interstitials recombine with vacancies. We can then show the damage profiles caused by these particles incident at energies of 1 MeV or other energies. The results confirm that approximately twice the number of vacancies are created in silicon compared to diamond. At room temperature, vacancies in silicon migrate to form complex defects with dopants, whereas in diamond, the vacancies are immobile, and the detectors are not doped. Therefore, the effect of the radiation damage in diamond on the operation of the detector is much less severe than equivalent damage would be on a silicon device.

Head and neck tumors after energetic proton irradiation in rats

This is a two-year progress report on a life span dose-response study of brain tumor risk at moderate to high doses of energetic protons. It was initiated because a joint NASA/USAF life span study of rhesus monkeys that were irradiated with 55-MeV protons (average surface dose, 3.5 Gy) indicated that the incidence of brain tumors per unit surface absorbed dose was over 19 times that of the human tinea capitis patients whose heads were exposed to 100 kv x-rays. Examination of those rats that died in the two-year interval after irradiation of the head revealed a linear dose-response for total head and neck tumor incidence in the dose range of 0–8.5 Gy. The exposed rats had a greater incidence of pituitary chromophobe adenomas, epithelial and mesothelial cell tumors than the unexposed controls but the excessive occurrence of malignant gliomas that was observed in the monkeys was absent in the rats. The estimated dose required to double the number of all types of head and neck tumors was 5.2 Gy. The highest dose, 18 Gy, resulted in high mortality due to obstructive squamous metaplasia at less than 50 weeks, prompting a new study of the relative bological effectiveness of high energy protons in producing this lesion.

Temperature emissivity of quartz excited by ionizing radiation

The authors investigate the influence of gamma photons in doses in excess of 10/sup 8/ R upon the thermoluminescence spectrum of quartz, and they study the irradiation of the crystals with high integral doses of electrons and protons. The results of the investigations of the thermoluminescence spectra of crystalline quartz are illustrated. The measurements have shown that energy is stored in the irradiated samples at impurity-type defects (A1/sup 3 +/, Li/sup +/, Li, and Na) as well as at defects formed by the radiation at oxygen vacancies.

Radiation damage studies in muscovite and biotite mica-track detectors

Muscovite and biotite mica sheets were exposed to high doses of electrons, protons, and α-particles, with a view to studying the effects of these radiations on their track registration properties. Gradual structural changes in mica crystals seem to take place with the increasing doses of the above mentioned particles. The results seem to suggest that the contribution of δ-rays alone is not sufficient to account for the etchable track formation in mica crystalline track detectors.

Changes produced by high doses of light charged particles in registration properties of mica track detectors

Sheets of muscovite and biotite mica track detectors were exposed to high doses of (a) electrons, (b) protons, and (c) alpha particles, in order to study the effect of these radiations on their track registration properties. Optical- and scanning-electron microscopes (SEM) were employed in these studies. In Muscovite mica, observable changes in the fission fragment etch-pit opening, the etched-track profile, and the general etching velocity occur around doses of (a) 3.5 × 106 Mrad of 1 MeV electrons, (b) 8.5 × 104 Mrad of 10 MeV protons, and (c) 2.2 × 104 Mrad of 40 MeV alpha particles. The values of these critical doses for biotite mica are (a) 2.7 × 105 Mrad of 1 MeV electrons, (b) 8.2 × 103 Mrad of 10 MeV protons, and (c) 1.6 × 103 Mrad of 40 MeV alpha particles. It has been concluded that the contribution of delta rays alone is not sufficient to account for the etchable track formation in mica solid state nuclear track detectors.

Influence of proton irradiations on Fe track stability in silicates

Abstract Muscovite mica and labradorite crystals have been irradiated by 1013-1014 cm−2 protons (12 MeV) and ∼106 Fe ions (1.9 MeV/amu). Three types of samples were prepared, having received respectively: (i) Fe ions only; (ii) protons followed by Fe ions; (iii) Fe ions followed by protons. The annealing behavior of Fe tracks was studied in the three types of samples. In samples first irradiated with high doses of protons, Fe tracks anneal at a higher temperature than in the other samples. We discuss implications on track formation mechanisms and the enhanced stability of fossil tracks compared to artificial tracks.