Mean Linear Energy Transfer Research Articles

Can the mean linear energy transfer of organs be directly related to patient toxicities for current head and neck cancer intensity-modulated proton therapy practice?

Background and purposeThe relative biological effectiveness (RBE) of proton therapy is predicted to vary with the dose-weighted average linear energy transfer (LETd). However, RBE values may substantially vary for different clinical endpoints. Therefore, the aim of this study was to assess the feasibility of relating mean D⋅LETd parameters to patient toxicity for HNC patients treated with proton therapy. Materials and methodsThe delivered physical dose (D) and the voxel-wise product of D and LETd (D⋅LETd) distributions were calculated for 100 head and neck cancer (HNC) proton therapy patients using our TPS (Raystation v6R). The means and covariance matrix of the accumulated D and D⋅LETd of all relevant organs-at-risk (OARs) were used to simulate 2.500 data sets of different sizes. For each dataset, an attempt was made to add mean D⋅LETd parameters to a multivariable NTCP model based on mean D parameters of the same OAR for xerostomia, tube feeding and dysphagia. The likelihood of creating an NTCP model with statistically significant parameters (i.e. power) was calculated as a function of the simulated sample size for various RBE models. ResultsThe sample size required to have a power of at least 80% to show an independent effect of mean D⋅LETd parameters on toxicity is over 15,000 patients for all toxicities. ConclusionFor current clinical practice, it is not feasible to directly model NTCP with both mean D and mean D⋅LETd of OARs. These findings should not be interpreted as a contradiction of previous evidence for the relationship between RBE and LETd.

Analysis of DNA methylation alterations in rice seeds induced by different doses of carbon-ion radiation.

To investigate the mechanism underlying differences in biological effects induced by low- versus high-dose heavy-ion radiation (HIR) in rice plants, two-dimensional gel electrophoresis (2-DE) coupled with methylation-sensitive amplification polymorphism (MSAP) analysis were used to check the expression changes in rice leaf proteome profiles and the changes in DNA methylation after exposure of seeds to ground-based carbon-ion radiation at various cumulative doses (0, 0.01, 0.02, 0.1, 0.2, 1, 2, 5 or 20 Gy; 12C6+; energy, 165 MeV/u; mean linear energy transfer, 30 KeV/μm). In this study, principal component analysis (PCA) and gene ontology (GO) functional analysis of differentially expressed proteins of rice at tillering stage showed that proteins expressed in rice samples exposed to 0.01, 0.02, 0.1, 0.2 or 1 Gy differed from those exposed to 2, 5 or 20 Gy. Correspondingly, the proportion of hypermethylation was higher than that of hypomethylation at CG sites following low-dose HIR (LDR; 0.01, 0.2 or 1 Gy), whereas this was reversed at high-dose HIR (HDR; 2, 5 or 20 Gy). The hypomethylation changes tended to occur at CHG sites with both low- and high-dose HIR. Furthermore, sequencing of MSAP variant bands indicated that the plants might activate more metabolic processes and biosynthetic pathways on exposure to LDR, but activate stress resistance on exposure to HDR. This study showed that radiation induced different biological effects with low- and high-dose HIR, and that this may have been caused by different patterns of hyper- and hypomethylation at the CG sites.

Stability of zinc stearate under alpha irradiation in the manufacturing process of SFR nuclear fuels

The manufacture of new fuels for sodium-cooled fast reactors (SFRs) will involve powders derived from recycling existing fuels in order to keep on producing electricity while saving natural resources and reducing the amount of waste produced by spent MOX fuels. Using recycled plutonium in this way will significantly increase the amount of 238Pu, a high energy alpha emitter, in the powders. The process of shaping powders by pressing requires the use of a solid lubricant, zinc stearate, to produce pellets with no defects compliant with the standards. The purpose of this study is to determine the impact of alpha radiolysis on this additive and its lubrication properties. Experiments were conducted on samples in contact with PuO2, as well as under external helium ion beam irradiation, in order to define the kinetics of radiolytic gas generation. The yield results relating to the formation of these gases (G0) show that the alpha radiation of plutonium can be simulated using external helium ion beam irradiation. The isotopic composition of plutonium has little impact on the yield. However, an increased yield was globally observed with increasing the mean linear energy transfer (LET). A radiolytic degradation process is proposed.

Effects of ion beam irradiation on size of mutant sector and genetic damage in Arabidopsis

Size of mutant sector and genetic damage were evaluated in Arabidopsis to further our understanding of effective ion beam use in plant mutation breeding. Arabidopsis seeds, heterozygous for the GLABRA1 (GL1) gene (GL1/gl1-1), were irradiated with 15.8MeV/u neon ions (mean linear energy transfer (LET): 352keV/μm), 17.3MeV/u carbon ions (113keV/μm), or 60Co gamma rays. The frequency and size of glabrous sectors generated because of inactivation of the GL1 allele were examined. The frequency and overall size of large deletions were evaluated based on the loss of heterozygosity of DNA markers using DNA isolated from glabrous tissue. Irrespective of the radiation properties, plants with mutant sectors were obtained at similar frequencies at the same effective dosage necessary for survival reduction. Ion beams tended to induce larger mutant sectors than gamma rays. The frequency of large deletions (>several kbp) increased as the LET value increased, with chromosome regions larger than 100kbp lost in most large deletions. The distorted segregation ratio of glabrous plants in the progenies of irradiated GL1/gl1-1 plants suggested frequent occurrence of chromosome rearrangement, especially those subjected to neon ions. Exposure to ion beams with moderate LET values (30–110keV/μm) is thought effective for inducing mutant sectors without causing extensive genetic damage.

DNA damage and oxidative stress induced by proton beam in Cymbidium hybrid

We investigated the radiation damages caused by two types of proton beam and gamma ray in the Cymbidium hybrid RB001 [(C. sinensis × C. goeringii) × Cymbidium spp.] to characterize proton beam as a new mutagen for Cymbidium mutation breeding. The protocorm-like bodies (PLBs) of Cymbidium hybrid were irradiated with a 45 MeV proton beam [mean linear energy transfer (LET) = 1.461 keV·μm−1], a 100 MeV proton beam (LET = 0.7306 keV·μm−1), and gamma ray (LET = 0.2 keV·μm−1). The PLBs treated with radiation doses of 0–100 Gy were analyzed using the comet assay and their physiological responses as indices of radiation damage. In the comet assay, the 45 MeV proton beam caused significant damage to the DNA integrity, but the 100 MeV proton beam and gamma ray showed relatively little radiation damage between the untreated control and treated PLBs. Malondialdehyde (MDA) content, an index of the indirect effects of ionizing radiation, was increased slightly by the 45 MeV proton beam with higher-LET, but highly increased by the 100 MeV proton beam with lower-LET. These results suggested that the 100 MeV proton beam caused extreme oxidative stress. Therefore, proton beam have unique characteristics in DNA mutagenesis pattern according to its LETs. Based on these results, proton beam is expected to be a useful tool for developing new mutant varieties of Cymbidium.

Luminescence characteristics of C5+ ions and 60Co irradiated Li2BaP2O7:Dy3+ phosphor

In this work a study on some thermoluminescence characteristics of Li2BaP2O7:Dy phosphor is presented. The phosphor was synthesized by solid state diffusion method and characterized for its phase purity by X-ray diffraction (XRD). FT-IR spectrum was also carried out to confirm the presence of phosphate family and vibrations corresponding to P–O–P group. Spectroscopic investigation was approached through photoluminescence (PL) and thermoluminescence (TL). PL emission spectrum of Dy3+ ions corresponding to 4F9/2→6H13/2 (483nm) and 4F9/2→6H15/2 (574nm) transitions is revealed under 351nm excitation wavelength. This characteristic emission confirms the presence of Dy3+ ions in the Li2BaP2O7 host matrix. To induce TL properties in Li2BaP2O7:Dy phosphor was irradiated with C5+ ion beams and gamma rays (60Co). A nearly simple glow curve was observed for Li2BaP2O7:Dy under two different excitation sources. TL response is almost linear over a wide range. Average absorbed dose (D¯) and mean linear energy transfer (LET‾) of C5+ ion beams in Li2BaP2O7:Dy have also been calculated. Values of parameters like E and S known as trap depth and frequency factor respectively were obtained by using TLanal computer program. Also SRIM based calculations were performed to study the effect of C5+ ion beams on the samples of Li2BaP2O7:Dy. SRIM calculations show that Ba2+ vacancies are highest in number. Till date no such luminescence information on Li2BaP2O7:Dy phosphor is available.

The relative biological effectiveness for carbon and oxygen ion beams using the raster-scanning technique in hepatocellular carcinoma cell lines.

BackgroundAim of this study was to evaluate the relative biological effectiveness (RBE) of carbon (12C) and oxygen ion (16O)-irradiation applied in the raster-scanning technique at the Heidelberg Ion beam Therapy center (HIT) based on clonogenic survival in hepatocellular carcinoma cell lines compared to photon irradiation.MethodsFour human HCC lines Hep3B, PLC, HepG2 and HUH7 were irradiated with photons, 12C and 16O using a customized experimental setting at HIT for in-vitro trials. Cells were irradiated with increasing physical photon single doses of 0, 2, 4 and 6 Gy and heavy ionsingle doses of 0, 0.125, 0.5, 1, 2, 3 Gy (12C and 16O). SOBP-penetration depth and extension was 35 mm +/−4 mm and 36 mm +/−5 mm for carbon ions and oxygen ions respectively. Mean energy level and mean linear energy transfer (LET) were 130 MeV/u and 112 keV/um for 12C, and 154 MeV/u and 146 keV/um for 16O. Clonogenic survival was computated and realtive biological effectiveness (RBE) values were defined.ResultsFor all cell lines and both particle modalities α- and β-values were determined. As expected, α-values were significantly higher for 12C and 16O than for photons, reflecting a steeper decline of the initial slope of the survival curves for high-LET beams. RBE-values were in the range of 2.1–3.3 and 1.9–3.1 for 12C and 16O, respectively.ConclusionBoth irradiation with 12C and 16O using the rasterscanning technique leads to an enhanced RBE in HCC cell lines. No relevant differences between achieved RBE-values for 12C and 16O were found. Results of this work will further influence biological-adapted treatment planning for HCC patients that will undergo particle therapy with 12C or 16O.

Mutagenic effects of carbon ions near the range end in plants

To gain insight into the mutagenic effects of accelerated heavy ions in plants, the mutagenic effects of carbon ions near the range end (mean linear energy transfer (LET): 425keV/μm) were compared with the effects of carbon ions penetrating the seeds (mean LET: 113keV/μm). Mutational analysis by plasmid rescue of Escherichia coli rpsL from irradiated Arabidopsis plants showed a 2.7-fold increase in mutant frequency for 113keV/μm carbon ions, whereas no enhancement of mutant frequency was observed for carbon ions near the range end. This suggested that carbon ions near the range end induced mutations that were not recovered by plasmid rescue. An Arabidopsis DNA ligase IV mutant, deficient in non-homologous end-joining repair, showed hyper-sensitivity to both types of carbon-ion irradiation. The difference in radiation sensitivity between the wild type and the repair-deficient mutant was greatly diminished for carbon ions near the range end, suggesting that these ions induce irreparable DNA damage. Mutational analysis of the Arabidopsis GL1 locus showed that while the frequency of generation of glabrous mutant sectors was not different between the two types of carbon-ion irradiation, large deletions (>∼30kb) were six times more frequently induced by carbon ions near the range end. When 352keV/μm neon ions were used, these showed a 6.4 times increase in the frequency of induced large deletions compared with the 113keV/μm carbon ions. We suggest that the proportion of large deletions increases with LET in plants, as has been reported for mammalian cells. The nature of mutations induced in plants by carbon ions near the range end is discussed in relation to mutation detection by plasmid rescue and transmissibility to progeny.

RBE of α-particles from 211At for complex DNA damage and cell survival in relation to cell cycle position

Purpose: To investigate cell cycle effects and relative biological effectiveness (RBE) of α-particles from the clinically relevant radionuclide Astatine-211 (211At), using X-rays as reference radiation. Double-strand breaks (DSB), non-DSB clusters containing oxidised purines and clonogenic survival were investigated.Materials and methods: Asynchronous V79-379A fibroblasts or cells synchronised with mimosine in G1, early, mid and late S phase or in mitosis were irradiated with X-rays (100 kVp) or 211At (mean linear energy transfer (LET) 110 keV/μm). Induction of DSB and clusters was determined using pulsed-field gel electrophoresis with fragment analysis. Cell survival was obtained with the clonogenic assay.Results: In asynchronous cells RBE for DSB- and cluster-induction was 3.5 and 0.59, respectively. RBE for 37% cell survival was 8.6. In different cell cycle phases RBE varied from 1.8–3.9 for DSB and 3.1–7.9 for 37% survival (survival at 2 Gy was 6.9–38 times lower after α-irradiation). 211At induced 6 times more DSB and X-rays induced 11 times more DSB in mitotic cells with highly compacted chromatin relative G1.Conclusions: The radio-response is cell cycle dependent and differs between proliferating and non-cycling cells for both low- and high-LET radiation, resulting in a variation in RBE of α-particles between 1.8 and 8.6.

Effects of ion beam irradiation on mutation induction and nuclear DNA content in chrysanthemum

We investigated the effects of ion beams, in comparison to gamma rays, on mutation induction and nuclear DNA content as an index of radiation damage in Chrysanthemum morifolium. Leaf segments were irradiated with 220 MeV carbon ions (mean linear energy transfer = 107 keV/μm), 320 MeV carbon ions (76 keV/μm), 100 MeV helium ions (9 keV/μm), and gamma rays. The nuclear DNA content was measured and frequency of flower color mutations was investigated in regenerated plants. The number of plants with reduced nuclear DNA content increased with increasing irradiation doses of 320 MeV carbon ions, 100 MeV helium ions, and gamma rays. In contrast, they did not increase with 220 MeV carbon ions, even when the dose was increased. Irradiation treatment with 220 and 320 MeV carbon ions and gamma rays had a similar effect on mutation induction, while the effect of 100 MeV helium ions was not as great. Thus, the effects of irradiation treatments on mutation induction and nuclear DNA content differed according to the type of ion beams. 220 MeV carbon ion beam seemed to be the most appropriate among the three types of ion beams because it gave a high mutation frequency with low damage to chromosomes.

Mutagenic effects of ion beam irradiation on rice

We investigated the usefulness of ion beams for mutation breeding in rice (Oryza sativa L.) by comparing the efficiency (i.e., the ratio of desirable mutations to plant damage such as lethality and sterility), mutation rate, spectrum, and optimum dose to that of gamma rays. Rice seeds were irradiated with carbon ions (mean linear energy transfer = 76 and 107 keV/μm), helium ions (9 keV/μm), and gamma rays, and their survival and fertility were examined in the M1 generation. The frequency of chlorophyll mutations and their types (albina, xantha, and viridis) were examined in the M2 generation, using the M1-plant progeny method. The efficiency of ion beams either equaled or exceeded that of gamma rays. In addition, the mutation rate of ion beams was higher than that of gamma rays. Thus, ion beams appeared to efficiently induce mutants with little radiation damage. No remarkable difference was observed in the relative frequencies of each type of mutation among 3 types of ion beams and gamma rays, thus suggesting that there was no difference in the spectrum. A shoulder dose, which hardly affected survival, was sufficient to efficiently obtain mutants for both types of radiation.

Mutation induction with ion beam irradiation of lateral buds of chrysanthemum and analysis of chimeric structure of induced mutants

We compared the effects of ion beam and gamma ray irradiation on mutation induction in axillary buds of chrysanthemum, and analyzed the chimeric structure of the resulting mutants. Axillary buds were irradiated with carbon ions at 2 Gy (mean linear energy transfer 122 keV/μm), helium ions at 10 Gy (mean 9 keV/μm), and gamma rays at 80 Gy, all of which have the similar effects on survival. The lower five nodes of the shoots elongating from the irradiated buds were cut one by one, and new shoots were allowed to grow from the axillary buds. This procedure was repeated twice, and flower color mutation was investigated. Chimeric structure was analyzed by comparing the flower color of mutants to that of plants regenerated from the roots. Flower color mutants emerged at a high frequency (17.4–28.8%), and there were no significant differences in the mutation frequency between the treatments. All the flower color mutants induced with gamma rays were periclinal chimeras. In contrast, some mutants obtained with ion beams had the same flower color as that of the plants derived from the roots. This suggests that they were solid mutants, where both LI and LIII tissues were derived from the same mutated cell. Solid mutants were also obtained when irradiated with 5 Gy of helium ions, which had less effect on survival and mutation than other treatments. Factors for obtaining solid mutants only with ion beams are also discussed.

Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with 211At-MX35 F(ab′)2

To elucidate the therapeutic efficacy of alpha-radioimmunotherapy of ovarian cancer in mice. This study: (i) estimated the minimum required activity (MRA), giving a reasonable high therapeutic efficacy; and (ii) calculated the specific energy to tumor cell nuclei and the metastatic cure probability (MCP) using various assumptions regarding monoclonal-antibody (mAb) distribution in measured tumors. The study was performed using the alpha-particle emitter Astatine-211 (211At) labeled to the mAb MX35 F(ab')2. Animals were inoculated intraperitoneally with approximately 1 x 10(7) cells of the cell line NIH:OVCAR-3. Four weeks later animals were treated with 25, 50, 100, or 200 kBq 211At-MX35 F(ab')2 (n = 74). Another group of animals was treated with a nonspecific mAb: 100 kBq 211At-Rituximab F(ab')2 (n = 18). Eight weeks after treatment the animals were sacrificed and presence of macro- and microscopic tumors and ascites was determined. An MCP model was developed and compared with the experimentally determined tumor-free fraction (TFF). When treatment was given 4 weeks after cell inoculation, the TFFs were 25%, 22%, 50%, and 61% after treatment with 25, 50, 100, or 200 kBq (211)At-MX35 F(ab')2, respectively, the specific energy to irradiated cell nuclei varying between approximately 2 and approximately 400 Gy. As a significant increase in the therapeutic efficacy was observed between the activity levels of 50 and 100 kBq (TFF increase from 22% to 50%), the conclusion was that the MRA is approximately 100 kBq (211)At-MX35 F(ab')2. MCP was most consistent with the TFF when assuming a diffusion depth of 30 mum of the mAbs in the tumors.

Neoplastic transformation in vitro induced by low doses of 232 MeV protons

The aim was to define the dose – response curve for high-energy proton-induced neoplastic transformation in vitro. The HeLa × skin fibroblast human hybrid cell assay was used to determine the frequency of neoplastic transformation following doses of 232 MeV protons (mean linear energy transfer, LET = 0.44 keV μm – 1) in the range 5 – 600 mGy. Proton irradiations were carried out at the Loma Linda University Proton Treatment Facility, CA, USA. The data indicate no evidence for induction of transformation below a dose of 100 mGy. At doses of 5 and 50 mGy, there is evidence for a possible suppression of transformation frequencies below that for spontaneous transformation. The shape of the dose – response curve for high-energy proton-induced transformation of the human hybrid cell line CGL1 does not follow a linear no-threshold model and shows evidence for a threshold as well as for possible suppression of transformation at doses < 100 mGy, similar to that seen for other low-LET radiations.

Why it is advisable to keep wR = 1 and Q = 1 for photons and electrons.

It has been well known for a long time that the biological effectiveness of photons and electrons depends on the mean linear energy transfer (LET) of the radiation considered, e.g. (60)Co gamma rays are less effective than soft or hard X rays. Nevertheless, the protection and operational dose quantities applied in radiological protection include weighting factors, w(R) or Q, respectively, which were set to 1 for all low-LET radiations. Lack of precise information, simplicity and general practical considerations are the main arguments for this convention. However, a more detailed discussion on the practical aspects supporting this procedure is missing. The paper discusses in more detail some of these aspects regarding internal and external exposure situations, which may support the idea of continuing to use w(R) = 1 for photons and electrons and, correspondingly, using Q(L) = 1 for L < 10 keV microm(-1).

Genomic Instability in Chinese Hamster Cells after Exposure to X Rays or Alpha Particles of Different Mean Linear Energy Transfer

Evidence has accumulated that radiation induces a transmissible persistent destabilization of the genome, which may result in effects arising in the progeny of irradiated but surviving cells. An enhanced death rate among the progeny of cells surviving irradiation persists for many generations in the form of a reduced plating efficiency. Such delayed reproductive death is correlated with an increased occurrence of micronuclei. Since it has been suggested that radiation-induced chromosomal instability might depend on the radiation quality, we investigated the effects of alpha particles of different LET by looking at the frequency of delayed micronuclei in Chinese hamster V79 cells after cytochalasin-induced block of cell division. A dose-dependent increase in the frequency of micronuclei was found in cells assayed 1 week postirradiation or later. Also, there was a persistent increase in the frequency of dicentrics in surviving irradiated cells. Moreover, we found an increased micronucleus frequency in all of the 30 clones isolated from individual cells which had been irradiated with doses equivalent to either one, two or three alpha-particle traversals per cell nucleus. We conclude that the target for genomic instability in Chinese hamster cells must be larger than the cell nucleus.

Radiation quality investigations around a neutron therapy beam, using a high‐pressure ionization chamber

The mean quality factor (Q) and the dose mean linear energy transfer [LET (LD)] a few centimeters outside a neutron therapy beam have been measured using a high-pressure ionization chamber. Measurements have been carried out in air, 5 and 100 cm outside the treatment field edge on the patient plane for p(46)-Be neurons and are compared with the results obtained at the same points with a low-pressure proportional counter (Rossi counter) and a Bonner spheres system. General agreement is found between these independent methods. The dose equivalent at 5 and 100 cm distances outside the field edge is 2% and 0.4% of the dose equivalent at the isocenter. Measurements were also performed at the same points as a function of proton energy on the Be target. Proton energies of 25-46 MeV on Be were applied. The results indicate increase in the mean quality factor at proton energies below 30 MeV.

Measurement of the restricted linear energy transfer of stray radiation close to the treatment volume of 12 and 18 MeV clinical photon beams

The restricted dose mean linear energy transfer (LET) (L500,D) of the stray radiation field a few centimeters outside the treatment volume has been measured for 12 and 18 MV photons produced by a clinical Therac-20 (AECL) accelerator. The measurements were performed as a function of field size and distance from the edge of the treatment volume, using the method of the high-pressure ionization chamber. Contrary to what was found in a previous investigation for a clinical Co-60 unit and despite the presence of photoneutrons (in the case of 18 MV photons), the L500,D outside the beam does not increase significantly relative to the L500,D of the primary beam.

The Oxygen Effect in the Killing of Diploid Yeast by Photon Irradiations of Different Energies

Diploid yeast was exposed to x rays of 10, 29, and 50 kV and to /sup 60/Co ..gamma.. rays in air, in nitrogen, and in nitrogen containing about 0.5% oxygen. It was found that the oxygen enhancement ratio for a given oxygen concentration did not vary with x-ray energy, but the maximal sensitization was greater with the ..gamma.. rays. The data indicate that with increasing mean linear energy transfer higher oxygen concentrations are required for sensitization.

Effect of gamma radiation and alpha particles on gene recombination in Chlamydomonas reinhardi.

Low doses of 60 Co γ radiation, which kill no more than about 5% of the zygospores, change gene recombination at only 2 short stages during the course of meiosis in Chlamydomonas reinhardi , but higher doses, which kill more than 10% of the spores, depress recombination at all stages up to pachytene. Irradiation with α particles having a mean linear energy transfer (LET) of about 1300 and 1600 MeV g −1 cm 2 changes recombination in a manner which appears to combine the effects characteristic of both low and high doses of γ-radiation simultaneously. The “γ high-dose” type of response has a relative biological effectiveness (RBE) of between 20 and 35, and the “γ low-dose” RBE is greater than 1 although precise evaluation is impossible due to the complexity of the response. The RBE for survival was 16.5 at the low dose levels studied.