Complex hprt deletion events are recovered after exposure of human lymphoblastoid cells to high-LET carbon and neon ion beams.
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Hypoxanthine phosphoribosyltransferase gene (hprt) mutations were induced in human TK-6 lymphoblastoid cells by irradiation at a linear energy transfer (LET) of 250 or 310 keV/micron for carbon and neon ions, respectively. At such a high level of LET, ions will lose most of their total energy and stop shortly after passing through the cell. The hprt mutations were analyzed by multiplex PCR, long-PCR and DNA sequencing of both genomic and cDNA. Over half of the C ion-induced hprt mutations (10 of 19) were point mutations, in contrast to 15% of the mutations induced by Ne ions (three of 20). The remaining 47 and 85% of the C and Ne ion-induced mutants, respectively, are deletion events. The latter events include three complex losses of multiple non-contiguous exon regions in both ion irradiation collections. We note that mutations involving the exon 6 region are frequent in the Ne ion collection: all three of the complex events retained the exon 6 region with flanking deletion of sequence and three other mutants involved deletion of this region. It may be concluded that these high-LET C and Ne ion irradiations produce different mutational spectra. (+info)
Relative biological effectiveness of carbon ions for causing fatal liver failure after partial hepatectomy in mice.
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To evaluate the acute phase damage to liver by carbon ions, BALB/c mice were irradiated with carbon ions or X-rays after two-thirds partial hepatectomy, and their survival was followed. The 50% lethal dose within 60 days (LD50/60) was 42.2 +/- 0.25 Gy (standard error) for X-rays, and 22.7 +/- 0.25 Gy for carbon ions. The relative biological effectiveness (RBE) of carbon ions was 1.86 (95% confident limits: 1.69-2.04) as calculated from the LD50/60. Mice irradiated at much higher doses, 60 Gy of X-rays or 24 Gy of carbon ions, showed significantly higher serum ammonia levels and lower serum albumin levels than normal, suggesting hepatic failure as a cause of death. Hepatocytes showed karyorrhexis and karyolysis in carbon ion irradiated and spotty necrosis in X-ray irradiated mice, suggesting nuclear damage. Mice irradiated with LD50 of X-rays or carbon ions had a remarkably lower bromodeoxyuridine (BrdU) labeling index and mitotic index than control. Treatments with both BrdU and vincristine showed that none of the hepatocytes that synthesized DNA after irradiation completed mitosis, indicating G2 arrest. The liver weight of irradiated mice significantly decreased depending on the dose. Carbon ions as well as X-rays damaged hepatocytes directly and suppressed liver regeneration leading to fatal liver failure. (+info)
LET dependency of heavy-ion induced apoptosis in V79 cells.
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We investigated the relationship between the LET values and cell death, defined as either apoptosis or loss of reproductive integrity (reproductive death), using Chinese hamster V79 cells. The cells were irradiated with X-rays or carbon-ion beams from the Heavy Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS). Apoptosis was defined based on the morphological change upon treating of cells with caffeine. The apoptotic index, the ratio of apoptotic cells to the total, after exposure to 2 Gy of X-rays was 0.043. Upon irradiation with carbon-ion beams, the index was gradually increased with increasing LET values, reaching a maximum of 0.076 at 110 keV/micron, and then decreased to 0.054 at 237 keV/micron. An analogous pattern of the LET dependence was observed between reproductive death and apoptotic death. The cell-survival values obtained after 2 Gy exposure (SF2) were 0.64, 0.13, and 0.24, respectively. A similar trend was found for the RBE values calculated from the initial slope for both apoptosis and reproductive death. These results strongly suggest that the target for both types of cell death is the same. (+info)
Different mechanisms of radiation-induced loss of heterozygosity in two human lymphoid cell lines from a single donor.
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Allelic loss is an important mutational mechanism in human carcinogenesis. Loss of heterozygosity (LOH) at an autosomal locus is one outcome of the repair of DNA double-strand breaks (DSBs) and can occur by deletion or by mitotic recombination. We report that mitotic recombination between homologous chromosomes occurred in human lymphoid cells exposed to densely ionizing radiation. We used cells derived from the same donor that express either normal TP53 (TK6 cells) or homozygous mutant TP53 (WTK1 cells) to assess the influence of TP53 on radiation-induced mutagenesis. Expression of mutant TP53 (Met 237 Ile) was associated with a small increase in mutation frequencies at the hemizygous HPRT (hypoxanthine phosphoribosyl transferase) locus, but the mutation spectra were unaffected at this locus. In contrast, WTK1 cells (mutant TP53) were 30-fold more susceptible than TK6 cells (wild-type TP53) to radiation-induced mutagenesis at the TK1 (thymidine kinase) locus. Gene dosage analysis combined with microsatellite marker analysis showed that the increase in TK1 mutagenesis in WTK1 cells could be attributed, in part, to mitotic recombination. The microsatellite marker analysis over a 64-cM region on chromosome 17q indicated that the recombinational events could initiate at different positions between the TK1 locus and the centromere. Virtually all of the recombinational LOH events extended beyond the TK1 locus to the most telomeric marker. In general, longer LOH tracts were observed in mutants from WTK1 cells than in mutants from TK6 cells. Taken together, the results demonstrate that the incidence of radi-ation-induced mutations is dependent on the genetic background of the cell at risk, on the locus examined, and on the mechanisms for mutation available at the locus of interest. (+info)
Treatment planning for heavy-ion radiotherapy: biological optimization of multiple beam ports.
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A crucial task in radiotherapy is dose conformation to the prescribed target volume whilst sparing the surrounding healthy tissue around as much as possible. One of the best approaches so far is active dose shaping in three dimensions using scanned beams of charged particles, like carbon ions. Besides their inverse dose profile and minimal lateral scattering, carbon ions have the advantage that their RBEs increase towards the end of their range. An active beam-delivery system for intensity-modulated carbon-ion beams has been operational at GSI since December, 1997. In order to ensure dose conformation, inverse treatment planning with respect to the biologically effective dose distribution must be applied. A typical patient irradiation comprises two singly optimized opposing fields. This paper discusses the superposition of biologically effective dose distributions for radiotherapy with 12C ions, which is non-trivial due to the nonlinear nature of the dose response of biological systems. Sum rules for the nonlinear addition of singly optimized fields are derived. This method is being used clinically, and has been successfully applied to more than 50 patients. (+info)
Effects of heavy-ion radiosurgery on the hemopoietic function of the silkworm Bombyx mori.
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To study the effects of heavy-ion radiosurgery on the hemopoietic function of a silkworm, hemopoietic organs of larvae were locally irradiated with carbon-ion beams, and the changes in the hemocyte density and in the hemocyte function were investigated. When the larvae were irradiated by 50 Gy to 300 Gy carbon ions on the 3rd day of the 4th instar, the hemocyte densities did not change for a while, though they gradually increased at a later stage, but were finally still significantly lower than those of unirradiated controls. The hemocyte densities of the larvae irradiated at different developmental stages showed suppressed increments, and carbon-ion irradiation given to larvae at early stages compared to the later stages had a significant suppressive effect on the hemocyte densities. On unilateral irradiated larvae a hemocyte intermediate increment between those of bilateral irradiated larvae and unirradiated controls was observed. The percentage of dead hemocytes was obviously higher for irradiated larvae than unirradiated controls during the later 5th instar. Thus, it is evident that carbon-ion radiosurgery on hemopoietic organs of silkworm induced not only a quantitative change, but also a qualitative change in the hemocytes. (+info)
Mutagenic effects of heavy charged particles.
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Heavy charged particles constitute the most important radiation risk in space. Since mutations can give rise to cancer the investigation of their induction may be helpful for risk quantification. This paper describes experiments in a number of mammalian cells performed with a large range of linear energy transfer (LET). RBE values are always found to increase with LET up to about 100 keV/microm and are similar to those suggested by ICRP. Molecular analyses demonstrate that heavy charged particles not only lead to sometimes very large deletions but also to smaller changes which might represent point mutations. Recent evidence shows that repair phenomena play an important role in the processing of initial DNA lesions to mutagenic alterations. (+info)
Intercomparison of radiation instruments for cosmic-ray with heavy ion beams at NIRS (ICCHIBAN project).
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The first InterComparison for Cosmic-ray with Heavy Ion Beams At NIRS (ICCHIBAN) project is an ongoing, international collaboration organized at the National Institute of Radiological Sciences (NIRS), Japan, for the purpose of characterizing and comparing at a controlled, ground-based heavy ion facility the radiation response of instruments used aboard piloted spacecraft for crew and area dosimetry. We present preliminary results from the first set of ICCHIBAN exposures made at HIMAC heavy ion accelerator in February 2002. The initial series of exposures (1st ICCHIBAN run) was designed to establish the response of active detectors to two well-characterized heavy ion beams; 400 MeV/nucleon 12C and 400 MeV/nucleon 56Fe. These beams are representative in charge and energy of two of the most significant heavy ion components present in the galactic cosmic radiation spectrum. The properties of the incident beam, including intensity, profile, charge and total energy, were characterized using several different detector systems, including silicon detectors, CR-39 plastic nuclear track detectors and plastic scintillation counters. Once the response of each detector to heavy ion beams of known composition has been measured, results from on-orbit measurements made by the different instruments can be more meaningfully compared. We conclude by discussing plans for future ICCHIBAN runs, including next 2nd ICCHIBAN run for passive detectors in early summer 2002. (+info)