Ultraviolet (UV) light induces specific mutations in the cellular and skin genome such as UV-signature and triplet mutations, the mechanism of which has been thought to involve translesion DNA synthesis (TLS) over UV-induced DNA base damage. Two models have been proposed: "error-free" bypass of deaminated cytosine-containing cyclobutane pyrimidine dimers (CPDs) by DNA polymerase η, and error-prone bypass of CPDs and other UV-induced photolesions by combinations of TLS and replicative DNA polymerases—the latter model has also been known as the two-step model, in which the cooperation of two (or more) DNA polymerases as misinserters and (mis)extenders is assumed. Daylight UV induces a characteristic UV-specific mutation, a UV-signature mutation occurring preferentially at methyl-CpG sites, which is also observed frequently after exposure to either UVB or UVA, but not to UVC. The wavelengths relevant to the mutation are so consistent with the composition of daylight UV that the mutation is called solar-UV signature, highlighting the importance of this type of mutation for creatures with the cytosine-methylated genome that are exposed to the sun in the natural environment. UVA has also been suggested to induce oxidative types of mutation, which would be caused by oxidative DNA damage produced through the oxidative stress after the irradiation. Indeed, UVA produces oxidative DNA damage not only in cells but also in skin, which, however, does not seem sufficient to induce mutations in the normal skin genome. In contrast, it has been demonstrated that UVA exclusively induces the solar-UV signature mutations in vivo through CPD formation.

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Exposure to radiation is one of the main concerns for space exploration by humans. By focusing deliberately on the works performed on human cells, we endeavored to review, decade by decade, the technological developments and conceptual advances of space radiation biology. Despite considerable efforts, the cancer and the toxicity risks remain to be quantified: 1) the nature and the frequency of secondary heavy ions need to be better characterized in order to estimate their contribution to the dose and to the final biological response; 2) the diversity of radiation history of each astronaut and the impact of individual susceptibility make very difficult any epidemiological analysis for estimating hazards specifically due to space radiation exposure. 3) Cytogenetic data undoubtedly revealed that space radiation exposure produce significant damage in cells. However, our knowledge of the basic mechanisms specific to low-dose, to repeated doses and to adaptive response is still poor. The application of new radiobiological techniques, like immunofluorescence, and the use of human tissue models different from blood, like skin fibroblasts, may help in clarifying all the above items.

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Genetics of susceptibility to radiation-induced hematopoietic neoplasms and somatic chromosomal aberrations were analyzed in 305 backcross (CcS-17xCcS-2)xCcS-2 mice of two CcS/Dem recombinant congenic strains. Irradiated CcS-2 mice were previously shown to exhibit high frequency of myeloid neoplasms whereas irradiated CcS-17 mice were susceptible to T-cell lymphomas. Mice were exposed to four whole-body irradiation doses of 1.7 Gy at one week intervals, which resulted in 139 hematopoietic neoplasms. The hematopoietic neoplasms were classified according to the Bethesda proposals for classification of lymphoid and nonlymphoid hematopoietic neoplasms in mice. Genotyping of mice with 24 microsatellite markers and subsequent statistical analysis indicated linkage of the radiation induced T-lymphomas to two loci on chromosome 10 (D10Mit134) and chromosome 12 (D12Mit52). T-lymphoma susceptibility appeared to be linked to D10Mit134 in a sex dependent way. In contrast, the myeloid-granulocytic leukemias susceptibility is linked to combined effects of chromosome 5 (D5Mit179) and 16 (D16Mit34). Cytogenetic analysis was performed according to the standard G-bands procedure and confirmed using FISH method. We found non-random numerical and structural chromosomal changes in lymphoid neoplasms. Cytogenetic analysis indicated chromosomal aberrations presumably associated with lymphomagenesis, no specific cancer-related rearrangements were observed.

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Non-targeted effects induced by ionizing radiation have been demonstrated both in vitro and in vivo. Previously, we have also demonstrated the existence of non-targeted effects in intact Arabidopsis seeds following low-energy heavy-ion radiation. In the present study, 6.5 MeV protons with 8 × 10¹¹ ions/cm² and 2 × 10¹¹ ions/cm² fluence respectively were used to irradiate non-shielded or partial-shielded Arabidopsis seeds to further explore the mechanisms which regulate in vivo non-targeted effects and to investigate the difference between damage caused by non-targeted effects and direct irradiation. Results showed that excess reactive oxygen species (ROS) are present in the non-irradiated part of the partially irradiated samples, indicating that in vivo non-targeted effects can promote the generation of excess metabolic ROS in the non-irradiated shoot apical meristem/root apical meristem cells. Furthermore, pretreatment with 0.5% ROS scavenger dimethyl sulfoxide (DMSO) or 0.02 mM reactive nitrogen species (RNS) scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) significantly suppresses the non-targeted effects in the partially irradiated samples, while in the whole-body irradiated samples, the cPTIO pretreatment has no effect. On the other hand using antioxidant enzyme assays, superoxide dismutase activity was found to increase for partial irradiated samples and decrease for the whole-body exposed seeds. Taken together, these results implicate that damage caused by non-targeted effects is different from that induced by direct irradiation in vivo. Metabolic products such as ROS and RNS are involved in the in vivo non-targeted effects.

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Purpose: To compare standard radiotherapy field (SRTF) with whole abdomen irradiation (WAI), used in conjunction with adjuvant chemotherapy following curative surgery in patients with gastric cancer. Methods and Material: Ninety patients were included in the study and divided into two treatment arms. In the first treatment arm, SRTF, including 45 Gy radiation to the primary tumor and regional lymph nodes, was performed in 45 patients. In the second treatment arm, a total of 45.2 Gy RT was delivered; 20 Gy to the whole abdomen followed by 25.2 Gy RT to the tumor and regional lymph nodes, in 45 patients. An intravenous bolus dose of 250 mg/m²/week 5-fluorouracil (5-FU) was administered concomitantly with RT in both treatment arms. Patients who completed concomitant chemoradiotherapy, received adjuvant treatment, including 4 cycles of 5-FU (425 mg/m²) and folinic acid (20 mg/m²) in 4 week intervals. Results: Median age was 56 years (range: 22–81), 89% of the patients (n = 80) had serosal involvement, 78% (n = 70) were node positive. The rate of hematological (40% vs. 16%, p = 0.010) and gastrointestinal toxicities (80% vs. 53%, p = 0.010) were higher, and performance loss (60% vs. 29%, p = 0.003) was greater in the second treatment arm. Number of patients who experienced Grade 3 and Grade 4 gastrointestinal toxicities (especially diarrhea) were higher in the second treatment arm (4% vs. 16%, p = 0.049). The median follow-up was 19 months (range: 7–96). The median 5-year survival was 29% and 17%, locoregional control was 30% and 25%, and disease-free survival was 27% and 16% in the first and second treatment arms, respectively. There was no significant difference between the treatment groups in terms of survival, locoregional control and disease-free survival rates (p > 0.05). Conclusion: Whole abdomen irradiation was not found to be superior to standard field radiotherapy used in conjunction with adjuvant chemotherapy in gastric cancer.

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The aim of this study is to investigate the effect of KGF (Keratinocyte growth factor) gene therapy mediated by the attenuated Salmonella typhimurium Ty21a on radiation-induced pulmonary injury in rats model. Sprague–Dawley rats were divided into three groups: TPK group (treated with TPK strain, attenuated Salmonella typhimurium Ty21a-recombined human KGF gene); TP group (treated with TP strain, attenuated Salmonella typhimurium Ty21a-recombined blank plasmid); and Saline group (treated with saline). After intraperitoneal administration for 48 h, the thoraxes of the rats were exposed to X-ray (20 Gy), and the rats were administered again two weeks after radiation. On the 3rd, 5th, 7th, 14th and 28th day after radiation, the rats were sacrificed and lung tissues were harvested. Histological analysis was performed, MDA contents and SOD activity were detected, mRNA levels of KGF, TGF-β, SP-A and SP-C were measured by Real-time RT-PCR, and their concentrations in the BALF were quantified with ELISA. Administration of TPK strain improved the pathological changes of the lung on the 28th day. In the TPK group, KGF effectively expressed since the 3rd day, MDA contents decreased and SOD activity increased significantly, on the 7th day and 14th day respectively. SP-A and SP-C expression elevated, whereas TGF-β expression was inhibited in the TPK group. These results suggest that this novel gene therapy of KGF could ameliorate radiation-induced pulmonary injury in rats, and may be a promising therapy for the treatment of radiative pulmonary injury.

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The increasing use of mobile phones has aroused public concern regarding the potential health risks of radiofrequency (RF) fields. We investigated the effects of exposure to RF fields (2.45 GHz, continuous wave) at specific absorption rate (SAR) of 1, 5, and 10 W/kg for 1, 4, and 24 h on gene expression in a normal human glial cell line, SVGp12, using DNA microarray. Microarray analysis revealed 23 assigned gene spots and 5 non-assigned gene spots as prospective altered gene spots. Twenty-two genes out of the 23 assigned gene spots were further analyzed by reverse transcription-polymerase chain reaction to validate the results of microarray, and no significant alterations in gene expression were observed. Under the experimental conditions used in this study, we found no evidence that exposure to RF fields affected gene expression in SVGp12 cells.

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Polymeric micelles loaded with cis-diamminedichloroplatinum(II), CDDP, (cisplatin micelles) enable higher accumulation in solid tumors and lower toxicities compared with CDDP alone. The combined use of cisplatin micelles with radiation is expected to enhance therapeutic effects and reduce side effects. The kinetics of cisplatin micelle uptake, however, have not been fully understood. Particle Induced X-Ray Emission has been employed in this study to measure the time transients of platinum in Chinese Hamster ovary cells. The results show that the platinum content of cells treated with cisplatin micelles increased more slowly than with CDDP alone, suggesting that cellular uptake could be controlled using micelles. The CDDP released from micelles was predominantly incorporated into the cells by diffusion. The uptake characteristics were further analyzed using micelles with different collapse rates. The results and techniques used in this study will be useful for designing an optimum treatment plan combining platinum-containing polymeric micelles and radiation in clinical applications.

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We evaluated the interrelationship between rectal content and intrafraction motion of the prostate. Forty seven prostate cancer patients instructed to remove their rectal gas were imaged by planning CT and MRI before radiotherapy (RT) and during RT. The total scan time was comparable to our cone-beam CT scanning and treatment times. Rectal content was qualitatively assessed into four different categories by T2-weighted axial MRI: empty (Group E), gas (Group G), combination of gas and feces (Group C), and feces (Group F). Eleven anatomic points of interest (POI) were determined on subsequent sagittal cine-MRI slices. The incidence of displacement of more than 3 mm for more than 10% of time (> 10% time over 3 mm) at least in one of the prostate POIs in Group E was 6.3%, Group G 40.9%, Group C 6.3%, and Group F 0%, respectively. Except for Group G, the mean probability of > 3 mm displacement was < 3%. More than 10% time over 3 mm displacement of the superior prostate in the AP direction (SAP) was noted in only Group G patients and was 45.5% before RT and 18.2% during RT. Only Group G patients were significantly related to both the mean of means and the mean of maxs of prostate displacement of SAP by multivariate analysis. Group G patients were also significantly related to the mean of the standard deviation of rectum width of superior rectum and mid-rectum by multivariate analysis. Patients with rectal gas only were significantly related to prostate displacement and rectal movement.

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Chick embryos have been used as alternative experimental animals in various research fields, including virology, immunology, toxicology, oncology, and embryology. Until now, there have been no in vivo models using chick embryo to evaluate radiosensitizing activity. Here, the in vivo radiosensitizing activity of etanidazole, a well-known hypoxic cell radiosensitizer, was evaluated using tumor-bearing chick embryo. On the basis of tumor growth, drug administration and X-ray irradiation were performed on day 15 chick embryo, with the endpoint being day 18 chick embryo. In day 15 chick embryo, an X-ray irradiation dose of equal or less than 10 Gy did not cause significant tumor growth suppression. Intravenous administration of equal or less than 1.0 mg of etanidazole did not cause tumor growth suppression. Neither doses of equal or less than 8 Gy of irradiation nor 1.0 mg of etanidazole caused fatality of the chick embryo. On the basis of these results, we evaluated the radiosensitizing effect of a combination treatment with 8 Gy of irradiation and 1.0 mg of etanidazole. As noted above, 1.0 mg of etanidazole alone and 8 Gy of irradiation alone did not show tumor growth suppression. In contrast, a combination treatment with 8 Gy of irradiation and 1.0 mg of etanidazole showed 35% of significant tumor growth suppression. Thus, we succeeded in evaluating the in vivo radiosensitizing activity of etanidazole using tumor-bearing chick embryo. These results suggest that the use of tumor-bearing chick embryo may be part of a promising system for evaluating radiosensitizing activity.

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To investigate whether impaired osteogenesis resulting from vitamin D deficiency can influence hematopoiesis recovery after radiation, the 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase) gene knockout (KO) mice and wild type (WT) mice were subjected to different doses of gamma ray. The survival rates, peripheral blood cell counts and bone marrow cellularity were studied after irradiation (IR). The survival rates of the KO mice were significantly lower than that of WT mice after 6 or 8 Gy dose of radiation. The recovery of white blood cells in KO mice was significantly delayed compared with that in WT mice after radiation. The red blood cell number in WT mice was observed to increase more than that in KO mice at days 14 and 28 after radiation. The nadir platelet count in KO mice was nearly half of that in WT mice. Dramatically higher bone marrow cell numbers were found in WT mice compared with KO mice. Our findings demonstrate the enhanced radiosensitivity in 1,25-dihydroxyvitamin D3 (1,25-(OH)₂D₃) deficient mice.

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Purpose: The purpose of this study is to quantify the magnitudes of the position shifts of internal structures together with the correlation between the day-to-day positioning of the prostate and the bony anatomy using an integrated CT-linear accelerator system for external beam radiation therapy for prostate cancer. Materials and methods: A total of 1176 pretreatment in-room CT images and their digitally reconstructed radio-graph (DRR) pairs from 33 patients were acquired over the course of the study. The differences between the isocenter of the prostate on in-room CT and the isocenter of the bony anatomy on DRR were analyzed. The agreement between positions in each direction was compared using Bland-Altman limits of agreement. Results: The 95% limits of agreement in lateral (LR), superoinferior (SI), and anteroposterior (AP) directions were –2.98 to 2.49 mm, –4.69 to 5.75 mm, and –8.23 to 7.30 mm, respectively. The isocenter was localized to within 3.0 mm on in-room CT images and DRR 99.0% in LR, 85.1% in SI, and 85.9% in AP. Conclusions: Considerable differences between in-room CT images and DRR exist. These data demonstrate that there is a significantly greater shift in the SI and AP directions than in the lateral direction for the entire patient group. Applications such as our image guide system will, with routine clinical use, continue to improve the precision of external beam radiation therapy for prostate cancer.

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This study was conducted to examine the utility of the combined use of ascorbic acid (AsA) and radiation in clinical applications. We investigated cell survival, DNA fragmentation, and caspase activation after X-ray irradiation and AsA treatment of human leukemia HL60 cells. The number of living cells decreased after combined X-ray irradiation and AsA treatment (2 Gy + 5 mM) in comparison with that after X-ray irradiation (2 Gy) or AsA treatment (5 mM) alone. DNA fragmentation was more in the cells subjected to combined X-ray irradiation and AsA treatment than in those subjected to X-ray irradiation alone. Caspase-3, caspase-8, and caspase-9 were highly activated following combined X-ray irradiation and AsA treatment, but caspase-8 activity was not markedly increased after X-ray irradiation alone. Bax levels in the mitochondrial membrane fractions were increased after AsA treatment alone and after combined X-ray irradiation and AsA treatment. However, there was no apparent increase in the Bax levels after X-ray irradiation treatment alone. Thus, this study confirmed that supplementing X-ray irradiation with AsA treatment results in increased apoptosis in HL60 cells. With regard to the apoptosis-inducing factors, we hypothesized that Bax and caspase-8 were activated after combined X-ray irradiation and AsA treatment compared with either treatment alone.

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To characterize a change in NPQ upon exposure to ultraviolet-B (UV-B), the xanthophyll cycle-dependent and -independent NPQs were compared in Cucumis sativus, Lycopersicum esculentum, and Arabidopsis thaliana leaves. The xanthophyll cycle-dependent NPQ was dramatically but reversibly suppressed by UV-B radiation. This suppression was correlated more strongly with a marked decrease in photosynthetic electron transport rather than changes in xanthophyll cycle enzymes such as violaxanthin de-epoxidase and zeaxanthin epoxidase. Accordingly, the UV-B-induced suppression of NPQ cannot be attributed to changes in expressions of VDE and ZEP. However, suppression of the xanthophyll cycle-dependent NPQ could only account for the 77 K fluorescence emission spectra of thylakoid membranes and the increased level of ¹O₂ production, but not for the decreased levels of •O₂^– production and H₂O₂ scavenging. These results suggest that a gradual reduction of H₂O₂ scavenging activity as well as a transient and reversible suppression of thermal energy dissipation may contribute differentially to increased photooxidative damages in cucumber, tomato, and Arabidopsis plants after acute exposure to UV-B radiation.

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In vivo modulation of gene expression profiles after low-dose and low-dose-rate irradiation has been observed in a variety of experimental systems. However, few studies actually investigated the underlying mechanisms for these genetic responses. In this study, we used pre-existing microarray data and searched for gene modulations in response to long-term, low-dose-rate irradiation. Nucleotide sequences in the neighboring region of the up-regulated, down-regulated, and unaffected genes were retrieved from the Entrez Gene database, and recognition sequences for transcription factors (TFs) were searched using the TFSEARCH database. As a result, we suggested 21 potential TF-binding sites with significantly different incidence between the three gene groups (up-regulated, down-regulated and unaffected gene groups). The binding sites for sterol regulatory element-binding protein 1 (SREBP-1), aryl hydrocarbon receptor (AhR/Ar) and olfactory 1 (Olf-1) were suggested to be involved in up-regulation, while the binding sites for glucocorticoid receptor (GR(GGTACAANNT GTYCTK) ) and hepatocyte nuclear factor 1 (HNF-1) were suggested to be involved in down-regulation of the genes. In addition, the binding sites for activating enhancer-binding protein 4 (AP-4), nuclear factor-κB (NFκB), GR (NNNNNNCNNTNTGTNCTNN) and early growth response 3 (Egr-3) were correlated with modulation of gene expression regardless of the direction of modulation. Our results suggest that these TF-binding sites are involved in gene modulations after long-term continuous irradiation with low-dose-rate γ rays. GR and/or SREBP-1 might be associated with the altered metabolic process observed in liver after exposure to low-dose-rate irradiation.

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