International Journal of Radiation Biology最新文献

Purpose: In the present paper we investigate how some stochastic effects are included in a class of radiobiological models with particular emphasis on how such randomnesses reflect into the predicted cell survival curve.

Materials and methods: We consider four different models, namely the Generalized Stochastic Microdosimetric Model GSM², in its original full form, the Dirac GSM² the Poisson GSM²$$ and the Repair-Misrepair Model (RMR). While GSM²$$ and the RMR models are known in literature, the Dirac and the Poisson GSM²$$ have been newly introduced in this work. We further numerically investigate via Monte Carlo simulation of four different particle beams, how the proposed stochastic approximations reflect into the predicted survival curves. To achieve these results, we consider different ion species at energies of interest for therapeutic applications, also including a mixed field scenario.

Results: We show how the Dirac GSM²$,$ the Poisson GSM²$$ and the RMR can be obtained from the GSM²$$ under suitable approximations on the stochasticity considered. We analytically derive the cell survival curve predicted by the four models, characterizing rigorously the high and low dose limits. We further study how the theoretical findings emerge also using Monte Carlo numerical simulations.

Conclusions: We show how different models include different levels of stochasticity in the description of cellular response to radiation. This translates into different cell survival predictions depending on the radiation quality.

Purpose: To evaluate the therapeutic efficacy of cyclin-dependent kinase (CDK) inhibition in combination with ionizing radiation for lung cancer.

Materials and methods: Human lung adenocarcinoma (A549) and squamous cell carcinoma (H520) cells were used to evaluate the therapeutic efficacy of CDK inhibition in combination with ionizing radiation in vitro using colony formation assay, γH2AX immunofluorescence staining, western blotting, and cell cycle phase analysis. We also performed in vivo evaluations of ectopic tumor growth.

Results: In vitro pretreatment with the CDK inhibitor, seliciclib, before irradiation significantly decreased the survival of A549 and H520 cells in a dose-dependent manner. Although CDK inhibition alone did not increase the intensity of γH2AX foci, its combination with ionizing radiation increased DNA double-strand breaks, as shown by γH2AX immunofluorescence staining and western blotting. The combination of CDK inhibition and ionizing radiation-induced G2/M arrest and increased apoptosis, as evidenced by the increased proportion of cells in G2/M arrest, subG1 apoptotic population, and expression of apoptotic markers (cleaved PARP-1 and cleaved caspase-3). Mechanistic studies showed reduced expression of cyclin A with combined treatment, indicating cell cycle shifting effects. An in vivo xenograft model showed that the combination of CDK inhibition and ionizing radiation delayed xenograft tumor growth, and increased the proportion of cleaved PARP-1- and cleaved caspase-3-positive cells, compared to either treatment alone.

Conclusions: We provide preclinical tumoricidal evidence that the combination of CDK inhibition and ionizing radiation is an efficacious treatment for lung cancer.

The era of high-throughput techniques created big data in the medical field and research disciplines. Machine intelligence (MI) approaches can overcome critical limitations on how those large-scale data sets are processed, analyzed, and interpreted. The 67^th Annual Meeting of the Radiation Research Society featured a symposium on MI approaches to highlight recent advancements in the radiation sciences and their clinical applications. This article summarizes three of those presentations regarding recent developments for metadata processing and ontological formalization, data mining for radiation outcomes in pediatric oncology, and imaging in lung cancer.

Purpose: To investigate the structural features of wild-type and phospho-mimicking mutated XRCC4 protein, a protein involved in DNA double-strand break repair.

Materials and methods: XRCC4 with a HisTag were expressed by E. coli harboring plasmid DNA and purified. Phospho-mimicking mutants in which one phosphorylation site was replaced with aspartic acid were also prepared in order to reproduce the negative charge resulting from phosphorylation. The proteins were separated into dimers and multimers by gel filtration chromatography. Circular dichroism (CD) spectroscopy was performed in the region from ultraviolet to vacuum-ultraviolet. The CD spectra were analyzed with two analysis programs to evaluate the secondary structures of the wild-type and phospho-mimicked dimers and multimers.

Result and discussion: The proportion of β-strand in the wild-type dimers was very low, particularly in their C-terminal region, including the five phosphorylation sites. The secondary structure of the phospho-mimic hardly changed in the dimeric form. In contrast, the β-strand content increased and the α-helix content decreased upon multimerization of the wild-type protein. The structural change of multimers slightly depended on the phospho-mimic site. These results suggest that the β-strand structure stabilizes the multimerization of XRCC4 and it is regulated by phosphorylation at the C-terminal site in living cells.

Conclusion: An increase in the β-strand content in XRCC4 is essential for stabilization of the multimeric form through C-terminal phosphorylation, allowing the formation of the large double-strand break repair machinery.

Purpose: This review considers issues related to interpreting the mixed legacy of >300 papers published during the past three decades on possible genotoxic effects of exposure of human and animal tissues to radiofrequency electromagnetic fields (RF-EMF). The main paper reviews the evolution of consensus guidelines for genotoxicity testing and the increasing emphasis on systematic reviews for evaluation of scientific studies for use in health risk assessments. An Appendix considers some issues in assessing the bioeffects literature by examining a subset of genotoxicity publications that employed the comet assay. While most studies found no statistically significant effects of exposure, a significant minority of studies (chiefly, in vivo studies) reported statistically significant effects of exposure. The quality of the studies was highly variable; while several studies were meticulously done and documented, none of these studies were compliant with currently accepted guidelines such as those of the Organization for Economic Cooperation and Development (OECD). Evaluation of the studies using risk of bias (RoB) criteria showed that, in this sample of studies, higher quality studies were less likely to find statistically significant results than those of lower quality.

Conclusion: The authors conclude that statistical significance should be only one consideration in evaluation of bioeffects studies. Simply listing 'statistically' significant effects identified using null hypothesis testing and the criterion p < 0.05 for statistical significance is misleading and uninformative in assessing health risks of exposure. A careful synthesis of evidence is needed, including assessment of study validity, biological significance of reported effects, and coherence of study results with those of other related studies.The authors recommend that all future RF genotoxicity studies intended for use in human health risk assessments and evaluations of the literature should be done in compliance with accepted quality guidelines, i.e. OECD or equivalent guidelines for genotoxicity screening studies and PRISMA or other accepted guideline for reviews of the literature. The positive studies in this group should be redone with tighter quality control to establish the reliability of the findings.

Purpose: Ionizing radiation causes various types of DNA damage e.g. single strand breaks (SSB) and double strand breaks (DSB), whereby the SSB/DSB ratio is shifted toward the DSB with increasing LET. For the DNA-incorporated Auger electron emitter Iodine-125 a SSB/DSB ratio of 5.4:1 is calculated based on computer simulations. In the presented work the SSB/DSB ratio of DNA-incorporated Iodine-125 was experimentally determined and compared to external homogenous γ-irradiation.

Materials and methods: Iodine-125-iododeoxyuridine (I-125-UdR) was incorporated into the DNA of SCL-II cells and cells were subsequently frozen for decay accumulation. Accordingly, external γ-irradiation (Cs-137) experiments were performed in frozen cells. After exposure the neutral or alkaline Comet Assay was performed to quantify DSB or DSB and SSB, respectively. Automated quantification of the comets was performed using the Olive Tail Moment (Metafer CometScan; MetaSystems). Calculation of absorbed dose for Auger electrons on cellular level is extremely biased due to the exclusive DNA localization of I-125-UdR. To avoid dose calculation the γ-H2AX assay was used in order to allow the comparison of the Comet Assay data between both investigated radiation qualities.

Results: For low-LET γ-radiation, a SSB/DSB ratio of 10:1 was determined. In contrast, a lower SSB/DSB ratio of 6:1 was induced by DNA-incorporated Iodine-125 which compares very well to the calculated values of Pomplun and co-authors.

Conclusion: DNA-incorporated Iodine-125 induces a high-LET type DNA damage pattern in respect to SSB/DSB ratio.

Purpose: PAKs proteins are speculated as new promising targets for cancer therapy due to their central role in many oncogenic pathways. Because PAKs proteins are very significant during carcinogenesis, we aimed to investigate the hypothesis that inhibition of PAKs with IPA-3 and PF-3758309 treatment could synergistically reduce colon carcinoma cell growth.

Materials and methods: The cytotoxic effects of both drugs were determined by a cell viability assay. Cell cycle and apoptosis were analyzed by flow cytometry. The effects of inhibitor drugs on marker genes of apoptosis, autophagy, cell cycle, and DNA damage were tested via immunoblotting.

Results and conclusions: We found out the synergistic effect of these drugs in pair on five colon cancer cell lines. Combined treatment with IPA-3+PF-3758309 in SW620 and Colo 205 cells markedly suppressed colon formation and induced apoptosis, cell cycle arrest, and autophagy compared with treatment with each drug alone. Additionally, this combination sensitized colon cancer cells to ionizing radiation that resulted in inhibition of cell growth.

Significance: Collectively, our findings show for the first time that cotreatment of IPA-3 with PF-3758309 exhibits superior inhibitory effects on colon carcinoma cell growth via inducing DNA damage-related cell death and also enforces a cell cycle arrest.

Purpose: Determination of the protective property of melanin, an organic polymer class consisting of phenolic and/or indolic compounds isolated from bacteria and fungi, against fast neutron radiation. To show that these melanin samples, which also have antioxidant and metal chelating properties, can be used as an active ingredient for a drug to be developed against neutrons used in nuclear research and medicine.

Materials and methods: Bacterial and fungal media were prepared, and melanin pigments were produced and isolated. For molecular characterization of pigments, bacterial genomic DNA extraction, 16S rDNA gene amplification processes, and fungal genomic DNA extraction, ITS1, and ITS4 Gene Regions amplification were performed. The DEL assay was implemented to determine the genotoxicity properties of bacterial and fungal melanin pigments. Samples were prepared in a pad measuring 10 ml volume (60 × 15 mm) at a concentration of 0.2-1 microgram in 1% agarose gel for radiation-absorbed dose measurements. Absorption measurements were made using ²⁴¹Am-Be fast neutron source and Canberra brand NP series BF₃ gaseous detector to determine the neutron radiation absorption capacity of all samples. The results obtained to determine the absorption degrees of melanin samples were compared with paraffin and normal concrete, which are widely used in neutron radiation shielding studies.

Results: Melanin pigments were obtained using different bacteria and fungi strains. Afterwards, the fast neutron radiation absorption capacity of these purified pigments were determined. Compared to reference samples, these pigments were found to have slightly lower radiation absorbing ability. In addition to these experiments, cytotoxicity tests were carried out using the Yeast DEL assay technique to evaluate the potential for use of these organic pigments in fields such as medicine and pharmacology. According to the results obtained from the tests, it was determined that these melanin samples did not have any toxic effects.

Conclusion: It was determined that these melanin samples have the potential to be used as a radioprotective drug active substance to protect the tissues and cells of people exposed to neutron radiation after a nuclear accident or nuclear war.Giving a drug that will be developed by using these active ingredients before or after people are exposed to a radiation environment can provide great benefits.

Purpose: Development of a model characterizing risk variation with RBE to investigate how the incidence risk for all solid cancers combined varies with higher neutron RBEs and different organ dose types.

Material and methods: The model is based on RERF data with separate neutron and gamma dose information.

Results: For both additive and multiplicative linear excess risks per unit organ averaged dose, a reduction of 50% in the risk coefficient per weighted dose arises when a neutron RBE of 110 is used instead of 10. Considering risk per unit liver dose, this reduction occurs for an RBE of 130 and for risks per unit colon dose for an RBE of 190. The change in the shape of the dose response curve when using higher neutron RBEs is evaluated. The curvature changed and became significantly negative for males at an RBE of 140 for colon dose, 100 for liver dose and 80 for organ averaged dose. For females this is the case at an RBE of 110, 80 and 60, respectively.

Conclusions: Uncertainties in neutron RBE values should be considered when radiation risks and the shape of dose responses are deduced from cancer risk data from the atomic bomb survivors.