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Objective: To determine the utility of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a sensitive biomarker for radiation-induced cellular DNA damage in children undergoing cardiac catheterization., Study Design: We enrolled pediatric patients with congenital heart diseases requiring cardiac catheterization in conjunction with healthy children and children under sedation as control. Demographic, clinical, laboratory and invasive hemodynamic data, urinary 8-OHdG levels, and radiation exposure measurements were collected prospectively., Results: Nineteen patients, 10 healthy children and 9 children under sedation, were studied. In 19 patients who underwent cardiac catheterization, the median level of 8-OHdG in urine obtained at 24-48 hours after the procedure was significantly higher than at baseline (44.0 vs 17.3 ng/mg creatinine, P = .0001). Furthermore, the urinary 8-OHdG level after the procedure increased in 18 of the 19 study subjects. In contrast, there was no significant difference in 8-OHdG levels between the 2 spot urine samples obtained at arbitrary intervals of 24-48 hours in 10 healthy children (P = .7213), and at baseline and 24-48 hours following echocardiography in 9 children under sedation (P = .1097). Stepwise multiple regression analysis revealed that the cumulative air kerma during the cardiac catheterization was the variable which was strongly and significantly associated with the ratio of post- to precardiac catheterization urinary 8-OHdG levels among the evaluated variables (R(2) = 0.7179, F = 11.0256, P = .0007)., Conclusions: Urinary 8-OHdG could be a useful biomarker for radiation-induced cellular DNA damage in children undergoing diagnostic cardiac catheterization., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The relationship between ERCC2 polymorphisms and the risk of radiotoxicity remains inconclusive. The aim of our study is to systematically evaluate the association between ERCC2 polymorphisms and the risk of radiotoxicity., Methods: Publications were identified through a search of the PubMed and Web of Science databases up to August 15, 2015. The pooled odds ratios (ORs) with corresponding 95 % confidence intervals (CIs) were calculated to evaluate the association between ERCC2 polymorphisms and radiotoxicity. Trial sequential analysis (TSA) and power calculation were performed to evaluate the type 1 and type 2 errors., Results: Eleven studies involving 2584 patients were ultimately included in this meta-analysis. Conventional meta-analysis identified a significant association between ERCC2 rs13181 polymorphism and radiotoxicity (OR = 0.71, 95 % CI: 0.55-0.93, P = 0.01), but this association failed to get the confirmation of TSA., Conclusions: The minor allele of rs13181 polymorphism may confer a protect effect against radiotoxicity. To confirm this correlation at the level of OR = 0.71, an overall information size of approximate 2800 patients were needed.

Radiotherapy is a major modality of cancer treatment responsible for a large proportion of cancer that is cured. Radiation exposure induces an inflammatory response which can be influenced by genetic, epigenetic, tumour, health and other factors which can lead to very different treatment outcomes between individuals. Molecules involved in the immunological response provide excellent potential biomarkers for the prediction of radiation-induced toxicity. The known molecular and cellular immunological responses in relation to radiation and the potential to improve cancer treatment are presented in this review. In particular, immunological biomarkers of radiation-induced fibrosis and pneumonitis in cancer radiotherapy patients are discussed., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The role of the immune system in the protection of the organism against biological aggressions is long established and well-studied. A new role emerged more recently in the protection from - and the response to - physical trauma such as exposure to ionizing radiation. A pre-existing inflammation, induced by administration of an inflammatory cytokine or of a Toll-like receptor agonist, is indeed able to mitigate the toxic effects of acute radiation exposure. Conversely, it appears that the innate immune system can be activated during the course of the cellular response to radiation. Activation of different sensors and pattern recognition receptors by intra-cellular molecules such as HMGB1 or DNA released in the extra-cellular milieu or in the cytosol by irradiated cells induces the production of inflammatory and anti-viral cytokines. In addition, in human monocytes and macrophages, the expression of inflammatory cytokine genes can be directly induced by p53- and ATM-dependent mechanisms. This last finding establishes a direct link between radiation-induced DNA damage response and radiation-induced inflammation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Radiation therapy is the most effective non-surgical treatment of primary brain tumors and metastases. Preclinical studies have provided valuable insights into pathogenesis of radiation-induced injury to the central nervous system. Radiation-induced brain injury can damage neuronal, glial and vascular compartments of the brain and may lead to molecular, cellular and functional changes. Given its central role in memory and adult neurogenesis, the majority of studies have focused on the hippocampus. These findings suggested that hippocampal avoidance in cranial radiotherapy prevents radiation-induced cognitive impairment of patients. However, multiple rodent studies have shown that this problem is more complex. As the radiation-induced cognitive impairment reflects hippocampal and non-hippocampal compartments, it is of critical importance to investigate molecular, cellular and functional modifications in various brain regions as well as their integration at clinically relevant doses and schedules. We here provide a literature overview, including our previously published results, in order to support the translation of preclinical findings to clinical practice, and improve the physical and mental status of patients with brain tumors.

Purpose: This study tested whether racial differences in genetic polymorphisms of 4 genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiation therapy and indicate potential therapeutic targets., Methods and Materials: This prospective study examined genetic polymorphisms that modulate the expression of 4 genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3, and TGFβ1). DNA from blood samples of 179 patients (∼ 80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis. Patient demographics were as follows: 56% white, 43% African American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared with those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later after therapy, were also analyzed., Results: Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African American and white populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFβ1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African Americans but not whites. A combined analysis of these polymorphisms revealed that >90% of African American patients with late effects had at least 1 of these minor alleles, and 58% had 2 or more. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity., Conclusions: These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the possibility of such ethnic heterogeneity in the late toxicities of radiation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: The aim of the study was to investigate DNA double strand break (DSB) formation and its correlation with the absorbed dose to the blood lymphocytes of patients undergoing their first peptide receptor radionuclide therapy (PRRT) with (177)Lu-labelled DOTATATE/DOTATOC., Methods: The study group comprised 16 patients receiving their first PRRT. At least six peripheral blood samples were obtained before, and between 0.5 h and 48 h after radionuclide administration. From the time-activity curves of the blood and the whole body, residence times for blood self-irradiation and whole-body irradiation were determined. Peripheral blood lymphocytes were isolated, fixed with ethanol and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was determined as a function of the absorbed dose to the blood and compared with an in vitro calibration curve established in our laboratory with (131)I and (177)Lu., Results: The average number of radiation-induced foci (RIF) per cell increased over the first 5 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 5 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time-points the number of RIF decreased, indicating progression of DNA repair., Conclusion: Measurements of RIF and the absorbed dose to the blood after systemic administration of (177)Lu may be used to obtain data on the individual dose-response relationships in vivo. Individual patient data were characterized by a linear dose-dependent increase and an exponential decay function describing repair.

Systematic biological measurement of "cytogenetic endpoints" has helped phenomenally in assessment of risks associated with radiation exposure. There has been a surge in recent times for the usage of radioactive materials in health care, agriculture, industrial, and nuclear power sectors. The likelihood of radiation exposure from accidental or occupational means is always higher in an overburdened ecosystem that is continuously challenged to meet the population demands. Risks associated with radiation exposure in this era of modern industrial growth are minimal as international regulations for maintaining the safety standards are stringent and strictly adhered to, however, a recent disaster like "Fukushima" impels us to think beyond. The major objective of radiobiology is the development of an orally effective radio-modifier that provides protection from radiation exposure. Once available for mass usage, these compounds will not only be useful for providing selective protection against accidental and occupational radiation exposure but also help to permit use of higher doses of radiation during treatment of various malignancies curtailing unwarranted adverse effects imposed on normal tissues. Bio-active compounds isolated from natural sources enriched with antioxidants possess unique immune-modulating properties, thus providing a double edged benefit over synthetic radioprotectors. We aim to provide here a comprehensive overview of the various agents originating from plant sources that portrayed promising radioprotection in various experimental models with special emphasis on studies that used cytogenetic biomarkers. The agents will include crude extracts of various medicinal plants, purified fractions, and herbal preparations.

The characteristic of medical and dosimetric register database of Siberian Group of Chemical Enterprises personnel is represented. This characteristic includes the description of the database structure, main sources of information, quantitative composition of the cohort under study, methods of evaluation of the external and internal irradiation doses, modern data on cancer incidence and reasons of death. The database is the basis for estimating the risk of the cancer and non-cancer effects after a long-term radiation exposure and dependence of "dose-response" at different levels: from population and group to cell and molecular. Now the database of register contains the information about more than 66,500 employees at the Siberian Group of Chemical Enterprises, about 22,000 of whom were exposed to external irradiation and more than 7500 employees--to internal irradiation. The register is the information resource of a large biological material bank. Using this bank, the research of chronic radiation exposure genetic effects and markers of individual radio sensitivity is performed.

The method for retrospective dose assessment based on the analysis of cell distribution by the number of dicentrics and unstable aberrations using a special computer program was earlier developed based on the data about the persons irradiated as a result of the accident at the Chernobyl nuclear power plant. This method was applied for the same purpose for data processing of repeated cytogenetic studies of the patients exposed to γ-, γ-β- or γ-neutron radiation in various situations. As a whole, this group was followed up in more distant periods (17-50 years) after exposure than Chernobyl patients (up to 25 years). The use for retrospective dose assessment of the multiple regression equations obtained for the Chernobyl cohort showed that the equation, which includes computer recovered estimate of the dose and the time elapsed after irradiation, was generally unsatisfactory (r = 0.069 at p = 0.599). Similar equations with recovered estimate of the dose and frequency of abnormal chromosomes in a distant period or with all three parameters as variables gave better results (r = 0.686 at p = 0.000000001 and r = 0.542 at p = 0.000008, respectively).

In addition to cytostatic treatment and surgery, the most common cancer treatment is gamma radiation. Despite sophisticated radiological techniques however, in addition to irradiation of the tumor, irradiation of the surrounding healthy tissue also takes place, which results in various side-effects, depending on the absorbed dose of radiation. Radiation either damages the cell DNA directly, or indirectly via the formation of oxygen radicals that in addition to the DNA damage, react with all cell organelles and interfere with their molecular mechanisms. The main features of radiation injury besides DNA damage is inflammation and increased expression of pro-inflammatory genes and cytokines. Endothelial damage and dysfunction of capillaries and small blood vessels plays a particularly important role in radiation injury. This review is focused on summarizing the currently available data concerning the mechanisms of radiation injury, as well as the effectiveness of various antioxidants, anti-inflammatory cytokines, and cytoprotective substances that may be utilized in preventing, mitigating, or treating the toxic effects of ionizing radiation on the heart.

TIGAR (TP53-induced glycolysis and apoptosis regulator) functions as a fructose-2,6-bisphosphatase and its expression results in a dampening of the glycolytic pathway, while increasing antioxidant capacity by increasing NADPH and GSH levels. In addition to being a p53 target, p53-independent expression of TIGAR is also seen in many human cancer cell lines that lack wild-type p53. Although human TIGAR expression can be induced by p53, TAp63 and TAp73, mouse TIGAR is less responsive to the p53 family members and basal levels of TIGAR expression does not depend on p53 or TAp73 expression in most mouse tissues in vivo. Although mouse TIGAR expression is clearly induced in the intestines of mice following DNA-damaging stress such as ionising radiation, this is also not dependent on p53 or TAp73.

Purpose: Computed tomography (CT) is a frequently used imaging modality that contributes to a tenfold increase in radiation exposure to the public when compared to other medical imaging modalities. The use of radiation for therapeutic need is always rationalized on the basis of risk versus benefit thereby increasing concerns on the dose received by patients undergoing CT imaging. Therefore, it was of interest to us to investigate the effects of low dose and low dose-rate X-irradiation in patients who underwent CT imaging by recording the doses received by the eye, forehead and thyroid, and to study the levels of damages in the lymphocytes in vivo., Materials and Methods: Lithium manganese borate doped with terbium (LMB:Tb) thermo luminescence dosimeters (TLD) were used to record the doses in the patient's (n = 27) eye, forehead, and thyroid and compared with the dose length product (DLP) values. The in vivo DNA damages measured were compared before and after CT imaging using chromosomal aberration (CA) and micronucleus (MN) assays., Results: The overall measured organ dose ranged between 2 ± 0.29 and 520 ± 41.63 mGy for the eye, 0.84 ± 0.29 and 210 ± 20.50 mGy for the forehead, and 1.79 ± 0.43 and 185 ± 0.70 mGy for the thyroid. The in vivo damages measured from the blood lymphocytes of the subjects showed an extremely significant (p < 0.0001) increase in CA frequency and significant (p < 0.001) increase in MN frequency after exposure, compared to before exposure., Conclusion: The results suggest that CT imaging delivers a considerable amount of radiation dose to the eye, forehead, and thyroid, and the observed increase in the CA and MN frequencies show low dose radiation effects calling for protective regulatory measures to increase patient's safety. This study is the first attempt to indicate the trend of doses received by the patient's eye, forehead and thyroid and measured directly in contrast to earlier values obtained by extrapolation from phantoms, and to assess the in vivo low dose effects in an Indian patient population undergoing CT procedures., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: To identify single-nucleotide polymorphisms (SNPs) in oxidative stress-related genes associated with risk of late toxicities in breast cancer patients receiving radiation therapy., Methods and Materials: Using a 2-stage design, 305 SNPs in 59 candidate genes were investigated in the discovery phase in 753 breast cancer patients from 2 prospective cohorts from Germany. The 10 most promising SNPs in 4 genes were evaluated in the replication phase in up to 1883 breast cancer patients from 6 cohorts identified through the Radiogenomics Consortium. Outcomes of interest were late skin toxicity and fibrosis of the breast, as well as an overall toxicity score (Standardized Total Average Toxicity). Multivariable logistic and linear regression models were used to assess associations between SNPs and late toxicity. A meta-analysis approach was used to summarize evidence., Results: The association of a genetic variant in the base excision repair gene XRCC1, rs2682585, with normal tissue late radiation toxicity was replicated in all tested studies. In the combined analysis of discovery and replication cohorts, carrying the rare allele was associated with a significantly lower risk of skin toxicities (multivariate odds ratio 0.77, 95% confidence interval 0.61-0.96, P=.02) and a decrease in Standardized Total Average Toxicity scores (-0.08, 95% confidence interval -0.15 to -0.02, P=.016)., Conclusions: Using a stage design with replication, we identified a variant allele in the base excision repair gene XRCC1 that could be used in combination with additional variants for developing a test to predict late toxicities after radiation therapy in breast cancer patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Autophagy is essentially a metabolic process, but its in vivo role in nuclear radioprotection remains unexplored. We observed that ex vivo autophagy activation reversed the proliferation inhibition, apoptosis, and DNA damage in irradiated hematopoietic cells. In vivo autophagy activation improved bone marrow cellularity following nuclear radiation exposure. In contrast, defective autophagy in the hematopoietic conditional mouse model worsened the hematopoietic injury, reactive oxygen species (ROS) accumulation and DNA damage caused by nuclear radiation exposure. Strikingly, in vivo defective autophagy caused an absence or reduction in regulatory proteins critical to both homologous recombination (HR) and non-homologous end joining (NHEJ) DNA damage repair pathways, as well as a failure to induce these proteins in response to nuclear radiation. In contrast, in vivo autophagy activation increased most of these proteins in hematopoietic cells. DNA damage assays confirmed the role of in vivo autophagy in the resolution of double-stranded DNA breaks in total bone marrow cells as well as bone marrow stem and progenitor cells upon whole body irradiation. Hence, autophagy protects the hematopoietic system against nuclear radiation injury by conferring and intensifying the HR and NHEJ DNA damage repair pathways and by removing ROS and inhibiting apoptosis.

Cytogenetic analysis of peripheral blood lymphocyte cultures of 22 persons was performed in remote terms after acute external γ-, γ-β- or γ-neutron irradiation as a result of various accidents using the classical me- thod. The initial dose estimates were obtained using physical calculations, the method of measuring the EPR signal in tooth enamel, according to haematological and/or cytogenetic parameters. The purpose of this study was to obtain evidence about the state of the lymphocyte chromosome apparatus of people approxi- mately 17-50 years after an accidental radiation exposure. In general, elevated levels of chromosome aberra- tions were detected. An average correlation was observed between the atypical chromosome frequency and absorbed dose. It is proposed to use the obtained results in the future to explore the possibility of retrospective dose evaluation on the basis of a special computer program.

The X-ray repair cross-complementing group 3 (XRCC3) protein plays an important role in the repair of DNA double-strand breaks. The relationship between XRCC3 polymorphisms and the risk of radiation-induced adverse effects on normal tissue remains inconclusive. Thus, we performed a meta-analysis to elucidate the association between XRCC3 polymorphisms and radiation-induced adverse effects on normal tissue. All eligible studies up to December 2014 were identified through a search of the PubMed, Embase and Web of Science databases. Seventeen studies involving 656 cases and 2193 controls were ultimately included in this meta-analysis. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between XRCC3 polymorphisms and the risk of radiation-induced normal tissue adverse effects. We found that the XRCC3 p.Thr241Met (rs861539) polymorphism was significantly associated with early adverse effects induced by radiotherapy (OR = 1.99, 95%CI: 1.31-3.01, P = 0.001). A positive association lacking statistical significance with late adverse effects was also identified (OR = 1.28, 95%CI: 0.97-1.68, P = 0.08). In addition, the rs861539 polymorphism was significantly correlated with a higher risk of adverse effects induced by head and neck area irradiation (OR = 2.41, 95%CI: 1.49-3.89, p = 0.0003) and breast irradiation (OR = 1.41, 95%CI: 1.02-1.95, p = 0.04), whereas the correlation was not significant for lung irradiation or pelvic irradiation. Furthermore, XRCC3 rs1799794 polymorphism may have a protective effect against late adverse effects induced by radiotherapy (OR = 0.47, 95%CI: 0.26-0.86, P = 0.01). Well-designed large-scale clinical studies are required to further validate our results.

Objective: To explore the associations between the genetic variations in the SDC2 gene and overall survival and risk of radiation esophagitis in patients with esophageal squamous cell carcinoma (ESCC)., Methods: Eleven functional haplotype-tagging single nucleotide polymorphisms (htSNPs) of SDC2 were genotyped in 296 ESCC patients who received radiotherapy alone, and had different response and esophagitis. The associations between genotypes and risk of esophagitis were measured by odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for sex, age, tumor location, staging, radiotherapy mode and total radiation dose. The hazard ratios (HRs) were estimated using Cox proportional hazards regression model., Results: The median survival time (MST) of these patients was 14 months. Of them, 260 (87.8%) had died until the last date of follow-up of 30 June, 2014. Clinical stage (stage IV vs. stage II) and total radiation dose (≥ 60 Gy vs. < 60 Gy) influence the overall survival time of the patient significantly. Cox proportional hazards regression model analysis showed that the subjects with rs61599409 T allele had an decreased hazard ratio as compared with those with C allele (adjusted HR = 0.82, 95% CI, 0.66-1.02), but the difference was not statistically significant (P = 0.071). The rest 10 htSNPs were not associated with the overall survival of ESCC patients treated with radiotherapy. Among this set of patients, 160 (54.1%) suffered from radiation esophagitis. We found that rs17788084 A > T SNP in the 3'-untranslational region of SDC2 was associated with esophagitis risk, with the OR being 0.48 (95% CI = 0.28-0.85, P = 0.011) for the TA or TT genotype compared with the AA genotype., Conclusions: These results suggest that rs17788084 genetic variation in SDC2 is associated with risk of radiation esophagitis and might serve as a potential biomarker for personalized radiotherapy of ESCC.

Background and Purpose: Late rectal bleeding is one of the severe adverse events after radiotherapy for prostate cancer. New biomarkers are needed to allow a personalized treatment., Materials and Methods: Four patients each with grade 0-1 or grade 2-3 rectal bleeding were randomly selected for miRNA array to examine miRNA expression in peripheral blood lymphocytes (PBLs). Based on results of miRNA array, 1 of 348 miRNAs was selected for microRNA assays. Then, expression of DNA-dependent protein kinase mRNA and miR-99a was analyzed in the PBLs of 97 patients. PBLs were exposed to 4Gy of X-ray ex-vivo., Results: In the discovery cohort, grade 2-3 rectal bleeding was significantly higher in the Ku80 <1.09 expression group compared with ⩾1.09 group (P=0.011). In radiation-induced expression of miR-99a, grade 2-3 rectal bleeding was significantly higher in the miR-99a IR(+)/IR(-) >0.93 group compared with ⩽0.93 group (P=0.013). Most patients with grade 2-3 rectal bleeding were in the group with low Ku80 and high miR-99a expression. In the validation cohort, similar results were obtained., Conclusion: A combination of low Ku80 expression and highly-induced miR-99a expression could be a promising marker for predicting rectal bleeding after radiotherapy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Radiotherapy is a major cancer treatment option but dose-limiting side effects such as late-onset fibrosis in the irradiated tissue severely impair quality of life in cancer survivors. Efforts to explain radiation-induced fibrosis, for example, by genetic variation remained largely inconclusive. Recently published molecular analyses on radiation response and fibrogenesis showed a prominent role of epigenetic gene regulation. This review summarizes the current knowledge on epigenetic modifications in fibrotic disease and radiation response, and it points out the important role for epigenetic mechanisms such as DNA methylation, microRNAs and histone modifications in the development of this disease. The synopsis illustrates the complexity of radiation-induced fibrosis and reveals the need for investigations to further unravel its molecular mechanisms. Importantly, epigenetic changes are long-term determinants of gene expression and can therefore support those mechanisms that induce and perpetuate fibrogenesis even in the absence of the initial damaging stimulus. Future work must comprise the interconnection of acute radiation response and long-lasting epigenetic effects in order to assess their role in late-onset radiation fibrosis. An improved understanding of the underlying biology is fundamental to better comprehend the origin of this disease and to improve both preventive and therapeutic strategies.

Purpose: Studies of the association between ataxia telangiectasia-mutated (ATM) gene polymorphisms and acute radiation injuries are often small in sample size, and the results are inconsistent. We conducted the first meta-analysis to provide a systematic review of published findings., Methods and Materials: Publications were identified by searching PubMed up to April 25, 2014. Primary meta-analysis was performed for all acute radiation injuries, and subgroup meta-analyses were based on clinical endpoint. The influence of sample size and radiation injury incidence on genetic effects was estimated in sensitivity analyses. Power calculations were also conducted., Results: The meta-analysis was conducted on the ATM polymorphism rs1801516, including 5 studies with 1588 participants. For all studies, the cut-off for differentiating cases from controls was grade 2 acute radiation injuries. The primary meta-analysis showed a significant association with overall acute radiation injuries (allelic model: odds ratio = 1.33, 95% confidence interval: 1.04-1.71). Subgroup analyses detected an association between the rs1801516 polymorphism and a significant increase in urinary and lower gastrointestinal injuries and an increase in skin injury that was not statistically significant. There was no between-study heterogeneity in any meta-analyses. In the sensitivity analyses, small studies did not show larger effects than large studies. In addition, studies with high incidence of acute radiation injuries showed larger effects than studies with low incidence. Power calculations revealed that the statistical power of the primary meta-analysis was borderline, whereas there was adequate power for the subgroup analysis of studies with high incidence of acute radiation injuries., Conclusions: Our meta-analysis showed a consistency of the results from the overall and subgroup analyses. We also showed that the genetic effect of the rs1801516 polymorphism on acute radiation injuries was dependent on the incidence of the injury. These support the evidence of an association between the rs1801516 polymorphism and acute radiation injuries, encouraging further research of this topic., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aging involves a deterioration of cell functions and changes that may predispose the cell to undergo an oncogenic transformation. The carcinogenic risks following radiation exposure rise with age among adults. Increasing inflammatory response, loss of oxidant/antioxidant equilibrium, ongoing telomere attrition, decline in the DNA damage response efficiency, and deleterious nuclear organization are age-related cellular changes that trigger a serious threat to genomic integrity. In this review, we discuss the mechanistic interplay between all these factors, providing an integrated view of how they contribute to the observed age-related increase in radiation sensitivity. As life expectancy increases and so it does the medical intervention, it is important to highlight the benefits of radiation protection in the elderly. Thus, a deep understanding of the mechanistic processes confining the threat of aging-related radiosensitivity is currently of foremost relevance., (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Importance: Conjunctival UV autofluorescence (CUVAF) photography was developed to detect and characterize preclinical sunlight-induced ocular damage. Ocular sun exposure has been related to cases of pterygia and was recently negatively correlated with myopia. Hence, CUVAF has excellent potential as an objective biomarker of sun exposure. However, much variation in CUVAF has been observed, and the relative contributions of genes and environment to this variation have not yet been identified., Objective: To investigate sources of variation in CUVAF in relation to its potential clinical relevance., Design, Setting, and Participants: We performed a cross-sectional analysis of 3 population-based cohort studies in the general community, including the Twins Eye Study in Tasmania, the Brisbane Adolescent Twin Study, and the Western Australian Pregnancy Cohort (Raine) Study. The twin studies were conducted between 2001 and 2009, and the 20-year follow-up of the Raine Study was completed between March 2010 and February 2012. We included genotypic and phenotypic data from 295 Australian families in the Tasmanian and Brisbane twin studies and from 661 participants in the 20-year follow-up of the Raine Study. We compared CUVAF levels in the 3 cohorts and performed a classic twin study to partition variation in CUVAF. We also conducted a genome-wide association analysis to identify specific genetic variants associated with CUVAF., Main Outcomes and Measures: The total area of CUVAF, heritability of CUVAF, and single-nucleotide polymorphisms (SNPs) associated with CUVAF from the genome-wide association study., Results: Within twin cohorts, individuals living closer to the equator (latitude, 27.47° S) had higher levels of CUVAF compared with individuals from southern regions (latitude, 42.88° S) (median [interquartile range], 45.4 [26.8-68.5] vs 28.7 [15.0-42.3] mm2; P < .001). The variation in CUVAF explained by the additive genetic component was 0.37 (95% CI, 0.22-0.56), whereas the variation due to the common environment was 0.50 (95% CI; 0.29-0.71). The SNP rs1060043, located approximately 800 base pairs away from the SLC1A5 gene, a member of the solute carrier family 1, had a genome-wide significant association with a P value of 3.2 × 10-8. Gene-based analysis did not improve our power to detect association with other genes., Conclusions and Relevance: Our findings confirm that, although a large environmental component to CUVAF (equivalent of sun exposure) exists, genes also play a significant role. We identified a SNP (rs1060043) as being significantly associated with CUVAF; replication of this finding in future studies is warranted.

Research activity in the field of estimation of genetic risks of ionizing radiation to human populations started in the late 1940s and now appears to be passing through a plateau phase. This paper provides a background to the concepts, findings and methods of risk estimation that guided the field through the period of its growth to the beginning of the 21st century. It draws attention to several key facts: (a) thus far, genetic risk estimates have been made indirectly using mutation data collected in mouse radiation studies; (b) important uncertainties and unsolved problems remain, one notable example being that we still do not know the sensitivity of human female germ cells to radiation-induced mutations; and (c) the concept that dominated the field thus far, namely, that radiation exposures to germ cells can result in single gene diseases in the descendants of those exposed has been replaced by the concept that radiation exposure can cause DNA deletions, often involving more than one gene. Genetic risk estimation now encompasses work devoted to studies on DNA deletions induced in human germ cells, their expected frequencies, and phenotypes and associated clinical consequences in the progeny. We argue that the time is ripe to embark on a human genome-based, mechanism-driven, computational modeling of genetic risks of ionizing radiation, and we present a provisional framework for catalyzing research in the field in the 21st century., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The aim of this current study was to quantitatively describe radiation-induced DNA damage and its distribution in leukocytes of cancer patients after fractionated partial- or total-body radiotherapy. Specifically, the impact of exposed anatomic region and administered dose was investigated in breast and prostate cancer patients receiving partial-body radiotherapy. DNA double-strand breaks (DSBs) were quantified by γ-H2AX immunostaining. The frequency of unstable chromosomal aberrations in stimulated lymphocytes was also determined and compared with the frequency of DNA DSBs in the same samples. The frequency of radiation-induced DNA damage was converted into dose, using ex vivo generated calibration curves, and was then compared with the administered physical dose. This study showed that 0.5 h after partial-body radiotherapy the quantity of radiation-induced γ-H2AX foci increased linearly with the administered equivalent whole-body dose for both tumor entities. Foci frequencies dropped 1 day thereafter but proportionality to the equivalent whole-body dose was maintained. Conversely, the frequency of radiation-induced cytogenetic damage increased from 0.5 h to 1 day after the first partial-body exposure with a linear dependence on the administered equivalent whole-body dose, for prostate cancer patients only. Only γ-H2AX foci assessment immediately after partial-body radiotherapy was a reliable measure of the expected equivalent whole-body dose. Local tumor doses could be approximated with both assays after one day. After total-body radiotherapy satisfactory dose estimates were achieved with both assays up to 8 h after exposure. In conclusion, the quantification of radiation-induced γ-H2AX foci, but not cytogenetic damage in peripheral leukocytes was a sensitive and rapid biodosimeter after acute heterogeneous irradiation of partial body volumes that was able to primarily assess the absorbed equivalent whole-body dose.

Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided therapy and dose fractionation, patients receiving radiation therapy are still at risk for side effects due to off-target radiation damage of normal tissues. To reduce normal tissue damage, researchers have sought radioprotectors, which are agents capable of protecting tissue against radiation by preventing radiation damage from occurring or by decreasing cell death in the presence of radiation damage. Although much early research focused on small-molecule radioprotectors, there has been a growing interest in gene therapy for radioprotection. The amenability of gene therapy vectors to targeting, as well as the flexibility of gene therapy to accomplish ablation or augmentation of biologically relevant genes, makes gene therapy an excellent strategy for radioprotection. Future improvements to vector targeting and delivery should greatly enhance radioprotection through gene therapy.

Reactive nitrogen species (RNS) generated after exposure to radiation have been implicated in lung injury. Surfactant protein D (SP-D) is a pulmonary collectin that suppresses inducible nitric oxide synthase (iNOS)-mediated RNS production. Herein, we analyzed the role of iNOS and SP-D in radiation-induced lung injury. Exposure of wild-type (WT) mice to γ-radiation (8 Gy) caused acute lung injury and inflammation, as measured by increases in bronchoalveolar lavage (BAL) protein and cell content at 24 h. Radiation also caused alterations in SP-D structure at 24 h and 4 weeks post exposure. These responses were blunted in iNOS(-/-) mice. Conversely, loss of iNOS had no effect on radiation-induced expression of phospho-H2A.X or tumor necrosis factor (TNF)-α. Additionally, at 24 h post radiation, cyclooxygenase expression and BAL lipocalin-2 levels were increased in iNOS(-/-) mice, and heme oxygenase (HO)-1(+) and Ym1(+) macrophages were evident. Loss of SP-D resulted in increased numbers of enlarged HO-1(+) macrophages in the lung following radiation, along with upregulation of TNF-α, CCL2, and CXCL2, whereas expression of phospho-H2A.X was diminished. To determine if RNS play a role in the altered sensitivity of SP-D(-/-) mice to radiation, iNOS(-/-)/SP-D(-/-) mice were used. Radiation-induced injury, oxidative stress, and tissue repair were generally similar in iNOS(-/-)/SP-D(-/-) and SP-D(-/-) mice. In contrast, TNF-α, CCL2, and CXCL2 expression was attenuated. These data indicate that although iNOS is involved in radiation-induced injury and altered SP-D structure, in the absence of SP-D, it functions to promote proinflammatory signaling. Thus, multiple inflammatory pathways contribute to the pathogenic response to radiation., (© The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

In the present study, a human transforming growth factor‑β1 (TGF‑β1) small interfering RNA (siRNA) plasmid vector (TGF‑β1‑siRNA) was constructed to investigate its effects on the proliferation and differentiation of human lung fibroblasts in vitro and its interference effects on radiation‑induced lung injury in vivo. Reverse transcription quantitative polymerase chain reaction and enzyme linked immunosorbent assay revealed that the mRNA and protein expression of TGF‑β1 in the HFL‑I cells were inhibited by TGF‑β1‑siRNA and flow cytometry demonstrated a significant increase in apoptosis of the HFL‑I cells. Adult, female, specific‑pathogen‑free C57BL/6 mice were used in the in vivo animal investigations and were randomly divided into the four following groups: control without any treatment, radiation alone, radiation followed by empty vector transfection and radiation followed by TGF‑β1‑siRNA vector transfection. Hematoxylin and eosin and Van‑Gieson staining revealed that certain radiation‑induced histopathological changes of the lung, including inflammation, edema, the density of surface pulmonary interstitial collagen fibers in the alveolar septum, TGF‑β1‑positive reactions in alveolar epithelial cells and pulmonary interstitial macrophages were less marked in the mice transfected with TGF‑β1‑siRNA compared with the mice without transfection or those transfected with empty vectors. The serum levels of TGF‑β1 levels in the irradiated mice increased significantly at four weeks and peaked at eight weeks after radiation, compared with the control. Serum levels of TGF‑β1 in the irradiated mice transfected with TGF‑β1‑siRNA also increased gradually and a significant difference was observed compared with those irradiated without transfection. The mRNA expression levels of TGF‑β1 in the mice transfected with TGF‑β1‑siRNA were markedly lower compared with those of the other radiation groups. The present study suggested that the TGF‑β1‑siRNA vector reduced the activity of TGF‑β1 by downregulating the mRNA expression of TGF‑β1 and thereby effectively suppressing inflammatory reactions and defending against radiation‑induced lung injury.

Cataract is the most common eye disease that causes blindness in patients. Ultraviolet B (UVB) irradiation is considered an important factor leading to cataract by inducing apoptosis in human lens epithelial cells (HLECs), but the mechanism is currently unclear. In this study, we investigated HLECs under different intensities of UVB irradiation and different exposure time. The annexin V-FITC/propidium iodide staining results showed that UVB irradiation could efficiently lead to HLECs apoptosis in time- and dose-dependent manner. The expression of pro-apoptotic Bax gene was promoted by UVB irradiation, while anti-apoptotic Bcl-2 gene expression was inhibited at both transcript and protein levels. Notably, the ratio of Bax/Bcl-2 displayed a high and positive correlation to the proportion of apoptotic HLECs. Mitochondrial dysfunction was also observed with rapid loss of potential (∆Ψ m), as well as changes of the levels of reactive oxygen species, malondialdehyde, total antioxidative capabilities, and superoxide dismutase. In caspase pathway, the level of caspase-3 protein increased after UVB irradiation. All these discovered changes may play important roles in UVB-induced HLECs apoptosis, and would be helpful in understanding the mechanism of UVB-induced cataract and providing potential prevention and treatment strategies.

Background: Although single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) has improved the diagnosis and risk stratification of patients with suspected coronary artery disease, it remains a primary source of low-dose radiation exposure for cardiac patients. To determine the biological effects of low-dose radiation from SPECT MPI, we measured the activation of the DNA damage response pathways using quantitative flow cytometry and single-cell gene expression profiling., Methods and Results: Blood samples were collected from patients before and after SPECT MPI (n=63). Overall, analysis of all recruited patients showed no marked differences in the phosphorylation of proteins (H2AX, protein 53, and ataxia telangiectasia mutated) after SPECT. The majority of patients also had either downregulated or unchanged expression in DNA damage response genes at both 24 and 48 hours post-SPECT. Interestingly, a small subset of patients with increased phosphorylation had significant upregulation of genes associated with DNA damage, whereas those with no changes in phosphorylation had significant downregulation or no difference, suggesting that some patients may potentially be more sensitive to low-dose radiation exposure., Conclusions: Our findings showed that SPECT MPI resulted in a variable activation of the DNA damage response pathways. Although only a small subset of patients had increased protein phosphorylation and elevated gene expression postimaging, continued care should be taken to reduce radiation exposure to both the patients and operators., (© 2015 American Heart Association, Inc.)

Objective: This study aims to explore the correlations of genetic polymorphisms in LIG4 and HSPB1 genes with the radiation-induced lung injury (RILI), especially radiation pneumonitis (RP), in lung cancer patients., Methods: A total of 160 lung cancer patients, who were diagnosed with inoperable lung cancer and received radiotherapy, were included in the present study from September 2009 to December 2011. TaqMan Real-Time PCR (RT-PCR) was used to verify the SNPs of LIG4 and HSPB1 genes. Chi-square criterion was used to compare the differences in demographic characteristics, exposure to risk factors, and SNPs genotypes. Crude odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated by logistic regression analysis. All statistical analyses were conducted in SPSS 18.0., Results: A total of 32 (20.0%) lung cancer patients had RP after receiving radiotherapy. Of the 32 cases, 4 cases were of grade 2, 24 cases were of grade 3, and 4 cases were of grade 4. However, our results indicated that the general condition and treatment of all patients had no significant difference with RP risk (P > 0.05). Meanwhile, our results revealed that there was no significant association between the frequencies of LIG4 rs1805388 and HSPB1 rs2868371 genotype distribution and the risk of RP (P > 0.05)., Conclusion: In conclusion, we demonstrated that the genetic polymorphisms in LIG4 rs1805388 and HSPB1 rs2868371 were not obviously correlated with the risk of RP and RILI of lung cancer.

Background and Purpose: The aim of this study was to determine the impact of functional single nucleotide polymorphism (SNP) pathways involved in the ROS pathway, DNA repair, or TGFB1 signaling on acute or late normal toxicity as well as individual radiosensitivity., Materials and Methods: Patients receiving breast-conserving surgery and radiotherapy were examined either for erythema (n = 83), fibrosis (n = 123), or individual radiosensitivity (n = 123). The 17 SNPs analyzed are involved in the ROS pathway (GSTP1, SOD2, NQO1, NOS3, XDH), DNA repair (XRCC1, XRCC3, XRCC6, ERCC2, LIG4, ATM) or TGFB signaling (SKIL, EP300, APC, AXIN1, TGFB1). Associations with biological and clinical endpoints were studied for single SNPs but especially for combinations of SNPs assuming that a SNP is either beneficial or deleterious and needs to be weighted., Results: With one exception, no significant association was seen between a single SNP and the three endpoints studied. No significant associations were also observed when applying a multi-SNP model assuming that each SNP was deleterious. In contrast, significant associations were obtained when SNPs were suggested to be either beneficial or deleterious. These associations increased, when each SNP was weighted individually. Detailed analysis revealed that both erythema and individual radiosensitivity especially depend on SNPs affecting DNA repair and TGFB1 signaling, while SNPs in ROS pathway were of minor importance., Conclusion: Functional pathways of SNPs may be used to form a risk score allowing to predict acute and late radiation-induced toxicity but also to unravel the underlying biological mechanisms.

Radiation-induced bystander effects (RIBE), demonstrate the induction of biological non-targeted effects in cells which have not directly hit by radiation or by free radicals produced by ionization events. Although RIBE have been demonstrated using a variety of biological endpoints the mechanism(s) of this phenomenon still remain unclear. The controversial results of the in vitro RIBE and the evidence of non-targeted effects in various in vivo systems are discussed. The experimental evidence on RIBE, indicate that a more analytical and mechanistic in depth approach is needed to secure an answer to one of the most intriguing questions in radiobiology., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

'Radiogenomics' is the study of genetic variation associated with response to radiotherapy. Radiogenomics aims to uncover the genes and biologic pathways responsible for radiotherapy toxicity that could be targeted with radioprotective agents and; identify genetic markers that can be used in risk prediction models in the clinic. The long-term goal of the field is to develop single nucleotide polymorphism-based risk models that can be used to stratify patients to more precisely tailored radiotherapy protocols. The field has evolved over the last two decades in parallel with advances in genomics, moving from narrowly focused candidate gene studies to large, collaborative genome-wide association studies. Several confirmed genetic variants have been identified and the field is making progress toward clinical translation.

Genome instability transmission in offspring was analyzed in order to evaluate the risk of delayed genetic effects of exposure in 95 family triplets in which only fathers experienced prolonged occupational radiation exposure. The mean total preconceptive absorbed dose (TPAD) of external gamma radiation in the paternal gonads was 1.65 ± 0.08 Gy (dose range of 0.57-5.70 Gy), and the mean TPAD of internal alpha radiation from incorporated plutonium-239 in.the gonads was 0.0015 ± 0.0003 Gy (dose range 0.000-0.015 Gy). The control group consisted of 50 family triplets in which parents were not occupationally exposed. The mutation process was studied using PCR based on hypervariable minisatellite marker CEB 1 (chromosome 2, 2q37.3). The paternal type of inheritance of mutations for minisatellite CEB 1 was found in 80% of cases. The analysis revealed a statistically significant increase in minisatellite CEB1 mutations in the common group of families in which fathers experienced prolonged occupational radiation exposure and in the group of families in which fathers were exposed to radiation in a dosage range of 0.5-1.0 Gy as compared to the control, reaching a significance level of p = 0.109 and p = 0.058, respectively. The dose threshold of mutation detection in the off-spring of Mayak PA workers was estimated.

Purpose: Lung inflammation leading to pulmonary toxicity after radiotherapy (RT) can occur in patients with non-small cell lung cancer (NSCLC). We investigated the kinetics of RT induced plasma inflammatory cytokines in these patients in order to identify clinical predictors of toxicity., Experimental Design: In 12 NSCLC patients, RT to 60 Gy (30 fractions over 6 weeks) was delivered; 6 received concurrent chemoradiation (chemoRT) and 6 received RT alone. Blood samples were taken before therapy, at 1 and 24 hours after delivery of the 1st fraction, 4 weeks into RT, and 12 weeks after completion of treatment, for analysis of a panel of 22 plasma cytokines. The severity of respiratory toxicities were recorded using common terminology criteria for adverse events (CTCAE) v4.0., Results: Twelve cytokines were detected in response to RT, of which ten demonstrated significant temporal changes in plasma concentration. For Eotaxin, IL-33, IL-6, MDC, MIP-1α and VEGF, plasma concentrations were dependent upon treatment group (chemoRT vs RT alone, all p-values <0.05), whilst concentrations of MCP-1, IP-10, MCP-3, MIP-1β, TIMP-1 and TNF-α were not. Mean lung radiation dose correlated with a reduction at 1 hour in plasma levels of IP-10 (r2 = 0.858, p<0.01), MCP-1 (r2 = 0.653, p<0.01), MCP-3 (r2 = 0.721, p<0.01), and IL-6 (r2 = 0.531, p = 0.02). Patients who sustained pulmonary toxicity demonstrated significantly different levels of IP-10 and MCP-1 at 1 hour, and Eotaxin, IL-6 and TIMP-1 concentration at 24 hours (all p-values <0.05) when compared to patients without respiratory toxicity., Conclusions: Inflammatory cytokines were induced in NSCLC patients during and after RT. Early changes in levels of IP-10, MCP-1, Eotaxin, IL-6 and TIMP-1 were associated with higher grade toxicity. Measurement of cytokine concentrations during RT could help predict lung toxicity and lead to new therapeutic strategies.

Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30min before exposure to 50mGy γ-ray daily for 30days in sequences (cumulative dose of 1.5Gy). Mice were victimized 24h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit(+) stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60-90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit(+) stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Terrorism using radiological dirty bombs or improvised nuclear devices is recognized as a major threat to both public health and national security. In the event of a radiological or nuclear disaster, rapid and accurate biodosimetry of thousands of potentially affected individuals will be essential for effective medical management to occur. Currently, health care providers lack an accurate, high-throughput biodosimetric assay which is suitable for the triage of large numbers of radiation injury victims. Here, we describe the development of a biodosimetric assay based on the analysis of irradiated mice, ex vivo-irradiated human peripheral blood (PB) and humans treated with total body irradiation (TBI). Interestingly, a gene expression profile developed via analysis of murine PB radiation response alone was inaccurate in predicting human radiation injury. In contrast, generation of a gene expression profile which incorporated data from ex vivo irradiated human PB and human TBI patients yielded an 18-gene radiation classifier which was highly accurate at predicting human radiation status and discriminating medically relevant radiation dose levels in human samples. Although the patient population was relatively small, the accuracy of this classifier in discriminating radiation dose levels in human TBI patients was not substantially confounded by gender, diagnosis or prior exposure to chemotherapy. We have further incorporated genes from this human radiation signature into a rapid and high-throughput chemical ligation-dependent probe amplification assay (CLPA) which was able to discriminate radiation dose levels in a pilot study of ex vivo irradiated human blood and samples from human TBI patients. Our results illustrate the potential for translation of a human genetic signature for the diagnosis of human radiation exposure and suggest the basis for further testing of CLPA as a candidate biodosimetric assay.

A need for more accurate and reliable radiation dosimetry has become increasingly important due to the possibility of a large-scale radiation emergency resulting from terrorism or nuclear accidents. Although traditional approaches provide accurate measurements, such methods usually require tedious effort and at least two days to complete. Therefore, we provide a new method for rapid prediction of radiation exposure. Eleven microarray datasets were classified into two groups based on their radiation doses and utilized as the training samples. For the two groups, Student's t-tests and resampling tests were used to identify biomarkers, and their gene expression ratios were used to develop a prediction model. The performance of the model was evaluated in four independent datasets, and Ingenuity pathway analysis was performed to characterize the associated biological functions. Our meta-analysis identified 29 biomarkers, showing approximately 90% and 80% accuracy in the training and validation samples. Furthermore, the 29 genes significantly participated in the regulation of cell cycle, and 19 of them are regulated by three well-known radiation-modulated transcription factors: TP53, FOXM1 and ERBB2. In conclusion, this study demonstrates a reliable method for identifying biomarkers across independent studies and high and reproducible prediction accuracy was demonstrated in both internal and external datasets.

There is increasing evidence supporting the role of genetic variants in the development of radiation-induced toxicity. However, previous candidate gene association studies failed to elucidate the common genetic variation underlying this phenotype, which could emerge years after the completion of treatment. We performed a genome-wide association study on a Spanish cohort of 741 individuals with prostate cancer treated with external beam radiotherapy (EBRT). The replication cohorts consisted of 633 cases from the UK and 368 cases from North America. One locus comprising TANC1 (lowest unadjusted P value for overall late toxicity=6.85×10(-9), odds ratio (OR)=6.61, 95% confidence interval (CI)=2.23-19.63) was replicated in the second stage (lowest unadjusted P value for overall late toxicity=2.08×10(-4), OR=6.17, 95% CI=2.25-16.95; Pcombined=4.16×10(-10)). The inclusion of the third cohort gave unadjusted Pcombined=4.64×10(-11). These results, together with the role of TANC1 in regenerating damaged muscle, suggest that the TANC1 locus influences the development of late radiation-induced damage.

Significance: Targeted irradiation is an effective cancer therapy but damage inflicted to normal tissues surrounding the tumor may cause severe complications. While certain pharmacologic strategies can temper the adverse effects of irradiation, stem cell therapies provide unique opportunities for restoring functionality to the irradiated tissue bed., Recent Advances: Preclinical studies presented in this review provide encouraging proof of concept regarding the therapeutic potential of stem cells for treating the adverse side effects associated with radiotherapy in different organs. Early-stage clinical data for radiation-induced lung, bone, and skin complications are promising and highlight the importance of selecting the appropriate stem cell type to stimulate tissue regeneration., Critical Issues: While therapeutic efficacy has been demonstrated in a variety of animal models and human trials, a range of additional concerns regarding stem cell transplantation for ameliorating radiation-induced normal tissue sequelae remain. Safety issues regarding teratoma formation, disease progression, and genomic stability along with technical issues impacting disease targeting, immunorejection, and clinical scale-up are factors bearing on the eventual translation of stem cell therapies into routine clinical practice., Future Directions: Follow-up studies will need to identify the best possible stem cell types for the treatment of early and late radiation-induced normal tissue injury. Additional work should seek to optimize cellular dosing regimes, identify the best routes of administration, elucidate optimal transplantation windows for introducing cells into more receptive host tissues, and improve immune tolerance for longer-term engrafted cell survival into the irradiated microenvironment.

This review article provides a comprehensive overview of the experimental data detailing the incidence, mechanism and significance of low dose hyper-radiosensitivity (HRS). Important discoveries gained from past and present studies are mapped and highlighted to illustrate the pathway to our current understanding of HRS and the impact of HRS on the cellular response to radiation in mammalian cells. Particular attention is paid to the balance of evidence suggesting a role for DNA repair processes in the response, evidence suggesting a role for the cell cycle checkpoint processes, and evidence investigating the clinical implications/relevance of the effect.

Background and Purpose: To develop predictive models for late radiation-induced hematuria and nocturia allowing a patient individualized estimation of pre-treatment risk., Materials and Methods: We studied 262 PCa patients treated with curative intensity modulated radiotherapy to the intact prostate or prostate bed. A total of 372 variables were used for prediction modeling, among which 343 genetic variations. Toxicity was scored using an in-house developed toxicity scale. Predictor selection is achieved by the EMLasso procedure, a penalized logistic regression method with an EM algorithm handling missing data and crossvalidation avoiding overfit. Model performance was expressed by the area under the curve (AUC) and by sensitivity and specificity., Results: Variables of the model predicting late hematuria (36/262) are bladder volume receiving ⩾75 Gy, prostatic transurethral resection and four polymorphisms. (AUC = 0.80, sensitivity = 83.3%, specificity = 61.5%). The AUC drops to 0.67 when the genetic markers are left out. The model that predicts for late nocturia (29/262) contains the minimal clinical target volume (CTV) dose, the CTV volume and three polymorphisms (AUC = 0.76, sensitivity = 75.9%, specify = 67.4%). This model is a better predictor for nocturia compared to the nongenetic model (AUC of 0.60)., Conclusions: We were able to develop models that predict for the occurrence of late radiation-induced hematuria and nocturia, including genetic factors which might improve the prediction of late urinary toxicity., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The calyculin A-induced premature chromosome condensation (PCC) assay is a simple and useful method for assessing the cell-cycle distribution in cells, since calyculin A induces chromosome condensation in various phases of the cell cycle. In this study, a novel parameter, the cell-cycle progression index (CPI), in the PCC assay was validated as a novel biomarker for biodosimetry. Peripheral blood was drawn from healthy donors after informed consent was obtained. CPI was investigated using a human peripheral blood lymphocyte (PBL) ex vivo irradiation ((60)Co-gamma rays: ∼0.6 Gy min(-1), or X ray: 1.0 Gy min(-1); 0-10 Gy) model. The calyculin A-induced PCC assay was performed for chromosome preparation. PCC cells were divided into the following five categories according to cell-cycle stage: non-PCC, G1-PCC, S-PCC, G2/M-PCC and M/A-PCC cells. CPI was calculated as the ratio of G2/M-PCC cells to G1-PCC cells. The PCC-stage distribution varied markedly with irradiation doses. The G1-PCC cell fraction was significantly reduced, and the G2/M-PCC cell fraction increased, in 10-Gy-irradiated PBL after 48 h of culture. CPI levels were fitted to an exponential dose-response curve with gamma-ray irradiation [y = 0.6729 + 0.3934 exp(0.5685D), r = 1.0000, p < 0.0001] and X-ray irradiation [y = -0.3743 + 0.9744 exp(0.3321D), r = 0.9999, p < 0.0001]. There were no significant individual (p = 0.853) or gender effects (p = 0.951) on the CPI in the human peripheral blood ex vivo irradiation model. Furthermore, CPI measurements are rapid (< 15 min per case). These results suggest that the CPI is a useful screening tool for the assessment of radiation doses received ranging from 0 to 10 Gy in radiation exposure early after a radiation event, especially after a mass-casualty radiological incident., (Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

This study investigated to what extent the serum microRNA 21 (miR-21) level alters in response to ionizing radiation (IR). Initially, we evaluated the appropriateness of our RNA extraction efficiency and microRNA assay in serum, and then investigated the serum miR-21 level in 4 patients with breast cancer in 4 stages: pre- and postoperation, at the beginning radiotherapy, and after 25 sessions of radiotherapy with a total of 50 Gy irradiation, as well as in 20 healthy volunteers. The initial analysis showed the appropriateness of our RNA extraction efficiency and microRNA assay in serum for identifying people exposed to IR. We then analyzed the serum miR-21 level in another group of 40 patients with breast cancer before and after radiotherapy. During our large-scale analysis, the miR-21 level before radiotherapy was comparable with healthy volunteers (P = 0.10) and increased significantly after radiotherapy (P < 0.001)-an indication that this could discriminate irradiated patients from nonirradiated ones with high specificity (75%) and sensitivity (80%). According to this study, serum miR-21 has the potential to be used as a biomarker for the identification of people exposed to ionizing radiation., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Radiation-induced gastrointestinal syndrome occurs when the body is exposed to a high dose of radiation. Currently, safe and effective radioprotectants are not available. Apoptosis was reported to play a primary role in radiation-induced injury. Recent evidence suggests that stimulation of α7 nicotinic acetylcholine receptor (α7nAChR) prevents cell death by inhibition of apoptosis. In this study, we demonstrated that a single dose of PNU282987 (100 μg/kg, i.p.), a selective α7nAChR agonist, protected mice from intestinal injury and significantly improved survival when administered prior to lethal 8 Gy total body irradiation. In vitro, PNU282987 protected against 8 Gy radiation-induced cell death in human umbilical venous endothelial cells by inhibiting apoptosis. We conclude that activation of α7nAChR may provide a new therapeutic pathway for the treatment of radiation-induced damage and mortality.