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Mark P Little - One of the best experts on this subject based on the ideXlab platform.
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inflammatory disease and c reactive protein in relation to therapeutic Ionising Radiation exposure in the us radiologic technologists
Scientific Reports, 2019Co-Authors: Mark P Little, Jason J Liu, Michelle Fang, Ann Marie Weideman, Martha S LinetAbstract:Chronic inflammation underlies many autoimmune diseases, including hypothyroidism, hyperthyroidism, and rheumatoid arthritis, also type-2 diabetes and osteoarthritis. Associations have been suggested of high-dose Ionising Radiation exposure with type-2 diabetes and elevated levels of C-reactive protein, a marker of chronic inflammation. In this analysis we used a proportional hazards model to assess effects of radiotherapy on risks of subsequent inflammatory disease morbidity in 110,368 US radiologic technologists followed from a baseline survey (1983–1989/1994–1998) through 2008. We used a linear model to assess log-transformed C-reactive protein concentration following radiotherapy in 1326 technologists. Relative risk of diabetes increased following radiotherapy (p < 0.001), and there was a borderline significant increasing trend per treatment (p = 0.092). For osteoarthritis there was increased relative risk associated with prior radiotherapy on all questionnaires (p = 0.005), and a significant increasing trend per previous treatment (p = 0.024). No consistent increases were observed for other types of inflammatory disease (hypothyroidism, hyperthyroidism, rheumatoid arthritis) associated with radiotherapy. There was a borderline significant (p = 0.059) increasing trend with dose for C-reactive protein with numbers of prior radiotherapy treatments. Our results suggest that radiotherapy is associated with subsequent increased risk of certain inflammatory conditions, which is reinforced by our finding of elevated levels of C-reactive protein.
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leukaemia and myeloid malignancy among people exposed to low doses 100 msv of Ionising Radiation during childhood a pooled analysis of nine historical cohort studies
The Lancet Haematology, 2018Co-Authors: Mark P Little, Richard Wakeford, David Borrego, Benjamin French, Lydia B Zablotska, Jacob M Adams, Rodrigue S Allodji, Florent De Vathaire, Choonsik Lee, Alina V BrennerAbstract:Summary Background Substantial evidence links exposure to moderate or high doses of Ionising Radiation, particularly in childhood, with increased risk of leukaemia. The association of leukaemia with exposure to low-dose ( Methods In this analysis of historical cohort studies, we pooled eligible cohorts reported up to June 30, 2014. We evaluated leukaemia and myeloid malignancy outcomes in these cohorts with the relevant International Classification of Diseases and International Classification of Diseases for Oncology definitions. The cohorts included had not been treated for malignant disease, had reported at least five cases of the relevant haematopoietic neoplasms, and estimated individual active bone marrow (ABM) doses. We restricted analysis to individuals who were younger than 21 years at first irRadiation who had mean cumulative ABM doses of less than 100 mSv. Dose-response models were fitted by use of Poisson regression. The data were received in fully anonymised form by the statistical analyst. Findings We identified nine eligible cohorts from Canada, France, Japan, Sweden, the UK, and the USA, including 262 573 people who had been exposed to less than 100 mSv enrolled between June 4, 1915, and Dec 31, 2004. Mean follow-up was 19·63 years (SD 17·75) and mean cumulative ABM dose was 19·6 mSv (SD 22·7). 154 myeloid malignancies were identified (which included 79 acute myeloid leukaemias, eight myelodysplastic syndromes, and 36 chronic myeloid leukaemias, in addition to other unspecified myeloid malignancies) and 40 acute lymphoblastic leukaemias, with 221 leukaemias (including otherwise unclassified leukaemias but excluding chronic lymphocytic leukaemia) identified overall. The fitted relative risks at 100 mSv were 3·09 (95% CI 1·41–5·92; p trend =0·008) for acute myeloid leukaemia and myelodysplastic syndromes combined, 2·56 (1·09–5·06; p trend =0·033) for acute myeloid leukaemia, and 5·66 (1·35–19·71; p trend =0·023) for acute lymphoblastic leukaemia. There was no clear dose-response for chronic myeloid leukaemia, which had a relative risk at 100 mSv of 0·36 (0·00–2·36; p trend =0·394). There were few indications of between-cohort heterogeneity or departure from linearity. For acute myeloid leukaemia and myelodysplastic syndromes combined and for acute lymphoblastic leukaemia, the dose-responses remained significant for doses of less than 50 mSv. Excess absolute risks at 100 mSv were in the range of 0·1–0·4 cases or deaths per 10 000 person-years. Interpretation The risks of acute myeloid leukaemia and acute lymphoblastic leukaemia were significantly increased after cumulative doses of Ionising Radiation of less than 100 mSv in childhood or adolescence, with an excess risk also apparent for cumulative Radiation doses of less than 50 mSv for some endpoints. These findings support an increased risk of leukaemia associated with low-dose exposure to Radiation and imply that the current system of radiological protection is prudent and not overly protective. Funding National Cancer Institute Intramural Research Program, National Cancer Institute, and US National Institutes for Health.
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low dose Ionising Radiation and cardiovascular diseases strategies for molecular epidemiological studies in europe
Mutation Research-reviews in Mutation Research, 2015Co-Authors: Michaela Kreuzer, Elisabeth Cardis, Mark P Little, Anssi Auvinen, Janet Hall, Dominique Laurier, Jeanrene Jourdain, Annette Peters, Kenneth RajAbstract:It is well established that high-dose Ionising Radiation causes cardiovascular diseases. In contrast, the evidence for a causal relationship between long-term risk of cardiovascular diseases after moderate doses (0.5-5 Gy) is suggestive and weak after low doses (<0.5 Gy). However, evidence is emerging that doses under 0.5 Gy may also increase long-term risk of cardiovascular disease. This would have major implications for Radiation protection with respect to medical use of Radiation for diagnostic purposes and occupational or environmental Radiation exposure. Therefore, it is of great importance to gain information about the presence and possible magnitude of Radiation-related cardiovascular disease risk at doses of less than 0.5 Gy. The biological mechanisms implicated in any such effects are unclear and results from epidemiological studies are inconsistent. Molecular epidemiological studies can improve the understanding of the pathogenesis and the risk estimation of Radiation-induced circulatory disease at low doses. Within the European DoReMi (Low Dose Research towards Multidisciplinary Integration) project, strategies to conduct molecular epidemiological studies in this field have been developed and evaluated. Key potentially useful European cohorts are the Mayak workers, other nuclear workers, uranium miners, Chernobyl liquidators, the Techa river residents and several diagnostic or low-dose radiotherapy patient cohorts. Criteria for informative studies are given and biomarkers to be investigated suggested. A close collaboration between epidemiology, biology and dosimetry is recommended, not only among experts in the Radiation field, but also those in cardiovascular diseases.
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non targeted effects of Ionising Radiation implications for low dose risk
Mutation Research-reviews in Mutation Research, 2013Co-Authors: Munira Kadhim, Sisko Salomaa, Eric G Wright, Guido Hildebrandt, O V Belyakov, Kevin M Prise, Mark P LittleAbstract:Non-DNA targeted effects of Ionising Radiation, which include genomic instability, and a variety of bystander effects including abscopal effects and bystander mediated adaptive response, have raised concerns about the magnitude of low-dose Radiation risk. Genomic instability, bystander effects and adaptive responses are powered by fundamental, but not clearly understood systems that maintain tissue homeostasis. Despite excellent research in this field by various groups, there are still gaps in our understanding of the likely mechanisms associated with non-DNA targeted effects, particularly with respect to systemic (human health) consequences at low and intermediate doses of Ionising Radiation. Other outstanding questions include links between the different non-targeted responses and the variations in response observed between individuals and cell lines, possibly a function of genetic background. Furthermore, it is still not known what the initial target and early interactions in cells are that give rise to non-targeted responses in neighbouring or descendant cells. This paper provides a commentary on the current state of the field as a result of the non-targeted effects of Ionising Radiation (NOTE) Integrated Project funded by the European Union. Here we critically examine the evidence for non-targeted effects, discuss apparently contradictory results and consider implications for low-dose Radiation health effects.
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updated estimates of the proportion of childhood leukaemia incidence in great britain that may be caused by natural background Ionising Radiation
Journal of Radiological Protection, 2009Co-Authors: Mark P Little, Richard Wakeford, G M KendallAbstract:The aetiology of childhood leukaemia remains generally unknown, although exposure to moderate and high levels of Ionising Radiation, such as was experienced during the atomic bombings of Japan or from radiotherapy, is an established cause. Risk models based primarily upon studies of the Japanese A-bomb survivors imply that low-level exposure to Ionising Radiation, including to ubiquitous natural background Radiation, also raises the risk of childhood leukaemia. In a recent paper (Wakeford et al 2009 Leukaemia 23 770-6) we estimated the proportion of childhood leukaemia incidence in Great Britain attributable to natural background Radiation to be about 20%. In this paper we employ the two sets of published leukaemia risk models used previously, but use recently published revised estimates of natural background Radiation doses received by the red bone marrow of British children to update the previous results. Using the newer dosimetry we calculate that the best estimate of the proportion of cases of childhood leukaemia in Great Britain predicted to be attributable to this source of exposure is 15-20%, although the uncertainty associated with certain stages in the calculation (e.g. the nature of the transfer of risk between populations and the pertinent dose received from naturally occurring alpha-particle-emitting radionuclides) is significant. The slightly lower attributable proportions compared with those previously derived by Wakeford et al (Leukaemia 2009 23 770-6) are largely due to the lower doses (and in particular lower high LET doses) for the first year of life.
C J H Kruip - One of the best experts on this subject based on the ideXlab platform.
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the escape of Ionising Radiation from high redshift dwarf galaxies
Astronomy and Astrophysics, 2011Co-Authors: Janpieter Paardekooper, F I Pelupessy, Gabriel Altay, C J H KruipAbstract:Context. The UV escape fraction from high-redshift galaxies plays a key role in models of cosmic reionisation. Because it is currently not possible to deduce the escape fractions during the epoch of reionisation from observations, we have to rely on numerical simulations. Aims. We aim to better constrain the escape fraction from high-redshift dwarf galaxies, as these are the most likely sources responsible for reIonising the Universe. Methods. We employ a N-body/SPH method that includes realistic prescriptions for the physical processes that are important for the evolution of dwarf galaxies. These models are post-processed with radiative transfer to determine the escape fraction of Ionising Radiation. We perform a parameter study to assess the influence of the spin parameter, gas fraction and formation redshift of the galaxy and study the importance of numerical parameters as resolution, source distribution and local gas clearing. Results. We find that the UV escape fraction from high-redshift dwarf galaxies that have formed a rotationally supported disc lie between 10 −5 and 0.1. The mass and angular momentum of the galaxy are the most important parameters that determine the escape fraction. We compare our results to previous work and discuss the uncertainties of our models. Conclusions. The low escape fraction we find for high-redshift dwarf galaxies is balanced by their high stellar content, resulting in an efficiency parameter for stars that is only marginally lower than the values found by semi-analytic models of reionisation. We therefore conclude that dwarf galaxies play an important role in cosmic reionisation also after the initial starburst phase, when the gas has settled into a disc.
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the escape of Ionising Radiation from high redshift dwarf galaxies
arXiv: Cosmology and Nongalactic Astrophysics, 2011Co-Authors: Janpieter Paardekooper, F I Pelupessy, Gabriel Altay, C J H KruipAbstract:The UV escape fraction from high-redshift galaxies plays a key role in models of cosmic reionisation. Because it is currently not possible to deduce the escape fractions during the epoch of reionisation from observations, we have to rely on numerical simulations. Our aim is to better constrain the escape fraction from high-redshift dwarf galaxies, as these are the most likely sources responsible for reIonising the Universe. We employ a N-body/SPH method that includes realistic prescriptions for the physical processes that are important for the evolution of dwarf galaxies. These models are post-processed with radiative transfer to determine the escape fraction of Ionising Radiation. We perform a parameter study to assess the influence of the spin parameter, gas fraction and formation redshift of the galaxy and study the importance of numerical parameters as resolution, source distribution and local gas clearing. We find that the UV escape fraction from high-redshift dwarf galaxies that have formed a rotationally supported disc lie between 1e-5 and 0.1. The mass and angular momentum of the galaxy are the most important parameters that determine the escape fraction. We compare our results to previous work and discuss the uncertainties of our models. The low escape fraction we find for high-redshift dwarf galaxies is balanced by their high stellar content, resulting in an efficiency parameter for stars that is only marginally lower than the values found by semi-analytic models of reionisation. We therefore conclude that dwarf galaxies play an important role in cosmic reionisation also after the initial starburst phase, when the gas has settled into a disc.
Janpieter Paardekooper - One of the best experts on this subject based on the ideXlab platform.
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the escape of Ionising Radiation from high redshift dwarf galaxies
Astronomy and Astrophysics, 2011Co-Authors: Janpieter Paardekooper, F I Pelupessy, Gabriel Altay, C J H KruipAbstract:Context. The UV escape fraction from high-redshift galaxies plays a key role in models of cosmic reionisation. Because it is currently not possible to deduce the escape fractions during the epoch of reionisation from observations, we have to rely on numerical simulations. Aims. We aim to better constrain the escape fraction from high-redshift dwarf galaxies, as these are the most likely sources responsible for reIonising the Universe. Methods. We employ a N-body/SPH method that includes realistic prescriptions for the physical processes that are important for the evolution of dwarf galaxies. These models are post-processed with radiative transfer to determine the escape fraction of Ionising Radiation. We perform a parameter study to assess the influence of the spin parameter, gas fraction and formation redshift of the galaxy and study the importance of numerical parameters as resolution, source distribution and local gas clearing. Results. We find that the UV escape fraction from high-redshift dwarf galaxies that have formed a rotationally supported disc lie between 10 −5 and 0.1. The mass and angular momentum of the galaxy are the most important parameters that determine the escape fraction. We compare our results to previous work and discuss the uncertainties of our models. Conclusions. The low escape fraction we find for high-redshift dwarf galaxies is balanced by their high stellar content, resulting in an efficiency parameter for stars that is only marginally lower than the values found by semi-analytic models of reionisation. We therefore conclude that dwarf galaxies play an important role in cosmic reionisation also after the initial starburst phase, when the gas has settled into a disc.
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the escape of Ionising Radiation from high redshift dwarf galaxies
arXiv: Cosmology and Nongalactic Astrophysics, 2011Co-Authors: Janpieter Paardekooper, F I Pelupessy, Gabriel Altay, C J H KruipAbstract:The UV escape fraction from high-redshift galaxies plays a key role in models of cosmic reionisation. Because it is currently not possible to deduce the escape fractions during the epoch of reionisation from observations, we have to rely on numerical simulations. Our aim is to better constrain the escape fraction from high-redshift dwarf galaxies, as these are the most likely sources responsible for reIonising the Universe. We employ a N-body/SPH method that includes realistic prescriptions for the physical processes that are important for the evolution of dwarf galaxies. These models are post-processed with radiative transfer to determine the escape fraction of Ionising Radiation. We perform a parameter study to assess the influence of the spin parameter, gas fraction and formation redshift of the galaxy and study the importance of numerical parameters as resolution, source distribution and local gas clearing. We find that the UV escape fraction from high-redshift dwarf galaxies that have formed a rotationally supported disc lie between 1e-5 and 0.1. The mass and angular momentum of the galaxy are the most important parameters that determine the escape fraction. We compare our results to previous work and discuss the uncertainties of our models. The low escape fraction we find for high-redshift dwarf galaxies is balanced by their high stellar content, resulting in an efficiency parameter for stars that is only marginally lower than the values found by semi-analytic models of reionisation. We therefore conclude that dwarf galaxies play an important role in cosmic reionisation also after the initial starburst phase, when the gas has settled into a disc.
Christian Frezza - One of the best experts on this subject based on the ideXlab platform.
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fumarate hydratase loss promotes mitotic entry in the presence of dna damage after Ionising Radiation
Cell Death and Disease, 2018Co-Authors: Timothy Isaac Johnson, Ana S.h. Costa, Ashley N Ferguson, Christian FrezzaAbstract:An altered response to DNA damage is commonly associated with genomic instability, a hallmark of cancer. Fumarate hydratase (FH) was recently characterised as a DNA repair factor required in non-homologous end-joining (NHEJ) through the local production of fumarate. Inactivating germline mutations in FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC), a cancer syndrome characterised by accumulation of fumarate. Recent data indicate that, in FH-deficient cells, fumarate suppresses homologous recombination DNA repair upon DNA double-strand breaks, compromising genome integrity. Here, we show that FH loss confers resistance to DNA damage caused by Ionising Radiation (IR), and promotes early mitotic entry after IR in a fumarate-specific manner, even in the presence of unrepaired damage, by suppressing checkpoint maintenance. We also showed that higher levels of DNA damage foci are detectable in untreated FH-deficient cells. Overall, these data indicate that FH loss and fumarate accumulation lead to a weakened G2 checkpoint that predisposes to endogenous DNA damage and confers resistance to IR.
Janet Hall - One of the best experts on this subject based on the ideXlab platform.
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low dose Ionising Radiation and cardiovascular diseases strategies for molecular epidemiological studies in europe
Mutation Research-reviews in Mutation Research, 2015Co-Authors: Michaela Kreuzer, Elisabeth Cardis, Mark P Little, Anssi Auvinen, Janet Hall, Dominique Laurier, Jeanrene Jourdain, Annette Peters, Kenneth RajAbstract:It is well established that high-dose Ionising Radiation causes cardiovascular diseases. In contrast, the evidence for a causal relationship between long-term risk of cardiovascular diseases after moderate doses (0.5-5 Gy) is suggestive and weak after low doses (<0.5 Gy). However, evidence is emerging that doses under 0.5 Gy may also increase long-term risk of cardiovascular disease. This would have major implications for Radiation protection with respect to medical use of Radiation for diagnostic purposes and occupational or environmental Radiation exposure. Therefore, it is of great importance to gain information about the presence and possible magnitude of Radiation-related cardiovascular disease risk at doses of less than 0.5 Gy. The biological mechanisms implicated in any such effects are unclear and results from epidemiological studies are inconsistent. Molecular epidemiological studies can improve the understanding of the pathogenesis and the risk estimation of Radiation-induced circulatory disease at low doses. Within the European DoReMi (Low Dose Research towards Multidisciplinary Integration) project, strategies to conduct molecular epidemiological studies in this field have been developed and evaluated. Key potentially useful European cohorts are the Mayak workers, other nuclear workers, uranium miners, Chernobyl liquidators, the Techa river residents and several diagnostic or low-dose radiotherapy patient cohorts. Criteria for informative studies are given and biomarkers to be investigated suggested. A close collaboration between epidemiology, biology and dosimetry is recommended, not only among experts in the Radiation field, but also those in cardiovascular diseases.
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control of the g2 m checkpoints after exposure to low doses of Ionising Radiation implications for hyper radiosensitivity
DNA Repair, 2010Co-Authors: Janet Hall, Marie Fernet, Frederique Megninchanet, Vincent FavaudonAbstract:Two molecularly distinct G2/M cell cycle arrests are induced after exposure to Ionising Radiation (IR) depending on the cell cycle compartment in which the cells are irradiated. The aims of this study were to determine whether there are threshold doses for their activation and investigate the molecular pathways and possible links between the G2 to M transition and hyper-radiosensitivity (HRS). Two human glioblastoma cell lines (T98G-HRS(+) and U373-HRS(-)) unsynchronized or enriched in G2 were irradiated and flow cytometry with BrdU or histone H3 phosphorylation analysis used to assess cell cycle progression and a clonogenic assay to measure Radiation survival. The involvement of ATM, Wee1 and PARP was studied using chemical inhibitors. We found that cells irradiated in either the G1 or S phase of the cell cycle transiently accumulate in G2 in a dose-dependent manner after exposure to doses as low as 0.2Gy. Only Wee1 inhibition reduced this G2 accumulation. A block of the G2 to M transition was found after irRadiation in G2 but occurs only above a threshold dose, which is cell line dependent, and requires ATM activity after exposure to doses above 0.5Gy. A failure to activate this early G2/M checkpoint correlates with low dose radiosensitization. These results provide evidence that after exposure to low doses of IR two distinct G2/M checkpoints are activated, each in a dose-dependent manner, with distinct threshold doses and involving different damage signalling pathways and confirm links between the early G2/M checkpoint and hyper-radiosensitivity.
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the role of the ataxia telangiectasia gene in the p53 waf1 cip1 p21 and gadd45 mediated response to dna damage produced by Ionising Radiation
Oncogene, 1995Co-Authors: M Artuso, A Esteve, H Bresil, M Vuillaume, Janet HallAbstract:The inducible response of the tumour suppressor gene p53 has been examined following exposure to DNA-damaging agents in Ataxia telangiectasia (AT) cell lines, an autosomal recessive disorder with multiple clinical and biological abnormalities including sensitivity to Ionising Radiation. The p53 induction was significantly delayed and reduced in the 8 AT cell lines examined over the 6 h following irRadiation with no dose response in p53 induction being observed compared to control cells. The increase of WAF1/CIP1(p21) and GADD45 mRNA, two genes transcriptionally activated by p53, was also reduced in the AT cell lines after such treatment. In contrast, the increase in p53 protein, WAF1/CIP1(p21) and GADD45 mRNA expression following exposure to the alkylating agent methylmethane sulphonate (25 and 100 micrograms ml-1) was similar in both cell types. No alterations in the expression of EBNA-5, an EBV-encoded nuclear antigen which has been shown to bind p53 or mutations in the p53 gene (exons 4 to 8) were found in the AT cell lines studied. The AT gene product would thus appear to be involved upstream of p53, GADD45 and WAF1/CIP1 (p21) in the signalling of the presence of strand breaks produced by Ionising Radiation, with this defect in response contributing to the high cancer risk and radiosensitivity observed in this disorder.
