Cellular senescence - its role in cancer and the response to ionizing radiation

© 2011 Sabin and Anderson; licensee BioMed Central Ltd. This article is available through the Brunel Open Access Publishing Fund. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Cellular senescence is a normal biological process that is initiated in response to a range of intrinsic and extrinsic factors that functions to remove irreparable damage and therefore potentially harmful cells, from the proliferative pool. Senescence can therefore be thought of in beneficial terms as a tumour suppressor. In contrast to this, there is a growing body of evidence suggesting that senescence is also associated with the disruption of the tissue microenvironment and development of a pro-oncogenic environment, principally via the secretion of senescence-associated pro-inflammatory factors. The fraction of cells in a senescent state is known to increase with cellular age and from exposure to various stressors including ionising radiation therefore, the implications of the detrimental effects of the senescent phenotype are important to understand within the context of the increasing human exposure to ionising radiation. This review will discuss what is currently understood about senescence, highlighting possible associations between senescence and cancer and, how exposure to ionising radiation may modify this

M-FISH analysis shows that complex chromosome aberrations induced by α-particle tracks are cumulative products of localised rearrangements

Complex chromosome aberrations are characteristically induced after exposure to low doses of densely ionising radiation, but little is understood about their formation. To address this, we irradiated human peripheral blood lymphocytes (PBL) in vitro with 0.5 Gy densely ionising α-particles (mean of 1 α-particle/cell) and analysed the chromosome aberrations produced using 24-colour M-FISH. Our data suggest that complex formation is a consequence of direct nuclear α-particle traversal and show that the likely product of illegitimate repair of damage from a single α-particle is a single complex exchange. From an assessment of the ‘cycle structure’ of each complex exchange we predict α-particle-induced damage to be repaired at specific localised sites, and complexes to be formed as cumulative products of this repair

Chromosome breakpoint distribution of damage induced in peripheral blood lymphocytes by densely ionising radiation

Purpose: To assess the chromosomal breakpoint distribution in human peripheral blood lymphocytes (PBL) after exposure to a low dose of high linear energy transfer (LET) α-particles using the technique of multiplex fluorescence in situ hybridisation (m-FISH). Materials and methods: Separated PBL were exposed in G0 to 0.5 Gy 238 Pu α-particles, stimulated to divide and harvested ~48-50 hours after exposure. Metaphase cells were assayed by m-FISH and chromosome breaks identified. The observed distribution of breaks were then compared with expected distributions of breaks, calculated on the assumption that the distribution of breaks is random with regard to either chromosome volume or chromosome surface area. Results: More breaks than expected were observed on chromosomes 2 and 11, however no particular region of either chromosome was identified as significantly contributing to this over-representation. The identification of hot or cold chromosome regions (pter,p,cen,q,qter) varied depending on whether the data were compared according to chromosome volume or surface area. Conclusions: A deviation from randomness in chromosome breakpoint distribution was observed, and this was greatest when data were compared according to the relative surface area of each individual chromosome (or region). The identification of breaks by m-FISH (i.e. more efficient observation of interchanges than intrachanges) and importance of territorial boundaries on interchange formation are thought to contribute to these differences. The significance of the observed non-random distribution of breaks on chromosomes 2 and 11 in relation to chromatin organisation is unclear

Reduced chromosome aberration complexity in normal human bronchial epithelial cells exposed to low-LET γ-rays and high-LET α-particles

This article is made available through the Brunel Open Access Publishing Fund.Copyright © 2013 The Author(s). Purpose: Cells of the lung are at risk from exposure to low and moderate doses of ionizing radiation from a range of environmental and medical sources. To help assess human health risks from such exposures, a better understanding of the frequency and types of chromosome aberration initially-induced in human lung cell types is required to link initial DNA damage and rearrangements with transmission potential and, to assess how this varies with radiation quality. Materials and methods: We exposed normal human bronchial lung epithelial (NHBE) cells in vitro to 0.5 and 1 Gy low-linear energy transfer (LET) γ-rays and a low fluence of high-LET α-particles and assayed for chromosome aberrations in premature chromosome condensation (PCC) spreads by 24-color multiplex-fluorescence in situ hybridization (M-FISH). Results: Both simple and complex aberrations were induced in a LET and dose-dependent manner; however, the frequency and complexity observed were reduced in comparison to that previously reported in spherical cell types after exposure to comparable doses or fluence of radiation. Approximately 1–2% of all exposed cells were categorized as being capable of transmitting radiation-induced chromosomal damage to future NHBE cell generations, irrespective of dose. Conclusion: One possible mechanistic explanation for this reduced complexity is the differing geometric organization of chromosome territories within ellipsoid nuclei compared to spherical nuclei. This study highlights the need to better understand the role of nuclear organization in the formation of exchange aberrations and, the influence three-dimensional (3D) tissue architecture may have on this in vivo.Department of Health, UK (Contract RRX115)

Extending backcalculation to analyse BSE data.

We review the origins of backcalculation (or back projection) methods developed for the analysis of AIDS (acquired immunodeficiency syndrome) incidence data. These techniques have been used extensively for >15 years to deconvolute clinical case incidence, given knowledge of the incubation period distribution, to obtain estimates of past HIV (human immunodeficiency virus) infection incidence and short-term predictions of future AIDS incidence. Adaptations required for the analysis of bovine spongiform encephalopathy (BSE) incidence included: stratification of BSE incidence by age as well as birth cohort; allowance for incomplete survival between infection and the onset of clinical signs of disease; and decomposition of the age- and time-related infection incidence into a time-dependent feed risk component and an age-dependent exposure/susceptibility function. The most recent methodological developments focus on the incorporation of data from clinically unaffected cattle screened using recently developed tests for preclinical BSE infection. Backcalculation-based predictions of future BSE incidence obtained since 1996 are examined. Finally, future directions of epidemiological analysis of BSE epidemics are discussed taking into account ongoing developments in the science of BSE and possible changes in BSE-related policies

Development and validation of 'AutoRIF': Software for the automated analysis of radiation-induced foci

Copyright @ 2012 McVean et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been made available through the Brunel Open Access Publishing Fund.Background: The quantification of radiation-induced foci (RIF) to investigate the induction and subsequent repair of DNA double strands breaks is now commonplace. Over the last decade systems specific for the automatic quantification of RIF have been developed for this purpose, however to ask more mechanistic questions on the spatio-temporal aspects of RIF, an automated RIF analysis platform that also quantifies RIF size/volume and relative three-dimensional (3D) distribution of RIF within individual nuclei, is required. Results: A java-based image analysis system has been developed (AutoRIF) that quantifies the number, size/volume and relative nuclear locations of RIF within 3D nuclear volumes. Our approach identifies nuclei using the dynamic Otsu threshold and RIF by enhanced Laplacian filtering and maximum entropy thresholding steps and, has an application ‘batch optimisation’ process to ensure reproducible quantification of RIF. AutoRIF was validated by comparing output against manual quantification of the same 2D and 3D image stacks with results showing excellent concordance over a whole range of sample time points (and therefore range of total RIF/nucleus) after low-LET radiation exposure. Conclusions: This high-throughput automated RIF analysis system generates data with greater depth of information and reproducibility than that which can be achieved manually and may contribute toward the standardisation of RIF analysis. In particular, AutoRIF is a powerful tool for studying spatio-temporal relationships of RIF using a range of DNA damage response markers and can be run independently of other software, enabling most personal computers to perform image analysis. Future considerations for AutoRIF will likely include more complex algorithms that enable multiplex analysis for increasing combinations of cellular markers.This article is made available through the Brunel Open Access Publishing Fund

Spread of Infectious Diseases with a Latent Period

Infectious diseases spread through human networks. Susceptible-Infected-Removed (SIR) model is one of the epidemic models to describe infection dynamics on a complex network connecting individuals. In the metapopulation SIR model, each node represents a population (group) which has many individuals. In this paper, we propose a modified metapopulation SIR model in which a latent period is taken into account. We call it SIIR model. We divide the infection period into two stages: an infected stage, which is the same as the previous model, and a seriously ill stage, in which individuals are infected and cannot move to the other populations. The two infectious stages in our modified metapopulation SIR model produce a discontinuous final size distribution. Individuals in the infected stage spread the disease like individuals in the seriously ill stage and never recover directly, which makes an effective recovery rate smaller than the given recovery rate.Comment: 6 pages, 3 figure

Effect of linear energy transfer (LET) on complexity of alpha-particle-induced chromosome aberrations in human CD34+ cells.

The aim of this study was to assess the relative influence of linear energy transfer (LET) of α-particles on chromosome aberration complexity in the absence of significant other track structure differences. To do this we irradiated human haemopoietic stem cells (CD34+) with The aim of this study was to assess the relative influence of linear energy transfer (LET) of α-particles of various incident LET values (110 - 152 keV/µm, with mean LETs through the cell of 119 – 182 keV/µm) at an equi-fluence of approximately 1 α-particle/cell and assayed for chromosome aberrations by m-FISH. Based on a single harvest time to collect early division mitosis , complex aberrations were observed at comparable frequencies irrespective of incident LET, however when expressed as a proportion of the total exchanges detected, their occurrence was seen to increase with increasing LET. Cycle analysis to predict theoretical DNA double strand break rejoining cycles was also carried out on all complex chromosome aberrations detected. By doing this we found that the majority of complex aberrations are formed in single non-reducible cycles that involve just 2 or 3 different chromosomes and 3 or 4 different breaks. Each non-reducible cycle is suggested to represent ‘an area’ of finite size within the nucleus where double strand break repair occurs. We suggest that local density of damage induced and proximity of independent repair areas within the interphase nucleus determine the complexity of aberration resolved in metaphase. Overall, the most likely outcome of a single nuclear traversal of a single α-particle in CD34+ cells is a single chromosome aberration per damaged cell. As the incident LET of the α-particle increases, the likelihood of this aberration being classed as complex is greater

m-FISH analysis reveals complexity of chromosome aberrations in individuals occupationally exposed with internal plutonium: A pilot study to assess the relevance of complex aberrations as biomarkers of exposure to high-LET α particles

We recently demonstrated that a significant proportion of apparently stable insertions induced after exposure to a mean of 1 α particle/cell, detected using 3-colour FISH, were part of larger unstable complexes when visualised by 24-colour FISH. Interestingly, regardless of the long-term persistence capability of the cell, the complexity of each α particle-induced complex appeared to be specific to the nuclear traversal of a single -particle. To assess whether aberrations of a similar complexity are observed in vivo and also to examine the usefulness of detecting such aberrations as a biomarker of chronic exposure to α particles, we have carried out a limited pilot study of Russian workers with large body burdens of -particle emitting plutonium (Pu). We found unstable cells containing non-transmissible complex aberrations in all of the Pu exposed subjects analysed by m-FISH. In addition, all of the complexes seen were consistent with those previously observed in vitro. Non-transmissible complex aberrations were more common than transmissible-type complexes, consistent with on-going/chronic exposure and insertions were dominant features of both type of complex. Accordingly, this preliminary study supports the proposal that aberration complexity and non-transmissibility are the major cytogenetic features of α particle exposure that could potentially be exploited as a specific indicator of chronic exposures to high-LET α particles

Reproductive dysfunction and associated pathology in women undergoing military training

Evidence from civilian athletes raises the question of whether reproductive dysfunction may be seen in female soldiers as a result of military training. Such reproductive dysfunction consists of impaired ovulation with or without long term subfertility. We critically review pertinent evidence, which points towards reduced energy availability as the most likely explanation for exercise-induced reproductive dysfunction. Evidence also suggests reproductive dysfunction is mediated by activation of the hypothalamic-pituitary-adrenal axis and suppression of the hypothalamic-pituitary-gonadal axis, with elevated ghrelin and reduced leptin likely to play an important role. The observed reproductive dysfunction exists as part of a female athletic triad, together with osteopenia and disordered eating. If this phenomenon was shown to exist with UK military training this would be of significant concern. We hypothesise that the nature of military training and possibly field exercises may contribute to greater risk of reproductive dysfunction among female military trainees compared with exercising civilian controls. We discuss the features of military training and its participants, such as energy availability, age at recruitment, body phenotype, type of physical training, psychogenic stressors, altered sleep pattern and elemental exposure as contributors to reproductive dysfunction. We identify lines of future research to more fully characterise reproductive dysfunction in military women, and suggest possible interventions which, if indicated, could improve their future wellbeing