Staff Profiles

Journal articles

• Coe S, Cossington J, Collett J, Soundy A, Izadi H, Ovington M, Durkin L, Kirsten M, Clegg M, Cavey A, Wade DT, Palace J, DeLuca G, Chapman K, Harrison JM, Buckingham E, Dawes H, 'A randomised double blind placebo-controlled feasibility trial of flavonoid-rich cocoa for fatigue in people with Relapsing and Remitting Multiple Sclerosis'
  Journal of Neurology, Neurosurgery and Psychiatry 90 (5) (2019) pp.507-513
  ISSN: 0022-3050 eISSN: 1468-330X
  Abstract

  The impact of flavonoids on fatigue has not been investigated in Relapsing and Remitting Multiple Sclerosis (RRMS). Objective. To determine the feasibility and estimate the potential effect of flavonoid-rich cocoa on fatigue and fatigability in RRMS.  Methods. A randomised double-blind placebo-controlled feasibility study in people recently diagnosed with RRMS and fatigue, throughout the Thames Valley (ISRCTN: 69897291). During a six week intervention participants consumed a high or low flavonoid cocoa beverage daily. Fatigue and fatigability were measured at three visits (weeks 0, 3 and 6). Feasibility and fidelity were assessed through recruitment and retention, adherence and a process evaluation. Results. 40 pwMS (10 men, 30 women, age 44 ± 10 yrs) were randomised and allocated to high (n=19) or low (n=21) flavonoid groups and included in analysis. Missing data was <20% and adherence to intervention of allocated individuals was >75%. There was a small effect on fatigue (Neuro-QoL: effect size {ES} 0.04; confidence interval {CI} -0.40-0.48) and a moderate effect on fatigability (six-minute walk test: ES 0.45; CI -0.18 - 1.07). There were seven adverse events (four control, three intervention), only one of which was possibly related and it was resolved.   Conclusion. A flavonoid beverage demonstrates the potential to improve fatigue and fatigability in RRMS. 

  
  
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• Al-Mayah A, Bright S, Chapman K, Irons S, Luo P, Carter D, Goodwin E, Kadhim M., 'The non-targeted effects of radiation are perpetuated by exosomes'
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 772 (2014) pp.38-45
  ISSN: 0027-5107
  Abstract Exosomes contain cargo material from endosomes, cytosol, plasma membrane and microRNA molecules, they are released by a number of non-cancer and cancer cells into both the extracellular microenvironment and body fluids such as blood plasma.
   
  Recently we demonstrated radiation-induced non-targeted effects [NTE: genomic instability (GI) and bystander effects (BE)] are partially mediated by exosomes, particularly the RNA content. However the mechanistic role of exosomes in NTE is yet to be fully understood.
   
  The present study used MCF7 cells to characterise the longevity of exosome-induced activity in the progeny of irradiated and unirradiated bystander cells. Exosomes extracted from conditioned media of irradiated and bystander progeny were added to unirradiated cells. Analysis was carried out at 1 and 20/24 population doublings following medium/exosome transfer for DNA/chromosomal damage. Results confirmed exosomes play a significant role in mediating NTE of ionising radiation (IR). This effect was remarkably persistent, observed >20 doublings post-irradiation in the progeny of bystander cells. Additionally, cell progeny undergoing a BE were themselves capable of inducing BE in other cells via exosomes they released. Furthermore we investigated the role of exosome cargo. Culture media from cells exposed to 2 Gy X-rays was subjected to ultracentrifugation and four inoculants prepared, (a) supernatants with exosomes removed, and pellets with (b) exosome proteins denatured, (c) RNA degraded, and (d) a combination of protein–RNA inactivation. These were added to separate populations of unirradiated cells. The BE was partially inhibited when either exosome protein or exosome RNA were inactivated separately, whilst combined RNA–protein inhibition significantly reduced or eliminated the BE. These results demonstrate that exosomes are associated with long-lived signalling of the NTE of IR. Both RNA and protein molecules of exosomes work in a synergistic manner to initiate NTE, spread these effects to naïve cells, and perpetuate GI in the affected cells.
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• Irons SL, Serra V, Bowler D, Chapman K, Militi S, Lyng F, Kadhim M, 'The Effect of Genetic Background and Dose on Non-targeted Effects of Radiation'
  International Journal of Radiation Biology 88 (2012) pp.735-742
  ISSN: 0955-3002 eISSN: 1362-3095
  Abstract

  PURPOSE:

  This work investigates the hypothesis that genetic background plays a significant role in the signalling mechanisms underlying induction and perpetuation of genomic instability following radiation exposure.

  MATERIALS AND METHODS:

  Bone marrow from two strains of mice (CBA and C57) were exposed to a range of X-ray doses (0, 0.01, 0.1, 1 and 3 Gy). Different cellular signalling endpoints: Apoptosis, cytokine levels and calcium flux, were evaluated at 2 h, 24 h and 7 d post-irradiation to assess immediate and delayed effects.

  RESULTS:

  In CBA (radiosensitive) elevated apoptosis levels were observed at 24 h post X-irradiation, and transforming growth factor-β (TGF-β) levels which increased with time and dose. C57 showed a higher background level of apoptosis, and sustained apoptotic levels 7 days after radiation exposure. Levels of tumor necrosis factor-α (TNF-α were increased in C57 at day 7 for higher X-ray doses. TGF-β levels were higher in CBA, whilst C57 exhibited a greater TNF-α response. Calcium flux was induced in reporter cells on exposure to conditioned media from both strains.

  CONCLUSIONS:

  These results show genetic and dose specific differences in radiation-induced signalling in the initiation and perpetuation of the instability process, which have potential implications on evaluation of non-targeted effects in radiation risk assessment.

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• Chapman KL, Al-Mayah AH, Bowler DA, Irons SL, Kadhim MA, 'No influence of serotonin levels in foetal bovine sera on radiation induced bystander effects and genomic instability'
  International Journal of Radiation Biology 88 (10) (2012) pp.781-785
  ISSN: 0955-3002 eISSN: 1362-3095
  Website 
• Kadhim MA, Lee R, Moore SR, Macdonald DA, Chapman KL, Patel G, Prise KM, 'Genomic instability after targeted irradiation of human lymphocytes: Evidence for inter-individual differences under bystander conditions'
  Mutation Research - Fundamental and Molecular Mechinisms of Mutagenesis 688 (40940) (2010) pp.91-94
  ISSN: 0027-5107
  Abstract

  Environmental (222) radon exposure is a human health concern, and many studies demonstrate that very low doses of high LET alpha-particle irradiation initiate deleterious genetic consequences in both radiated and non-irradiated bystander cells. One consequence, radiation-induced genomic instability (RIGI), is a hallmark of tumorigenesis and is often assessed by measuring delayed chromosomal aberrations We utilised a technique that facilitates transient immobilization of primary lymphocytes for targeted microbeam irradiation and have reported that environmentally relevant doses, e.g. a single (3)He(2+) particle traversal to a single cell, are sufficient to Induce RIGI Herein we sought to determine differences in radiation response in lymphocytes isolated from five healthy male donors Primary lymphocytes were irradiated with a single particle per cell nucleus. We found evidence for inter-individual variation in radiation response (Rid, measured as delayed chromosome aberrations) Although this was not highly significant, it was possibly masked by high levels of intra-individual variation While there are many studies showing a link between genetic predisposition and RIGI, there are few studies linking genetic background with bystander effects in normal human lymphocytes In an attempt to investigate inter-individual variation in the induction of bystander effects, primary lymphocytes were irradiated with a single particle under conditions where fractions of the population were traversed We showed a marked genotype-dependent bystander response in one donor after exposure to 15% of the population The findings may also be regarded as a radiation-induced genotype-dependent bystander effect triggering an instability phenotype

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• Chapman KL, Kelly JW, Lee R, Goodwin EH, Kadhim MA, 'Tracking Genomic Instability Within Irradiated and Bystander Populations'
  Journal of Pharmacy and Pharmacology 60 (8) (2008) pp.959-968
  ISSN: 0022-3573 eISSN: 2042-7158
  Abstract

  Over the past two decades, our understanding of radiation biology has undergone a fundamental shift in paradigms away from deterministic ‘hit-effect’ relationships and towards complex ongoing ‘cellular responses’. These responses include now familiar, but still poorly understood, phenomena associated with radiation exposure such as genomic instability and bystander effects. Although these responses share some common features (e.g. they occur at high frequency following very low doses, are heterogeneous in their induction and are observed at time points far removed from the initial radiation exposure), the precise relationship between genomic instability and bystander effects remains to be elucidated. This review will provide a synthesis of the known, and proposed, interrelationships among irradiated and bystander cellular responses to radiation. It also discusses our current experimental approach for gaining a clearer understanding of the relationship between damage induction and long-term effects in both irradiated and bystander cells.

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