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1.  Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype 
Oncogene  2013;33(50):5666-5674.
Castration-resistant prostate cancer (CRPC) continues to pose a significant clinical challenge with new generation second line hormonal therapies affording limited improvement in disease outcome. As the androgen receptor (AR) remains a critical driver in CRPC, understanding the determinants of its transcriptional activity is important for developing new AR targeted therapies. FOXA1 is a key component of the AR transcriptional complex yet its role in prostate cancer progression and the relationship between AR and FOXA1 are not completely resolved. It is well established that FOXA1 levels are elevated in advanced prostate cancer and metastases. We mimicked these conditions by over-expressing FOXA1 in the androgen-responsive LNCaP prostate cancer cell line and observed a significant increase in AR genomic binding at novel regions that possess increased chromatin accessibility. High levels of FOXA1 resulted in increased proliferation at both sub-optimal and high 5α-dihydrotestosterone (DHT) concentrations. Immunohistochemical staining for FOXA1 in a clinical prostate cancer cohort revealed that high FOXA1 expression is associated with shorter time to biochemical recurrence after radical prostatectomy (HR 5.0, 95% CI 1.2-21.1, p=0.028), positive surgical margins and higher stage disease at diagnosis. The gene expression program that results from FOXA1 over-expression is enriched for PTEN, Wnt and other pathways typically represented in CRPC gene signatures. Together these results suggest that in an androgen-depleted state, elevated levels of FOXA1 enhance AR binding at genomic regions not normally occupied by AR, which in turn facilitates prostate cancer cell growth.
PMCID: PMC4051595  PMID: 24292680
Androgen receptor; FOXA1; prostate cancer; CRPC; genomics
2.  5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer 
Genome Biology  2015;16(1):69.
The discovery of cytosine hydroxymethylation (5hmC) as a mechanism that potentially controls DNA methylation changes typical of neoplasia prompted us to investigate its behaviour in colon cancer. 5hmC is globally reduced in proliferating cells such as colon tumours and the gut crypt progenitors, from which tumours can arise.
Here, we show that colorectal tumours and cancer cells express Ten-Eleven-Translocation (TET) transcripts at levels similar to normal tissues. Genome-wide analyses show that promoters marked by 5hmC in normal tissue, and those identified as TET2 targets in colorectal cancer cells, are resistant to methylation gain in cancer. In vitro studies of TET2 in cancer cells confirm that these promoters are resistant to methylation gain independently of sustained TET2 expression. We also find that a considerable number of the methylation gain-resistant promoters marked by 5hmC in normal colon overlap with those that are marked with poised bivalent histone modifications in embryonic stem cells.
Together our results indicate that promoters that acquire 5hmC upon normal colon differentiation are innately resistant to neoplastic hypermethylation by mechanisms that do not require high levels of 5hmC in tumours. Our study highlights the potential of cytosine modifications as biomarkers of cancerous cell proliferation.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-015-0605-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4380107  PMID: 25853800
4.  HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network 
EMBO Molecular Medicine  2014;6(5):651-661.
Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies.
PMCID: PMC4023887  PMID: 24737870
androgen receptor; castrate-resistant prostate cancer; gene expression signature; HES6; PLK1
5.  Do as you would be done by: write as you would wish to read 
British Journal of Pharmacology  2013;168(5):1043-1047.
PMCID: PMC3594664  PMID: 23425256
6.  Type I: families, planning and errors 
PMCID: PMC3569996  PMID: 23252664
7.  Not different is not the same as the same: how can we tell? 
PMCID: PMC3569997  PMID: 23252665
9.  Making do with what we have: use your bootstraps 
British Journal of Pharmacology  2012;167(2):233-237.
PMCID: PMC3481035  PMID: 22913626
10.  Variation: use it or misuse it – replication and its variants 
British Journal of Pharmacology  2012;166(7):1977-1980.
PMCID: PMC3402764  PMID: 22776018
11.  Categorized or continuous? Strength of an association – and linear regression 
British Journal of Pharmacology  2012;166(5):1513-1517.
PMCID: PMC3419895  PMID: 22724923
12.  Analysis of variance: variably complex 
British Journal of Pharmacology  2012;166(3):801-805.
PMCID: PMC3417410  PMID: 22568561
13.  Different tests for a difference: how do we do research? 
British Journal of Pharmacology  2012;165(5):1217-1222.
PMCID: PMC3372709  PMID: 22324388
14.  CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection 
Journal of Hepatology  2010;53(2):252-260.
Background & Aims
Increasing age is associated with impaired immune function and in chronic HCV infection specifically, with progressive fibrosis, liver failure, HCC and impaired responses to antiviral therapy. T-lymphocyte telomere length declines with age. We hypothesised that shorter T-lymphocyte telomere length would be associated with poor clinical outcome in HCV infection.
Circulating T-lymphocyte telomere length, an objective measure of immune senescence, was measured by flow-FISH in 135 HCV-RNA-positive, treatment-naïve patients and 41 healthy controls in relation to clinical outcome.
Shorter CD4+CD45RO+ T-lymphocyte telomeres were associated with severe fibrosis (p = 0.003), independent of male sex (p = 0.04), CMV positivity (p = 0.003), previous HBV infection (p = 0.007), and age (p = ns) in viraemic patients compared to controls. There were inverse correlations between CD4+CD45RO+ telomere length and fibrosis stage (p <0.001), portal tract inflammatory grade (p = 0.035), prothrombin time (p <0.001) and bilirubin (p = 0.001). One hundred and twenty-four viraemic individuals were followed prospectively to a composite endpoint of death, hepatic decompensation or HCC. Independent of age, those with shorter CD4+CD45RO+ telomeres were less likely to be complication free after 2-years than those with longer telomeres (86% versus 96%, p = 0.009) with an age-adjusted hazard ratio of 0.93 (0.90–0.96). In addition, CD4+CD45RO+ telomere length predicted successful antiviral therapy (p = 0.001) independent of other factors.
CD4+ T-lymphocyte telomere length, independent of age, was related to inflammatory grade, fibrosis stage, laboratory indices of severity, subsequent hepatic decompensation and treatment outcome in patients with chronic HCV infection.
PMCID: PMC2913243  PMID: 20462651
HCV, hepatitis C virus; HCC, hepatocellular carcinoma; CMV, cytomegalovirus; HBV, hepatitis B virus; EBV, Epstein–Barr virus; HIV, human immunodeficiency virus; IFN-α, interferon-α; PBMCs, peripheral blood mononuclear cells; APCs, antigen presenting cells; HR, hazard ratio; Hepatitis C; Telomere; T-lymphocyte; Immune senescence; Human; Ageing; Hepatocellular carcinoma; Outcome study; Interferon-α
15.  Morphologic Characteristics of Chernobyl-Related Childhood Papillary Thyroid Carcinomas Are Independent of Radiation Exposure but Vary with Iodine Intake 
Thyroid  2008;18(8):847-852.
The Chernobyl accident caused an unprecedented increase in papillary thyroid carcinoma (PTC) incidence with a surprisingly short latency and unusual morphology. We have investigated whether unexpected features of the PTC incidence after Chernobyl were radiation specific or influenced by iodine deficiency.
PTCs from children from Belarus, Ukraine, and the Russian Federation exposed to fallout from Chernobyl were compared with PTCs from children not exposed to radiation from the same countries, from England and Wales (E&W) and from Japan. The degree and type of differentiation, fibrosis, and invasion were quantified.
There were no significant differences between PTCs from radiation-exposed children from Belarus, Ukraine, and the Russian Federation and PTCs from children from the same countries who were not exposed to radiation. Childhood PTCs from Japan were much more highly differentiated (p < 0.001), showed more papillary differentiation (p < 0.001) and were less invasive (p < 0.01) than “Chernobyl” tumors, while tumors from E&W generally showed intermediate levels of degree and type of differentiation and invasion. There was a marked difference between the sex ratios of children with PTCs who were radiation exposed and those who were not exposed (F:M exposed vs. unexposed 1.5:1 vs. 4.2:1; χ2 = 7.90, p ≤ 0.01005).
The aggressiveness and morphological features of Chernobyl childhood PTCs are not associated with radiation exposure. The differences found between tumors from the Chernobyl area, E&W, and Japan could be influenced by many factors. We speculate that dietary iodine levels may have wide implications in radiation-induced thyroid carcinogenesis, and that iodine deficiency could increase incidence, reduce latency, and influence tumor morphology and aggressiveness.
PMCID: PMC2879486  PMID: 18651805
16.  Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer 
Human Molecular Genetics  2008;17(17):2633-2643.
The imprinted insulin-like growth factor 2 (IGF2) gene is expressed predominantly from the paternal allele. Loss of imprinting (LOI) associated with hypomethylation at the promoter proximal sequence (DMR0) of the IGF2 gene was proposed as a predisposing constitutive risk biomarker for colorectal cancer. We used pyrosequencing to assess whether IGF2 DMR0 methylation is either present constitutively prior to cancer or whether it is acquired tissue-specifically after the onset of cancer. DNA samples from tumour tissues and matched non-tumour tissues from 22 breast and 42 colorectal cancer patients as well as peripheral blood samples obtained from colorectal cancer patients [SEARCH (n=case 192, controls 96)], breast cancer patients [ABC (n=case 364, controls 96)] and the European Prospective Investigation of Cancer [EPIC-Norfolk (n=breast 228, colorectal 225, controls 895)] were analysed. The EPIC samples were collected 2–5 years prior to diagnosis of breast or colorectal cancer. IGF2 DMR0 methylation levels in tumours were lower than matched non-tumour tissue. Hypomethylation of DMR0 was detected in breast (33%) and colorectal (80%) tumour tissues with a higher frequency than LOI indicating that methylation levels are a better indicator of cancer than LOI. In the EPIC population, the prevalence of IGF2 DMR0 hypomethylation was 9.5% and this correlated with increased age not cancer risk. Thus, IGF2 DMR0 hypomethylation occurs as an acquired tissue-specific somatic event rather than a constitutive innate epimutation. These results indicate that IGF2 DMR0 hypomethylation has diagnostic potential for colon cancer rather than value as a surrogate biomarker for constitutive LOI.
PMCID: PMC2515372  PMID: 18541649
17.  Waiting time for primary hip replacement--a matter of priority. 
INTRODUCTION: Government reformers often allocate priority to patients based on the time spent on a waiting list. This may conflict with the surgeon's agenda of priority based upon clinical need. METHODS: We reviewed 125 consecutive patients who were awaiting total hip replacement on one consultant's surgical waiting list. We assessed hip pain and function by using a modified Harris Hip Score, which was calculated at the time of addition to the surgical waiting list, at pre-operative assessment and at 6 months' follow-up. RESULTS: Analysis showed that although many patients (31.2%) deteriorate on a surgical waiting list, not all do so. Some stay clinically the same (53.8%) and some improve (15%) while awaiting surgery. CONCLUSION: Patients should not be prioritised solely on the length of time they have spent on a surgical waiting list. Waiting lists should be continually reviewed.
PMCID: PMC1963949  PMID: 16053688
18.  Regulatory T Cells Suppress In Vitro Proliferation of Virus-Specific CD8+ T Cells during Persistent Hepatitis C Virus Infection 
Journal of Virology  2005;79(12):7852-7859.
The basis of chronic infection following exposure to hepatitis C virus (HCV) infection is unexplained. One factor may be the low frequency and immature phenotype of virus-specific CD8+ T cells. The role of CD4+CD25+ T regulatory (Treg) cells in priming and expanding virus-specific CD8+ T cells was investigated. Twenty HLA-A2-positive patients with persistent HCV infection and 46 healthy controls were studied. Virus-specific CD8+ T-cell proliferation and gamma interferon (IFN-γ) frequency were analyzed with/without depletion of Treg cells, using peptides derived from HCV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). CD4+CD25+ Treg cells inhibited anti-CD3/CD28 CD8+ T-cell proliferation and perforin expression. Depletion of CD4+CD25+ Treg cells from chronic HCV patients in vitro increased HCV and EBV peptide-driven expansion (P = 0.0005 and P = 0.002, respectively) and also the number of HCV- and EBV-specific IFN-γ-expressing CD8+ T cells. Although stimulated CD8+ T cells expressed receptors for transforming growth factor beta and interleukin-10, the presence of antibody to transforming growth factor beta and interleukin-10 had no effect on the suppressive effect of CD4+CD25+ regulatory T cells on CD8+ T-cell proliferation. In conclusion, marked CD4+CD25+ regulatory T-cell activity is present in patients with chronic HCV infection, which may contribute to weak HCV-specific CD8+ T-cell responses and viral persistence.
PMCID: PMC1143649  PMID: 15919939

Results 1-18 (18)