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    ABSTRACT: To ensure proper gene regulation within constrained nuclear space, chromosomes facilitate access to transcribed regions, while compactly packaging all other information. Recent studies revealed that chromosomes are organized into megabase-scale domains that demarcate active and inactive genetic elements, suggesting that compartmentalization is important for genome function. Here, we show that very specific long-range interactions are anchored by cohesin/CTCF sites, but not cohesin-only or CTCF-only sites, to form a hierarchy of chromosomal loops. These loops demarcate topological domains and form intricate internal structures within them. Post-mitotic nuclei deficient for functional cohesin exhibit global architectural changes associated with loss of cohesin/CTCF contacts and relaxation of topological domains. Transcriptional analysis shows that this cohesin-dependent perturbation of domain organization leads to widespread gene deregulation of both cohesin-bound and non-bound genes. Our data thereby support a role for cohesin in the global organization of domain structure and suggest that domains function to stabilize the transcriptional programmes within them.
    The EMBO Journal 11/2013;
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    ABSTRACT: The field of epigenetics has evolved rapidly over recent years providing insight into the tumorigenesis of many solid and haematological malignancies. Determination of epigenetic modifications in neuroendocrine tumour (NET) development is imperative if we are to improve our understanding of the biology of this heterogenous group of tumours. Epigenetic marks such as methylation of RASSF1A are frequent findings in NETs of all origins and may be associated with worse prognosis. Micro RNA signatures and histone modifications have been identified which differentiate subtypes of NET and distinguish NET from adenocarcinoma in cases of diagnostic uncertainty. Historically candidate gene driven approaches have yielded limited insight to the epigenetics of NET. Recent progress has been facilitated by development of high throughput tools including second generation sequencing and arrays for analysis of the 'epigenome' of tumour and normal tissue, permitting unbiased approaches such as exome sequencing which identified mutations of chromatin remodelling genes ATRX/DAXX in 44% of pancreatic NETs. Epigenetic changes are reversible and therefore represent an attractive therapeutic target, to date clinical outcomes of epigenetic therapies in solid tumours have been disappointing, however in vitro studies on NET are promising and further clinical trials are required to determine utility of this class of novel agents. In this review we perform a comprehensive evaluation of epigenetic changes found in neuroendocrine tumours to date, including rare NETs such as phaeochromocytoma and adrenocortical tumours. We suggest priorities for future research and discuss potential clinical applications and novel therapies.
    Endocrine Related Cancer 02/2013;
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    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2012;
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    ABSTRACT: Background:Many clinical trials show no overall benefit. We examined futility analyses applied to trials with different effect sizes.Methods:Ten randomised cancer trials were retrospectively analysed; target sample size reached in all. The hazard ratio indicated no overall benefit (n=5), or moderate (n=4) or large (n=1) treatment effects. Futility analyses were applied after 25, 50 and 75% of events were observed, or patients were recruited. Outcomes were conditional power (CP), and time and cost savings.Results:Futility analyses could stop some trials with no benefit, but not all. After observing 50% of the target number of events, 3 out of 5 trials with no benefit could be stopped early (low CP15%). Trial duration for two studies could be reduced by 4-24 months, saving £44 000-231 000, but the third had already stopped recruiting, hence no savings were made. However, of concern was that 2 of the 4 trials with moderate treatment effects could be stopped early at some point, although they eventually showed worthwhile benefits.Conclusions:Careful application of futility can lead to future patients in a trial not being given an ineffective treatment, and should therefore be used more often. A secondary consideration is that it could shorten trial duration and reduce costs. However, studies with modest treatment effects could be inappropriately stopped early. Unless there is very good evidence for futility, it is often best to continue to the planned end.
    British Journal of Cancer 08/2012; 107(6):910-7.
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    ABSTRACT: A new platform for DNA methylome analysis is Illumina's Infinium HumanMethylation450. This technology is an extension of the previous HumanMethylation27 BeadChip and allows the methylation status of 12 samples per chip and 4 to 8 chips (total of 48 to 96 samples) to be assessed simultaneously for more than 480,000 cytosines across the genome. The platform incorporates two different probe types using different assay designs (InfiniumI and InfiniumII). Although this has allowed the assessment of more CpG sites, it has also introduced technical variation between the two probe types, which has complicated the analysis process. Many groups are working on normalization methods and analysis pipelines while many others are struggling to make sense of their new data sets. This motivated the organization of a meeting held at University College London that focused solely on the analysis methods and problems related to this new platform. The meeting was attended by 125 computational and bench scientists from 11 countries. There were 10 speakers, a small poster session and a discussion session.
    Epigenetics: official journal of the DNA Methylation Society 08/2012; 7(8):961-2.
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    ABSTRACT: Urinary biomarkers for bladder cancer detection are constrained by inadequate sensitivity or specificity. Here we evaluate the diagnostic accuracy of Mcm5, a novel cell cycle biomarker of aberrant growth, alone and in combination with NMP22. 1677 consecutive patients under investigation for urinary tract malignancy were recruited to a prospective blinded observational study. All patients underwent ultrasound, intravenous urography, cystoscopy, urine culture and cytologic analysis. An immunofluorometric assay was used to measure Mcm5 levels in urine cell sediments. NMP22 urinary levels were determined with the FDA-approved NMP22® Test Kit. Genito-urinary tract cancers were identified in 210/1564 (13%) patients with an Mcm5 result and in 195/1396 (14%) patients with an NMP22 result. At the assay cut-point where sensitivity and specificity were equal, the Mcm5 test detected primary and recurrent bladder cancers with 69% sensitivity (95% confidence interval = 62-75%) and 93% negative predictive value (95% CI = 92-95%). The area under the receiver operating characteristic curve for Mcm5 was 0.75 (95% CI = 0.71-0.79) and 0.72 (95% CI = 0.67-0.77) for NMP22. Importantly, Mcm5 combined with NMP22 identified 95% (79/83; 95% CI = 88-99%) of potentially life threatening diagnoses (i.e. grade 3 or carcinoma in situ or stage ≥pT1) with high specificity (72%, 95% CI = 69-74%). The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways.
    PLoS ONE 07/2012; 7(7):e40305.
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    ABSTRACT: Electrosurgery-induced tubal thermal injury obscures cellular detail and hampers histomorphological assessment for occult pathology. The objectives of this study were to report on diathermy-related thermal injuries to the fallopian tube observed at RRSO and explore its potential impact on the detection of occult tubal epithelial lesions. This study was composed of high-risk women from breast and/or ovarian cancer families attending a tertiary high-risk familial gynecologic cancer clinic. This was a retrospective case-control analysis of high-risk women who underwent RRSO. Cases were all women detected to have occult lesions (tubal atypia/carcinoma in situ/cancer) between January 2005 and December 2010. Control subjects were all women with normal tubal/ovarian histology between August 2006 and December 2007. Two pathologists performed histopathologic assessment for grade of thermal injury. Tubal diathermy injury rates were compared between cases and controls. Statistical analysis was undertaken using SPSS version 18. The Mann-Whitney U test compared age distributions; χ/Fisher tests, the difference between proportions, and γ test, the difference in ordinal variables between the groups. A novel tubal thermal index to describe the severity of injury is reported. Lack of fimbrial thermal injury is twice as likely (odds ratio, 2.04; 95% confidence interval, 1.06-3.92) to be associated with detection of occult tubal pathology, whereas isthmic injury does not affect detection rate (P = 0.744). The groups were comparable with respect to age at RRSO (P = 0.531) and the presence of BRCA mutations (P = 0.192). This report highlights the potential impact of electrosurgical thermal injury on detection of occult tubal pathology following RRSO. It is important for surgeons to avoid thermal injury to the distal end of the tube.
    International Journal of Gynecological Cancer 05/2012; 22(5):881-8.
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    ABSTRACT: Neuroendocrine tumours (NETs) are a rare and heterogeneous group of tumours whose incidence is increasing and their prevalence is now greater than that of any other upper gastrointestinal tumour. Diagnosis can be challenging, and up to 25% of patients present with metastatic disease. Following the recent FDA approval of two new molecularly targeted therapies for the treatment of advanced pancreatic NETs (pNETs), the first in 25 years, we review all systemic therapies and suggest where these newer targeted therapies fit in the treatment schedule for these challenging tumours. Clinical trial data relating to the routine use of sunitinib and everolimus in low-intermediate-grade pNETs are summarised alongside newer molecularly targeted agents undergoing clinical assessment in NETs. We particularly focus on the challenge of optimal scheduling of molecularly targeted treatments around existing systemic and localised treatment such as chemotherapy or radiotargeted therapy. We also discuss application of current evidence to subgroups of patients who have not so far been directly addressed such as those with poorer performance status or patients receiving radical surgery who may benefit from adjuvant treatment.
    Endocrine Related Cancer 04/2012; 19(3):R73-92.
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    ABSTRACT: Biology, biomedicine and healthcare have become data-driven enterprises, where scientists and clinicians need to generate, access, validate, interpret and integrate different kinds of experimental and patient-related data. Thus, recording and reporting of data in a systematic and unambiguous fashion is crucial to allow aggregation and re-use of data. This paper reviews the benefits of existing biomedical data standards and focuses on key elements to record experiments for therapy development. Specifically, we describe the experiments performed in molecular, cellular, animal and clinical models. We also provide an example set of elements for a therapy tested in a phase I clinical trial. We introduce the Guidelines for Information About Therapy Experiments (GIATE), a minimum information checklist creating a consistent framework to transparently report the purpose, methods and results of the therapeutic experiments. A discussion on the scope, design and structure of the guidelines is presented, together with a description of the intended audience. We also present complementary resources such as a classification scheme, and two alternative ways of creating GIATE information: an electronic lab notebook and a simple spreadsheet-based format. Finally, we use GIATE to record the details of the phase I clinical trial of CHT-25 for patients with refractory lymphomas. The benefits of using GIATE for this experiment are discussed. While data standards are being developed to facilitate data sharing and integration in various aspects of experimental medicine, such as genomics and clinical data, no previous work focused on therapy development. We propose a checklist for therapy experiments and demonstrate its use in the 131Iodine labeled CHT-25 chimeric antibody cancer therapy. As future work, we will expand the set of GIATE tools to continue to encourage its use by cancer researchers, and we will engineer an ontology to annotate GIATE elements and facilitate unambiguous interpretation and data integration.
    BMC Research Notes 01/2012; 5:10.
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    ABSTRACT: Deregulation of the cell cycle underlies the aberrant cell proliferation that characterizes cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades, cancer genetics has shown that hyperactivating mutations in growth signalling networks, coupled to loss of function of tumour suppressor proteins, drives oncogenic proliferation. Gene expression profiling of these complex and redundant mitogenic pathways to identify prognostic and predictive signatures and their therapeutic targeting has, however, proved challenging. The cell cycle machinery, which acts as an integration point for information transduced through upstream signalling networks, represents an alternative target for diagnostic and therapeutic interventions. Analysis of the DNA replication initiation machinery and mitotic engine proteins in human tissues is now leading to the identification of novel biomarkers for cancer detection and prognostication, and is providing target validation for cell cycle-directed therapies.
    The Journal of Pathology 01/2012; 226(2):352-64.
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