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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; 32(24). DOI:10.1038/emboj.2013.237
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    ABSTRACT: Human umbilical cord blood (hUCB) has been proposed to contain not only haematopoietic stem cells, but also a rare pluripotent embryonic-like stem cell (ELSc) population that is negative for hematopoietic markers (Lin(-)CD45(-)) and expresses markers typical of pluripotent cells. The aim of this work was to isolate, characterise and expand this ELSc fraction from hUCB, as it may provide a valuable cell source for regenerative medicine applications. We found that we could indeed isolate a Lin(-)CD45(-) population of small cells (3-10 µm diameter) with a high nucleus to cytoplasm ratio that expressed the stem cell markers CD34 and CXCR4. However, in contrast to some previous reports, this fraction was not positive for CD133. Furthermore, although these cells expressed transcripts typical of pluripotent cells, such as SOX2, OCT3/4, and NANOG, they were not able to proliferate in any of the culture media known to support stem cell growth that we tested. Further analysis of the Lin(-)CD45(-) population by flow cytometry showed the presence of a Lin(-)CD45(-)Nestin(+) population that were also positive for CD34 (20%) but negative for CXCR4. These data suggest that the Lin(-)CD45(-) stem cell fraction present in the cord blood represents a small heterogeneous population with phenotypic characteristics of stem cells, including a Lin(-)CD45(-)Nestin(+) population not previously described. This study also suggests that heterogeneity within the Lin(-)CD45(-) cell fraction is the likely explanation for differences in the hUCB cell populations described by different groups that were isolated using different methods. These populations have been widely called "embryonic-like stem cell" on the basis of their phenotypical similarity to embryonic stem cells. However, the fact they do not seem to be able to self-renew casts some doubt on their identity, and warns against defining them as "embryonic-like stem cell" at this stage.
    PLoS ONE 06/2013; 8(6):e67968. DOI:10.1371/journal.pone.0067968
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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; 20(3). DOI:10.1530/ERC-12-0338
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    ABSTRACT: PURPOSEThe standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. PATIENTS AND METHODS In total, 477 patients with CD20(+) DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. RESULTS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01). CONCLUSION In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT.
    Journal of Clinical Oncology 10/2012; 30(36). DOI:10.1200/JCO.2012.41.9416
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    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2012; DOI:10.1038/leu.2012.306
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    ABSTRACT: Natural killer (NK) cells belong to the innate immune system and are key effectors in the immune response against cancer and infection. Recent studies have contributed to the knowledge of events controlling NK cell fate. The use of knockout mice has enabled the discovery of key transcription factors (TFs) essential for NK cell development and function. Yet, unwrapping the downstream targets of these TFs and their influence on NK cells remains a challenge. In this review, we discuss the latest TFs described to be involved in the regulation of NK cell development and maturation.
    Frontiers in Immunology 10/2012; 3:319. DOI:10.3389/fimmu.2012.00319
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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. DOI:10.1038/bjc.2012.344
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    ABSTRACT: Cell size is highly variable; cells from various tissues differ in volume over orders of magnitudes, from tiny lymphocytes to giant neurons, and cells of a given type change size during the cell cycle. Larger cells need to produce and maintain higher amounts of RNA and protein to sustain biomass and function, although the genome content often remains constant. Available data indicate that the transcriptional and translational outputs scale with cell size at a genome-wide level, but how such remarkably coordinated regulation is achieved remains largely mysterious. With global and systems-level approaches becoming more widespread and quantitative, it is worth revisiting this fascinating problem. Here, we outline current knowledge of the fundamental relations between genome regulation and cell size, and highlight the biological implications and potential mechanisms of the global tuning of gene expression to cellular volume.
    Trends in Genetics 08/2012; 28(11):560-5. DOI:10.1016/j.tig.2012.07.003
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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. DOI:10.4161/epi.20941
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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. DOI:10.1371/journal.pone.0040305
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