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    ABSTRACT: Background:The prognosis for hepatocellular carcinoma (HCC) is dependent upon tumour stage, performance status (PS), severity of underlying liver disease, and the availability of appropriate therapies. The unavailability of sorafenib may have a significantly adverse effect on the prognosis of UK patients with advanced HCC. During the study period, access to sorafenib was at the discretion of local health funding bodies, a process that may delay or deny access to the drug and that remains in place for Wales, Scotland, and Northern Ireland. Here, we attempt to address the impact of this system on patients with advanced HCC in the United Kingdom.Methods:This is a retrospective study performed in the two largest specialist hepatobiliary oncology units in the United Kingdom. Funding applications were made to local funding bodies for patients with advanced HCC for whom sorafenib was considered appropriate (advanced HCC not suitable for loco-regional therapies, compensated chronic liver disease, PS 0-2).Results:A total of 133 applications were made, of which 57 (43%) were approved and 76 (57%) declined. Demographics and prognostic factors were balanced between the two groups. This cohort had a number of adverse prognostic features: patients were predominantly PS 1-2; the majority had multifocal disease with the largest lesion being >5 cm; and macroscopic vascular invasion, metastases, and AFP >1000 ng ml(-1), were each present in one-third of cases. The median time from application to funding decision was 17 days (range 3-260 days). For the primary 'intention-to-treat' analysis, median overall survival was 4.1 months when funding was declined, and 9.5 months when funding was approved (hazard ratio (HR) 0.48; 95% CI 0.3186-0.7267; P=0.0005).Conclusion:These data support the use of sorafenib for patients with advanced HCC as an effective intervention. In the United Kingdom, this applies to a relatively small group of patients, estimated to total ∼800 per year who, unfortunately, do not survive long enough to themselves lobby for the availability of this drug. These data provide a comparison of sorafenib with supportive care and demonstrate the potential detrimental impact on patient outcomes of rationing health-care resources on the basis of cost.British Journal of Cancer advance online publication, 23 July 2013; doi:10.1038/bjc.2013.410 www.bjcancer.com.
    British Journal of Cancer 07/2013;
  • Journal of Clinical Oncology 06/2013;
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    ABSTRACT: Nucleoli perform a crucial cell function, ribosome biogenesis, and of critical relevance to the subject of this review, they are also extremely sensitive to cellular stresses, which can cause loss of function and/or associated structural disruption. In recent years, we have learned that cells take advantage of this stress sensitivity of nucleoli, using them as stress sensors. One major protein regulated by this role of nucleoli is the tumor suppressor p53, which is activated in response to diverse cellular injuries in order to exert its onco-protective effects. Here we discuss a model of nucleolar regulation of p53, which proposes that key steps in the promotion of p53 degradation by the ubiquitin ligase MDM2 occur in nucleoli, thus providing an explanation for the observed link between nucleolar disruption and p53 stability. We review current evidence for this compartmentalization in p53 homeostasis and highlight current limitations of the model. Interestingly, a number of current chemotherapeutic agents capable of inducing a p53 response are likely to do so by targeting nucleolar functions and these compounds may serve to inform further improved therapeutic targeting of nucleoli.
    Cellular and Molecular Life Sciences CMLS 05/2013;
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    ABSTRACT: Bread wheat (Triticum aestivum) is a globally important crop, accounting for 20 per cent of the calories consumed by humans. Major efforts are underway worldwide to increase wheat production by extending genetic diversity and analysing key traits, and genomic resources can accelerate progress. But so far the very large size and polyploid complexity of the bread wheat genome have been substantial barriers to genome analysis. Here we report the sequencing of its large, 17-gigabase-pair, hexaploid genome using 454 pyrosequencing, and comparison of this with the sequences of diploid ancestral and progenitor genomes. We identified between 94,000 and 96,000 genes, and assigned two-thirds to the three component genomes (A, B and D) of hexaploid wheat. High-resolution synteny maps identified many small disruptions to conserved gene order. We show that the hexaploid genome is highly dynamic, with significant loss of gene family members on polyploidization and domestication, and an abundance of gene fragments. Several classes of genes involved in energy harvesting, metabolism and growth are among expanded gene families that could be associated with crop productivity. Our analyses, coupled with the identification of extensive genetic variation, provide a resource for accelerating gene discovery and improving this major crop.
    Nature 11/2012; 491(7426):705-10.
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    Genome biology 09/2012; 13(9):171.
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    ABSTRACT: Periorbital cellulitis is inflammation of the eye anterior to the palpebral ligament. The sequeale may be life or vision threatening. There is no consensus on the optimal management strategies. A two year retrospective case note analysis was performed on all hospital admissions to a tertiary children's hospital with the diagnosis. 226 notes were retrieved, 13 were excluded. The incidence of periorbital cellulitis was nearly 9 cases per month (8.875): the median length of stay was 2 days: all were treated with antibiotics. Only 7 children (3%) underwent surgical intervention. Due to potentially serious intracranial and orbital complications, authors have previously argued that all patients with periorbital cellulitis need daily otorhinolaryngology assessment. This current review showed a much larger incidence than in the published literature, with the majority being managed by the paediatricians and ophthalmologists. Escalation to otorhinolaryngology when first line treatment has failed is a more appropriate use of resources.
    International journal of pediatric otorhinolaryngology 05/2012; 76(8):1073-7.
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    ABSTRACT: The pancreatic ductal adenocarcinoma (PDAC) microenvironment accommodates a variety of cell types and a plethora of complex interactions between tumor cells, host cells and extracellular matrix (ECM) components. Here we review the role of inflammatory cells, in particular mast cells, myeloid-derived suppressor cells, macrophages, T regulatory cells, T helper cells and neutrophils. The picture that emerges is that of a tumor microenvironment, in which the immune response is actively suppressed, and inflammatory cells contribute in a variety of ways to tumor progression.
    Frontiers in Physiology 01/2012; 3:270.
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    ABSTRACT: Dynamic control of protein phosphorylation is necessary for the regulation of many cellular processes, including mitosis and cytokinesis. Indeed, although the central role of protein kinases is widely appreciated and intensely studied, the importance of protein phosphatases is often overlooked. Recent studies, however, have highlighted the considerable role of protein phosphatases in both the spatial and temporal control of protein kinase activity, and the modulation of substrate phosphorylation. Here, we will focus on recent advances in our understanding of phosphatase structure, and the importance of phosphatase function in the control of mitotic spindle formation, chromosome architecture and cohesion, and cell division.
    Journal of Cell Science 07/2011; 124(Pt 14):2323-34.
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    ABSTRACT: Since the discovery of cytoglobin (Cygb) a decade ago, growing amounts of data have been gathered to characterise Cygb biochemistry, functioning and implication in human pathologies. Its molecular roles remain under investigation, but nitric oxide dioxygenase and lipid peroxidase activities have been demonstrated. Cygb expression increases in response to various stress conditions including hypoxia, oxidative stress and fibrotic stimulation. When exogenously overexpressed, Cygb revealed cytoprotection against these factors. Cygb was shown to be upregulated in fibrosis and neurodegenerative disorders and downregulated in multiple cancer types. CYGB was also found within the minimal region of a hereditary tylosis with oesophageal cancer syndrome, and its expression was reduced in tylotic samples. Recently, Cygb has been shown to inhibit cancer cell growth in vitro, thus confirming its suggested tumour suppressor role. This article aims to review the biochemical and functional aspects of Cygb, its involvement in various pathological conditions and potential clinical utility.
    Cellular and Molecular Life Sciences CMLS 07/2011; 68(23):3869-83.
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    ABSTRACT: Astrin is a mitotic spindle-associated protein required for the correct alignment of all chromosomes at the metaphase plate. Astrin depletion delays chromosome alignment and causes the loss of normal spindle architecture and sister chromatid cohesion before anaphase onset. Here we describe an astrin complex containing kinastrin/SKAP, a novel kinetochore and mitotic spindle protein, and three minor interaction partners: dynein light chain, Plk1, and Sgo2. Kinastrin is the major astrin-interacting protein in mitotic cells, and is required for astrin targeting to microtubule plus ends proximal to the plus tip tracking protein EB1. Cells overexpressing or depleted of kinastrin mislocalize astrin and show the same mitotic defects as astrin-depleted cells. Importantly, astrin fails to localize to and track microtubule plus ends in cells depleted of or overexpressing kinastrin. These findings suggest that microtubule plus end targeting of astrin is required for normal spindle architecture and chromosome alignment, and that perturbations of this pathway result in delayed mitosis and nonphysiological separase activation.
    The Journal of Cell Biology 03/2011; 192(6):959-68.
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Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2011; 6(10):1632-8.
Proceedings of the National Academy of Sciences 03/2013;