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  • The Lancet 11/2013; 382(9904):1552.
  • The Journal of trauma 08/2013;
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    ABSTRACT: Pancreatic secretory trypsin inhibitor is expressed in most bladder carcinomas where its pathophysiological relevance is unclear. Using recombinant normal sequence PSTI/TATI, a variant associated with familial pancreatitis (N34S), an active site inactivated variant (R18/V19) and immunoneutralization and RNA interference-mediated knockdown (KD) techniques, we investigated the actions of PSTI/TATI on cell migration (wounding monolayers), collagen invasion (gel invasion assays) and proliferation (Alamar blue) on 253J, RT4 and HT1376 human bladder carcinoma cell lines. All three forms of PSTI/TATI stimulated migration two-fold and normal sequence PSTI/TATI showed synergistic promigratory effects when added with EGF. Addition of structurally unrelated soya bean trypsin inhibitor had no pro-migratory activity. Similar results were seen using collagen invasion assays although the active site mutated variant had no pro-invasive activity, probably due to reduced Akt2 activation. PSTI/TATI did not stimulate proliferation despite acting, at least partially, through the EGF receptor as effects of PSTI/TATI were truncated by adding an EGFR blocking antibody or the tyrosine kinase inhibitor Tyrphostin. Cell lines produced endogenous PSTI/TATI and PSTI/TATI RNA interference knockdown or addition of PSTI/TATI, EGF-receptor or Tyrphostin blocking agents reduced migration and invasion below baseline. PSTI/TATI induced phosphorylation of the EGF receptor, ERK1 and 2, Akt2 and 3, JNK1, MKK3 and RSK1. This profile was more limited than that induced by EGF and did not include Akt1, probably explaining lack of pro-proliferative activity. Our findings of autocrine stimulation and synergistic responses between EGF & PSTI/TATI at concentrations found in urine and tissue suggest PSTI/TATI has pathophysiological relevance.
    AJP Renal Physiology 05/2013;
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    ABSTRACT: Multiple sclerosis (MS) is a central nervous system (CNS) disorder characterised by demyelination and neurodegeneration. Although hallmarks of recovery (remyelination and repair) have been documented in early MS, the regenerative capacity of the adult CNS per se remains uncertain with the wide held belief that it is either limited or non-existent. The neural cell adhesion molecule (NCAM) is a cell adhesion molecule that has been widely implicated in axonal outgrowth, guidance and fasciculation. Here, we used in vitro and in vivo of MS to investigate the role of NCAM in disease progression. We show that in health NCAM levels decrease over time, but this occurs acutely after demyelination and remains reduced in chronic disease. Our findings suggest that depletion of NCAM is one of the factors associated with or possibly responsible for disease progression in MS. © 2012 International Society for Neurochemistry, J. Neurochem. (2013)10.1111/jnc.12236.
    Journal of Neurochemistry 03/2013;
  • Movement Disorders 03/2013;
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    ABSTRACT: Cytochrome p450 (CYP)2J2 is an epoxygenase enzyme that metabolises arachidonic acid to epoxyeicosatrienoic acids (EETs). EETs are inactivated by soluble epoxide hydrolase (sEH), which converts them in to their corresponding dihydroxyeicosatrienoic acids (DHETs). CYP2J2 is highly expressed in cardiovascular tissue including the heart and vascular endothelial cells. CYP2J2 and the EETs it produces have been shown to have a diverse range of effects on the vasculature, including the regulation of inflammation, vascular tone, cellular proliferation, angiogenesis, and metabolism. This review will examine these established and emerging roles of CYP2J2 in the biology of vascular endothelial cells.
    Prostaglandins & other lipid mediators 03/2013;
  • Journal of Hepatology 01/2013;
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    ABSTRACT: Nucleic acids are the ultimate biomarker and real-time PCR (qPCR) is firmly established as the method of choice for nucleic acid detection. Together, they allow the accurate, sensitive and specific identification of pathogens, and the use of qPCR has become routine in diagnostic laboratories. The reliability of qPCR-based assays relies on a combination of optimal sample selection, assay design and validation as well as appropriate data analysis and the "Minimal Information for the Publication of real-time PCR" (MIQE) guidelines aim to improve both the reliability of assay design as well as the transparency of reporting, essential conditions if qPCR is to remain the benchmark technology for molecular diagnosis.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 943:1-16.
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    ABSTRACT: Galactomannan (GM) is widely used for detection of invasive aspergillosis in high-risk haemato-oncology patients. Recent publications have reported a lack of repeatability of GM detection. The objective of this retrospective study was to assess the repeatability of GM levels during storage of clinical samples. In a GM screening strategy, positive sera were repeat tested as per manufacturer's recommendations. Short-term (ST) storage of samples was at +4 °C while long-term (LT) storage was at -80 °C. Bronchoalveolar (BAL) fluid was also repeating tested after ST storage and LT storage. Wilcoxon Signed Ranks Test was employed to assess the repeatability of GM levels. In a subset of 14 GM positive sera, repeat testing was performed on both the original serum and ethylenediaminetetraacetic acid (EDTA) pre-treated sample. There was a significant reduction in GM signals on repeat testing following ST storage (median GM index: 0.65 vs. 0.19; p < 0.001) and LT storage (median GM index: 0.56 vs. 0.10; p < 0.001) of serum samples. Of samples that were initially GM positive, an average GM index reduction of 50% was seen, with approximately two-thirds becoming GM negative on repeat testing of the same sample. In contrast, GM signal loss was not seen on repeat testing of BAL fluid following ST or LT storage. When GM positive serum samples were repeat tested using EDTA pre-treated serum from the first step of the testing protocol, all samples remained GM positive. In contrast, when the same samples were repeat tested from the original collected serum, 9 samples (64%) became GM negative. The significant reduction in GM signals during ST and LT storage of serum samples has implications for clinical management. Although the reasons for GM decline are unknown, they occur prior to the EDTA pre-treatment stage, indicating that the time from phlebotomy to testing should be minimized. BAL fluid GM index values remain stable.
    International Journal of Molecular Sciences 01/2013; 14(7):12970-12977.
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    ABSTRACT: BACKGROUND & AIMS: For hepatitis C virus (HCV)-infected patients who have not responded to previous peginterferon/ribavirin treatment, it is unclear whether subsequent direct-acting antiviral therapy outcomes are better predicted by prior treatment response or by on-treatment response to a peginterferon/ribavirin lead-in. METHODS: In REALIZE, treatment-experienced patients randomized to the lead-in telaprevir arm received 4 weeks of peginterferon alfa-2a (180μg/week) and ribavirin (1000-1200mg/day), then 12 weeks of telaprevir (750mg every 8 hours) plus peginterferon alfa-2a/ribavirin, followed by 32 weeks of peginterferon alfa-2a/ribavirin. This subanalysis only included patients in the lead-in telaprevir arm with available Week 4 on-treatment response data (n=240). RESULTS: After 4 weeks of peginterferon/ribavirin, 90% of relapsers, 60% of partial responders, and 41% of null responders in the lead-in telaprevir arm had ⩾1 log(10) HCV RNA reduction. Sustained virologic response (SVR) rates for telaprevir-treated patients with ⩾1 versus <1 log(10) HCV RNA reduction after the peginterferon/ribavirin lead-in were 94% versus 62% in relapsers, 59% versus 56% in partial responders and 54% versus 15% in null responders. CONCLUSIONS: In prior relapsers and partial responders there is no apparent benefit of assessing response after a peginterferon/ribavirin lead-in with the aim of guiding telaprevir-based treatment. For patients known to be prior null responders, on-treatment response after a 4-week peginterferon/ribavirin lead-in may provide clinically useful prognostic information. However, withholding telaprevir-containing therapy in uncategorised treatment-experienced patient populations (i.e. that could include prior relapsers or partial responders) using response after a peginterferon/ribavirin lead-in could potentially exclude some patients with a high chance of SVR.
    Journal of Hepatology 11/2012;
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