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    ABSTRACT: Women with breast cancer (BC) and anti thyroid peroxidase (TPO) autoantibodies (TPOAb) have a better prognosis than women lacking TPOAb. Sera from women with TPOAb displayed immunoreactivity to BC tissue by immunofluorescence that was not apparent in women without TPOAb. We hypothesize a BC/thyroid shared antigen that provides a target for humoral or cell-mediated immune activity; candidates include the sodium/iodide symporter (NIS, expressed in thyroid and BC), cross-reacting epitopes in TPO and lactoperoxidase (LPO) or TPO itself. Since the association is with TPOAb, we investigated TPO expression in BC, breast peri-tumoral tissue (PT), other tissues (tumoral and not) and thyroid as positive control. Transcripts for known and novel TPO isoforms were detected in BC (n=8) and PT (n=8) but at approximately 10(4) fold lower than in thyroid while in non-BC tumours (n=5) they were at the limit of detection. TPO was expressed also in adipose tissue (n=17), 10(3) fold lower than in thyroid. Full length TPO (Mr 105-110 kDa) was detected in western blots in the majority of examined tissues; pre-absorption of the TPO antibody with recombinant TPO (but not LPO) reduced the signal, indicating specificity. The same occurred with some lower molecular weight bands, which could correspond to smaller TPO transcript isoforms, present in all samples. In conclusion TPO is weakly expressed in BC and other tissues; this could partly explain the high frequency and protective role of TPOAb in BC patients. Further studies will investigate tissue specificity, function and immunogenicity of the novel TPO variants (some BC-specific) identified. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 04/2014; 134(7). DOI:10.1002/ijc.28493
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    ABSTRACT: This review discusses the role that the sperm-specific phospholipase C zeta (PLCζ) is proposed to play during the fertilization of mammalian eggs. At fertilization, the sperm initiates development by causing a series of oscillations in cytosolic concentrations of calcium [Ca2] within the egg. PLCζ mimics the sperm at fertilization, causing the same pattern of Ca2+ release as seen at fertilization. Introducing PLCζ into mouse eggs also mimics a number of other features of the way in which the fertilizing sperm triggers Ca2+ oscillations. We discuss the localization of PLCζ within the egg and present a hypothesis about the localization of PLCζ within the sperm before the initiation of fertilization.
    Biochemical and Biophysical Research Communications 01/2014;
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    ABSTRACT: The ability of neutrophils to rapidly change shape underlies their physiological functions of phagocytosis and spreading. A major problem in establishing the mechanism is that conventional microinjection of substances and indicators interferes with this dynamic cell behavior. Here we show that electroinjection, a “no-touch” point-and-shoot means of introducing material into the cell, is sufficiently gentle to allow neutrophils to be injected whilst undergoing chemokinesis and spreading without disturbing cell shape change behavior. Using this approach, a fluorogenic calpain-1 selective peptide substrate was introduced into the cytosol of individual neutrophils undergoing shape changes. These data showed that (i) physiologically elevated cytosolic Ca2 +concentrations were sufficient to trigger calpain-1 activation, blockade of Ca2 + influx preventing calpain activation and(ii) calpain-1 activity was elevated in spreading neutrophil.. These findings provide the first direct demonstration of a physiological role for Ca2 + elevation in calpain-1 activation and rapid cell spreading. Electroinjection of cells undergoing dynamic shape changes thus opens new avenues of investigation for defining the molecular mechanism underlying dynamic cell shape changes.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 01/2014;
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    ABSTRACT: The role of magnesium sulfate (MgSO4) in the treatment of acute asthma is not clear. Four recent systematic reviews suggest a limited role of intravenous (i.v.) and inhaled nebulized treatment. The purpose of this review is to summarize the current literature, focus on two recent large multicenter randomized controlled trials, and discuss future research directions. The Magnesium Nebulized Trial In Children (MAGNETIC) trial has shown little benefit to routine use of nebulized MgSO4 in children with acute asthma, but there may be a benefit in those with severe exacerbations and a shorter duration of symptoms. The 3Mg trial has shown no role for nebulized MgSO4 in adults and, at best a limited role for i.v. MgSO4 in only the most severe exacerbations. This is the only study with direct comparison of nebulized and i.v. MgSO4. MgSO4 has a role in severe exacerbations of acute asthma and there is no evidence of benefit outside this clinical situation. Both nebulized and i.v. treatments are well tolerated and inexpensive. In adults, the most effective route of administration is i.v. There are no direct comparison studies in children. Further research should focus on more severe exacerbations.
    Current opinion in pulmonary medicine 11/2013; DOI:10.1097/MCP.0000000000000008
  • Thrombosis and Haemostasis 10/2013; 111(2). DOI:10.1160/TH13-05-0394
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    ABSTRACT: Phospholipase C-zeta (PLCζ) is a sperm-specific protein believed to cause Ca(2+) oscillations and egg activation during mammalian fertilization. PLCζ is very similar to the somatic PLCδ1 isoform but is far more potent in mobilising Ca(2+) in eggs. To investigate how discrete protein domains contribute to Ca(2+) release, we assessed the function of a series of PLCζ/PLCδ1 chimeras. We examined their ability to cause Ca(2+) oscillations in mouse eggs, enzymatic properties using in vitro PIP2 hydrolysis and their binding to PIP2 and PI(3)P with a liposome interaction assay. Most chimeras hydrolysed PIP2 with no major differences in Ca(2+) sensitivity and enzyme kinetics. Insertion of a PH domain or replacement of the PLCζ EF hands domain had no deleterious effect on Ca(2+) oscillations. In contrast, replacement of either XY-linker or C2 domain of PLCζ completely abolished Ca(2+) releasing activity. Notably, chimeras containing the PLCζ XY-linker bound to PIP2-containing liposomes, while chimeras containing the PLCζ C2 domain exhibited PI(3)P binding. Our data suggest that the EF hands are not solely responsible for the nanomolar Ca(2+) sensitivity of PLCζ and that membrane PIP2 binding involves the C2 domain and XY-linker of PLCζ. To investigate the relationship between PLC enzymatic properties and Ca(2+) oscillations in eggs we have developed a mathematical model that incorporates Ca(2+)-dependent InsP3 generation by the PLC chimeras and their levels of intracellular expression. These numerical simulations can for the first time predict the empirical variability in onset and frequency of Ca(2+) oscillatory activity associated with specific PLC variants.
    Molecular Human Reproduction 10/2013; DOI:10.1093/molehr/gat070
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    ABSTRACT: Age-related defects in fibroblast differentiation was previously shown to be associated with impaired hyaluronan synthase 2 (HAS2) and epidermal growth factor receptor (EGFR) function, with both required for normal fibroblast functionality. In fibroblasts, transforming growth factor-beta 1 (TGF-β1) dependent phenotypic activation uses two distinct but co- operating pathways that involve TGF-β receptor (TGF-βR)/Smad2 activation and HA-mediated CD44-EGFR co-localisation and signalling through extracellular signal-regulated kinase 1/2 (ERK1/2). The HA-mediated CD44-EGFR pathway was found to be compromised with in vitro aging, through loss of EGFR expression and a reduced movement of CD44 throughout the cellular membrane. Here we also investigate the involvement of microRNAs (miRNAs) in age- related loss of differentiation, through investigation of miRNA-7 (miR-7) regulation of the HA- mediated EGFR signalling pathway. The transcription of miR-7 was found to be upregulated in aged cells. In young cells, age-related loss of differentiation could be mimicked through transfection of pre-miR-7, and in aged cells, could be reversed through transfection of locked nucleic acids (LNA) targeting miR-7. Additionally, miR-7 was found to be involved in the regulation of CD44 membrane motility, which was down-regulated in instances of miR-7 upregulation, and partially restorable through either miR-7 inhibition or HAS2 overexpression. The altered dynamics of CD44 in the cell membrane demonstrated a further action of miR-7 in regulating the HA-dependent CD44/EGFR pathway. We explain this novel mechanism of age- associated functional consequence due to miR-7 upregulation and demonstrate that it is reversible; highlighting miR-7 as a potential target for restoring the healing capabilities in chronic wounds in the elderly. This article is protected by copyright. All rights reserved.
    Aging cell 10/2013; DOI:10.1111/acel.12167
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    ABSTRACT: Pulmonary surfactant protein-D (SP-D) is a soluble collagenous C-type lectin with important anti-microbial and anti-inflammatory properties. Although it is subject to functionally relevant modification by common polymorphisms and unregulated inflammation, the functional status of SP-D in cystic fibrosis (CF) remains unclear. Given the importance of infection and inflammation in CF lung pathology we have undertaken the first systematic analysis of SP-D lectin activity in this population. By ELISA, we found that airway lavage fluid SP-D expression was greater in CF compared to control patients but was reduced in CF patients with infection and correlated negatively with markers of neutrophilic inflammation. In a functional assay, the percentage of SP-D capable of binding zymosan rarely exceeded 60% in CF or control patients and similarly restricted binding activity was observed towards maltose-agarose. SP-D lectin activity also correlated negatively with infection and neutrophilic inflammation but there was little evidence of major proteolytic degradation among the non-bound material. SP-D which failed to bind zymosan exhibited features of lower oligomeric form compared to bound material when tested by native gel electrophoresis. Furthermore, when separated by gel chromatography, high and low oligomeric populations of SP-D were observed in CF lavage fluid but only high oligomeric forms exhibited substantial lectin activity towards yeast derived mannan. Our data demonstrate that oligomeric heterogeneity underlies functional diversity amongst SP-D in health and disease and that dynamic regulation of oligomerisation is an important feature of SP-D biology.
    Biochimica et Biophysica Acta 10/2013; 1832(12). DOI:10.1016/j.bbadis.2013.10.002
  • Clinical Toxicology 07/2013; 51(7). DOI:10.3109/15563650.2013.820313
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    ABSTRACT: Context:Overt thyroid disease is associated with profound adverse health outcomes; however, data are conflicting for studies of borderline/subclinical thyroid dysfunction. Many studies of subclinical thyroid disease have had low power and were prone to selection bias. In contrast, large datasets are available from community studies in healthy individuals. Studies of the effects of variation of thyroid function across the reference range on health outcomes in these populations may provide useful information regarding thresholds for treatment of abnormal thyroid function.Evidence Acquisition:MEDLINE and the Cochrane Database of Systematic Reviews and Controlled Trials Register were searched for articles studying the effect of variation in thyroid hormone parameters within the reference range on cardiovascular, bone, metabolic, pregnancy, neurological, and psychological outcomes.Evidence Synthesis:Higher TSH/lower thyroid hormone levels are associated with more cardiovascular risk factors and cardiovascular events and worse metabolic parameters and pregnancy outcomes, whereas lower TSH/higher thyroid hormone levels are associated with reduced bone mineral density and increased fracture risk. The evidence base was good for cardiovascular, metabolic, bone, and pregnancy outcomes; however, high-quality data remained lacking for neurological and psychological outcomes.Conclusions:Common variations in persons with thyroid function in the normal range are associated with adverse health outcomes. These data suggest, by extrapolation, that carefully monitored treatment of even modest elevations of TSH may have substantial health benefits. Appropriately powered large-scale clinical trials analyzing the risks vs benefits of treating subclinical thyroid disease are required to determine whether these benefits can be achieved with levothyroxine therapy.
    The Journal of Clinical Endocrinology and Metabolism 07/2013; 98(9). DOI:10.1210/jc.2013-1315
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Nature Communications 01/2015; 6. DOI:10.1038/ncomms6681
Heart (British Cardiac Society) 06/2015; 101(Suppl 4-Suppl 4):A68-A68. DOI:10.1136/heartjnl-2015-308066.118