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Port Glasgow, United Kingdom

Muinonen-Martin A.J.,CRUK Beatson Institute | Susanto O.,CRUK Beatson Institute | Zhang Q.,Babraham Institute | Smethurst E.,Babraham Institute | And 14 more authors.
PLoS Biology | Year: 2014

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient. © 2014 Muinonen-Martin et al. Source


Blaydon D.C.,Queen Mary, University of London | Lind L.K.,Umea University | Plagnol V.,University College London | Linton K.J.,Queen Mary, University of London | And 9 more authors.
American Journal of Human Genetics | Year: 2013

Autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma is characterized by the adoption of a white, spongy appearance of affected areas upon exposure to water. After exome sequencing, missense mutations were identified in AQP5, encoding water-channel protein aquaporin-5 (AQP5). Protein-structure analysis indicates that these AQP5 variants have the potential to elicit an effect on normal channel regulation. Immunofluorescence data reveal the presence of AQP5 at the plasma membrane in the stratum granulosum of both normal and affected palmar epidermis, indicating that the altered AQP5 proteins are trafficked in the normal manner. We demonstrate here a role for AQP5 in the palmoplantar epidermis and propose that the altered AQP5 proteins retain the ability to form open channels in the cell membrane and conduct water. © 2013 The American Society of Human Genetics. Source


Lamb R.C.,Alan Lyell Center for Dermatology | Dawn G.,Monklands Hospital
International Journal of Dermatology | Year: 2014

Mycobacteria cause a range of diseases in both immunocompetent and immunosuppressed individuals and may affect many different organs. The most noticeable recent change in patterns of cutaneous mycobacterial infection refers to the increase in non-tuberculous mycobacterial (NTM) infections. This review focuses on the clinical manifestations, diagnosis, and treatment of cutaneous NTM infections. The MEDLINE, PubMed, and Cochrane Library databases were searched using the keywords "nontuberculous mycobacteria," "atypical mycobacteria," and "mycobacteria other than tubercle bacilli". Publications on cutaneous NTM infections written in English were included in this review. Literature published by the World Health Organization was examined for further material. References in review articles were screened for other studies not already identified. The clinical features, diagnosis, and treatment of NTM infections were reviewed. Cutaneous mycobacterial disease may take many guises and may appear benign in nature. Chronic cutaneous lesions at the sites of trauma or surgical procedures, especially those that fail to respond to standard antibiotic therapy, should prompt the consideration of mycobacterial disease. The lack of rapid techniques for the identification of pathogens makes diagnosis challenging. The lack of randomized controlled trials on the efficacy of antimicrobial agents means that empiric therapy may fail, necessitate prolonged combinations of antibiotics, and increase the probability of side effects and diminished compliance. © 2014 The International Society of Dermatology. Source


Kerr A.C.,Photobiology Unit | Ferguson J.,Photobiology Unit | Attili S.K.,Photobiology Unit | Beattie P.E.,Alan Lyell Center for Dermatology | And 12 more authors.
Clinical and Experimental Dermatology | Year: 2012

Whole-body ultraviolet (UV)A1 (340-400 nm) phototherapy was first introduced 30 years ago, but is currently available in the UK in only three dermatology departments. A workshop to discuss UVA1 was held by the British Photodermatology Group in May 2009, the aim of which was to provide an overview of UVA1 phototherapy and its role in practice, and to identify areas in which further studies are required. The conclusions were that UVA1 phototherapy is an effective treatment in several inflammatory skin diseases, including localized scleroderma and atopic eczema (AE); however, deficiencies and limitations exist in the published evidence base. For most diseases, such as AE, other treatments also exist, which are generally more effective than UVA1. However, for some diseases, particularly morphoea, the evidence of efficacy is stronger for UVA1 than for other treatments. Acute adverse effects of UVA1 are minimal. The risk of long-term adverse effects, particularly skin cancer, is unknown. Medium to high doses of UVA1 are needed for efficacy in most situations, but the equipment to deliver such doses is large, expensive and difficult to install. UVA1 is currently underprovided, and the recommendation of the workshop is that more tertiary centres should have access to UVA1 phototherapy in the UK. Click for the corresponding questions to this CME article. © 2012 British Association of Dermatologists. Source


Shams K.,Alan Lyell Center for Dermatology | Grindlay D.J.C.,University of Nottingham | Williams H.C.,University of Nottingham
Clinical and Experimental Dermatology | Year: 2011

This review provides a summary of key findings from 18 systematic reviews on atopic eczema, published or indexed between January 2009 and 24 August 2010. There was no good evidence on the possible benefit of organic food consumption and eczema. Maternal intake of fish or fish oil may be associated with a reduced risk of eczema in offspring, although further studies are needed. There is some evidence that partially hydrolysed infant formulas rather than standard formulas may be associated with a reduced risk of eczema in infants, but there are shortcomings in the existing evidence. An inverse relationship has been found between gliomas/acute lymphoblastic leukaemia and allergic disease/eczema, but there appears to be no association between multiple sclerosis and eczema. Attention deficit hyperactivity disorder does appear to be associated with eczema, but there is no evidence of a causal link. The risk of eczema seems to be increased in urban compared with rural areas. Some new evidence has suggested superiority of 1% pimecrolimus over potent and mild corticosteroids at 6 months but not 12 months, and there is some evidence for superiority of 0.03% and 0.1% tacrolimus over 1% pimecrolimus. An updated Cochrane Review still found no evidence of a benefit from any form of antistaphylococcal treatment in managing clinically infected or uninfected eczema. The evidence base is poor for bath emollients, occlusive treatments (e.g. wet and dry wraps) and woven silk clothing in treating eczema. In general, the methods used in most systematic reviews of eczema need to be reported more clearly, especially with regard to a more vigorous quality assessment of included studies. Included studies are frequently heterogeneous, proxy reporting is common, and appropriate disease definitions are often lacking. Better adherence to existing guidance on trial reporting and prospective registration of clinical trials may help improve the quality of studies. Click for the corresponding questions to this CME article. © 2011 British Association of Dermatologists. Source

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