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    ABSTRACT: To investigate tumour progression mechanism in transgenic mouse skin carcinogenesis, inducible PTEN ablation (Δ5PTEN(flx)) was targeted to the epidermis of mice expressing activated ras(Ha)/fos oncogenes (HK1.ras and HK1.fos). RU486-treated HK1.ras/fos-Δ5PTEN(flx) epidermis exhibited significant keratinocyte proliferation resulting in hyperplasia and proliferating cysts. While HK1.ras/fos-Δ5PTEN(flx) papillomatogenesis was accelerated, malignant conversion was delayed and tumours exhibited well-differentiated squamous cell carcinoma (wdSCC) histotypes, suggesting inhibition of early-stage malignant progression. Immediate elevated p53/p21 expression was observed in HK1.ras/fos-Δ5PTEN(flx) hyperplasia, cysts and papillomas, and while malignant conversion required p53 loss, elevated p21 expression persisted in most wdSCCs to limit further progression, unless p21 was also lost and wdSCC progressed to more aggressive carcinomas. In contrast, TPA-promoted (that is, c-fos-activated) bi-genic HK1.ras-Δ5PTEN(flx) cohorts lost p53/p21 expression during early papillomatogenesis and rapidly produced poorly differentiated carcinomas (pdSCCs) with high BrdU-labelling and elevated cyclin D1/E2 expression levels, indicative of a progression mechanism driven by failures in cell-cycle control. Intriguingly, HK1.ras/fos-Δ5PTEN(flx) wdSCCs did not exhibit similar failures, as western and immunofluorescence analysis found downregulated cyclin E2 whenever p21 persisted; further, while westerns detected elevated cyclin D1, immunofluorescence identified reduced expression in proliferative basal layer nuclei and a redistributed expression profile throughout p21-positive wdSCC keratinocytes. These data demonstrate that rapid early epidermal responses to ras(Ha)/fos/ΔPTEN co-operation involve induction of p53/p21 to alter differentiation and divert excessive proliferation into cyst formation. Further, despite three potent oncogenic insults p53 loss was required for malignant conversion, and following p53 loss persistent, p53-independent p21 expression possessed the potency to limit early-stage malignant progression via cyclin D1/E2 inhibition.Oncogene advance online publication, 16 September 2013; doi:10.1038/onc.2013.372.
    Oncogene 09/2013;
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    ABSTRACT: Scar tissue formation during healing of extensive skin wounds may be related to delayed reepithelialization, while elevated levels of hyaluronan may suppress scar tissue formation. This study investigates the expression of hyaluronan by human skin fibroblasts in response to keratinocyte-conditioned medium (KCM), and attempts to identify any active factors within the conditioned medium. Serum-free KCM was assessed for its ability to stimulate the incorporation of (3) H-glucosamine into fibroblast glycosaminoglycans, and hyaluronan synthesis. Conditioned medium was concentrated with an ultrafiltration membrane with a 30 kDa cutoff. Stratifin was assessed for its ability to stimulate hyaluronan synthesis and its role in KCM. KCM stimulated fibroblast glycosaminoglycan synthesis up to a 3.3-fold increase and a 6.5-fold increase in hyaluronan synthesis compared with serum-free controls. Preliminary characterization of the active factors showed that they are retained by a >30 kDa ultrafiltration membrane, and are protease sensitive and heat resistant. Emmprin and stratifin were shown to stimulate fibroblast hyaluronan synthesis, and the hyaluronan-stimulating activity of KCM was removed following stratifin depletion and to a lesser extent by emmprin depletion. Keratinocytes release soluble factors, including stratifin, that stimulate fibroblast hyaluronan synthesis, and this stimulation of fibroblast hyaluronan may contribute to the suppression of scar tissue formation.
    Wound Repair and Regeneration 05/2011; 19(3):379-86.
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    ABSTRACT: We have examined the clearance of UVB-induced erythema in 10 non-melanoma skin cancer (NMSC) patients, comparing their responses to a control group. All participants were followed to resolution of erythema, as measured by a chromameter. The resultant response pattern was modelled in three phases, with comparison of the rates of decay in erythema carried out. Analysis of the rapid decay phase demonstrated a significantly slower rate of resolution of erythema in the NMSC group, compared with the controls. Further elucidation of the molecular and genetic mechanisms controlling this response may improve our understanding of UV-induced carcinogenesis.
    Photodermatology Photoimmunology and Photomedicine 01/2011; 13(5-6):189-92.
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    ABSTRACT: To determine the ability of different types of gadolinium-based contrast agents (GBCAs) to stimulate fibroblast proliferation in monolayer cell culture. The National Health Service West Glasgow Ethics Committee granted approval for this study. Fibroblasts established from healthy volunteers (control subjects) and from lesional skin of patients with nephrogenic systemic fibrosis were exposed to a range of concentrations of ionic and nonionic linear and macrocyclic contrast agents over 4 days, and the effect on growth was determined. The lowest concentration of contrast agent that stimulated the maximum effect on fibroblast growth was selected for determination of its effect on fibroblast growth over 8 days. The effect of contrast agents on hyaluronan and collagen synthesis was determined with an enzyme-linked immunosorbent assay. Responses were assessed with analysis of variance (general linear model). The linear gadolinium contrast agents (gadodiamide, gadoversetamide, gadopentetate dimeglumine, and gadobenate dimeglumine) produced a maximum stimulation of fibroblast proliferation at a concentration of 0.1 mmol/L, with cell numbers increasing up to 2.3-fold. The macrocyclic contrast agents (gadoteric acid and gadoteridol) produced a maximum stimulation of fibroblast proliferation at a concentration of 5 mmol/L. The reference gadolinium agents (N-methylglucamine gadolinium ethylenediaminetetraacetic acid and gadolinium trichloride) stimulated fibroblast proliferation at a concentration of 0.01 mmol/L and were toxic at a concentration greater than 1 mmol/L. Growth curves supported the dose-response observations. Hyaluronan synthesis was stimulated by gadoversetamide, gadobenate dimeglumine, gadodiamide, and gadopentetate dimeglumine at a concentration of 0.1 mmol/L and by gadolinium trichloride at a concentration of 0.01 mmol/L, whereas collagen synthesis was unaffected. Conclusion: This study provides evidence that different classes of gadolinium chelates stimulate human fibroblast proliferation.
    Radiology 09/2010; 256(3):735-43.
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    ABSTRACT: There is a close correlation between tumour progression and hyaluronan production, either by tumour cells or by stromal cells that are stimulated by tumour-derived factors. Inhibition of tumour stimulation of fibroblast hyaluronan may suppress tumour growth and invasion. To examine the effect of the hyaluronan synthesis inhibitor 4-methylumbelliferone (4-MU) on the growth of and hyaluronan synthesis by fibroblasts and C8161 and MV3 melanoma cell lines, invasion, and inhibition of tumour cell-derived factor activation of fibroblasts. Effects of 4-MU on growth and hyaluronan synthesis by fibroblasts and melanoma cells were examined in monolayer culture and fibroblast-contracted collagen lattices, and their effects on the growth and invasion of tumour cells into collagen lattices were also studied. 4-MU caused a dose-dependent growth inhibition of fibroblast and melanoma cells with maximum inhibition at 0·5 mmol L(-1) 4-MU. At this dose, 4-MU inhibited (3) H-glucosamine incorporation into fibroblast glycosaminoglycans by 52%, and hyaluronan synthesis by 64%. The relative inhibition was more pronounced when fibroblasts were stimulated with C8161 melanoma cell-conditioned medium. 4-MU reduced the level of hyaluronan in fibroblast-contracted collagen lattices, and inhibited both the growth on and invasion into the lattices by melanoma cells. This growth inhibition appears to be predominantly independent of inhibition of hyaluronan synthesis. The effect on growth inhibition was reversible, and 4-MU had no effect on apoptosis. 4-MU is a potent inhibitor of hyaluronan synthesis, induction of stromal hyaluronan accumulation by tumour cells, and fibroblast and melanoma cell proliferation, and results suggest that 4-MU may have potential as a tumour cell anti-invasive and antiproliferative agent.
    British Journal of Dermatology 02/2010; 162(6):1224-32.
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    ABSTRACT: During recent decades, discoveries in genetic skin disease have produced insights into the biology of the skin, and in some cases permitted preventive prenatal diagnosis, but application of this knowledge in palliation or cure remains a tantalising prospect.
    Clinical medicine (London, England) 12/2009; 9(6):591-2.
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    ABSTRACT: Fungal infections of the scalp commonly affect the paediatric population and are caused by dermatophytes which have the ability to invade the keratinised structures of skin, hair and nails. This study analyses the changes in the epidemiology of fungal scalp infections in the West of Scotland during the period 2000-2006. Skin and hair from scalp specimens sent by General Practitioners and Dermatologists throughout the West of Scotland were examined microscopically for the presence of fungal hyphae and/or spores and cultured to determine the identity of the fungi. The most common dermatophyte to be isolated from scalps during 2000-2006 was Trichophyton violaceum with 29 reported cases followed by 23 cases of Trichophyton tonsurans infection. During 2000-2002, over 90% of patients were British but during 2003-2006, greater than 50% of patients were of non-UK origin. The majority of T. violaceum and T. tonsurans infections during this study were from patients originating in either Africa or Pakistan and were from people known to be seeking asylum in the UK. The overall increase and the change in pattern of reported fungal scalp infections in the West of Scotland may be explained by the migration of people to Scotland from Africa or Pakistan where T. violaceum and T. tonsurans are endemic. The increase in numbers of infections in the later period of this study reflects an increase in the awareness of General Practitioners and Dermatologists to send samples to Clinical Mycology.
    Scottish medical journal 06/2009; 54(2):13-6.
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    ABSTRACT: The effect of amorolfine (Ro 14–4767/002) on phagocytosis and intracellular killing of Candida ulbicuns blastospores was determined in human neutrophil mono-layer assays. At 0.2, 2 and 5 p, g/ml amorolfine did not have any significant inhibitory or enhancing effect on phagocytosis whether following simultaneous addition of blastospores and drug to the neutrophils, prior treatment of neutrophils for 2 h before addition of blastospores or prior treatment of blastospores for 2 h. Simultaneous addition of amorolfine resulted in a significant increase in killing at all concentrations. This increase was not significantly enhanced by either preincubation of neutrophils or blastospores for 2h with the drug.Zusammenfassung: Es wurde die Wirkung von Amorolfin (Ro 14–4767/002) auf die Phagozytose und die intrazellulare Abtotung von Cundida ulbicuwBlastosporen in Monolayern menschlischer Neutrophiler untersucht. Bei 0,2,2 und 5 pg/ml Amorolfin wurde keine signifikante Hemm- oderForderwirkung auf die Phagozytose beob-achtet, und zwar weder bei simultaner Zu-gabe von Wirkstoff und Blastosporen zu den Neutrophilen noch bei 2 h Amorolfin-Vor-behandlung der Neutrophilen oder der Blastosporen. Die Simultanzugabe von Amorolfin bewirkte jedoch einen Anstieg der Abtotungsrate bei allen Konzentrationen. Diese wurde durch 2 h Prainkubation der Neutrophilen oder der Blastosporen mit Amorolfin nicht mehr signifikant gestei-gert.
    Mycoses 05/2009; 32(5):245-249.
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    ABSTRACT: Combination treatment with amphotericin B and 5-fluorocytosine is synergistic and has become clinically useful in the treatment of various forms of systemic candidosis. The synergy between these two compounds may be explained in part by their combined effect on the interaction between fungal cells and host phagocytes. Pretreatment of Candida albicans for 2 h with either amphotericin B or 5-fluorocytosine or the two agents in combination did not inhibit or enhance phagocytosis by glass-adherent human neutrophils (P greater than 0.05). Intracellular killing of pretreated yeast cells was not influenced by antifungals alone (P greater than 0.05), but pretreatment of C. albicans with 5.0 mg l-1 amphotericin B + 10 l-1 5-fluorocytosine or 5.0 mg l-1 amphotericin B + 50 mg l-1 5-fluorocytosine significantly enhanced the ability of neutrophils to kill the number of viable yeast cells intracellularly (P less than 0.001).
    Mycoses 05/2009; 34(5-6):201-4.
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    ABSTRACT: To investigate gene synergism in multistage skin carcinogenesis, the RU486-inducible cre/lox system was employed to ablate Pten function (K14.cre/Delta5Pten flx) in mouse epidermis expressing activated Fos (HK1.Fos). RU486-treated HK1.Fos/Delta5Pten flx mice exhibited hyperplasia, hyperkeratosis and tumours that progressed to highly differentiated keratoacanthomas, rather than to carcinomas, owing to re-expression of high p53 and p21 WAF levels. Despite elevated MAP kinase activity, cyclin D1 and cyclin E2 overexpression, and increased AKT activity that produced areas of highly proliferative papillomatous keratinocytes, increasing levels of GSK3beta inactivation induced a novel p53/p21 WAF expression profile, which subsequently halted proliferation and accelerated differentiation to give the hallmark keratosis of keratoacanthomas. A pivotal facet to this GSK3beta-triggered mechanism centred on increasing p53 expression in basal layer keratinocytes. This increase in expression reduced activated AKT expression and released inhibition of p21 WAF, which accelerated keratinocyte differentiation, as indicated by unique basal layer expression of differentiation-specific keratin K1 alongside premature filaggrin and loricrin expression. Thus, Fos synergism with Pten loss elicited a benign tumour context where GSK3beta-induced p53/p21 WAF expression continually switched AKT-associated proliferation into differentiation, preventing further progression. This putative compensatory mechanism required the critical availability of normal p53 and/or p21 WAF, otherwise deregulated Fos, Akt and Gsk3beta associate with malignant progression.
    Journal of Cell Science 06/2008; 121(Pt 10):1758-69.
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