The Journal of investigative dermatology
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J. Invest. Dermatol. · Feb 2012
Substance P (SP) induces expression of functional corticotropin-releasing hormone receptor-1 (CRHR-1) in human mast cells.
Corticotropin-releasing hormone (CRH) is secreted under stress and regulates the hypothalamic-pituitary-adrenal axis. However, CRH is also secreted outside the brain where it exerts proinflammatory effects through activation of mast cells, which are increasingly implicated in immunity and inflammation. Substance P (SP) is also involved in inflammatory diseases. ⋯ However, repeated stimulation of mast cells with CRH (1 μM) leads to downregulation of CRHR-1 and upregulation in NK-1 gene expression. These results indicate that SP can stimulate mast cells and also increase expression of functional CRHR-1, whereas CRH induces NK-1 gene expression. These results may explain CRHR-1 and NK-1 expression in lesional skin of psoriatic patients.
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J. Invest. Dermatol. · Aug 2011
Randomized Controlled TrialTopical treatment of Basal cell carcinomas in nevoid Basal cell carcinoma syndrome with a smoothened inhibitor.
Basal cell carcinoma (BCC) is a distinctive manifestation in nevoid basal cell carcinoma syndrome (NBCCS) patients. Both inherited and acquired mutations of patched 1 (PTCH1), a tumor-suppressor gene controlling the activity of Smoothened (SMO), are the primary cause of the constitutive activation of the Hedgehog (HH) pathway, leading to the emergence of BCCs in NBCCS. LDE225, a distinct, selective antagonist of SMO, showed potent inhibition of basaloid tumor nest formation and mediated regression of preformed basaloid tumors in organ cultures of skin derived from Ptch1 heterozygous knockout mice. ⋯ Except for one partial response, the vehicle produced no clinical response in any of the 14 treated BCCs. Treatment with 0.75% LDE225 cream in NBCCS patients was very well tolerated and caused BCC regression, thus potentially offering an attractive therapeutic alternative to currently available therapies for this indication. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub.
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J. Invest. Dermatol. · May 2011
Development of skin-humanized mouse models of pachyonychia congenita.
Molecular characterization and assessment of therapeutic outcomes for inherited cutaneous disorders requires faithful preclinical models. In this study we report the establishment of two different skin-humanized pachyonychia congenita (PC) model systems, based on permanent engraftment of bioengineered skin equivalents generated from patient skin cells onto immunodeficient mice. Using keratinocytes and fibroblasts isolated from unaffected skin biopsies of two PC patients carrying the p. ⋯ In contrast, the use of keratinocytes from an affected area (i.e., plantar callus) from a different patient carrying the KRT6A mutation p. Asn171Asp led to a full recapitulation of the phenotype that included marked acanthosis and epidermal blistering after minor trauma. The ability to generate large numbers of PC skin-engrafted mice will enable the testing of novel pharmacological or gene-based therapies for this as yet untreatable disease.
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J. Invest. Dermatol. · Apr 2011
Safety of topical corticosteroids in pregnancy: a population-based cohort study.
Topical corticosteroids may be indicated in pregnant women with skin conditions, but their safety in pregnancy is unclear. We used the UK General Practice Research Database to conduct a population-based cohort study to investigate whether maternal exposure to topical corticosteroids results in adverse pregnancy outcomes. We identified 35,503 pregnant women prescribed topical corticosteroids during the period from 85 days before last menstrual period (LMP) to delivery or fetal death and 48,630 unexposed women. ⋯ The findings were similar when excluding exposure before LMP. In contrast, maternal exposure to potent/very potent topical corticosteroids shortly before and during pregnancy was significantly associated with fetal growth restriction (adjusted relative risk 2.08; 95% confidence interval 1.40-3.10; number needed to harm, 168), which was confirmed by a significant dose-response relationship (P=0.025) and the sensitivity analysis excluding exposure before LMP. The increased risk for fetal growth restriction should be considered when prescribing potent/very potent topical corticosteroids to pregnant women, and appropriate obstetric care should be provided.