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Post-zygotic mutations in GNAQ/GNA11 genes encoding heterotrimeric G protein alpha subunits account for skin mosaic conditions with vascular or pigmentary anomalies (Shirley et al. 2013; Thomas et al. 2016; Couto et al. 2017; Siegel et al. 2018). We sought to delineate the phenotype of 32 patients with skin capillary malformations (CMs) harbouring an activating post-zygotic mutation in GNA11 or GNAQ in affected skin. Nevus flammeus, ipsilateral segmental overgrowth, varicose veins and macrocephaly were associated with GNAQ mutations, whereas cutis marmorata, nevus anemicus, and ipsilateral hypotrophy were associated with GNA11 mutations.
Many psoriasis patients treated with biologics do not achieve total skin clearance. These patients possess “residual plaques” despite ongoing biologic treatment. To elucidate mechanisms of plaque persistence despite overall good drug response, we studied fifty subjects: psoriasis patients with residual plaques treated with one of three different biologics, untreated patients, and healthy controls. Skin biopsies from all subjects were characterized using three methods: mRNA expression, histology, and FACS of skin hematopoietic cells.
G-protein-coupled receptors (GPCRs) and their associated heterotrimeric G proteins impinge on pathways that control epithelial cell self-renewal and differentiation. While it is known that Gαs signaling regulates skin homeostasis in vivo, the role of GPCR-coupled Gαi proteins in the skin is unclear. Here, by using a chemogenetic approach, we demonstrate that GPCR-Gαi activation can regulate keratinocyte proliferation and differentiation and that overactivation of Gαi-signaling in the basal compartment of the mouse skin can lead to epidermal hyperplasia.
We carried out an siRNA screen to identify targets for cutaneous squamous cell carcinoma (cSCC) therapy in the ubiquitin/ubiquitin-like (UBL) system. We provide evidence for selective anti-cSCC activity of knockdown of the E3 ubiquitin ligase MARCH4, the ATPase p97/VCP, the deubiquitinating enzyme USP8, the cullin-RING ligase (CRL) 4 substrate receptor CDT2/DTL and components of the anaphase promoting complex/cyclosome (APC/C). Specifically attenuating CRL4CDT2 by CDT2 knockdown can be more potent in killing cSCC cells than targeting CRLs or CRL4s in general by RBX1 or DDB1 depletion.
The application of machine-learning to longitudinal gene-expression profiles has demonstrated potential to decrease the “assessment gap”, between biochemical determination and clinical manifestation, of a patient’s response to treatment. Although Psoriasis is a proven testing ground for treatment-response prediction using transcriptomic data from clinically accessible skin-biopsies, these biopsies are expensive, invasive and challenging to obtain from certain body areas. Response prediction from blood biochemical measurements could be a cheaper, less invasive predictive platform.
Keratitis-ichthyosis-deafness (KID) syndrome is a severe, untreatable condition characterized by ocular, auditory and cutaneous abnormalities, with major complications of infection and skin cancer. 86% of cases are caused by a heterozygous missense mutation (c.148G>A, p.D50N) in the GJB2 gene, encoding gap junction protein connexin 26 (Cx26), which alters gating properties of Cx26 channels in a dominant manner. We hypothesized that a mutant-allele-specific siRNA (AS-siRNA) could rescue the cellular phenotype in patient keratinocytes.
Papulopustular rosacea (PPR) is a chronic, incurable disease with limited systemic treatment options (Holmes et al., 2018, van Zuuren and Fedorowicz, 2016). Expanding knowledge of the molecular underpinnings provides future directions for investigation to better combat PPR.
Despite anti-TNF therapies’ effectiveness in treating inflammatory diseases such as psoriasis, inflammatory bowel disease and inflammatory arthritis (Toussirot and Aubin, 2016), there is a small cohort that upon treatment, develop psoriasis-like lesions, termed paradoxical, or reactive, psoriasis. Although paradoxical psoriasis can often be treated topically, discontinuation of the anti-TNF therapy is necessary in approximately one third of cases. The incidence of anti-TNF induced paradoxical psoriasis was reported to be 1.7% (Guerra et al., 2016), and the number of cases is likely to rise in parallel with the increasing use of biologics.
The incidence of basal cell carcinoma (BCC) is higher among men than women. Susceptibility loci for BCC have been identified through genome-wide association studies (GWAS), and two previous studies have found polygenic risk scores (PRS) to be significantly associated with risk of BCC. However, to our knowledge, sex-stratified PRS analyses examining the genetic contribution to BCC risk among men and women have not been previously reported. To quantify the contribution of genetic variability on BCC risk by sex, we derived a polygenic risk score and estimated the genetic relative risk distribution for men and women.
The PI3K/AKT/mTOR pathway is hyperactivated in many tumors, as well as in cutaneous T-cell lymphoma (CTCL) which includes mycosis fungoides (MF) and the aggressive variant known as Sezary syndrome (SS). TORC1 signaling is activated in SS cells by cytokines and chemokines, which are overexpressed in SS tissues. Furthermore, the recurrent copy number variation (CNV) of genes belonging to this cascade, such as PTEN, LKB1, and P70S6K, contributes to the hyperactivation of the pathway. The aim of this study was to investigate the therapeutic potential of mTOR inhibitors in CTCL.
TP63 mutations underlie several autosomal dominant ectodermal dysplasias (EDs) characterized by various combinations of limb, ectodermal and orofacial abnormalities (Rinne et al., 2007). We describe a family with prominent alopecia and mild ED features, which co-segregate with a TP63 mutation.
In skin homeostasis, dermal fibroblasts are responsible for coordinating the migration and differentiation of overlying epithelial keratinocytes. As hairy skin heals faster than non-hairy skin, we took bio-inspiration from the follicle and hypothesised that follicular fibroblasts would accelerate skin re-epithelialisation after injury faster than interfollicular fibroblasts. Using both in vitro and ex vivo models of human skin wound closure, we found that hair follicle dermal papilla fibroblasts could accelerate closure of in vitro scratch wounds by 1.8-fold and epithelial growth capacity by 1.5-fold compared to controls (p<0.05).
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by painful deep-seated recurrent nodules and abscesses in axillary, inguinal and perineal areas (Jemec, 2012). It is a complex disease with an aetiology including genetic variations, environmental factors and aberrant innate and adaptive immune functions (Alikhan et al., 2009, Kelly et al., 2014, Moran et al., 2017).
The current issue of the BJD contains a set of scholarly reviews on acne, with an editorial from the guest editor Maurice van Steensel. These can be found at the links below.
Basosquamous carcinomas (BSCs), which comprise 1.2–2.7% of skin carcinomas, are aggressive skin tumors that feature histopathologic characteristics of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BSC origin and genetic etiology remain controversial. Chiang and colleagues reported underlying PTCH and SMO mutations in BSCs, suggesting that Hedgehog signaling drives BSC similar to BCC. Principal component analysis indicated that BSC has greater genetic similarity to BCC than to SCC, supporting the concept that BSCs are derived from BCCs.
Although laboratory mice have enabled important immunological advances, divergent microbiota often contribute to variable results at different institutions and limit translational relevance. Rosshart and colleagues implanted C57BL/6 embryos into wild mice to generate a wild mouse microbial genome on an isogenic laboratory strain background. The microbiome of these “wildlings” resembled wild mice at barrier sites in the gut, skin, and vagina and was stable for generations. These “natural” microbiota were resilient to antibiotic and microbiological challenge.