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Cutaneous squamous cell carcinoma (SCC) has the clinical and molecular features of a tumor that is likely to respond to systemic immunotherapy, as this tumor harbors a high mutational load and incidence is increased in immunocompromised patients. While nearly all cases are cured with surgery, in the remaining 5%, the tumor becomes metastatic or locally advanced, requiring palliative systemic therapy due to a lack of efficacious approved systemic therapies. In early phase I trials, the human monoclonal antibody to programmed death-1 (PD-1), cemiplimab, elicited a durable response in patients with advanced disease.
The opportunistic skin bacterium Propionibacterium acnes has been linked to acne vulgaris, a condition that affects more than 40 million people in the United States and has mostly inadequate or intolerable therapies. Following prior studies indicating that the P. acnes secretory virulence factor Christie-Atkins-Munch-Peterson (CAMP) factor is the main source of inflammation in acne vulgaris, Wang and colleagues demonstrated that a vaccination strategy targeting CAMP factor reduced the growth of P. acnes, diminished associated erythema, and limited production of proinflammatory cytokines in mice.
Transepidermal water loss (TEWL) is the most widely used objective measurement for assessing the barrier function of skin in healthy individuals but also patients with skin diseases that are associated with skin barrier dysfunction, such as atopic dermatitis. TEWL is the quantity of condensed water that diffuses across a fixed area of stratum corneum to the skin surface per unit time. The water evaporating from the skin is measured using a probe that is placed in contact with the skin surface and contains sensors that detect changes in water vapor density.
Editorial note: Welcome to the Journal of Investigative Dermatology (JID) SnapshotDx Quiz. In this monthly online-only quiz, the first question (“What is your diagnosis?”) relates to the clinical images above, while additional questions concern the findings reported in the JID article by Rahbar et al. (https://doi.org/10.1016/j.jid.2017.11.035).
Editorial note: Welcome to the Journal of Investigative Dermatology (JID) Cells to Surgery Quiz. In this monthly online-only quiz, the first question (“What is your diagnosis?”) relates to the clinical image above, while additional questions concern the findings reported in a JID article by Tucker et al (https://doi.org/10.1016/j.jid.2018.01.021).
Zebrafish represent a powerful model system with which to study human biology and pathology. Recently developed CRISPR/Cas9 technology enables genetic manipulation with precision. Using CRISPR/Cas9 methodology, van Gils et al. generated knockout zebrafish for abcc6a, the orthologue of human ABCC6 that is mutated in pseudoxanthoma elasticum. Although similarities exist between this and other abcc6a zebrafish models, none fully recapitulate phenotypes of human pseudoxanthoma elasticum.
Large and giant congenital melanocytic nevi (CMN) are rare melanocytic lesions mostly caused by post-zygotic NRAS alteration. Molecular characterization is usually focused on NRAS and BRAF genes in a unique biopsy of the CMN. However, large/giant CMN may exhibit phenotypic differences among distinct areas, and patients differ in features such as presence of multiple CMN or Spilus-like lesions. Herein, we have characterized a series of 21 large/giant CMN including Spilus-type nevus patients (9/21 cases, 42.8%).
Late epidermal differentiation is a key step of skin barrier formation; however, the specific genetic factors that distinguish late differentiation from early differentiation remain unknown. Here, we demonstrated that early growth response factor 3 (EGR3) is highly expressed in the stratum granulosum, and that it contributes to late epidermal differentiation. However, its expression is lost under poorly differentiated conditions such as the parakeratosis-lesional skin. EGR3 mediated the regulation of genes located in the epidermal differentiation complex (EDC) through activation of enhancers and induction of enhancer RNAs.
Immune-mediated diseases affect >20% of the population and many autoimmune diseases affect the skin. Drug repurposing (aka repositioning) is a cost-effective approach for revealing drugs that can be used to treat diseases for which they are currently not prescribed. We implemented an efficient bioinformatics approach using “word embedding” to summarize drug information from >20 million articles, and applied machine learning to model the drug-disease relationship. We trained our drug repurposing approach separately on 9 cutaneous diseases (including psoriasis, atopic dermatitis and alopecia areata), as well as 8 other immune-mediated diseases, and obtained a mean AUROC of 0.93 in cross-validation.
Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers.
The vast majority of polymorphisms for human dermatologic diseases fall in non-coding DNA regions, leading to difficulty interpreting their functional significance. Recent work utilizing chromosome conformation capture (3C) technology in combination with chromatin immunoprecipitation (ChIP) has provided a systematic means of linking non-coding variants within active enhancer loci to putative gene targets. Here, we apply H3K27ac HiChIP high-resolution contact maps, generated from primary human T-cell subsets (CD4+ Naïve, TH17, and Treg), to 21 dermatologic conditions associated with single nucleotide polymorphisms (SNPs) from 106 genome-wide association studies (GWAS).