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Innovative technologies, including novel communication and imaging tools, are affecting dermatology in profound ways. A burning question for the field is whether we will retrospectively react to innovations or proactively leverage them to benefit precision medicine. Early detection of melanoma is a dermatologic area particularly poised to benefit from such innovation. This session of the Montagna Symposium on Biology of Skin focused on provocative, potentially disruptive advances, including crowdsourcing of patient advocacy efforts, rigorous experimental design of public education campaigns, research with mobile phone applications, advanced skin imaging technologies, and the emergence of artificial intelligence as a diagnostic supplement.
To delineate causal pathways for melanoma, it is essential to derive unbiased estimates of risk. Extant knowledge derives largely from case-control studies with potential for bias. In a population-based prospective study (QSkin, n=38,854), we assessed melanoma risks associated with pigmentation characteristics and other phenotypes, and explored additive interactions.We fitted Cox proportional hazards models adjusting for other factors to estimate independent effects of each characteristic on melanoma risk.
Besides skin inflammation, patients with severe psoriasis suffer from an increased risk of cardiovascular mortality. Interleukin-17A (IL-17A) plays a central role in the development of psoriasis and might connect skin and vascular disease. The aim of this study was to clarify whether anti-IL-17A therapy could also ameliorate the vascular dysfunction associated with severe psoriasis.We analyzed three murine models with varying severity of psoriasis-like skin disease concerning their vascular function and inflammation: K14-IL-17Aind/+ mice with keratinocyte-specific IL-17A overexpression and an early onset severe psoriasis-like phenotype, homozygous CD11c-IL-17Aind/ind and heterozygous CD11c-IL-17Aind/+ mice overexpressing IL-17A in CD11c+ cells leading to a delayed onset of moderate psoriasis-like skin disease, and the acute model of imiquimod-induced psoriasis-like skin inflammation.
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).
Neurological patients have an increased risk for bullous pemphigoid (BP) in which autoantibodies target BP180, a cutaneous basement membrane protein also expressed in the brain. Here we show that 53.6% sera of patients with multiple sclerosis (MS) (n=56) had IgG reactivity against full-length BP180 in immunoblotting, while in BP180-NC16A ELISA (n=143), only 7.7% MS samples studied were positive. Epitope mapping with 13 fusion proteins covering the entire BP180 polypeptide revealed that, in MS and Alzheimer’s disease (AD) patients, IgG autoantibodies target regions located in the intracellular and mid-extracellular parts of BP180, but not the well-known BP epitopes located in the NC16A domain and the distal part of extracellular domain.