Dermoscopy aids in melanoma detection; however, agreement on dermoscopic features, including those of high clinical relevance, remains poor. Herein we attempted to evaluate agreement among experts on 'exemplar images' not only for the presence of melanocytic-specific features but also for spatial localization. This was a cross-sectional, multicenter, observational study. Dermoscopy images exhibiting at least one of 31 melanocytic-specific features were submitted by 25 world experts as 'exemplars'. Using a web-based platform that allows for image mark-up of specific contrast-defined regions (superpixels), 20 expert readers annotated 248 dermoscopic images in collections of 62 images. Each collection was reviewed by five independent readers. A total of 4,507 feature observations were performed. Good-to-excellent agreement was found for 14 of 31 features (45.2%), with 8 achieving excellent agreement (Gwet's AC >0.75) and 7 of them being melanoma-specific features. These features were: 'Peppering /Granularity' (0.91); 'Shiny White Streaks' (0.89); 'Typical Pigment network' (0.83); 'Blotch Irregular' (0.82); 'Negative Network' (0.81); 'Irregular Globules' (0.78); 'Dotted Vessels' (0.77) and 'Blue Whitish Veil' (0.76). By utilizing an exemplar dataset, good-to-excellent agreement was found for 14 features that have previously been shown useful in discriminating nevi from melanoma. All images are public (www.isic-archive.com) and can be used for education, scientific communication and machine learning experiments.

Vitiligo is a common skin depigmentation disorder characterized by the patchy loss of skin color. Nowadays, it's recognized as being correlated with multiple genetic factors as well as the psychological conditions of individuals. Long non-coding RNAs (lncRNAs) have been reported to underlie the pathogenesis of vitiligo; however, the role of lncRNAs in the stress-related depigmentation process remains largely unknown. In this study, the inhibition of melanocyte function was observed in C57BL/6J mice modeled by chronic restraint stress. Furthermore, downregulation of the expression of the lncRNA Mir17hg was identified by RNA sequencing. The regulatory role of Mir17hg in melanogenesis was also investigated in melanocytes and zebrafish embryos by overexpression or knockdown. Finally, transforming growth factor β receptor II (TGFβR2) was shown to be a downstream target in Mir17hg-mediated melanogenesis regulation, in which the classical TGFβ/SMAD signaling cascade and the PI3K/AKT/mTOR signaling cascade play important roles. In conclusion, our results revealed an important regulatory role of Mir17hg in melanogenesis via inhibition of TGFβR2, which can provide a potential therapeutic target for treating skin depigmentation disorders.

Secondary lymphedema often develops after lymph node dissection or radiation therapy for cancer treatment, resulting in marked skin fibrosis and increased stiffness due to insufficiency of the lymphatic system caused by abnormal structure and compromised function. However, little is known about the associated changes of the dermal lymphatic vessels. Here, using the lower limb skin of secondary lymphedema patients, classified as types 1-4 by lymphoscintigraphy, we first confirmed the presence of epidermal thickening and collagen accumulation in the dermis, closely associated with the progression of lymphedema. Three-dimensional characterization of lymphatic capillaries in skin revealed prominent lymphangiogenesis in types 1 and 2 lymphedema. In contrast, increased recruitment of smooth muscle cells accompanied by development of the basement membrane in lymphatic capillaries was observed in types 3 and 4 lymphedema. Remarkably, the junctions of dermal lymphatic capillaries were dramatically remodeled from a discontinuous button-like structure to a continuous zipper-like structure. This finding is consistent with previous findings in an infection-induced mouse model. Such junction tightening (zippering) could reduce fluid transport and cutaneous viral sequestration during the progression of lymphedema, and might explain the aggravation of secondary lymphedema. These findings may be helpful in developing stage-dependent treatment of lymphedema patients.

A potential role for fibroblast growth factor receptor-2 (FGFR2) in cutaneous squamous cell carcinoma (cSCC) has been reported. To demonstrate the specific role of FGFR2 in UVB-induced skin carcinogenesis and development of cSCC, we generated a keratinocyte specific, tamoxifen inducible mouse model of FGFR2 deficiency. In this mouse model, topical application of 4-hydroxy-tamoxifen led to the induction of Cre recombinase to delete FGFR2 in epidermal keratinocytes of both male and female transgenic mice. Analysis of epidermal protein lysates isolated from FGFR2 deficient mice exposed to UVB showed significant reductions of phospho-FGFR (pFGFR; Y653/654) and p-FRS2α as well as downstream effectors of mTORC1 signaling. Phosphorylation of STAT1 and STAT3 was significantly reduced as well as levels of IRF-1, DUSP6, EGR1 and PD-L1 compared to the control groups. Keratinocyte specific ablation of FGFR2 also significantly inhibited epidermal hyperproliferation, hyperplasia and inflammation following exposure to UVB. Finally, keratinocyte specific deletion of FGFR2 significantly inhibited UVB-induced cSCC formation. Collectively, the current data demonstrate an important role of FGFR2 in UVB-induced oncogenic signaling as well a development of cSCC. In addition, the current preclinical findings suggest that inhibition of FGFR2 signaling may provide a previously unreported strategy to prevent and/or treat UVB-induced cSCC.

The epidermis is a constantly renewing stratified epithelial tissue that provides essential protective barrier functions. The major barrier is located at the outermost layers of the epidermis, formed by terminally differentiated keratinocytes reinforced by proteins of their cornified envelope (CE) and sequestered intercellular lipids. Disruptions to epidermal differentiation characterize various skin disorders. ZNF750 is an epithelial transcription factor essential for in vitro keratinocyte differentiation, whose truncating mutation in humans causes autosomal dominant psoriasis-like skin disease. Here, we utilized an epidermal-specific Znf750 conditional knockout mouse model to uncover the role ZNF750 plays in epidermal development. We show that deletion of Znf750 in the developing skin does not block epidermal differentiation completely, suggesting in vivo compensatory feedback mechanisms, although it does result in impaired barrier function and perinatal lethality. Molecular dissection revealed ultrastructural defects in the differentiated layers of the epidermis, accompanied by alterations in the expression of ZNF750-dependent genes encoding key CE precursor proteins and lipid processing enzymes, including gene subsets known to be mutated in human skin diseases involving impaired barrier function. Together, our findings provide molecular insights into the pathogenesis of human skin disease by linking ZNF750 to a subset of epidermal differentiation genes involved in barrier formation pathways.