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Multiphoton microscopy (MPM) is a promising non‐invasive imaging tool for discriminating benign nevi from melanoma. In this study, we establish a MPM morphologic catalogue of common nevi, information that will be critical in devising strategies to distinguish them from nevi that are evolving to melanoma that may present with more subtle signs of malignancy. Thirty common melanocytic nevi were imaged in vivo using MPM. Quantitative parameters that can distinguish between different types of nevi were developed and confirmed by examining the histology of eleven of the imaged nevi. MPM features of nevi examined included cytologic morphology of melanocytes in the epidermis and dermis, the size and distribution of nevomelanocytes both within and around nests, the size of rete ridges, and the presence of immune cells in the dermis. Distinguishing features include cytological morphology, the size of nevomelanocytes, the size of nevomelanocyte nests, and the distribution of nevomelanocytes. Notably, these distinguishing characteristics were not easily appreciated in fixed tissues, highlighting essential differences in the morphology of live skin. Taken together, this work provides a morphologic compendium of normal nevi, information that will be critical in future studies directed at identifying melanocytic nevi that are evolving to melanoma. [ABSTRACT FROM AUTHOR]

MITF, a gene that is mutated in familial melanoma and Waardenburg syndrome, encodes multiple isoforms expressed from alternative promoters that share common coding exons but have unique amino termini. It is not completely understood how these isoforms influence pigmentation in different tissues and how the expression of these independent isoforms of MITF is regulated. Here, we show that melanocytes express two isoforms of MITF, MITF‐A and MITF‐M. The expression of MITF‐A is partially regulated by a newly identified retinoid enhancer element located upstream of the MITF‐A promoter. Mitf‐A knockout mice have only subtle changes in melanin accumulation in the hair and reduced Tyr expression in the eye. In contrast, Mitf‐M‐null mice have enlarged kidneys, lack neural crest‐derived melanocytes in the skin, choroid, and iris stroma, yet maintain pigmentation within the retinal pigment epithelium and iris pigment epithelium of the eye. Taken together, these studies identify a critical role for MITF‐M in melanocytes, a minor role for MITF‐A in regulating pigmentation in the hair and Tyr expression in the eye, and a novel role for MITF‐M in size control of the kidney. [ABSTRACT FROM AUTHOR]

Background: Clinical trial data for dupilumab, a monoclonal antibody against the interleukin‐4 receptor (IL‐4Rα), have shown that it is safe and effective for the treatment of moderate to severe atopic dermatitis in patients whose disease is resistant to other therapies. However, little real‐world experience with dupilumab use has been reported thus far. The aim of this retrospective study was to assess overall outcomes in adult patients with atopic dermatitis (AD) treated with dupilumab. Methods: A retrospective review of electronic medical records was conducted for patients treated with dupilumab in the Department of Dermatology at the University of California, Irvine. Results: We analyzed the medical records of 77 AD patients who received dupilumab according to standard dosing and had at least one documented follow‐up visit. In 66 patients (86%), dupilumab improved clinical disease severity, with 23 patients (30%) experiencing complete clearance on dupilumab. Dupilumab was generally well‐tolerated and caused no serious adverse events. The most common side effects included dry eyes, conjunctivitis, and keratitis. The most common reason for discontinuation of treatment was lack of substantial clinical improvement or progression of disease severity, followed by ophthalmologic side effects. Conclusions: Overall, dupilumab was well‐tolerated and resulted in clinical improvement in our patient population. These results provide additional important information on the safety and utility of dupilumab treatment for moderate to severe atopic dermatitis in the real‐world clinical setting. [ABSTRACT FROM AUTHOR]

Rho family GTPases regulate diverse processes in human melanoma ranging from tumor formation to metastasis and chemoresistance. In this study, a combination of in vitro and in vivo approaches was utilized to determine whether RHOJ, a CDC42 homologue that regulates melanoma chemoresistance, also controls melanoma migration. Depletion or overexpression of RHOJ altered cellular morphology, implicating a role for RHOJ in modulating actin cytoskeletal dynamics. RHOJ depletion inhibited melanoma cell migration and invasion in vitro and melanoma tumor growth and lymphatic spread in mice. Molecular studies revealed that RHOJ alters actin cytoskeletal dynamics by inducing the phosphorylation of LIMK, cofilin, and p41- ARC ( ARP2/3 complex subunit) in a PAK1-dependent manner in vitro and in tumor xenografts. Taken together, these observations identify RHOJ as a melanoma linchpin determinant that regulates both actin cytoskeletal dynamics and chemoresistance by activating PAK1. [ABSTRACT FROM AUTHOR]

Aldehyde dehydrogenase 1 A1 ( ALDH1 A1), an enzyme that catalyses the conversion of lipid aldehydes to lipid carboxylic acids, plays pleiotropic roles in UV-radiation resistance, melanogenesis and stem cell maintenance. In this study, a combination of RNAi and pharmacologic approaches were used to determine which ALDH1 A1 substrates and products regulate melanogenesis. Initial studies revealed that neither the UV-induced lipid aldehyde 4-hydroxy-2-nonenal nor the ALDH1 A1 product all- trans retinoic acid appreciably induced melanogenesis. In contrast, both the ALDH1 A1 substrate 9- cis retinal and its corresponding product 9- cis retinoic acid potently induced the accumulation of MITF m RNA, Tyrosinase m RNA and melanin. ALDH1 A1 depletion inhibited the ability of 9- cis retinal but not 9- cis retinoic acid to stimulate melanogenesis, indicating that ALDH1 A1 regulates melanogenesis by catalysing the conversion of 9- cis retinal to 9- cis retinoic acid. The addition of potent ALDH1 A inhibitors (cyanamide or Angeli's salt) suppressed Tyrosinase and MITF m RNA accumulation in vitro and also melanin accumulation in skin equivalents, suggesting that 9- cis retinoids regulate melanogenesis in the intact epidermis. Taken together, these studies not only identify cyanamide as a potential novel treatment for hyperpigmentary disorders, but also identify 9- cis retinoic acid as a pigment stimulatory agent that may have clinical utility in the treatment of hypopigmentary disorders, such as vitiligo. [ABSTRACT FROM AUTHOR]

Summary Melanin pigments protect the skin and eyes from toxic insults and are critical for the normal functioning of multiple organ systems including the skin, eyes, and brain. Biochemical and genetic studies in both human and mice have revealed the molecular machinery controlling the transcription of genes encoding enzymes that produce melanin and the trafficking of these enzymes to the melanosome, a lysosome-related organelle dedicated to melanin synthesis. Recent functional genomic studies have identified a role for genes previously known to regulate autophagy, a cellular process that facilitates nutrient recycling during starvation, in the biogenesis of melanosomes in vitro and in vivo. In this review, we describe the pleiotropic roles of autophagy regulators in multiple vesicle trafficking processes, define a specific role for autophagy regulators in melanosome biogenesis, and shed light on how autophagy and autophagy regulators may play different roles in both the biogenesis of melanosomes and melanosome destruction. [ABSTRACT FROM AUTHOR]