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Calpains, intracellular proteases specifically inhibited by calpastatin, play a major role in neo-angiogenesis involved in tumor invasiveness and metastasis. They are partly exteriorized via the ABCA1 transporter, but the importance of this process in tumor growth is still unknown. The aim of our study was to investigate the role of extracellular calpains in a model of melanoma, by blocking their extracellular activity or their exteriorization. In the first approach, a B16F10 model of melanoma was developed in transgenic mice expressing high extracellular levels of calpastatin.
Atopic dermatitis (AD) is an inflammatory skin condition characterized by scaling, lichenification, excoriations and pruritus. Vascular endothelial growth factor (VEGF) has previously been underscored as a contributor to skin inflammation in AD (Varricchi et al., 2015). This is supported by the evidence that: i) VEGF causes hyperpermeability of vessels (Ferrara et al., 2003), leading to edema and spongiosis, ii) VEGF induces chemotaxis of myeloid cells expressing VEGF receptor 1 (e.g. macrophages, mast cells) (Sawano et al., 2001), and iii) VEGF activates endothelial cells, leading to increased expression of adhesion molecules in these cells (Kim et al., 2001), thereby promoting tissue infiltration of leukocytes.
The formation and maintenance of the epidermis depend on epidermal stem cell differentiation and must be tightly regulated. Epigenetic mechanisms such as DNA methylation allow the precise gene expression cascade needed during cellular differentiation. However, these mechanisms become deregulated during aging and tumorigenesis, where cellular function and identity become compromised. Here we provide a review of this rapidly developing field. We discuss recent discoveries related to epidermal homeostasis, aging, and cancer, including the functional role of DNA methyltransferases, the methylation clock, and the determination of tumor cells-of-origin.
Total body nevus counts (TNC) is a highly heritable trait, with twin studies estimating that 60 to 70% of variance is explained by genetic factors (Lee et al., 2016). Polymorphisms within IRF4, MTAP, PLA2G6 and MITF have been shown to strongly influence TNC, and many other nevus-associated genes have been recognized (Duffy et al., 2018). Dermoscopy has allowed the recognition of distinct morphological classes of nevi, including reticular, globular and homogenous/complex, that tightly correlate with histopathological subtypes (Tan et al., 2019).
Both Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis (SSc) are autoimmune diseases sharing similar genetic backgrounds. Genome-wide association studies (GWASs) have constantly disclosed numerous genetic variants conferring to both disease risks at 7q32.1, but the functional mechanisms underlying them are still largely unknown. Through a series of bioinformatics and functional analyses, we prioritized a potential independent functional SNP (rs13239597) within TNPO3 promoter region, residing in a putative enhancer element and validated that IRF5 is the distal target gene (∼118kb) of rs13239597, which is a key regulator involved in pathogenic autoantibody dysregulation increasing risk of both SLE and SSc.
Activation of Th17 signaling plays a critical role in psoriasis pathogenesis, and systemically-administered IL-17 inhibitors are highly effective therapy for moderate-to-severe disease. We generated topically-delivered gene-regulating nanoconstructs, comprised of spherically-arrayed antisense DNA (liposomal spherical nucleic acids/L-SNAs), which are able to penetrate human skin to knock down cutaneous gene targets. Topically-applied L-SNAs targeting the gene encoding the mouse IL-17A receptor (Il17ra) reversed the development of psoriasis clinically, histologically, and transcriptionally in imiquimod-treated psoriasis-like mouse skin.
Prurigo nodularis (PN) is a chronic dermatosis characterized by intensely pruritic, symmetrically-distributed hyperkeratotic nodules. Although the disease etiology is unknown, PN often develops in the context of systemic, dermatologic, and neuropsychiatric conditions. (Iking et al, 2013; Winhoven and Gawkrodger, 2007; Boozalis et al, 2018). Despite this, limited data is available on the epidemiology of PN and burden of associated diseases. (Iking et al, 2013; Boozalis et al, 2018). Here we estimate the prevalence of PN and the burden of associated conditions in a real-world, US population using a national claims database.
SHARPIN, as a tumor-associated gene, is involved in the metastatic process of many kinds of tumors. Herein, we studied the function of SHARPIN in melanoma metastasis and the relevant molecular mechanisms. We found that SHARPIN expression was increased in melanoma tissues and activated the process of proliferation, migration and invasion in vitro and in vivo, resulting in a poor prognosis of the disease. Functional analysis demonstrated that SHARPIN promoted melanoma migration and invasion by regulating Rap1 and its downstream pathways, including p38 and JNK/c-Jun.
Reactivation of functionally-impaired anticancer T cells by programmed cell death protein 1 (PD-1) and programmed cell death receptor ligand-1 (PD-L1)–blocking antibodies shows prominent therapeutic benefit in advanced melanoma and patients with non–small cell lung cancer. However, current PD-L1–blocking antibodies lack intrinsic tumor selectivity. Therefore, efficacy may be reduced resulting from on-target and off-tumor binding to PD-L1–expressing normal cells. This may lead to indiscriminate activation of antigen-experienced T cells, including those implicated in autoimmune-related adverse events.
The evolution of a child’s skin microbiome is associated with the development of the immune system and skin environment. As only few studies have analyzed the microbiota in young children, we investigated changes in the skin microbiota of children (158 subjects; ≤10 years old) and compared the microbiota structures between children and their mothers using 16S rRNA gene amplicon sequencing. Sample location and age were the primary factors determining a child’s skin bacterial composition, which differed significantly among the face, ventral forearm, and calf.
Keratinocytes express many pattern recognition receptors (PRRs) that enhance the skin’s adaptive immune response to epicutaneous antigens. We have shown that these PRRs are expressed below tight junctions (TJ), strongly implicating TJ disruption as a critical step in antigen responsiveness. To disrupt TJ we designed peptides inspired by the first extracellular loop of the TJ transmembrane protein, claudin-1. These peptides transiently disrupted TJ in the human lung epithelial cell line 16HBE, and delayed TJ formation in primary human keratinocytes.
In this issue of JID, Shukla et al show that the Society of Investigative Dermatology has improved gender diversity of its awards, lectureships, and its leadership. Additional initiatives that promote participation in the Society based on education, gender, race, sexual orientation, and other types of diversity can improve the quality of investigative dermatology and clinical progress for skin diseases.
van Zuuren and colleagues updated their systematic review of interventions for rosacea, using the phenotype approach recommended by the global ROSacea COnsensus (ROSCO) panel. For background erythema, they found high-quality evidence for topical brimonidine and moderate-quality evidence for oxymetazoline. For papules and pustules, high-quality evidence exists for topical azelaic acid and topical ivermectin, with moderate-to-high-quality evidence for oral doxycycline and oral isotretinoin, and moderate evidence for topical metronidazole and topical minocycline.
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 shown, while additional questions concern the findings reported in the JID article by Bhat et al. (2019) (https://doi.org/10.1016/j.jid.2018.10.024).
Two papers in this issue highlight gene therapy for skin fragility diseases. March and colleagues employed the transcription activator-like effector nuclease to disrupt dominant-negative epidermolytic ichthyosis–causing mutations in keratin 10 (KRT10) alleles in keratinocytes, showing abrogation of disease phenotypes in a murine model. Takashima and colleagues employed a different nuclease system, CRISPR/Cas9, to co-opt non-homologous end-joining to correct a common frameshift mutation in one of the alleles of the collagen type VII (COL7A1) gene, restoring COL7A1 expression in recessive dystrophic epidermolysis bullosa fibroblast cell lines and COL7A1 function and distribution in vivo.
Using shotgun metagenomic sequencing in a longitudinal prospective study, Kalan and colleagues examined the strain-level diversity of the microbiota in neuropathic diabetic foot ulcers, which are chronic wounds that cause considerable morbidity and mortality in the increasing population of patients with diabetes. These investigators identified Staphylococcus aureus strains that were present in a majority of the wounds, as well as those that were exclusively associated with unhealed wounds. Strains associated with poor wound healing harbored antibiotic resistance genes and genes encoding enterotoxins.
Editorial note: Welcome to the Journal of Investigative Dermatology (JID) Snapshot Dx Quiz. In this monthly online-only quiz, the first question (“What is your diagnosis?”) relates to the clinical image shown, while additional questions concern the findings reported in the JID article by Hochfeld et al. (2019) (https://doi.org/10.1016/j.jid.2018.06.182).