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The incidence and survival of melanoma have increased over the last several decades, with a growing population of patients who develop multiple primary melanomas (MPM). To determine risk factors for developing MPM and compare the survival of patients with MPM to those with single primary melanomas (SPM), a prospective, multidisciplinary database of patients with melanoma at a single tertiary care institution was retrospectively reviewed. From 1985 to 2013, 6963 patients with SPM and 305 patients with MPM were identified.
Human HSP70iQ435A carries a single amino acid modification within the dendritic cell (DC) activating region and tolerizes DCs in vitro. The underlying DNA was used to prevent and treat disease in vitiligo mouse models through reduced dendritic cell activation and diminished skin T cell infiltration, suggesting the same may be useful for patients. Physiologic differences between mouse and human skin then called for studies in large animals with human-like skin. We established the efficiency of DNA jet injection into swine skin before subcloning HSP70iQ435A into clinically suitable vector pUMVC3.
Biologic therapies have shown high efficacy in psoriasis, but individual response varies and is poorly understood. To inform biomarker discovery in the Psoriasis Stratification to Optimise Relevant Therapy (PSORT) study, we evaluated a comprehensive array of omics platforms across three time-points and multiple tissues in a pilot investigation of ten severe psoriasis patient, treated with the tumor necrosis factor (TNF) inhibitor, etanercept. We used RNA-sequencing to analyse mRNA and small-RNA transcriptome in blood, lesional and non-lesional skin and the Somascan platform to investigate the serum proteome.
The major modifiable risk factor in melanomagenesis is UV exposure and mutagenesis of melanocytes. Other UV-induced events that contribute to early tumorigenesis are poorly understood. Herein we show the repeated exposure of human primary melanocytes to UVB results in a sustained senescence response, increases in expression of STAT1, MX1, OAS2 and IRF7 proteins of up to 75-fold, and resistance to subsequent UVB-induced apoptosis. In the setting of UVB-induced DNA damage, we detected time-dependent increases in the release of damage-associated molecular patterns (DAMPs) such as HMGB1.
High-risk skin cancer is a rare, but severe, complication associated with discoid lupus erythematosus (DLE). Chronic scar, inflammation, ultraviolet radiation and immunosuppressive medications are proposed explanations for this heightened skin cancer risk; however, the exact mechanism driving skin carcinogenesis in DLE is unknown. The distinct co-localization of multiple independent skin cancers with areas of active inflammation in two DLE patients followed over eight years strongly suggested that lupus inflammation promotes skin carcinogenesis in DLE.
Pseudoxanthoma elasticum is an ectopic mineralization disease due to biallelic ABCC6 mutations. As no treatment options are currently available a reliable zebrafish model is invaluable for high throughput compound screening. However, data from previously reported knockdown and mutant zebrafish models for abcc6a, the functional orthologue of ABCC6, showed phenotypic discrepancies. To address this, we developed a complete abcc6a knockout model using CRISPR/Cas9 and compared its phenotype to that of a mutant model (Sa963) and a splice junction morpholino model.
Chemokines mold the tumor microenvironment by recruiting distinct immune cell populations, thereby strongly influencing disease progression. Previously, we showed that CXCL5 expression is upregulated in advanced stages of primary melanomas, which correlates with the presence of neutrophils in the tumor.Analysis of neutrophil populations in various tissues revealed a distinct phenotype of tumor associated neutrophils (TANs). TANs expressed PD-L1, CXCR4, CCR5, Adam17, Nos2 and were immunosuppressive in a T cell proliferation assay.
Psoriasis is a chronic inflammatory skin disease characterized by abnormal proliferation of epidermal keratinocytes and infiltration of inflammatory cells. Cornulin (CRNN) is a major component of the cornified cell envelope and implicated in several epithelial malignancies. Here, we show that CRNN expression was increased in the lesioned epidermis from the patients with psoriasis vulgaris and the skin lesions from the imiquimod (IMQ)-treated mice. Expression of CRNN in cultured keratinocytes (HEKa and HaCaT) was also induced by M5, a mixture of 5 pro-inflammatory cytokines including IL-17Α, IL-22, IL-1α, Oncostatin M and TNF-α.
Pachyonychia congenita (PC) is a cutaneous disorder caused by a mutation in the KRT6A, KRT6B, KRT6C, KRT16 or KRT17 genes that encode a subset of epithelial keratins. The main features of the disease are painful palmoplantar keratoderma and variable nail dystrophy. In a recent study, we reported that these keratins are incorporated into mature enamel. Moreover, genetic association study showed that common polymorphisms in KRT6A, KRT6B and KRT6C are associated with increased susceptibility to tooth decay.
Defects in Cockayne syndrome type A (CSA), a gene involved in nucleotide excision repair, cause an autosomal recessive syndrome characterized by growth failure, progressive neurological dysfunction, premature aging, and skin photosensitivity and atrophy. Beyond its role in DNA repair, the CSA protein has additional functions in transcription and oxidative stress response, which are not yet fully elucidated.Here, we investigated the role of CSA protein in primary human keratinocyte senescence. Primary keratinocytes from three CS-A patients displayed premature aging features, namely premature clonal conversion, high steady-state levels of ROS and 8-OH-hydroxyguanine (8-OH-Gua) and senescence-associated secretory phenotype (SASP).
Melanocytes can group together in nevi, commonly thought to form due to intrinsic somatic mutations involving MAPK pathway activation. However, the role of the microenvironment, in particular keratinocytes, in nevogenesis, is rarely studied. Melanocytes proliferate during the hair follicle growth phase and in some basal cell carcinomas, allowing us to construct keratinocyte gene expression clusters correlated with melanocyte activation. We asked whether such correlations are evident in the more subtle context of regulation of melanocyte behaviour in normal skin.