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5-Fluorouracil delivery profiles in the form of chitosan-folate submicron particles through skin and melanoma cells in vitro were examined using microwave as the penetration enhancer. Its in vivo pharmacokinetics profiles were also determined. Chitosan-carboxymethyl-5-fluorouracil-folate conjugate was synthesized and processed into submicron particles by spray drying technique. The size, zeta potential, morphology, drug content, drug release, as well as skin permeation and retention, pharmacokinetics, in vitro SKMEL-28 melanoma cell line cytotoxicity and intracellular trafficking profiles of drug/particles were examined, as a function of skin/melanoma cell treatment by microwave at 2450 MHz for 5 + 5 min.
To identify possible additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed a genome-wide association study (GWAS) of 240 PV cases and 1,031 controls, and we selected the top single nucleotide polymorphisms (SNPs) for replication in independent samples, with 252 cases and 1,852 controls. We identified rs11218708 (P= 3.1 × 10-8, OR=1.54) at 11q24.1 as significantly associated with PV. A fine-mapping analysis of PV risk in the MHC region demonstrated three independent variants predisposed to PV using stepwise analysis: HLA-DRB1*14:04 (P = 2.47 × 10-38;OR = 6.28), rs7454108 at the TAP2 gene (P = 2.78 × 10-12; OR= 3.25), and rs1051336 at the HLA-DRA gene (P= 3.06 × 10-6; OR = 0.33).
Itch is a somatosensory modality that serves to alert the organism to harmful elements removable by scratching, such as parasites and chemical irritants. Recently, ablation or silencing of neuropeptide Y (NPY)-expressing spinal interneurons was reported to selectively enhance mechanical itch whereas chemical itch was unaffected. We have examined the effect of activating the NPY/Y1 receptor system on scratch behavior in mouse. We found that intrathecal administration of the Y1 agonist [Leu31,Pro34]-NPY (LP-NPY) attenuated itch behavior induced by application of 0.07 g von Frey filament in the nape of the neck, compared to saline treatment, indicating that activation of the spinal NPY/Y1 system dampens mechanical itch.
DNA hydroxymethylation at the 5 position of cytosine (5-hmC) is a product of the ten-eleven translocation (TET) family of DNA hydroxylases. Accumulating evidence shows that loss of 5-hmC is critical for various biological and pathological processes. However, its level in cutaneous T cell lymphoma remains largely unknown. Here we report that the loss of 5-hmC is an epigenetic hallmark of cutaneous T cell lymphoma (CTCL), with diagnostic and prognostic implications. Immunohistochemistry staining on 90 mycosis fungoides (MF) cases demonstrated a significant decrease of 5-hmC staining in CD4+ T cells in patch and tumor stages, especially in MF-LCT, compared to benign inflammatory dermatoses.
High-mobility group box 1 (HMGB1) protein is a multifunctional cytokine involved in inflammatory reactions and is known to play a key role in tissue repair and fibrosis. However, the function of HMGB1 in fibrotic skin diseases, such as hypertrophic scar formation, remains unclear. In this study, HMGB1 was detected in the nuclei of epidermal cells in normal skin and had accumulated in the cytoplasm in hypertrophic scars. By establishing a keratinocyte-fibroblast co-culture and conditional medium treatment models, we found that a reduced hydration condition increased the expression and secretion of HMGB1 in keratinocytes, subsequently activating dermal fibroblasts.
Epidermal stem cells residing in the skin play an essential role in epidermal regeneration. When skin is injured, the stem cells are first activated to proliferate, and subsequently the progeny migrate and differentiate to regenerate the epidermis. Here, we demonstrate that the vitamin D receptor (VDR) is essential for these processes to occur. The requirement for VDR on epidermal stem cell function was revealed in conditional VDR knockout (cKO) mice, in which VDR was deleted from stem cells and progeny, and mice were maintained on a low calcium diet.
Virus-encoded miRNAs are emerging as key regulators of persistent infection and host-cell immune evasion. Merkel cell polyomavirus (MCPyV), the predominant aetiological agent of Merkel cell carcinoma (MCC), encodes a single miRNA, MCV-miR-M1, which targets the oncogenic MCPyV large T antigen (LT). MCV-miR-M1 has previously been shown to play an important role in establishment of long-term infection, however, the underlying mechanism is not fully understood. A key unanswered question is whether, in addition to auto-regulating LT, MCV-miR-M1 also targets cellular transcripts to orchestrate an environment conducive for persistent infection.
Formation of scars following wounding or trauma represents a significant healthcare burden costing the economy billions of dollars every year. Activation of focal adhesion kinase (FAK) has been shown to play a pivotal role in transducing mechanical signals to elicit fibrotic responses and scar formation during wound repair. We have previously shown that inhibition of FAK using local injections of a small molecule FAK inhibitor (FAKI) can attenuate scar development in a hypertrophic scar model. Clinical translation of FAKI therapy has been challenging, however, due to the lack of an effective drug delivery system for extensive burn injuries, blast injuries, and large excisional injuries.
Peeling skin syndromes form a large and heterogeneous group of inherited disorders characterized by superficial detachment of the epidermal cornified cell layers, often associated with inflammatory features. Here we report on a consanguineous family featuring non-inflammatory peeling of the skin exacerbated by exposure to heat and mechanical stress. Whole exome sequencing revealed a homozygous nonsense mutation in FLG2, encoding filaggrin 2, which co-segregated with the disease phenotype in the family.
Current cutaneous T cell lymphoma (CTCL) therapies are marked by an abbreviated response, subsequent drug resistance, and poor prognosis for patients with advanced disease. An understanding of molecular regulators involved in CTCL is needed to develop effective targeted therapies. One candidate regulator is p38γ, a mitogen-activated protein kinase crucial for malignant T cell activity and growth. p38γ gene expression is selectively increased in CTCL patient samples as well as cell lines, but not in healthy T cells.
Basal cell carcinoma (BCC) is the most frequent human cancer and is becoming an important health problem in an ageing population. Based on their clinical and histological characteristics, thick BCC are typically divided into low-risk nodular and high-risk infiltrative subtypes, although the underlying mechanisms are poorly understood. We have identified molecular mechanisms that explain the aggressiveness of high-risk infiltrative BCC, with a potential direct clinical impact. In this study, we first show that fibroblasts, TGFβ and fibronectin are found preferentially in infiltrative human BCC.
Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) is a rare, severe mucocutaneous reaction with few large cohorts reported. This multicenter retrospective study included patients with SJS/TEN seen by inpatient consultative dermatologists at 18 academic medical centers in the United States. 377 adult patients with SJS/TEN between 1/1/2000 and 6/1/2015 were entered, including 69.0% from 2010 onward. The most frequent cause of SJS/TEN was medication reaction (89.7%), most often trimethoprim / sulfamethoxazole (27.2%).
BRAF and NRAS mutations arise early in melanoma development but their associations with low-penetrance melanoma susceptibility loci remain unknown. In the Genes, Environment and Melanoma (GEM) Study, 1223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms (SNPs) identified as low-penetrant melanoma risk variants. We used multinomial logistic regression to simultaneously examine each SNP’s relationship to BRAF V600E, BRAF V600K, BRAF other, and NRAS+ relative to BRAF-/NRAS- melanoma adjusted for study features.
In addition to playing a role in adhesion, desmoglein 2 (Dsg2) is an important regulator of growth and survival signaling pathways, cell proliferation, migration and invasion, and oncogenesis. While low-level Dsg2 expression is observed in basal keratinocytes and is downregulated in non-healing venous ulcers, overexpression has been observed in both melanomas and non-melanoma malignancies. Here, we show that transgenic mice overexpressing Dsg2 in basal keratinocytes primed the activation of mitogenic pathways, but did not induce dramatic epidermal changes or susceptibility to chemical-induced tumor development.
Despite critical functions in cutaneous health and disease, it is unclear how resident skin microbial communities are altered by topical antimicrobial interventions commonly used in personal and clinical settings. Here we show that acute exposure to antiseptic treatments elicits rapid but short-term depletion of microbial community diversity and membership. Thirteen subjects were enrolled in a longitudinal treatment study to analyze the effects of topical treatments (ethanol, povidone-iodine, chlorhexidine, water) on the skin microbiome at two skin sites of disparate microenvironment: forearm and back.