Journal Of Investigative Dermatology

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Major role for TRPV1 and InsP3R in PAR-2-elicited inflammatory mediator production in differentiated human keratinocytes

Sat, 2018-02-17 00:00
Proteinase-activated receptor-2 (PAR-2) activation in basal keratinocytes stimulates inflammation via the Ca2+-dependent production of mediators such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α and thymic stromal lymphopoietin (TSLP). In this study, we investigated PAR-2 calcium signaling and the consequent production of inflammatory mediators in differentiated human primary keratinocytes (DhPKs). Stimulation with the PAR-2 activating peptide SLIGKV promoted Ca2+ store depletion in both undifferentiated human primary keratinocytes (UhPKs) and DhPKs.

The function of HLA-B*13:01 involved in the pathomechanism of dapsone-induced severe cutaneous adverse reactions

Sat, 2018-02-17 00:00
Dapsone-induced hypersensitivity reactions may cause severe cutaneous adverse reactions (SCAR), such as drug reaction with eosinophilia and systemic symptoms (DRESS). It has been reported that HLA-B*13:01 is strongly associated with dapsone-induced hypersensitivity reactions among leprosy patients. However, the phenotype specificity and detailed immune mechanism of HLA-B*13:01 remains unclear. We investigated the genetic predisposition, HLA-B*13:01 function, and cytotoxic T cells (CTLs) involved in pathogenesis of dapsone-SCAR.

Bioactive Lipid Mediators Profiles In Human Psoriasis Skin And Blood

Thu, 2018-02-15 00:00
Psoriasis (PSO) is a chronic immune-mediated disease that represents a unique model for investigating inflammation at local and systemic levels. Bioactive lipid mediators (LM) are potent compounds reported to play a role in the development and resolution of inflammation. Currently, it is not known to what extent these LM are involved in PSO pathophysiology and related metabolic dysfunction. Here we use targeted and untargeted liquid chromatography-tandem mass spectrometry (LC-MS-MS) approaches to quantify LM in skin and peripheral blood from PSO and compared them to those of healthy subjects.

An Open-Label Pilot Study to Evaluate the Efficacy of Tofacitinib in Moderate to Severe Patch Type Alopecia Areata, Totalis and Universalis

Tue, 2018-02-13 00:00
Alopecia areata (AA) is a common autoimmune disease, with a lifetime risk of ∼2%. In AA, the immune systems targets the hair follicle, resulting in clinical hair loss. AA prognosis is unpredictable, and currently there is no definitive treatment. Our previous whole genome expression studies identified active immune circuits in AA lesions, including common γ-chain cytokine and IFN pathways. Since these pathways are mediated through JAK kinases, we prioritized clinical exploration of small molecule JAK inhibitors.

Quantifying the polygenic contribution to cutaneous squamous cell carcinoma risk

Tue, 2018-02-13 00:00
Genetic factors play an important role in cutaneous squamous cell carcinoma (cSCC) risk. Genome-wide association studies have identified 21 single nucleotide polymorphisms (SNPs) associated with cSCC risk. Yet no studies have attempted to quantify the contribution of heritability to cSCC risk by calculating the population attributable risk (PAR) using a combination of all discovered genetic variants. Using an additive multi-locus linear logistic model, we determined the cumulative association of these 21 genetic regions to cSCC PAR.

miRs-103/107 regulate autophagy in the epidermis

Tue, 2018-02-13 00:00
We have shown that microRNAs-103 and -107(miRs-103/107) positively regulate end-stage autophagy via ensuring dynamin activity in cultured keratinocytes. Most work in end-stage autophagy has been conducted using in vitro model systems. In vivo regulation of end-stage autophagy in epidermis remains unknown. Here, we used antagomirs to subcutaneously knock-down miR-107 in the skin; conversely, we delivered miR-107 mimic subcutaneously via in vivo transfection to increase this miRNA. We found that antagomir-107 treatment in epidermis: (i) depleted endogenous miR-107; (ii) increased GFP-LC3 puncta in epidermal basal layers of GFP-LC3 transgenic mice, indicative of an accumulation of autophagosomes; (iii) inhibited LC3 turnover and increased p62, suggesting an inhibition of autophagy flux; and (iv) increased phosphorylated dynamin (p-dynamin, an inactive form), a key enzyme in end-stage autophagy.

Dissecting Wnt signaling for melanocyte regulation during wound healing

Thu, 2018-02-08 00:00
Abnormal pigmentation is commonly seen in the wound scar. Despite advancements in the research of wound healing, little is known about the repopulation of melanocytes in the healed skin. Previous studies have demonstrated the capacity of melanocyte stem cells (McSCs) in the hair follicle to contribute skin epidermal melanocytes following injury in mice and humans. Here, we focused on the Wnt pathway, known to be a vital regulator of McSCs in efforts to better understand the regulation of follicle-derived epidermal melanocytes during wound healing.

Uncommon filaggrin variants are associated with persistent atopic dermatitis in African Americans

Thu, 2018-02-08 00:00
Atopic dermatitis (AD) is a common illness that has been associated with filaggrin gene (FLG) loss of function (LoF) variation. In African-Americans, a group that commonly has AD and has not been well studied, FLG LoF variation is rarely found. The objective was to use massively parallel sequencing to evaluate FLG LoF variation in children of African ancestry to evaluate the association between FLG LoF variation and AD and AD persistence. We studied 262 African American children with AD. Nine unique FLG exon 3 LoF variants were identified for an overall minor variant frequency (MVF) of 6.30% (95% CI: 4.37, 8.73).

Classification of the clinical images for benign and malignant cutaneous tumors using a deep learning algorithm

Thu, 2018-02-08 00:00
We tested the use of a deep learning algorithm to classify the clinical images of 12 skin diseases—basal cell carcinoma, squamous cell carcinoma, intraepithelial carcinoma, actinic keratosis, seborrheic keratosis, malignant melanoma, melanocytic nevus, lentigo, pyogenic granuloma, hemangioma, dermatofibroma, and wart. The convolutional neural network (Microsoft ResNet-152 model) was fine-tuned with images from the training portion of the Asan dataset, MED-NODE dataset, and atlas site images (20,826 images in total).

Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different from Mushroom Tyrosinase

Wed, 2018-02-07 00:00
Tyrosinase is the rate-limiting enzyme of melanin production and, accordingly, is the most prominent target to inhibit hyperpigmentation. Numerous tyrosinase inhibitors have been identified, but most of those lack clinical efficacy because they were identified using mushroom tyrosinase as the target. Therefore, we used recombinant human tyrosinase to screen a library of 50,000 compounds and compared the active screening hits with well-known whitening ingredients. Hydroquinone and its derivative arbutin only weakly inhibited human tyrosinase with a half-maximal inhibitory concentration (IC50) in the millimolar range, while kojic acid showed a weak efficacy (IC50 > 400 μM).

Melatonin: A Cutaneous Perspective on its Production, Metabolism, and Functions

Wed, 2018-02-07 00:00
Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. Although melatonin is best known to regulate circadian rhythmicity and lower vertebrate skin pigmentation, the full spectrum of functional activities of this free radical-scavenging molecule, which also induces/promotes complex antioxidative and DNA repair systems, includes immunomodulatory, thermoregulatory, and antitumor properties. Because this plethora of functional melatonin properties still awaits to be fully appreciated by dermatologists, the current review synthesizes the main features that render melatonin a promising candidate for the management of several dermatoses associated with substantial oxidative damage.

Hidradenitis suppurativa is associated with polycystic ovary syndrome: a population-based analysis in the United States

Sun, 2018-02-04 00:00
Polycystic ovary syndrome (PCOS) has been linked to hidradenitis suppurativa (HS). However, evidence establishing a relationship between the two conditions is limited. We sought to determine prevalence of PCOS among HS patients and the strength of the association. We performed a cross-sectional analysis involving 22,990 HS patients using clinical data from a multi-health system analytics platform (Explorys Inc., 2017) comprising over 50 million unique patients across all census regions of the United States.

Propionibacterium acnes-derived extracellular vesicles promote acne-like phenotypes in human epidermis

Sun, 2018-02-04 00:00
Acne vulgaris is an inflammatory disease occurring in the pilosebaceous unit and is the most common skin condition in young people. A gram-positive bacterium, Propionibacterium acnes (P. acnes), has been suspected to contribute to the development of acne. Here, we report that P. acnes constitutively releases extracellular vesicles (EVs) exhibiting typical EV morphology and size. Moreover, the P. acnes-derived EVs (PEVs) can induce acne-like phenotypes in human epidermal keratinocytes and a reconstituted human skin model.

A rationally designed multi-functional antibiotic for the treatment of drug-resistant acne

Sun, 2018-02-04 00:00
Acne is a multifactorial skin disease, underpinned by colonization of Propionibacterium acnes and inflammation. The emergence of resistant Propionibacterium acnes strains has affected the current acne treatment algorithm. This setback served as an impetus for rationally designing a library of next-generation antibiotics that exhibit a bactericidal effect on resistant Propionibacterium acnes as well as exert an immunomodulatory function to reduce inflammation. In silico screening revealed that one of the molecules, VCD-004, exhibits improved mode of binding to bacterial DNA gyrase.

Visualization of T cell-regulated monocyte clusters mediating keratinocyte death in acquired cutaneous immunity

Sat, 2018-02-03 00:00
It remains unclear how monocytes are mobilized to amplify inflammatory reactions in T cell-mediated adaptive immunity. Here, we investigate dynamic cellular events in the cascade of inflammatory responses through intravital imaging of a multicolor-labeled murine contact hypersensitivity (CHS) model. We found that monocytes formed clusters around hair follicles in the CHS model. In this process, effector T cells encountered dendritic cells under regions of monocyte clusters and secreted IFN-γ, which mobilizes CCR2-dependent monocyte interstitial migration and CXCR2-dependent monocyte cluster formation.

EB2017 - Progress in Epidermolysis Bullosa Research Towards Treatment and Cure

Sat, 2018-02-03 00:00
Epidermolysis bullosa (EB), a group of heritable blistering disorders, demonstrates extensive phenotypic variability due to mutations in as many as 20 distinct genes. There is no cure for this devastating group of disorders, however, a number of preclinical developments show promise, and some approaches have already reached the stage of early clinical trials. Dystrophic Epidermolysis Bullosa Research Association (DEBRA) International, a global coalition of national patient organizations advocating on behalf of the patients and families with EB, supports research and organizes periodic scientific and clinical meetings on this disease.

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