Journal Of Investigative Dermatology

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994 Risk and association of HLA alleles with methimazole induced cutaneous adverse reactions in Chinese Han population

Wed, 2019-05-01 00:00
Background: Methimazole (MMI), a common prescribed medication for hyperthyroidism caused by Graves’ disease (GD), is a frequent cause of cutaneous adverse drug reactions (cADRs). Currently, no tests are available to predict the risk of the MMI induced cADRs. Identification of the susceptibility locus of MMI induced cADRs is important for clinical management. The aim of this study was to analyze the association of human leukocyte antigen (HLA) alleles with MMI induced cADRs in the Chinese, and evaluate their predictive ability and potential clinical implications.

993 Molecular abnormalities of early-onset pediatric atopic dermatitis are captured by tape strips

Wed, 2019-05-01 00:00
Molecular profiling of adult and recently also pediatric atopic dermatitis (AD) whole skin biopsies has increased our understanding of AD pathomechanisms, facilitating therapeutic development. However, biopsies are not feasible in pediatric studies. We thus explored whether minimally invasive tape-strip biomarkers can be a surrogate to those identified through biopsies. Non-lesional and lesional tape-strips were collected from 21 infants with moderate-to-severe AD (<5yo, <6mo of initiation) and 30 age-matched controls, and compared with biopsies from 19 AD and 17 healthy infants.

992 A new innovative approach combining comparative transcriptomics from three unique psoriasis models to identify predictive PsA biomarkers

Wed, 2019-05-01 00:00
We present here an unconventional bench-to-bedside, mouse-to-patient approach for identifying novel biomarkers of psoriatic arthritis (PsA). We performed RNAseq transcriptomic and bioinformatics analyses on 3 unique chronic skin-specific psoriasis mouse models generated in our lab, including the well-characterized KC-Tie2 and IL-17C+ models which never develop a PsA-like phenotype, and the newly generated KLK6+ model, which spontaneously develops a reproducible joint and bone phenotype resembling PsA, including forelimb dactylitis, periarticular osteopenia, as well as fusion and erosive changes in the sacroiliac joint and pubic symphysis.

991 Deep neural networks empower medical professionals in diagnosing skin cancer and predicting treatment options for general skin disorders

Wed, 2019-05-01 00:00
The aim of this study was to develop automated classification algorithms for diagnosing melanoma and 134 skin diseases using a convolutional neural network. Our models were trained with 220,680 images, comprising 174 disorders and validated with 3,652 images from three datasets. We tested our algorithm in a situation that was representative of a real clinical practice, where dermatologists are required to differentiate between malignancy from numerous types of skin diseases. The AUC for malignancy detection among the 134 disorders was 0.944 ± 0.003, which is on par with dermatology residents.

990 0.005% hypochlorite reduces serine protease in cultured human keratinocytes and alleviates itch of atopic skin

Wed, 2019-05-01 00:00
Proper serine protease (SP) regulation is essential for the homeostasis of epidermal permeability barrier. The imbalance between the activities of SPs and SP inhibitors contributes to disease flares in atopic dermatitis (AD). Bleach bath (0.005% hypochlorite (HOCl) has been included in the armamentarium for treating AD, but the mechanism involved in this treatment strategy remains unclear. This study aimed to determine the direct effect of 0.005% HOCl on cultured human keratinocytes in terms of SP expressions and to document the clinical effects of bleach bath on atopic skin.

989 Biophysical and biomechanical properties of American cutaneous leishmaniasis lesions

Wed, 2019-05-01 00:00
Cutaneous leishmaniasis (CL) is a debilitating and disfiguring parasitic disease that clinically presents as an ulcerative dermal lesion. Multiple therapeutic strategies are possible; however, neither front-line treatment for CL in the Americas is topically delivered despite the fact that the host immune response drives disease severity and the wound healing response controls clinical outcome. Although topical therapeutics exist for Old World CL, efficacy of these formulations has not been established with New World (American) CL.

988 An open-label phase 2 clinical trial of topical remetinostat gel for basal cell carcinoma

Wed, 2019-05-01 00:00
There is a great need for non-surgical therapies for patients with frequent basal cell cancers (BCCs) as the repeated surgeries can lead to severe morbidity and functional impairment. We conducted a systematic computational drug repositioning screen which identified histone deacetylase (HDAC) inhibitors as a potential therapy for BCC. We showed that HDAC inhibitors can suppress Hedgehog signaling and growth of BCC cells and murine BCC allografts, though optimal therapeutic effect was limited by systemic toxicity.

987 Molecular mapping to characterize and differentiate pyoderma gangrenosum from venous ulcers

Wed, 2019-05-01 00:00
Pyoderma gangrenosum (PG) is a rare skin disease characterized by leg ulcers, often misdiagnosed due to lack of a diagnostic gold standard, thus requiring a thorough work up in order to rule out similar conditions. We hypothesized that differences in gene expression in skin of patients with PG will help characterize and differentiate PG from more common, chronic venous insufficiency (CVI) ulcers. Paired skin biopsies were collected from perilesional and unaffected skin in four patients with PG or CVI ulcers.

986 Neutrophil extracellular traps induced by causative drug-specific CD8+ T cells initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis

Wed, 2019-05-01 00:00
Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are caused by type IV allergic drug reaction and thereby believed to be primarily mediated by T cells. Hence, the involvement of innate immune cells in the pathogenesis of SJS/TEN has been not expected. Here we show an involvement of neutrophils in the pathogenesis of SJS/TEN. We analyzed skin specimens and peripheral blood from SJS/TEN patients. Isolated circulating neutrophils from SJS/TEN patients showed neutrophil extracellular trap (NET) formation.

985 Understanding the skin sensitization capacity of oxidized fragrances: study in an epidermal skin environment

Wed, 2019-05-01 00:00
Allergic contact dermatitis is the clinical outcome of skin sensitization, one of the most important occupational and environmental health issues, considered also as the most frequent expression of immunotoxicity in humans. Fragrance compounds, ingredients in up to 60% of cosmetic and household products, remain the most commonly detected allergens in consecutive dermatitis patients in Europe. Among them, allylic hydroperoxides ROOHs derived from autoxidation of natural odorant terpenes such as linalool and limonene.

984 Formation of radicals from endoperoxide ascaridole in a 3D epidermis model and activation of the innate immune response

Wed, 2019-05-01 00:00
Skin contact allergy is a major public health problem and is considered as the most important immunotoxicity reaction in humans. Because of the increase in the prevalence, it is necessary to predict the sensitizing potential of all chemicals before their use in consumer products. Thus, understanding all the mechanisms leading to allergic reactions is essential in order to evaluate the molecules at risk. Chemicals form antigenic triggers inducing sensitization and further contact dermatitis by binding to skin proteins through nucleophilic-electrophilic mechanisms but also by radical-mediated processes.

983 Fatty-acid-binding protein 5 induces Th17 polarization in atopic dermatitis patients with allergic march

Wed, 2019-05-01 00:00
The incidence of patients with atopic dermatitis (AD) and respiratory allergic comorbidities, allergic asthma and/or rhinitis, or the so-called allergic march (AM), has been steadily increasing. However, the mechanism underlying the development of AM in patients with AD is unclear. To identify the mechanism, RNA microarray, flow cytometry, quantitative real-time polymerase chain reaction, and immunofluorescence staining were performed using skin, lung tissues, and T-cells from humans and mice with AD and AM compared to AD without AM.

982 Development and validation of a comprehensive acne grading system linking visual acne characteristics to clinician recommended treatment choices

Wed, 2019-05-01 00:00
Measurement of acne severity is performed routinely by clinicians as part of evaluation and treatment selection, as well as by researchers to assess drug efficacy. While clinicians often rely on qualitative descriptions, researchers can choose from over three dozen extant acne severity scales, many of which include lesion counts but largely avoid evaluation of secondary inflammatory changes. As a result, no universally accepted acne severity scale currently exists. We propose a two-dimensional scale that includes simultaneous evaluation of the current and recent past acne activity, by quantifying lesion counts and presence of secondary inflammatory changes such as erythema, hyperpigmentation, and scarring.

981 Alterations of gene expression in papulopustular rosacea by whole transcriptome analysis

Wed, 2019-05-01 00:00
Rosacea is a common and incurable skin disorder. Identification of key molecular pathways found in rosacea may lead to new and better directions to treat this disease. The main objective was to identify differentially expressed genes in papulopustular rosacea skin in an unbiased fashion by whole transcriptome analysis. After IRB approval and written informed consent, rosacea skin biopsies from 6 individuals with untreated, papulopustular rosacea and their adjacent non-lesional skin were obtained.

980 Single-cell RNA sequencing-guided patient care in refractory drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms

Wed, 2019-05-01 00:00
Drug-induced hypersensitivity syndrome, or drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS), is a potentially fatal multi-organ inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases. Pathomechanisms remain elusive and management of cases refractory to corticosteroids poses significant challenge in clinical practice. We encountered a case of sulfamethoxazole/trimethoprim-triggered DiHS/DRESS in which treatment with prednisone, cyclosporine and mycophenolate mofetil failed, leaving the patient with active disease, renal hypertension and high risk for developing life-threatening infections, and further, with the lack of therapeutic options.

979 Caffeine boosts skin’s mitochondrial activity

Wed, 2019-05-01 00:00
Mitochondrial dysfunction has been associated with accelerated aging. Caffeine, a well-known methylxanthine, is known to alter cellular metabolism and may potentially have a protective effect against mitochondrial impairment. We sought to investigate the effects of caffeine on cellular respiration in keratinocytes and reconstructed skin models. We found that caffeine significantly increases ATP production in primary human keratinocytes following 24 hours of treatment. Moreover, a significant increase in oxygen consumption rate, which provides a measure of oxidative phosphorylation (OXPHOS), was observed in keratinocytes and in reconstructed skin models in the presence of caffeine.

978 CD44 expression on leukocytes is dynamically regulated by ECRG4

Wed, 2019-05-01 00:00
The protease rich microenvironment of the wound bed mediates the activation of latent chemokines responsible for the recruitment of leukocytes involved in the wound repair process. Esophageal Cancer Related Gene 4 (ECRG4) encodes a cell surface protein that can be processed by proteases into multiple active peptides. It is highly expressed on circulating leukocytes in humans and mice and has been described as a novel chemokine with a role in injury, infection and cancer. Our lab previously used ECRG4 knockout (ECRG4 KO) mice to establish that the absence of ECRG4 leads to a delay in the wound healing response, while addition of a thrombin-mediated ECRG4 peptide, CT16, increases the recruitment of CD11b+Ly6G+leukocytes.

977 The wound healing of fractional photothermolysis mimicks scarless healing with minimal myofibroblast activation

Wed, 2019-05-01 00:00
Fractional photothermolysis (FP) has been recently used for improving scars. By creating multiple columns of microthermal injury, FP allows for effective treatment depths without the traditional lengthy downtime and possible complications in traditional fully ablative laser resurfacing. In our animal study using mice as models, we found that, fractional photothermolysis induced epidermal necrosis with dermal collagen denaturation, while there was minimal myofibroblast activation. The skin fastly reepithelialized within 24 hours through migration of surrounding keratinocytes but the restoration of dermal collagen network showed a distinct slow process, contrasting the quick myofibroblast-mediated collagen production in macrothermal damage.

976 Knockout of mTOR/Akt inhibitor REDD1 results in hair cycle-independent dermal adipose expansion by promoting adipocyte differentiation

Wed, 2019-05-01 00:00
Dermal white adipose tissue (dWAT) expansion is associated with important homeostatic and pathologic processes in the skin. One of the key signaling pathways that regulates adipogenesis is the mTOR/Akt axis, however the role of REDD1, a major negative regulator of mTOR/Akt, in adipogenesis is poorly understood. Here we show that loss of REDD1 in mice resulted in ∼ 20% reduction of body mass, significant decrease of total fat, size of gonadal and subcutaneous WAT, and size of interscapular brown adipose.

975 Antifibrogenic activities of novel vitamin D3 analogs are dependent on VDR expression in human fibroblasts

Wed, 2019-05-01 00:00
We have previously discovered new pathways of vitamin D and lumisterol activation by CYP11A1. The vitamin D receptor (VDR) is expressed in dermal fibroblasts and serves as the receptor for active hydroxylated vitamin D analogs. In continuation of our previous studies that showed that non-calcemic 20(OH)D3 has antifibrotic activity in human dermal fibroblasts, we tested the role of VDR in the action of 20(OH)D3, its metabolites including 20,23(OH)2D3, 1,20(OH)2D3, or 1,20,23(OH)3D3 in comparison to canonical 1,25(OH)2D3 using human fibroblasts isolated from the skin of white or black donors.

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