Journal Of Investigative Dermatology

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Research Techniques Made Simple:Teledermatology in Clinical Trials

Thu, 2019-08-01 00:00
Telemedicine is well established as a means of providing high-quality healthcare at a distance, particularly to patients in underserved populations. Technologies in teledermatology can be used to complement traditional methodologies of clinical trials, expanding accessibility of trials to people typically unable to participate in research. Tools of communication technology may enhance many aspects of clinical trials in dermatology, from recruitment and retention of participants to collection of real-time data.

Gene Therapy for Skin Fragility Diseases: The New Generation

Thu, 2019-08-01 00:00
Ex vivo gene therapy is a promising approach to treat devastating skin fragility diseases. March et al. and Takashima et al. report that programmable nucleases—TALENs and CRISPR/Cas9—can safely and efficiently correct genetic defects in cultured adult skin cells, paving the way for broader clinical applications of gene therapies in dermatology.

MicroRNA-34 family enhances wound inflammation by targeting LGR4

Wed, 2019-07-31 00:00
Venous ulcers (VU) are the most common type of human chronic non-healing wounds and stalled in a constant and excessive inflammatory state. The molecular mechanisms underlying the chronic wound inflammation remains elusive. Moreover, little is known about the role of regulatory RNAs, such as microRNAs (miRNAs), in the pathogenesis of VU. We found that both miR-34a and miR-34c were upregulated in the wound-edge epidermal keratinocytes of VU compared with normal wounds or the skin. In keratinocytes, miR-34a and miR-34c promoted inflammatory chemokine and cytokine production.

Frequent and persistent PLCG1 mutations in Sézary cells directly enhance PLCγ1 activity and stimulate NFκB, AP-1 and NFAT signaling. Short title: Gain-of-function PLCG1 mutations in Sézary Syndrome

Wed, 2019-07-31 00:00
Phospholipase C Gamma 1 (PLCG1) is frequently mutated in primary cutaneous T-cell lymphoma (CTCL). This study functionally interrogated 9 PLCG1 mutations (p.R48W, p.S312L, p.D342N, p.S345F, p.S520F, p.R1158H, p.E1163K, p.D1165H and the in-frame indel p.VYEEDM1161V) identified in Sézary Syndrome, the leukemic variant of CTCL. The mutations were demonstrated in diagnostic samples and persisted in multiple tumor compartments over time, except in patients who achieved a complete clinical remission. In basal conditions, the majority of the mutations confer PLCγ1 gain-of-function activity through increased inositol phosphate production and downstream activation of NFκB, AP-1 and NFAT transcriptional activity.

Exome-wide rare loss-of-function variant enrichment study of 21,347 Han Chinese individuals identifies four susceptibility genes for psoriasis

Wed, 2019-07-31 00:00
Most psoriasis-related genes or loci identified by genome-wide association studies (GWASs) represent common clusters and are located in noncoding regions of the human genome, providing only limited evidence for the roles of rare coding variants in psoriasis. Two exome-wide case-control genotyping data sets (11,245 cases and 11,177 controls) were obtained from our previous study. Quality controls were established for each data set, and the markers remaining in each set were annotated using ANNOVAR.

First glimpse of epigenetic effects on pemphigus foliaceus

Wed, 2019-07-31 00:00
Pemphigus foliaceus (PF) is an autoimmune disease, sporadic across the globe, but endemic in Brazil. A significant proportion of PF autoantibodies target desmosomal glycoproteins (principally desmoglein-1), associated with painful blisters in the granular skin layer (Spindler et al. 2007). Epigenetic mechanisms have been implicated in autoimmune skin diseases. Among them, dysregulated DNA and histone methylation contribute to systemic lupus erythematosus (SLE) (Hung et al. 2018), psoriasis (Manczinger et al.

The phytocannabinoid (-)-cannabidiol (CBD) operates as a complex, differential modulator of human hair growth: Anti-inflammatory submicromolar versus hair growth inhibitory micromolar effects

Mon, 2019-07-29 00:00
Most cases of excessive hair loss and unwanted hair growth (effluvium, alopecia, hirsutism, hypertrichosis) result in part from major disturbances in the cyclic transformation of hair follicles (HFs), namely in their switch from active growth and pigmented hair shaft production (anagen) to apoptosis-driven HF involution (catagen) (Oh et al. 2016; Paus and Cotsarelis 1999). It is now clear that this switch also underlies profound neuroendocrine controls that still await systematic therapeutic targeting (Paus et al.

Severe Skin Permeability Barrier Dysfunction in Knockout Mice Deficient in a Fatty Acid ω-Hydroxylase Crucial to Acylceramide Production

Fri, 2019-07-26 00:00
The skin permeability barrier is indispensable for maintaining water inside the body and preventing the invasion of pathogens and allergens; abnormalities lead to skin disorders such as atopic dermatitis and ichthyosis. Acylceramide is an essential lipid for skin barrier formation, and CYP4F22 is a fatty acid ω-hydroxylase involved in its synthesis. Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis, although the symptoms vary among mutation sites and types. Here, we generated knockout mice deficient in Cyp4f39, the mouse ortholog of human CYP4F22, to investigate the effects of completely abrogating the function of the fatty acid ω-hydroxylase involved in acylceramide production on skin barrier formation.

Rac-Dependent Signaling from Keratinocytes Promotes Differentiation of Intradermal White Adipocytes

Tue, 2019-07-23 00:00
Rac signaling affects numerous downstream targets in vitro; however, few studies have established in vivo levels. We generated mice with a single knockout (KO) of Rac1 (Keratin5 (K5)-Cre;Rac1flox/flox, Rac1-KO) and double KO of Rac1 and Rac3 (K5-Cre;Rac1flox/flox;Rac3−/−, Rac1/Rac3-DKO) in keratinocytes. Hairless phenotype in Rac1-KO mice was markedly exacerbated in Rac1/Rac3-DKO mice. Strikingly, Rac1-KO mice exhibited thinner dermal white adipose tissue, which was considerably further reduced in Rac1/Rac3-DKO mice.

Melanoma to Vitiligo: The Melanocyte in Biology & Medicine—Joint Montagna Symposium on the Biology of Skin/PanAmerican Society for Pigment Cell Research Annual Meeting

Tue, 2019-07-23 00:00
Melanoma to Vitiligo: The Melanocyte in Biology & Medicine generated and amplified a growing understanding of the scientific basis of and clinical and pathologic relationship between melanoma, a bi-product of uncontrolled growth of melanocytes, and vitiligo, a disorder of undesirable death of melanocytes. This meeting, held Oct. 17–22, 2018, at Salishan Resort on the Oregon Coast, incorporated the full spectrum of pigment cell biology and chemistry, as well as the biological underpinnings of clinical disease.

Accumulation of Progerin Affects the Symmetry of Cell Division and Is Associated with Impaired Wnt Signaling and the Mislocalization of Nuclear Envelope Proteins

Tue, 2019-07-23 00:00
Hutchinson-Gilford progeria syndrome (HGPS) is the result of a defective form of the lamin A protein called progerin. While progerin is known to disrupt the properties of the nuclear lamina, the underlying mechanisms responsible for the pathophysiology of HGPS remain less clear. Previous studies in our laboratory have shown that progerin expression in murine epidermal basal cells results in impaired stratification and halted development of the skin. Stratification and differentiation of the epidermis is regulated by asymmetric stem cell division.

LRG1 promotes keratinocyte migration and wound repair through regulation of HIF-1α stability

Mon, 2019-07-22 00:00
Re-epithelialization is a complex process during skin wound healing, and cell migration is an integral part of this phenomenon. Here we identified a role for LRG1: a key regulator of epidermal keratinocyte migration where LRG1 acts via enhancement of HIF-1α stability. We showed that LRG1 is upregulated at murine skin wound edges and that addition of recombinant human LRG1 accelerates keratinocyte migration and skin wound healing. Furthermore, we identified transcription factor ELK3 as a downstream effector of LRG1.

TARgeting the cutaneous microbiota in atopic dermatitis by coal tar via AHR-dependent induction of antimicrobial peptides.

Mon, 2019-07-22 00:00
Skin colonization by Staphylococcus aureus and its relative abundance is associated with atopic dermatitis (AD) disease severity and treatment response. Low levels of antimicrobial peptides (AMPs) in AD skin may be related to the microbial dysbiosis. Therapeutic targeting of the skin microbiome and AMP expression can therefore restore skin homeostasis and combat AD. In this study, we analyzed the cutaneous microbiome composition in 7 AD patients and 10 healthy volunteers upon topical coal tar (CT) or vehicle treatment.

Essential Role for Integrin-Linked Kinase in Melanoblast Colonization of the Skin

Fri, 2019-07-19 00:00
Melanocytes are pigment-producing cells found in the skin and other tissues. Alterations in the melanocyte lineage give rise to a plethora of human diseases, from neurocristopathies and pigmentation disorders, to melanoma. During embryogenesis, neural crest cell subsets give rise to two waves of melanoblasts, which migrate dorsolaterally, homing to the skin and differentiating into melanocytes. However, the mechanisms that govern colonization of the skin by the first wave of melanoblasts are poorly understood.

Understanding curly hair mechanics: Fibre strength

Fri, 2019-07-19 00:00
The relationship between the geometric and mechanical profiles of hair fibres has been studied, with special focus on curly samples. Incidental observations pointed to a significantly different viscoelastic character with varying curliness. Further investigations confirmed initial observations, showing an initial distinct toe-region behaviour for curly-fibres on the stress-strain plot, which is absent for straight fibres. This behaviour suggested a difference in viscoelastic nature of the curly fibre that is linked to mechanical energy stored in the fibre.

Response to Clarifying the Current Understanding of Syndromic Basal Cell Carcinomas.

Fri, 2019-07-19 00:00
A majority of individuals with BCNS have germline mutations affecting PTCH1, and BCCs that develop in these individuals are highly responsive to Smoothened inhibitors. However, BCCs which develop in minority of BCNS patients with underlying SUFU mutations may be less responsive to Smoothened inhibitors because inactivation of SUFU is downstream of SMO. Development of next-generation HH antagonists that target components downstream of SMO are under development for efficacy in Smoothened inhibitor resistant BCCs and may have efficacy in BCCs with SUFU mutations.

Human mesenchymal stromal cells engineered to express collagen VII can restore anchoring fibrils in recessive dystrophic epidermolysis bullosa skin graft chimeras

Fri, 2019-07-19 00:00
Recessive dystrophic epidermolysis bullosa (RDEB) is a debilitating genodermatosis caused by loss-of-function mutations in COL7A1 encoding type VII collagen (C7), the main component of anchoring fibrils (AFs) at the dermal-epidermal junction (DEJ).With no curative treatments presently available, retrovirally-transduced autologous epidermal grafts and intradermal lentivirally-engineered fibroblast injections are being investigated. Alternative approaches aim to infuse allogeneic mesenchymal stromal cells (MSCs) to provide a more generalised treatment for RDEB.

Clarifying the current understanding of syndromic basal cell carcinomas

Fri, 2019-07-19 00:00
Chiang et al. presented important data on the lower mutational load and increased genomic stability of basal cell nevus syndrome (BCNS) – basal cell carcinomas (BCCs) in contrast to sporadic BCCs in an original article titled “Genomic Stability in Syndromic Basal Cell Carcinoma” (Chiang et al., 2018).

A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (the VIP-U trial)

Thu, 2019-07-18 00:00
Psoriasis is a Th17 autoimmune disease associated with an increased risk cardiovascular events and mortality. Ustekinumab, an antibody to p40, blocks cytokines IL12 and IL23, and is a highly effective and safe treatment for psoriasis.

Variation in cutaneous patterns of melanomagenesis according to germline CDKN2A/CDK4 status in melanoma-prone families

Thu, 2019-07-18 00:00
CDKN2A and CDK4 are well-established melanoma susceptibility genes, but their effect on tumor location/distribution is unknown. We used a case-case study design to assess for differences in tumor location between mutation carriers (CDKN2A = 141 patients, 348 melanomas; CDK4 = 15 patients, 54 melanomas) and non-carriers (104 patients, 157 melanomas) in U.S. melanoma-prone families. Associations between groups were assessed with chi-square tests. Odds ratios (ORs) for tumor location were adjusted for diagnosis age, gender, and superficial spreading subtype.

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