Journal Of Investigative Dermatology

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Recent Advances in Understanding Pemphigus and Bullous Pemphigoid

Wed, 2020-04-01 00:00
For many years, The Journal of Investigative Dermatology (JID) has been a leader in our understanding of many aspects of the major autoimmune blistering skin diseases, pemphigus and bullous pemphigoid. The purpose of this review is to highlight and summarize those advances by discussing the respective articles, published in the JID from 2015 to 2019. Seminal articles from elsewhere in the literature that set the stage for those advances, or that are “classics” in the area, are also included to provide context and a more complete picture.

Innate Cancer Immunoediting

Wed, 2020-04-01 00:00
Immune cells detect and destroy cancer cells; however, very early changes in cancer genome and phenotype coupled with immune system selection cause escape variant survival in a process called cancer immunoediting. Although adaptive immunity is important for this process, the report by Kubick et al. provides novel insights into the role of innate immune cells for immunoediting of early transformed epithelial cells.

Theranostic Advances in Vascular Malformations

Wed, 2020-04-01 00:00
Vascular malformations are subdivided into capillary, lymphatic, venous, arteriovenous, and mixed malformations, according to the type of affected vessels. Until a few years ago, treatment options were limited to sclerotherapy and/or surgery. Since, it has been demonstrated that the majority of vascular malformations are caused by inherited or somatic mutations in various genes. These mutations lead to hyperactivity of two major signaling pathways: the RAS/mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathways.

PABPN1, a target of p63, modulates keratinocyte differentiation through regulation of p63α mRNA translation

Tue, 2020-03-31 00:00
p63 is expressed from two promoters and produces two N-terminal isoforms, TAp63 and ΔNp63. Alternative splicing creates three C-terminal isoforms p63α/β/δ whereas alternative polyadenylation in coding sequence (CDS-APA) creates two more C-terminal isoforms p63γ/ε. While several transcription factors have been identified to differentially regulate the N-terminal p63 isoforms, it is unclear how the C-terminal p63 isoforms are regulated. Thus, we determined whether PABPN1, a key regulator of APA, may differentially regulate the C-terminal p63 isoforms.

Augmented Intelligence Dermatology: Deep Neural Networks Empower Medical Professionals in Diagnosing Skin Cancer and Predicting Treatment Options for 134 Skin Disorders

Tue, 2020-03-31 00:00
Although deep learning algorithms have demonstrated expert-level performance, previous efforts were mostly binary classifications of limited disorders. We trained an algorithm with 220,680 images of 174 disorders and validated it using Edinburgh (1,300 images; 10 disorders) and SNU datasets (2,201 images; 134 disorders). The algorithm could accurately predict malignancy, suggest primary treatment options, render multi-class classification among 134 disorders, and improve the performance of medical professionals.

REGULATION OF MELANOGENESIS BY THE AMINO-ACID TRANSPORTER SLC7A5.

Mon, 2020-03-30 00:00
Integration of ChIPseq and microarray data allowed to identify to our knowledge previously unreported MITF target genes, among which, the amino acid transporter, SLC7A5. We showed that siRNA-mediated SLC7A5 knock-down decreased pigmentation in B16F10 cells, without affecting morphology nor dendricity. Treatment with the SLC7A5 inhibitors BCH, or JPH203, also decreased melanin synthesis in B16F10 cells. Our findings indicated that BCH was as potent as reference depigmenting agent, Kojic Acid, but acted through a different pathway not affecting tyrosinase activity.

The suppression of very long chain fatty acids is associated with skin carcinogenesis

Mon, 2020-03-30 00:00
Very long chain fatty acids (VLCFA) remain understudied in skin hyperplasia and cancer. VLCFA are carboxylic acids with saturated or unsaturated long hydrocarbon tails of greater than 18 carbons in length (Zarate et al., 2017). They are made from smaller de novo synthesized or dietary fatty acids (FA) by the actions of a family of fatty acyl elongases (ELOVL1-7) (Figure 1a). FA can also be desaturated by the enzymatic removal of hydrogen from methylene groups along its acyl chain. VLCFA can be structural components of membranes, precursors of signaling cytokines, or can be catabolized via the mitochondrial β-oxidation pathway for cellular energy demands (de Carvalho and Caramujo, 2018).

Molecular Hydrogen Protects Human Melanocytes from Oxidative Stress by Activating Nrf2 Signaling

Sat, 2020-03-28 00:00
Oxidative stress is proven to be critical for the initiation and progression of vitiligo. Molecular hydrogen (H2) possesses potent antioxidant activity and has been shown to protect against various oxidative stress-related diseases. In this study, we first investigated the effects and mechanisms of H2 in human melanocytes damaged by hydrogen peroxide (H2O2). We initially found that H2 reduced intracellular reactive oxygen species (ROS) accumulation and malondialdehyde (MDA) levels in both vitiligo specimens and H2O2-treated melanocytes in vitro in a concentration- and time-dependent manner, concomitant with the enhancement of antioxidant enzyme activity.

Loss of wild-type CDKN2A is an early event in the development of melanoma in FAMMM syndrome

Sat, 2020-03-28 00:00
The development of melanoma involves a sequence of genetic and epigenetic alterations. Somatic mutations typically sequentially induce MAPK pathway activation (BRAF, NRAS), upregulation of telomerase (TERT) and disruption of the G1/S cell cycle checkpoint (CDKN2A) in addition to other pathogenic alterations (Shain et al., 2018). Bi-allelic CDKN2A loss is the most common genetic alteration distinguishing melanocytic nevi from invasive melanomas (Shain et al., 2015). Homozygous deletion of CDKN2A has been reported in a small proportion of dysplastic nevi but never in common nevi.

Molecular signature of pruriceptive MrgprA3+ neurons

Sat, 2020-03-28 00:00
Itch, initiated by the activation of sensory neurons, is frequently associated with dermatological diseases. MrgprA3+ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulations of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here we performed RNA sequencing of genetically labeled MrgprA3+ neurons under both naïve and allergic contact dermatitis conditions.

Artificial Intelligence in Dermatology: A Primer

Fri, 2020-03-27 00:00
Artificial intelligence (AI) is becoming increasingly important in dermatology, with studies reporting accuracy matching or exceeding dermatologists for the diagnosis of skin lesions from clinical and dermoscopic images. However, real-world clinical validation is currently lacking. We review dermatological applications of deep learning, the leading AI technology for image analysis, and discuss its current capabilities, potential failure modes, and challenges surrounding performance assessment and interpretability.

CRITICAL SIGNALING EVENTS IN THE MECHANOACTIVATION OF HUMAN MAST CELLS VIA P.C492Y-ADGRE2

Wed, 2020-03-25 00:00
A role for the adhesion G-protein coupled receptor ADGRE2 (EMR2) in mechanosensing was revealed by the finding of a missense substitution (p.C492Y) associated with familial vibratory urticaria (VU). In these patients, friction of the skin induces mast cell hyper-degranulation through p.C492Y-ADGRE2, causing localized hives, flushing and hypotension. We have now characterized the responses and intracellular signals elicited by mechanical activation in human mast cells expressing p.C492Y-ADGRE2 and attached to dermatan sulfate, a ligand for ADGRE2.

Rosacea is Characterized by a Profoundly Diminished Skin Barrier

Thu, 2020-03-19 00:00
Rosacea is a common, chronic inflammation of sebaceous gland-rich facial skin characterized by severe skin dryness, elevated pH, transepidermal water loss, and decreased hydration levels. Until now, there has been no thorough molecular analysis of permeability barrier alterations in the skin of rosacea patients. Thus, we aimed to investigate the barrier alterations in papulopustular rosacea (PPR) samples compared to healthy sebaceous gland-rich (SGR) skin, using RNASeq analysis (n=8). Pathway analyses by Cytoscape ClueGo revealed 15 significantly enriched pathways related to skin barrier formation.

Epidermal Mineralocorticoid Receptor inactivation affects the homeostasis of all skin layers in chronologically aged mice

Wed, 2020-03-18 00:00
The endogenous increased production of glucocorticoids (GCs) in the skin of the elderly population contributes to age-related defects strikingly similar to those occurring after pharmacological treatments with GCs.GCs act through the ligand-dependent transcription factors GC receptor (GR) and mineralocorticoid receptor (MR). We demonstrated that epidermal MR plays non-redundant roles relative to GR in adult mouse skin homeostasis; however, its relative contribution to natural skin aging has not been previously investigated.

Meeting Report of the 16th International Langerhans Cell Workshop: Recent developments in Langerhans cell and skin dendritic cell biology and their therapeutic application

Wed, 2020-03-18 00:00
The 16th International Workshop on Langerhans Cells was organized by Björn E. Clausen, with the help of Patrizia Stoitzner and Nikolaus Romani in Budenheim near Mainz, Germany. From October 3rd through 6th, 2019, more than 100 scientists from all over the world presented their cutting-edge work and technological advances in the field of skin immunity with a special focus on Langerhans cells (LC) and dermal dendritic cells (DC). Novel insights into the development and homeostasis of LC and dermal DC and their respective functional roles in health and disease were discussed.

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