Journal Of Investigative Dermatology

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Treatment of Advanced Melanoma in 2020 and Beyond

Sun, 2020-04-05 00:00
The melanoma field has seen an unprecedented set of clinical advances over the past decade. Therapeutic efficacy for advanced or metastatic melanoma went from being one of the most poorly responsive to one of the more responsive. Perhaps most strikingly, the advances which transformed management of the disease are based upon modern mechanism-based therapeutic strategies. The targeted approaches which primarily suppress the BRAF oncoprotein pathway, have high predictability of efficacy although less optimal depth or durability of response.

Loss-of-function variants in SERPINA12 underlie autosomal recessive palmoplantar keratoderma

Thu, 2020-04-02 00:00
Inherited palmoplantar keratodermas (PPKs) refer to a large and heterogeneous group of conditions resulting from abnormal epidermal differentiation and featuring thickening of the skin of the palms and soles. Here, we aimed at delineating the genetic basis of an autosomal recessive form of PPK manifesting with erythematous hyperkeratotic plaques over the palms and soles, extending to non-palmoplantar areas. Whole exome sequencing revealed in affected individuals homozygous nonsense variants in the SERPINA12 gene.

Anti-apoptotic molecule BCL2 is a therapeutic target in steroid-refractory graft-versus-host disease

Thu, 2020-04-02 00:00
Graft-versus-host disease (GVHD) is the leading cause of mortality after hematopoietic stem cell transplantation (HSCT) and primarily affects barrier organs, such as the skin. One third of cases are refractory to steroid treatment resulting in poor outcomes and the need for novel therapies.Longitudinal analysis of T cell transcriptomes in patients before appearance of GVHD symptoms revealed up-regulation of anti-apoptotic regulator BCL2 at GVHD initiation. To determine the potential of BCL2 inhibition in active GVHD, we analyzed tissues of 88 patients with acute or chronic GVHD.

Enhanced thermal sensitivity of TRPV3 in keratinocytes underlies heat-induced pruritogens release and pruritus in atopic dermatitis

Thu, 2020-04-02 00:00
Itch in atopic dermatitis (AD) is aggravated under warm conditions. Transient receptor potential vanilloid 3 (TRPV3), a member of the thermosensitive TRP channels, is activated by innocuous heat and is abundantly expressed in keratinocytes. The potential role of TRPV3 in itch is illustrated in TRPV3 channelopathies of human and mice. However, the role of TRPV3 in heat-induced itch in AD and the underlying mechanisms are unclear. Here we showed that keratinocytes isolated from patients with AD exhibit enhanced expression and heat sensitivity with hyperactive channel function of TRPV3.

Secretome components from Faecalibacterium prausnitzii strains A2-165 and AHMP21 Modulate Cutaneous Wound Inflammation

Thu, 2020-04-02 00:00
Chronic leg ulcers are a major health burden globally, increasing in incidence with ageing and morbidity from diabetes. A common mechanism highlighted in chronic hard to heal wounds is exaggerated and sustained inflammation, which inhibits their closure and therefore represents a therapeutic target (Lee et al, 2018, Mirza et al, 2013). As a consequence, dampening inflammation to improve cutaneous chronic wound healing is a major therapeutic goal. The use of microbial products, and/or viable cells as “probiotics”, is a novel approach to dampen inflammation.

The Return of the Mast Cell: New Roles in Neuroimmune Itch Biology

Thu, 2020-04-02 00:00
The mast cell–nerve unit classically has represented a fundamental neuroimmune axis in the development of itch because of the traditional prominence of histamine as a pruritogen. However, it is appreciated increasingly that most chronic itch disorders are likely nonhistaminergic in nature, provoking the hypothesis that other novel effector itch mechanisms derived from mast cells are important. In this review, we present an overview of classical mast cell biology and put these concepts into the context of recent advances in our understanding of the regulation and function of the mast cell–nerve unit in itch biology.

SnapshotDx Quiz: April 2020

Wed, 2020-04-01 00:00
Editorial note: Welcome to the Journal of Investigative Dermatology (JID) Snapshot Dx Quiz. In this monthly online-only quiz, the first question (“What is your diagnosis?”) relates to the clinical image shown, while additional questions concern the findings reported in the JID article by Pogatzki-Zahn et al. (2020) (https://doi.org/10.1016/j.jid.2019.05.029).

Table of Contents

Wed, 2020-04-01 00:00

Subscription Information

Wed, 2020-04-01 00:00

Editorial Board

Wed, 2020-04-01 00:00

Cells to Surgery Quiz: April 2020

Wed, 2020-04-01 00:00
Editorial note: Welcome to the Journal of Investigative Dermatology (JID) Cells to Surgery Quiz. In this monthly online-only quiz, the first question (“What is your diagnosis?”) relates to the clinical image shown, while additional questions concern the findings reported in the JID article by Liu et al. (https://doi.org/10.1016/j.jid.2019.06.152).

Editors’ Picks

Wed, 2020-04-01 00:00
Mistry et al. examined the transcription, epigenetic, and functional characteristics of low-density granulocytes (LPGs), proinflammatory neutrophils that are more frequent in patients with systemic lupus erythematosus (SLE) and that have been implicated in endothelial damage and vascular dysfunction. Two distinct populations of LPGs were identified in patients with SLE based on expression of CD10. A small subset of CD10– LPGs displays a more immature neutrophil type and exhibits upregulation of genes associated with neutrophil precursors and downregulation of immune response genes.

Clinical Snippets

Wed, 2020-04-01 00:00
Urticaria is a common feature that results from multiple etiologies, including NLRP3-associated autoinflammatory disease. Assrawi et al. identified two distinct mosaic mutations in the key inflammasome protein NLRP3 in two unrelated elderly patients with late-onset chronic urticaria accompanied by systemic inflammation. These gain-of-function mutations resulted in increased inflammasome activation and secretion of IL-1β, and treatment of these patients with the IL-1β antagonist anakinra resulted in complete remission of symptoms.

Research Techniques Made Simple: CRISPR Genetic Screens

Wed, 2020-04-01 00:00
CRISPR and Cas proteins, often referred to as CRISPR/Cas, are the components of a bacterial genome editing system that can be used to perturb genes in cells and tissues. A classic application is to use CRISPR/Cas to generate genetic loss-of-function. When performed at large scale and combined with deep sequencing techniques, CRISPR-based perturbations can be performed in a high throughput setting to screen many candidate genomic elements for their roles in a phenotype of interest. Here, we discuss major considerations in the design, execution, and analysis of CRISPR screens.

Cellular Phenotypic Plasticity of Cutaneous Melanoma: A Complex Puzzle

Wed, 2020-04-01 00:00
Wenzina et al. (2020) explore the potential role of E-cadherin (CDH1) as a marker for invasive behavior in melanoma. The authors show that CDH1 expression is modulated by p38 signaling, and that manipulation of this pathway can impede endothelial disruption and lung dissemination in vivo and in vitro. The downstream markers PODXL and DEL of the invasive phenotype are associated with a poor prognosis.

Kallikrein-6–Regulated Pathways Shed Light on New Potential Targets in Varicella Zoster Virus Infection

Wed, 2020-04-01 00:00
Varicella zoster virus, the worldwide infectious human virus responsible for acute varicella and chickenpox, commonly spreads from exposure through contact with a skin lesion or airborne respiratory droplets. Keratinocytes, major targets and source of transmission of the virus present in the skin, represent an ideal choice of cell to stop early virus progression. In their recent study, Tommasi et al. show regulatory mechanisms of cytokeratin 10 through the protease kallikrein-6 as a suitable and druggable pathway to reduce varicella zoster virus dissemination.

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.

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