Journal Of Investigative Dermatology

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588 Identification of highly potent and selective Interleukin-1 receptor associated kinase 4 (IRAK4) degraders for the treatment of hidradenitis suppurativa

Wed, 2020-07-01 00:00
Interleukin-1 receptor associated kinase 4 (IRAK4) plays a central role in myddosome signaling via kinase and scaffolding functions, making it an attractive target for the treatment of TLR- and IL-1R-driven inflammatory diseases. IL-1 family cytokines and TLRs, are central to the pathophysiology of hidradenitis suppurativa (HS), a Th1- and Th17-mediated neutrophilic, chronic inflammatory skin disease. Kymera has developed orally administered hetero-bifunctional molecules that selectively target IRAK4 for degradation and elimination by the ubiquitin proteasome pathway.

587 Investigation of omega-3 mechanisms involve in psoriatic plaque healing using a psoriatic skin model produced by tissue engineering

Wed, 2020-07-01 00:00
Psoriasis is a dermatosis characterized by keratinocyte hyperproliferation, and abnormal epidermal differentiation. Clinical studies have shown that supplementation of the diet with omega-3 fatty acids could improve the symptoms of psoriatic patients. However, the mechanisms involved are still poorly understood.The aim of this study was to investigate the effects of α-linolenic acid (ALA) on the keratinocyte proliferation and differentiation of a psoriatic skin model. Healthy (HS) and psoriatic skin substitutes (PS) were produced according to the self-assembly method of tissue engineering, using culture media supplemented with 10 μM ALA.

583 The evaluation of the application of glucocorticoids

Wed, 2020-07-01 00:00
The administration of glucocorticoids is widely used in the treatment of bullous diseases. However, long-term use of systemic glucocorticoids will cause some side effects, such as infection, diabetes, hypertension, osteoporosis and so on. Recently, the topical steroids were applied to reduce the side effects. [1,2] In order to investigation the side effects between the topical and systemic application of the steroids, we tried to designed the experiments based on the betamethasone application on 8-week-old C57BL / 6 male mice.

582 The discovery of new therapeutic combinations for Merkel cell carcinoma by small-molecule synergy screening

Wed, 2020-07-01 00:00
Merkel cell carcinoma (MCC) is a rare and highly metastatic neuroendocrine skin cancer. The majority of MCC tumors are virus positive (VP-MCC) and are associated with integrated Merkel cell polyomavirus, whereas the remainder of MCC are virus-negative (VN-MCC) tumors that are characterized by ultraviolet light associated mutations. Metastatic MCC is treated by immunotherapy or chemotherapy. Conventional chemotherapy is usually unbeneficial in MCC, and although immune checkpoint inhibitor (ICI) therapy can be effective, it is contraindicated in many patients and others have disease progression despite immunotherapy.

580 Validation of an atopic dermatitis model in mice by repeated intra-dermal challenges with ovalbumin

Wed, 2020-07-01 00:00
Background: Atopic dermatitis (AD) is a chronic inflammatory skin condition that significantly affects quality of life. A number of animal models have been developed over the years to mimic pathophysiology of AD. Among the different AD models, those induced by epicutaneous application of allergens and haptens are more common. However, limited absorption of peptide and protein allergens after epicutaneous application is challenging and requires long-term application of adhesive skin patches. In this present study, we examined induction of AD-like symptoms in mice with repeated intra-dermal challenges with the protein allergen, ovalbumin.

579 Rationale and design for the Kallikrein Inhibitor in Netherton Syndrome (KINS) pivotal clinical trial

Wed, 2020-07-01 00:00
Netherton Syndrome (NS) is a potentially life-threatening autosomal recessive disorder involving skin barrier breakdown, inflammation, and allergy. NS affects individuals from birth through adulthood, but standard interventions provide limited benefit and there are no FDA- or EMA-approved therapeutics. We summarize the Kallikrein Inhibitor in Netherton Syndrome (KINS) study, the first Phase 2/3, multicenter, randomized, double-blind, vehicle-controlled trial to evaluate the safety, efficacy and tolerability of a novel topical therapeutic (LM-030) in NS patients.

578 Improved local drug delivery with bioadhesive nanoparticles in the treatment of skin cancer

Wed, 2020-07-01 00:00
Nanoparticles (NPs) have been utilized to enhance delivery of rapidly-degraded chemotherapies in multiple animal tumor models. We explored the role of NPs in the local treatment of squamous cell carcinoma (SCC). Using biodegradable poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG), we encapsulated camptothecin (CPT) to create nonadhesive NPs (NNPs), which were then chemically converted to bioadhesive NPs (BNPs) that have previously exhibited augmented association with tumor microenvironments.

577 Plasma exosomal miR-375-3p regulates ferroptosis in keratinocytes by targeting lipid transporter GPX4 in SJS/TEN

Wed, 2020-07-01 00:00
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, cutaneous adverse drug reactions that are accompanied by keratinocyte cell death. Ferroptosis is a recently recognized form of regulated cell death driven by lipid-based reactive oxygen species (ROS) accumulation. However, the molecular mechanisms of ferroptosis regulation are still largely unknown in SJS/TEN. Exosomes are nanometer-sized membranous vesicles in various body fluids. They contain functional proteins, mRNAs, and miRNAs.

576 Crystal structure of sarecycline bound to the 70S bacterial ribosome reveals structural differences from other tetracyclines at atomic resolution

Wed, 2020-07-01 00:00
Sarecycline is a new tetracycline-class antibiotic approved for the treatment of acne vulgaris. Tetracyclines share a common four-ring naphthacene core and inhibit protein synthesis by interacting with the 70S bacterial ribosome. Sarecycline is distinguished chemically from other tetracyclines because it has a 7-{[methoxy(methyl)amino]methyl]} group attached at the C-7 position of ring D. It represents the longest and largest C-7 moiety for any antibiotic in its class. To investigate the functional role of this C-7 moiety, we determined the crystal structure of sarecycline bound to the Thermus thermophilus 70S ribosome complex.

575 GZ17-6.02 promotes autophagy and cell death in actinic keratoses via ATM-dependent mTOR inhibition

Wed, 2020-07-01 00:00
GZ17-6.02 (602) is a novel investigational compound composed of curcumin, harmine, and isovanillin undergoing phase I clinical trials in oncology for solid tumors and lymphoma (NCT03775525). The goal of the present study is to determine the efficacy of 602 in killing actinic keratoses (AK) and to elucidate the molecular mechanisms underlying these effects. In a trypan assay, low concentrations of 602 killed AK cells to a greater degree than 5-fluorouracil (p<0.05). Alterations in cell signaling caused by 602 in AK cells were evaluated via fluorescence microscopy.

574 To assess the antifungal activity of Jublia® under real-world conditions

Wed, 2020-07-01 00:00
Onychomycosis affects up to 8% of the population and is most commonly caused by Trichophyton rubrum (T. rubrum) and Trichophyton mentagrophytes (T. mentagrophytes). Systemic antifungals provide higher rates of clearance compared to topical antifungals, but are associated with potentially serious side effects and drug-drug interactions. Efinaconazole, a triazole antifungal, is approved by the FDA as a 10% nail solution (Jublia®) for the treatment of distal and lateral subungual onychomycosis. Efinaconazole’s activity has been demonstrated using agar diffusion assays (ADAs) centered on cadaveric nail clippings; however, it has not been studied under real-world conditions that may provide a more accurate approximation of its true effectiveness.

573 Improved effect on two cases of different subtypes of porokeratosis with superficial X-ray radiotherapy

Wed, 2020-07-01 00:00
Porokeratosis (PK) is a heterogeneous group of skin disorders with unclear aetiology. This group includes multiple clinical variants. PK can cause cosmetic disturbances and poses the risk of malignant transformation. However, the current therapies for PK yield unsatisfactory results. To evaluate the therapeutic effects of superficial X-ray radiotherapy (SXRT) on PK, two patients with local PK who experienced failed multiple topical treatments were treated with SXRT. One patient with porokeratosis of Mibelli (PM) received one course of treatment for the lesion on their buttocks and two courses for neck lesions.

571 Quantitative ligand and receptor binding studies reveal IL-36 activation mode

Wed, 2020-07-01 00:00
IL-36 cytokines are pro-inflammatory members of the IL-1 family upregulated in a host of inflammatory skin disorders. They signal through the IL-36 receptor (IL-36R) and a shared subunit IL-1 receptor accessory protein (IL-1RAcP). Targeting antagonism of IL-36/IL-36R binding by biologics and small molecules is being actively pursued for several dermatological disorders. Therefore, it is critical to gain understanding of the mechanism of ligand-receptor binding. The mode of activation for the IL-36 pathway is proposed to be similar to IL-1 in that the IL-36 agonist forms a binary complex with IL-36R, which recruits IL-1RAcP.

569 Rilzabrutinib (PRN1008) shows BTK-mediated mechanisms of action supporting clinical development for immune-mediated diseases

Wed, 2020-07-01 00:00
Bruton tyrosine kinase (BTK) is a critical immune signaling enzyme expressed in B and innate immune cells and is an essential element downstream of BCR and FcR signaling. Rilzabrutinib (PRN1008) is an oral, reversible, covalent BTK inhibitor that drives durable BTK occupancy with low off-target effects shown by other BTK inhibitors. Preclinical PRN1008 activity was evaluated in biochemical studies and in vivo models of inflammation and canine pemphigus. PRN1008 showed kinase selectivity for BTK with an enzyme inhibition IC50 of 1.3 nM; functional BTK target occupancy of 91% (±2%) was achieved in PBMCs at 4 h.

568 Comparing molecular cutaneous improvement in atopic dermatitis with various treatment modalities facilitates personalized approaches

Wed, 2020-07-01 00:00
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. Recently, there is active therapeutic development in AD, with testing of targeted and broad treatments, to address various disease mechanisms. A comparison of the molecular effects of these treatments on AD skin abnormalities can facilitate a deeper understanding of the key pathogenic elements in AD, fostering further therapeutic developments, but it is still lacking. Using a meta-analysis-based approach, we are comparing immune and barrier effects of key systemic treatments used or tested in AD, including cyclosporine A, narrow-band ultraviolet B, dupilumab/anti IL-4R, fezakinumab/anti-IL-22, ASN002/JAK-SYK antagonist, ustekinumab/anti IL-12/23p40, as well as topicals (topical corticosteroids, crisaborole/anti PDE4) on lesions of AD patients.

567 Mechanisms by which combined inhibition of BET and HDAC inhibits proliferation and induces apoptosis in CTCL

Wed, 2020-07-01 00:00
Previously, we showed that the combination of BET inhibitors (BETi) and histone deacetylase inhibitors (HDACi) acted synergistically to induce significant apoptosis (60-80%) in CTCL lines and leukemic CTCL cells within 96 hours without significant apoptosis of normal CD4+ T cells (<10%) (Zhao et al., Neoplasia, 2019). We showed that mediators of apoptosis (e.g. cleaved caspases 8 and 9) were increased and proliferative drivers (e.g. NFkB, cyclin D1, c-Myc) were decreased. Our current gene expression studies showed that BETi/HDACi treatment of CTCL cells at nanomolar levels suppressed several pro-survival factors early (e.g.

564 Preclinical rationale for a first-in-human trial to evaluate the safety and preliminary efficacy of desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) for mucosal pemphigus vulgaris

Wed, 2020-07-01 00:00
We previously established proof-of-concept that antigen-specific B cell depletion can be achieved with gene-engineered T cells expressing chimeric autoantibody receptors (CAARs) comprising DSG3, the autoantigen in the autoimmune blistering disease mucosal pemphigus vulgaris (PV), fused to CD137-CD3ζ signaling domains. After specific lysis of anti-DSG3 B cells, DSG3-CAART cells are stimulated to proliferate and engraft, leading to potentially durable remissions of autoimmune disease. Here we present final preclinical studies supporting the DSG3-CAART investigational new drug application.

563 ATx201 modulates biomarkers of skin barrier function and cutaneous inflammation in patients with moderate atopic dermatitis

Wed, 2020-07-01 00:00
ATx201 is a small molecule, which decolonizes Staphylococcus aureus and improves the diversity of the skin microbiome in patients with mild-to-severe atopic dermatitis (AD) (DECOLAD). We now report the safety and immune-modulatory effect of ATx201 in patients with moderate AD. In this randomized, double-blind, intraindividual, and vehicle-controlled Phase 2 trial, thirty-one patients received ATx201 CREAM 2% and matching vehicle (1:1) once daily for 3 weeks (NCT03304470), with a 12-day follow-up period.

562 Biological evaluation of litchi derived products as dermatological agents

Wed, 2020-07-01 00:00
Litchi (Litchi chinensis Sonn.) is a fruit native to South China, and popular for the taste and health benefits. Litchi products, such as litchi juice and vinegar (extracted or fermented from litchi fruit) have potential dermatological benefits. In this paper, we have evaluated litchi vinegar and juice regarding protective effects on HaCaT keratinocytes following either UVB irradiation or poly (I:C) by assessing cell survival (OD, optical density; MTT assay), reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity.

561 Development and first-in-human characterization of a potent oral CCR4 antagonist for the treatment of atopic dermatitis

Wed, 2020-07-01 00:00
Atopic dermatitis (AD) is predominantly driven by T helper type 2 cells (Th2). Accumulation of Th2 cells depends on CCR4-mediated recruitment of Th2 cells by the CCR4 ligands CCL17 and CCL22. Both are elevated in inflamed tissue, and levels correlate with disease activity and severity. Here, we describe RPT193, a novel, highly potent and specific oral CCR4 antagonist. In multiple preclinical mouse models of allergic skin inflammation, we demonstrated efficacy and reduction of Th2 cytokines with once daily dosing of RPT193 that is comparable to antibodies specific to IL-4 receptor and IL-13.

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