查看更多>>摘要：Single gene disorders are ideally suited to establish robust genotype-phenotype correlations and provide excellent opportunities to understand molecular pathomechanisms with relevance to complex disorders. The observation that patients diagnosed with the same causative mutation can present with phenotypic disease variability illustrates the significant role of disease modifiers and warns against oversimplification. In a new article in the Journal of Investigative Dermatology, Zimmer et al. (2021) analyze two mutations located in the desmoglein (DSG) 1 transmembrane domain (TMD) and find that both mutants fail to assemble into desmosomes owing to reduced membrane trafficking and lipid raft targeting. One mutation maintained normal protein expression levels and turnover relative to those of wild-type (WT) DSG1, and behaved as a dominant negative. The second mutant showed reduced stability and increased turnover compared with WT DSG1 as well as reduced desmosome size and abundance. A full understanding of the TMD of DSG1 requires cell biological approaches, underscoring the value of cell biology in biomedical research in general.
查看更多>>摘要：Drug repurposing has the potential to discover new treatments for diseases with high unmet medical needs. Lee et al. (2021) combined transcriptomics and computational analysis of drug-target databases to identify novel therapies for epidermolysis bullosa simplex. Differential gene expression analysis of blister epidermis identified the phosphoinositide 3-kinase/protein kinase B/mTOR signaling pathway as central. A pilot study using a topical mTOR inhibitor showed marked improvement.
查看更多>>摘要：Nardin et al's (2021) study on melanoma reports anti-TERT CD4 T helper type (Th) 1 responses in more than half of patients. Besides indicating a trend for improved survival, increased anti-TERT CD4 Th1 responses predicted better outcomes for patients treated with immune checkpoint inhibitors. Thus, harnessing systemic anti-TERT CD4 Th1 responses together with tumor-specific elevation of telomerase can potentially open new avenues for biomarkers and treatment in melanoma.
查看更多>>摘要：Palmoplantar skin has several unique characteristics such as increased thickness, high resilience, hypopigmentation, and lack of hair follicles. The establishment of palmoplantar identity occurs through keratinocyte-fibroblast interactions, with keratin 9 expression and Wnt signaling playing key roles. Understanding how palmoplantar features develop may help efforts to reproduce them at both palmoplantar and nonpalmoplantar body sites.
查看更多>>摘要：A major role of the skin is to serve as a barrier toward the environment. The skin's permeability barrier consists of a lipid structure positioned in the stratum corneum. Recent progress in high-resolution cryoelectron microscopy (cryo-EM) has allowed for elucidation of the architecture of the skin's barrier and its stepwise formation process representing the final stage of epidermal differentiation. In this review, we present an overview of the skin's barrier structure and its formation process, as evidenced by cryo-EM.
查看更多>>摘要：IRF6 is a transcription factor that is required for craniofacial development and epidermal morphogenesis. Specifically, Irf6-deficient mice lack the terminally differentiated epidermal layers, leading to an absence of barrier function. This phenotype also includes intraoral adhesions due to the absence of the oral periderm, leading to the mislocalization of E-cadherin and other cell-cell adhesion proteins of the oral epithelium. However, the mechanisms by which IRF6 controls the localization of cell adhesion proteins are not understood. In this study, we show that in human and murine keratinocytes, loss of IRF6 leads to a breakdown of epidermal sheets after mechanical stress. This defect is due to a reduction of adhesion proteins at the plasma membrane. Dynamin inhibitors rescued the IRF6-dependent resistance of epidermal sheets to mechanical stress, but only inhibition of clathrin-mediated endocytosis rescued the localization of junctional proteins at the membrane. Our data show that E-cadherin recycling but not its endocytosis is affected by loss of IRF6. Overall, we demonstrate a role for IRF6 in the delivery of adhesion proteins to the cell membrane.
查看更多>>摘要：This systematic review aims to provide an update on measurement properties of patient-reported outcome measures for pruritus. A Medline literature search was conducted to update the systematic review published in this journal in 2017 and to identify new validation studies published between October 2015 and July 2019. The methodological quality of validation studies was assessed on the basis of the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist, and the measurement properties of patient-reported outcome measures were evaluated. A total of 19 new studies were included and added to the 22 studies identified in the previously published review. Evidence from all the 41 studies evaluating 38 different measures was summarized. Outcome measures were mapped to one of three constructs where possible: pruritus intensity, pruritus severity, pruritus-specific health-related QOL. COSMIN rating revealed mixed results, with deficiencies in the methodological quality of many studies across all constructs. The most appropriate pruritus severity measure was the Itch Severity Scale. ItchyQoL and the disease-specific Uremic Pruritus in Dialysis Scale achieved the most promising results considering the construct pruritus-specific health-related QOL. For pruritus intensity, nine measures performed similarly well.
Kaundinya, TrishaRakita, UrosGuraya, ArmaanAbboud, Donna Maria...
18页
查看更多>>摘要：The psychometric validity and reliability of widely used atopic dermatitis (AD) outcome measures across different races and ethnicities are unclear. We describe the rates of reporting race, ethnicity, and skin tone in studies testing the psychometric properties of AD outcome measures and compare the psychometric analyses across race, ethnicity, and skin tone. We systematically reviewed MEDLINE and EMBASE for studies reporting psychometric properties of clinician-reported or patient-reported outcome measures in AD (International Prospective Register of Systematic Reviews: CRD42021239614). Overall, 16,100 nonduplicate articles were screened; 165 met inclusion criteria. Race and/or ethnicity were reported in 55 (33.3%) studies; of those, race was assessed by self-report in 10 studies (6.1%) or was unspecified in 45 (27.3%). A total of 16 studies (9.7%) evaluated psychometric property differences by race, and only five (4.4%) of those did not recognize it as a limitation. Properties assessed across race, ethnicity, or skin tone were differential item functioning, convergent validity feasibility, inter-rater reliability, intrarater reliability, test-retest reliability, and known-groups validity. Multiple instruments demonstrated performance differences across ethnoracial groups. This review highlights the paucity of race/ethnicity consideration for psychometric property testing in AD outcome measurement instruments. More AD outcomes instruments should be validated in diverse populations.
查看更多>>摘要：Expression-based systematic drug repositioning has been explored to predict novel treatments for a number of skin disorders. In this study, we utilize this approach to identify, to our knowledge, previously unreported therapies for epidermolysis bullosa simplex (EBS). RNA sequencing analysis was performed on skin biopsies of acute blisters (<1 week old) (n = 9) and nonblistered epidermis (n = 11) obtained from 11 patients with EBS. Transcriptomic analysis of blistered epidermis in patients with EBS revealed a set of 1,276 genes dysregulated in EBS blisters. The IL-6, IL-8, and IL-10 pathways were upregulated in the epidermis from EBS. Consistent with this, predicted upstream regulators included TNF-alpha, IL-1 beta, IL-2, IL-6, phosphatidylinositol 3-kinase, and mTOR. The 1,276 gene EBS blister signature was integrated with molecular signatures from cell lines treated with 2,423 drugs using the Connectivity Map CLUE platform. The mTOR inhibitors and phosphatidylinositol 3-kinase inhibitors most opposed the EBS signature. To determine whether mTOR inhibitors could be used clinically in EBS, we conducted an independent pilot study of two patients with EBS treated with topical sirolimus for painful plantar keratoderma due to chronic blistering. Both individuals experienced marked clinical improvement and a notable reduction of keratoderma. In summary, a computational drug repositioning analysis successfully identified, to our knowledge, previously unreported targets in the treatment of EBS.
查看更多>>摘要：Psoriasis is a chronic immune-mediated disease characterized by excessive proliferation of epidermal keratinocytes and increased immune cell infiltration to the skin. Although it is well-known that psoriasis pathogenesis is driven by aberrant production of proinflammatory cytokines, the mechanisms underlying the imbalance between proinflammatory and anti-inflammatory cytokine expression are incompletely understood. In this study, we report that the transcriptional coregulators CtBP1 and 2 can transactivate a common set of proinflammatory genes both in the skin of imiquimod-induced mouse psoriasis model and in human keratinocytes and macrophages stimulated by imiquimod. We find that mice overexpressing CtBP1 in epidermal keratinocytes display severe skin inflammation phenotypes with increased expression of T helper type 1 and T helper type 17 cytokines. We also find that the expression of CtBPs and CtBP-target genes is elevated both in human psoriatic lesions and in the mouse imiquimod psoriasis model. Moreover, we were able to show that topical treatment with a peptidic inhibitor of CtBP effectively suppresses the CtBP-regulated proinflammatory gene expression and thus attenuates psoriatic inflammation in the imiquimod mouse model. Together, our findings suggest to our knowledge previously unreported strategies for therapeutic modulation of the immune response in inflammatory skin diseases.
NSTL
Elsevier