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IQGAP proteins mediate many processes important for the development of hyperproliferative skin diseases, namely the EGF signaling, WNT and MAPK kinase cascades, they are required for cell adhesion and migration processes, tight junction and zonula occludens formation, cell cycle regulation. However, the possible contribution of the IQGAP3 in the development of hyperproliferative psoriatic plaques is unknown. We have shown earlier that IQGAP3 is overexpressed in the lesional skin of patients with psoriasis.
We previously published a genome-wide association study (GWAS) and meta-analysis to search for common alleles that contribute to risk of AA, and identified several genomic regions harboring potential susceptibility genes. One candidate susceptibility gene expressed in the hair follicle (HF) in AA is peroxiredoxin 5 (PRDX5) (p= of 8.7*10-14), which is also a GWAS gene in Crohn’s disease, sarcoidosis, and psoriasis. PRDX5 is a member of the family of antioxidant enzymes that are crucial for regulating oxidative stress.
Discoid lupus erythematosus (DLE) is a severely disfiguring and difficult to treat autoimmune skin disease for which no new therapies have been FDA-approved in over 60 years. One potential therapeutic target is cutaneous B cells. Though rare in healthy skin, B cells are prevalent in DLE lesions, comprising 10-20% of the robust lymphocytic infiltrate. However, the phenotype and function of this expanded B cell population have not been evaluated in detail and it is unknown whether cutaneous B cells play a role in DLE pathogenesis.
Psoriasis, a chronic, immune-mediated disease dependent upon the interleukin (IL)-23/Th17 pathway, is thought to be initiated through plasmacytoid dendritic cell activation and induction of Type I interferons (IFNs). BMS-986165 is a novel oral, selective tyrosine kinase 2 (TYK2) inhibitor that blocks signal transduction of IL-23, IL-12, and Type I IFNs in cellular assays. Its selectivity for TYK2 over Janus kinases 1–3 is driven by binding to the pseudokinase domain, rather than the conserved kinase domain.
Atopic dermatitis (AD) is reported to be an allergic dermatitis characterized by eczematous lesions and pruritus. Qing-Re Chu-Shi Decoction (QRCSD) is the herbal formula long used as a complementary and alternative therapy for inflammatory skin diseases in China. However, the role and mechanism of action for QRCSD in AD remained poorly understood. The study was designed to explore the underlying effects of the formula and identify the components accounting for the therapeutic effects in2,4-Dinitrochlorobenzene(DNCB)-induced AD-like model of NC/Nga mice.
Anti-p19 treatments, such as tildrakizumab, distinguish themselves from existing biological treatments by their capability of inducing long-term remission in psoriasis. The magnitude and particularly the prolonged clinical response seen with tildrakizumab indicates a fundamentally different mechanism of action than other biological treatments, including anti-TNF, anti-IL-17, and anti-p40 treatments. To explore these mechanisms, we utilized a method for isolation and ex vivo culture of skin-resident T cells in the presence of tildrakizumab, etanercept, or IgG isotype control followed by combination single-cell RNA-seq (scRNA-seq) and mass spectrometry (CyTOF) profiling.
Langerhans cells (LC) represent a specialized subset of evolutionarily conserved dendritic cells (DC) in skin, which are essential for induction of skin immunity and tolerance. They self-renew in the skin at steady state, but could repopulate from peripheral blood Gr-1hi monocytes and bone marrow (BM) hematopoietic stem cells at inflammatory state. Transforming growth factor-beta1 (TGFβ1) is a crucial factor in the regulation of LC maintenance and function after birth, however the underlying TGFβ signaling pathways are still unclear.
Background: Psoriasis is an inflammatory disease associated with aberrant crosstalk between the epidermis and immune system. However, the role of Langerhans cells (LCs) in psoriasis remains controversial. Objectives: To elucidate whether LCs are functionally involved in the development of psoriasis using a mouse model. Methods: Two lines of transgenic mice were used and crossed. They included K5.Stat3C, the psoriasis-model mouse and langerin DTR knock-in (KI) mouse. We performed immunofluorescence staining for LCs in psoriatic lesion of human and model mice.
The maintenance of psoriasis as a skin-confined chronic inflammatory condition requires the abnormal interplay between hyperproliferative epidermal keratinocytes and self-reactive immune cells. In this context, targeting metabolism of keratinocytes is recently reported to be an approach for treating psoriasis, however whether and how the metabolic adaptations of keratinocytes introduce inflammatory cues are unknown. We report that in psoriatic lesions, Protein Phosphatase 6 (PP6) is diminished in the epidermis, and its levels negatively correlate with the disease severity.
AcneLB1103, LB1108, LB1117, LB1118, LB1131
Abdelaziz, Alexa R.LB1053
The primary goals of modern genetics are to identify disease-causing mutations and to define the functions of genes in biological processes. Two complementary approaches, reverse and forward genetics, can be used to achieve this goal. Reverse genetics is a gene-driven approach that comprises specific gene targeting followed by phenotypic assessment. Conversely, forward genetics is a phenotype-driven approach that involves the phenotypic screening of organisms with randomly induced mutations followed by subsequent identification of the causative mutations (i.e., those responsible for phenotype).
Hemidesmosomes and focal adhesions attach keratinocytes to the dermis and act as bidirectional signaling centers to control epidermal renewal. Pora and colleagues (Pora et al., 2019) demonstrate that in migrating primary human keratinocytes, hemidesmosomes cluster as ordered arrays consisting of multiple chevrons, flanked by actin-associated focal adhesions. These and related findings have implications for wound healing, cancer invasion, blistering skin diseases, and skin aging.
The clinical management of large and giant congenital melanocytic nevi (lgCMN) relies heavily upon iterative surgical procedures. In this issue Rouille et al. (2019) use lgCMN explants and a newly developed patient-derived xenograft model to show that the local administration of MEK and Akt inhibitors limits the lgCMN proliferative potential. These findings, along with emerging reports, support continued investigation of targeted therapies in lgCMN.
Skin depigmentation diseases, such as vitiligo, are pigmentation disorders that often destroy melanocytes. However, their pathological mechanisms remain unclear and, therefore, promising treatments or prevention have been lacking. Here we demonstrate that a zebrafish insertional mutant showing a significant reduction of nicastrin transcript possesses melanosome maturation defect, Tyrosinase-dependent mitochondrial swelling and melanophore cell death. The depigmentation phenotypes are proven to be a result of γ-secretase inactivation.
Genome editing represents a promising strategy for therapeutic correction of COL7A1 mutations that cause recessive dystrophic epidermolysis bullosa (RDEB). DNA cleavage followed by homology-directed repair (HDR) using an exogenous template has previously been used to correct COL7A1 mutations. HDR rates can be modest and the double-strand DNA breaks that initiate HDR commonly result in accompanying undesired insertions and deletions (indels). To overcome these limitations, we applied an A•T→G•C adenine base editor (ABE) to correct two different COL7A1 mutations in primary fibroblasts derived from RDEB patients.
Atopic dermatitis (AD) is often concomitant with increased level of IgE against not only foreign allergens but also autoallergens. AD patients with autoallergy are likely to be more severe and difficult to treat, and self-reactive IgE might be a contributing factor in the pathogenesis of AD. However, how autoallergens are recognized by immune system and what immune responses are induced subsequently remain largely unknown. We found that the serum level of IgE against Transglutaminase 3 (TGase3) was significantly higher in AD patients than that of healthy individuals, and was positively correlated with disease severity.
While TERT promoter mutations have been associated with a worsened prognosis in melanoma, the relationship between mutation status and downstream telomerase activity and telomere length remains convoluted. Using Sanger sequencing and qPCR-based techniques, we evaluated 60 melanoma cell lines for TERT promoter mutational status, copy number, gene expression, and telomere length in order to provide a comprehensive analysis of the TERT/telomere pathway and establish a classification system whereby the associations between TERT mutations and their downstream molecular manifestations can more easily be ascertained.
Lack of basic resources within a society (deprivation) is associated with increased cancer mortality and this relationship has been described for melanoma. We have previously reported the association of smoking and low vitamin D levels with melanoma death. In this study we further explored the associations of these with melanoma, in addition to deprivation and socio-economic stressors. In this analysis of 2183 population-ascertained primary cutaneous melanoma patients; clinical, demographic and socio-economic variables were assessed as predictors of tumour thickness, melanoma death and overall death.