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Atmospheric factors such as air pollution have been implicated in premature skin aging and also being associated with several skin pathologies. Among the pollutants to which cutaneous tissues is daily exposed, ozone has been shown to be one of the most noxious. The skin damage caused by ozone exposure is largely related to its ability to generate a complex cascade of oxidative stress related reactions. Indeed ozone is not able to penetrate the skin and although it is not a radical per se it is able to react with the stratum corneum fatty acids and generate oxidized lipids that can act as second messengers.
Subcutaneous (SC) injections can evoke local reactions such as inflammation or necrosis. Preclinical development of SC therapies relies on animal models to characterize these responses, however, translation of these models to the clinic is often limited and no single model has emerged as an accepted standard. Furthermore, animal testing is expensive, time consuming and poses ethical issues. There are currently no in vitro human models to test toxicological effects of SC injections. We developed a new ex vivo human skin model called HypoSkin, containing all skin layers including epidermis, dermis and hypodermis.
Immunotherapy is the indispensable part for melanoma. Polyethylenimine (PEI) is a kind of cationic polymer, which has shown great adjuvanticity in previous studies, possessing as both immunostimulant and antigen vehicle. However, its positive charge-related cytotoxicity limits its medical application. Here, we systematically quantified and balanced these two properties in a series of branched PEI. First, we found that only certain branched PEI has direct immunoactivation effects, and the cytotoxicity of proper intensity induced by branched PEI seems essential to its adjuvanticity.
Cutaneous T cell lymphoma (CTCL) is a debilitating malignancy of skin-homing lymphocytes, thought to arise from a combination of genetic, epigenetic and environmental factors, but specific triggers remain unknown. We propose a model in which adaptive immune responses to particular skin commensals evolve into clonal proliferation of T cells in genetically predisposed individuals. The skin & blood of 10 CTCL patients were sampled three times for V1-3 & V4 16S rRNA sequencing, skin cultures, and T cell isolations for interaction studies with candidate commensals.
Polycyclic aromatic hydrocarbons (PAH) are ubiquitous combustion-related air pollutants that are frequently found in the atmosphere. Due to their widespread distribution, environmental PAH pollution has raised global concern. Recently, there is a growing interest in understanding the effects and the underlying mechanisms of PAH pollution on skin health and aging. To test whether PAH induce oxidative stress leading to adverse effects on the skin, we treated primary human keratinocytes with a PAH formulation that mimics the urban ambient exposure and PAH composition in New York City or diesel particulate matter (DPM).
Hypothesis: the dermal fibroblast is a gatekeeper of the inflammatory response in wound healing; inflammatory cytokines alter the fibroblast phenotype in chronically inflamed non-healing wounds, leading to loss of function. Aim: to identify functional and secretory changes with TNF-α. Primary human dermal fibroblasts cultured from female facial skin (age 52-64) were incubated +/-TNF-α (2.5, 25, 250ng/ml), and metabolic activity, proliferation, migration, secretion of paracrine factors, MMP-2 activation and induction of β-galactosidase determined.
Epidermal growth factor (EGF) is known to stimulate skin cell growth and synthesis of extracellular matrix such as hyaluronan(HA) which is decreased with aging in skin. However, EGF is hard to penetrate the stratum corneum and permeate into skin due to its size and hydrophilicity. To improve the skin delivery of EGF, we have used multi-lamellar complexes consist of EGF and 1,2-dioleoyl-3-tirmethylammonium-propane (DOTAP). EGF-DOTAP complex showed higher permeation rate in human skin and synthesis of hyaluronan in human skin equivalent model than normal liposome.
During embryonic development, lymphatic vessels grow from specialized endothelial cells present in preexisting blood vessels. Molecular signals that regulate the separation or differentiation of blood to lymph vessels as well as the proliferation of lymphatics throughout the embryonic body are not well defined. Here, we present a mouse model that displays with severe edema, anemia and vascular hemorrhaging during mid-gestation (14.5-16.5 days post-coitum) at elevated penetrance (∼90%) resulting in embryonic lethality.
Inflammatory skin diseases such as psoriasis (PS) are complex pathologies involving large groups of interacting proteins. The central mechanism of PS development is still unclear as different researchers suggest different cell types to initiate the disease. The central paradigm of the disease shifted from keratinocyte-specific alternations to the immune cell population changes, besides, there is a high level of heterogeneity between the patients in the therapy response, thus the development of a classifier capable for the identification of the genetic basis of the disease and the disease subtypes is the topical issue.
Designer nuclease-mediated gene editing constitutes a novel approach to precisely correct disease-causing gene mutations. Frame shift mutations in genes such as COL7A1, causing recessive dystrophic Epidermolysis Bullosa (RDEB), are amenable to non-homologous end joining-based corrective approaches. In previous studies using TALE nucleases designed to produce NHEJ-induced frame-restoring indels in RDEB keratinocytes, cloning, selection and expansion of corrected epidermal stem cells had been a pre-requisite to obtain sufficient cells to achieve skin regeneration with therapeutic potential.
We used next-generation sequencing strategies to comprehensively classify an epidermolysis bullosa (EB) cohort from South East Asia. A combination of whole exome sequencing, targeted sequencing and/or candidate gene analysis was used for mutation identification, alongside immuno-mapping of cleavage plane in fresh blister biopsies. We received 48 blister induced skin biopsies and 41 DNA samples from 61 probands (43 from Malaysia, 18 from Singapore). A higher frequency of dystrophic EB cases was identified in Malaysia (16/43) than in Singapore (2/18), whereas 50% of Singapore patients were classified as EB simplex.
Netherton syndrome (NS) is a severe autosomal recessive skin disorder caused by loss-of-function mutations in SPINK5. The disease is characterized by severe skin desquamation and hair shaft defect, which are accompanied by inflammation and allergic reactions. SPINK5 encodes the serine protease inhibitor LEKTI, which regulates epidermal protease activity during the desquamation process in normal epidermis. Absence of LEKTI expression leads to disturbed epidermal protease activity, resulting in stratum corneum detachment from the granular layer, loss of skin barrier function and Par2 activation with skin inflammation.
Amyloidosis cutis dyschromica (ACD) is a form of primary cutaneous amyloidosis that mainly affects Eastern and South-Eastern Asians. Bi-allelic mutations in GPNMB, encoding glycoprotein nonmetastatic gene B, have been identified recently as the causative pathology underlying ACD. Here, we analyzed the clinicopathologic features and molecular basis of ACD in 8 Taiwanese subjects (3M, 5F). Onset of disease was from 6 to 44 years (mean 26.3 years). Skin lesions comprised diffuse hyperpigmented patches interspersed with hypopigmented macules on the trunk and extremities.
Hyperhidrosis affects 220 million people worldwide. The hallmark of this condition is excessive sweating, which negatively impacts the social, emotional and occupational lives of these individuals. A familial predisposition has been established, but studies have failed in identifying what specific genes are involved. This study seeks to determine possible genetic variations contributing to primary hyperhidrosis, specifically single nucleotide polymorphisms (SNPs). We hypothesize that those individuals with primary hyperhidrosis have a genetic variation in the Butyrylcholinesterase (BCHE) gene that inhibits acetylcholine breakdown and removal.
Post-zygotic mutations in GNAQ/GNA11 genes account for mosaic conditions with vascular or pigmentary anomalies. We sought to delineate the phenotype of 32 patients with an activating post-zygotic mutation in GNA11/GNAQ. All patients were studied because of skin vascular anomalies suggestive of involvement of G-proteins. GNAQ and GNA11 mutations were identified on ultradeep NGS on affected skin. A postzygotic PIK3CA mutation was ruled out in 9 patients. Capillary malformations (CM) were subclassified as suggested by Happle: nevus flammeus, nevus roseus, cutis marmorata and anemic nevus.
“Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation” (APLAID syndrome) is due to autosomal dominant hypermorphic missense mutations in the PLCG2 gene encoding phospholipase Cγ2 (PLCγ2), an immune and inflammatory regulatory enzyme. Zhou et. al. reported a novel de novo variant in c.2120C>A nucleotide (p.Ser707Tyr) in the SH2 domain of exon 20 with constitutive activation of PlCy2 in the only two previously reported cases. They described a constellation of features including recurrent intermittent rashes and infections, arthralgias, ocular inflammation, and mild immunodeficiency.
The hyperproliferative human epidermal keratinocytes HaCaT are often used in experimental studies of psoriasis. Recently, we reported that Th1 cytokines TNF, IFN-γ and IL17 exhibited an antiproliferative effect on HaCaT cells. The aim of this paper was to explore how knocking matrix metalloproteinase 1 (MMP1) down in epidermal keratinocytes affected their proliferation, migration and differentiation and be beneficial for psoriasis. MMP1-deficient and control cells were generated by lentiviral transduction.
We describe an uncommon presentation of focal dermal hypoplasia (FDH), or Goltz syndrome, in three consecutive generations. FDH is a rare multisystem disorder affecting mesodermal and ectodermal structures, with the skin, eyes, teeth, and musculoskeletal systems most commonly affected (1). FDH results from mutations in the PORCN gene (2, 3). Ninety five percent of cases arise from novo mutations, whereas 5% are hereditary with an X-linked dominant inheritance pattern (1, 4, 5). Patient 1 is an 8-month-old female born of non-consanguineous marriage who presented with diffuse alopecia of the scalp, linear hypopigmented, atrophic papules, and plaques with peripheral hyperpigmentation on the left hemiabdomen and right lateral leg along Blaschko's lines as well as syndactyly of the right second and third toes.
Patients with epidermolysis bullosa (EB) require care of wounds that are often colonized with bacteria. A subset of EB patients are at risk for squamous cell carcinoma (SCC) and certain bacterial-host interactions have been implicated in this risk. The EB Clinical Characterization and Outcomes Database serves as a repository of information from EB patients at multiple centers in the US and Canada. Using this resource, we conducted a retrospective analysis of 739 wound culture results reported from 159 patients between 2001 and 2017 in the Research Electronic Data Capture Research Electronic Data Capture registry.
MicroRNA-140-3p is known to play critical role in tumor suppressor in various cancer. However, the biological mechanisms of miR-140-3p in human skin, including epidermal homeostasis and keratinocyte differentiation, remain unknown. Here, we demonstrate miR-140-3p is rapidly upregulated during early differentiation in human epidermal keratinocytes (HEKs). miR-140-3p overexpression led to rounded morphology, triggered keratinocyte differentiation in proliferating keratinocytes and in human skin reconstructs.