Journal Of Investigative Dermatology

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Clonal expansion of second-hit cells with somatic recombinations or C>T transitions form porokeratosis in MVD or MVK mutant heterozygotes

Sat, 2019-06-15 00:00
Patients with disseminated superficial actinic porokeratosis (DSAP) and linear porokeratosis exhibit monoallelic germline mutations in genes encoding mevalonate pathway enzymes, MVD or MVK. Here, we showed that each skin lesion of DSAP exhibited an individual second-hit genetic change in the wild-type allele of the corresponding gene specifically in the epidermis, indicating that a postnatal second hit triggering biallelic deficiency of the gene is required for porokeratosis to develop. Most skin lesions exhibited one of two principal second hits, i.e., somatic homologous recombinations rendering the monoallelic mutation biallelic or C>T transition mutations in the wild-type allele.

Genetic mutations underlying phenotypic plasticity in basosquamous carcinoma

Sat, 2019-06-15 00:00
Basosquamous carcinoma (BSC) is an aggressive skin neoplasm with features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). While genetic drivers of BCC and SCC development have been extensively characterized, BSC has not been well studied and it remains unclear whether these tumors originally derive from BCC or SCC. In addition, it is unknown which molecular pathways mediate reprogramming of tumor keratinocytes towards basaloid or squamatized phenotypes. We sought to characterize genomic alterations underlying sporadic BSC to elucidate the derivation of these mixed tumors.

Next generation sequencing identifies the keratinocyte-specific miRNA signature of psoriasis

Sat, 2019-06-15 00:00
Psoriasis is the most common immune-mediated skin disease in adults (Lowes et al., 2014), in which the disturbed interplay between keratinocytes and immune cells leads to chronic skin inflammation (Lowes et al., 2014). Conventionally, keratinocytes were thought to be passive bystanders, however recent research suggests their active involvement in the disease (Lowes et al., 2014, Swindell et al., 2011). In psoriasis, keratinocytes acts as an amplifier of skin inflammation by producing antimicrobial peptides, cytokines and chemokines (Lowes et al., 2014).

Guselkumab efficacy after withdrawal is associated with suppression of serum IL-23-regulated IL-17 and IL-22 in psoriasis: VOYAGE 2 study

Sat, 2019-06-15 00:00
Guselkumab selectively inhibits interleukin (IL)-23 and in psoriasis, produces high clinical responses including durable maintenance following treatment withdrawal in some patients. The relationships between IL-23 blockade, serum markers downstream of IL-23 signaling, and withdrawal were explored with guselkumab in VOYAGE 2.

Quantitative Trait Locus and Integrative Genomics Revealed Candidate Modifier Genes for Ectopic Mineralization in Mouse Models of Pseudoxanthoma Elasticum

Fri, 2019-06-14 00:00
Pseudoxanthoma elasticum (PXE), a prototype of heritable multi-system ectopic mineralization disorders, is caused by mutations in the ABCC6 gene encoding a putative efflux transporter, ABCC6. The phenotypic spectrum of PXE varies, and the correlation between genotype and phenotype has not been established. To identify genetic modifiers, we performed quantitative trait locus analysis in inbred mouse strains that carry the same hypomorphic allele in Abcc6 yet with highly variable ectopic mineralization phenotypes of PXE.

TITLE: HPV16 E7-driven epithelial hyperplasia promotes impaired antigen presentation and regulatory T cell development.

Fri, 2019-06-14 00:00
Human papillomaviruses (HPV) infect keratinocytes and can lead to hyperproliferative dysplasia and malignant transformation if not cleared by the immune system. HPV has evolved an array of mechanisms to evade and manipulate the immune system to improve replication efficiency and promote persistent infection. We here demonstrate that hyperproliferative skin expressing the high-risk HPV16 E7 oncogene as a transgene drives immune-modulation of dendritic cells (DCs) resulting in reduced capacity to take up antigen and prime effector CD4+ T cell responses.

SIRT3 Regulates Macrophage-Mediated Inflammation in Diabetic Wound Repair

Fri, 2019-06-14 00:00
Control of inflammation is critical for the treatment of non-healing wounds, but a delicate balance exists between early inflammation that is essential for normal tissue repair and the pathologic inflammation that can occur later in the repair process. This necessitates the development of novel therapies that can target inflammation at the appropriate time during repair. Here, we found that SIRT3 is essential for normal healing and regulates inflammation in wound macrophages post-injury. Under ‘pre-diabetic’ conditions, SIRT3 was decreased in wound macrophages and resulted in dysregulated inflammation.

miR-146a inhibits biofilm-derived Cutibacterium acnes induced inflammatory reactions in human keratinocytes

Mon, 2019-06-10 00:00
Acne is a chronic inflammatory skin disorder that often involves the formation of C. acnes biofilms. Several microRNAs (miRNAs) are known to be involved in inflammatory responses. However, it is unknown whether miRNAs play a role in the inflammatory reaction triggered by C. acnes biofilm. Here we investigated the role of miR-146a in biofilm-derived C. acnes induced inflammatory responses. Increased expressions of miR-146a and toll-like receptor (TLR) 2 were detected in acne lesions. In presence of biofilm-derived C.

Harnessing the Power of Regenerative Therapy for Vitiligo and Alopecia Areata

Mon, 2019-06-10 00:00
Vitiligo and alopecia areata (AA) are common autoimmune conditions characterized by white spots on the skin (vitiligo) and bald spots on the scalp (AA), which significantly impact patients’ lives by damaging their appearance and function. Melanocytes are the target of immune destruction in vitiligo and are hypothesized to be the site of immune attack in AA. This inflammatory process can be partially reversed by immunosuppressive drugs. Both conditions demonstrate regenerative components that are just now being identified.

Reduced iron in diabetic wounds: An oxidative stress-dependent role for STEAP3 in extracellular matrix deposition and remodelling

Fri, 2019-06-07 00:00
Iron is crucial for maintaining normal bodily function, with well-documented roles in erythropoiesis, haemostasis and inflammation. Despite this, little is known about the temporal regulation of iron during wound healing, nor how iron contributes to wound biology and pathology. Here we profiled tissue iron levels across a healing time-course, identifying iron accumulation during late-stage repair. Interestingly, diabetic murine wounds displayed significantly reduced iron levels, delayed extracellular matrix deposition and dysregulation of iron gene expression.

Side-by-side Comparison of Skin Biopsies and Skin Tape Stripping Highlights Abnormal Stratum Corneum in Atopic Dermatitis

Thu, 2019-06-06 00:00
Skin biopsies are commonly used for the assessment of skin pathology in various skin diseases including atopic dermatitis (AD). However, due to the invasive nature of skin biopsies, many patients, particularly children, decline participation. This can lead to potential subject sampling bias as data could be skewed toward more severe, older patients willing to give biopsies. Recently, researchers have began studying the skin with a minimal, non-invasive technique using skin tape strips (STS) to profile the epidermal transcriptome, proteins, and lipids in the skin.

The sphingosine-1-phospate receptor modulator fingolimod aggravates murine epidermolysis bullosa acquisita

Thu, 2019-06-06 00:00
Fingolimod (FTY720) is the first orally available disease-modifying drug against relapsing-remitting multiple sclerosis (MS) and the first drug of the class of sphingosine-1-phosphate (S1P) receptor modulators (S1PRMs). S1P receptors are extracellular, G protein-coupled receptors regulating diverse cell responses, including cell migration and lymphocyte egress from the lymph nodes. Fingolimod is a functional antagonist of the receptors S1P2 and S1P3-5 (Thieme et al., 2017).

Therapeutic potential of rottlerin for skin hyperpigmentary disorders by inhibiting the transcriptional activity of CREB-regulated transcription coactivators

Thu, 2019-06-06 00:00
Exposure to ultraviolet radiation (UVR) stimulates the cyclic AMP (cAMP) signaling pathway, which leads to melanin deposits in skin tissues. Although melanogenesis can be beneficial by protecting skin from UVR-induced damage, excessive or uneven deposits of melanin can cause various skin hyperpigmentation disorders. Because cAMP responsive element–binding protein (CREB) and CREB-regulated transcription coactivators (CRTCs) play a major role in conveying cAMP signals that induce transcription of microphthalmia-associated transcription factor (MITF) and melanin production, we screened for a CREB/CRTC inhibitor and identified rottlerin (Rot) as a potent inhibitor of its transcriptional activity.

Role of immune response, inflammation and tumor immune response–related cytokines/chemokines in melanoma progression

Thu, 2019-06-06 00:00
To investigate the role of tumor cytokines/chemokines in melanoma immune response, we estimated proportions of immune cell subsets in melanoma tumors from TCGA, followed by evaluation of association between cytokine/chemokine expression and these subsets. We then investigated association of immune cell subsets, chemokines, and cytokines with patient survival. Finally, we evaluated immune cell TIL score for correlation with melanoma patient outcome in a separate cohort. There was good agreement between RNA-seq estimation of T-cell subset with pathologist-determined TIL score.

Caspase-11 Mediated Cell Death Contributes to the Pathogenesis of Imiquimod-Induced Psoriasis

Tue, 2019-06-04 00:00
Inflammasomes are multiprotein complexes that respond to infection or injury to activate inflammation. Inflammatory caspases, caspase-1, 4 and 5 in humans, and their murine orthologues caspase-1 and 11 are crucial components of inflammasomes, responsible for the maturation and secretion of IL-1β and IL-18, and for pyroptosis (inflammatory cell death) (Creagh, 2014). Psoriasis is a chronic inflammatory skin condition with a range of clinical manifestations. The most common manifestation is chronic plaque psoriasis, where the adaptive immune response predominates.

Role of SNAREs in the Atopic Dermatitis-related Cytokine Secretion and Skin-Nerve Communication

Tue, 2019-06-04 00:00
The role of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) in atopic dermatitis (AD) is unknown. This study is envisioned to lead to the previously unreported SNARE function in AD-related cytokine secretion and epidermis-nerve communication. Herein, we report that various cytokines were simultaneously upregulated and co-released in the innate immunity-activated primary human keratinocytes (phKCs). AD-related cytokines thymic stromal lymphopoietin (TSLP), endothelin-1 (ET-1) or inflammatory TNF-α activated distinct but overlapping sensory neurons.

BJD Editor’s Choice

Sat, 2019-06-01 00:00
Palmgren and colleagues from Sweden were concerned that the diagnosis of a surgical-site infection (SSI) in dermatological surgery may be based entirely on a subjective assessment. Their aim with this study was to investigate the interobserver agreement between dermatologists in their diagnosis of SSI of dermatosurgical wounds. They carried out an international electronic photographic survey of dermatologists using eight photographs of wounds 1 week after full-thickness skin grafting. All wounds were assessed in terms of visual criteria beforehand.

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Sat, 2019-06-01 00:00

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Sat, 2019-06-01 00:00

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