Journal Of Investigative Dermatology

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Updated: 2 hours 47 min ago

Genomic heterogeneity and branched evolution of early-stage primary acral melanoma revealed by multi-regional microdissection sequencing

Wed, 2019-01-30 00:00
Acral melanoma (AM) is an extremely aggressive subtype of melanoma that is prevalent in east Asia. AM exhibits high intertumoral and intratumoral heterogeneities with poor prognosis. To associate the genomic heterogeneities with phenotypic traits and efficacy of treatments, a method is needed to recover genomic information from limited samples with high specificity and sensitivity from early stage AM specimens. We performed laser capture microdissection (LCM) to isolate single micro-tumor-nests, containing only dozens of cells, from stained tissue slices and then applied multiple annealing and looping based amplification cycles (MALBAC), a highly efficient whole genome amplification methods originally developed for single cells, to amplify the whole genome of each tumor nest for sequencing.

Loss of primary cilia drives switching from Hedgehog to Ras/MAPK pathway in resistant basal cell carcinoma

Tue, 2019-01-29 00:00
Basal cell carcinomas (BCCs) rely on Hedgehog (HH) pathway growth signal amplification by the microtubule-based organelle, the primary cilium. Despite naïve tumors responsiveness to Smoothened inhibitors (Smoi), resistance in advanced tumors remains frequent. While the resistant BCCs usually maintain HH pathway activation, squamous cell carcinomas with Ras/MAPK pathway activation also arise, with the molecular basis of tumor type and pathway selection still obscure. Here we identify the primary cilium as a critical determinant controlling tumor pathway switching.

Chronic inflammation in response to injury: retention of myeloid cells in injured tissue is driven by myeloid cell-intrinsic factors

Mon, 2019-01-28 00:00
Chronic inflammation is a hallmark of impaired healing in a plethora of tissues, including skin, and is associated with aging and diseases such as diabetes. Diabetic chronic skin wounds are characterized by excessive myeloid cells that display an aberrant phenotype, partially mediated by stable intrinsic changes induced during hematopoietic development. However, the relative contribution of myeloid cell-intrinsic factors to chronic inflammation versus aberrant signals from the local environmental was unknown.

Itraconazole induces regression of infantile hemangioma via down-regulation of the PDGF-D/PI3K/Akt/mTOR pathway

Fri, 2019-01-25 00:00
Infantile hemangioma (IH) is the most common benign vascular tumor of infancy. We have previously reported that itraconazole, a common anti-fungal agent, can clinically improve or cure IH; however, the underlying molecular mechanisms are still unclear. Here, we show that itraconazole treatment significantly inhibits the proliferation and promotes apoptosis of the endothelial cells of mouse hemangioma (EOMA) cell line and infantile primary hemangioma endothelial cell (HemEC). Itraconazole also remarkably reduced angiogenesis of HemEC in vitro.

MicroRNAs in Cutaneous T-Cell Lymphoma: The Future of Therapy

Thu, 2019-01-24 00:00
MicroRNAs (miRs) are small, noncoding RNAs with numerous cellular functions. With advancing knowledge of the many functions of miRs in cancer pathogenesis, there is emerging interest in miRs as therapeutic targets in cancers. One disease that poses an intriguing model for miR therapy is cutaneous T-cell lymphoma, a rare disease featuring malignant CD4+ T cells that proliferate in the skin. The hallmark of cutaneous T-cell lymphoma progression is epigenetic dysregulation, with aberrant miR levels being a common feature.

IL-17 and IL-22 promote keratinocyte stemness in the germinative compartment in psoriasis

Wed, 2019-01-23 00:00
Psoriasis is an inflammatory skin disorder characterized by the hyperproliferation of basal epidermal cells. It is regarded as T-cell mediated, but the role of keratinocytes (KCs) in the disease pathogenesis has reemerged with genetic studies identifying KC-associated genes. We applied flow cytometry on KCs from lesional and non-lesional epidermis to characterize the phenotype in the germinative compartment in psoriasis and observed an overall increase in the stemness markers CD29 (2.4 fold), CD44 (2.9 fold), CD49f (2.8 fold) and p63 (1.4 fold).

Yin-yang of IL-33 in human skin mast cells: reduced degranulation, but augmented histamine synthesis through p38 activation

Wed, 2019-01-23 00:00
Mast cells (MCs) are the principal effector cells of IgE-mediated allergy. IL-33 is released by resident skin cells as alarmin upon tissue damage or allergen contact. Owing to their pronounced receptor expression, MCs are important targets of IL-33 action, but consequences for skin MCs are ill-defined, especially upparon chronic exposure to IL-33.Mimicking the inflammatory milieu of skin disorders, we found that persistent exposure to IL-33 (over a 5-week-period) strengthened skin MC numbers through accelerated cell-cycle progression and restriction of apoptosis.

A polymorphic variant in p19Arf confers resistance to chemically-induced skin tumors by activating the p53 pathway

Wed, 2019-01-23 00:00
Identification of the specific genetic variants responsible for the increased susceptibility to familial or sporadic cancers is important. Using a forward genetics approach to map such loci in a mouse skin cancer model, we previously identified a strong genetic locus, Stmm3 (skin tumor modifier of MSM 3), conferring resistance to chemically-induced skin papillomas on chromosome 4. Here, we report the cyclin-dependent kinase inhibitor gene Cdkn2a/p19Arf as a major responsible gene for the Stmm3 locus.

Topical application of a dual ABC transporter substrate and NF-κB inhibitor blocks multiple sources of cutaneous inflammation in mouse skin

Wed, 2019-01-23 00:00
Among the molecular signals underlying cutaneous inflammation is the transcription complex NF-κB, its upstream modulators, and cytokines and chemokines that are the downstream pro-inflammatory effectors. Central to NF-κB activation is I kappa B kinase (IKK) that phosphorylates IκBα releasing NF-κB to the nucleus. In a screen of a kinase inhibitor library, we identified two IKK inhibitors that were high affinity substrates for Pgp (p-glycoprotein, ABCB1), the multidrug resistance protein known to facilitate transdermal drug delivery.

Exposure to solar ultraviolet radiation suppresses cell-mediated immunisation responses in humans: the Australian Ultraviolet Radiation and Immunity Study

Wed, 2019-01-23 00:00
Animal and human studies show that exposure to solar-simulated ultraviolet radiation (UVR) is immunomodulatory. Human studies using natural sun exposure and controlling for confounding are rare.We immunised 217 healthy adults (18-40 years) with a T-cell dependent antigen, keyhole limpet haemocyanin (KLH) and measured personal clothing-adjusted UVR (ca-UVR) exposure (for five days before and after immunisation), lifetime cumulative UVR exposure, serum 25-hydroxyvitamin D (25(OH)D) concentration at immunisation, and potential confounding factors.

Thrombospondin-1 is a major activator of TGF-beta signaling in recessive dystrophic epidermolysis bullosa fibroblasts

Wed, 2019-01-23 00:00
Mutations in the gene encoding collagen VII (C7) cause the devastating blistering disease recessive dystrophic epidermolysis bullosa (RDEB). RDEB is characterized by severe skin fragility and non-healing wounds aggravated by scarring and fibrosis. We previously demonstrated that thrombospondin-1 (TSP1) is increased in RDEB fibroblasts. Because transforming growth factor-beta (TGFβ) signaling is also increased in RDEB, and TSP1 is known to activate TGFβ, we investigated the role of TSP1 in TGFβ signaling in RDEB patient cells.

Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

Wed, 2019-01-23 00:00
Cutaneous squamous cell carcinoma (cSCC) from the head and neck typically metastasizes to the lymph nodes of the neck and parotid glands. When a primary is not identified, they are difficult to distinguish from metastases of mucosal origin and primary salivary gland SCC. Ultraviolet radiation causes a mutation pattern that predominantly features cytosine to thymine transitions at dipyrimidine sites and has been associated with cSCC. In this study, we used whole genome sequencing data from 15 cSCC metastases and show that a UV signature mutation is pervasive across the cohort and distinct from mucosal SCC.

Analysis of the tumor reactivity of tumor-infiltrating lymphocytes in a metastatic melanoma lesion that lost MHC class I expression after anti-PD-1 therapy

Wed, 2019-01-23 00:00
MHC class I loss due to the abnormality of β2-microgloburin (B2M) gene is one of the mechanism underlying delayed relapses in melanoma patients long after the initial positive responses to anti-PD-1 therapy. However, the tumor-specific reactivity of tumor-infiltrating lymphocytes (TILs) in tumor lesions that lost MHC class I expression has not been well evaluated.We report the case of a 55-year-old woman with two metastatic melanoma lesions. After a 12-month period of successful tumor suppression by anti-PD-1 antibody therapy, one lesion started to grow again.

Imiquimod-induced psoriasis in mice depends on the IL-17 signaling of keratinocytes

Wed, 2019-01-23 00:00
Pathology of psoriasis strongly depends on IL-17A. Monoclonal antibodies blocking either the cytokine or its receptor are amongst the most efficient treatments for psoriatic patients. Keratinocytes can be activated upon exposure to IL-17A and TNFα and secrete secondary cytokines and chemokines in the inflamed skin. In psoriasis and its imiquimod (IMQ)-induced mouse model, a strong skin-infiltration of neutrophils and inflammatory monocytes can be observed. But it is not clear to date how exactly those cellular populations are attracted to the skin and what their contribution to the pathogenesis of the disease is.

Elevated local senescence in diabetic wound healing is linked to pathological repair via CXCR2.

Wed, 2019-01-23 00:00
Cellular senescence can be broadly defined as a stable, yet essentially irreversible, loss of proliferative capacity. Historically, senescence is described as a negative outcome of advanced cellular age. It is now clear, however, that senescence represents a dynamic autonomous stress response, integral to long-term tumour suppression. Intriguingly, transient induction of a senescent phenotype has actually been suggested to promote regeneration in both liver and skin. Here we explored the role of senescence in pathological aged and diabetic murine wound healing.

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