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Skin pigmentation is essential to balance skin cancer risk and vitamin D production. The exact underlying mechanisms are however unclear, resulting in few available treatment options. Our work describes the existence of a novel conserved mechanism of skin pigmentation. Intramelanosomal redox changes impact ubiquitin-proteasome system-mediated tyrosinase protein degradation, changing the eu- and pheomelanin levels in in vitro, ex vivo and in vivo. Targeting of the nicotinamide nucleotide transhydrogenase (NNT) enzyme by topical small-molecules induces striking skin color changes.
DNA methylation and subsequent oxidation of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) catalyzed by the TET family enzymes are key epigenetic events regulating development and stem cell differentiation in mammals, while genetic ablation of all three Tet genes is embryonic lethal. Here, we show that 5hmC level and Tet1/2/3 expression display dynamic changes in the developing hair follicles (HFs), as well as during the hair cycle. High level of 5hmC and high expression of Tet2 and Tet3 were seen in differentiating hair matrix keratinocytes (KCs), outer and inner root sheaths, hair shaft and dermal papilla.
Metastatic melanoma is one of the most aggressive and drug-resistant cancers with very poor overall survival. Circulating melanoma cells (CMCs) detection was described since 1991 and numerous studies have been reported. However, there is no general consensus of clinical utility of CMC detection, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. Here, we chose to explore the possibility of using a newly developed S100-EPISPOT assay to detect viable CMCs in a homogeneous population of metastatic melanoma patients and compared these results with those obtained with the CellSearch® CMC kit.
In the era of effective molecular targeted treatments and immunotherapies, there is an urgent need to implement the use of circulating biomarkers in the clinic to facilitate personalized therapy and predict treatment response. We conducted a retrospective study to demonstrate the involvement of circulating PD-L1 exosomes in melanoma patients. One hundred melanoma patients were included. Exosomes were isolated by ultracentrifugation. PD-L1 expression was mesured in tumor tissue, in plasma and in melanoma plasma-derived exosomes (ExoPD-L1).
Epidermal cancers are the most prevalent form of malignancy and are strongly linked to ultraviolet exposure. Although significant progress has been made in our understanding of skin cancer, its origin is to date unclear. It is not understood how photodamaged skin, actinic keratosis and SCCs can harbour the same mutations. In this project, using unique Rainbow mouse genetics technology, we aim to show how different clones of epidermal cells respond to ultraviolet radiation injury and progress. This allowed to track the fate of individual epidermal cells over long periods of chronic ultraviolet exposure.
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. Most MCC tumors are virus positive and express Merkel cell polyomavirus oncogenes, whereas virus negative MCC are associated with abundant UV signature mutations. The majority of MCC tumors express CK20. Staining for CK20 and other intermediate filaments in a paranuclear dot pattern is a histological feature used to diagnose MCC. The functional significances of these paranuclear protein aggregates is unknown. We immunostained native MCC tumors with a pan-CK antibody and found areas of paranuclear dot staining in 94% of tumors.
Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. In this retrospective cohort study we have defined factors associated with the risk of metastasis of primary cSCCs. By automated screenings and manual review cohorts of metastatic primary cSCCs (n=85) and non-metastatic primary cSCCs (n=238) treated at a tertiary care center in Finland were generated for comparison. The rate of metastasis was determined utilizing statistics from Finnish Cancer Registry. Mean rate of metastasis of primary cSCC in the study region was 2.4%.
Despite significant efforts in treating Basal cell carcinomas (BCC), surgical excision of the tumours is still the primary mode of treatment. The high risk of recurrence post-excision (∼70% within 5 years) imposes a heavy burden on the health care system worldwide costing approximately $700 million annually just in Australia. Accumulation of ultra-violet induced mutations in the basal layer of the epidermis is the primary risk factor for BCC occurrence. Therefore, we hypothesise that laser ablating the mutations bearing basal layer using dermabrasion technique will allow epidermal cells from the deeper skin layers to re-populate the dermabrased area resulting in mutation free epidermis therefore preventing further BCC recurrence.
Clinical and laboratory diagnostics of mycosis fungoides (MF), the most common cutaneous lymphoma is challenging. Our previous work described 4 promising markers of Sézary syndrome (SS): T-plastin, Twist, NKp46 and KIR3DL2 (Michel et al. 2013). Tox has been shown to be an additional marker for MF and SS. The aim of the present study was to confirm this combination of blood-derived markers in a validation cohort of SS, erythodermic and earlier MF for improving diagnosis and predicting prognosis. Patients with a confirmed diagnosis of MF or SS and patients with other skin diseases were included.
Targeted therapies with B-RAF/MEK-inhibitors are a promising therapeutic option for B-RAF mutated melanoma. However, patients frequently acquire resistance during treatment. Potential resistance mechanisms have been described, most of which bypass mutant BRAF by reactivating MAPK and Pl3K/Akt signaling. The aim of this study was to analyze the alterations in protease, ECM and soluble factors expression in drug-resistant melanoma cells that may contribute to alter the microenvironment and drive resistance.
Anti-PD1 therapy (pembrolizumab and nivolumab) is one of the treatment options for metastatic melanoma. According to literature there are predictors such as the neutrophil-lymphocyte ratio, the level of which at the time of initiation of the therapy indicates well the probability of biological therapy effectiveness. In our study stage IV melanoma patients treated with biological therapy were followed from the beginning of therapy to the week 12 at the Department of Dermatology of the University of Debrecen.
Cutaneous angiosaroma(CAS) is a rare type of soft tissue sarcoma (STS) from endothelial origin. The prognosis is poor and 5-year survival rate is around 20 to 35%. Recent years, immune checkpoints including programmed cell death ligand 1 (PD-L1) and its receptor programmed cell death (PD-1) blockade therapy for various cancers are showing successful results. PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the cancer progression. Overexpression of PD-L1 in almost cancers such as malignant melanoma is associated with poor clinical prognosis.
Melanoma is a highly heterogeneous neoplasm, composed of subpopulations of tumor cells with distinct molecular and biological phenotypes and genotypes. To determine the genetic heterogeneity between primary and metastatic melanoma in Korean melanoma patients, we evaluated several well-known genetic alterations of melanoma. Moreover, clinical relevance of each genetic alteration and heterogeneity between primary and metastatic lesions were also investigated. In addition to clinical data, BRAF, NRAS, GNAQ/11 mutation and KIT amplification data was acquired from an archived primary Korean melanoma cohort (KMC) of 188 patients.
Cutaneous SCC (cSCC) represents the most frequently occurring cancer with metastatic potential accounting for 20% of all skin cancer-related deaths. The incidence of cSCC has been increasing alarmingly especially in Nordic countries. Long noncoding RNAs (lncRNAs) are operationally defined subclass of ncRNAs, representing transcripts that are larger than 200 nt that do not appear to have protein-coding potential and play important role in gene regulation. To identify candidate clinically relevant lncRNAs in cSCC, we performed RNA sequencing in human cSCCs.
Cutaneous Squamous Cell Carcinoma (cSCC) represents about 20% of all non-melanoma skin cancers, with a dramatic increase in incidence in immunosuppressed patients. Since metastases of this disease are associated with a poor prognosis, there is interest in identifying new biomarkers of SCC metastasis as this could indicate new therapeutic targets. One potential candidate is the serine/threonine kinase AKT. AKT exists in two isoforms in the skin- AKT1 and AKT2- which perform different functions during skin homeostasis.
As 2D cultures as well as animal models do have their restrictions concerning predictability of human response, we are developing 3D melanoma skin models to study metastasis and possible anti-melanoma therapies in vitro. Our full-thickness skin equivalents (FTSE) comprise the dermis and the epidermis. For the dermal part, primary human dermal fibroblasts are cast in collagen type I which is subsequently plastic compressed to prevent matrix contraction. The epidermal part is built up by seeding primary human keratinocytes together with melanoma cells onto the dermis.
Melanoma is the solid tumor with high mutational burden, which leads the generation of neo-antigens and the infiltration of cytotoxic T cells (CTLs) recognizing these antigens. Recent improvement of prognosis of melanoma resulting from anti PD-1 antibody elucidated the importance of the expression of PD-1 on tumor-infiltrating CTLs for melanoma cells to evade the cytotoxic activity of CTLs. Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that responds to a wide range of chemicals and induces the battery of genes associated with detoxification, including CYP1A1 and CYP1B1.
Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) is a rare Epstein-Barr virus (EBV) associated T-cell lymphoproliferative disease. The term HVLPD has been renamed from hydroa vacciniforme-like lymphoma to lymphoproliferative disorder according to 2016 WHO classification due to its relationship with chronic active EBV infection and a spectrum in terms of its clinical course. It usually affects children and young adolescents, although adult and elderly cases have been reported. Clinically, it is characterized by recurrent erythematous papules and vesicles leaving pitted scars on the sun-exposed area including face and forearms.
The proportion of the acral melanoma (AM) is much higher in Asians compared to that in Caucasians. In previous studies, the most common mutations in the AMs were NRAS, BRAFV600, and KIT. The nail apparatus melanoma (NAM) is a subtype of the AM. It has been reported that the NAM and the non-nail AM (NNAM) have different aspects of genetic alterations. The aim of this study was to uncover previously unidentified novel mutations for the AM patients and explore genomic differences between the NAM and the NNAM.
Propranolol is currently the first-line treatment for severe infantile hemangioma (IH), the most frequent skin tumor in childhood. Neither the molecular mechanism of action of propranolol nor the cell type target of the drug has been identified with a strong proof of concept. We have developed an IH in vitro model using patient-derived endothelial cells, pericytes and PDGFR-α + stromal cells. The aim of this study is to investigate the role of these perivascular cells in IH vascular proliferation and in the antitumor effect of propranolol on IH angiogenesis.