Journal Of Investigative Dermatology

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484 Pericytes from Infantile Hemangioma regulate vessels formation in vitro

Sun, 2019-09-01 00:00
Infantile hemangiomas (IH) or “strawberry tumors” are benign cutaneous tumors associated with abnormal proliferation of small vessels. Very common in infants (7%) and often innocuous, these vascular tumor appear few days after birth. They grow during the first weeks of life. Then they spontaneously regress for several years. However, 10% require a surgery or a treatment by propranolol depending on IH location and in case of vital threat (blocking breathing, heart failure) or if they lead to complications sometimes painful and dangerous for children (ulcerations, functional risks such as loss of vision).

483 Next-generation target sequencing analysis identifies multiple somatic mutations in basal cell carcinoma

Sun, 2019-09-01 00:00
Basal cell carcinoma (BCC) is the most common cutaneous neoplasia in fair-skinned individuals usually characterized by locally destructive growth and invasion of surrounding tissue. BCC is primarily driven by the aberrant activation of the Sonic Hedgehog pathway (HH), with the majority of BCCs carrying mutations in PTCH1 or SMO genes. However, the great variability in morphology, aggressiveness and response to treatment of BCC remains unexplained and highlights the hypothesis that additional genes might contribute to tumorigenesis of different BCC subtypes.

482 Biomolecular profile and reflectance confocal microscopy refine diagnosis and predict response to therapy in melanoma subsets

Sun, 2019-09-01 00:00
Dermoscopy and reflectance confocal microscopy (RCM) give clinicians the opportunity to analyze architectural and cytological features at nearly histological resolution in vivo. RCM allows the identification of four malignant melanoma (MM) subtypes: dendritic-cell (DC), round cell (RN), dermal-nest (DN) and combined-type (CT). This work aims to characterize the MM RCM-subtypes in terms of biomarkers, gene expression, aggressiveness and response to therapy. RNA extracts from melanoma tissues are analysed by NanoString, revealing significant differences in the expression of genes involved in chemotaxis, inflammation, cell-cell adhesion, cell motility and angiogenesis.

481 Exploring the molecular discordance between primary and metastatic melanoma

Sun, 2019-09-01 00:00
The majority of melanoma arise through the gradual accumulation of genetic abnormalities at the somatic level involving critical signaling pathways such as MAPK signaling, making the treatment with kinase inhibitors a preferred option in the advanced disease. Intra-patient molecular heterogeneity between the primary melanoma and the related metastasis may exist, and changes of mutational status over time might occur. We investigated the mutational status of BRAF, NRAS and c-KIT in primary melanoma and related metastases and evaluated the intra-patient heterogeneity of mutational profiles during progression.

480 Role of Kruppel-like factor 4 (KLF4) in cutaneous squamous cell carcinoma

Sun, 2019-09-01 00:00
Kruppel-like factor 4 (KLF4) is a zinc-finger transcription factor. KLF4 is a tumor suppressor in colorectal cancer and esophageal squamous cell carcinoma, however, in oral squamous cell carcinoma and breast ductal carcinoma, KLF4 may act as a tumor promoter. The function and mechanism of KLF4 in cutaneous squamous cell carcinoma are still unclear. In present study, we investigated the functional roles of KLF4 in cutaneous SCC. We examined the expression of KLF4 in normal skin and SCC tissues. KLF4 expression was detected in epidermis of normal skin but rarely detected in SCC tissues.

479 B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

Sun, 2019-09-01 00:00
Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Here we show that tumor-associated B cells (TAB) are vital to tumor associated inflammation. In human melanoma, TAB are located at the invasive tumor-stroma margin arguing for a preferentially cell contact-independent communication with tumor cells. We therefore exposed in vitro peripheral blood- and melanoma-derived B cells to conditioned medium from autologous melanoma cells. In proteomics and RNA-seq data, we observed induction of several pro- and anti-inflammatory factors and differentiation towards a plasmablast-like phenotype.

478 Expression of meiosis regulatory genes in cutaneous T-cell lymphoma

Sun, 2019-09-01 00:00
Cutaneous T-cell lymphoma (CTCL) is a non-Hodgkin lymphoma characterized by infiltrating malignant monoclonal T-lymphocytes. Differential diagnosis of CTCL poses a challenge to clinicians due to its propensity to mimic benign dermatoses such as psoriasis and eczema. Meiosis-specific cancer/testis (meiCT) antigens are a specialized group of genes expressed specifically in meiosis and epigenetically silenced in normal somatic cells, however recent research has demonstrated that a number of meiosis genes are ectopically upregulated in cancers, including CTCL.

477 Generating Merkel cell polyomavirus reactive T cells from healthy donors for adoptive immunotherapy

Sun, 2019-09-01 00:00
Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine skin cancer that is highly immunogenic. Approximately 80% of MCC tumors are virus positive (VP-MCC) and express Merkel cell polyomavirus (MCPyV) T antigens that drive oncogenesis. As VP-MCC have a low mutation burden with few predicted neoantigens, viral oncogenes are thought to be the primary target for anti-cancer immunity. Immune checkpoint inhibitors improve MCC survival, yet <50% of patients have durable benefit. Patients who fail checkpoint inhibition or who have immune dysfunction may benefit from adoptive cellular therapy using virus reactive T cells from HLA-matched donors.

476 GJB5 association with BRAF mutation and survival in cutaneous melanoma

Sun, 2019-09-01 00:00
Gap junctional intercellular communication is crucial for epidermal cellular homeostasis. Inability to establish melanocyte-keratinocytes contacts and loss of intercellular junction’s integrity may contribute to melanoma development. Connexins, laminins and desmocollins have been implicated in the control of melanoma growth where their reduced expression has been reported in metastatic lesions. We have investigated Connexin 31.1 (GJB5) expression and looked for any association with BRAF mutational status, patient prognosis and MAPK inhibitors (MAPKi) treatment.

475 Targeting the JAK/STAT3 pathway with ruxolitinib for RDEB-cSCC therapy

Sun, 2019-09-01 00:00
The most lethal complication of recessive dystrophic epidermolysis bullosa (RDEB) is the development of aggressive cutaneous squamous cell carcinoma (cSCCs), which lead the high mortality rates in these patients. Elevated levels of phospho-STAT3 have been found in two RDEB-derived cSCC cell lines, demonstrating that constitutive activation and dysregulation of the JAK/STAT pathway may play a role in RDEB-cSCC pathogenesis. Ruxolitininb is an FDA approved JAK1/2 inhibitor that has efficacy in myelofibroblast, human head, and neck squamous cell carcinomas, as well as lung and breast carcinomas.

474 Inherited duplications of PPP2R3B promote naevi and melanoma via a novel C21orf91-driven proliferative phenotype

Sun, 2019-09-01 00:00
The majority of the heredity of melanoma remains unexplained, however inherited copy number changes have not yet been systematically studied. The genetic environment is highly relevant to treatment stratification, and new gene discovery is therefore desirable. Using an unbiased whole genome screening approach for copy number we identify here a novel melanoma predisposing factor, familial duplications of gene PPP2R3B, encoding a regulatory unit of critical phosphatase PP2A. Significant correlation between expression of PPP2R3B in tumour tissue and survival in a large melanoma cohort was confirmed, and associated with a non-immunological expression profile.

473 WITHDRAWN

Sun, 2019-09-01 00:00

472 MicroRNA-130a: a tumor suppressive miRNA in cutaneous squamous cell carcinoma

Sun, 2019-09-01 00:00
Cutaneous Squamous Cell Carcinoma (cSCC) is a malignant neoplasm of the skin resulting from the accumulation of somatic mutations due to solar radiation. It is one of the fastest increasing malignancies that represents a particular problem among immunosuppressed individuals. MicroRNAs (miRNAs) are short non-coding RNAs that regulate the expression of protein-coding genes at the posttranscriptional level. Global analysis of miRNA expression in human cSCC identified miR-130a as one of the miRNAs that downregulated in cSCC and in this study we investigated its function in the disease in in vitro and in vivo disease models.

471 Genetic mutations underlying phenotypic plasticity in basosquamous carcinoma

Sun, 2019-09-01 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 and molecular drivers of BCC and SCC development have been extensively characterized, BSC pathogenesis remains unclear, in particular regarding the reprogramming of tumor keratinocytes towards basaloid or squamatized phenotypes. Here, by analogy to pathway switching previously observed in BCC escaping Hedgehog (Hh) inhibition, we demonstrate loss of Hh signaling and MAPK pathway activation associated with squamatization of BSC.

470 Endoglin enhances the progression of angiosarcoma through the regulation of non-Smad TGF-β signaling

Sun, 2019-09-01 00:00
Angiosarcoma is a rare malignant tumor derived from endothelial cells and its prognosis is poor because advanced angiosarcoma is resistant to standard chemotherapy, and new therapies are urgently needed. Endoglin (CD105) is a membrane glycoprotein that acts as a coreceptor for transforming growth factor-β (TGF-β) signaling. Endoglin is overexpressed in the tumor-associated endothelial cells, and it enhances angiogenesis. Numerous clinical trials are testing the effectiveness of anti-endoglin antibody in various types of malignancies.

469 Epigenomic characterization of non-melanoma skin cancer

Sun, 2019-09-01 00:00
Non-melanoma skin cancers (NMSC) arise from keratinocytes, the main epidermal cell type, and are considered one of the most frequent malignancies worldwide. Among them, cutaneous squamous cell carcinoma (cSCC) represents the clinically most important tumor type due to its substantial risk of metastasis. Chronic exposure to ultraviolet radiation (UVR) is the main cause of cSCC, which typically arises in highly exposed regions like the head or the neck from precursor and in situ lesions, such as actinic keratosis (AK) or Bowen’s disease, respectively.

468 Cutaneous squamous cell carcinomas are infiltrated with CD8+CD103+ resident memory T cells which express inhibitory markers and are associated with metastasis

Sun, 2019-09-01 00:00
Human skin contains multiple memory T cell subtypes which are crucial in protective cutaneous immunity and in mediating inflammatory dermatoses, but their roles in cutaneous squamous cell carcinoma (cSCC) are unclear. In this study, phenotypic and functional characterisation of memory T cells in human cSCCs and patient-matched normal skin and peripheral blood was performed. Flow cytometry of lymphocytes from cSCCs (n=53) showed 77.2% of tumoral T cells were CCR7-CD45RA- effector memory T cells, with fewer CCR7+CD45RA- central memory, CCR7-CD45RA+ effector memory RA, CCR7+CD45RA+ naive and CCR7+L-selectin- migratory memory T cells.

467 Immunotherapy with 4-1BBL-expressing iPScell-derived myeloid lines

Sun, 2019-09-01 00:00
We have established an immune cell therapy with immortalized induced pluripotent stem-cell-derived myeloid lines (iPS-ML). The benefits of using iPS-ML is the infinite proliferative capacity and ease of genetical modification. 4-1BB is an inducible receptor of the TNF superfamily expressed on activated T cells. The interaction between the receptor 4-1BB and its ligand 4-1BBL provides co-stimulatory signals for T-cell activation. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expressions of CD80 and CD86 were upregulated in iPS-ML-41BBL compared to control iPS-ML.

466 OVO-like2/ZEB1 axis inhibits a promotion of actinic keratosis towards squamous cell carcinoma

Sun, 2019-09-01 00:00
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and actinic keratosis (AK) is one of the superficial variant of cSCC. Since there are not enough treatments established for advanced cSCC, it is necessary to control the development. Most AK cases are restricted to the epidermis for a long time through the suppression of epithelial-to-mesenchymal transition (EMT). OVO-like (OVOL) 1 and OVOL2 are known as important factors against EMT, but their function is not wholly understood in skin tumors.

465 Cutaneous T-cell lymphoma cells release proapoptotic Fas ligand in lysosomal secretory vesicles

Sun, 2019-09-01 00:00
Advanced-stage cutaneous T-cell lymphomas (CTCL) are associated with a global decrease in normal T cell numbers and diversity, leading to a profound immunodeficiency and recurrent severe infections. The mechanisms of this normal T-cell depletion remain unclear, although several mechanisms may be suggested. Here we observed that CTCL cell lines and tumor cells from patients with Sezary syndrome expressed Fas ligand mRNA. Fas ligand was not expressed at the cell surface of CTCL cells but was present in the cytoplasm and localized in secretory microvesicles.

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