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Pigment Cell & Melanoma Research

Nicholas Theodosakis, Casey G Langdon, Goran Micevic, Irina Krykbaeva, Robert E Means, David F Stern, Marcus W Bosenberg
This study evaluates the use of HMG-CoA reducatase inhibitors, or statins, as an adjunctive to BRAF and MEK inhibition as a treatment in melanomas and other tumors with driver mutations in the MAPK pathway. Experiments used simvastatin in conjunction with vemurafenib and selumetinib in vitro and simvastatin with vemurafenib in vivo to demonstrated additional growth abrogation beyond MAPK blockade alone. Additional studies demonstrated that statin anti-tumor effects appeared to depend on inhibition of isoprenoid synthesis given rescue with add-back of downstream metabolites...
October 3, 2018: Pigment Cell & Melanoma Research
Fabian V Filipp, Stanca Birlea, Marcus W Bosenberg, Douglas Brash, Pamela B Cassidy, Suzie Chen, John A D'Orazio, Mayumi Fujita, Boon-Kee Goh, Meenhard Herlyn, Arup K Indra, Lionel Larue, Sancy A Leachman, Caroline Le Poole, Feng Liu-Smith, Prashiela Manga, Lluis Montoliu, David A Norris, Yiqun Shellman, Keiran S M Smalley, Richard A Spritz, Richard A Sturm, Susan M Swetter, Tamara Terzian, Kazumasa Wakamatsu, Jeffrey S Weber, Neil F Box
In this perspective, we identify emerging frontiers in clinical and basic research of melanocyte biology and its associated biomedical disciplines. We describe challenges and opportunities in clinical and basic research of normal and diseased melanocytes that impact current approaches to research in melanoma and the dermatological sciences. We focus on four themes: (1) clinical melanoma research, (2) basic melanoma research, (3) clinical dermatology, and (4) basic pigment cell research, with the goal of outlining current highlights, challenges, and frontiers associated with pigmentation and melanocyte biology...
October 3, 2018: Pigment Cell & Melanoma Research
Michael P Smith, Sareena Rana, Jennifer Ferguson, Emily J Rowling, Keith T Flaherty, Jennifer A Wargo, Richard Marais, Claudia Wellbrock
The BRAF-kinase and the MAPK-pathway are targets of current melanoma therapies. However, MAPK-pathway inhibition results in dynamic changes of down-stream targets that can counteract inhibitor-action not only during treatment, but also in acquired resistant tumours. One such dynamic change involves the expression of the transcription factor MITF, a crucial regulator of cell survival and proliferation in untreated as well as drug-addicted acquired resistant melanoma. Tight control over MITF expression levels is required for optimal melanoma growth, and while it is well established that the MAPK-pathway regulates MITF expression, the actual mechanism is insufficiently understood...
October 1, 2018: Pigment Cell & Melanoma Research
Nicholas D'Arcy, Nicholas Matigian, Kim-Anh Lê Cao, Brian Gabrielli
Ultraviolet Radiation (UVR) is the major environmental mutagen driving the development of melanoma. The major UVR-induced DNA lesions, 6-4 photoproducts and cyclobutane pyrimidine dimers are primarily repaired by Nucleotide Excision Repair (NER). The very high levels of UV signature mutations (USM; Signature 7 mutations) that are observed in melanomas are the direct outcome of unrepaired UV-induced lesions (Alexandrov et al., 2013; Hodis et al., 2012), suggesting that there must be defects in the repair of these lesions, and thus potentially in NER...
September 30, 2018: Pigment Cell & Melanoma Research
Timothy Budden, Nikola A Bowden
Melanocortin 1 receptor (MC1R) is a G protein-coupled receptor expressed in melanocytes where it plays an important role in skin pigmentation and the UV response, and has implications in melanoma development. Here we show that methylation of a CpG island (CGI) within the MC1R gene can control expression of MC1R in melanoma. This CGI overlaps with a potential enhancer region, and is unmethylated in normal melanocytes but highly methylated in other skin cells, suggesting a melanocyte specific function. Analysis showed that MC1R was the only gene significantly differentially expressed by methylation of this region...
September 28, 2018: Pigment Cell & Melanoma Research
Marco Ranzani, Constantine Alifrangis, Nicola A Thompson, Alistair G Rust, Amin Allahyar, Vivek Iyer, Stacey Price, Peter Ellis, Gemma Turner, Jeroen de Ridder, Ultan McDermott, David J Adams
The treatment of melanoma patients has been revolutionized by the development of targeted therapies such as BRAF and MEK inhibitors which have achieved response rates above 50% and median overall survival of more than 12 months. Similarly, immunotherapies such as checkpoint inhibitors have been used to obtain response rates of up to 70%, with a proportion of patients having long-term durable responses (Luke et al., 2017). Despite these advances, the majority of melanoma patients cannot be cured with available treatments...
September 15, 2018: Pigment Cell & Melanoma Research
Filipe V Almeida, Stephen M Douglass, Mitchell E Fane, Ashani T Weeraratna
This review will focus on the role of the tumor microenvironment (TME) in the development of drug resistance in melanoma. Resistance to mitogen-activated protein kinase inhibitors (MAPKi) in melanoma is observed months after treatment, a phenomenon that is often attributed to the incredible plasticity of melanoma cells but may also depend on the TME. The TME is unique in its cellular composition - it contains fibroblasts, immune cells, endothelial cells, adipocytes and amongst others. In addition, the TME provides "non-homeostatic" levels of oxygen, nutrients (hypoxia and metabolic stress) and extracellular matrix proteins, creating a pro-tumorigenic niche that drives resistance to MAPKi treatment...
September 14, 2018: Pigment Cell & Melanoma Research
Joshua D Webster, Trang H Pham, Xiumin Wu, Nicolas W Hughes, Zhongwu Li, Klara Totpal, Ho-June Lee, Philamer C Calses, Mira S Chaurushiya, Eric W Stawiski, Zora Modrusan, Matthew T Chang, Christopher Tran, Wyne P Lee, Sreedevi Chalasani, Jeffrey Hung, Neeraj Sharma, Sara Chan, Kathy Hotzel, Eric Talevich, Alan Shain, Mengshu Xu, Jennie Lill, Vishva M Dixit, Boris C Bastian, Anwesha Dey
The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk for mesothelioma and melanocytic tumors. Here, we show that Bap1 deletion in melanocytes cooperates with the constitutively active, oncogenic form of Braf (BrafV600E ) and UV to cause melanoma in mice, albeit at very low frequency. In addition, Bap1 null melanoma cells derived from mouse tumors are more aggressive and colonize and grow at distant sites more than their wild-type counterparts. Molecularly, Bap1 null melanoma cell lines have increased DNA damage measured by γH2aX and hyperubiquitination of histone H2a...
August 29, 2018: Pigment Cell & Melanoma Research
Jung Min Bae, Sang Ho Oh, Hee Young Kang, Young Wook Ryoo, Cheng-Che E Lan, Lei-Hong Xiang, Ki-Ho Kim, Tamio Suzuki, Ichiro Katayama, Seung-Chul Lee
Since localized treatment for vitiligo is as essential as systemic treatment, a reliable instrument for target evaluation is needed besides those for whole body evaluation. We developed the Vitiligo Extent Score for a Target Area (VESTA) using reference images of both marginal and perifollicular repigmentation to measure the repigmentation rate (%) in a target lesion. In the validation study, a total of 65 dermatologists in 10 institutes evaluated 17 pairs of vitiligo images (pre- and post-treatment) using both a rough estimate and the VESTA...
August 17, 2018: Pigment Cell & Melanoma Research
Takako Shibata, Kentaro Kajiya, Kiyoshi Sato, Jisun Yoon, Hee Young Kang
No abstract text is available yet for this article.
August 17, 2018: Pigment Cell & Melanoma Research
Barbara Hernando, Viki B Swope, Steven Guard, Renny J Starner, Kevin Choi, Ayesha Anwar, Pamela Cassidy, Sancy Leachman, Ana Luisa Kadekaro, Dorothy C Bennett, Zalfa A Abdel-Malek
Coinheritance of germline mutation in cyclin-dependent kinase inhibitor 2A (CDKN2A) and loss-of-function (LOF) melanocortin 1 receptor (MC1R) variants is clinically associated with exaggerated risk for melanoma. To understand the combined impact of these mutations, we established and tested primary human melanocyte cultures from different CDKN2A mutation carriers, expressing either wild-type MC1R or MC1RLOF variant(s). These cultures expressed the CDKN2A product p16 (INK4A) and functional MC1R. Except for 32ins24 mutant melanocytes, the remaining cultures showed no detectable aberrations in proliferation or capacity for replicative senescence...
August 16, 2018: Pigment Cell & Melanoma Research
Marc-Alexander Rauschendorf, Andreas D Zimmer, Astrid Laut, Philipp Demmer, Bernd Rösler, Rudolf Happle, Silvina Sartori, Judith Fischer
No abstract text is available yet for this article.
August 16, 2018: Pigment Cell & Melanoma Research
Janine Regneri, Barbara Klotz, Brigitta Wilde, Verena A Kottler, Michael Hausmann, Susanne Kneitz, Martina Regensburger, Katja Maurus, Ralph Götz, Yuan Lu, Ronald B Walter, Amaury Herpin, Manfred Schartl
In humans, the CDKN2A locus encodes two transcripts, INK4A and ARF. Inactivation of either one by mutations or epigenetic changes is a frequent signature of malignant melanoma and one of the most relevant entry points for melanomagenesis. To analyze whether cdkn2ab, the fish ortholog of CDKN2A, has a similar function as its human counterpart, we studied its action in fish models for human melanoma. Overexpression of cdkn2ab in a Xiphophorus melanoma cell line led to decreased proliferation and induction of a senescence-like phenotype, indicating a melanoma-suppressive function analogous to mammals...
August 16, 2018: Pigment Cell & Melanoma Research
Nhu T Nguyen, David E Fisher
Ultraviolet radiation (UVR) has numerous effects on skin, including DNA damage, tanning, vitamin D synthesis, carcinogenesis, and immunomodulation. Keratinocytes containing damaged DNA secrete both α-melanocyte-stimulating hormone (α-MSH), which stimulates pigment production by melanocytes, and the opioid β-endorphin, which can trigger addiction-like responses to UVR. The pigmentation (tanning) response is an adaptation that provides some delayed protection against further DNA damage and carcinogenesis, while the opioid response may be an evolutionary adaptation for promoting sun-seeking behavior to prevent vitamin D deficiency...
July 17, 2018: Pigment Cell & Melanoma Research
Ken Okamura, Masahiro Hayashi, Osamu Nakajima, Michihiro Kono, Yuko Abe, Yutaka Hozumi, Tamio Suzuki
Oculocutaneous albinism (OCA) type 4 is one of the most common types of albinism among Japanese population. In some patients who were clinically diagnosed with OCA, we have found a heterozygous pathological mutation in the coding region of SLC45A2, the gene responsible for OCA4, not leading to a DNA-based diagnosis. In this study, we evaluated pathological variants in the promoter region of SLC45A2 in these patients. The results indicated that the majority of the patients had a 4-bp deletion in the said region (c...
July 17, 2018: Pigment Cell & Melanoma Research
Mitchell E Fane, Richard A Sturm
No abstract text is available yet for this article.
July 17, 2018: Pigment Cell & Melanoma Research
Jonathan M Eby, Angela R Smith, Timothy P Riley, Cormac Cosgrove, Christian M Ankney, Steven W Henning, Chrystal M Paulos, Elizabeth Garrett-Mayer, Rosalie M Luiten, Michael I Nishimura, Brian M Baker, I Caroline Le Poole
To study the contribution of T-cell receptors (TCR) to resulting T-cell responses, we studied three different human αβ TCRs, reactive to the same gp100-derived peptide presented in the context of HLA-A*0201. When expressed in primary CD8 T cells, all receptors elicited classic antigen-induced IFN-γ responses, which correlated with TCR affinity for peptide-MHC in the order T4H2 > R6C12 > SILv44. However, SILv44 elicited superior IL-17A release. Importantly, in vivo, SILv44-transgenic T cells mediated superior antitumor responses to 888-A2 + human melanoma tumor cells upon adoptive transfer into tumor-challenged mice while maintaining IL-17 expression...
July 15, 2018: Pigment Cell & Melanoma Research
Tatiana P Rogasevskaia, Robert T Szerencsei, Ali H Jalloul, Frank Visser, Robert J Winkfein, Paul P M Schnetkamp
NCKX5 is a bidirectional K+ -dependent Na+ -Ca2+ exchanger, which belongs to the SLC24A gene family. In particular, the A111T mutation of NCKX5 has been associated with reduced pigmentation in European populations. In contrast to other NCKX isoforms, which function in the plasma membrane (PM), NCKX5 has been shown to localize either in the trans-Golgi network (TGN) or in melanosomes. Moreover, sequences responsible for retaining its intracellular localization are unknown. This study addresses two major questions: (i) clarification of intracellular location of NCKX5 and (ii) identification of sequences that retain NCKX5 inside the cell...
July 7, 2018: Pigment Cell & Melanoma Research
Vijayasaradhi Setaluri
No abstract text is available yet for this article.
July 2018: Pigment Cell & Melanoma Research
Shosuke Ito, Misa Agata, Kotono Okochi, Kazumasa Wakamatsu
RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol, RD), a skin-whitening agent, is known to induce leukoderma in some consumers. To explore the mechanism underlying this effect, we previously showed that the oxidation of RD with mushroom or human tyrosinase produces cytotoxic quinone oxidation products and RD-eumelanin exerts a potent pro-oxidant activity. Cellular antioxidants were oxidized by RD-eumelanin with a concomitant production of H2 O2 . In this study, we examined whether this pro-oxidant activity of RD-eumelanin is enhanced by ultraviolet A (UVA) radiation because most RD-induced leukoderma lesions are found in sun-exposed areas...
July 2018: Pigment Cell & Melanoma Research
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