Journal Of Investigative Dermatology

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673 Semi-quantitative 5-hmC expression by immunohistochemistry is a useful adjunctive technique to help distinguish spitz nevi from spitzoid malignant melanomas

Wed, 2020-07-01 00:00
The differentiation between Spitz nevi (SN), Atypical Spitzoid neoplasms (ASN) and Spitzoid malignant melanomas (SMM) represents a challenge to dermatopathologists. ASN are lesions in the gray zone for which a definitive histopathologic diagnosis of benign or malignant cannot be made with absolute certainty. We sought to investigate whether the major epigenetic biomarker, 5-hydroxymethylcytosine (5-hmC), is differentially expressed and can aid in the diagnosis of benign and malignant Spitzoid neoplasms.

672 Targeting lncRNAs AC and BX reveals their critical role in melanoma and allows to identify novel phosphor-catalytic vulnerabilities

Wed, 2020-07-01 00:00
More than 80% percent of melanomas harbor mutations in either NRAS or BRAF. Our goal was to identify targets that are key in the process of melanocyte tumorigenesis and molecules that can be used to prevent this event. We have identified two long non-coding RNA (lncRNA) transcripts AC and BX key in the process of melanocyte tumorigenesis and melanoma progression. Tested in a variety of BRAF and NRAS mutated, drug resistant melanoma cell lines and other NRAS cancers such as lung ca and neuroblastoma, RNAi and antisense oligonucleotide (ASO) mediated knockdown of AC and BX lead to a vast reduction of tumor growth in vivo.

669 CD147 promotes tumorigenesis in squamous cutaneous cancer through recruiting MDSC into epidermis through CXCL1/2

Wed, 2020-07-01 00:00
CD147, a transmembrane glycoprotein belongs to the immunoglobulin superfamily, was highly expressed in various cancers. Recent studies demonstrated that CD147 promoted tumor progression by regulating inflammatory factors and chemokines. Our previous studies found CD147 promoted cutaneous squamous-cell carcinoma (cSCC) through inducing EGFR endocytosis. However, whether CD147 could regulate cSCC by influencing immune cells remains unclear. In this study, we found spontaneous tumors in CD147 epidermal over-expressing transgenic mice (TgCD147-Epi).

668 Ulcerated melanomas exhibit epigenetic changes in epidermal and immune response genes

Wed, 2020-07-01 00:00
The purpose of this study is to identify the genetic and epigenetic changes associated with melanoma ulceration. Clinically, ulceration is consistently associated with shorter disease-free and shorter overall melanoma-specific survival. Ulcerated melanomas have also been associated with a higher risk of melanoma recurrence. However, the molecular changes associated with ulceration are largely unknown. In this study, we examined the differences in DNA methylation patterns between ulcerated and nonulcerated melanoma samples.

667 β3-tubulin knockdown interferes with microtubule dynamics, cell-cycle regulation, and microvesicle release in human melanoma cells

Wed, 2020-07-01 00:00
Introduction: Microvesicles (MV), ranging in size from 100 nm to 1000 nm, play an important role in carcinogenesis by promoting angiogenesis and tumor metastasis, interfering with anti-tumor immunity, and inducing multidrug resistance. The release of MVs requires structural changes in microfilaments, intermediate filaments, and microtubules. Class III β-tubulin (β3-tubulin), one of seven β-tubulin isotypes, is a microtubule component involved in malignant transformation and cancer development. Herein, we characterize the effects of β3-tubulin knockdown on microtubule dynamics, cell cycle regulation, and microvesicle formation in human melanoma cells.

665 Associations of BIRC2/3/5 copy number gains with clinicopathological features of acral melanomas in Taiwan

Wed, 2020-07-01 00:00
Anti-apoptotic molecules can protect melanoma cells from apoptosis, thus enhancing their aggression. One of the factors responsible for the difficulties in engaging the apoptotic cascade efficiently in melanoma is the up-regulation of conserved inhibitor of apoptosis proteins (IAPs). All IAPs share up to three conserved zinc-binding baculoviral IAP repeats domains. The best described members are cIAP1, cIAP2, X-linked IAP, and surviving, which are encoded by Baculovirus inhibitor of apoptosis repeat containing genes (BIRC2, BIRC3, BIRC4, and BIRC5).

664 Oncogenic melanocyte stem cells, driven by regenerative niche signals, give rise to heterogeneous melanoma resembling human melanoma

Wed, 2020-07-01 00:00
Melanoma, the most lethal form of skin cancer, is rarely curable at its advanced stages. The early events of this disease, during which treatment would be beneficial, remain poorly elucidated. Melanocyte stem cells (McSCs) residing in the hair follicle niche were proposed to be cells-of-origin for melanoma. To understand the cellular and molecular mechanisms regulating the initiation and progression of McSC-derived melanoma, we established a novel c-Kit-CreER-driven melanoma mouse model that enabled us to specifically target McSCs and trace their oncogenic behaviors.

662 Targeting the α9-nAChR/PD-L1 axis in antiproliferative effects of Allium cepa L. var. proliferum Regel extract on melanoma cells

Wed, 2020-07-01 00:00
Programmed cell death ligand-1 (PD-L1) is critical for melanoma development, progression and treatment. The α9 nicotinic acetylcholine receptor (nAChR) is shown to affect melanoma cell proliferation. Allium cepa L. var. proliferum Regel extract possesses anticancer properties. However, the mechanism of Allium cepa L. var. proliferum Regel extract in the antiproliferative effects of melanoma cells remains unclear. Using UPLC-ESI-MS/MS method, a total of 42 compounds were identified in Allium cepa L.

661 A20 determines the therapeutic effect of anti-PD-1 immunotherapy in melanoma

Wed, 2020-07-01 00:00
The therapeutic effect of immune checkpoint blockade (ICB) therapy, especially the inhibition of programmed cell death protein 1 (PD-1) and its ligand PD-L1, has been verified in melanoma treatment. However, the dissatisfied response rate and therapeutic efficacy of anti-PD-1/PD-L1 therapy remains a major challenge for melanoma treatment. Here, we reported A20 as a critical regulator that determines the therapeutic effect of anti-PD-1 immunotherapy in melanoma. Through the un-targeted MS-based proteomic analysis, we first found that high expression of A20 was significantly associated with therapeutic resistance to anti-PD-1 immunotherapy in melanoma patients.

660 Dual HDAC and LSD1 inhibition as a novel strategy to overcome BRAF inhibitor resistance

Wed, 2020-07-01 00:00
Despite recent advances in the development of targeted and immunotherapies for metastatic melanoma, the majority of tumors demonstrate intrinsic or acquired therapeutic resistance. While the mechanisms of therapeutic resistance in melanoma are varied and often undefined, epigenetic regulation of gene expression and transcriptional programming may play a pivotal role. The potential role of epigenetic changes in the development of resistance to therapies in melanoma and other cancers has led to the development of numerous epigenetic agents as potential anti-cancer therapies; however, the lack of target selectivity of such agents results in a narrow therapeutic window.

658 Inactivating p53 is essential for nerve growth factor receptor to promote melanoma initiating cells-stemmed tumorigenesis

Wed, 2020-07-01 00:00
Nerve growth factor receptor (NGFR, CD271 or p75NTR) is highly expressed in melanoma initiating cells (MICs) and critical for their proliferation and tumorigenesis, and yet the underlying mechanism(s) remain largely elusive. We previously showed that NGFR inhibits p53 activity in a negative feedback fashion in other cancer cells. Here we report that this feedback inhibition of p53 by NGFR plays an essential role in maintaining the sphere formation (stem-like phenotype) and proliferation of MICs and in promoting MICs-derived melanoma growth in vivo.

657 TGF-β2 upregulates OPN3 in human epidermal melanocytes independent of TGF-β2R in vitro

Wed, 2020-07-01 00:00
Background: Previous studies have shown that OPN3 belongs to the photosensitive G Protein-Coupled Receptors families and is involved in the growth and melanogenesis of human epidermal melanocytes. However, the question whether OPN3 is regulated by TGF-β2 is yet to be answered. Objective: To explore the relationship between TGF-β2 and OPN3 in human epidermis melanocytes. Methods: Human epidermal melanocytes were stimulated with various concentrations of TGF-β2 in vitro. The expressions of OPN3 gene was monitored after the treatment of 10ng/ml TGF-β2, 10μM LY2109761 and 9 mM U73122.

656 GDP/GTP exchange inhibitor, FR900359, synergizes with chloroquine in GNAQ/11-mutant melanoma

Wed, 2020-07-01 00:00
GNAQ and GNA11 (GNAQ/11) encode for G-alpha proteins, and mutations in these genes are found in approximately 2% of melanoma, including 80% of uveal melanoma. Constitutive activation of G-alpha proteins leads to downstream activation of multiple oncogenic pathways, such as MAPK signaling. Unfortunately, metastatic uveal melanoma is generally refractory to all available systemic therapies, including MAPK targeted therapies, indicating a critical need for novel therapies. Recently, the GDP/GTP nucleotide exchange inhibitor, FR900359, was characterized to inhibit growth of GNAQ-mutant uveal melanoma cells in vitro, but has been limited in translatability due to a narrow therapeutic window.

655 α-MSH induces melanogenesis via up-regulation of Opsin1 in cultured human skin melanocytes in vitro

Wed, 2020-07-01 00:00
Background: Physiological skin color change is regulated by environmental cues such as sun light and also modulated through the neurological and/or endocrine control of chromatophores. Opsin1 found in bird and fish pineal gland and hypothalamus was suggested to have roles in regulating skin color change. Our previous studies have shown that Opsin1 is expressed in human skin melanocytes. α-MSH is a well known endocrine hormone that induces pigmentation in human skin. However, the question whether this hormone interacts with Opsin1 in modulating human skin melanogenesis has not been fully addressed.

653 The relationship between genetic mutations and clinicopathological manifestations in Korean cutaneous melanoma: A study based on next-generation sequencing

Wed, 2020-07-01 00:00
Identifying individual mutated genes have been proposed for effective biomarkers and therapeutic targets in cutaneous melanoma. Next-generation sequencing (NGS) shows comprehensive genomic mutations with high sensitivity. We assessed the genetic alteration in patients with melanoma and their prognosis according to clinicopathological manifestations. We analyzed clinicopathological features of 11 patients with melanoma who obtained surgical resection and examined genetic mutations using NGS. Among 11 cases of melanoma, gene mutations were identified in five.

651 Risk factors for recurrence with topical imiquimod cream for lentigo maligna: Survival analysis with 17 years follow-up

Wed, 2020-07-01 00:00
Topical imiquimod 5% cream has been investigated as an off-label primary or adjuvant treatment for melanoma in situ lentigo maligna (LM) type, although long-term follow-up data are lacking. In this single-institution retrospective analysis we evaluated treatment response and recurrence from 2002-2019 for LM treated with primary or adjuvant topical imiquimod (5%) with or without tazarotene gel 0.1% as pretreatment. 98 patients were identified with a total of 103 lesions analyzed. Mean follow-up time was 5.9 years (SD: 5.2), with 29.1% of cases having >10 years follow-up.

650 Imiquimod spares disfiguring surgery for large facial lentigo maligna

Wed, 2020-07-01 00:00
Surgical excision of lentigo maligna (LM) in anatomically constrained sites such as the face can result in adverse functional and cosmetic consequences. Patient age, comorbidities, lesion size, or location can make adequate margins impossible and/or disfiguring. The off-label use of topical imiquimod has been considered as an alternative. This case represents clearance of LM in an 86-year-old female with a 10 cm facial LM involving the eyelid treated with topical imiquimod. An 86-year-old Caucasian female with no personal/family history of skin cancer presented with a 24-month history of an enlarging, 10 cm, irregularly brown, pigmented, macule, without nodules, ulcerations, or erosions on the left zygomatic cheek extending to the lateral superior and inferior eyelids.

649 A retrospective multicenter study of melanoma in children and adolescents

Wed, 2020-07-01 00:00
Background: Melanoma in the pediatric population is rare, with distinct clinical features compared to adult disease. Risk factors are not well understood in children and adolescents. This study aims to characterize melanoma in the pediatric population and explore potential risk factors and negative patient outcomes. Methods: Multicenter retrospective study of patients <20 years of age diagnosed with melanoma between 1/1/1995 – 6/30/2015 from 11 academic medical centers. Information was compared to control patients, matched to each study patient by gender and age group, from healthy patients seen in the Dermatology Program at Boston Children’s Hospital from 2000-2015.

648 Association between the frequency of indoor tanning and pain among women in the United States

Wed, 2020-07-01 00:00
Some people may use indoor tanning as a treatment for chronic pain. We tested the association of indoor tanning frequency with pain feeling and pain medication usage in the Nurses’ Health Study II, a large well-characterized cohort in the United States. The study population consists of 75,957 female Caucasian nurses. We used the linear regression model and logistic regression model for the association of indoor tanning frequency with pain feeling and pain medication usage, respectively. The frequency of indoor tanning is significantly association with pain after controlling for various confounding factors.

646 Late-stage melanoma diagnosis in New York State (NYS)

Wed, 2020-07-01 00:00
Early-stage (ES) melanoma at diagnosis is independently prognostic for improved survival compared to late-stage (LS) melanoma, defined as having regional or advanced spread. Additionally, decreased physician supply and lower socioeconomic status are associated with diagnosis at more advanced stages. We investigated population-level and county-level associations with LS diagnosis in NYS, a region of lower ambient sun exposure than areas frequently the subject of melanoma epidemiology studies in the US.

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