Journal Of Investigative Dermatology

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834 Rational design of recombinant modified vaccinia virus Ankara for cancer immunotherapy

Wed, 2019-05-01 00:00
Poxviruses are large cytoplasmic DNA viruses and modified vaccinia virus Ankara (MVA) is a highly attenuated vaccinia strain. Intratumoral (IT) delivery of inactivated MVA (iMVA) eradicates injected tumors and generates systemic antitumor immunity, which synergizes with immune chekpoint blockade antibodies (Dai et al. Science Immunology, 2017). The antitumor effects induced by iMVA requires CD8+ T cells and CD103+ dendritic cells (DCs), and is dependent on cGAS/STING. We hypothesize that MVA encodes viral inhibitor(s) of the cGAS/STING pathway and therefore deleting such inhibitor(s) from MVA would improve the antitumor effects of the virus.

833 High-dose recombinant interferon-α1b: An effective immunotherapy with low toxicity for melanoma patients

Wed, 2019-05-01 00:00
High-dose recombinant interferon-α2b (IFN-α2b) is a postsurgery adjuvant therapy approved by FDA. However, itis moderate in improving overall survival (OS) and may cause substantial side effects, thus necessitating dose reduction or even discontinuation of therapy. Recent studies have reported that recombinant IFN-α1b that differs from IFN-α2b in amino-acid sequences is biologically and therapeutically active, but there is no long-term clinical follow-up with large sample size to investigate the efficacy of IFN-α1b in oncotherapy.

832 Total body photography facilitates early melanoma detection and improves survival

Wed, 2019-05-01 00:00
Total body photography (TBP) has been associated with detection of thin melanomas, fewer biopsies, and decreased patient anxiety in high risk patients. However, its effect on survival has not been studied. In this retrospective study, we reviewed charts of patients who received TBP at our center between 2004-2013 and were advised to return every 3-12 months for follow-up. Using medical records, the Utah Cancer Registry, and the Utah Population Database, we documented number of post-TBP follow-up visits, melanoma history, and mortality data.

831 Bortezomib-induced immunogenic cell death enhances immune response in melanoma

Wed, 2019-05-01 00:00
Neo-antigens derived from apoptotic tumor cells are sensed by the immune system and drive effective antitumour immunity. This ‘immunogenic cell death’ (ICD) can be elicited in vivo following bortezomib (26S proteasome inhibitor) treatment in some cancers. Here, we test the dynamics of bortezomib-induced ER stress and apoptosis in melanoma and whether this promotes ICD in the tumour microenvironment. We first confirmed that a clinically-relevant dose of bortezomib induced hallmarks of ICD in vitro.

830 Loss of 5-hydroxymethylcytosine in conjunctival melanoma

Wed, 2019-05-01 00:00
Recent studies suggest that conjunctival and cutaneous melanomas partially share similar molecular features. In cutaneous melanoma, loss of 5-hydroxymethylcytosine (5-hmC) was recently discovered and associated with a poorer outcome. We decided to explore whether similar epigenetic events occur in tumor progression of conjunctival melanoma and evaluated 5-hmC expression in benign and malignant conjunctival melanocytic proliferations. 5-hmC expression was evaluated by immunohistochemistry in 32 conjunctival nevi and 36 conjunctival melanomas from respectively 32 and 31 patients.

829 Folic acid protects melanocytes from oxidative damage by Keap1-Nrf2 pathway

Wed, 2019-05-01 00:00
This study aims to investigate whether folic acid could protect human melanocyte against oxidative damage and to elucidate the underlying pharmacological mechanism. And we demonstrate that folic acid could protect melanocytes form oxidative damage. Folic acid is of great therapeutic potential in the treatment of vitiligo. Vitiligo is a common skin disease characterized by the loss of functional melanocytes. Previous studies have indicated that oxidative stress plays a pivotal role in the onset of vitiligo.

828 Dermatopathologist-level classification of skin cancer with deep neural networks at multi-magnification

Wed, 2019-05-01 00:00
Artificial intelligence technologies, as novel diagnostic tools, are now affecting medical community in profound ways. Since melanocytic lesions exhibit significant morphological heterogeneity, automated classification of skin lesions is a challenging task with limited dataset. With the support of Xiangya Hospital Medical Association and TCGA open-access dataset, we collected 2186 whole histopathology slide images at magnifications of 20x and 40x in the project. We train a deep convolutional neural network (CNN), using 224x224 pixel size with labeled lesion tissue as inputs.

827 CuxS-controlled chemotherapeutics release and photothermal- photodynamic therapeutic strategy to inhibit progression and metastasis of melanoma by eliciting immunogenic cell death

Wed, 2019-05-01 00:00
Conventional monotherapies only benefit a minority of melanoma patients while combined immunotherapy exhibited extremely high rates of treatment-related adverse events. Herein, we created a multifunctional and immunogenic nanoplatform, AuNR@mSiO2@DOX-CuxS-PEG, which integrating photothermal properties of gold nanoparticles, photodynamic properties of CuxS and chemotherapy into a single nanoplatform. Upon near-infrared laser irradiation (NIR), the CuxS were uncapped and triggered chemotherapy drugs release into tumor environment.

826 The Role of TRAF6 in the tumor microenvironment of melanoma

Wed, 2019-05-01 00:00
TRAF6, an important signal molecule, plays a key role in the invasion and metastasis of melanoma. However, the mechanism of TRAF6 in activating stromal fibroblasts has not been clearly elucidated yet. We aim to investigate the effects of TRAF6 on the interaction between melanoma and stromal fibroblasts, and to reveal the role of TRAF6 in the tumor microenvironment of melanoma. MTS, wound healing, transwell and western blot were used to investigate the proliferation, migration, and invasion of TRAF6-overexpress / knockdown fibroblasts(BJ).

825 Keratinocyte desmoglein 1 controls keratinocyte/melanocyte paracrine signaling to regulate the tanning response

Wed, 2019-05-01 00:00
Epidermal melanocytes and keratinocytes respond to ultraviolet (UV) light by initiating a protective tanning response, but underlying mechanisms remain unknown. We previously found that UV exposure decreases the keratinocyte specific cell-cell adhesion molecule desmoglein-1 (Dsg1). We hypothesized that loss of Dsg1 stimulates keratinocyte/melanocyte paracrine signaling to elicit the tanning response. Organotypic 3D co-cultures of melanocytes and Dsg1-deficient keratinocytes appear more highly pigmented compared to controls.

824 DC-HIL expression determines response of metastatic B16 melanoma and LL2 lung carcinoma to anti-PDL1 treatment

Wed, 2019-05-01 00:00
While anti-PDL1 (αPDL1) immune checkpoint blockers are effective at prolonging survival of metastatic melanoma and lung cancer, this industry standard benefits <30% of treated patients, and the reasons for treatment resistance are unclear. We discovered DC-HIL receptor to be a new checkpoint whose signal pathways differ from PDL1. Myeloid-derived suppressor cells (MDSC) are a major cause of immunosuppression and expand exponentially as cancers grow and metastasize. Since MDSC express DC-HIL highly but PDL1 lowly, we posit their expansion to account for αPDL1 resistance.

823 Biomarker approaches for anti-PD-1 in melanoma: A meta-analysis

Wed, 2019-05-01 00:00
Background: Anti-PD-1 is now standard-of-care for advanced melanoma, benefitting ∼50% of patients treated. While different candidate biomarkers have been proposed to predict response to anti-PD-1, their relative predictive performances have not yet been determined. The purpose of this study was to assess the relative sensitivity and specificity of 1)PD-L1 immunohistochemistry (IHC), 2)tumor mutational burden (TMB), 3)gene expression profiling (GEP) and 4)quantitative and/or spatial assessment of multiple proteins by multiplex IHC/immunofluorescence (mIHC/IF).

822 Favorable response of melanoma to TIL therapy associated with IFN-g regulated inflammatory pathway

Wed, 2019-05-01 00:00
Tumor infiltrated lymphocyte (TIL) into the melanoma microenvironment has been associated with improved survival for some patients and also has been exploited to grow TIL in vitro for adoptive therapy. However, prognostic significance of immune infiltrating cells in melanoma and other tumors remains a relatively new concept, and markers related to suppressive versus active functional TIL remain unclear. From an ongoing clinical trial using TIL intended for adoptive immunotherapy, we have studied the melanoma patient tumors specimens (FFPE) from 20 patients whose autologous TIL lines grew to sufficient number for possible use clinically.

821 Anti-tumor activity induced by topical delivery of HSP70iQ435A

Wed, 2019-05-01 00:00
Inducible HSP70 (HSP70i) is implicated in the development of autoimmune vitiligo and is overexpressed in melanoma. We generated an expression construct encoding a single amino acid modification to the dendritic cell (DC) activating moiety (HSP70iQ435A). A topical application of the DNA construct has now demonstrated efficacy in reversing autoimmunity in Sinclair swine without obstructing anti-melanoma responses. We postulate that treatment with the HSP70iQ435A construct elicits a humoral response to stress protein selectively expressed on the surface of melanoma cells, providing measurable anti-tumor protection.

820 m6A mRNA demethylase FTO regulates tumorigenicity and response to anti-PD-1 immunotherapy in melanoma

Wed, 2019-05-01 00:00
Analogous to epigenetic regulation of gene expression through the reversible DNA and histone modifications, post-transcriptional N6-methyladenosine (m6A) methylation of adenosine residues in mRNA as well as lncRNA provides an additional layer of regulation that may alter mRNA metabolism and gene expression. Recently, m6A RNA methylation research was revived by the discovery of the fat mass- and obesity-associated protein (FTO) as the first RNA demethylase, implying that m6A RNA methylation is a reversible and dynamic modification and may have critical biological functions.

819 Extragenital lichen sclerosus is an immune-related adverse event with nivolumab

Wed, 2019-05-01 00:00
Nivolumab is a programmed cell death (PD)-1 ligand inhibitor used in treatment of melanoma and other malignancies. Immune-related adverse events (IRAEs) affect nearly all organ systems, most commonly the skin, the gastrointestinal tract (enterocolitis), the liver (hepatitis), and the endocrine system. Skin reactions related to immunotherapy occur in 4-27% of patients, including lichenoid mucocutaneous eruptions, vitiligo, psoriasis, lichen planus, and bullous pemphigoid. Most recently, genital lichen sclerosus (LS) and relapse of morphea have been reported.

818 Oriented analysis for transposon mutagenesis screening to study drug resistance

Wed, 2019-05-01 00:00
Several high-throughput screenings have been performed to study drug resistance. In comparison to the reverse genetic screening, the forward screening by transposon insertional mutagenesis does not need a priori target panel. We have performed piggyBac transposon mutagenesis screening by hyperactive transposase and pGG134 transposon carrying MSCV promoter in SK-MEL-28 melanoma cell line for resistant factor of the BRAF inhibitor, encorafenib. This study aimed to develop an appropriate computational analysis to identify the candidate genes.

817 Ethanol induces skin hyperpigmentation in mice with aldehyde dehydrogenase 2 deficiency

Wed, 2019-05-01 00:00
Excessive alcohol consumption leads to alcohol use disorder. Alcohol is metabolized to acetaldehyde, which is then oxidized to acetic acid by aldehyde dehydrogenases (ALDH), a class of enzymes that facilitate the conversion of aldehydes to their corresponding acids. Among ALDHs, mitochondrial ALDH2 is the primary enzyme involved in the metabolism of acetaldehyde. In addition to its well-known role in ethanol metabolism, recent studies have suggested that ALDH2 dysfunction is associated with a variety of human diseases including cardiovascular diseases, diabetes, neurodegenerative diseases, stroke, cancer, anemia, pain, osteoporosis and aging.

816 Autophagy inhibition sensitizes targeted therapy-resistant melanoma to MEK1/2 inhibitors

Wed, 2019-05-01 00:00
Targeted therapy has dramatically improved the treatment landscape for metastatic melanoma, however is limited to those with BRAF(V600) mutations. GNAQ/GNA11 mutations are found in approximately 2% of melanoma, including 80% of uveal melanoma. Mutations in these G-alpha proteins lead to constitutive activation of multiple oncogenic pathways, including MAPK (RAF-->MEK1/2-->ERK1/2) signaling. Unfortunately, metastatic uveal melanoma is refractory to pharmacologic targeted therapies inhibiting MEK1/2, including trametinib and binimetinib.

815 Genetic alterations in primary melanoma in Taiwan

Wed, 2019-05-01 00:00
Acral melanoma is the most common subtype of melanoma in Asians. However, differences in genetic alterations between acral melanoma and cutaneous melanoma in Asians are not well studied. To augment the understanding of the prevalence, patterns, and associations of mutations between different subtypes of melanoma, we performed next-generation sequencing of coding regions in 409 cancer-associated genes of 66 primary melanomas comprised of 45 acral melanomas and 21 cutaneous melanomas. The most common mutation in cutaneous melanoma was BRAF (66.7%), while in acral melanoma, KIT (24.4%), KRAS (15.6%), and NRAS (13.3%) were the most common mutations.

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