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https://www.readbyqxmd.com/read/29233972/irf8-dependent-molecular-complexes-control-the-th9-transcriptional-program
#1
Etienne Humblin, Marion Thibaudin, Fanny Chalmin, Valentin Derangère, Emeric Limagne, Corentin Richard, Richard A Flavell, Sandy Chevrier, Sylvain Ladoire, Hélène Berger, Romain Boidot, Lionel Apetoh, Frédérique Végran, François Ghiringhelli
Interferon regulatory factors (IRF) have critical functions in lymphoid development and in immune response regulation. Although many studies have described the function of IRF4 in CD4+ T cells, few have focused on the IRF4 homologue, IRF8. Here, we show that IRF8 is required for Th9 differentiation in vitro and in vivo. IRF8 functions through a transcription factor complex consisting of IRF8, IRF4, PU.1 and BATF, which binds to DNA and boosts Il9 transcription. By contrast, IRF8 deficiency promotes the expression of other genes such as Il4, as IRF8 dimerises with the transcriptional repressor ETV6 and inhibits Il4 expression...
December 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29224244/a-histopathological-classification-system-of-tyr-nrasq61k-murine-melanocytic-lesions-a-reproducible-simplified-classification
#2
Pierre Sohier, Léa Legrand, Zackie Aktary, Christine Grill, Véronique Delmas, Florence Bernex, Edouard Reyes-Gomez, Lionel Larue, Béatrice Vergier
Genetically engineered mouse models offer essential opportunities to investigate the mechanisms of initiation and progression in melanoma. Here we report a new simplified histopathology classification of mouse melanocytic lesions in Tyr::NRASQ61K derived models, using an interactive decision tree that produces homogeneous categories. Reproducibility for this classification system was evaluated on a panel of representative cases of murine melanocytic lesions by pathologists and basic scientists. Reproducibility, measured as inter-rater agreement between evaluators using a modified Fleiss' kappa statistic revealed a very good agreement between observers...
December 10, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29221137/ev20-sap-a-novel-anti-her-3-antibody-drug-conjugate-displays-promising-antitumor-activity-in-melanoma
#3
Emily Capone, Francesco Giansanti, Sara Ponziani, Alessia Lamolinara, Manuela Iezzi, Annamaria Cimini, Francesco Angelucci, Rossana La Sorda, Vincenzo De Laurenzi, Pier Giorgio Natali, Rodolfo Ippoliti, Stefano Iacobelli, Gianluca Sala
Melanoma is the most biologically aggressive skin cancer of well established constitutive and induced resistance to pharmacological treatment. Despite the recent progresses in immunotherapies, many advanced metastatic melanoma patients still face a significant mortality risk. The aggressive nature of this disease sustains an urgent need for more successful, effective drugs. HER-3 - one of the four member of the tyrosin kinase epidermal growth factor receptors (EGFRs) family- is frequently overexpressed in solid tumors, including melanoma...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29183378/vascular-abnormalities-and-development-of-hypoxia-in-microscopic-melanoma-xenografts
#4
Jon-Vidar Gaustad, Trude G Simonsen, Lise Mari K Andersen, Einar K Rofstad
BACKGROUND: Studies investigating the oxygenation status and the development of hypoxia in microscopic tumors are sparse. The purpose of this study was to measure the extent of hypoxia in microscopic melanoma xenografts and to search for possible mechanisms leading to the development of hypoxia in these tumors. METHODS: A-07, D-12, R-18, and U-25 human melanoma xenografts grown in dorsal window chambers or as flank tumors were used as preclinical tumor models. Morphologic and functional parameters of vascular networks were assessed with intravital microscopy, and the expression of angiogenesis-related genes was assessed with quantitative PCR...
November 28, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29162497/expression-signatures-of-early-stage-and-advanced-medaka-melanomas
#5
Barbara Klotz, Susanne Kneitz, Martina Regensburger, Lena Hahn, Michael Dannemann, Janet Kelso, Birgit Nickel, Yuan Lu, William Boswell, John Postlethwait, Wesley Warren, Manfred Kunz, Ronald B Walter, Manfred Schartl
Melanoma is one of the most aggressive tumors with a very low survival rate once metastasized. The incidence of newly detected cases increases every year suggesting the necessity of development and application of innovative treatment strategies. Human melanoma develops from melanocytes localized in the epidermis of the skin to malignant tumors because of deregulated effectors influencing several molecular pathways. Despite many advances in describing the molecular changes accompanying melanoma formation, many critical and clinically relevant molecular features of the transformed pigment cells and the underlying mechanisms are largely unknown...
November 18, 2017: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
https://www.readbyqxmd.com/read/29135861/in-vitro-and-in-vivo-antimelanoma-effect-of-ethyl-ester-cyclohexyl-analog-of-ethylenediamine-dipropanoic-acid
#6
Andjelka M Isakovic, Sasa M Petricevic, Slavica M Ristic, Dusan M Popadic, Tamara K Kravic-Stevovic, Nevena S Zogovic, Jelena M Poljarevic, Tatjana V Zivanovic Radnic, Tibor J Sabo, Aleksandra J Isakovic, Ivanka D Markovic, Vladimir S Trajkovic, Sonja T Misirlic-Dencic
Melanoma, an aggressive skin tumor with high metastatic potential, is associated with high mortality and increasing morbidity. Multiple available chemotherapeutic and immunotherapeutic modalities failed to improve survival in advanced disease, and the search for new agents is ongoing. The aim of this study was to investigate antimelanoma effects of O,O-diethyl-(S,S)-ethylenediamine-N,N'di-2-(3-cyclohexyl) propanoate dihydrochloride (EE), a previously synthesized and characterized organic compound. Mouse melanoma B16 cell viability was assessed using acid phosphatase, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, sulforhodamine B, and lactate dehydrogenase assays...
November 13, 2017: Melanoma Research
https://www.readbyqxmd.com/read/29133622/ceritinib-enhances-the-efficacy-of-trametinib-in-braf-nras-wild-type-melanoma-cell-lines
#7
Daniel Verduzco, Brent M Kuenzi, Fumi Kinose, Vernon K Sondak, Zeynep Eroglu, Uwe Rix, Keiran S M Smalley
Targeted therapy options are currently lacking for the heterogeneous population of patients whose melanomas lack BRAF or NRAS mutations (~35% of cases). We undertook a chemical biology screen to identify potential novel drug targets for this understudied group of tumors. Screening a panel of 8 BRAF/NRAS-WT melanoma cell lines against 240 targeted drugs identified ceritinib and trametinib as potential hits with single agent activity. Ceritinib enhanced the efficacy of trametinib across the majority of the BRAF/NRAS-WT cell lines, and the combination showed increased cytotoxicity in both 3D spheroid culture and long-term colony formation experiments...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29129959/cancer-targeting-ultrasmall-silica-nanoparticles-for-clinical-translation-physicochemical-structure-and-biological-property-correlations
#8
Feng Chen, Kai Ma, Miriam Benezra, Li Zhang, Sarah M Cheal, Evan Phillips, Barney Yoo, Mohan Pauliah, Michael Overholtzer, Pat Zanzonico, Sonia Sequeira, Mithat Gonen, Thomas Quinn, Ulrich Wiesner, Michelle S Bradbury
Although a large body of literature exists on the potential use of nanoparticles for medical applications, the number of probes translated into human clinical trials is remarkably small. A major challenge of particle probe development and their translation is the elucidation of safety profiles associated with their structural complexity, not only in terms of size distribution and heterogeneities in particle composition but also their effects on biological activities and the relationship between particle structure and pharmacokinetics...
October 24, 2017: Chemistry of Materials: a Publication of the American Chemical Society
https://www.readbyqxmd.com/read/29124314/prophylactic-dna-vaccine-targeting-foxp3-regulatory-t-cells-depletes-myeloid-derived-suppressor-cells-and-improves-anti-melanoma-immune-responses-in-a-murine-model
#9
Afshin Namdar, Reza Mirzaei, Arash Memarnejadian, Roobina Boghosian, Morteza Samadi, Hamid Reza Mirzaei, Hamid Farajifard, Mehdi Zavar, Kayhan Azadmanesh, Shokrollah Elahi, Farshid Noorbakhsh, Abbas Rezaei, Jamshid Hadjati
Regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) are the two important and interactive immunosuppressive components of the tumor microenvironment that hamper anti-tumor immune responses. Therefore, targeting these two populations together might be beneficial for overcoming immune suppression in the tumor microenvironment. We have recently shown that prophylactic Foxp3 DNA/recombinant protein vaccine (Foxp3 vaccine) promotes immunity against Treg in tumor-free conditions. In the present study, we investigated the immune modulatory effects of a prophylactic regimen of the redesigned Foxp3 vaccine in the B16F10 melanoma model...
November 9, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29123332/target-or-clear-zirconium-89-labeled-silica-nanoparticles-for-enhanced-cancer-directed-uptake-in-melanoma-a-comparison-of-radiolabeling-strategies
#10
Feng Chen, Kai Ma, Li Zhang, Brian Madajewski, Pat Zanzonico, Sonia Sequeira, Mithat Gonen, Ulrich Wiesner, Michelle S Bradbury
Designing a nanomaterials platform with high target-to-background ratios has long been one of the major challenges in the field of nanomedicine. Here, we introduce a "target-or-clear" multifunctional nanoparticle platform that demonstrates high tumor-targeting efficiency and retention while minimizing off-target effects. Encouraged by the favorable preclinical and clinical pharmacokinetic profiles derived after fine-tuning surface chemical properties of radioiodinated ((124)I, t1/2 = 100.2 h) ultrasmall cRGDY-conjugated fluorescent silica nanoparticles (C dots), we sought to investigate how the biological properties of these radioconjugates could be influenced by the conjugation of radiometals such as zirconium-89 ((89)Zr, t1/2 = 78...
October 10, 2017: Chemistry of Materials: a Publication of the American Chemical Society
https://www.readbyqxmd.com/read/29123081/resistance-to-cancer-immunotherapy-mediated-by-apoptosis-of-tumor-infiltrating-lymphocytes
#11
Jingjing Zhu, Céline G Powis de Tenbossche, Stefania Cané, Didier Colau, Nicolas van Baren, Christophe Lurquin, Anne-Marie Schmitt-Verhulst, Peter Liljeström, Catherine Uyttenhove, Benoit J Van den Eynde
Despite impressive clinical success, cancer immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance. Here we use the autochthonous TiRP melanoma model, which recapitulates the tumoral resistance signature observed in human melanomas. TiRP tumors resist immunotherapy based on checkpoint blockade, cancer vaccines or adoptive T-cell therapy. TiRP tumors recruit and activate tumor-specific CD8(+) T cells, but these cells then undergo apoptosis. This does not occur with isogenic transplanted tumors, which are rejected after adoptive T-cell therapy...
November 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/29109980/the-abundance-of-metabolites-related-to-protein-methylation-correlates-with-the-metastatic-capacity-of-human-melanoma-xenografts
#12
Xiaolei Shi, Alpaslan Tasdogan, Fang Huang, Zeping Hu, Sean J Morrison, Ralph J DeBerardinis
Metabolic reprogramming is a major factor in transformation, and particular metabolic phenotypes correlate with oncogenotype, tumor progression, and metastasis. By profiling metabolites in 17 patient-derived xenograft melanoma models, we identified durable metabolomic signatures that correlate with biological features of the tumors. BRAF mutant tumors had metabolomic and metabolic flux features of enhanced glycolysis compared to BRAF wild-type tumors. Tumors that metastasized efficiently from their primary sites had elevated levels of metabolites related to protein methylation, including trimethyllysine (TML)...
November 2017: Science Advances
https://www.readbyqxmd.com/read/29108231/trpm5-mediates-acidic-extracellular-ph-signaling-and-trpm5-inhibition-reduces-spontaneous-metastasis-in-mouse-b16-bl6-melanoma-cells
#13
Toyonobu Maeda, Atsuko Suzuki, Kaori Koga, Chihiro Miyamoto, Yojiro Maehata, Shigeyuki Ozawa, Ryu-Ichiro Hata, Yoji Nagashima, Kazuki Nabeshima, Kaoru Miyazaki, Yasumasa Kato
Extracellular acidity is a hallmark of solid tumors and is associated with metastasis in the tumor microenvironment. Acidic extracellular pH (pH e ) has been found to increase intracellular Ca(2+) and matrix metalloproteinase-9 (MMP-9) expression by activating NF-κB in the mouse B16 melanoma model. The present study assessed whether TRPM5, an intracellular Ca(2+)-dependent monovalent cation channel, is associated with acidic pH e signaling and induction of MMP-9 expression in this mouse melanoma model. Treatment of B16 cells with Trpm5 siRNA reduced acidic pH e -induced MMP-9 expression...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29094184/braf-peptide-vaccine-facilitates-therapy-of-murine-braf-mutant-melanoma
#14
Qi Liu, Hongda Zhu, Yun Liu, Sara Musetti, Leaf Huang
Approximately, 50% of human melanomas are driven by BRAF mutations, which produce tumors that are highly immunosuppressive and often resistant to vaccine therapy. We introduced lipid-coated calcium phosphate nanoparticles (LCP NPs) as a carrier to efficiently deliver a tumor-specific antigen, the BRAF(V600E) peptide, to drive dendritic cell (DC) maturation and antigen presentation in C57BL6 mice. The BRAF peptide vaccine elicited a robust, antigen-specific cytotoxic T cell response and potent tumor growth inhibition in a murine BRAF-mutant melanoma model...
November 1, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29089297/ccr5-myeloid-derived-suppressor-cells-are-enriched-and-activated-in-melanoma-lesions
#15
Carolin Blattner, Viktor Fleming, Rebekka Weber, Bianca S Himmelhan, Peter Altevogt, Christoffer Gebhardt, Torsten J Schulze, Hila Razon, Elias Hawila, Gizi Wildbaum, Jochen Utikal, Nathan Karin, Viktor Umansky
Accumulation of myeloid-derived suppressor cells (MDSC) in melanoma microenvironment is supported by chemokine receptor/chemokine signaling. Although different chemokines were suggested to be involved in this process, the role of CCR5 and its ligands is not established. Using a ret transgenic mouse melanoma model, we found an accumulation of CCR5+ MDSC in melanoma lesions associated with both increased concentrations of CCR5 ligands and tumor progression. Tumor-infiltrating CCR5+ MDSC displayed higher immunosuppressive activity than their CCR5- counterparts...
October 31, 2017: Cancer Research
https://www.readbyqxmd.com/read/29079306/ousting-rage-in-melanoma-a-viable-therapeutic-target
#16
REVIEW
Deeba N Syed, Ahmed Aljohani, Durdana Waseem, Hasan Mukhtar
Melanoma remains an important health concern, given the steady increase in incidence and acquisition of resistance to systemic therapies. The receptor for advanced glycation end products (RAGE) initially identified for its binding to advanced glycation end products was subsequently acknowledged as a pattern recognition receptor given its ability to recognize similar structural elements within numerous ligands. Recent studies have elucidated a plausible role of RAGE in melanoma progression through modulation of inflammatory, proliferative and invasive cellular responses...
October 24, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29062313/dead-tumor-cells-expressing-infectious-salmon-anemia-virus-fusogenic-protein-favor-antigen-cross-priming-in-vitro
#17
Jonathan Morales, Carlos Barrera-Avalos, Carlos Castro, Stephanie Castillo, Claudio Barrientos, Claudia Robles-Planells, Ximena López, Ernesto Torres, Margarita Montoya, Marcelo Cortez-San Martín, Denise Riquelme, Alejandro Escobar, Ricardo Fernández, Mónica Imarai, Daniela Sauma, Leonel E Rojo, Elias Leiva-Salcedo, Claudio Acuña-Castillo
Antigen cross-presentation is a crucial step in the assembly of an antitumor immune response leading to activation of naïve CD8 T cells. This process has been extensively used in clinical trials, in which dendritic cells generated in vitro are loaded with tumor antigens and then autotransplanted to the patients. Recently, the use of autologous transplant of dendritic cells fused with dying tumor cells has demonstrated good results in clinical studies. In this work, we generated a similar process in vivo by treating mice with dead tumor cells [cell bodies (CBs)] expressing the fusogenic protein of the infectious salmon anemia virus (ISAV)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29057046/synthesis-and-pharmacological-evaluation-of-selective-histone-deacetylase-6-inhibitors-in-melanoma-models
#18
Maurício T Tavares, Sida Shen, Tessa Knox, Melissa Hadley, Zsófia Kutil, Cyril Bařinka, Alejandro Villagra, Alan P Kozikowski
Only a handful of therapies offer significant improvement in the overall survival in cases of melanoma, a cancer whose incidence has continued to rise in the past 30 years. In our effort to identify potent and isoform-selective histone deacetylase (HDAC) inhibitors as a therapeutic approach to melanoma, a series of new HDAC6 inhibitors based on the nexturastat A scaffold were prepared. The new analogues 4d, 4e, and 7b bearing added hydrophilic substituents, so as to establish additional hydrogen bonding on the rim of the HDAC6 catalytic pocket, exhibit improved potency against HDAC6 and retain selectivity over HDAC1...
October 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29050620/safe-therapeutics-of-murine-melanoma-model-using-a-novel-antineoplasic-the-partially-methylated-mannogalactan-from-pleurotus-eryngii
#19
S M P Biscaia, E R Carbonero, D L Bellan, B S Borges, C R Costa, G R Rossi, J P Gonçalves, C M Melo, F A R Lívero, A C Ruthes, R Zotz, E V Silva, C C Oliveira, A Acco, H B Nader, R Chammas, M Iacomini, C R C Franco, E S Trindade
A heteropolysaccharide was isolated by cold aqueous extraction from edible mushroom Pleurotus eryngii ("King Oyster") basidiocarps and its biological properties were evaluated. Structural assignments were carried out using mono- and bidimensional NMR spectroscopy, monosaccharide composition, and methylation analyses. A mannogalactan having a main chain of (1→6)-linked α-d-galactopyranosyl and 3-O-methyl-α-d-galactopyranosyl residues, both partially substituted at OH-2 by β-d-Manp (MG-Pe) single-unit was found...
December 15, 2017: Carbohydrate Polymers
https://www.readbyqxmd.com/read/29045061/suppression-of-mapk-signaling-in-braf-activated-pten-deficient-melanoma-by-blocking-%C3%AE-catenin-signaling-in-cancer-associated-fibroblasts
#20
Linli Zhou, Kun Yang, Spencer Dunaway, Zalfa Abdel-Malek, Thomas Andl, Ana Luisa Kadekaro, Yuhang Zhang
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment have been associated with formation of a dynamic and optimized niche for tumor cells to grow and evade cell death induced by therapeutic agents. We recently reported that ablation of β-catenin expression in stromal fibroblasts and CAFs disrupted their biological activities in in vitro studies and in an in vivo B16F10 mouse melanoma model. Here, we show that the development of a BRAF-activated PTEN-deficient mouse melanoma was significantly suppressed in vivo after blocking β-catenin signaling in CAFs...
October 17, 2017: Pigment Cell & Melanoma Research
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