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https://www.readbyqxmd.com/read/27903862/improved-cancer-immunotherapy-by-a-cd25-mimobody-conferring-selectivity-to-human-interleukin-2
#1
Natalia Arenas-Ramirez, Chao Zou, Simone Popp, Daniel Zingg, Barbara Brannetti, Emmanuelle Wirth, Thomas Calzascia, Jiri Kovarik, Lukas Sommer, Gerhard Zenke, Janine Woytschak, Catherine H Regnier, Andreas Katopodis, Onur Boyman
Interleukin-2 (IL-2) immunotherapy is an attractive approach in treating advanced cancer. However, by binding to its IL-2 receptor α (CD25) subunit, IL-2 exerts unwanted effects, including stimulation of immunosuppressive regulatory T cells (Tregs) and contribution to vascular leak syndrome. We used a rational approach to develop a monoclonal antibody to human IL-2, termed NARA1, which acts as a high-affinity CD25 mimic, thereby minimizing association of IL-2 with CD25. The structure of the IL-2-NARA1 complex revealed that NARA1 occupies the CD25 epitope of IL-2 and precisely overlaps with CD25...
November 30, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27903500/primary-resistance-to-pd-1-blockade-mediated-by-jak%C3%A2-mutations
#2
Daniel Sanghoon Shin, Jesse M Zaretsky, Helena Escuin-Ordinas, Angel Garcia-Diaz, Siwen Hu-Lieskovan, Anusha Kalbasi, Catherine S Grasso, Willy Hugo, Salemiz Sandoval, Davis Y Torrejon, Nicolaos Palaskas, Gabriel Abril Rodriguez, Giulia Parisi, Ariel Azhdam, Bartosz Chmielowski, Grace Cherry, Elizabeth Seja, Beata Berent-Maoz, I Peter Shintaku, Dung Thi Le, Drew M Pardoll, Luis A Diaz, Paul C Tumeh, Thomas G Graeber, Roger S Lo, Begoña Comin-Anduix, Antoni Ribas
Loss of function mutations in JAK½ can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned they may also be involved in primary resistance to anti-PD-1 therapy. JAK½ inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK½ mutations, which led to lack of PD-L1 expression upon interferon gamma exposure mediated by inability to signal through the interferon gamma receptor pathway...
November 30, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27883926/application-of-genetically-engineered-salmonella-typhimurium-for-interferon-gamma-induced-therapy-against-melanoma
#3
Wonsuck Yoon, Yoo Chang Park, Jinseok Kim, Yang Seok Chae, Jung Hye Byeon, Sang-Hyun Min, Sungha Park, Young Yoo, Yong Keun Park, Byeong Mo Kim
Salmonella have been experimentally used as anti-cancer agents, because they show selective growth in tumours. In this study, we genetically modified attenuated Salmonella typhimurium to express and secrete interferon-gamma (IFN-γ) as a tumouricidal agent to enhance the therapeutic efficacy of Salmonella. IFN-γ was fused to the N-terminal region (residues 1-160) of SipB (SipB160) for secretion from bacterial cells. Attenuated S. typhimurium expressing recombinant IFN-γ (S. typhimurium (IFN-γ)) invaded the melanoma cells and induced cytotoxicity...
November 21, 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27878431/aqueous-immune-mediators-in-malignant-uveal-melanomas-in-comparison-to-benign-pigmented-intraocular-tumors
#4
Yoshihiko Usui, Kinya Tsubota, Tsuyoshi Agawa, Shunichiro Ueda, Kazuhiko Umazume, Yoko Okunuki, Takeshi Kezuka, Naoyuki Yamakawa, Hiroshi Goto
BACKGROUND: To examine the usefulness of measuring immune mediators in aqueous humor samples for differentiating malignant uveal melanoma from benign pigmented intraocular tumors. METHODS: Thirteen eyes of 13 patients with uveal melanoma were studied, and 13 eyes of 13 patients with benign pigmented intraocular tumors served as controls. Undiluted samples of aqueous humor were collected, and a cytometric bead array was used to determine the aqueous humor concentrations of 35 immune mediators comprising 14 interleukins (IL), interferon-γ, interferon-γ-inducible protein-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation normal T cell expressed and secreted, monokine induced by interferon-γ, basic fibroblast growth factor, Fas ligand, granzyme A, granzyme B, eotaxin, interferon-inducible T-cell alpha chemoattractant, fractalkine, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor, vascular endothelial growth factor, angiogenin, tumor necrosis factor-α, lymphotoxin-α, and CD40L...
November 22, 2016: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/27861370/preferences-of-german-melanoma-patients-for-interferon-ifn-%C3%AE-2b-toxicities-the-decog-germelatox-survey-versus-melanoma-recurrence-to-quantify-patients-relative-values-for-adjuvant-therapy
#5
Katharina C Kaehler, Christine Blome, Andrea Forschner, Ralf Gutzmer, Thomas Haalck, Lucie Heinzerling, Thomas Kornek, Elisabeth Livingstone, Carmen Loquai, Lara Valeska Maul, Berenice M Lang, Dirk Schadendorf, Barbara Stade, Patrick Terheyden, Jochen Utikal, Tobias Wagner, Axel Hauschild, Claus Garbe, Matthias Augustin
Currently interferon alfa-2b (IFNα-2b) is an approved adjuvant drug for high-risk melanoma patients that leads to an improvement in disease-free survival (DFS). However, it is unclear whether it also impacts overall survival. Widespread use of adjuvant high-dose IFNα has been tempered by its significant toxicity and its limited efficacy. Current therapeutic strategies like immune checkpoint blockade or targeted therapy may also be useful in the adjuvant setting. Therefore, it is important to weigh the trade-offs between possible side effects and therapeutic benefit...
November 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27853652/human-blood-myeloid-and-plasmacytoid-dendritic-cells-cross-activate-each-other-and-synergize-in-inducing-nk-cell-cytotoxicity
#6
Jasper J P van Beek, Mark A J Gorris, Annette E Sköld, Ibrahim Hatipoglu, Heleen H Van Acker, Evelien L Smits, I Jolanda M de Vries, Ghaith Bakdash
Human blood dendritic cells (DCs) hold great potential for use in anticancer immunotherapies. CD1c(+) myeloid DCs and plasmacytoid DCs (pDCs) have been successfully utilized in clinical vaccination trials against melanoma. We hypothesize that combining both DC subsets in a single vaccine can further improve vaccine efficacy. Here, we have determined the potential synergy between the two subsets in vitro on the level of maturation, cytokine expression, and effector cell induction. Toll-like receptor (TLR) stimulation of CD1c(+) DCs induced cross-activation of immature pDCs and vice versa...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27847343/fish-trim32-functions-as-a-critical-antiviral-molecule-against-iridovirus-and-nodavirus
#7
Yepin Yu, Xiaohong Huang, Jiaxin Liu, Jingcheng Zhang, Yin Hu, Ying Yang, Youhua Huang, Qiwei Qin
Tripartite motif-containing 32 (TRIM32) has been demonstrated to pay vital roles in cancer, genetic disorders and antiviral immunity. However, the molecular functions of fish TRIM32 still remained largely unknown. Here, a novel TRIM32 gene from orange spotted grouper (EcTRIM32) was cloned and characterized. EcTRIM32 encoded a 685-aa protein which showed 93%, and 60% identity to large yellow croaker (Larimichthys crocea) and human (Homo sapiens), respectively. Amino acid alignment showed that EcTRIM32 contained a conserved RING-finger domain, a BBOX domain and NHL domain...
November 12, 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27835061/peginterferon-beta-1a-shows-antitumor-activity-as-a-single-agent-and-enhances-efficacy-of-standard-of-care-cancer-therapeutics-in-human-melanoma-breast-renal-and-colon-xenograft-models
#8
Antonio Boccia, Cyrus Virata, Daniel Lindner, Nicki English, Nuzhat Pathan, Margot Brickelmaier, Xiao Hu, Jennifer L Gardner, Liaomin Peng, Xinzhong Wang, Xiamei Zhang, Lu Yang, Keli Perron, Grace Yco, Rebecca Kelly, James Gamez, Thomas Scripps, Donald Bennett, Ingrid B Joseph, Darren P Baker
Because of its tumor-suppressive effect, interferon-based therapy has been used for the treatment of melanoma. However, limited data are available regarding the antitumor effects of pegylated interferons, either alone or in combination with approved anticancer drugs. We report that treatment of human WM-266-4 melanoma cells with peginterferon beta-1a induced apoptotic markers. Additionally, peginterferon beta-1a significantly inhibited the growth of human SK-MEL-1, A-375, and WM-266-4 melanoma xenografts established in immunocompromised mice...
November 11, 2016: Journal of Interferon & Cytokine Research
https://www.readbyqxmd.com/read/27827850/interferon-%C3%AE-induces-the-apoptosis-of-cervical-cancer-hela-cells-by-activating-both-the-intrinsic-mitochondrial-pathway-and-endoplasmic-reticulum-stress-induced-pathway
#9
Wei-Ye Shi, Cheng Cao, Li Liu
The interferon α (IFN-α) has been often used as a sensitizing agent for the treatment of various malignancies such as hepatocellular carcinoma, malignant melanoma, and renal cell cancer by promoting the apoptosis of thesetumor cell types. However, the effect of IFN-α on cervical cancer remains unknown. In this study, HeLa cells were used as a testing model for the treatment of IFN-α on cervical cancer. The results indicate that IFN-α markedly inhibits the proliferation and induces the apoptosis of HeLa cells...
November 2, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27821803/oncolytic-adenovirus-coexpressing-interleukin-12-and-shvegf-restores-antitumor-immune-function-and-enhances-antitumor-efficacy
#10
Hyo Min Ahn, Jin Woo Hong, Chae-Ok Yun
Tumor microenvironment is extremely immunosuppressive, preventing efficient induction of antitumor immunity. To overcome tumor-mediated immunosuppression and enhance the potency of immunogene therapy, oncolytic adenovirus (Ad) co-expressing interleukin (IL)-12 and vascular endothelial growth factor (VEGF)-specific short hairpin ribonucleic acid (shVEGF; RdB/IL12/shVEGF) was generated. Intratumoral injection of RdB/IL12/shVEGF induced a strong antitumor effect in an immune competent B16-F10 melanoma model. RdB/IL12/shVEGF restored immune surveillance function in tumor tissues and actively recruited immune cells by elevating the expression levels of IL-12 and interferon-γ...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27821490/suppression-of-type-i-ifn-signaling-in-tumors-mediates-resistance-to-anti-pd-1-treatment-that-can-be-overcome-by-radiotherapy
#11
Xiaohong Wang, Jonathan E Schoenhals, Ailin Li, David R Valdecanas, Huiping Ye, Fenglin Zhang, Chad Tang, Ming Tang, Chang-Gong Liu, Xiuping Liu, Sunil Krishnan, James P Allison, Padmanee Sharma, Patrick Hwu, Ritsuko Komaki, Willem W Overwijk, Daniel R Gomez, Joe Y Chang, Stephen M Hahn, Maria Angelica Cortez, James W Welsh
Immune checkpoint therapies exhibit impressive efficacy in some patients with melanoma or lung cancer, but the lack of response in most cases presses the question of how general efficacy can be improved. In addressing this question, we generated a preclinical tumor model to study anti-PD-1 resistance by in vivo passaging of Kras-mutated, p53-deficient murine lung cancer cells (p53R172HΔg/+K-rasLA1/+) in a syngeneic host exposed to repetitive dosing with anti-mouse PD-1 antibodies. PDL1 (CD274) expression did not differ between the resistant and parental tumor cells...
November 7, 2016: Cancer Research
https://www.readbyqxmd.com/read/27816830/adjuvant-ipilimumab-in-stage-iii-melanoma-new-landscape-new-questions
#12
Alexander M M Eggermont
The recently reported significant prolongation of overall survival with ipilimumab as adjuvant in high-risk stage III melanoma patients represents an important event in the adjuvant treatment landscape. The European Organisation for Research and Treatment of Cancer 18071 trial demonstrated a 28% reduction in risk of death in patients treated with ipilimumab at 10 mg/kg (hazard ratio for death, 0.72; 95.1% CI, 0.58-0.88; P = 0.001) compared with placebo. All end-points-recurrence-free survival (RFS), distant-metastasis-free survival (DMFS) and overall survival (OS)-showed similar benefits...
November 3, 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27815200/fish-trim16l-exerts-negative-regulation-on-antiviral-immune-response-against-grouper-iridoviruses
#13
Yepin Yu, Xiaohong Huang, Jingcheng Zhang, Jiaxi Liu, Yin Hu, Ying Yang, Jia Cai, Youhua Huang, Qiwei Qin
Tripartite motif 16 (TRIM16), has been demonstrated to act as a tumor suppressor through affecting cell proliferation and migration or tumorigenicity in carcigenesis. However, the roles of TRIM16 in immune response were unknown up to now. Here, we cloned a TRIM16-like gene (TRIM16L) from orange spotted grouper (EcTRIM16L) and investigated its roles in response to virus infection. EcTRIM16L encoded a 478 amino acid peptide which showed 72% and 29% identity to large yellow croaker (Larimichthys crocea) and human (Homo sapiens), respectively...
December 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27783987/the-combination-of-mln2238-ixazomib-with-interferon-alpha-results-in-enhanced-cell-death-in-melanoma
#14
Lorena P Suarez-Kelly, Gregory M Kemper, Megan C Duggan, Andrew Stiff, Tiffany C Nole, Joseph Markowitz, Eric A Luedke, Vedat O Yildiz, Lianbo Yu, Alena Cristina Jaime-Ramirez, Volodymyr Karpa, Xiaoli Zhang, William E Carson
The ubiquitin-proteasome signaling pathway is critical for cell cycle regulation and neoplastic growth. Proteasome inhibition can activate apoptotic pathways. Bortezomib, a selective proteasome inhibitor, has anti-melanoma activity. MLN2238 (ixazomib), an oral proteasome inhibitor, has improved pharmacotherapeutic parameters compared to bortezomib. Interferon-alpha (IFN-α), an immune boosting agent, is FDA-approved for treatment of melanoma. In this study in vitro and in vivo evaluation of the antitumor potential of ixazomib and combination treatments with ixazomib and IFN-α were performed...
October 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/27754528/-clinical-trials-and-licensing-of-monoclonal-antibodies-and-biological-medicines-for-cancer-treatment-in-brazil
#15
Cecilia Ferreira da Silva, Miriam Ventura da Silva, Claudia Garcia Serpa Osorio-de-Castro
Objective To analyze the pathway of clinical trials of monoclonal antibodies and biological medicines for cancer treatment involving Brazilian institutions from 2003 to 2012. Method This retrospective, descriptive study was based on review of two clinical trial registries, ClinicalTrials.gov and the Brazilian registry ReBEC. Phase II or III studies with participation from Brazilian institutions listed in at least one of the registries were included. Following selection of the trials, the pathway of monoclonal antibodies and biological medicines was investigated from the research stage until licensing by the Brazilian Agency for Sanitary Surveillance (Anvisa), Food and Drug Administration (FDA), and European Medicines Agency (EMA)...
March 2016: Revista Panamericana de Salud Pública, Pan American Journal of Public Health
https://www.readbyqxmd.com/read/27729802/microrna-profiling-of-patient-plasma-for-clinical-trials-using-bioinformatics-and-biostatistical-approaches
#16
Joseph Markowitz, Zachary Abrams, Naduparambil K Jacob, Xiaoli Zhang, John N Hassani, Nicholas Latchana, Lai Wei, Kelly E Regan, Taylor R Brooks, Sarvani R Uppati, Kala M Levine, Tanios Bekaii-Saab, Kari L Kendra, Gregory B Lesinski, J Harrison Howard, Thomas Olencki, Philip R Payne, William E Carson
BACKGROUND: MicroRNAs (miRNAs) are short noncoding RNAs that function to repress translation of mRNA transcripts and contribute to the development of cancer. We hypothesized that miRNA array-based technologies work best for miRNA profiling of patient-derived plasma samples when the techniques and patient populations are precisely defined. METHODS: Plasma samples were obtained from five sources: melanoma clinical trial of interferon and bortezomib (12), purchased normal donor plasma samples (four), gastrointestinal tumor bank (nine), melanoma tumor bank (ten), or aged-matched normal donors (eight) for the tumor bank samples...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27697524/mouse-apolipoprotein-l9-is-a-phosphatidylethanolamine-binding-protein
#17
Thekkinghat Anantharaman Arvind, Pundi N Rangarajan
Mouse Apolipoprotein L9 (ApoL9) is an understudied cytoplasmic, interferon-inducible protein. The details of its intracellular localization and normal cellular functions are unclear. We report here that ApoL9 localizes to small puncta diffusely distributed in the cytoplasm, as well as to larger granules of varying size and number that are similar to aggresome-like induced structures (ALIS) and contain the autophagy receptor Sqstm1/p62, the autophagosome marker Lc3, and ubiquitin. Transfection of B16F10 mouse melanoma cells stably expressing ApoL9 (B16F10(L9)) with certain liposome-based transfection reagents causes dramatic disturbances in its subcellular distribution...
October 28, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27687232/mda7-il-24-is-an-anti-viral-factor-that-inhibits-influenza-virus-replication
#18
Rak-Kyun Seong, Young-Ki Choi, Ok Sarah Shin
Melanoma differentiation associated gene-7 (mda-7)/interleukin- 24 (IL-24) is a secreted cytokine, which plays an essential role in tumor suppression. Although its role as a multifunctional protein affecting broad types of cancers is well described, functions of IL-24 in host defense against virus infection are yet to be determined. In this study, we explored the anti-viral effect of recombinant IL-24 treatment during influenza infection. Infection of human lung adenocarcinoma cells (A549) with the influenza A virus up-regulated IL-24 mRNA and protein expression in a time-dependent manner...
October 2016: Journal of Microbiology / the Microbiological Society of Korea
https://www.readbyqxmd.com/read/27680683/recurrent-loss-of-sting-signaling-in-melanoma-correlates-with-susceptibility-to-viral-oncolysis
#19
Tianli Xia, Hiroyasu Konno, Glen N Barber
The innate immune regulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells (APC) to stimulate antitumor T cell immunity. Here we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase (cGAS), which generates STING-activating cyclic dinucleotides (CDNs) after binding cytosolic DNA species...
September 28, 2016: Cancer Research
https://www.readbyqxmd.com/read/27678219/bypassing-stat3-mediated-inhibition-of-the-transcriptional-regulator-id2-improves-the-antitumor-efficacy-of-dendritic-cells
#20
Haiyan S Li, Chengwen Liu, Yichuan Xiao, Fuliang Chu, Xiaoxuan Liang, Weiyi Peng, Jianhua Hu, Sattva S Neelapu, Shao-Cong Sun, Patrick Hwu, Stephanie S Watowich
Despite the potent ability of dendritic cells (DCs) to stimulate lymphocyte responses and host immunity, granulocyte-macrophage colony-stimulating factor-derived DCs (GM-DCs) used as antitumor vaccines have demonstrated relatively modest success in cancer immunotherapy. We found that injecting GM-DCs into melanoma tumors in mice, or culturing GM-DCs with melanoma-secreted cytokines or melanoma-conditioned medium, rapidly suppressed DC-intrinsic expression of the gene encoding inhibitor of differentiation 2 (ID2), a transcriptional regulator...
September 27, 2016: Science Signaling
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