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https://www.readbyqxmd.com/read/29242193/crystal-structure-of-murine-4-1bb-and-its-interaction-with-4-1bbl-support-a-role-for-galectin-9-in-4-1bb-signaling
#1
Aruna Bitra, Tzanko Doukov, Jing Wang, Gaelle Picarda, Chris A Benedict, Michael Croft, Dirk M Zajonc
4-1BB (CD137) is a TNF receptor superfamily (TNFRSF) member that is thought to undergo receptor trimerization upon binding to its trimeric TNF superfamily ligand (4-1BBL) to stimulate immune responses. 4-1BB also can bind to the tandem repeat-type lectin Galectin-9 (Gal-9), and signaling through mouse (m)4-1BB is reduced in Galectin-9 (Gal-9) deficient mice, suggesting a pivotal role of Gal-9 in m4-1BB activation. Here, using sulfur-SAD phasing, we determined the crystal structure of m4-1BB to 2.2 Å resolution...
December 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29236301/synergistic-effect-of-carnosine-on-browning-of-adipose-tissue-in-exercised-obese-rats-a-focus-on-circulating-irisin-levels
#2
Mona F Schaalan, Basma K Ramadan, Azza H Abd Elwahab
BACKGROUND: The recent appreciation of the energy burning capacity of brown adipose tissue turns it to an attractive target as anti-obesity therapy. OBJECTIVE: to evaluate the effect of L-carnosine on browning of white adipose tissue in exercised obese rats. METHODS: Sixty adult male Wistar albino rats between 7-8 weeks-old weighing 130-150 g were allocated into six groups;(i) normal control rats fed normal diet; (ii) high fat diet (HFD)-induced obese rats, (iii) normal control rats fed normal diet and injected with L-carnosine (250mg/kg), (iv) HFD-rats injected with L-carnosine (250mg/kg),(v): HFD-rats subjected to exercise training; (vi): HFD- rats subjected to exercise training and L-carnosine together...
December 13, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29217172/nobiletin-induces-brown-adipocyte-like-phenotype-and-ameliorates-stress-in-3t3-l1-adipocytes
#3
Jameel Lone, Hilal Ahmad Parray, Jong Won Yun
Browning of white adipocytes (beiging) is an attractive therapeutic strategy against obesity and its associated metabolic complications. Nobiletin (NOB) is a polymethoxylated flavone present in Citrus fruits and has been reported to have anti-obesity effects. Here, we report that nobiletin exerts dual modulatory effects on adipocytes via induction of browning in 3T3-L1 white adipocytes and amelioration of stress in adipocytes. Nobiletin-induced beiging was investigated by determining expression levels of beige-specific genes and proteins by RT-PCR and immunoblot analysis, respectively...
December 4, 2017: Biochimie
https://www.readbyqxmd.com/read/29188818/no-evidence-of-white-adipocyte-browning-after-endurance-exercise-training-in-obese-men
#4
T Tsiloulis, A L Carey, J Bayliss, B Canny, R C R Meex, M J Watt
BACKGROUND/OBJECTIVES: The phenomenon of adipocyte 'beiging' involves the conversion of non-classic brown adipocytes to brown-like adipose tissue with thermogenic, fat-burning properties, and this phenomenon has been shown in rodents to slow the progression of obesity-associated metabolic diseases. Rodent studies consistently report adipocyte beiging after endurance exercise training, indicating that increased thermogenic capacity in these adipocytes may underpin the improved health benefits of exercise training...
November 30, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/29179214/cetuximab-enhanced-the-cytotoxic-activity-of-immune-cells-during-treatment-of-colorectal-cancer
#5
Lin Wang, Yingfeng Wei, Weijia Fang, Chong Lu, Jianing Chen, Guangying Cui, Hongyan Diao
BACKGROUND/AIMS: Cetuximab is a chimeric IgG1 monoclonal antibody which targets the extracellular domain of epidermal growth factor receptor. This antibody is widely used for colorectal cancer (CRC) treatment but its influence on the immune system is incompletely understood. METHODS: The immune influence of cetuximab therapy in CRC patients was investigated by analyzing peripheral blood mononuclear cells using flow cytometry. We undertook in vitro cytotoxicity and cytokine-profile assays to ascertain the immunomodulatory effect of cetuximab treatment...
November 27, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29151956/strategies-for-bispecific-single-chain-antibody-in-cancer-immunotherapy
#6
REVIEW
Shu-Juan Zhou, Jia Wei, Shu Su, Fang-Jun Chen, Yu-Dong Qiu, Bao-Rui Liu
Genetic engineering has resulted in more than 50 recombinant bispecific antibody formats over the past two decades. Bispecific scFv antibodies represent a successful and promising immunotherapy platform that retargets cytotoxic T cells to tumor cells, with one scFv directed to tumor-associated antigens and the other to T cells. Based on this antibody construct, strategies for both specific tumor targeting and T cell activation are reviewed here. Three distinct types of tumor antigens are considered to optimize specificity and safety in bispecific scFv based treatment: cancer-testis antigens, neo-antigens and virus-associated antigens...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29133290/cd137-4-1bb-costimulation-modifies-dna-methylation-in-cd8-t-cell-relevant-genes
#7
M Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Carmen Molina, Saray Garasa, Arantza Azpilicueta, Inaki Etxeberria, Alfonso R Sanchez-Paulete, Alan J Korman, Manel Esteller, Juan Sandoval, Ignacio Melero
CD137 (4-1BB) costimulation imprints long-term changes that instruct the ultimate behavior of T cells that have previously experienced CD137 ligation. Epigenetic changes could provide a suitable mechanism for these long-term consequences. Genome-wide DNA-methylation arrays were carried out on human peripheral blood CD8+ T lymphocytes stimulated with agonist monoclonal antibody to CD137, including urelumab, which is in phase I/II clinical trials for cancer immunotherapy. Several genes showed consistent methylation patterns in response to CD137 costimulation, which were confirmed by pyrosequencing in a series of healthy donors...
November 13, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29118009/immunotherapy-targeting-4-1bb-mechanistic-rationale-clinical-results-and-future-strategies
#8
Cariad Chester, Miguel F Sanmamed, Jun Wang, Ignacio Melero
4-1BB (CD137, TNFRSF9) is an inducible costimulatory receptor expressed on activated T and natural killer (NK) cells. 4-1BB ligation on T cells triggers a signaling cascade that results in upregulation of antiapoptotic molecules, cytokine secretion, and enhanced effector function. In dysfunctional T cells that have a decreased cytotoxic capacity, 4-1BB ligation demonstrates a potent ability to restore effector functions. On NK cells, 4-1BB signaling can increase antibody-dependent cell-mediated cytotoxicity...
November 8, 2017: Blood
https://www.readbyqxmd.com/read/29114608/4-1bb-cd137-and-radiation-therapy-a-case-report-and-literature-review
#9
Jay C Shiao, Nathan Bowers, Tahseen H Nasti, Faisal Khosa, Mohammad K Khan
No abstract text is available yet for this article.
July 2017: Advances in Radiation Oncology
https://www.readbyqxmd.com/read/29103912/optimization-of-il13r%C3%AE-2-targeted-chimeric-antigen-receptor-t-cells-for-improved-anti-tumor-efficacy-against-glioblastoma
#10
Christine E Brown, Brenda Aguilar, Renate Starr, Xin Yang, Wen-Chung Chang, Lihong Weng, Brenda Chang, Aniee Sarkissian, Alfonso Brito, James F Sanchez, Julie R Ostberg, Massimo D'Apuzzo, Behnam Badie, Michael E Barish, Stephen J Forman
T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8(+) T cells that had shown evidence for bioactivity in patients...
October 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29079845/glycolipid-peptide-conjugate-vaccines-enhance-cd8-t-cell-responses-against-human-viral-proteins
#11
M Speir, A Authier-Hall, C R Brooks, K J Farrand, B J Compton, R J Anderson, A Heiser, T L Osmond, C W Tang, J A Berzofsky, M Terabe, G F Painter, I F Hermans, R Weinkove
An important goal of vaccination against viruses and virus-driven cancers is to elicit cytotoxic CD8(+) T cells specific for virus-derived peptides. CD8(+) T cell responses can be enhanced by engaging help from natural killer T (NKT) cells. We have produced synthetic vaccines that induce strong peptide-specific CD8(+) T cell responses in vivo by incorporating an NKT cell-activating glycolipid. Here we examine the effect of a glycolipid-peptide conjugate vaccine incorporating an NKT cell-activating glycolipid linked to an MHC class I-restricted peptide from a viral antigen in human peripheral blood mononuclear cells...
October 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29067023/selection-of-shared-and-neoantigen-reactive-t-cells-for-adoptive-cell-therapy-based-on-cd137-separation
#12
Sivan Seliktar-Ofir, Efrat Merhavi-Shoham, Orit Itzhaki, Sharon Yunger, Gal Markel, Jacob Schachter, Michal J Besser
Adoptive cell therapy (ACT) of autologous tumor infiltrating lymphocytes (TIL) is an effective immunotherapy for patients with solid tumors, yielding objective response rates of around 40% in refractory patients with metastatic melanoma. Most clinical centers utilize bulk, randomly isolated TIL from the tumor tissue for ex vivo expansion and infusion. Only a minor fraction of the administered T cells recognizes tumor antigens, such as shared and mutation-derived neoantigens, and consequently eliminates the tumor...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29056539/tumor-cell-associated-immune-checkpoint-molecules-drivers-of-malignancy-and-stemness
#13
REVIEW
Fabrizio Marcucci, Cristiano Rumio, Angelo Corti
Inhibitory or stimulatory immune checkpoint molecules are expressed on a sizeable fraction of tumor cells in different tumor types. It was thought that the main function of tumor cell-associated immune checkpoint molecules would be the modulation (down- or upregulation) of antitumor immune responses. In recent years, however, it has become clear that the expression of immune checkpoint molecules on tumor cells has important consequences on the biology of the tumor cells themselves. In particular, a causal relationship between the expression of these molecules and the acquisition of malignant traits has been demonstrated...
October 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29036980/-cd137-induces-vascular-muscle-cells-phenotype-transformation-through-activating-nuclear-factor-of-activated-t-cells-1-signaling
#14
W Zhong, B Li, J Liu, Y Xu, R Chen, C Shao, Z Q Wang, J C Yan
Objective: To investigate whether CD137 induces primary vascular muscle cells (VSMCs) phenotype transformation through activating nuclear factor of activated T-cells 1(NFATc1) signaling. Methods: VSMCs were obtained from aorta of C57BL/6J mice (8 weeks, male) through tissue-piece inoculating. Cells were divided into control group, CD137 agonist group (treated with CD137L recombinant protein) and anti-CD137 group (treated with anti-CD137 antibody). In si-RNA transfection assay, cells were divided into si-control group and si-NFATc1 group which were transfected with control or si-NFATc1 sequence respectively...
September 24, 2017: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/28955345/protective-cytomegalovirus-cmv-specific-t-cell-immunity-is-frequent-in-kidney-transplant-patients-without-serum-anti-cmv-antibodies
#15
Nicolle H R Litjens, Ling Huang, Burç Dedeoglu, Ruud W J Meijers, Jaap Kwekkeboom, Michiel G H Betjes
The absence of anti-cytomegalovirus (CMV) immunoglobulin G (IgG) is used to classify pretransplant patients as naïve for CMV infection (CMV(neg) patients). This study assessed whether pretransplant CMV-specific T-cell immunity exists in CMV(neg) patients and whether it protects against CMV infection after kidney transplantation. The results show that CMV-specific CD137(+)IFNγ(+)CD4(+) and CD137(+)IFNγ(+)CD8(+) memory T cells were present in 46 and 39% of CMV(neg) patients (n = 28) although at much lower frequencies compared to CMV(pos) patients (median 0...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28945841/antigen-cross-presentation-and-t-cell-cross-priming-in-cancer-immunology-and-immunotherapy
#16
Alfonso R Sánchez-Paulete, Álvaro Teijeira, Francisco J Cueto, Saray Garasa, José L Pérez-Gracia, Álvaro Sánchez-Arráez, David Sancho, Ignacio Melero
Dendritic cells are the main professional antigen-presenting cells for induction of T cell adaptive responses. Cancer cells express tumor antigens, including neoantigens generated by non-synonymous mutations, but are poor for antigen presentation and for providing costimulatory signals for T-cell priming. Mounting evidence suggests that antigen transfer to dendritic cells (DCs) and their surrogate presentation on MHC class I and II molecules together with costimulatory signals is paramount for induction of viral and cancer immunity...
September 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28928380/predictors-of-responses-to-immune-checkpoint-blockade-in-advanced-melanoma
#17
N Jacquelot, M P Roberti, D P Enot, S Rusakiewicz, N Ternès, S Jegou, D M Woods, A L Sodré, M Hansen, Y Meirow, M Sade-Feldman, A Burra, S S Kwek, C Flament, M Messaoudene, C P M Duong, L Chen, B S Kwon, A C Anderson, V K Kuchroo, B Weide, F Aubin, C Borg, S Dalle, O Beatrix, M Ayyoub, B Balme, G Tomasic, A M Di Giacomo, M Maio, D Schadendorf, I Melero, B Dréno, A Khammari, R Dummer, M Levesque, Y Koguchi, L Fong, M Lotem, M Baniyash, H Schmidt, I M Svane, G Kroemer, A Marabelle, S Michiels, A Cavalcanti, M J Smyth, J S Weber, A M Eggermont, L Zitvogel
Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28923858/anti-cd137-suppresses-tumor-growth-by-blocking-reverse-signaling-by-cd137-ligand
#18
Sang W Kang, Sang C Lee, So H Park, Juyang Kim, Hyeon H Kim, Hyeon-Woo Lee, Su K Seo, Byoung S Kwon, Hong R Cho, Byungsuk Kwon
CD137 (4-1BB) is a T-cell costimulatory molecule, and agonstic CD137 antibodies are currently being evaluated in the clinic as cancer immunotherapy. Recently, it was found that CD137(-/-) mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here, we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results...
September 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28905118/administration-of-low-dose-combination-anti-ctla4-anti-cd137-and-anti-ox40-into-murine-tumor-or-proximal-to-the-tumor-draining-lymph-node-induces-systemic-tumor-regression
#19
Jonathan P O Hebb, Adriane R Mosley, Felipe Vences-Catalán, Narendiran Rajasekaran, Anna Rosén, Peter Ellmark, Dean W Felsher
The delivery of immunomodulators directly into the tumor potentially harnesses the existing antigen, tumor-specific infiltrating lymphocytes, and antigen presenting cells. This can confer specificity and generate a potent systemic anti-tumor immune response with lower doses and less toxicity compared to systemic administration, in effect an in situ vaccine. Here, we test this concept using the novel combination of immunomodulators anti-CTLA4, -CD137, and -OX40. The triple combination administered intratumorally at low doses to one tumor of a dual tumor mouse model had dramatic local and systemic anti-tumor efficacy in lymphoma (A20) and solid tumor (MC38) models, consistent with an abscopal effect...
September 13, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28875845/new-trends-in-anti-cancer-therapy-combining-conventional-chemotherapeutics-with-novel-immunomodulators
#20
Amy L Wilson, Magdalena Plebanski, Andrew N Stephens
Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1...
August 29, 2017: Current Medicinal Chemistry
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