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https://www.readbyqxmd.com/read/28804691/combination-of-celecoxib-celebrex-%C3%A2-and-cd19-car-redirected-ctl-immunotherapy-for-the-treatment-of-b-cell-non-hodgkin-s-lymphomas
#1
REVIEW
Tam Nm Dinh, Alexandra S Onea, Ali R Jazirehi
The nonsteroidal anti-inflammatory drug (NSAID) Celecoxib (Celebrex(®)) received Food and Drug Administration (FDA) approval in 1998 for treatment of osteoarthritis and rheumatoid arthritis, and in recent years, its use has been extended to various types of malignancies, such as breast, colon, and urinary cancers. To maintain the survival of malignant B cells, non-Hodgkin's Lymphoma (NHL) is highly dependent on inflammatory microenvironment, and is inhibited by celecoxib. Celecoxib hinders tumor growth interacting with various apoptotic genes, such as cyclooxygenase-2 (Cox-2), B-cell lymphoma 2 (Bcl-2) family, phosphor-inositide-3 kinase/serine-threonine-specific protein kinase (PI3K/Akt), and inhibitors of apoptosis proteins (IAP) family...
2017: American Journal of Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28802563/metabolic-circuit-involving-free-fatty-acids-microrna-122-and-triglyceride-synthesis-in-liver-and-muscle-tissues
#2
Chofit Chai, Mila Rivkin, Liav Berkovits, Alina Simerzin, Elina Zorde-Khvalevsky, Nofar Rosenberg, Shiri Klein, Dayana Yaish, Ronen Durst, Shoshana Shpitzen, Shiran Udi, Joseph Tam, Joerg Heeren, Anna Worthmann, Christoph Schramm, Johannes Kluwe, Revital Ravid, Eran Hornstein, Hilla Giladi, Eithan Galun
BACKGROUND & AIMS: Effective treatments are needed for hepatic steatosis characterized by accumulation of triglycerides in hepatocytes, which leads to hepatocellular carcinoma. MicroRNA 122 (MIR122) is expressed only in the liver, where it regulates lipid metabolism. We investigated the mechanism by which free fatty acids (FFAs) regulate MIR122 expression and the effect of MIR122 on triglyceride synthesis. METHODS: We analyzed MIR122 promoter activity and validated its target mRNAs by transfection of luciferase reporter plasmids into Huh7, BNL-1ME, and HEK293 cultured cell lines...
August 9, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28795252/ipet-study-an-flt-pet-window-study-to-assess-the-activity-of-the-steroid-sulfatase-inhibitor-irosustat-in-early-breast-cancer
#3
Carlo Palmieri, Richard Szydlo, Marie Miller, Laura Barker, Neva H Patel, Hironobu Sasano, Tara Barwick, Henry Tam, Dimitri Hadjiminas, Jasmin Lee, Abeer Shaaban, Hanna Nicholas, R Charles Coombes, Laura M Kenny
BACKGROUND: Steroid sulfatase (STS) is involved in oestrogen biosynthesis and irosustat is a first generation, irreversible steroid sulfatase inhibitor. A pre-surgical window-of-opportunity study with irosustat was undertaken in estrogen receptor-positive (ER+) breast cancer to assess the effect of irosustat on tumour cell proliferation as measured by 3'-deoxy-3'-[18F] fluorothymidine uptake measured by PET scanning (FLT-PET) and Ki67. METHODS: Postmenopausal women with untreated ER+ early breast cancer were recruited, and imaged with FLT-PET at baseline and after at least 2 weeks treatment with irosustat, 40 mg once daily orally...
August 9, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28783667/tumor-location-determines-tissue-specific-recruitment-of-tumor-associated-macrophages-and-antibody-dependent-immunotherapy-response
#4
Birgit Lehmann, Markus Biburger, Christin Brückner, Andrea Ipsen-Escobedo, Sina Gordan, Christian Lehmann, David Voehringer, Thomas Winkler, Niels Schaft, Diana Dudziak, Horia Sirbu, Georg F Weber, Falk Nimmerjahn
Despite recent advances in activating immune cells to target tumors, the presence of some immune cells, such as tumor-associated macrophages (TAMs) or tumor-associated neutrophils (TANs), may promote rather than inhibit tumor growth. However, it remains unclear how antibody-dependent tumor immunotherapies, such as cytotoxic or checkpoint control antibodies, affect different TAM or TAN populations, which abundantly express activating Fcγ receptors. In this study, we show that the tissue environment determines which cellular effector pathways are responsible for antibody-dependent tumor immunotherapy...
January 6, 2017: Science Immunology
https://www.readbyqxmd.com/read/28775145/bypassing-drug-resistance-mechanisms-of-prostate-cancer-with-small-molecules-that-target-androgen-receptor-chromatin-interactions
#5
Kush Dalal, Meixia Che, Nanette S Que, Aishwariya Sharma, Rendong Yang, Nada Lallous, Hendrik Borgmann, Deniz Ozistanbullu, Ronnie Tse, Fuqiang Ban, Huifang Li, Kevin J Tam, Mani Roshan-Moniri, Eric Leblanc, Martin E Gleave, Daniel T Gewirth, Scott M Dehm, Artem Cherkasov, Paul S Rennie
Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug-target in the treatment of prostate cancer. Current small molecule AR-antagonists, such as enzalutamide, compete with androgens that bind to the steroid binding pocket of the AR ligand binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug-resistance can manifest through AR-LBD mutations that convert AR-antagonists into agonists, or by expression of AR-variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR...
August 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28768810/mouse-macrophages-show-different-requirements-for-phosphatidylserine-receptor-tim4-in-efferocytosis
#6
Yuichi Yanagihashi, Katsumori Segawa, Ryota Maeda, Yo-Ichi Nabeshima, Shigekazu Nagata
Protein S (ProS) and growth arrest-specific 6 (Gas6) bind to phosphatidylserine (PtdSer) and induce efferocytosis upon binding TAM-family receptors (Tyro3, Axl, and Mer). Here, we produced mouse ProS, Gas6, and TAM-receptor extracellular region fused to IgG fragment crystallizable region in HEK293T cells. ProS and Gas6 bound Ca(2+) dependently to PtdSer (Kd 20-40 nM), Mer, and Tyro3 (Kd 15-50 nM). Gas6 bound Axl strongly (Kd < 1.0 nM), but ProS did not bind Axl. Using NIH 3T3-based cell lines expressing a single TAM receptor, we showed that TAM-mediated efferocytosis was determined by the receptor-binding ability of ProS and Gas6...
August 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28758875/functional-optimization-of-agonistic-antibodies-to-ox40-receptor-with-novel-fc-mutations-to-promote-antibody-multimerization
#7
Di Zhang, Anthony A Armstrong, Susan H Tam, Stephen G McCarthy, Jinquan Luo, Gary L Gilliland, Mark L Chiu
Immunostimulatory receptors belonging to the tumor necrosis factor receptor (TNFR) superfamily are emerging as promising targets for cancer immunotherapies. To optimize the agonism of therapeutic antibodies to these receptors, Fc engineering of antibodies was applied to facilitate the clustering of cell surface TNFRs to activate downstream signaling pathways. One engineering strategy is to identify Fc mutations that facilitate antibody multimerization on the cell surface directly. From the analyses of the crystal packing of IgG1 structures, we identified a novel set of Fc mutations, T437R and K248E, that facilitated antibody multimerization upon binding to antigens on cell surface...
July 31, 2017: MAbs
https://www.readbyqxmd.com/read/28750803/metabolic-profiling-of-cb1-neutral-antagonists
#8
Herbert H Seltzman, Rangan Maitra, Katharine Bortoff, Jay Henson, Patricia H Reggio, Daniel Wesley, Joseph Tam
PIMSR is among the first neutral antagonists for the CB1R and was demonstrated pharmacologically to bind to the CB1R, yet not alter calcium flux. It was further shown computationally to be able to stabilize both the active and inactive states of CB1R revealing the molecular interactions that mechanistically afford the property of neutral antagonism. PIMSR shows dramatic positive effects in reducing weight, food intake, and adiposity as well as in improving glycemic control and lipid homeostasis in high-fat diet-induced obese mice, but also shows increased ALT and liver weight as markers of liver injury with chronic administration...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28747086/menthol-enhances-nicotine-induced-locomotor-sensitization-and-in-vivo-functional-connectivity-in-adolescence
#9
Matthew F Thompson, Guillaume L Poirier, Martha I Dávila-García, Wei Huang, Kelly Tam, Maxwell Robidoux, Michelle L Dubuke, Scott A Shaffer, Luis Colon-Perez, Marcelo Febo, Joseph R DiFranza, Jean A King
Mentholated cigarettes capture a quarter of the US market, and are disproportionately smoked by adolescents. Menthol allosterically modulates nicotinic acetylcholine receptor function, but its effects on the brain and nicotine addiction are unclear. To determine if menthol is psychoactive, we assessed locomotor sensitization and brain functional connectivity. Adolescent male Sprague Dawley rats were administered nicotine (0.4 mg/kg) daily with or without menthol (0.05 mg/kg or 5.38 mg/kg) for nine days. Following each injection, distance traveled in an open field was recorded...
July 1, 2017: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/28747013/estrogen-can-restore-tamoxifen-sensitivity-in-breast-cancer-cells-amidst-the-complex-network-of-resistance
#10
REVIEW
Sepideh Mansouri, Leila Farahmand, Aysooda Hosseinzade, Zahra Eslami-S, Keivan Majidzadeh-A
Breast cancer-related deaths have been on the decline ever since the application of systemic therapies. Chiefly, endocrine therapy, such as Tamoxifen, enhances the survival of estrogen receptor (ER)-positive patients. More than a decade has passed since the introduction of Tamoxifen, however, drug resistance, particularly to Tamoxifen, still remains a major challenge. It has been shown that not only does chronic Tamoxifen exposures induce resistance, but estrogen deprivation can as well. There are two Tamoxifen resistant cell lines, long term estrogen deprived (LTED) cells and cells that have acquired resistance due to long-term exposure to Tamoxifen (Tam-R)...
September 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28743542/the-endocannabinoid-system-expression-in-the-female-reproductive-tract-is-modulated-by-estrogen
#11
J Maia, M Almada, A Silva, G Correia-da-Silva, N Teixeira, S I Sá, B M Fonseca
The endocannabinoid system (ECS) is involved in several physiological events that resulted in a growing interest in its modulation. Moreover, the uterine levels of anandamide (AEA), the major endocannabinoid, must be tightly regulated to create proper embryo implantation conditions. However, there are no evidences about the regulation of AEA in uterus by estrogen. Thus, the aim of this study is to elucidate whether estradiol benzoate (EB) and tamoxifen (TAM) administration to ovariectomized (OVX) rats can induce changes in the expression of cannabinoid receptors and AEA-metabolic enzymes in uterus by evaluating gene transcription and protein levels by qPCR, Western blot and immunohistochemistry...
July 22, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28739604/s1pr1-on-tumor-associated-macrophages-promotes-lymphangiogenesis-and-metastasis-via-nlrp3-il-1%C3%AE
#12
Benjamin Weichand, Rüdiger Popp, Sarah Dziumbla, Javier Mora, Elisabeth Strack, Eiman Elwakeel, Ann-Christin Frank, Klaus Scholich, Sandra Pierre, Shahzad N Syed, Catherine Olesch, Julia Ringleb, Bilge Ören, Claudia Döring, Rajkumar Savai, Michaela Jung, Andreas von Knethen, Bodo Levkau, Ingrid Fleming, Andreas Weigert, Bernhard Brüne
Metastasis is the primary cause of cancer death. The inflammatory tumor microenvironment contributes to metastasis, for instance, by recruiting blood and lymph vessels. Among tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) take a center stage in promoting both tumor angiogenesis and metastatic spread. We found that genetic deletion of the S1P receptor 1 (S1pr1) alone in CD11b(hi) CD206(+) TAMs infiltrating mouse breast tumors prevents pulmonary metastasis and tumor lymphangiogenesis. Reduced lymphangiogenesis was also observed in the nonrelated methylcholanthrene-induced fibrosarcoma model...
July 24, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28734578/phosphatidylserine-is-the-signal-for-tam-receptors-and-their-ligands
#13
REVIEW
Greg Lemke
Nature repeatedly repurposes, in that molecules that serve as metabolites, energy depots, or polymer subunits are at the same time used to deliver signals within and between cells. The preeminent example of this repurposing is ATP, which functions as a building block for nucleic acids, an energy source for enzymatic reactions, a phosphate donor to regulate intracellular signaling, and a neurotransmitter to control the activity of neurons. A series of recent studies now consolidates the view that phosphatidylserine (PtdSer), a common phospholipid constituent of membrane bilayers, is similarly repurposed for use as a signal between cells and that the ligands and receptors of the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases (RTKs) are prominent transducers of this signal...
July 19, 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28728794/myeloid-suppressor-cells-in-cancer-and-autoimmunity
#14
REVIEW
Antonio Sica, Marco Massarotti
A bottleneck for immunotherapy of cancer is the immunosuppressive microenvironment in which the tumor cells proliferate. Cancers harness the immune regulatory mechanism that prevents autoimmunity from evading immunosurveillance and promoting immune destruction. Regulatory T cells, myeloid suppressor cells, inhibitory cytokines and immune checkpoint receptors are the major components of the immune system acting in concert with cancer cells and causing the subversion of anti-tumor immunity. This redundant immunosuppressive network poses an impediment to efficacious immunotherapy by facilitating tumor progression...
July 17, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28727830/the-receptor-tyrosine-kinase-axl-promotes-migration-and-invasion-in-colorectal-cancer
#15
Diana J Uribe, Edward K Mandell, Adam Watson, Jesse D Martinez, Jonathan A Leighton, Sourav Ghosh, Carla V Rothlin
The receptor tyrosine kinases (RTKs) TYRO3, AXL and MERTK (TAM) have well-described oncogenic functions in a number of cancers. Notwithstanding, TAM RTKs are also potent and indispensable inhibitors of inflammation. The combined deletion of Axl and Mertk in mice enhances chronic inflammation and autoimmunity, including increased inflammation in the gut and colitis-associated cancer. On the other hand, deletion of Tyro3 increases the risk of allergic responses. Therefore, the indiscriminate inhibition of these TAM RTKs could result in undesirable immunological diseases...
2017: PloS One
https://www.readbyqxmd.com/read/28725426/colony-stimulating-factor-1-receptor-csf1r-inhibitors-in-cancer-therapy
#16
REVIEW
Michael A Cannarile, Martin Weisser, Wolfgang Jacob, Anna-Maria Jegg, Carola H Ries, Dominik Rüttinger
The tumor-permissive and immunosuppressive characteristics of tumor-associated macrophages (TAM) have fueled interest in therapeutically targeting these cells. In this context, the colony-stimulating factor 1 (CSF1)/colony-stimulating factor 1 receptor (CSF1R) axis has gained the most attention, and various approaches targeting either the ligands or the receptor are currently in clinical development. Emerging data on the tolerability of CSF1/CSF1R-targeting agents suggest a favorable safety profile, making them attractive combination partners for both standard treatment modalities and immunotherapeutic agents...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28724631/the-axl-kinase-domain-in-complex-with-a-macrocyclic-inhibitor-offers-first-structural-insights-into-an-active-tam-receptor-kinase
#17
Ketan S Gajiwala, Neil Grodsky, Ben Bolaños, Junli Feng, RoseAnn Ferre, Sergei Timofeevski, Meirong Xu, Brion W Murray, Ted W Johnson, Al Stewart
The receptor tyrosine kinase (RTK) family consisting of Tyro3, Axl and Mer (TAM) is one of the most recently identified RTK families. TAM receptors are upregulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination...
July 19, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28724364/tamoxifen-reverses-epithelial-mesenchymal-transition-by-demethylating-mir-200c-in-triple-negative-breast-cancer-cells
#18
Qian Wang, Yu Cheng, Yan Wang, Yibo Fan, Ce Li, Ye Zhang, Yiding Wang, Qian Dong, Yanju Ma, Yue-E Teng, Xiujuan Qu, Yunpeng Liu
BACKGROUND: Although the efficacy of tamoxifen (TAM) for breast cancer has been attributed to inducing cell cycle arrest and apoptosis by inhibiting estrogen receptor (ER) signaling, recent evidence indicates that TAM also possesses ER-independent antitumor activity through an unclear mechanism. The present study investigated the anti-tumor mechanism of TAM on mesenchymal triple-negative breast cancer (TNBC). METHODS: The inhibitory effect of TAM on tumor migration and metastasis was analyzed by transwell chamber in vitro and by murine xenograft model in vivo...
July 19, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28723268/assay-of-calcium-transients-and-synapses-in-rat-hippocampal-neurons-by-kinetic-image-cytometry-and-high-content-analysis-an-in-vitro-model-system-for-postchemotherapy-cognitive-impairment
#19
Patrick M McDonough, Natalie L Prigozhina, Ranor C B Basa, Jeffrey H Price
Postchemotherapy cognitive impairment (PCCI) is commonly exhibited by cancer patients treated with a variety of chemotherapeutic agents, including the endocrine disruptor tamoxifen (TAM). The etiology of PCCI is poorly understood. Our goal was to develop high-throughput assay methods to test the effects of chemicals on neuronal function applicable to PCCI. Rat hippocampal neurons (RHNs) were plated in 96- or 384-well dishes and exposed to test compounds (forskolin [FSK], 17β-estradiol [ES]), TAM or fulvestrant [FUL], aka ICI 182,780) for 6-14 days...
July 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28722681/the-role-of-toll-like-receptor-4-in-tumor-microenvironment
#20
REVIEW
Jing Li, Fan Yang, Feng Wei, Xiubao Ren
Tumors are closely related to chronic inflammation, during which there are various changes in inflammatory sites, such as immune cells infiltration, pro-inflammation cytokines production, and interaction between immune cells and tissue cells. Besides, substances, released from both tissue cells attacked by exogenous etiologies, also act on local cells. These changes induce a dynamic and complex microenvironment favorable for tumor growth, invasion, and metastasis. The toll-like receptor 4 (TLR4) is the first identified member of the toll-like receptor family that can recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattern (DAMPs)...
July 8, 2017: Oncotarget
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