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Frank Cackowski, Matthew R Eber, James Rhee, Ann Decker, Kenji Yumoto, Janice E Berry, Eunsohl Lee, Yusuke Shiozawa, Younghun Jung, Julio A Aguirre-Ghiso, Russell S Taichman
Many prostate cancer (PCa) recurrences are thought to be due to reactivation of disseminated tumor cells (DTCs). We previously found a role of the TAM family of receptor tyrosine kinases TYRO3, AXL and MERTK in PCa dormancy regulation. However, the mechanism and contributions of the individual TAM receptors is largely unknown. Knockdown of MERTK, but not AXL or TYRO3 by shRNA in PCa cells induced a decreased ratio of P-Erk1/2 to P-p38, increased expression of p27, NR2F1, SOX2, and NANOG, induced higher levels of histone H3K9me3 and H3K27me3, and induced a G1/G0 arrest, all of which are associated with dormancy...
October 18, 2016: Journal of Cellular Biochemistry
R Krishnan Kutty, William Samuel, Kaifa Boyce, Aswini Cherukuri, Todd Duncan, Cynthia Jaworski, Chandrasekharam N Nagineni, T Michael Redmond
PURPOSE: Proinflammatory cytokines interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) secreted by infiltrating lymphocytes or macrophages may play a role in triggering RPE dysfunction associated with age-related macular degeneration (AMD). Binding of these proinflammatory cytokines to their specific receptors residing on the RPE cell surface can activate signaling pathways that, in turn, may dysregulate cellular gene expression. The purpose of the present study was to investigate whether IFN-γ, TNF-α, and IL-1β have an adverse effect on the expression of genes essential for RPE function, employing the RPE cell line ARPE-19 as a model system...
2016: Molecular Vision
Deborah DeRyckere, Alisa B Lee Sherick, Madeline G Huey, Amanda A Hill, Jeffrey W Tyner, Kristen M Jacobsen, Lauren S Page, Gregory D Kirkpatrick, Fatma Eryildiz, Stephanie A Montgomery, Weihe Zhang, Xiaodong Wang, Stephen V Frye, H Shelton Earp, Douglas K Graham
PURPOSE: MerTK tyrosine kinase is ectopically expressed in 30-50% of acute lymphoblastic leukemias (ALL) and over 80% of acute myeloid leukemias (AML) and is a potential therapeutic target. Here, we evaluated the utility of UNC2025, a MerTK tyrosine kinase inhibitor, for treatment of acute leukemia. EXPERIMENTAL DESIGN: Pre-clinical in vitro and in vivo assays using cell lines and primary leukemia patient samples were utilized to evaluate anti-leukemic effect of UNC2025...
September 20, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
R R Montgomery
West Nile virus (WNV) is the most important causative agent of viral encephalitis worldwide and an important public health concern in the United States due to its high prevalence, severe disease, and the absence of effective treatments. Infection with WNV is mainly asymptomatic, but some individuals develop severe, possibly fatal, neurological disease. Individual host factors play a role in susceptibility to WNV infection, including genetic polymorphisms in key anti-viral immune genes, but age is the most well-defined risk factor for susceptibility to severe disease...
September 10, 2016: Clinical and Experimental Immunology
Jonathan J Miner, Abdoulaye Sene, Justin M Richner, Amber M Smith, Andrea Santeford, Norimitsu Ban, James Weger-Lucarelli, Francesca Manzella, Claudia Rückert, Jennifer Govero, Kevin K Noguchi, Gregory D Ebel, Michael S Diamond, Rajendra S Apte
Zika virus (ZIKV) is an emerging flavivirus that causes congenital abnormalities and Guillain-Barré syndrome. ZIKV infection also results in severe eye disease characterized by optic neuritis, chorioretinal atrophy, and blindness in newborns and conjunctivitis and uveitis in adults. We evaluated ZIKV infection of the eye by using recently developed mouse models of pathogenesis. ZIKV-inoculated mice developed conjunctivitis, panuveitis, and infection of the cornea, iris, optic nerve, and ganglion and bipolar cells in the retina...
September 20, 2016: Cell Reports
Marka R Crittenden, Jason Baird, David Friedman, Talicia Savage, Lauren Uhde, Alejandro Alice, Benjamin Cottam, Kristina Young, Pippa Newell, Cynthia Nguyen, Shelly Bambina, Gwen Kramer, Emmanuel Akporiaye, Anna Malecka, Andrew Jackson, Michael J Gough
Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location resulting in the release of tumor-specific antigens and endogenous adjuvants. However, by activating pathways involved in apoptotic cell recognition and phagocytosis, irradiated cancer cells engender suppressive phenotypes in macrophages. We demonstrate that the macrophage-specific phagocytic receptor, Mertk is upregulated in macrophages in the tumor following radiation therapy. Ligation of Mertk on macrophages results in anti-inflammatory cytokine responses via NF-kB p50 upregulation, which in turn limits tumor control following radiation therapy...
September 2, 2016: Oncotarget
Stanley G Kimani, Sushil Kumar, Viralkumar Davra, Yun-Juan Chang, Canan Kasikara, Ke Geng, Wen-I Tsou, Shenyan Wang, Mainul Hoque, Andrej Boháč, Anita Lewis-Antes, Mariana S De Lorenzo, Sergei V Kotenko, Raymond B Birge
BACKGROUND: Tyro3, Axl, and Mertk (TAMs) are a family of three conserved receptor tyrosine kinases that have pleiotropic roles in innate immunity and homeostasis and when overexpressed in cancer cells can drive tumorigenesis. METHODS: In the present study, we engineered EGFR/TAM chimeric receptors (EGFR/Tyro3, EGFR/Axl, and EGF/Mertk) with the goals to interrogate post-receptor functions of TAMs, and query whether TAMs have unique or overlapping post-receptor activation profiles...
2016: Cell Communication and Signaling: CCS
Marco Cavalli, Gang Pan, Helena Nord, Emelie Wallén Arzt, Ola Wallerman, Claes Wadelius
AIM: Infection by hepatitis C virus (HCV) can result in the development of liver fibrosis and may eventually progress into cirrhosis and hepatocellular carcinoma but the molecular mechanisms for this process are not fully known. Several genome wide association studies (GWAS) have been performed to pinpoint causative variants in HCV-infected patient cohorts but these variants are usually not the functional ones. The aim of this study was to identify the regulatory SNP associated to the risk of HCV induced liver fibrosis and elucidate its molecular mechanism...
August 30, 2016: Hepatology Research: the Official Journal of the Japan Society of Hepatology
Pratima Rawat, Stephen A Spector
Microglia cells are the major reservoir of HIV-1 (HIV) within the CNS. However, current models using transformed cell lines are not representative of primary microglia and fetal brain samples for isolation of primary human microglia (HMG) are increasingly difficult to obtain. Here, we describe a monocyte-derived microglia (MMG) cell model of HIV infection that recapitulates infection of primary HMG. CD14(+) cells isolated from healthy donors were cultured with M-CSF, beta-nerve growth factor, GM-CSF, and CCL2, and compared to HMG...
August 18, 2016: Journal of Neurovirology
Claudia Lanterna, Andrea Musumeci, Laura Raccosta, Gianfranca Corna, Marta Moresco, Daniela Maggioni, Raffaella Fontana, Claudio Doglioni, Claudio Bordignon, Catia Traversari, Vincenzo Russo
Tumor-derived metabolites dampen tumor-infiltrating immune cells and antitumor immune responses. Among the various metabolites produced by tumors, we recently showed that cholesterol oxidized products, namely oxysterols, favor tumor growth through the inhibition of DC migration toward lymphoid organs and by promoting the recruitment of pro-tumor neutrophils within the tumor microenvironment. Here, we tested different drugs capable of blocking cholesterol/oxysterol formation. In particular, we tested efficacy and safety of different administration schedules, and of immunotherapy-based combination of a class of compounds, namely zaragozic acids, which inhibit cholesterol pathway downstream of mevalonate formation, thus leaving intact the formation of the isoprenoids, which are required for the maturation of proteins involved in the immune cell function...
August 12, 2016: Cancer Immunology, Immunotherapy: CII
Lisheng Jiang, Yingmin Chen, Xiaojing Huang, Ancai Yuan, Qin Shao, Jun Pu, Ben He
AIMS: Recent evidence indicates that the defective ability to clear apoptotic cells by macrophages (efferocytosis) and the resultant apoptotic cells accumulation in atherosclerotic plaques play an important role during the progression of unstable plaques. The cannabinoid type 2 receptor (CB2), has recently been emerging as a new target to reduce vulnerability and promote stability of plaques, however, the underlying mechanisms have not been studied in detail. In the present study, we investigated whether selective activation of CB2 improves efferocytosis of macrophages...
September 15, 2016: Life Sciences
Bing Zhang, Lei Fang, Hui-Mei Wu, Pei-Shan Ding, Ke Xu, Rong-Yu Liu
Activation of toll-like receptor (TLR) signaling that initiates an innate immune response to pathogens must be strictly regulated to prevent excessive inflammatory damage in the host. Here, we demonstrate that Mer receptor tyrosine kinase (MerTK) is a negative regulatory molecule in the lipoteichoic acid (LTA)-induced inflammatory response. LTA that activated TLR2 signaling concomitantly induced activation of MerTK signaling in RAW264.7 macrophages, including phosphoinositide 3-kinase (PI3K)/Akt and suppressor of cytokine signaling 3 (SOCS3)...
August 2016: Molecular Immunology
Oliver H Voss, Linjie Tian, Yousuke Murakami, John E Coligan, Konrad Krzewski
Engulfment of apoptotic cells is predominantly executed by phagocytes via the recognition of "eat me" signals like phosphatidylserine (PS). Various PS-specific receptors exist on phagocytes, including Tyro3, Axl, and MerTK receptor tyrosine kinases (TAMs), T-cell immunoglobulin and mucin domain containing 1 and 4 (TIM1/4), and the newly identified CD300 family. The aim of the present auto-commentary is to highlight recent findings regarding the Cd300lf and Cd300lb receptors and their emerging roles in the development of autoimmune disease...
October 2015: Molecular & Cellular Oncology
Timothy M Shaver, Brian D Lehmann, J Scott Beeler, Chung-I Li, Zhu Li, Hailing Jin, Thomas P Stricker, Yu Shyr, Jennifer A Pietenpol
Triple-negative breast cancer (TNBC) and other molecularly heterogeneous malignancies present a significant clinical challenge due to a lack of high-frequency "driver" alterations amenable to therapeutic intervention. These cancers often exhibit genomic instability, resulting in chromosomal rearrangements that affect the structure and expression of protein-coding genes. However, identification of these rearrangements remains technically challenging. Using a newly developed approach that quantitatively predicts gene rearrangements in tumor-derived genetic material, we identified and characterized a novel oncogenic fusion involving the MER proto-oncogene tyrosine kinase (MERTK) and discovered a clinical occurrence and cell line model of the targetable FGFR3-TACC3 fusion in TNBC...
August 15, 2016: Cancer Research
Derek W Gilroy, Matthew L Edin, Roel P H De Maeyer, Jonas Bystrom, Justine Newson, Fred B Lih, Melanie Stables, Darryl C Zeldin, David Bishop-Bailey
Resolution of inflammation has emerged as an active process in immunobiology, with cells of the mononuclear phagocyte system being critical in mediating efferocytosis and wound debridement and bridging the gap between innate and adaptive immunity. Here we investigated the roles of cytochrome P450 (CYP)-derived epoxy-oxylipins in a well-characterized model of sterile resolving peritonitis in the mouse. Epoxy-oxylipins were produced in a biphasic manner during the peaks of acute (4 h) and resolution phases (24-48 h) of the response...
June 7, 2016: Proceedings of the National Academy of Sciences of the United States of America
Bishuang Cai, Edward B Thorp, Amanda C Doran, Manikandan Subramanian, Brian E Sansbury, Chyuan-Sheng Lin, Matthew Spite, Gabrielle Fredman, Ira Tabas
The acute inflammatory response requires a coordinated resolution program to prevent excessive inflammation, repair collateral damage, and restore tissue homeostasis, and failure of this response contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated in part by long-chain fatty acid-derived lipid mediators called specialized proresolving mediators (SPMs). However, how SPMs are regulated during the inflammatory response, and how this process goes awry in inflammatory diseases, are poorly understood...
June 7, 2016: Proceedings of the National Academy of Sciences of the United States of America
Katherine A Minson, Catherine C Smith, Deborah DeRyckere, Clara Libbrecht, Alisa B Lee-Sherick, Madeline G Huey, Elisabeth A Lasater, Gregory D Kirkpatrick, Michael A Stashko, Weihe Zhang, Craig T Jordan, Dmitri Kireev, Xiaodong Wang, Stephen V Frye, H Shelton Earp, Neil P Shah, Douglas K Graham
FMS-like tyrosine kinase 3-targeted (FLT3-targeted) therapies have shown initial promise for the treatment of acute myeloid leukemia (AML) expressing FLT3-activating mutations; however, resistance emerges rapidly. Furthermore, limited options exist for the treatment of FLT3-independent AML, demonstrating the need for novel therapies that reduce toxicity and improve survival. MERTK receptor tyrosine kinase is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis. Here, we describe MRX-2843, a type 1 small-molecule tyrosine kinase inhibitor that abrogates activation of both MERTK and FLT3 and their downstream effectors...
March 2016: JCI Insight
Worapoj Jinda, Naravat Poungvarin, Todd D Taylor, Yutaka Suzuki, Wanna Thongnoppakhun, Chanin Limwongse, Patcharee Lertrit, Prapat Suriyaphol, La-Ongsri Atchaneeyasakul
PURPOSE: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of inherited retinal degenerations characterized by progressive loss of photoreceptor cells and RPE functions. More than 70 causative genes are known to be responsible for RP. This study aimed to identify the causative gene in a patient from a consanguineous family with childhood-onset severe retinal dystrophy. METHODS: To identify the defective gene, whole exome sequencing was performed...
2016: Molecular Vision
Anne von Mässenhausen, Christine Sanders, Britta Thewes, Mario Deng, Angela Queisser, Wenzel Vogel, Glen Kristiansen, Stefan Duensing, Andreas Schröck, Friedrich Bootz, Peter Brossart, Jutta Kirfel, Lynn Heasley, Johannes Brägelmann, Sven Perner
Although head and neck cancer (HNSCC) is the sixth most common tumor entity worldwide therapy options remain limited leading to 5-year survival rates of only 50 %. MERTK is a promising therapeutic target in several tumor entities, however, its role in HNSCC has not been described yet. The aim of our study was to investigate the biological significance of MERTK and to evaluate its potential as a novel therapeutic target in this dismal tumor entity. In two large HNSCC cohorts (n=537 and n=520) we found that MERTK is overexpressed in one third of patients...
May 31, 2016: Oncotarget
Jamila Daragmeh, Waseim Barriah, Bashar Saad, Hilal Zaid
Recent advances in genomics, proteomics, cell biology and biochemistry of tumors have revealed new pathways that are aberrantly activated in numerous cancer types. However, the enormous amount of data available in this field may mislead scientists in focused research. As cancer cell growth and progression is often dependent upon the phosphoinositide 3-kinase (PI3K)/AKT pathway, there has been extensive research into the proteins implicated in the PI3K pathway. Using data available in the Human Protein Atlas database, the current study investigated the expression of 25 key proteins that are known to be involved with PI3K pathway activation in a distinct group of 20 cancer types...
April 2016: Oncology Letters
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