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https://www.readbyqxmd.com/read/28551502/promiscuity-and-selectivity-of-small-molecule-inhibitors-across-tam-receptor-tyrosine-kinases-in-pediatric-leukemia
#1
Mao-Hua Liu, Shi-Bing Chen, Juan Yu, Cheng-Jun Liu, Xiao-Jing Zhang
The TAM receptor tyrosine kinase family member Mer has been recognized as an attractive therapeutic target for pediatric leukemia. Beside Mer the family contains other two kinases, namely, Tyro3 and Axl, which are highly homologues with Mer and thus most existing small-molecule inhibitors show moderate or high promiscuity across the three kinases. Here, the structural basis and energetic property of selective binding of small-molecule inhibitors to the three kinases were investigated at molecular level. It is found that the selectivity is primarily determined by the size, shape and configuration of kinase's ATP-binding site; the Mer and Axl possess a small, closed active pocket as compared to the bulky, open pocket of Tyro3...
May 15, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28537534/elevated-plasma-growth-arrest-specific-6-protein-levels-are-associated-with-the-severity-of-disease-during-hantaan-virus-infection-in-humans
#2
Chunmei Zhang, Kang Tang, Yusi Zhang, Ying Ma, Ran Zhuang, Xuyang Zheng, Boquan Jin, Yun Zhang
Hemorrhagic fever with renal syndrome (HFRS) is caused by Hantaan virus (HTNV) and Seoul virus infection in Asia. The clinical manifestation of HFRS is characterized by the rapid loss of renal function (acute kidney injury) and thrombocytopenia. The specific immune mechanisms that cause thrombocytopenia in HFRS are not well described. The growth arrest-specific 6 (Gas6) protein and TAM (Tyro3, Axl and Mer) receptors have been recently shown to play prominent roles in immune regulation, and high plasma levels of Gas6 may predict the severity of diseases...
May 24, 2017: Viral Immunology
https://www.readbyqxmd.com/read/28526769/tam-receptor-tyrosine-kinases-in-cancer-drug-resistance
#3
REVIEW
Mikaella Vouri, Sassan Hafizi
Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy...
May 19, 2017: Cancer Research
https://www.readbyqxmd.com/read/28514441/pd-1-expression-by-tumour-associated-macrophages-inhibits-phagocytosis-and-tumour-immunity
#4
Sydney R Gordon, Roy L Maute, Ben W Dulken, Gregor Hutter, Benson M George, Melissa N McCracken, Rohit Gupta, Jonathan M Tsai, Rahul Sinha, Daniel Corey, Aaron M Ring, Andrew J Connolly, Irving L Weissman
Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance. Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system. Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin's lymphoma...
May 25, 2017: Nature
https://www.readbyqxmd.com/read/28512240/sting-activation-reverses-lymphoma-mediated-resistance-to-antibody-immunotherapy
#5
Lekh N Dahal, Lang Dou, Khiyam Hussain, Rena Liu, Alexander Earley, Kerry L Cox, Salome Murinello, Ian Tracy, Francesco Forconi, Andrew J Steele, Patrick Duriez, Diego Gomez-Nicola, Jessica L Teeling, Martin J Glennie, Mark S Cragg, Stephen A Beers
Tumors routinely attract and co-opt macrophages to promote their growth, angiogenesis and metastasis. Macrophages are also the key effector cell for monoclonal antibody (mAb) therapies. Here we report that the tumor microenvironment creates an immunosuppressive signature on tumor-associated macrophages (TAM) which favors expression of inhibitory rather than activating Fcγ receptors (FcγR), thereby limiting the efficacy of mAb immunotherapy. We assessed a panel of TLR and STING agonists (a) for their ability to reprogram macrophages to a state optimal for mAb immunotherapy...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28507810/tie-2-expressing-monocytes-in-human-cancers
#6
Riccardo Turrini, Angélique Pabois, Ioannis Xenarios, George Coukos, Jean-François Delaloye, Marie-Agnès Doucey
Tumor-associated macrophages (TAM) are well known as a key player in the tumor microenvironment, which support cancer progression. More recently, a lineage of monocytes characterized by the expression of the TIE-2/Tek angiopoietin receptor identified a subset of circulating and tumor-associated monocytes endowed with proangiogenic activity. TIE-2 expressing monocytes (TEM) were found both in humans and mice. Here, we review the phenotypes and functions of TEM reported so far in human cancer and their potential use as markers of cancer progression and metastasis...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28502299/-tumor-associated-macrophages-promote-the-proliferation-and-migration-as-well-as-invasion-of-sorafenib-resistant-hepatocellular-carcinoma-cells
#7
Xufu Wei, Junliang Pu, Zhen Guo, Tingting Li, Di Zhu, Zhongjun Wu
Objective To investigate the roles of tumor-associated macrophages (TAMs) and epithelial growth factor receptor (EGFR)/β-catenin signaling pathway in sorafenib resistance of hepatocellular carcinoma cells. Methods Macrophages were isolated from peripheral blood mononuclear cells (PBMCs) and cultured in the presence of colony-stimulating factor (M-CSF) to obtain TAMs. Phenotypes of TAMs were identified. The level of epithelial growth factor (EGF) secreted by TAMs was detected by ELISA. CCK-8 assay was performed to verify the effects of EGF on HepG2 and SMMC7721 cell proliferation...
May 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/28498427/effect-of-macrophages-on-breast-cancer-cell-proliferation-and-on-expression-of-hormone-receptors-upar-and-her-2
#8
Therése Lindsten, Alexander Hedbrant, Anna Ramberg, Jonny Wijkander, Anja Solterbeck, Margareta Eriksson, Dick Delbro, Ann Erlandsson
Malignant tumors, including breast cancers, are frequently infiltrated with innate immune cells and tumor-associated macrophages (TAMs) represent the major inflammatory component in stroma of many tumors. In this study, we examined the immunoreactivity of the macrophage markers CD68 and CD163 as well as the hormone receptors estrogen receptor α (ERα), progesterone receptor (PR), estrogen receptor β1 (ERβ1), human epidermal growth factor receptor 2 (HER-2), matrix metalloproteinase 9 (MMP‑9), urokinase-type plasminogen activator receptor (uPAR) and the proliferations marker Ki67 in 17 breast cancer biopsies...
May 11, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28488871/spatial-targeting-of-tumor-associated-macrophages-and-tumor-cells-with-a-ph-sensitive-cluster-nanocarrier-for-cancer-chemo-immunotherapy
#9
Song Shen, Hong-Jun Li, Kai-Ge Chen, Yucai Wang, Xian-Zhu Yang, Zhe-Xiong Lian, Jinzhi Du, Jun Wang
Chemo-immunotherapy, which combines chemotherapeutics with immune-modulating agents, represents an appealing approach for improving cancer therapy. To optimize its therapeutic efficacy, differentially delivering multiple therapeutic drugs to target cells is desirable. Here we developed an immunostimulatory nanocarrier (denoted as (BLZ-945)SCNs/Pt) that could spatially target tumor-associated macrophages (TAMs) and tumor cells for cancer chemo-immunotherapy. (BLZ-945)SCNs/Pt undergo supersensitive structure collapse in the prevascular regions of tumor tissues, and enable simultaneous release of platinum (Pt)-prodrug conjugated small particles and BLZ-945, a small molecule inhibitor of colony stimulating factor 1 receptor (CSF-1R) of TAMs...
May 10, 2017: Nano Letters
https://www.readbyqxmd.com/read/28481877/cyp4a-in-tumor-associated-macrophages-promotes-pre-metastatic-niche-formation-and-metastasis
#10
X W Chen, T J Yu, J Zhang, Y Li, H L Chen, G F Yang, W Yu, Y Z Liu, X X Liu, C F Duan, H L Tang, M Qiu, C L Wang, H Zheng, J Yue, A M Guo, J Yang
Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A(+) TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1(+)) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma...
May 8, 2017: Oncogene
https://www.readbyqxmd.com/read/28465354/egfr-inhibition-by-epigallocatechin-3-gallate-and-iif-treatments-reduces-breast-cancer-cell-invasion
#11
Fulvia Farabegoli, Marzia Govoni, Enzo Spisni, Alessio Papi
Epidermal growth factor receptor (EGFR) expression is an important marker in breast carcinoma pathology and is considered a pivotal molecule for cancer cell proliferation, invasion and metastasis. We investigated the effects of epigallocatechin-3-gallate (EGCG), the most active green tea catechin, in combination with 6-OH-11-O-hydroxyphenanthrene (IIF), a synthetic retinoid X receptor-γ (RXRγ) agonist, on three breast carcinoma cell lines: MCF-7, MCF-7TAM and MDA-MB-231. EGFR and AKT activation and molecular markers of cell motility and migration (CD44, extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN), MMP-2, MMP-9 and tissue inhibitor of metalloproteinases (TIMPs)) were studied after EGCG and IIF treatments...
June 30, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28459461/mir-181b-modulates-egfr-dependent-vcam-1-expression-and-monocyte-adhesion-in-glioblastoma
#12
Y-S Liu, H-Y Lin, S-W Lai, C-Y Huang, B-R Huang, P-Y Chen, K-C Wei, D-Y Lu
Tumor-associated macrophages (TAMs) originate as circulating monocytes, and are recruited to gliomas, where they facilitate tumor growth and migration. Understanding the interaction between TAM and cancer cells may identify therapeutic targets for glioblastoma multiforme (GBM). Vascular cell adhesion molecule-1 (VCAM-1) is a cytokine-induced adhesion molecule expressed on the surface of cancer cells, which is involved in interactions with immune cells. Analysis of the glioma patient database and tissue immunohistochemistry showed that VCAM-1 expression correlated with the clinico-pathological grade of gliomas...
May 1, 2017: Oncogene
https://www.readbyqxmd.com/read/28453960/implication-of-a-novel-gla-containing-protein-gas6-in-the-pathogenesis-of-insulin-resistance-impaired-glucose-homeostasis-and-inflammation-a-review
#13
REVIEW
Anjum Dihingia, Jatin Kalita, Prasenjit Manna
Growth arrest specific 6 (Gas6), a vitamin K-dependent protein plays a significant role in the regulation of cellular homeostasis via binding with TAM-receptor tyrosine kinases. Several studies reported the role of Gas6 in cancer, glomerular injury, obesity, and inflammation, however, very little is known about its role in insulin resistance (IR) and impaired glucose metabolism. Majority of the studies reported an inverse correlation of Gas6 protein levels or gene polymorphism with plasma glucose, HbA1c, IR, and inflammatory cytokines among type 2 diabetes (T2D) and obese subjects...
April 13, 2017: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/28441391/apigenin-inhibits-tnf%C3%AE-il-1%C3%AE-induced-ccl2-release-through-ikbk-epsilon-signaling-in-mda-mb-231-human-breast-cancer-cells
#14
David Bauer, Natalie Redmon, Elizabeth Mazzio, Karam F Soliman
Mortality associated with breast cancer is attributable to aggressive metastasis, to which TNFα plays a central orchestrating role. TNFα acts on breast tumor TNF receptors evoking the release of chemotactic proteins (e.g. MCP-1/CCL2). These proteins direct inward infiltration/migration of tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory cells (Tregs), T helper IL-17-producing cells (Th17s), metastasis-associated macrophages (MAMs) and cancer-associated fibroblasts (CAFs)...
2017: PloS One
https://www.readbyqxmd.com/read/28439566/inflammatory-markers-and-risk-for-cognitive-decline-in-chronic-kidney-disease-the-cric-study
#15
Manjula Kurella Tamura, Karman Tam, Eric Vittinghoff, Dominic Raj, Stephen M Sozio, Sylvia E Rosas, Gail Makos, Claudia Lora, Jiang He, Alan S Go, Chi-Yuan Hsu, Kristine Yaffe
INTRODUCTION: Chronic kidney disease (CKD) is associated with an increased risk of cognitive decline, but the mechanisms remain poorly defined. We sought to determine the relation between serum inflammatory markers and risk of cognitive decline among adults with CKD. METHODS: We studied 757 adults aged ≥55 years with CKD participating in the Chronic Renal Insufficiency Cohort Cognitive study. We measured interleukin (IL)-1β, IL-1 receptor antagonist, IL-6, tumor necrosis factor (TNF)-α, high-sensitivity C-reactive protein (hs-CRP), and fibrinogen in baseline plasma samples...
March 2017: KI Reports
https://www.readbyqxmd.com/read/28434946/hyperglycemia-induced-renal-p2x7-receptor-activation-enhances-diabetes-related-injury
#16
Robert I Menzies, John W R Booth, John J Mullins, Matthew A Bailey, Frederick W K Tam, Jill T Norman, Robert J Unwin
Diabetes is a leading cause of renal disease. Glomerular mesangial expansion and fibrosis are hallmarks of diabetic nephropathy and this is thought to be promoted by infiltration of circulating macrophages. Monocyte chemoattractant protein-1 (MCP-1) has been shown to attract macrophages in kidney diseases. P2X7 receptors (P2X7R) are highly expressed on macrophages and are essential components of pro-inflammatory signaling in multiple tissues. Here we show that in diabetic patients, renal P2X7R expression is associated with severe mesangial expansion, impaired glomerular filtration (≤40ml/min/1...
April 20, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28427165/prognostic-significance-of-tumor-associated-macrophages-in-breast-cancer-a-meta-analysis-of-the-literature
#17
REVIEW
Xixi Zhao, Jingkun Qu, Yuchen Sun, Jizhao Wang, Xu Liu, Feidi Wang, Hong Zhang, Wen Wang, Xingcong Ma, Xiaoyan Gao, Shuqun Zhang
PURPOSE: Tumor associated macrophages (TAMs) are important prognostic factors and have been proved to be associated with the invasion and migration of various cancer. However, the relationship between TAMs and breast cancer outcomes remains unclear. EXPERIMENTAL DESIGN: Sixteen studies with a total of 4,541 breast cancer patients were included in this meta-analysis. Correlation of TAMs with overall survival (OS), disease-free survival(DFS), relapse-free survival (RFS), breast cancer special survival (BCSS) and clinicopathological features were analyzed...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423597/hrd1-sensitizes-breast-cancer-cells-to-tamoxifen-by-promoting-s100a8-degradation
#18
YanYang Wang, AiBin Guo, XiuBin Liang, Min Li, Ming Shi, Yan Li, Gareth Jenkins, XiaWen Lin, XueFei Wei, ZhiJun Jia, XueFeng Feng, DongMing Su, WanHua Guo
Estrogen receptor alpha positive (ER+) of breast cancer could develop resistance to antiestrogens including Tamoxifen. Our previous study showed that the E3 ubiquitin ligase HRD1 played an important role in anti-breast cancer. However, its role in chemotherapy resistance hasn't been reported. In this study, we found that HRD1 expression was downregulated in Tamoxifen-resistant breast cancer cell line MCF7/Tam compared to the Tamoxifen sensitive cell line MCF7. Moreover, S100A8 is the direct target of HRD1 by proteome analysis...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423319/tam-receptors-are-not-required-for-zika-virus-infection-in-mice
#19
Andrew K Hastings, Laura J Yockey, Brett W Jagger, Jesse Hwang, Ryuta Uraki, Hallie F Gaitsch, Lindsay A Parnell, Bin Cao, Indira U Mysorekar, Carla V Rothlin, Erol Fikrig, Michael S Diamond, Akiko Iwasaki
Tyro3, Axl, and Mertk (TAM) receptors are candidate entry receptors for infection with the Zika virus (ZIKV), an emerging flavivirus of global public health concern. To investigate the requirement of TAM receptors for ZIKV infection, we used several routes of viral inoculation and compared viral replication in wild-type versus Axl(-/-), Mertk(-/-), Axl(-/-)Mertk(-/-), and Axl(-/-)Tyro3(-/-) mice in various organs. Pregnant and non-pregnant mice treated with interferon-α-receptor (IFNAR)-blocking (MAR1-5A3) antibody and infected subcutaneously with ZIKV showed no reliance on TAMs for infection...
April 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28422875/jagged1-modulated-tumor-associated-macrophage-differentiation-predicts-poor-prognosis-in-patients-with-invasive-micropapillary-carcinoma-of-the-breast
#20
Hang Liu, Jingxuan Wang, Zhaoliang Liu, Le Wang, Shoujun Liu, Qingyuan Zhang
OBJECTIVES: Invasive micropapillary carcinoma of the breast (IMPC) constitutes a unique and aggressive subtype of breast cancer. We aimed to evaluate the prognostic significance of the Jagged1 (a ligand of the Notch pathway) expression, and infiltration density of tumor-associated macrophages (TAMs) in patients with IMPC. METHODS: Jagged1 expression and CD163+, CD68+ macrophage infiltration were evaluated by immunohistochemistry in 222 tumor samples, and the clinical significance was analyzed...
April 2017: Medicine (Baltimore)
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