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Spleen tyrosine kinase

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https://www.readbyqxmd.com/read/28100269/a-spleen-tyrosine-kinase-inhibitor-attenuates-the-proliferation-and-migration-of-vascular-smooth-muscle-cells
#1
Hyang-Hee Seo, Sang Woo Kim, Chang Youn Lee, Kyu Hee Lim, Jiyun Lee, Eunhyun Choi, Soyeon Lim, Seahyoung Lee, Ki-Chul Hwang
BACKGROUND: Pathologic vascular smooth muscle cell (VSMC) proliferation and migration after vascular injury promotes the development of occlusive vascular disease. Therefore, an effective chemical agent to suppress aberrant proliferation and migration of VSMCs can be a potential therapeutic modality for occlusive vascular disease such as atherosclerosis and restenosis. To find an anti-proliferative chemical agent for VSMCs, we screened an in-house small molecule library, and the selected small molecule was further validated for its anti-proliferative effect on VSMCs using multiple approaches, such as cell proliferation assays, wound healing assays, transwell migration assays, and ex vivo aortic ring assay...
January 18, 2017: Biological Research
https://www.readbyqxmd.com/read/28097631/force-dependent-calcium-signaling-and-its-pathway-of-human-neutrophils-on-p-selectin-in-flow
#2
Bing Huang, Yingchen Ling, Jiangguo Lin, Xin Du, Ying Fang, Jianhua Wu
P-selectin engagement of P-selectin glycoprotein ligand-1 (PSGL-1) causes circulating leukocytes to roll on and adhere to the vascular surface, and mediates intracellular calcium flux, a key but unclear event for subsequent arresting firmly at and migrating into the infection or injured tissue. Using a parallel plate flow chamber technique and intracellular calcium ion detector (Fluo-4 AM), the intracellular calcium flux of firmly adhered neutrophils on immobilized P-selectin in the absence of chemokines at various wall shear stresses was investigated here in real time by fluorescence microscopy...
January 18, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28064214/hsp90-promotes-burkitt-lymphoma-cell-survival-by-maintaining-tonic-b-cell-receptor-signaling
#3
Roland Walter, Kuan-Ting Pan, Carmen Doebele, Federico Comoglio, Katarzyna Tomska, Hanibal Bohnenberger, Ryan M Young, Laura Jacobs, Ulrich Keller, Halvard Bönig, Michael Engelke, Andreas Rosenwald, Henning Urlaub, Louis M Staudt, Hubert Serve, Thorsten Zenz, Thomas Oellerich
Burkitt lymphoma (BL) is an aggressive B cell neoplasm that is currently treated by intensive chemotherapy in combination with anti-CD20 antibodies. Due to their toxicity, current treatment regimens are often not suitable for elderly patients or for patients in developing countries where BL is endemic. Targeted therapies for BL are therefore needed. In this study, we performed a compound screen in 17 BL cell lines to identify small molecule inhibitors affecting cell survival. We found that inhibitors of heat shock protein 90 (HSP90) induced apoptosis in BL cells in vitro at concentrations that did not affect normal B cells...
November 15, 2016: Blood
https://www.readbyqxmd.com/read/28056193/reduced-cd62l-expression-on-t-cells-and-increased-soluble-cd62l-levels-predict-molecular-response-to-tyrosine-kinase-inhibitor-therapy-in-early-chronic-phase-chronic-myelogenous-leukemia
#4
Sieghart Sopper, Satu Mustjoki, Deborah White, Timothy Hughes, Peter Valent, Andreas Burchert, Bjørn T Gjertsen, Günther Gastl, Matthias Baldauf, Zlatko Trajanoski, Frank Giles, Andreas Hochhaus, Thomas Ernst, Thomas Schenk, Jeroen J W M Janssen, Gert J Ossenkoppele, Kimmo Porkka, Dominik Wolf
Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry-based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts...
January 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28054556/phosphorylation-impact-on-spleen-tyrosine-kinase-conformation-by-surface-enhanced-raman-spectroscopy
#5
Maximilien Cottat, Ryohei Yasukuni, Yo Homma, Nathalie Lidgi-Guigui, Nadine Varin-Blank, Marc Lamy de la Chapelle, Christine Le Roy
Spleen Tyrosine Kinase (Syk) plays a crucial role in immune cell signalling and its altered expression or activation are involved in several cancers. Syk activity relies on its phosphorylation status and its multiple phosphorylation sites predict several Syk conformations. In this report, we characterized Syk structural changes according to its phosphorylation/activation status by Surface Enhanced Raman Spectroscopy (SERS). Unphosphorylated/inactive and phosphorylated/active Syk forms were produced into two expression systems with different phosphorylation capability...
January 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28011996/the-kinase-inhibitors-r406-and-gs-9973-impair-t-cell-functions-and-macrophage-mediated-anti-tumor-activity-of-rituximab-in-chronic-lymphocytic-leukemia-patients
#6
Ana Colado, María Belén Almejún, Enrique Podaza, Denise Risnik, Carmen Stanganelli, Esteban Enrique Elías, Patricia Dos Santos, Irma Slavutsky, Horacio Fernández Grecco, María Cabrejo, Raimundo Fernando Bezares, Mirta Giordano, Romina Gamberale, Mercedes Borge
Small molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from CLL patients...
December 23, 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28011623/sunitinib-treatment-enhances-metastasis-of-innately-drug-resistant-breast-tumors
#7
Joseph W Wragg, Victoria L Heath, Roy Bicknell
Anti-angiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date there has not been an inquiry into roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the anti-angiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance...
December 23, 2016: Cancer Research
https://www.readbyqxmd.com/read/28000738/immunomodulatory-and-antitumor-effects-of-a-novel-tlr7-agonist-combined-with-lapatinib
#8
Ningning Gao, Jingjing Zhong, Xiaodong Wang, Zhenchao Jin, Wang Li, Yu Liu, Yuwen Diao, Zhulin Wang, Wenqi Jiang, Guangyi Jin
As new treatment approaches, both immunotherapy and targeted treatments have been used in the clinical treatment of cancers. These therapies are different from traditional surgery, chemotherapy and radiotherapy. Use of a combination of immunotherapy and targeted treatments may improve tumor clearance. We investigated the feasibility of combining tyrosine kinase inhibitors (TKIs, targeted drugs) and SZU-101 (a novel TLR7 agonist synthesized by our laboratory). Thirteen different TKIs were combined with or without SZU-101 and studied to determine their effects on immunocytes...
December 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27994755/carboxamide-spleen-tyrosine-kinase-syk-inhibitors-leveraging-ground-state-interactions-to-accelerate-optimization
#9
J Michael Ellis, Michael D Altman, Brandon Cash, Andrew M Haidle, Rachel L Kubiak, Matthew L Maddess, Youwei Yan, Alan B Northrup
Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27966556/mv140-a-sublingual-polyvalent-bacterial-preparation-to-treat-recurrent-urinary-tract-infections-licenses-human-dendritic-cells-for-generating-th1-th17-and-il-10-responses-via-syk-and-myd88
#10
C Benito-Villalvilla, C Cirauqui, C M Diez-Rivero, M Casanovas, J L Subiza, O Palomares
Recurrent urinary tract infections (RUTIs) are one of the most common bacterial infectious diseases, especially in women. Antibiotics remain the mainstay of treatment, but their overuse is associated with antibiotic-resistant infections and deleterious effects in the microbiota. Therefore, alternative approaches are fully demanded. Sublingual immunization with MV140 (Uromune), a polyvalent bacterial preparation (PBP) of whole heat-inactivated bacteria, demonstrated clinical efficacy for the treatment of RUTIs, but the involved immunological mechanisms remain unknown...
December 14, 2016: Mucosal Immunology
https://www.readbyqxmd.com/read/27942010/limited-impact-of-imatinib-in-a-murine-model-of-sclerodermatous-chronic-graft-versus-host-disease
#11
Ludovic Belle, Gilles Fransolet, Joan Somja, Marilène Binsfeld, Philippe Delvenne, Pierre Drion, Muriel Hannon, Yves Beguin, Grégory Ehx, Frédéric Baron
BACKGROUND: Sclerodermatous chronic Graft-versus-Host Disease (scl-cGVHD) is one of the most severe form of cGVHD. The Platelet-derived Grotwth Factor (PDGF) and the Transforming Growth Factor-β (TGF-β) play a significant role in the fibrosing process occurring in scl-cGVHD. This prompted us to assess the impact of the PDGF-r and c-Abl tyrosine kinase inhibitor imatinib on scl-cGVHD. METHODS: To assess the impact of imatinib on T cell subset proliferation in vivo, Balb/cJ recipient mice were lethally (7 Gy) irradiated and then injected with 10x106 bone marrow cells from B10...
2016: PloS One
https://www.readbyqxmd.com/read/27906453/spleen-tyrosine-kinase-inhibition-blocks-airway-constriction-and-protects-from-th2-induced-airway-inflammation-and-remodeling
#12
C Tabeling, J Herbert, A C Hocke, D J Lamb, S L Wollin, K J Erb, E Boiarina, H Movassagh, J Scheffel, J M Doehn, S Hippenstiel, M Maurer, A S Gounni, W M Kuebler, N Suttorp, M Witzenrath
BACKGROUND: Spleen tyrosine kinase (Syk) is an intracellular nonreceptor tyrosine kinase, which has been implicated as central immune modulator promoting allergic airway inflammation. Syk inhibition has been proposed as a new therapeutic approach in asthma. However, the direct effects of Syk inhibition on airway constriction independent of allergen sensitization remain elusive. METHODS: Spectral confocal microscopy of human and murine lung tissue was performed to localize Syk expression...
December 1, 2016: Allergy
https://www.readbyqxmd.com/read/27903679/the-bruton-s-tyrosine-kinase-btk-inhibitor-acalabrutinib-demonstrates-potent-on-target-effects-and-efficacy-in-two-mouse-models-of-chronic-lymphocytic-leukemia
#13
Sarah E M Herman, Arnau Montraveta, Carsten U Niemann, Helena Mora-Jensen, Michael Gulrajani, Fanny Krantz, Rose Mantel, Lisa L Smith, Fabienne McClanahan, Bonnie Harrington, Dolors Colomer, Todd Covey, John C Byrd, Raquel Izumi, Allard Kaptein, Roger Ulrich, Amy Johnson, Brian J Lannutti, Adrian Wiestner, Jennifer A Woyach
PURPOSE: Acalabrutinib (ACP-196) is a novel, potent, and highly selective BTK inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the anti-tumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). EXPERIMENTAL DESIGN: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model...
November 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27899962/new-emerging-therapies-in-the-management-of-chronic-lymphocytic-leukemia
#14
Xiao-Lin Li, Ci-Xian Zhang
Chronic lymphocytic leukemia (CLL) is considered incurable despite advances in management strategies. New drugs targeting cell pathways are currently being developed for the efficient management of CLL. Various strategies involving different targets have been developed, or are currently in the developing stage. A search was conducted in the electronic database PubMed, for pre-clinical as well as clinically controlled trials reporting various strategies against CLL currently under investigation. Novel strategies included use of antibodies, small cell inhibitors, such as spleen tyrosine kinase, LYN, cyclin-dependent kinase, and histone deacetylase inhibitors...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27894895/molecular-characterization-and-expression-analysis-of-olive-flounder-paralichthys-olivaceus-phospholipase-c-gamma-1-and-gamma-2
#15
Soo Ji Woo, Hyae In Jo, Hyung Ho Lee, Joon Ki Chung
Phospholipase C gamma 1 and gamma 2 (PLCG1 and PLCG2) are influential in modulating Ca(2+) and diacylglycerol, second messengers involved in tyrosine kinase-dependent signaling, including growth factor activation. Here, we used RACE (rapid amplification of cDNA ends) to clone cDNA encoding PLCG1 (PoPLCG1) and PLCG2 (PoPLCG2) in the olive flounder (Paralichthys olivaceus). The respective 1313 and 1249 amino acid sequences share high identity with human PLCG1 and PLCG2, and contain the following domains: pleckstrin homology (PH), EF-hand, catalytic X and Y, Src homology 2 (SH2), Src homology 3 (SH3), and C2...
November 25, 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27837109/characterization-of-the-syk-dependent-t-cell-signaling-response-to-an-altered-peptide
#16
Jeoung-Eun Park, Jeffrey A Rotondo, David L Cullins, David D Brand, Ae-Kyung Yi, John M Stuart, Andrew H Kang, Linda K Myers
Rheumatoid arthritis is an autoimmune disorder characterized by T cell dysregulation. We have shown that an altered peptide ligand (A9) activates T cells to use an alternate signaling pathway that is dependent on FcRγ and spleen tyrosine kinase, resulting in downregulation of inflammation. In the experiments described in this study, we have attempted to determine the molecular basis of this paradox. Three major Src family kinases found in T cells (Lck, Fyn, and Lyn) were tested for activation following stimulation by A9/I-A(q) Unexpectedly we found they are not required for T cell functions induced by A9/I-A(q), nor are they required for APL stimulation of cytokines...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27825101/dynamic-contributions-of-p-and-e-selectins-to-%C3%AE-2-integrin-induced-neutrophil-transmigration
#17
Yixin Gong, Yan Zhang, Shiliang Feng, Xiaofeng Liu, Shouqin Lü, Mian Long
Leukocyte transendothelial migration is a key step in their recruitment to sites of inflammation. However, synergic regulation of endothelium-expressed selectins on leukocyte transmigration remains unclear. In this study, an in vitro model was developed to investigate the dynamic contributions of P- and E-selectin to polymorphonuclear neutrophil (PMN) transmigration under static conditions. Human umbilical vein endothelial cells (HUVECs) were treated with LPS for 4 or 12 h to induce different expression of selectins and intercellular adhesion molecule (ICAM)-1...
January 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27822175/keyhole-limpet-hemocyanin-induces-innate-immunity-via-syk-and-erk-phosphorylation
#18
Kyoko Yasuda, Hideki Ushio
Hemocyanin is an extracellular respiratory protein containing copper in hemolymph of invertebrates, such as Mollusk and Arthropod. Keyhole limpet hemocyanin (KLH) is one of hemocyanins and has many years of experience for vaccine developments and immunological studies in mammals including human. However, the association between KLH and the immune systems, especially the innate immune systems, remains poorly understood. The aim of this study is to clarify the direct effects of KLH on the innate immune systems...
2016: EXCLI journal
https://www.readbyqxmd.com/read/27795434/clec5a-mediated-enhancement-of-the-inflammatory-response-in-myeloid-cells-contributes-to-influenza-virus-pathogenicity-in-vivo
#19
Ooiean Teng, Szu-Ting Chen, Tsui-Ling Hsu, Sin Fun Sia, Suzanne Cole, Sophie A Valkenburg, Tzu-Yun Hsu, Jian Teddy Zheng, Wenwei Tu, Roberto Bruzzone, Joseph Sriyal Malik Peiris, Shie-Liang Hsieh, Hui-Ling Yen
: Human infections with influenza viruses exhibit mild to severe clinical outcomes as a result of complex virus-host interactions. Induction of inflammatory mediators via pattern recognition receptors may dictate subsequent host responses for pathogen clearance and tissue damage. We identified that human C-type lectin domain family 5 member A (CLEC5A) interacts with the hemagglutinin protein of influenza viruses expressed on lentiviral pseudoparticles through lectin screening. Silencing CLEC5A gene expression, blocking influenza-CLEC5A interactions with anti-CLEC5A antibodies, or dampening CLEC5A-mediated signaling using a spleen tyrosine kinase inhibitor consistently reduced the levels of proinflammatory cytokines produced by human macrophages without affecting the replication of influenza A viruses of different subtypes...
January 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/27789138/synthesis-and-optimization-of-furano-3-2-d-pyrimidines-as-selective-spleen-tyrosine-kinase-syk-inhibitors
#20
Michael Hoemann, Noel Wilson, Maria Argiriadi, David Banach, Andrew Burchat, David Calderwood, Bruce Clapham, Phil Cox, David B Duignan, Don Konopacki, Gagandeep Somal, Anil Vasudevan
A series of furano[3,2-d]pyrimidine Syk inhibitors were synthesized and optimized for their enzyme potency and selectivity versus other kinases. In addition, ADME properties were assessed and compounds were prepared with optimized profiles for in vivo experiments. Compound 23 was identified as having acceptable pharmacokinetic properties and demonstrated efficacy in a rat collagen induced arthritis model.
November 15, 2016: Bioorganic & Medicinal Chemistry Letters
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