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https://www.readbyqxmd.com/read/28446278/-clinical-analysis-for-42-imatinib-resistant-patients-with-chronic-myelogenous-leukemia
#1
Xi Liu, Si-Lin Gan, Jie Ma, Yan-Fang Liu, Xin-Sheng Xie, Zhong-Xing Jiang, Yuan-Dong Cheng, Hui Sun
OBJECTIVE: To analyze the kinase mutation ratio, related factors, effectiveness and safety of the second generation drugs for imatinib-resistant patients with chronic myeloid leukemia(CML). METHODS: COX proportional hazard regression model was used for unvariate and multvariate analysis of various factors affecting the kinase mutation and for evaluating the effectiveness and safety of second generation tyrosine kinase inhibitor(TKI). RESULTS: 13 kinds of mutation were detected in 19 out of 42 cases for 22 times, including 4 times of F359V, 3 times of E255K, 2 time for F359C, F317L, T315I, Y253H, 1 time for D256R, C250R, D276G, F486S, M244V, Y256H and G250E, 3 cases with mixed mutations...
April 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28445193/a-pilot-randomized-trial-on-safety-and-efficacy-of-a-novel-topical-combined-inhibitor-of-janus-kinase-1-3-and-spleen-tyrosine-kinase-for-gvhd-associated-ocular-surface-disease
#2
Ahmad Kheirkhah, Antonio Di Zazzo, Vannarut Satitpitakul, Merle Fernandez, Daniel Magilavy, Reza Dana
PURPOSE: Janus kinase (JAK) and spleen tyrosine kinase (SYK) play critical functions in T-cell activation and in inflammation. Because of their antiinflammatory effects, JAK and SYK inhibitors have recently been evaluated in several immunopathogenic disorders. This pilot study was designed to assess the safety and efficacy of a topical combined JAK/SYK inhibitor, R348, ophthalmic solution for treatment of ocular surface disease in graft-versus-host disease (GVHD). METHODS: This phase 2, double-masked, randomized, pilot trial included 30 patients with ocular surface disease due to GVHD who were randomized to receive topical 0...
April 25, 2017: Cornea
https://www.readbyqxmd.com/read/28423730/the-sclttaxbcr-abl-transgenic-mouse-model-closely-reflects-the-differential-effects-of-dasatinib-on-normal-and-malignant-hematopoiesis-in-chronic-phase-cml-patients
#3
Claudia Schubert, Nicolas Chatain, Till Braunschweig, Mirle Schemionek, Kristina Feldberg, Melanie Hoffmann, Olli Dufva, Satu Mustjoki, Tim H Brümmendorf, Steffen Koschmieder
The second generation tyrosine kinase inhibitor (TKI) dasatinib is a clinically approved drug for chronic myeloid leukemia (CML) as well as Ph+ acute lymphoblastic leukemia. In addition to its antileukemic effects, dasatinib was shown to impact on normal hematopoiesis and cells of the immune system.Due to the fact that the murine in vivo studies so far have not been performed in a chronic-phase CML model under steady-state conditions, our aim was to study the hematopoietic effects of dasatinib (20 mg/kg p.o...
March 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28405610/btk-specific-inhibition-blocks-pathogenic-plasma-cell-signatures-and-myeloid-cell-associated-damage-in-ifn%C3%AE-driven-lupus-nephritis
#4
Arna Katewa, Yugang Wang, Jason A Hackney, Tao Huang, Eric Suto, Nandhini Ramamoorthi, Cary D Austin, Meire Bremer, Jacob Zhi Chen, James J Crawford, Kevin S Currie, Peter Blomgren, Jason DeVoss, Julie A DiPaolo, Jonathan Hau, Adam Johnson, Justin Lesch, Laura E DeForge, Zhonghua Lin, Marya Liimatta, Joseph W Lubach, Sami McVay, Zora Modrusan, Allen Nguyen, Chungkee Poon, Jianyong Wang, Lichuan Liu, Wyne P Lee, Harvey Wong, Wendy B Young, Michael J Townsend, Karin Reif
Systemic lupus erythematosus (SLE) is often associated with exaggerated B cell activation promoting plasma cell generation, immune-complex deposition in the kidney, renal infiltration of myeloid cells, and glomerular nephritis. Type-I IFNs amplify these autoimmune processes and promote severe disease. Bruton's tyrosine kinase (Btk) inhibitors are considered novel therapies for SLE. We describe the characterization of a highly selective reversible Btk inhibitor, G-744. G-744 is efficacious, and superior to blocking BAFF and Syk, in ameliorating severe lupus nephritis in both spontaneous and IFNα-accelerated lupus in NZB/W_F1 mice in therapeutic regimens...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28391340/targeting-the-tyrosine-kinase-signalling-pathways-for-treatment-of-immune-mediated-glomerulonephritis-from-bench-to-bedside-and-beyond
#5
Terry King-Wing Ma, Stephen P McAdoo, Frederick Wai Keung Tam
Glomerulonephritis (GN) affects patients of all ages and is an important cause of morbidity and mortality. Non-selective immunosuppressive drugs have been used in immune-mediated GN but often result in systemic side effects and occasionally fatal infective complications. There is increasing evidence from both preclinical and clinical studies that abnormal activation of receptor and non-receptor tyrosine kinase signalling pathways are implicated in the pathogenesis of immune-mediated GN. Activation of spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and discoidin domain receptor 1 (DDR1) have been demonstrated in anti-GBM disease...
January 1, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28385506/divergent-synthesis-of-kinase-inhibitor-derivatives-leading-to-discovery-of-selective-gck-inhibitors
#6
Takanori Matsumaru, Makoto Inai, Kana Ishigami, Toshiki Iwamatsu, Hiroshi Maita, Satoko Otsuguro, Takao Nomura, Akira Matsuda, Satoshi Ichikawa, Masahiro Sakaitani, Satoshi Shuto, Katsumi Maenaka, Toshiyuki Kan
We accomplished divergent synthesis of potent kinase inhibitor BAY 61-3606 (1) and 27 derivatives via conjugation of imidazo[1,2-c]pyrimidine and indole ring compounds with aromatic (including pyridine) derivatives by means of palladium-catalyzed cross-coupling reaction. Spleen tyrosine kinase (Syk) and germinal center kinase (Gck, MAP4K2) inhibition assays showed that some of the synthesized compounds were selective Gck inhibitors.
March 23, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28359287/activity-of-the-novel-bcr-kinase-inhibitor-iqs019-in-preclinical-models-of-b-cell-non-hodgkin-lymphoma
#7
P Balsas, A Esteve-Arenys, J Roldán, L Jiménez, V Rodríguez, J G Valero, A Chamorro-Jorganes, R Puig de la Bellacasa, J Teixidó, A Matas-Céspedes, A Moros, A Martínez, E Campo, A Sáez-Borderías, J I Borrell, P Pérez-Galán, D Colomer, G Roué
BACKGROUND: Pharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton's kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents. METHODS: We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib...
March 31, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28353016/new-therapeutic-strategies-in-acute-lymphocytic-leukemia
#8
REVIEW
Louise M Man, Amy L Morris, Michael Keng
Most drugs used in standard regimens for acute lymphoblastic leukemia (ALL) were developed more than 30 years ago. Since that time, several new drugs have been developed and incorporated into ALL treatment. In spite of this, novel therapeutic approaches are still needed to improve outcomes for high-risk or relapsed ALL. This manuscript discusses newer treatment strategies, including purine nucleoside analogs, monoclonal antibodies, antibody drug conjugates, mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitors, hypomethylating agents, spleen tyrosine kinase inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, anti-programmed cell death protein (anti-PD-1) antibodies, mitogen-activated protein kinase (MEK) inhibitors, CXCR4 antagonists, poly (ADP-ribose) polymerase (PARP) inhibitors, and FMS-like tyrosine kinase 3 (FLT3) inhibitors...
March 28, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28336564/identification-of-a-novel-syk-c-myc-malat1-signaling-pathway-and-its-potential-therapeutic-value-in-ewing-sarcoma
#9
Haibo Sun, De-Chen Lin, Qi Cao, Brendan Pang, David D Gae, Victor Km Lee, Huey Jin Lim, Ngan Doan, Jonathan W Said, Sigal Gery, Marilynn Chow, Anand Mayakonda, Charles Forscher, Jeffrey W Tyner, H Phillip Koeffler
PURPOSE: Ewing Sarcoma (EWS) is a devastating soft tissue sarcoma affecting predominantly young individuals. Tyrosine kinases (TKs) and associated pathways are continuously activated in many malignancies including EWS; these enzymes provide candidate therapeutic targets. EXPERIMENTAL DESIGN: Two high-throughput screens (a siRNA library and a small-molecule inhibitor library) were performed in EWS cells to establish candidate targets. Spleen tyrosine kinase (SYK) phosphorylation was assessed in EWS patients and cell lines...
March 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28335387/dectin-1-mediated-pathway-contributes-to-fusarium-proliferatum-induced-cxcl-8-release-from-human-respiratory-epithelial-cells
#10
Chang-Ching Yeh, Huann-Cheng Horng, Hong Chou, Hsiao-Yun Tai, Horng-Der Shen, Shie-Liang Hsieh, Peng-Hui Wang
Fusarium species are causative agents of human respiratory disorders and are distributed widely in our environment. Little is known of their interaction with human respiratory epithelial cells, which may contribute to allergic airway responses. In this study, we report on the release of C-X-C motif chemokine ligand 8 (CXCL-8) from human bronchial epithelial BEAS-2B cells upon stimulation with Fusarium proliferatum extracts. F. proliferatum-induced cytokine release from BEAS-2B cells was determined by cytokine array and CXCL-8 enzyme-linked immunosorbent assay (ELISA) kits...
March 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28326700/-in-vitro-investigation-on-the-mechanism-of-cyclooxygenase-2-upregulation-induced-by-spleen-tyrosine-kinase-nuclear-factor-%C3%AE%C2%BAb-signaling-in-cancer-pain-caused-by-oral-cancer-associated-macrophage
#11
Lin Jie, Wang Miao, Ji Yang, Liu Le, Gao Pan, Li Chunjie
OBJECTIVE: This study explores the mechanism of cyclooxygenase-2 (COX-2) upregulation in oral cancers associated with macrophage by using molecular biology techniques and primary culture of murine macrophage. METHODS: Murine macrophage was induced by macrophage colony-stimulating factor (M-CSF) and Cal27 conditional medium (CM). Purity of the macrophage was detected through CD68 immunofluorescence staining. Inhibitors of spleen tyrosine kinase (Syk) and nuclear factor κB (NFκB) were used to inhibit these pathways...
October 1, 2016: Hua Xi Kou Qiang Yi Xue za Zhi, Huaxi Kouqiang Yixue Zazhi, West China Journal of Stomatology
https://www.readbyqxmd.com/read/28314222/radiation-induced-decrease-of-cd8-dendritic-cells-contributes-to-th1-th2-shift
#12
Hu Liu, Bailong Li, Xiaojing Jia, Yan Ma, Yifeng Gu, Pei Zhang, Qun Wei, Jianming Cai, Jianguo Cui, Fu Gao, Yanyong Yang
Exposure to ionizing radiation (IR) often reduce the helper T (Th) 1 like function, resulting in a Th1/Th2 imbalance, which could affect the efficacy of cancer radiotherapy. As the most potent antigen presenting cells, dendritic cells (DC) can be divided into several subsets with specialized function. However, there is no literature covering the changes of DC subsets and their roles in immune regulation in response to IR. In the present study, we were aimed to investigate the changes of DC subsets after IR and its relationship with Th1/Th2 immunity...
March 14, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28306714/reconstruction-and-signal-propagation-analysis-of-the-syk-signaling-network-in-breast-cancer-cells
#13
Aurélien Naldi, Romain M Larive, Urszula Czerwinska, Serge Urbach, Philippe Montcourrier, Christian Roy, Jérôme Solassol, Gilles Freiss, Peter J Coopman, Ovidiu Radulescu
The ability to build in-depth cell signaling networks from vast experimental data is a key objective of computational biology. The spleen tyrosine kinase (Syk) protein, a well-characterized key player in immune cell signaling, was surprisingly first shown by our group to exhibit an onco-suppressive function in mammary epithelial cells and corroborated by many other studies, but the molecular mechanisms of this function remain largely unsolved. Based on existing proteomic data, we report here the generation of an interaction-based network of signaling pathways controlled by Syk in breast cancer cells...
March 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28293439/proteomic-analysis-of-hdac3-selective-inhibitor-in-the-regulation-of-inflammatory-response-of-primary-microglia
#14
Mingxu Xia, Qiuchen Zhao, He Zhang, Yanting Chen, Zengqiang Yuan, Yun Xu, Meijuan Zhang
HDAC3 has been shown to regulate inflammation. However, the role of HDAC3 in primary microglia is largely unknown. RGFP966 is a newly discovered selective HDAC3 inhibitor. In this study, we used protein mass spectrometry to analyze protein alterations in LPS-treated primary microglia with the application of RGFP966. Generally, about 2000 proteins were studied. 168 of 444 (37.8%) LPS-induced proteins were significantly reduced with the treatment of RGFP966, which mainly concentrated on Toll-like receptor signaling pathway...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28286257/grouper-epinephelus-coioides-tcr-signaling-pathway-was-involved-in-response-against-cryptocaryon-irritans-infection
#15
Ze-Xiang Li, Yan-Wei Li, Shun Xu, Yang Xu, Ze-Quan Mo, Xue-Ming Dan, Xiao-Chun Luo
T cell activation is a complicated process accompanying with the activation of T cell receptor (TCR) signaling pathway, which is not well described in teleost fish. The initiation of this pathway depends on the interaction of membrane TCR co-receptors (e.g. CD4/8, CD3 and CD45) and a series of cytoplasmic protein tyrosine kinases (e.g. Lck, Fyn and ZAP70). Cyptocaryon irritans is a ciliate pathogen of marine fish white spot disease causing huge economic lost in marine aquaculture. This parasite can infect fish gill and skin and is considered to be a good pathogen model for fish gill and skin mucosal immunity...
May 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28268139/discovery-of-new-syk-inhibitors-through-structure-based-virtual-screening
#16
Yahui Huang, Youjun Zhang, Kexin Fan, Guoqiang Dong, Bohua Li, Wannian Zhang, Jian Li, Chunquan Sheng
Spleen tyrosine kinase (Syk) is an attractive target for the discovery of new treatments for inflammatory and autoimmune disorders. Structure-based virtual screening was performed for identifying novel scaffolds of Syk inhibitors. A total of 16 hits were discovered in the enzyme assay and 8 compounds had an IC50 value lower than 10μM. In particular, compound 11 (IC50=3.2μM) was active in the cellular Syk assay and could inhibit lymphocytes proliferation in a dose-dependent manner, which could be used as a good starting point for the discovery of new class of Syk inhibitors...
February 24, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28260035/screening-of-potential-gene-markers-for-predicting-carotid-atheroma-plaque-formation-using-bioinformatics-approaches
#17
Guiming Wang, Dong Kuai, Yudong Yang, Gaochao Yang, Zhigang Wei, Wenbo Zhao
The present study aimed to investigate potential gene markers for predicting the formation of carotid atheroma plaques using high‑throughput bioinformatics methods. The GSE43292 gene expression profile was downloaded from the Gene Expression Omnibus database. Following data processing, differentially expressed genes (DEGs) were screened using a paired t‑test in the Linear Models for Microarray Data package with the criteria of a false discovery rate of P<0.05 and |log2 fold‑change| ≥0.58, followed by functional enrichment, protein‑protein interaction (PPI) network construction, key node and module analysis, and prediction of transcription factors (TFs) targeting genes in the significant modules...
April 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28259713/jte-852-a-novel-spleen-tyrosine-kinase-inhibitor-blocks-mediator-secretion-from-mast-cells-with-immunoglobulin-e-crosslinking
#18
Toshinobu Kato, Hidenori Iwasaki, Hatsue Kobayashi, Naoki Miyagawa, Akira Matsuo, Takahiro Hata, Mutsuyoshi Matsushita
Mast cells stimulated by immunoglobulin E (IgE)-crosslinking secrete mediators, which are mainly categorized into three groups: granule contents, arachidonate metabolites, and cytokines. These mediators play important roles in pathogenesis of allergic diseases; indeed, some conventional drugs which target the mediators are used in clinical practices. However, these drugs are not yet sufficient enough in their efficacy. That is because most of them are blockers of single mediators and are unable to prevent simultaneously various reactions caused by the three group mediators...
April 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28202166/m1-macrophage-triggered-by-mincle-leads-to-a-deterioration-of-acute-kidney-injury
#19
Tsuyoshi Inoue
In the early stage of acute kidney injury, M1 macrophages are proinflammatory and destructive. In this study, Lv et al. reveal that Mincle (macrophage-inducible C-type lectin, Clec4e) is expressed on M1 macrophages in acute kidney injury, and the kidney is protected in a murine model of cisplatin-induced renal injury by inhibiting Mincle expression on macrophages. Mincle expression is regulated by Toll-like receptor 4/nuclear factor κB signaling, and Mincle maintains the inflammatory phenotype through spleen tyrosine kinase signaling, leading to acute kidney injury...
March 2017: Kidney International
https://www.readbyqxmd.com/read/28178664/identification-of-distinct-molecular-subtypes-of-uterine-carcinosarcoma
#20
Yang An, Haojie Wang, Jingyao Jie, Yitai Tang, Weijuan Zhang, Shaoping Ji, Xiangqian Guo
Uterine carcinosarcoma (UCS) is a rare but lethal neoplasm with high metastasis and recurrence rate, and to date, no molecular classification of UCS has been defined to achieve targeted therapies. In this study, we identified two distinct molecular subtypes of UCS with distinct gene expression patterns and clinicopathologic characteristics. Subtype I UCS recapitulates low-grade UCS, in contrast subtype II UCS represents high-grade UCS with higher tumor invasion rate and tumor weight. Interestingly, subtype I UCS is characterized by cell adhesion and apoptosis pathways, whereas genes over-expressed in subtype II UCS are more involved in myogenesis/muscle development...
February 28, 2017: Oncotarget
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