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https://www.readbyqxmd.com/read/28368423/myc-enhances-b-cell-receptor-signaling-in-precancerous-b-cells-and-confers-resistance-to-btk-inhibition
#1
T K Moyo, C S Wilson, D J Moore, C M Eischen
Dysregulation of the oncogenic transcription factor MYC induces B-cell transformation and is a driver for B-cell non-Hodgkin lymphoma (B-NHL). MYC overexpression in B-NHL is associated with more aggressive phenotypes and poor prognosis. Although genomic studies suggest a link between MYC overexpression and B-cell receptor (BCR) signaling molecules in B-NHL, signaling pathways essential to Myc-mediated B-cell transformation have not been fully elucidated. We utilized intracellular phospho-flow cytometry to investigate the relationship between Myc and BCR signaling in pre-malignant B cells...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28272351/methyl-gallate-inhibits-osteoclast-formation-and-function-by-suppressing-akt-and-btk-plc%C3%AE-2-ca-2-signaling-and-prevents-lipopolysaccharide-induced-bone-loss
#2
Jong Min Baek, Ju-Young Kim, Chang Hoon Lee, Kwon-Ha Yoon, Myeung Su Lee
In the field of bone research, various natural derivatives have emerged as candidates for osteoporosis treatment by targeting abnormally elevated osteoclastic activity. Methyl gallate, a plant-derived phenolic compound, is known to have numerous pharmacological effects against inflammation, oxidation, and cancer. Our purpose was to explore the relation between methyl gallate and bone metabolism. Herein, we performed screening using methyl gallate by tartrate resistant acid phosphatase (TRAP) staining and revealed intracellular mechanisms responsible for methyl gallate-mediated regulation of osteoclastogenesis by Western blotting and quantitative reverse transcription polymerase chain reaction (RT-PCR)...
March 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28235842/acquired-mutations-associated-with-ibrutinib-resistance-in-waldenstr%C3%A3-m-macroglobulinemia
#3
Lian Xu, Nicholas Tsakmaklis, Guang Yang, Jiaji G Chen, Xia Liu, Maria Demos, Amanda Kofides, Christopher J Patterson, Kirsten Meid, Joshua Gustine, Toni Dubeau, M Lia Palomba, Ranjana Advani, Jorge J Castillo, Richard R Furman, Zachary R Hunter, Steven P Treon
Ibrutinib produces high response rates and durable remissions in Waldenström macroglobulinemia (WM) that are impacted by MYD88 and CXCR4(WHIM) mutations. Disease progression can develop on ibrutinib, although the molecular basis remains to be clarified. We sequenced sorted CD19(+) lymphoplasmacytic cells from 6 WM patients who progressed after achieving major responses on ibrutinib using Sanger, TA cloning and sequencing, and highly sensitive and allele-specific polymerase chain reaction (AS-PCR) assays that we developed for Bruton tyrosine kinase (BTK) mutations...
May 4, 2017: Blood
https://www.readbyqxmd.com/read/28212557/using-high-sensitivity-sequencing-for-the-detection-of-mutations-in-btk-and-plc%C3%AE-2-genes-in-cellular-and-cell-free-dna-and-correlation-with-progression-in-patients-treated-with-btk-inhibitors
#4
Adam Albitar, Wanlong Ma, Ivan DeDios, Jeffrey Estella, Inhye Ahn, Mohammed Farooqui, Adrian Wiestner, Maher Albitar
Patients with chronic lymphocytic leukemia (CLL) that develop resistance to Bruton tyrosine kinase (BTK) inhibitors are typically positive for mutations in BTK or phospholipase c gamma 2 (PLCγ2). We developed a high sensitivity (HS) assay utilizing wild-type blocking polymerase chain reaction achieved via bridged and locked nucleic acids. We used this high sensitivity assay in combination with Sanger sequencing and next generation sequencing (NGS) and tested cellular DNA and cell-free DNA (cfDNA) from patients with CLL treated with the BTK inhibitor, ibrutinib...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28054640/honokiol-as-a-specific-collagen-receptor-glycoprotein-vi-antagonist-on-human-platelets-functional-ex-vivo-and-in-vivo-studies
#5
Tzu-Yin Lee, Chao-Chien Chang, Wan-Jung Lu, Ting-Lin Yen, Kuan-Hung Lin, Pitchairaj Geraldine, Jiun-Yi Li, Joen-Rong Sheu
Honokiol, derived from Magnolia officinalis, has various pharmacological properties. Platelet activation plays a critical role in cardiovascular diseases. Honokiol has been reported to inhibit collagen-stimulated rabbit platelet aggregation. However, detailed further studies on the characteristics and functional activity of honokiol in platelet activation are relatively lacking. In the present study, honokiol specifically inhibited platelet aggregation and Ca(+2) ion mobilization stimulated with collagen or convulxin, an agonist of glycoprotein (GP) VI, but not with aggretin, an agonist of integrin α2β1...
January 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/27941021/phospholipase-c%C3%AE-1-plc%C3%AE-1-controls-osteoclast-numbers-via-colony-stimulating-factor-1-csf-1-dependent-diacylglycerol-%C3%AE-catenin-cyclind1-pathway
#6
Zhengfeng Yang, Seokho Kim, Sahil Mahajan, Ali Zamani, Roberta Faccio
Phospholipases Cγ (PLCγ) 1 and 2 are a class of highly homologous enzymes modulating a variety of cellular pathways through production of inositol 1,4,5-trisphosphate and diacylglycerol (DAG). Our previous studies demonstrated the importance of PLCγ2 in osteoclast (OC) differentiation by modulating inositol 1,4,5-trisphosphate-mediated calcium oscillations and the up-regulation of the transcription factor NFATc1. Surprisingly, despite being expressed throughout osteoclastogenesis, PLCγ1 did not compensate for PLCγ2 deficiency...
January 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27912872/anti-allergic-potential-of-typhonium-blumei-inhibition-of-degranulation-via-suppression-of-pi3k-plc%C3%AE-2-phosphorylation-and-calcium-influx
#7
Michal Korinek, Kuan-Ming Chen, Yu-Han Jiang, Mohamed El-Shazly, Joel Stocker, Chon-Kit Chou, Tsong-Long Hwang, Yang-Chang Wu, Bing-Hung Chen, Fang-Rong Chang
BACKGROUND: Typhonium blumei Nicolson & Sivadasan (Araceae) is a traditional Chinese medicinal herb possessing detumescent, detoxifying, and anti-inflammatory activities. It is used in Taiwan as a folk medicine to treat cancer and inflammatory diseases. Typhonium blumei is usually not distinguished from Typhonium roxburghii Schott and they are commonly used interchangeably. PURPOSE: To evaluate and compare the anti-allergic and anti-inflammatory properties of T...
December 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/27903679/the-bruton-tyrosine-kinase-btk-inhibitor-acalabrutinib-demonstrates-potent-on-target-effects-and-efficacy-in-two-mouse-models-of-chronic-lymphocytic-leukemia
#8
Sarah E M Herman, Arnau Montraveta, Carsten U Niemann, Helena Mora-Jensen, Michael Gulrajani, Fanny Krantz, Rose Mantel, Lisa L Smith, Fabienne McClanahan, Bonnie K Harrington, Dolors Colomer, Todd Covey, John C Byrd, Raquel Izumi, Allard Kaptein, Roger Ulrich, Amy J Johnson, Brian J Lannutti, Adrian Wiestner, Jennifer A Woyach
Purpose: Acalabrutinib (ACP-196) is a novel, potent, and highly selective Bruton tyrosine kinase (BTK) inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the antitumor 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/27896950/ppar%C3%AE-agonists-negatively-regulate-%C3%AE-iib%C3%AE-3-integrin-outside-in-signaling-and-platelet-function-through-up-regulation-of-protein-kinase-a-activity
#9
A J Unsworth, N Kriek, A P Bye, K Naran, T Sage, G D Flora, J M Gibbins
Essentials peroxisome proliferator-activated receptor γ (PPARγ) agonists inhibit platelet function. PPARγ agonists negatively regulate outside-in signaling via integrin αIIbβ3. PPARγ agonists disrupt the interaction of Gα13 with integrin β3. This is attributed to an upregulation of protein kinase A activity. SUMMARY: Background Agonists for the peroxisome proliferator-activated receptor (PPARγ) have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists...
February 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27883180/mitochondrial-reactive-oxygen-species-suppress-humoral-immune-response-through-reduction-of-cd19-expression-in-b-cells-in-mice
#10
Masato Ogura, Takeshi Inoue, Junko Yamaki, Miwako K Homma, Tomohiro Kurosaki, Yoshimi Homma
Reactive oxygen species (ROS) are implicated in the modulation of diverse processes including immune responses. To evaluate the effects of metabolic ROS produced by mitochondria on B-cell function and development, we created transgenic (Tg) mice expressing a phosphorylation-defective mutant of succinate dehydrogenase A in B cells (bSDHA(Y215F) ). Splenic B cells in male, but not female, bSDHA(Y215F) mice produced three times more ROS than those in the control mice, and had decreased production of IgM, IgG1 , and IgG3 , and affinity maturation of IgG1 against T-cell-dependent antigens...
November 24, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27803667/wedelolactone-enhances-osteoblastogenesis-but-inhibits-osteoclastogenesis-through-sema3a-nrp1-plexina1-pathway
#11
Yan-Qiu Liu, Xiao-Fei Han, Jun-Xia Bo, Hui-Peng Ma
Bone remodeling balance is maintained by tight coupling of osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Thus, agents with the capacity to regulate osteoblastogenesis and osteoclastogenesis have been investigated for therapy of bone-related diseases such as osteoporosis. In this study, we found that wedelolactone, a compound isolated from Ecliptae herba, and a 9-day incubation fraction of conditioned media obtained from wedelolactone-treated bone marrow mesenchymal stem cell (BMSC) significantly inhibited tartrate-resistant acid phosphatase (TRAP) activity in RANKL-stimulated osteoclastic RAW264...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27776353/bruton-tyrosine-kinase-inhibitor-ono-gs-4059-from-bench-to-bedside
#12
REVIEW
Jingjing Wu, Mingzhi Zhang, Delong Liu
The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been approved for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Acquired resistance to ibrutinib due to BTK C481S mutation has been reported. Mutations in PLCγ2 can also mediate resistance to ibrutinib. Untoward effects due to off-target effects are also disadvantages of ibrutinib. More selective and potent BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292) are being investigated. This review summarized the preclinical research and clinical data of ONO/GS-4059...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/27763263/endothelial-cell-derived-cd95-ligand-serves-as-a-chemokine-in-induction-of-neutrophil-slow-rolling-and-adhesion
#13
Liang Gao, Gülce Sila Gülcüler, Lieke Golbach, Helena Block, Alexander Zarbock, Ana Martin-Villalba
Integrin activation is crucial for the regulation of leukocyte rolling, adhesion and trans-vessel migration during inflammation and occurs by engagement of myeloid cells through factors presented by inflamed vessels. However, endothelial-dependent mechanisms of myeloid cell recruitment are not fully understood. Here we show using an autoperfused flow chamber assay of whole blood neutrophils and intravital microscopy of the inflamed cremaster muscle that CD95 mediates leukocyte slow rolling, adhesion and transmigration upon binding of CD95-ligand (CD95L) that is presented by endothelial cells...
October 20, 2016: ELife
https://www.readbyqxmd.com/read/27758892/e2a-pbx1-remodels-oncogenic-signaling-networks-in-b-cell-precursor-acute-lymphoid-leukemia
#14
Jesús Duque-Afonso, Chiou-Hong Lin, Kyuho Han, Michael C Wei, Jue Feng, Jason H Kurzer, Corina Schneidawind, Stephen Hon-Kit Wong, Michael C Bassik, Michael L Cleary
There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5%-7% of pediatric and 50% of pre-B-cell receptor (preBCR(+)) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL, which results in hyperactivation of the key oncogenic effector enzyme PLCγ2...
December 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27755951/construction-of-recombinant-adenovirus-ad-rat-plc%C3%AE-2-and-its-effects-on-apoptosis-of-rat-liver-cell-brl-3a-in-vitro
#15
X Chen, Q Lv, Y Liu, W Deng
Although the role of PLCγ2 in apoptotic response has been reported, too little is known about whether PLCγ2 induces liver cell apoptosis during liver regeneration. Therefore, this study firstly packaged Ad-PLCγ2 recombinant adenovirus and primarily evaluated its effect on apoptosis of rat liver cell BRL-3A in vitro. Following ten days of co-transfection of pHBAd-MCMV-GFP-PLCγ2 and pHBAd-BHG into HEK293 cells, viral cytopathic effect (CPE) was apparent. Following three rounds of amplification, tissue culture infectious dose 50 (TCID50) assay showed that the titer value reached 1×1010 PFU/mL...
September 30, 2016: Cellular and Molecular Biology
https://www.readbyqxmd.com/read/27558332/tyrosine-kinase-signaling-pathways-in-neutrophils
#16
REVIEW
Krisztina Futosi, Attila Mócsai
Neutrophils play a critical role in antimicrobial host defense, but their improper activation also contributes to inflammation-induced tissue damage. Therefore, understanding neutrophil biology is important for the understanding, diagnosis, and therapy of both infectious and inflammatory diseases. Neutrophils express a large number of cell-surface receptors that sense extracellular cues and trigger various functional responses through complex intracellular signaling pathways. During the last several years, we and others have shown that tyrosine kinases play a critical role in those processes...
September 2016: Immunological Reviews
https://www.readbyqxmd.com/read/27542411/the-phospholipase-c%C3%AE-2-mutants-r665w-and-l845f-identified-in-ibrutinib-resistant-chronic-lymphocytic-leukemia-patients-are-hypersensitive-to-the-rho-gtpase-rac2-protein
#17
Claudia Walliser, Elisabeth Hermkes, Anja Schade, Sebastian Wiese, Julia Deinzer, Marc Zapatka, Laurent Désiré, Daniel Mertens, Stephan Stilgenbauer, Peter Gierschik
Mutations in the gene encoding phospholipase C-γ2 (PLCγ2) have been shown to be associated with resistance to targeted therapy of chronic lymphocytic leukemia (CLL) with the Bruton's tyrosine kinase inhibitor ibrutinib. The fact that two of these mutations, R665W and L845F, imparted upon PLCγ2 an ∼2-3-fold ibrutinib-insensitive increase in the concentration of cytosolic Ca(2+) following ligation of the B cell antigen receptor (BCR) led to the assumption that the two mutants exhibit constitutively enhanced intrinsic activity...
October 14, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27443285/slp76-integrates-into-the-b-cell-receptor-signaling-cascade-in-chronic-lymphocytic-leukemia-cells-and-is-associated-with-an-aggressive-disease-course
#18
Nili Dezorella, Ben-Zion Katz, Mika Shapiro, Aaron Polliack, Chava Perry, Yair Herishanu
I In the last decade, the B-cell receptor has emerged as a pivotal stimulus in the pathogenesis of chronic lymphocytic leukemia, and a very feasible therapeutic target in this disease. B-cell receptor responsiveness in chronic lymphocytic leukemia cells is heterogeneous among patients and correlates with aggressiveness of the disease. Here we show, for the first time, that SLP76, a key scaffold protein in T-cell receptor signaling, is ectopically expressed in chronic lymphocytic leukemia cells, with variable levels among patients, and correlates positively with unmutated immunoglobulin heavy chain variable gene status and ZAP-70 expression...
December 2016: Haematologica
https://www.readbyqxmd.com/read/27282255/substitution-scanning-identifies-a-novel-catalytically-active-ibrutinib-resistant-btk-cysteine-481-to-threonine-c481t-variant
#19
A Hamasy, Q Wang, K E M Blomberg, D K Mohammad, L Yu, M Vihinen, A Berglöf, C I E Smith
Irreversible Bruton tyrosine kinase (BTK) inhibitors, ibrutinib and acalabrutinib have demonstrated remarkable clinical responses in multiple B-cell malignancies. Acquired resistance has been identified in a sub-population of patients in which mutations affecting BTK predominantly substitute cysteine 481 in the kinase domain for catalytically active serine, thereby ablating covalent binding of inhibitors. Activating substitutions in the BTK substrate phospholipase Cγ2 (PLCγ2) instead confers resistance independent of BTK...
January 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27221712/dephosphorylation-of-the-adaptor-lat-and-phospholipase-c-%C3%AE-by-shp-1-inhibits-natural-killer-cell-cytotoxicity
#20
Omri Matalon, Sophia Fried, Aviad Ben-Shmuel, Maor H Pauker, Noah Joseph, Danielle Keizer, Marina Piterburg, Mira Barda-Saad
Natural killer (NK) cells discriminate between healthy cells and virally infected or transformed self-cells by tuning activating and inhibitory signals received through cell surface receptors. Inhibitory receptors inhibit NK cell function by recruiting and activating the tyrosine phosphatase Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-1 (SHP-1) to the plasma membrane. However, to date, the guanine nucleotide exchange factor VAV1 is the only direct SHP-1 substrate identified in NK cells...
2016: Science Signaling
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