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Bruton tyrosine kinase

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https://www.readbyqxmd.com/read/28716053/ibrutinib-a-bruton-s-tyrosine-kinase-inhibitor-exhibits-antitumoral-activity-and-induces-autophagy-in-glioblastoma
#1
Jin Wang, Xiaoyang Liu, Yongzhi Hong, Songtao Wang, Pin Chen, Aihua Gu, Xiaoyuan Guo, Peng Zhao
BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM. METHODS: Cell proliferation was determined by using cell viability, colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell cycle and cell apoptosis were analyzed by flow cytometry...
July 17, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28714866/ibrutinib-treatment-improves-t-cell-number-and-function-in-cll-patients
#2
Meixiao Long, Kyle Beckwith, Priscilla Do, Bethany L Mundy, Amber Gordon, Amy M Lehman, Kami J Maddocks, Carolyn Cheney, Jeffrey A Jones, Joseph M Flynn, Leslie A Andritsos, Farrukh Awan, Joseph A Fraietta, Carl H June, Marcela V Maus, Jennifer A Woyach, Michael A Caligiuri, Amy J Johnson, Natarajan Muthusamy, John C Byrd
BACKGROUND: Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS: Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially...
July 17, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28714377/ibrutinib-associated-tumor-lysis-syndrome-in-chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma-and-mantle-cell-lymphoma-a-case-series-and-review-of-the-literature
#3
Krystal S Titus-Rains, Jamie N Brown, Julia M Hammond
Background Tumor lysis syndrome results when intracellular contents are released during cell lysis. Ibrutinib, a Bruton tyrosine kinase inhibitor, is used for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström's macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Tumor lysis syndrome caused by ibrutinib therapy is potentially life threatening, but is rare and not often reported in clinical trials. Objective The purpose of this case series is to describe the occurrence of tumor lysis syndrome in two patients initiated on ibrutinib, and to highlight the importance of close monitoring during therapy...
January 1, 2017: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/28710282/function-of-inhibitor-of-brutons-tyrosine-kinase-isoform-%C3%AE-ibtk%C3%AE-in-nonalcoholic-steatohepatitis-links-autophagy-and-the-unfolded-protein-response
#4
Jeffrey A Willy, Sara K Young, Amber L Mosley, Samer Gawrieh, James L Stevens, Howard C Masuoka, Ronald C Wek
Nonalcoholic fatty liver disease (steatosis) is the most prevalent liver disease in the Western world. One of the advanced pathologies is non Non-alcoholic steatohepatitis (NASH), which is associated with induction of the Unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein we identify the α isoform of the inhibitor of Brutons tyrosine kinase (IBTKα) as a member of the UPR whose expression is preferentially translated during endoplasmic reticulum (ER) stress...
July 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28708231/ibrutinib-treatment-of-a-patient-with-relapsing-chronic-lymphocytic-leukemia-and-sustained-remission-of-richter-syndrome
#5
Elisa Albi, Stefano Baldoni, Patrizia Aureli, Erica Dorillo, Beatrice Del Papa, Stefano Ascani, Mauro Di Ianni, Franca Falzetti, Paolo Sportoletti
PURPOSE: Richter syndrome (RS) is a rare event in chronic lymphocytic leukemia (CLL) that is influenced by biological factors and prior CLL treatments. Ibrutinib is a Bruton tyrosine kinase inhibitor that has shown remarkable efficacy in CLL; however, little is known about its relationship to RS. We report a case of ibrutinib efficacy against CLL in a patient with prolonged remission of RS. METHODS: The patient was diagnosed with CLL in 2003. Biological findings at onset included absent ZAP70 expression, mutated IGVH, and NOTCH1 mutation...
July 5, 2017: Tumori
https://www.readbyqxmd.com/read/28699667/mantle-cell-lymphoma-2017-update-on-diagnosis-risk-stratification-and-clinical-management
#6
Julie M Vose
DISEASE OVERVIEW: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood and bone marrow with a short remission duration to standard therapies and a median overall survival (OS) of 4-5 years. DIAGNOSIS: Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t (11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1...
August 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28665232/integrating-novel-drugs-to-chemoimmunotherapy-in-diffuse-large-b-cell-lymphoma
#7
Annalisa Chiappella, Elisa Santambrogio, Alessia Castellino, Maura Nicolosi, Umberto Vitolo
Diffuse Large B-cell Lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), with an incidence in Europe of 3.8/100.000/year. A multi-drugs chemoimmunotherapy regimen, containing rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone (R-CHOP) administrated every 21 days, is the standard therapy for DLBCL patients. The discovery of several biological features of DLBCL has encouraged the introduction of novel drugs in the treatment. Areas covered: In this article, the use of standard therapies will be reviewed and will be investigated adoption of novel drugs such as Bortezomib, Bruton's tyrosine kinase, IMiDs, Venetoclax, mTOR inhibitors and other biological agents...
June 30, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28663935/differential-gene-expression-analysis-by-rna-seq-reveals-the-importance-of-actin-cytoskeletal-proteins-in-erythroleukemia-cells
#8
Vanessa Fernández-Calleja, Pablo Hernández, Jorge B Schvartzman, Mario García de Lacoba, Dora B Krimer
Development of drug resistance limits the effectiveness of anticancer treatments. Understanding the molecular mechanisms triggering this event in tumor cells may lead to improved therapeutic strategies. Here we used RNA-seq to compare the transcriptomes of a murine erythroleukemia cell line (MEL) and a derived cell line with induced resistance to differentiation (MEL-R). RNA-seq analysis identified a total of 596 genes (Benjamini-Hochberg adjusted p-value < 0.05) that were differentially expressed by more than two-fold, of which 81...
2017: PeerJ
https://www.readbyqxmd.com/read/28661188/bruton-s-tyrosine-kinase-inhibitors-in-b-cell-lymphoma-current-experience-and-future-perspectives
#9
T Seiler, M Dreyling
The Bruton tyrosine kinase (BTK) is a central hub in the B cell receptor (BCR) pathway and strongly influences B cell maturation, differentiation and proliferation. Not surprisingly, BTK plays an essential role in the pathogenesis of various B cell lymphomas. Inhibitors of BTK have broadened our therapeutic options in several B cell lymphomas and already are an integral element in the treatment of Mantle Cell Lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Waldenström's marcoglobulinemia. Several second generation BTK inhibitors are in clinical development and might further improve tolerability and efficacy of therapy in advanced stage CLL and MCL...
July 10, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28647392/a-novel-dual-inhibitor-of-microtubule-and-bruton-s-tyrosine-kinase-inhibits-survival-of-multiple-myeloma-and-osteoclastogenesis
#10
Manoj K Pandey, Krishne Gowda, Shen-Shu Sung, Thomas Abraham, Tulin Budak-Alpdogan, Giampolo Talamo, Sinisa Dovat, Shantu Amin
Bruton's tyrosine kinase (BTK) regulates many vital signaling pathways and plays a critical role in cell proliferation, survival, migration, and resistance. Previously, we reported that a small molecule, KS99, is an inhibitor of tubulin polymerization. In the present study, we explored whether KS99 is a dual inhibitor of BTK and tubulin polymerization. Although it is known that BTK is required for clonogenic growth and resistance, and microtubules are essential for cancer cell growth, dual targeting of these two components has not been explored previously...
June 22, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28641100/bruton-s-tyrosine-kinase-btk-as-a-promising-target-in-solid-tumors
#11
REVIEW
J Molina-Cerrillo, T Alonso-Gordoa, P Gajate, E Grande
Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase that belongs to the TEC-family tyrosine kinases together with bone marrow-expressed kinase (BMX), redundant-resting lymphocyte kinase (RLK), and IL-2 inducible T-Cell kinase (ITK). All these proteins play a key role in the intracellular signaling of both B and T lymphocytes. Recently, some preclinical data have demonstrated that BTK is present in certain tumor subtypes and in other relevant cells that are contributing to the tumor microenvironment such as dendritic cells, macrophages, myeloid derived suppressor cells and endothelial cells...
June 9, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28636208/a-phase-i-trial-of-prn1008-a-novel-reversible-covalent-inhibitor-of-bruton-s-tyrosine-kinase-in-healthy-volunteers
#12
Patrick F Smith, Janakan Krishnarajah, Philip A Nunn, Ron J Hill, Dane Karr, D Tam, Mohammad Masjedizadeh, Jens O Funk, Steve G Gourlay
AIM: To evaluate the safety, tolerability, and PK/PD of PRN1008, a novel BTK inhibitor, in healthy volunteers, and thus determine the dose range for future clinical studies. METHODS: This was a two-part randomized, placebo controlled study in healthy volunteers using a liquid formulation. Part I was a single ascending dose design with dose levels of 50 to 1200 mg (n=6 active, 2 placebo per cohort); Part II was a multiple ascending dose design, with dose regimens ranging from 300 mg to 900 mg daily, either qd or bd for 10 days...
June 21, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28629235/atrial-fibrillation-as-a-complication-of-ibrutinib-therapy-clinical-features-and-challenges-of-management
#13
Bronwyn C Thorp, Xavier Badoux
Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor finding increasingly widespread use in non-Hodgkin lymphoma. Evidence of an increased risk of atrial fibrillation (AF) emerged in Phase III studies with a median incidence of approximately 6%. The mechanism remains unknown, but inhibition of a cardioprotective pathway has been proposed. Ibrutinib induces a platelet function defect, increasing the bleeding risk of anticoagulation for AF stroke prophylaxis. Multiple potential drug interactions are an added complication...
June 20, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28628824/structure-activity-relationship-investigation-for-benzonaphthyridinone-derivatives-as-novel-potent-bruton-s-tyrosine-kinase-btk-irreversible-inhibitors
#14
Beilei Wang, Yuanxin Deng, Yongfei Chen, Kailin Yu, Aoli Wang, Qianmao Liang, Wei Wang, Cheng Chen, Hong Wu, Chen Hu, Weili Miao, Wooyoung Hur, Wenchao Wang, Zhenquan Hu, Ellen L Weisberg, Jinhua Wang, Tao Ren, Yinsheng Wang, Nathanael S Gray, Qingsong Liu, Jing Liu
Through a structure-based drug design approach, a tricyclic benzonaphthyridinone pharmacophore was used as a starting point for carrying out detailed medicinal structure-activity relationhip (SAR) studies geared toward characterization of a panel of proposed BTK inhibitors, including 6 (QL-X-138), 7 (BMX-IN-1) and 8 (QL47). These studies led to the discovery of the novel potent irreversible BTK inhibitor, compound 18 (CHMFL-BTK-11). Kinetic analysis of compound 18 revealed an irreversible binding efficacy (kinact/Ki) of 0...
September 8, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28627951/the-safety-of-bruton-s-tyrosine-kinase-inhibitors-for-the-treatment-of-chronic-lymphocytic-leukemia
#15
Phu N Tran, Susan O'Brien
The approval of ibrutinib has revolutionized the therapeutic landscape of chronic lymphocytic leukemia (CLL). Currently ibrutinib is indicated for patients that are both treatment naïve as well as those with relapsed CLL. Ibrutinib is generally well-tolerated with durable responses that improve over time in most patients. Important toxicities include atrial fibrillation and bleeding. Areas Cover: This review covers the pharmacokinetics, pharmacodynamics, safety and efficacy of ibrutinib in the treatment of CLL...
June 19, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28626519/discovery-of-potent-and-selective-tricyclic-inhibitors-of-bruton-s-tyrosine-kinase-with-improved-druglike-properties
#16
Xiaojing Wang, James Barbosa, Peter Blomgren, Meire C Bremer, Jacob Chen, James J Crawford, Wei Deng, Liming Dong, Charles Eigenbrot, Steve Gallion, Jonathon Hau, Huiyong Hu, Adam R Johnson, Arna Katewa, Jeffrey E Kropf, Seung H Lee, Lichuan Liu, Joseph W Lubach, Jen Macaluso, Pat Maciejewski, Scott A Mitchell, Daniel F Ortwine, Julie DiPaolo, Karin Reif, Heleen Scheerens, Aaron Schmitt, Harvey Wong, Jin-Ming Xiong, Jianjun Xu, Zhongdong Zhao, Fusheng Zhou, Kevin S Currie, Wendy B Young
In our continued effort to discover and develop best-in-class Bruton's tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28619981/ibrutinib-unmasks-critical-role-of-bruton-tyrosine-kinase-in-primary-cns-lymphoma
#17
Christian Grommes, Alessandro Pastore, Nicolaos Palaskas, Sarah S Tang, Carl Campos, Derrek Schartz, Paolo Codega, Donna Nichol, Owen Clark, Wan-Ying Hsieh, Daniel Rohle, Marc K Rosenblum, Agnes Viale, Viviane Tabar, Cameron W Brennan, Igor T Gavrilovic, Thomas J Kaley, Craig Nolan, Antonio M P Omuro, Elena Pentsova, Alissa A Thomas, Elina Tsyvkin, Ariela Noy, M Lia Palomba, Paul A Hamlin, Craig Sauter, Craig H Moskowitz, Julia Wolfe, Ahmet Dogan, Minhee Won, Jon Glass, Scott Peak, Enrico C Lallana, Vaios Hatzoglou, Anne S Reiner, Philip Gutin, Jason T Huse, Katherine Panageas, Thomas G Graeber, Nikolaus Schultz, Lisa M DeAngelis, Ingo K Mellinghoff
Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with Nuclear factor kappa B (NF-κB). The role of BTK in primary CNS lymphoma (PCNSL) is unknown. We performed a Phase 1 clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS Lymphoma. Clinical responses to ibrutinib occurred in 10/13 (77%) PCNSL patients, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of Caspase Recruitment Domain Family Member 11, a known ibrutinib resistance mechanism...
June 15, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28617062/novel-approaches-to-targeting-myd88-in-waldenstr%C3%A3-m-macroglobulinemia
#18
Jorge J Castillo, Zachary R Hunter, Guang Yang, Steven P Treon
Waldenström macroglobulinemia (WM) is an incurable lymphoma characterized by the accumulation of IgM-producing lymphoplasmacytic cells in the bone marrow and other organs. Although WM patients can experience prolonged remissions, the disease invariably recurs advocating for the need of novel treatments in order to achieve higher response and survival rates. The discovery of a recurrent mutation in the MYD88 gene and an increased understanding behind the biology of MYD88 signaling have provided the opportunity to developing novel agents targeting the MYD88 pathway...
June 15, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28615655/secreted-igm-deficiency-leads-to-increased-bcr-signaling-that-results-in-abnormal-splenic-b-cell-development
#19
Dimitrios Tsiantoulas, Mate Kiss, Barbara Bartolini-Gritti, Andreas Bergthaler, Ziad Mallat, Hassan Jumaa, Christoph J Binder
Mice lacking secreted IgM (sIgM (-/-)) antibodies display abnormal splenic B cell development, which results in increased marginal zone and decreased follicular B cell numbers. However, the mechanism by which sIgM exhibit this effect is unknown. Here, we demonstrate that B cells in sIgM (-/-) mice display increased B cell receptor (BCR) signaling as judged by increased levels of phosphorylated Bruton's tyrosine kinase (pBtk), phosphorylated Spleen tyrosine kinase (pSyk), and nuclear receptor Nur77. Low dosage treatment with the pBtk inhibitor Ibrutinib reversed the altered B cell development in the spleen of sIgM (-/-) mice, suggesting that sIgM regulate splenic B cell differentiation by decreasing BCR signaling...
June 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28614781/cell-lines-generated-from-a-chronic-lymphocytic-leukemia-mouse-model-exhibit-constitutive-btk-and-akt-signaling
#20
Simar Pal Singh, Saravanan Y Pillai, Marjolein J W de Bruijn, Ralph Stadhouders, Odilia B J Corneth, Henk Jan van den Ham, Alice Muggen, Wilfred van IJcken, Erik Slinger, Annemieke Kuil, Marcel Spaargaren, Arnon P Kater, Anton W Langerak, Rudi W Hendriks
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature CD5+ B cells in blood. Spontaneous apoptosis of CLL cells in vitro has hampered in-depth investigation of CLL pathogenesis. Here we describe the generation of three monoclonal mouse cell lines, EMC2, EMC4 and EMC6, from the IgH.TEμ CLL mouse model based on sporadic expression of SV40 large T antigen. The cell lines exhibit a stable CD5+CD43+IgM+CD19+ CLL phenotype in culture and can be adoptively transferred into Rag1-/- mice...
May 26, 2017: Oncotarget
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