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Bruton tyrosine kinase

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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
#1
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...
February 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28202458/sensitivity-to-pi3k-and-akt-inhibitors-is-mediated-by-divergent-molecular-mechanisms-in-subtypes-of-dlbcl
#2
Tabea Erdmann, Pavel Klener, James T Lynch, Michael Grau, Petra Vočková, Jan Molinsky, Diana Tuskova, Kevin Hudson, Urszula M Polanska, Michael Grondine, Michele Mayo, Beiying Dai, Matthias Pfeifer, Kristian Erdmann, Daniela Schwammbach, Myroslav Zapukhlyak, Annette M Staiger, German Ott, Wolfgang E Berdel, Barry R Davies, Francisco Cruzalegui, Marek Trneny, Peter Lenz, Simon T Barry, Georg Lenz
Activated B-cell-like (ABC) and germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) represent the two major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these two subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) alpha/delta (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype...
February 15, 2017: Blood
https://www.readbyqxmd.com/read/28199309/phosphatidylinositol-3-kinase-%C3%AE-blockade-increases-genomic-instability-in-b-cells
#3
Mara Compagno, Qi Wang, Chiara Pighi, Taek-Chin Cheong, Fei-Long Meng, Teresa Poggio, Leng-Siew Yeap, Elif Karaca, Rafael B Blasco, Fernanda Langellotto, Chiara Ambrogio, Claudia Voena, Adrian Wiestner, Siddha N Kasar, Jennifer R Brown, Jing Sun, Catherine J Wu, Monica Gostissa, Frederick W Alt, Roberto Chiarle
Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation...
February 15, 2017: Nature
https://www.readbyqxmd.com/read/28185174/current-treatment-of-chronic-lymphocytic-leukemia
#4
REVIEW
Krzysztof Jamroziak, Bartosz Puła, Jan Walewski
A number of new treatment options have recently emerged for chronic lymphocytic leukemia (CLL) patients, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3-kinase (PI3K) delta isoform inhibitor idelalisib combined with rituximab, the Bcl-2 antagonist venetoclax, and the new anti-CD20 antibodies obinutuzumab and ofatumumab. Most of these agents are already included into treatment algorithms defined by international practice guidelines, but more clinical investigations are needed to answer still remaining questions...
January 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28182323/ibrutinib-associated-bleeding-pathogenesis-management-and-risk-reduction-strategies
#5
REVIEW
Joseph J Shatzel, Sven R Olson, Derrick L Tao, Owen J T McCarty, Alexey V Danilov, Thomas G DeLoughery
Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk) that has proven to be an effective therapeutic agent for multiple B-cell mediated lymphoproliferative disorders. Ibrutinib, however, carries an increased bleeding risk compared to standard chemotherapy. Bleeding events range from minor mucocutaneous bleeding to life-threatening hemorrhage, due in large part to the effects of ibrutinib on several distinct platelet signaling pathways. There is currently minimal data to guide clinicians regarding the use of ibrutinib in patients at high risk for bleeding or on anticoagulant or antiplatelet therapy...
February 9, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28178345/pi3k%C3%AE-inhibitor-idelalisib-in-combination-with-btk-inhibitor-ono-gs-4059-in-diffuse-large-b-cell-lymphoma-with-acquired-resistance-to-pi3k%C3%AE-and-btk-inhibitors
#6
Anella Yahiaoui, Sarah A Meadows, Rick A Sorensen, Zhi-Hua Cui, Kathleen S Keegan, Robert Brockett, Guang Chen, Christophe Quéva, Li Li, Stacey L Tannheimer
Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton's tyrosine kinase and phosphoinositide 3-kinase δ offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma...
2017: PloS One
https://www.readbyqxmd.com/read/28171709/long-term-outcomes-for-patients-with-chronic-lymphocytic-leukemia-who-discontinue-ibrutinib
#7
Preetesh Jain, Philip A Thompson, Michael Keating, Zeev Estrov, Alessandra Ferrajoli, Nitin Jain, Hagop Kantarjian, Jan A Burger, Susan O'Brien, William G Wierda
BACKGROUND: Ibrutinib is a Bruton tyrosine kinase inhibitor and is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) in frontline and relapsed/refractory settings. The authors previously reported poor outcomes for patients who discontinued ibrutinib; however, long-term outcomes were not reported. METHODS: Data from 320 patients who received ibrutinib on clinical studies between 2010 and 2015 at The University of Texas MD Anderson Cancer Center were retrospectively analyzed...
February 7, 2017: Cancer
https://www.readbyqxmd.com/read/28166283/metalloproteinase-9-contributes-to-endothelial-dysfunction-in-atherosclerosis-via-protease-activated-receptor-1
#8
Jon M Florence, Agnieszka Krupa, Laela M Booshehri, Timothy C Allen, Anna K Kurdowska
The atherosclerotic process begins when vascular endothelial cells undergo pro-inflammatory changes such as aberrant activation to dysfunctional phenotypes and apoptosis, leading to loss of vascular integrity. Our laboratory has demonstrated that exposure of mice to second hand smoke triggers an increase in expression of metalloproteinase-9. Further, metalloproteinase-9 released by second hand smoke-activated leukocytes may propagate pro-atherogenic alterations in endothelial cells. We have shown that levels of metalloproteinase-9 were increased in the plasma from apolipoprotein E deficient (ApoE-/-) mice exposed to second hand smoke relative to non-exposed controls...
2017: PloS One
https://www.readbyqxmd.com/read/28163195/positive-selection-of-type-ii-collagen-reactive-cd80-high-marginal-zone-b-cells-in-dba-1-mice
#9
Chanho Park, In Seong Kho, Jeong In Yang, Min-Jung Kim, Sunhoo Park, Hoon-Suk Cha, Jaejoon Lee, Tae Jin Kim
To investigate whether dysregulated selection of autoreactive marginal zone (MZ) B cells is involved in autoimmune diseases, we examined MZ B cell profile in multiple strains of mice, and found that type II collagen (CII)-reactive autoreactive CD80(high) MZ B cells spontaneously developed in the DBA/1, but not in C57BL/6 mice. CD80(high) MZ B cells that were characteristically found in DBA/1 mice expressed higher levels of TACI, SLAM3, and SLAM6 than the usual CD80(low) MZ B cells. Notably, the CD80(high) MZ B cells were more sensitive to ibrutinib, a Bruton's tyrosine kinase inhibitor, than CD80(low) MZ or follicular B cells and their transient depletion via intravenous injection of ibrutinib significantly delayed the induction of collagen-induced arthritis (CIA)...
February 2, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28141917/enhanced-bruton-s-tyrosine-kinase-activity-in-peripheral-blood-b-lymphocytes-of-autoimmune-disease-patients
#10
Odilia B J Corneth, Gwenny M P Verstappen, Sandra M J Paulissen, Marjolein J W de Bruijn, Jasper Rip, Melanie Lukkes, Jan Piet van Hamburg, Erik Lubberts, Hendrika Bootsma, Frans G M Kroese, And Rudi W Hendriks
OBJECTIVE: Bruton's tyrosine kinase (BTK) transmits crucial survival signals from the B cell receptor (BCR) in B cells. Pharmacological BTK inhibition effectively diminishes disease symptoms in mouse models of autoimmunity and, conversely, transgenic BTK overexpression induces systemic autoimmunity in mice. We investigated BTK expression and activity in human B cells in the context of autoimmune disease. METHODS: Using intracellular flow cytometry, we quantified BTK expression and phosphorylation in peripheral blood B cell subsets in patients with rheumatoid arthritis (RA; n=30) and primary Sjogren's Syndrome (pSS; n=26) and matched healthy controls...
January 31, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28138560/leukemia-cell-proliferation-and-death-in-chronic-lymphocytic-leukemia-patients-on-therapy-with-the-btk-inhibitor-ibrutinib
#11
Jan A Burger, Kelvin W Li, Michael J Keating, Mariela Sivina, Ahmed M Amer, Naveen Garg, Alessandra Ferrajoli, Xuelin Huang, Hagop Kantarjian, William G Wierda, Susan O'Brien, Marc K Hellerstein, Scott M Turner, Claire L Emson, Shih-Shih Chen, Xiao-Jie Yan, Dominik Wodarz, Nicholas Chiorazzi
BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. METHODS. We used stable isotopic labeling with deuterated water ((2)H2O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL. RESULTS. The measured average CLL cell proliferation ("birth") rate before ibrutinib therapy was 0.39% of the clone per day (range 0...
January 26, 2017: JCI Insight
https://www.readbyqxmd.com/read/28131592/the-role-of-chromatographic-and-chiroptical-spectroscopic-techniques-and-methodologies-in-support-of-drug-discovery-for-atropisomeric-drug-inhibitors-of-bruton-s-tyrosine-kinase
#12
Jun Dai, Chunlei Wang, Sarah C Traeger, Lorell Discenza, Mary T Obermeier, Adrienne A Tymiak, Yingru Zhang
Atropisomers are stereoisomers resulting from hindered bond rotation. From synthesis of pure atropisomers, characterization of their interconversion thermodynamics to investigation of biological stereoselectivity, the evaluation of drug candidates subject to atropisomerism creates special challenges and can be complicated in both early drug discovery and later drug development. In this paper, we demonstrate an array of analytical techniques and systematic approaches to study the atropisomerism of drug molecules to meet these challenges...
March 3, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28126969/the-bruton-tyrosine-kinase-inhibitor-ibrutinib-abrogates-triggering-receptor-on-myeloid-cells-1-mediated-neutrophil-activation
#13
Nicole Stadler, Astrid Hasibeder, Pamela Aranda Lopez, Daniel Teschner, Alexander Desuki, Oliver Kriege, Alexander N R Weber, Christoph Schulz, Christian Michel, Georg Heß, Markus P Radsak
No abstract text is available yet for this article.
January 25, 2017: Haematologica
https://www.readbyqxmd.com/read/28118202/from-mechanism-to-therapies-in-systemic-lupus-erythematosus
#14
Michael A Paley, Vibeke Strand, Alfred H J Kim
PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is a disabling and deadly disease. Development of novel therapies for SLE has historically been limited by incomplete understanding of immune dysregulation. Recent advances in lupus pathogenesis, however, have led to the adoption or development of new therapeutics, including the first Food and Drug Administration-approved drug in 50 years. RECENT FINDINGS: Multiple cytokines (interferon, B lymphocyte stimulator, IL-6, and IL-17), signaling pathways (Bruton's Tyrosine Kinase, Janus kinase/signal transducer and activator of transcription), and immune cells are dysregulated in SLE...
March 2017: Current Opinion in Rheumatology
https://www.readbyqxmd.com/read/28114285/hsp90-stabilizes-b-cell-receptor-kinases-in-a-multi-client-interactome-pu-h71-induces-cll-apoptosis-in-a-cytoprotective-microenvironment
#15
A Guo, P Lu, J Lee, C Zhen, G Chiosis, Y L Wang
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B cells in the hematopoietic system and lymphoid tissues. Although inhibitors targeting the B-cell receptor (BCR) pathway have been successful in the treatment of the disease, the underlying mechanisms leading to BCR over-activity in CLL are not fully understood. In this study, we found that HSP90, a highly conserved molecular chaperone, is overexpressed in CLL compared with resting B cells. HSP90 overexpression is accompanied by the overexpression of several BCR kinases including LYN, spleen tyrosine kinase, Bruton tyrosine kinase and AKT...
January 23, 2017: Oncogene
https://www.readbyqxmd.com/read/28111464/bruton-s-tyrosine-kinase-inhibition-increases-bcl-2-dependence-and-enhances-sensitivity-to-venetoclax-in-chronic-lymphocytic-leukemia
#16
J Deng, E Isik, S M Fernandes, J R Brown, A Letai, M S Davids
Although the BTK inhibitor ibrutinib has transformed the management of patients with chronic lymphocytic leukemia (CLL), it does not induce substantial apoptosis in vitro, and as such the mechanisms underlying its ability to kill CLL cells are not well understood. Acalabrutinib, a more specific BTK inhibitor now in development, also appears to be highly effective in CLL, but the connection of its mechanism with CLL cell death is also unclear. Using dynamic BH3 profiling, we analyzed alterations in the function of the mitochondrial apoptotic pathway induced by ibrutinib and acalabrutinib...
February 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28105602/ibrutinib-a-review-in-chronic-lymphocytic-leukaemia
#17
Emma D Deeks
Ibrutinib (Imbruvica(®)) is an oral irreversible inhibitor of Bruton's tyrosine kinase, a B-cell receptor (BCR) signalling kinase expressed by various haematopoietic cells, B-cell lymphomas and leukaemias. The drug is indicated for the treatment of certain haematological malignancies, including chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL), which are the focus of this review. In phase III CLL/SLL trials, ibrutinib monotherapy was more effective than chlorambucil in the first-line treatment of elderly patients (RESONATE-2) and more effective than ofatumumab in previously-treated adults (RESONATE)...
February 2017: Drugs
https://www.readbyqxmd.com/read/28096090/how-i-manage-ibrutinib-refractory-chronic-lymphocytic-leukemia
#18
Jennifer A Woyach
The introduction of the Bruton's Tyrosine Kinase inhibitor ibrutinib has dramatically changed the management of chronic lymphocytic leukemia. Although responses have been durable in the majority of patients, relapses do occur, especially in the high risk patient population. Most relapses occur as the result of acquired mutations in BTK and PLCG2, which may facilitate success with alternative targeted therapies. As outcomes following ibrutinib relapse have been reported to be poor, specific strategies are needed for this patient population...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28077600/ibrutinib-therapy-increases-t-cell-repertoire-diversity-in-patients-with-chronic-lymphocytic-leukemia
#19
Qingsong Yin, Mariela Sivina, Harlan Robins, Erik Yusko, Marissa Vignali, Susan O'Brien, Michael J Keating, Alessandra Ferrajoli, Zeev Estrov, Nitin Jain, William G Wierda, Jan A Burger
The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy...
February 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28073846/extended-treatment-with-single-agent-ibrutinib-at-the-420-mg-dose-leads-to-durable-responses-in-chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma
#20
Steven E Coutré, Richard R Furman, Ian W Flinn, Jan A Burger, Kristie Blum, Jeff Sharman, Jeffrey Jones, William Wierda, Weiqiang Zhao, Nyla A Heerema, Amy J Johnson, Anh Tran, Cathy Zhou, Elizabeth Bilotti, Danelle F James, John C Byrd, Susan O'Brien
Purpose: Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naïve (TN) or had relapsed/refractory (R/R) CLL after ≥1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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