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Bruton tyrosine kinase

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https://www.readbyqxmd.com/read/29243946/ibrutinib-and-its-use-in-the-treatment-of-chronic-lymphocytic-leukemia
#1
Anna Maria Frustaci, Alessandra Tedeschi, Marina Deodato, Maddalena Mazzucchelli, Roberto Cairoli, Marco Montillo
Ibrutinib represents a revolution in chronic lymphocytic leukemia treatment scenario providing results never seen before and offering an effective therapy even in high-risk patients with really poor outcome after chemoimmunotherapy. Thanks to longer updates, on one hand, ibrutinib has confirmed its efficacy continuing to show clinical benefits over time; on the other hand, resistance mechanisms are slowly emerging. Moreover, clinicians should be aware of ibrutinib-related side effects, paying attention to screen patients that could benefit more from the drug and try to prevent adverse events...
December 15, 2017: Future Oncology
https://www.readbyqxmd.com/read/29242301/in-vitro-and-in-vivo-evidence-for-uncoupling-of-bcr-internalization-and-signaling-in-chronic-lymphocytic-leukemia
#2
Eve M Coulter, Andrea Pepper, Silvia Mele, Najeem'deen Folarin, William Townsend, Kirsty Cuthill, Elizabeth Phillips, Piers Patten, Stephen Devereux
B-cell receptor activation, occurring within lymph nodes, plays a key role in the pathogenesis of chronic lymphocytic leukemia and is linked to prognosis. As well as activation of downstream signaling, receptor ligation triggers internalization, transit to acidified endosomes and degradation of ligand-receptor complexes. In the present study we investigated the relationship between these two processes in normal and leukemic B-cells. We found that leukemic B-cells, particularly anergic cases lacking the capacity to initiate downstream signaling, internalize and accumulate ligand in acidified endosomes more efficiently than normal B-cells...
December 14, 2017: Haematologica
https://www.readbyqxmd.com/read/29241979/acalabrutinib-in-relapsed-or-refractory-mantle-cell-lymphoma-ace-ly-004-a-single-arm-multicentre-phase-2-trial
#3
Michael Wang, Simon Rule, Pier Luigi Zinzani, Andre Goy, Olivier Casasnovas, Stephen D Smith, Gandhi Damaj, Jeanette Doorduijn, Thierry Lamy, Franck Morschhauser, Carlos Panizo, Bijal Shah, Andrew Davies, Richard Eek, Jehan Dupuis, Eric Jacobsen, Arnon P Kater, Steven Le Gouill, Lucie Oberic, Taduesz Robak, Todd Covey, Richa Dua, Ahmed Hamdy, Xin Huang, Raquel Izumi, Priti Patel, Wayne Rothbaum, J Greg Slatter, Wojciech Jurczak
BACKGROUND: Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise off-target activity. METHODS: In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants...
December 11, 2017: Lancet
https://www.readbyqxmd.com/read/29222280/toward-personalized-treatment-in-waldenstr%C3%A3-m-macroglobulinemia
#4
REVIEW
Jorge J Castillo, Steven P Treon
Waldenström macroglobulinemia (WM) is a rare lymphoma with 1000 to 1500 new patients diagnosed per year in the United States. Patients with WM can experience prolonged survival times, which seem to have increased in the last decade, but relapse is inevitable. The identification of recurrent mutations in the MYD88 and CXCR4 genes has opened avenues of research to better understand and treat patients with WM. These developments are giving way to personalized treatment approaches for these patients, focusing on increasing depth and duration of response alongside lower toxicity rates...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29209955/acalabrutinib-first-global-approval
#5
Anthony Markham, Sohita Dhillon
Acerta Pharma is developing the Bruton's tyrosine kinase inhibitor acalabrutinib (Calquence®) for the treatment of various haematological and solid malignancies. The drug has received accelerated approval from the US FDA for the treatment of mantle cell lymphoma based on the results of a phase II study, and phase III trials in mantle cell lymphoma and chronic lymphocytic leukaemia are currently underway. This article summarizes the milestones in the development of acalabrutinib leading to this first approval for mantle cell lymphoma...
December 5, 2017: Drugs
https://www.readbyqxmd.com/read/29208667/etk-interaction-with-pfkfb4-modulates-chemoresistance-of-small-cell-lung-cancer-by-regulating-autophagy
#6
Qiongyao Wang, Fanrui Zeng, Yanqin Sun, Qianqian Qiu, Jian Zhang, Weimei Huang, Jie Huang, Xiaomin Huang, Linlang Guo
PURPOSE: Epithelial and endothelial tyrosine kinase (Etk), also known as bone marrow X kinase (Bmx), was found to be critical in modulating the chemoresistance of small cell lung cancer (SCLC) in our preliminary study. However, the molecular mechanisms of Etk in SCLC chemoresistance remain poorly understood. The present study investigated the downstream factor and pathway involved. EXPERIMENTAL DESIGN: We demonstrated first that knockdown of Etk by siRNAs suppressed autophagy in chemoresistant SCLC cells, and that direct inhibition of autophagy sensitized cells to chemotherapy...
December 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29206660/recent-developments-in-systemic-lupus-erythematosus-pathogenesis-and-applications-for-therapy
#7
Mindy S Lo, George C Tsokos
PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) pathogenesis is complex. Aberrancies of immune function that previously were described but not well understood are now becoming better characterized, in part through recognition of monogenic cases of lupus-like disease. RECENT FINDINGS: We highlight here recent descriptions of metabolic dysfunction, cytokine dysregulation, signaling defects, and DNA damage pathways in SLE. Specifically, we review the effects of signaling abnormalities in mammalian target of rapamycin, Rho kinase, Bruton's tyrosine kinase, and Ras pathways...
December 4, 2017: Current Opinion in Rheumatology
https://www.readbyqxmd.com/read/29202590/delayed-diagnosis-in-x-linked-agammaglobulinemia-and-its-relationship-to-the-occurrence-of-mutations-in-btk-non-kinase-domains
#8
Eduardo Carrillo-Tapia, Elizabeth García-García, Norma Estela Herrera-González, Marco Antonio Yamazaki-Nakashimada, Aidee Tamara Staines-Boone, Nora Hilda Segura-Mendez, Selma Cecilia Scheffler-Mendoza, Patricia O Farrill-Romanillos, Maria E Gonzalez-Serrano, Juan Carloa Rodriguez-Alba, Leopoldo Santos-Argumedo, Laura Berron-Ruiz, Alejandro Sanchez-Flores, Gabriela López-Herrera
BACKGROUND: X-linked agammaglobulinemia (XLA) is characterized by the absence of immunoglobulin and B cells. Patients suffer from recurrent bacterial infections from early childhood, and require lifelong immunoglobulin replacement therapy. Mutations in BTK (Bruton's Tyrosine Kinase) are associated with this phenotype. Some patients that present XLA do not show typical clinical symptoms, resulting in delayed diagnosis due to the lack of a severe phenotype. OBJECTIVE: This study presents a report of five XLA patients from four different families and attempts to determine a relationship between delayed diagnosis and the occurrence of BTK mutations...
December 5, 2017: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/29167667/bruton-s-tyrosine-kinase-an-emerging-key-player-in-innate-immunity
#9
REVIEW
Alexander N R Weber, Zsofia Bittner, Xiao Liu, Truong-Minh Dang, Markus Philipp Radsak, Cornelia Brunner
Bruton's tyrosine kinase (BTK) was initially discovered as a critical mediator of B cell receptor signaling in the development and functioning of adaptive immunity. Growing evidence also suggests multiple roles for BTK in mononuclear cells of the innate immune system, especially in dendritic cells and macrophages. For example, BTK has been shown to function in Toll-like receptor-mediated recognition of infectious agents, cellular maturation and recruitment processes, and Fc receptor signaling. Most recently, BTK was additionally identified as a direct regulator of a key innate inflammatory machinery, the NLRP3 inflammasome...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29160911/simultaneous-use-of-erythropoietin-and-lfm-a13-as-a-new-therapeutic-approach-for-colorectal-cancer
#10
Anna Tankiewicz-Kwedlo, Justyna Magdalena Hermanowicz, Tomasz Domaniewski, Krystyna Pawlak, Małgorzata Rusak, Anna Pryczynicz, Arkadiusz Surazynski, Tomasz Kaminski, Adam Kazberuk, Dariusz Pawlak
BACKGROUND AND PURPOSE: Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase involved in the activation of signaling pathways responsible for cell maturation and viability. BTK has previously been reported to be overexpressed in colon cancers. This kind of cancer is often accompanied by anemia, which is treated with an erythropoietin supplement. The goal of the present study was to assess the effects of combination therapy with erythropoietin beta (Epo) and LFM-A13 (BTK inhibitor) on colon cancer in in vitro and in vivo models...
November 21, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29142210/millisecond-dynamics-of-btk-reveal-kinome-wide-conformational-plasticity-within-the-apo-kinase-domain
#11
Mohammad M Sultan, Rajiah Aldrin Denny, Ray Unwalla, Frank Lovering, Vijay S Pande
Bruton tyrosine kinase (BTK) is a key enzyme in B-cell development whose improper regulation causes severe immunodeficiency diseases. Design of selective BTK therapeutics would benefit from improved, in-silico structural modeling of the kinase's solution ensemble. However, this remains challenging due to the immense computational cost of sampling events on biological timescales. In this work, we combine multi-millisecond molecular dynamics (MD) simulations with Markov state models (MSMs) to report on the thermodynamics, kinetics, and accessible states of BTK's kinase domain...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29130484/the-bruton-s-tyrosine-kinase-inhibitor-prn473-inhibits-neutrophil-recruitment-via-inhibition-of-mac-1-signaling
#12
Jan M Herter, Andreas Margraf, Stephanie Volmering, Benedito Eduardo Correia, J Michael Bradshaw, Angelina Bisconte, Ronald J Hill, Claire L Langrish, Clifford A Lowell, Alexander Zarbock
BACKGROUND AND PURPOSE: Following inflammatory stimuli neutrophils are recruited to sites of inflammation and exert effector functions that often have deleterious effects on tissue integrity, which can lead to organ failure. Btk is expressed in neutrophils, and constitutes a promising pharmacological target for neutrophil mediated tissue damage. Here we evaluate a selective reversible inhibitor of the Bruton's tyrosine kinase (PRN473) for its ability to dampen neutrophil influx via inhibition of adhesion receptor signaling pathways...
November 11, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29127674/pharmacotherapeutic-management-of-pediatric-lymphoma
#13
REVIEW
Christine Mauz-Körholz, Natascha Ströter, Julia Baumann, Ante Botzen, Katharina Körholz, Dieter Körholz
Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) comprise approximately 15% of all childhood malignancies. Cure rates for both lymphoma entities have evolved tremendously during the last couple of decades, raising the 5-year survival rates to almost 100% for HL and to 85% for NHL. The mainstay therapy for both malignancies is still chemotherapy-with different regimens recommended for different types of disease. In HL, combined modality treatment, i.e., chemotherapy followed by radiotherapy, has long been the standard regimen...
November 10, 2017: Paediatric Drugs
https://www.readbyqxmd.com/read/29125406/bruton-s-tyrosine-kinase-inhibitors-first-and-second-generation-agents-for-patients-with-chronic-lymphocytic-leukemia-cll
#14
Philip A Thompson, Jan A Burger
The BTK inhibitor ibrutinib is effective in both low- and high-risk CLL patients, achieving durable remissions with continuous therapy in the majority of patients. Ibrutinib lacks myelotoxicity and is generally well tolerated by older and unfit patients; however, side effects, such as atrial fibrillation or hemorrhage, can result in treatment interruption or discontinuation. Given the high efficacy and overall safety, ibrutinib is increasingly used in untreated and previously treated CLL patients. Second-generation BTK inhibitors are being developed, with different and generally more BTK-selective kinase inhibition profiles, which may increase the safety and/or efficacy...
November 10, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29115892/management-of-patients-with-chronic-lymphocytic-leukemia-at-high-risk-of-relapse-on-ibrutinib-therapy
#15
Ayed O Ayed, Sameer A Parikh
The past two decades have witnessed a paradigm shift in the management of patients with chronic lymphocytic leukemia (CLL), particularly with the introduction of targeted therapies to clinical practice. Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and has shown significant efficacy and tolerability, even in heavily treated patients. Despite improvement in outcomes, patients do ultimately relapse. Those who develop disease progression on ibrutinib are a particularly high-risk population with poor outcomes...
November 8, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29109446/bruton-s-tyrosine-kinase-and-rac1-promote-cell-survival-in-mll-rearranged-acute-myeloid-leukemia
#16
S C Nimmagadda, S Frey, B Edelmann, C Hellmich, L Zaitseva, G M König, E Kostenis, K M Bowles, T Fischer
Leukemia accepted article preview online, 07 November 2017. doi:10.1038/leu.2017.324.
November 7, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29108275/functional-imaging-in-combination-with-mutation-status-aids-prediction-of-response-to-inhibiting-b-cell-receptor-signaling-in-lymphoma
#17
Laura Jacobs, Stefan Habringer, Jolanta Slawska, Katharina Huber, Elke Hauf, Zhoulei Li, Yosef Refaeli, Markus Schwaiger, Martina Rudelius, Axel Walch, Ulrich Keller
Aberrant B-cell receptor (BCR) signaling is known to contribute to malignant transformation. Two small molecule inhibitors targeting BCR pathway signaling include ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, and idelalisib, a specific Phosphatidylinositol-4,5-bisphosphate 3-kinase delta (PI3Kδ) inhibitor, both of which have been approved for use in haematological malignancies. Despite the identification of various diffuse large B-cell lymphoma (DLBCL) subtypes, mutation status alone is not sufficient to predict patient response and therapeutic resistance can arise...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29099493/pharmacodynamics-and-proteomic-analysis-of-acalabrutinib-therapy-similarity-of-on-target-effects-to-ibrutinib-and-rationale-for-combination-therapy
#18
V K Patel, B Lamothe, M L Ayres, J Gay, J Cheung, K Balakrishnan, C Ivan, J Morse, M Nelson, M J Keating, W G Wierda, J R Marszalek, V Gandhi
Acalabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, is associated with high overall response rates and durable remission in previously treated chronic lymphocytic leukemia (CLL), however, complete remissions were limited. To elucidate on-target and pharmacodynamic effects of acalabrutinib, we evaluated several laboratory endpoints, including proteomic changes, chemokine modulation, and impact on cell migration. Pharmacological profiling of samples from acalabrutinib-treated CLL patients was used to identify strategies for achieving deeper responses, and to identify additive/synergistic combination regimens...
November 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29091884/advances-in-chronic-lymphocytic-leukemia-pharmacotherapy
#19
REVIEW
Lorena Caixeta Gomes, Aline Lúcia Menezes Ferrão, Fernanda Cristina Gontijo Evangelista, Tâmara Dauare de Almeida, Rayson Carvalho Barbosa, Maria das Graças Carvalho, Adriano de Paula Sabino
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease that affects B lymphocytes in most cases. Leukemic lymphocytes have prolonged longevity, defined by resistance to apoptosis. These cells can accumulate in peripheral blood, bone marrow, and solid lymphoid organs. CLL may be indolent or aggressive and has a range of prognostic factors such as expression of CD38 and ZAP-70, immunophenotypic and cytogenetic changes, imbalanced apoptosis proteins, and others. Although CLL has a low mortality rate, this disease is generally not considered curable until today...
October 26, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29080970/ibrutinib-does-not-prolong-the-corrected-qt-interval-in-healthy-subjects-results-from-a-thorough-qt-study
#20
Jan de Jong, Peter Hellemans, James Juhui Jiao, Yuhan Huang, Sofie Mesens, Juthamas Sukbuntherng, Daniele Ouellet
PURPOSE: Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. METHODS: Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval...
December 2017: Cancer Chemotherapy and Pharmacology
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