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https://www.readbyqxmd.com/read/29326436/p66shc-deficiency-enhances-cxcr4-and-ccr7-recycling-in-cll-b-cells-by-facilitating-their-dephosphorylation-dependent-release-from-%C3%AE-arrestin-at-early-endosomes
#1
Laura Patrussi, Nagaja Capitani, Francesca Cattaneo, Noemi Manganaro, Alessandra Gamberucci, Federica Frezzato, Veronica Martini, Andrea Visentin, Pier Giuseppe Pelicci, Mario M D'Elios, Livio Trentin, Gianpietro Semenzato, Cosima T Baldari
Neoplastic cell traffic abnormalities are central to the pathogenesis of chronic lymphocytic leukemia (CLL). Enhanced CXC chemokine receptor-4 (CXCR4) and chemokine receptor-7 (CCR7) recycling contributes to the elevated surface levels of these receptors on CLL cells. Here we have addressed the role of p66Shc, a member of the Shc family of protein adaptors the expression of which is defective in CLL cells, in CXCR4/CCR7 recycling. p66Shc reconstitution in CLL cells reduced CXCR4/CCR7 recycling, lowering their surface levels and attenuating B-cell chemotaxis, due to their accumulation in Rab5+ endosomes as serine-phosphoproteins bound to β-arrestin...
January 12, 2018: Oncogene
https://www.readbyqxmd.com/read/29324347/design-synthesis-and-biological-evaluation-of-7h-pyrrolo-2-3-d-pyrimidin-4-amine-derivatives-as-selective-btk-inhibitors-with-improved-pharmacokinetic-properties-for-the-treatment-of-rheumatoid-arthritis
#2
Linhong He, Heying Pei, Chufeng Zhang, Mingfeng Shao, Dan Li, Mingli Tang, Taijing Wang, Xiaoxin Chen, Mingli Xiang, Lijuan Chen
Bruton's tyrosine kinase (Btk) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) and Fcγ receptor (FcR) signaling pathways, which makes it a uniquely attractive target for the treatment of autoimmune diseases, such as rheumatoid arthritis (RA). We reported a series of compounds bearing 7H-pyrrolo [2,3-d]pyrimidin-4-amine scaffold that potently inhibited Btk in vitro. Analysis of the structure-activity relationships (SAR) and drug-like profiles led to the discovery of the optimal compound B16...
December 28, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29317997/experience-with-ibrutinib-for-first-line-use-in-patients-with-chronic-lymphocytic-leukemia
#3
REVIEW
Gilad Itchaki, Jennifer R Brown
Ibrutinib is the first in-class, orally administered, Bruton's tyrosine kinase (BTK) inhibitor that abrogates the critical signaling downstream of the B-cell receptor (BCR). This signaling is required for B-cell survival, proliferation and interaction with the microenvironment. Ibrutinib proved active in preclinical models of lymphoproliferative diseases and achieved impressive response rates in heavily pretreated relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). Ibrutinib prolonged survival compared to standard therapy and mitigated the effect of most poor prognostic factors in CLL, thus becoming the main therapeutic option in high-risk populations...
January 2018: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/29301866/functional-and-clinical-relevance-of-vla-4-cd49d-cd29-in-ibrutinib-treated-chronic-lymphocytic-leukemia
#4
Erika Tissino, Dania Benedetti, Sarah E M Herman, Elisa Ten Hacken, Inhye E Ahn, Kari G Chaffee, Francesca Maria Rossi, Michele Dal Bo, Pietro Bulian, Riccardo Bomben, Elisabeth Bayer, Andrea Härzschel, Julia Christine Gutjahr, Massimiliano Postorino, Enrico Santinelli, Ayed Ayed, Francesco Zaja, Annalisa Chiarenza, Gabriele Pozzato, Alexandre Chigaev, Larry A Sklar, Jan A Burger, Alessandra Ferrajoli, Tait D Shanafelt, Adrian Wiestner, Giovanni Del Poeta, Tanja Nicole Hartmann, Valter Gattei, Antonella Zucchetto
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells...
January 4, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29296914/severe-platelet-dysfunction-in-nhl-patients-receiving-ibrutinib-is-absent-in-patients-receiving-acalabrutinib
#5
Alexander P Bye, Amanda J Unsworth, Michael J Desborough, Catherine A T Hildyard, Niamh Appleby, David Bruce, Neline Kriek, Sophie H Nock, Tanya Sage, Craig E Hughes, Jonathan M Gibbins
The Bruton tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side effects of ibrutinib. The second-generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with non-Hodgkin lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear...
December 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296874/crosstalk-between-ror1-and-bcr-pathways-defines-novel-treatment-strategies-in-mantle-cell-lymphoma
#6
Hanna Karvonen, David Chiron, Wilhelmiina Niininen, Sara Ek, Mats Jerkeman, Elaheh Moradi, Matti Nykter, Caroline A Heckman, Olli Kallioniemi, Astrid Murumägi, Daniela Ungureanu
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin B-cell lymphoma with poor prognosis due to drug resistance. Introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has markedly improved MCL therapy outcome, but drug resistance remains a challenge. The selective cell-surface expression of oncogenic receptor tyrosine kinase-like orphan receptor 1 (ROR1) pseudokinase in hematological malignancies has made this receptor a promising candidate for targeted therapy. We sought to identify the molecular mechanism underlying divergent ROR1-mediated apoptotic responses in MCL cell lines and primary samples...
November 14, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296715/clonal-evolution-underlying-leukemia-progression-and-richter-transformation-in-patients-with-ibrutinib-relapsed-cll
#7
Sabah Kadri, Jimmy Lee, Carrie Fitzpatrick, Natalie Galanina, Madina Sukhanova, Girish Venkataraman, Shruti Sharma, Brad Long, Kristin Petras, Megan Theissen, Mei Ming, Yuri Kobzev, Wenjun Kang, Ailin Guo, Weige Wang, Nifang Niu, Howard Weiner, Michael Thirman, Wendy Stock, Sonali M Smith, Chadi Nabhan, Jeremy P Segal, Pin Lu, Y Lynn Wang
Ibrutinib has generated remarkable responses in patients with chronic lymphocytic leukemia (CLL), including those with an unfavorable cytogenetic profile. However, patients develop resistance, with poor outcomes and no established treatment options. Mutations in BTK and PLCG2 have emerged as main mechanisms of drug resistance, but not all patients carry these mutations. Further understanding of mechanisms of resistance is urgently needed and will support rational development of new therapeutic strategies. To that end, we characterized the genomic profiles of serial samples from 9 patients with ibrutinib-relapsed disease, including 6 who had Richter transformation...
May 9, 2017: Blood Advances
https://www.readbyqxmd.com/read/29290977/btk-blocks-the-inhibitory-effects-of-mdm2-on-p53-activity
#8
Miran Rada, Mohammad Althubiti, Akang E Ekpenyong-Akiba, Koon-Guan Lee, Kong Peng Lam, Olga Fedorova, Nickolai A Barlev, Salvador Macip
p53 is a tumour suppressor that is activated in response to various types of stress. It is regulated by a complex pattern of over 50 different post-translational modifications, including ubiquitination by the E3 ligase MDM2, which leads to its proteasomal degradation. We have previously reported that expression of Bruton's Tyrosine Kinase (BTK) induces phosphorylation of p53 at the N-terminus, including Serine 15, and increases its protein levels and activity. The mechanisms involved in this process are not completely understood...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29290094/a-candidate-tolerance-gene-identified-in-a-natural-population-of-field-voles-microtus-agrestis
#9
Klara M Wanelik, Michael Begon, Richard J Birtles, Janette E Bradley, Ida M Friberg, Joseph A Jackson, Christopher H Taylor, Anna G Thomason, Andrew K Turner, Steve Paterson
The animal immune response has hitherto been viewed primarily in the context of resistance only. However, individuals, can also employ a tolerance strategy to maintain good health in the face of on-going infection. To shed light on the genetic and physiological basis of tolerance, we use a natural population of field voles, Microtus agrestis, to search for an association between the expression of the transcription factor Gata3, previously identified as a marker of tolerance in this system, and polymorphism in 84 immune and non-immune genes...
December 31, 2017: Molecular Ecology
https://www.readbyqxmd.com/read/29285806/systematic-review-of-infectious-events-with-the-btk-inhibitor-ibrutinib-in-the-treatment-of-haematologic-malignancies
#10
REVIEW
Benjamin F Tillman, James M Pauff, Gowri Satyanarayana, Mahsa Talbott, Jeremy L Warner
OBJECTIVE: Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK) in B-lymphocytes as well as other kinases including interleukin-2-inducible T-cell kinase (ITK) in CD4+ Th2 regulatory T-cells. Increased infections have been observed in patients taking ibrutinib. The overall incidence has not been systematically evaluated. METHODS: The published literature and conference abstracts of prospective clinical trials using ibrutinib in haematologic malignancies were identified and reviewed using PubMed, Google Scholar, and HemOnc...
December 28, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/29276997/cancer-immunotherapy-in-a-neglected-population-the-current-use-and-future-of-t-cell-mediated-checkpoint-inhibitors-in-organ-transplant-patients
#11
REVIEW
Young Kwang Chae, Carlos Galvez, Jonathan F Anker, Wade T Iams, Manali Bhave
Although the indications for immune checkpoint inhibitors continue to grow, organ transplant recipients with advanced malignancies have been largely excluded from clinical trials testing the safety and efficacy of these therapies given their need for chronic immunosuppression and the risk of allograft rejection. With the rapid growth of transplant medicine and the increased risk of malignancy associated with chronic immunosuppression, it is critical that we systematically analyze the available data describing immune checkpoint blockade in the organ transplant population...
December 8, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29259203/the-evolutionary-landscape-of-chronic-lymphocytic-leukemia-treated-with-ibrutinib-targeted-therapy
#12
Dan A Landau, Clare Sun, Daniel Rosebrock, Sarah E M Herman, Joshua Fein, Mariela Sivina, Chingiz Underbayev, Delong Liu, Julia Hoellenriegel, Sarangan Ravichandran, Mohammed Z H Farooqui, Wandi Zhang, Carrie Cibulskis, Asaf Zviran, Donna S Neuberg, Dimitri Livitz, Ivana Bozic, Ignaty Leshchiner, Gad Getz, Jan A Burger, Adrian Wiestner, Catherine J Wu
Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo-immunotherapy to targeted agents. To define the evolutionary dynamics induced by targeted therapy in CLL, we perform serial exome and transcriptome sequencing for 61 ibrutinib-treated CLLs. Here, we report clonal shifts (change >0.1 in clonal cancer cell fraction, Q < 0.1) in 31% of patients during the first year of therapy, associated with adverse outcome. We also observe transcriptional downregulation of pathways mediating energy metabolism, cell cycle, and B cell receptor signaling...
December 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/29250834/comparison-of-drug-eluting-balloon-angioplasty-to-infrapopliteal-artery-critical-lesions-with-or-without-additional-pedal-artery-angioplasty-in-patients-with-diabetes-mellitus-and-critical-limb-ischemia
#13
Burak Teymen, Süleyman Aktürk
BACKGROUND: The purpose of this study is to investigate the feasibility and outcome of balloon angioplasty for the treatment of below the ankle (BTA) lesions in addition to below the knee (BTK) lesions in diabetic patients with critical limb ischemia (CLI). METHODS: Inclusion criteria are diabetes mellitus (DM), CLI (Rutherford class 4 or higher) and revascularized significant stenosis or occlusion of at least 1 below-the-knee vessel with incomplete or no pedal loop...
December 17, 2017: Journal of Interventional Cardiology
https://www.readbyqxmd.com/read/29249817/drug-induced-inhibition-of-phosphorylation-of-stat5-overrides-drug-resistance-in-neoplastic-mast-cells
#14
B Peter, S Bibi, G Eisenwort, B Wingelhofer, D Berger, G Stefanzl, K Blatt, H Herrmann, E Hadzijusufovic, G Hoermann, T Hoffmann, J Schwaab, M Jawhar, M Willmann, W R Sperr, J Zuber, K Sotlar, H-P Horny, R Moriggl, A Reiter, M Arock, P Valent
Systemic mastocytosis (SM) is a mast cell (MC) neoplasm with complex pathology and a variable clinical course. In aggressive SM (ASM) and MC leukemia (MCL), responses to conventional drugs are poor and the prognosis is dismal. R763 is a multi-kinase inhibitor that blocks the activity of Aurora-kinase-A/B, ABL1, AKT and FLT3. We examined the effects of R763 on proliferation and survival of neoplastic MC. R763 produced dose-dependent inhibition of proliferation in the human MC lines HMC-1.1 (IC50 5-50 nM), HMC-1...
November 29, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29246942/synergistic-targeting-of-the-regulatory-and-catalytic-subunits-of-pi3k%C3%AE-in-mature-b-cell-malignancies
#15
Jeffrey Cooney, An-Ping Lin, Daifeng Jiang, Long Wang, Avvaru N Suhasini, Jamie Myers, ZhiJun Qiu, Albert Wölfler, Heinz Sill, Ricardo C T Aguiar
PURPOSE: Aberrant activation of the B cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3Kδ (Phosphatidylinositol-4,5-bisphosphate 3-kinase delta). These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, towards identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies...
December 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29246803/venetoclax-for-chronic-lymphocytic-leukaemia-progressing-after-ibrutinib-an-interim-analysis-of-a-multicentre-open-label-phase-2-trial
#16
Jeffrey A Jones, Anthony R Mato, William G Wierda, Matthew S Davids, Michael Choi, Bruce D Cheson, Richard R Furman, Nicole Lamanna, Paul M Barr, Lang Zhou, Brenda Chyla, Ahmed Hamed Salem, Maria Verdugo, Rod A Humerickhouse, Jalaja Potluri, Steven Coutre, Jennifer Woyach, John C Byrd
BACKGROUND: Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy...
December 12, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29239533/corrigendum-discovery-of-a-potent-btk-inhibitor-with-a-novel-binding-mode-by-using-parallel-selections-with-a-dnaencoded-chemical-library
#17
John W Cuozzo, Paolo A Centrella, Diana Gikunju, Sevan Habeshian, Christopher D Hupp, Anthony D Keefe, Eric A Sigel, Holly H Soutter, Heather A Thomson, Ying Zhang, Matthew A Clark
No abstract text is available yet for this article.
December 14, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29208667/etk-interaction-with-pfkfb4-modulates-chemoresistance-of-small-cell-lung-cancer-by-regulating-autophagy
#18
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/29202590/delayed-diagnosis-in-x-linked-agammaglobulinemia-and-its-relationship-to-the-occurrence-of-mutations-in-btk-non-kinase-domains
#19
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/29198867/design-and-synthesis-of-novel-pyrimidine-analogs-as-highly-selective-non-covalent-btk-inhibitors
#20
Wataru Kawahata, Tokiko Asami, Takayuki Irie, Masaaki Sawa
BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.
November 24, 2017: Bioorganic & Medicinal Chemistry Letters
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