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https://www.readbyqxmd.com/read/29160911/simultaneous-use-of-erythropoietin-and-lfm-a13-as-a-new-therapeutic-approach-for-colorectal-cancer
#1
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/29146136/identification-of-highly-potent-btk-and-jak3-dual-inhibitors-with-improved-activity-for-the-treatment-of-b-cell-lymphoma
#2
Yang Ge, Changyuan Wang, Shijie Song, Jiaxin Huang, Zhihao Liu, Yongming Li, Qiang Meng, Jianbin Zhang, Jihong Yao, Kexin Liu, Xiaodong Ma, Xiuli Sun
The BTK and JAK3 receptor tyrosine kinases are two validated and therapeutically amenable targets in the treatment of B-cell lymphomas. Here we report the identification of several classes of pyrimidine derivatives as potent BTK and JAK3 dual inhibitors. Among these molecules, approximately two thirds displayed strong inhibitory capacity at less than 10 nM concentration, and four compounds (7e, 7g, 7m and 7n) could significantly inhibit the phosphorylation of BTK and JAK3 enzymes at concentrations lower than 1 nM...
November 13, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29144032/microrna-106b-overexpression-alleviates-inflammation-injury-of-cardiac-endothelial-cells-by-targeting-blnk-via-the-nf-%C3%AE%C2%BAb-signaling-pathway
#3
Zhe An, Guang Yang, Wei Nie, Jin Ren, Dan Wang
We aim to investigate whether microRNA-106b (miR-106b) affects the inflammation injury of cardiac endothelial cells (ECs) by targeting B-cell linker (BLNK) via the NF-κB signaling pathway. Human cardiac microvascular endothelial cells (HCMECs) were assigned into the control, hypoxia/reoxygenation (H/R), negative control (NC), pyrrolidine dithiocarbamate (PDTC), miR-106b mimic, miR-106b inhibitor, and si-BLNK and miR-106b inhibitor + si-BLNK groups. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were conducted for miR-106b expression and expressions of BLNK, interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, NF-κB, pIκBα, BTK, and PLC-γ2...
November 16, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29142210/millisecond-dynamics-of-btk-reveal-kinome-wide-conformational-plasticity-within-the-apo-kinase-domain
#4
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
#5
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/29129717/a-chemoproteomic-approach-to-query-the-degradable-kinome-using-a-multi-kinase-degrader
#6
Hai-Tsang Huang, Dennis Dobrovolsky, Joshiawa Paulk, Guang Yang, Ellen L Weisberg, Zainab M Doctor, Dennis L Buckley, Joong-Heui Cho, Eunhwa Ko, Jaebong Jang, Kun Shi, Hwan Geun Choi, James D Griffin, Ying Li, Steven P Treon, Eric S Fischer, James E Bradner, Li Tan, Nathanael S Gray
Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. In this study, we designed a multi-kinase degrader by conjugating a highly promiscuous kinase inhibitor with a cereblon-binding ligand, and used quantitative proteomics to discover 28 kinases, including BTK, PTK2, PTK2B, FLT3, AURKA, AURKB, TEC, ULK1, ITK, and nine members of the CDK family, as degradable...
November 7, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29127086/mainstreaming-cryo-em-in-cancer-research
#7
(no author information available yet)
Cryo-electron microscopy, whose pioneers won the 2017 Nobel Prize in Chemistry, is gaining favor among scientists as a tool to probe cancer at the molecular level. To that end, the NCI recently launched a centralized, free service facility to better meet the needs of researchers interested in utilizing this otherwise highly expensive technology.
November 10, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29125406/bruton-s-tyrosine-kinase-inhibitors-first-and-second-generation-agents-for-patients-with-chronic-lymphocytic-leukemia-cll
#8
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/29122993/the-microenvironmental-stromal-cells-abrogate-nf-%C3%AE%C2%BAb-inhibitor-induced-apoptosis-in-chronic-lymphocytic-leukemia
#9
Carl Philipp Simon-Gabriel, Katharina Foerster, Shifa Saleem, Dorothee Bleckmann, Marco Benkisser-Petersen, Nicolas Thornton, Kazuo Umezawa, Sarah Decker, Meike Burger, Hendrik Veelken, Rainer Claus, Christine Dierks, Justus Duyster, Katja Zirlik
NF-κB is known to play an important role in the pathogenesis of chronic lymphocytic leukemia. Several NF-κB inhibitors have been shown to successfully induce apoptosis of chronic lymphocytic leukemia cells in vitro. Since the microenvironment is known to be crucial for the survival of chronic lymphocytic leukemia cells, we tested here whether NF-κB inhibition may still induce apoptosis in these leukemic cells in the presence of protective stromal interaction. We used the specific NF-κB inhibitor Dehydroxymethylepoxyquinomicin...
November 9, 2017: Haematologica
https://www.readbyqxmd.com/read/29119244/enterovirus-associated-changes-in-blood-transcriptomic-profiles-of-children-with-genetic-susceptibility-to-type-1-diabetes
#10
Niina Lietzen, Le T T An, Maria K Jaakkola, Henna Kallionpää, Sami Oikarinen, Juha Mykkänen, Mikael Knip, Riitta Veijola, Jorma Ilonen, Jorma Toppari, Heikki Hyöty, Riitta Lahesmaa, Laura L Elo
AIMS/HYPOTHESIS: Enterovirus infections have been associated with the development of type 1 diabetes in multiple studies, but little is known about enterovirus-induced responses in children at risk for developing type 1 diabetes. Our aim was to use genome-wide transcriptomics data to characterise enterovirus-associated changes in whole-blood samples from children with genetic susceptibility to type 1 diabetes. METHODS: Longitudinal whole-blood samples (356 samples in total) collected from 28 pairs of children at increased risk for developing type 1 diabetes were screened for the presence of enterovirus RNA...
November 8, 2017: Diabetologia
https://www.readbyqxmd.com/read/29115892/management-of-patients-with-chronic-lymphocytic-leukemia-at-high-risk-of-relapse-on-ibrutinib-therapy
#11
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/29108275/functional-imaging-in-combination-with-mutation-status-aids-prediction-of-response-to-inhibiting-b-cell-receptor-signaling-in-lymphoma
#12
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/29101212/teaching-an-old-pathway-new-tricks-targeting-btk-to-block-nlrp3
#13
Sarah E Henrickson
A proteomics screen identified BTK as a novel inflammasome regulator and demonstrated that blocking BTK can inhibit inflammasome activity.
November 3, 2017: Science Immunology
https://www.readbyqxmd.com/read/29094461/specific-dermatological-benefits-associated-with-quantities-of-lotion-transferred-to-the-skin
#14
Miranda A Farage, Juan Esquerra, Richard Cheng, Stacey Carpenter, Kathryn Bunasky, Denise Gutshall, Ann Lawrence, Andre Messerschmidt
BACKGROUND: A growing number of manufacturers are taking advantage of the ability of absorbent consumer products to deliver lotion to the skin. The lotion is included on these products to help protect the skin from adverse skin effects that can occur, including: 1) irritation, 2) over hydration of the stratum corneum, 3) dryness that can occur from extended exposure to highly absorbent consumer products and 4) changes in pH. OBJECTIVE: This manuscript presents results of a quantitative lotion transfer study of adult incontinence products...
November 2, 2017: Journal of Cosmetic Dermatology
https://www.readbyqxmd.com/read/29082795/treatment-approach-for-elderly-and-unfit-patients-with-chronic-lymphocytic-leukemia
#15
Idanna Innocenti, Francesco Autore, Raffaella Pasquale, Francesca Morelli, Dimitar G Efremov, Luca Laurenti
Elderly patients with chronic lymphocytic leukemia (CLL) or patients with comorbidities are often treated with chlorambucil (Chl) as front-line therapy despite relatively low response rates. The addition of a monoclonal anti-CD20 antibody to Chl substantially increases response rates and prolongs progression-free survival (PFS) in these patients, without increasing toxicity. As a result, the ESMO guidelines recommend that previously untreated CLL patients with relevant co-morbidity, but without TP53 deletion/mutation, should be treated with the combination of Chl plus an anti-CD20 antibody (rituximab, ofatumumab or obinutuzumab)...
October 30, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/29074501/single-agent-ibrutinib-in-relapsed-or-refractory-follicular-lymphoma-a-phase-2-consortium-trial
#16
Nancy L Bartlett, Brian A Costello, Betsy R LaPlant, Stephen M Ansell, John G Kuruvilla, Craig B Reeder, Lim S Thye, Daniel M Anderson, Kilannin Krysiak, Cody Ramirez, Jing Qi, Barry A Siegel, Malachi Griffith, Obi L Griffith, Felicia Gomez, Todd A Fehniger
Most patients with follicular lymphoma experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase inhibitor approved for the treatment of several B-cell malignancies, showed promising activity in follicular lymphoma in a Phase 1 study. We report the results of a Phase 2 trial evaluating ibrutinib in recurrent follicular lymphoma. Forty patients with recurrent follicular lymphoma were treated with ibrutinib, 560 mg/day until progression or intolerance. The primary endpoint was overall response rate...
October 26, 2017: Blood
https://www.readbyqxmd.com/read/29070143/-differential-regulation-of-bruton-s-tyrosine-kinase-by-the-ubiquitin-pathway
#17
Yi-Jia Fang, Yuan-Yuan Hu, Lan-Lan Ling, Yue Chen, Yu-Ye Shi, Li Zhang, Chun-Ling Wang, Liang Yu
OBJECTIVE: To investigate the regulation of Bruton's tyrosine kinase (Btk) and to explore its possible mechanism. METHODS: After treatment with the proteasome inhibitors and/or phorbol esters (PMA), the mRNA and protein expression level of Btk was detected by RT-PCR and Western blot, respectively. The ubiquitination level of Btk in B lymphoblastoid A20 cells was estimated after stimulation via the crosslinking of BCR with anti-IgM antibody. The cotransfection of COS-7 cell with Btk, ubiquitin and Cbl was performed, then the ubiquitination level of Btk was measured...
October 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29069762/cell-lines-generated-from-a-chronic-lymphocytic-leukemia-mouse-model-exhibit-constitutive-btk-and-akt-signaling
#18
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...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29061802/myd88-inhibitor-st2825-suppresses-the-growth-of-lymphoma-and-leukaemia-cells
#19
Erika Shiratori, Mai Itoh, Shuji Tohda
BACKGROUND/AIM: Myeloid differentiation primary response gene 88 (MYD88), which activates the nuclear factor kappa B (NF-κB) pathway, is important for the growth of lymphoma and leukaemia cells. In this study, we investigated the effects of ST2825, a synthetic peptidomimetic compound which inhibits MYD88 homodimerization, on their growth. MATERIALS AND METHODS: Seven lymphoma and leukaemia cell lines including TMD8, a B-cell lymphoma line with MYD88-activating mutation, were treated with ST2825 and analysed for cell proliferation and expression of NF-κB signalling-related molecules...
November 2017: Anticancer Research
https://www.readbyqxmd.com/read/28993409/malt1-inhibition-is-efficacious-in-both-na%C3%A3-ve-and-ibrutinib-resistant-chronic-lymphocytic-leukemia
#20
Nakhle S Saba, Deanna H Wong, Georges Tanios, Jessica R Iyer, Patricia Lobelle-Rich, Eman L Dadashian, Delong Liu, Lorena Fontan, Erik K Flemington, Cydney M Nichols, Chingiz Underbayev, Hana Safah, Ari Melnick, Adrian Wiestner, Sarah E M Herman
The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma...
October 9, 2017: Cancer Research
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