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https://www.readbyqxmd.com/read/29768934/a-safety-profile-of-medications-used-to-treat-waldenstr%C3%A3-m-s-macroglobulinemia
#1
Ramón García-Sanz, Cristina Jiménez, Verónica González de la Calle, María Eugenia Sarasquete
Waldenström's macroglobulinemia (WM) is a B-cell lymphoproliferative disease with serum IgM monoclonal component and bone marrow infiltration by lymphoplasmacytic lymphoma. Traditional therapy was based on that regimens used for closely related entities, such as chronic lymphocytic leukemia or multiple myeloma. This resulted in a lack of drugs specifically approved for WM, until the discovery of the BTK inhibitors. Areas covered. Two main therapeutic attitudes are possible: 1) conventional therapies based on combinations with alkylating agents or proteasome inhibitors with steroids and anti-CD20 monoclonal antibodies, or; 2) new approaches with BTK inhibitors, usually alone...
May 17, 2018: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/29750146/sensitive-detection-of-the-natural-killer-cell-mediated-cytotoxicity-of-anti-cd20-antibodies-and-its-impairment-by-b-cell-receptor-pathway-inhibitors
#2
Floyd Hassenrück, Eva Knödgen, Elisa Göckeritz, Safi Hasan Midda, Verena Vondey, Lars Neumann, Sylvia Herter, Christian Klein, Michael Hallek, Günter Krause
The antibody-dependent cell-mediated cytotoxicity (ADCC) of the anti-CD20 monoclonal antibodies (mAbs) rituximab and obinutuzumab against the cell line Raji and isolated CLL cells and its potential impairment by kinase inhibitors (KI) was determined via lactate dehydrogenase release or calcein retention, respectively, using genetically modified NK92 cells expressing CD16-176V as effector cells. Compared to peripheral blood mononuclear cells, recombinant effector cell lines showed substantial alloreactivity-related cytotoxicity without addition of mAbs but afforded determination of ADCC with reduced interassay variability...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29743179/a-cd19-cd3-bispecific-antibody-for-effective-immunotherapy-of-chronic-lymphocytic-leukemia-in-the-ibrutinib-era
#3
Hannah R Robinson, Junpeng Qi, Erika M Cook, Cydney Nichols, Eman L Dadashian, Chingiz Underbayev, Sarah E M Herman, Nakhle S Saba, Keyvan Keyvanfar, Clare Sun, Inhye E Ahn, Sivasubramanian Baskar, Christoph Rader, Adrian Wiestner
The Bruton's tyrosine kinase inhibitor ibrutinib induces high rates of clinical response in chronic lymphocytic leukemia (CLL). However, there remains a need for adjunct treatments to deepen response and to overcome drug resistance. Blinatumomab, a CD19/CD3 bispecific antibody (bsAb) designed in the BiTE® format, is FDA approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Due to its short half-life of 2.1 hours, blinatumomab requires continuous intravenous dosing for efficacy...
May 9, 2018: Blood
https://www.readbyqxmd.com/read/29742076/update-on-hairy-cell-leukemia
#4
Robert J Kreitman, Evgeny Arons
Hairy cell leukemia (HCL) is a chronic B-cell malignancy with multiple treatment options, including several that are investigational. Patients present with pancytopenia and splenomegaly, owing to the infiltration of leukemic cells expressing CD22, CD25, CD20, CD103, tartrate-resistant acid phosphatase (TRAP), annexin A1 (ANXA1), and the BRAF V600E mutation. A variant lacking CD25, ANXA1, TRAP, and the BRAF V600E mutation, called HCLv, is more aggressive and is classified as a separate disease. A molecularly defined variant expressing unmutated immunoglobulin heavy variable 4-34 (IGHV4-34) is also aggressive, lacks the BRAF V600E mutation, and has a phenotype of HCL or HCLv...
March 2018: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/29741794/targeting-bruton-s-tyrosine-kinase-for-the-treatment-of-b-cell-associated-malignancies-and-autoimmune-diseases-preclinical-and-clinical-developments-of-small-molecule-inhibitors
#5
Zhen Zhang, Daoguang Zhang, Yang Liu, Dezhi Yang, Fansheng Ran, Michael L Wang, Guisen Zhao
B cell receptor (BCR) signaling plays a key role in B cell development and function. Aberrant BCR signaling has been confirmed as a central driver for the pathogenesis of various B cell malignancies. Bruton's tyrosine kinase (BTK) is a vital component of BCR signaling and exhibits overexpression in various B cell leukemias and lymphomas. Inhibiting BTK has been proved as an efficient way for B cell malignancy intervention. Remarkable achievements have been made in the pursuit of selective BTK inhibitors, represented by the success of the irreversible BTK inhibitors, ibrutinib and acalabrutinib...
May 9, 2018: Archiv der Pharmazie
https://www.readbyqxmd.com/read/29737219/use-of-acalabrutinib-in-patients-with-mantle-cell-lymphoma
#6
Farrukh T Awan, Wojciech Jurczak
Acalabrutinib, a selective, Bruton tyrosine kinase (BTK) inhibitor, was granted accelerated approval by the FDA on 31 October 2017 for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Areas covered: This narrative review provides an overview of acalabrutinib, its use in clinical practice and potential future developments. Expert commentary: BTK inhibitors have demonstrated efficacy in patients with relapsed or refractory MCL. To prepare patients for therapy, all preexisting infections should be diagnosed and treated, and infection prophylaxis undertaken...
May 8, 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29736687/cyclooxygenase-and-lipoxygenase-gene-expression-in-the-inflammogenesis-of-breast-cancer
#7
Brian M Kennedy, Randall E Harris
We examined the expression of major inflammatory genes, cyclooxygenase-1 and 2 (COX1, COX2) and arachidonate 5-lipoxygenase (ALOX5) in 1090 tumor samples of invasive breast cancer from The Cancer Genome Atlas (TCGA). Mean cyclooxygenase expression (COX1 + COX2) ranked in the upper 99th percentile of all 20,531 genes and surprisingly, the mean expression of COX1 was more than tenfold higher than COX2. Highly significant correlations were observed between COX2 with eight tumor-promoting genes (EGR2, IL6, RGS2, B3GNT5, SGK1, SLC2A3, SFRP1 and ETS2) and between ALOX5 and ten tumor promoter genes (CD33, MYOF1, NLRP1, GAB3, CD4, IFR8, CYTH4, BTK, FGR, CD37)...
May 7, 2018: Inflammopharmacology
https://www.readbyqxmd.com/read/29735551/novel-richter-s-syndrome-xenograft-models-to-study-genetic-architecture-biology-and-therapy-responses
#8
Tiziana Vaisitti, Esteban Braggio, John N Allan, Francesca Arruga, Sara Serra, Alberto Zamò, Wayne Tam, Amy Chadburn, Richard R Furman, Silvia Deaglio
Richter's syndrome (RS) represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemo-immunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft models of RS, RS9737 and RS1316. RS xenografts were genetically, morphologically and phenotypically stable and similar to the corresponding primary tumor...
May 7, 2018: Cancer Research
https://www.readbyqxmd.com/read/29725548/a-case-report-of-nongerminal-center-b-cell-type-diffuse-large-b-cell-lymphoma-treated-to-complete-response-with-rituximab-and-ibrutinib
#9
Geoffrey Shouse, Miemie Thinn
Diffuse large B-cell lymphoma (DLBCL) is a molecularly heterogeneous disease consisting of different subtypes with varying clinical behaviors. For example, the activated B-cell-like (ABC) type of DLBCL has lower cure rates with traditional chemotherapy regimens. The molecular pathway promoting tumorigenic growth of the ABC type includes a dependence on intracellular signaling by Bruton's agammaglobulinemia tyrosine kinase (BTK). This specific pathway has led to the investigation of the utility of ibrutinib in treatment of this type of lymphoma at relapse or in combination with standard chemotherapy...
2018: Case Reports in Hematology
https://www.readbyqxmd.com/read/29721381/foxo1-promotes-resistance-of-non-hodgkin-lymphomas-to-anti-cd20-based-therapy
#10
Beata Pyrzynska, Michal Dwojak, Abdessamad Zerrouqi, Giulia Morlino, Piotr Zapala, Nina Miazek, Agnieszka Zagozdzon, Kamil Bojarczuk, Malgorzata Bobrowicz, Marta Siernicka, Marcin M Machnicki, Stefania Gobessi, Joanna Barankiewicz, Ewa Lech-Maranda, Dimitar G Efremov, Przemyslaw Juszczynski, Dinis Calado, Jakub Golab, Magdalena Winiarska
Diminished overall survival rate of non-Hodgkin lymphoma (NHL) patients treated with a combination regimen of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has been recently linked to recurrent somatic mutations activating FOXO1. Despite of the clinical relevance of this finding, the molecular mechanism driving resistance to R-CHOP therapy remains largely unknown. Herein, we investigated the potential role of FOXO1 in the therapeutic efficacy of rituximab, the only targeted therapy included in the R-CHOP regimen...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29717662/the-role-of-bruton-s-tyrosine-kinase-in-immune-cell-signaling-and-systemic-autoimmunity
#11
Jasper Rip, Esmee K Van Der Ploeg, Rudi W Hendriks, Odilia B J Corneth
Bruton's tyrosine kinase (BTK) is an intracellular signaling molecule first identified as the molecule affected in X-linked agammaglobulinemia (XLA) patients, who almost completely lack peripheral B cells and serum immunoglobulins. BTK is crucial for B cell development and various B cell functions, including cytokine and natural antibody production. Importantly, it is also expressed in numerous other cells, including monocytes, macrophages, granulocytes, dendritic cells, and osteoclasts. A few rare cases of autoimmune disease in XLA patients have been described...
2018: Critical Reviews in Immunology
https://www.readbyqxmd.com/read/29715023/discovery-of-4-7-diamino-5-4-phenoxyphenyl-6-methylene-pyrimido-5-4-b-pyrrolizines-as-novel-bruton-s-tyrosine-kinase-btk-inhibitors
#12
Yu Xue, Peiran Song, Zilan Song, Aoli Wang, Linjiang Tong, Mei-Yu Geng, Jian Ding, Qingsong Liu, Liping Sun, Hua Xie, Ao Zhang
An alternative medicinal chemistry approach was conducted on BTK inhibitor 1 (ibrutinib) by merging the pyrazolo[3,4-d]pyrimidine component into a tricyclic skeleton. Two types of compounds were prepared, and their biochemical activities on BTK as well as stereochemistry effects were determined. Structural optimization focusing on the reactive binding group to BTK Cys481 and on the metabolic site guided by metabolic study were conducted. 7S was identified as the most potent showing an IC50 value of 0.4 nM against BTK and 16 nM against BTK-dependent TMD8 cells...
May 1, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29709555/genetic-screening-of-male-patients-with-primary-hypogammaglobulinemia-can-guide-diagnosis-and-clinical-management
#13
Nicolas Vince, Gaël Mouillot, Marion Malphettes, Sophie Limou, David Boutboul, Angélique Guignet, Véronique Bertrand, Philippe Pellet, Pierre-Antoine Gourraud, Patrice Debré, Eric Oksenhendler, Ioannis Théodorou, Claire Fieschi
The precise diagnosis of an immunodeficiency is sometimes difficult to assess, especially due to the large spectrum of phenotypic variation reported among patients. Common variable immunodeficiency disorders (CVID) do not have, for a large part, an identified genetic cause. The identification of a causal genetic mutation is important to confirm, or in some cases correct, the diagnosis. We screened >150 male patients with hypogammaglobulinemia for mutations in three genes involved in pediatric X-linked primary immunoglobulin deficiency: CD40LG, SH2D1A and BTK...
April 27, 2018: Human Immunology
https://www.readbyqxmd.com/read/29699458/pancreatic-effects-of-a-bruton-s-tyrosine-kinase-small-molecule-inhibitor-in-rats-are-strain-dependent
#14
Manoj Bhaskaran, Paul D Cornwell, Steven D Sorden, Michael R Elwell, Natalie R Russell, Michael L Pritt, John L Vahle
Inhibitors of Bruton's tyrosine kinase (BTK) are under development as potential therapies for various autoimmune diseases. In repeat-dose toxicity studies, small-molecule BTK inhibitors (BTKi) have been reported to cause a constellation of histologic effects at the pancreatic endocrine-exocrine interface in male rats; however, similar findings were not reported in other species. Since the BTKi-induced pancreatic effect is morphologically similar to well-documented spontaneous changes (predominantly characterized by insular/peri-insular hemorrhage, pigment deposition, chronic inflammation, and fibrosis) that are known to vary by rat strain, we investigated potential strain-dependent differences in the pancreatic effects of a small-molecule BTKi, LY3337641...
January 1, 2018: Toxicologic Pathology
https://www.readbyqxmd.com/read/29690649/responses-to-the-selective-bruton-s-tyrosine-kinase-btk-inhibitor-tirabrutinib-ono-gs-4059-in-diffuse-large-b-cell-lymphoma-cell-lines
#15
Ryohei Kozaki, Meike Vogler, Harriet S Walter, Sandrine Jayne, David Dinsdale, Reiner Siebert, Martin J S Dyer, Toshio Yoshizawa
Bruton's tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines...
April 23, 2018: Cancers
https://www.readbyqxmd.com/read/29690619/erythropoietin-intensifies-the-proapoptotic-activity-of-lfm-a13-in-cells-and-in-a-mouse-model-of-colorectal-cancer
#16
Anna Tankiewicz-Kwedlo, Justyna Magdalena Hermanowicz, Krystyna Pawlak, Robert Czarnomysy, Krzysztof Bielawski, Izabela Prokop, Dariusz Pawlak
The Bruton’s tyrosine kinase (BTK) inhibitor LFM-A13 has been widely employed as an antileukemic agent, but applications in solid cancer have been found recently. The compound promotes apoptosis, has an antiproliferative effect, and increases cancer cell sensitivity to chemotherapy drugs. We decided to assess the impact of the simultaneous use of erythropoietin (Epo) and LFM-A13 on signal transduction in colon DLD-1 and HT-29 cells, as well as in tumor xenografts. The induction of apoptosis by Epo and LFM-A-13 in the cells was confirmed by phosphatidylserine externalization, loss of mitochondrial membrane potential, and modulation of the expression of apoptotic protein BAX and antiapoptotic protein BCL-2 in colon adenocarcinoma cells...
April 23, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29688737/endovascular-procedures-in-treatment-of-infrapopliteal-arterial-occlusive-disease-single-center-experience-with-69-infrapopliteal-procedures
#17
Pasternak J Janko, Budakov B Nebojsa, Petres V Andrej
BACKGROUND: Peripheral arterial occlusive disease (PAD) includes acute and chronic disorders of the blood supply as a result of obstruction of blood flow in the arteries of the limb. Treatment of PAD can be conservative, surgical and endovascular. Percutaneous transluminal angioplasty with or without stenting has become a recognized method, which is increasingly used in treatment of arterial occlusive disease. This study aimed to determine early results of endovascular treatment of critical limb ischemia (CLI) patients with infrapopliteal lesions...
March 1, 2018: Archives of Iranian Medicine
https://www.readbyqxmd.com/read/29671827/molecular-modeling-studies-on-carbazole-carboxamide-based-btk-inhibitors-using-docking-and-structure-based-3d-qsar
#18
Rui Li, Yongli Du, Zhipei Gao, Jingkang Shen
Rheumatoid arthritis (RA) is the second common rheumatic immune disease with chronic, invasive inflammatory characteristics. Non-steroidal anti-inflammatory drugs (NSAIDs), slow-acting anti-rheumatic drugs (SAARDs), or glucocorticoid drugs can improve RA patients’ symptoms, but fail to cure. Broton’s tyrosine kinase (BTK) inhibitors have been proven to be an efficacious target against autoimmune indications and B-cell malignancies. Among the current 11 clinical drugs, only BMS-986142, classified as a carbazole derivative, is used for treating RA...
April 19, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29669753/pilot-trial-of-ibrutinib-in-patients-with-relapsed-or-refractory-t-cell-lymphoma
#19
Anita Kumar, Santosha Vardhana, Alison J Moskowitz, Pierluigi Porcu, Ahmet Dogan, Jason A Dubovsky, Matthew J Matasar, Zhigang Zhang, Anas Younes, Steven M Horwitz
Ibrutinib has previously been shown to inhibit Bruton's tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK), which mediate B-cell and T-cell receptor signaling, respectively. BTK inhibition with ibrutinib has demonstrated impressive clinical responses in a variety of B-cell malignancies. Whether ibrutinib inhibition of ITK can lead to clinical response in T-cell malignancies is unknown. We hypothesized that ibrutinib-mediated ITK inhibition in T-cell lymphoma would result in decreased signaling through the T-cell receptor pathway and promote antitumor immune response by driving selective cytotoxic Th1 CD4 effector T-cell differentiation...
April 24, 2018: Blood Advances
https://www.readbyqxmd.com/read/29658452/-clinical-features-and-gene-mutations-of-primary-immunodeficiency-disease-an-analysis-of-7-cases
#20
Jun-Chao Wang, Xiao-Xue Liu
This research investigated the clinical features of immunodeficiency disease and the features of the mutation of its pathogenic genes. All 7 patients were boys aged 5 months to 4 years and 6 months and had a history of recurrent respiratory infection and pneumonia, low levels of IgM and IgG, and abnormal absolute values or percentages of lymphocyte subsets. High-throughput sequencing showed c.1684C>T mutations in the BTK gene in patient 1 and IVS8+2T>C splice site mutations in the BTK gene in patient 2...
April 2018: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
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