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https://www.readbyqxmd.com/read/28544907/micrornas-that-affect-the-fanconi-anemia-brca-pathway-are-downregulated-in-imatinib-resistant-chronic-myeloid-leukemia-patients-without-detectable-bcr-abl-kinase-domain-mutations
#1
E Yap, Z A Norziha, A Simbun, N R Tumian, S K Cheong, C F Leong, C L Wong
Chronic myeloid leukemia (CML) patients who do not achieve landmark responses following treatment with imatinib mesylate (IM) are considered IM-resistant. Although IM-resistance can be due to BCR-ABL kinase domain (KD) mutations, many IM-resistant patients do not have detectable BCR-ABL KD mutations. MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression. To investigate the role of miRNAs in IM-resistance, we recruited 8 chronic phase CML patients with IM-resistance who tested negative for BCR-ABL KD mutations and 2 healthy normal controls...
May 18, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28544567/chemoproteomics-aided-medicinal-chemistry-for-the-discovery-of-epha2-inhibitors
#2
Stephanie Heinzlmeir, Jonas Lohse, Tobias Treiber, Denis Kudlinzki, Verena Linhard, Santosh Lakshmi Gande, Sridhar Sreeramulu, Krishna Saxena, Xiaofeng Liu, Mathias Wilhelm, Harald Schwalbe, Bernhard Kuster, Guillaume Médard
The receptor tyrosine kinase EPHA2 has gained interest as therapeutic drug target in cancer and infectious diseases. However, EPHA2 research and EPHA2-based therapies have been hampered by the lack of selective small molecule inhibitors. Here, we report on the synthesis and evaluation of dedicated EPHA2 inhibitors based on the clinical BCR-ABL/SRC inhibitor Dasatinib as a lead structure. We designed hybrid structures of Dasatinib and the previously known EPHA2 binders CHEMBL249097, PD-173955 and a known EPHB4 inhibitor in order to exploit both the ATP pocket entrance as well as the ribose pocket as binding epitopes in the kinase EPHA2...
May 24, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28542127/functional-screen-analysis-reveals-mir-3142-as-central-regulator-in-chemoresistance-and-proliferation-through-activation-of-the-pten-akt-pathway-in-cml
#3
Lifen Zhao, Yujia Shan, Bing Liu, Yang Li, Li Jia
Chronic myeloid leukemia (CML) is caused by the constitutively active BCR-ABL tyrosine kinase. Although great progress has been made for improvement in clinical treatment during the past decades, it is common for patients to develop chemotherapy resistance. Therefore, further exploring novel therapeutic strategies are still crucial for improving disease outcome. MicroRNAs (miRNAs) represent a novel class of genes that function as negative regulators of gene expression. Recently, miRNAs have been implicated in several cancers...
May 25, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28539298/-fine-needle-aspiration-cell-pathology-for-diagnosis-of-intrathoracic-extramedullary-hematopoiesis-presenting-as-a-posterior-mediastinal-tumor-a-case-report
#4
Jie Zhou, Tong Zhao, Min Deng
To study the feasibility of in a A patient with extramedullary hematopoiesis presenting as a posterior mediastinal tumor underwent fine-needle aspiration for cell pathology diagnosis. The primary locus of a posterior mediastinal extramedullary hematopoiesis was examined with Papanicolaou staining and HE staining, and the expressions of cytokeratin, epithelial membrane antigen (EMA), terminal deoxynucleotidyl transferase, CD3, CD20, anaplastic lymphoma kinase, CD34, CD235a, myeloperoxidase, CD61, P53, CD30, S-100, CD1a, and Ki-67 with immunohistochemistry...
May 20, 2017: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/28533480/deregulated-expression-of-mir-29a-3p-mir-494-3p-and-mir-660-5p-affects-sensitivity-to-tyrosine-kinase-inhibitors-in-cml-leukemic-stem-cells
#5
Simona Salati, Valentina Salvestrini, Chiara Carretta, Elena Genovese, Sebastiano Rontauroli, Roberta Zini, Chiara Rossi, Samantha Ruberti, Elisa Bianchi, Greta Barbieri, Antonio Curti, Fausto Castagnetti, Gabriele Gugliotta, Gianantonio Rosti, Micaela Bergamaschi, Agostino Tafuri, Enrico Tagliafico, Roberto Lemoli, Rossella Manfredini
The development of Imatinib mesylate (IM), which targets the oncogenic BCR-ABL fusion protein, has greatly improved the outcome of Chronic Myeloid Leukemia (CML) patients. However, BCR-ABL-positive progenitors can be detected in CML patients in complete cytogenetic response. Several evidence suggests that CML stem cells are intrinsically resistant to Tyrosine Kinase Inhibitors (TKI), and therefore they represent the most likely candidate responsible for disease relapse.In this work, we investigated the microRNA (miRNA) expression profile of different subpopulations of CML Leukemic Stem Cells (LSCs): Lin-CD34+CD38- and Lin-CD34-CD38- cells...
May 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28531278/cardiovascular-toxic-effects-of-targeted-cancer-therapy
#6
Kazuko Tajiri, Kazutaka Aonuma, Ikuo Sekine
Over the past decade, there has been a major shift in chemotherapy from non-specific cytotoxic drugs to molecular targeted drug therapies. As more molecular targeted therapies are developed, new types of cardiovascular toxicities induced by targeted therapies are a growing problem. Cardiotoxicity induced by the human epidermal growth factor receptor-2 inhibitor trastuzumab manifests as decreased left ventricular ejection fraction. In contrast to anthracycline treatment, most cardiac events occur during trastuzumab treatment, but are reversed quickly when treatment is interrupted and cardiac intervention is established...
May 20, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28524659/synthesis-molecular-docking-molecular-dynamics-studies-and-biological-evaluation-of-4h-chromone-1-2-3-4-tetrahydropyrimidine-5-carboxylate-derivatives-as-potential-antileukemic-agents
#7
Zahra Dolatkhah, Shahrzad Javanshir, Ahmad Shahir Sadr, Jaber Hosseini, Soroush Sardari
A series of 4H-chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylates derivatives were synthesized via a three component one-pot condensation of chromone-3-carbaldehyde, alkyl acetoacetate, and urea or thiourea, using MCM-41-SO3H as efficient nanocatalysts and evaluated for their anticancer activity using a combined in silico docking and molecular dynamics protocol to estimate the binding affinity of the title compounds with the Bcr-Abl oncogene. Two programs, AutoDock 4 and AutoDock Vina software were applied to dock the target protein with synthesized compounds and ATP...
May 25, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28523104/3-aroyl-1-4-diarylpyrroles-inhibit-chronic-myeloid-leukemia-cell-growth-through-an-interaction-with-tubulin
#8
Giuseppe La Regina, Ruoli Bai, Antonio Coluccia, Valeria Famiglini, Sara Passacantilli, Valentina Naccarato, Giorgio Ortar, Carmela Mazzoccoli, Vitalba Ruggieri, Francesca Agriesti, Claudia Piccoli, Tiziana Tataranni, Marianna Nalli, Andrea Brancale, Stefania Vultaggio, Ciro Mercurio, Mario Varasi, Concetta Saponaro, Sara Sergio, Michele Maffia, Addolorata Maria Luce Coluccia, Ernest Hamel, Romano Silvestri
We designed 3-aroyl-1,4-diarylpyrrole (ARDAP) derivatives as potential anticancer agents having different substituents at the 1- or 4-phenyl ring. ARDAP compounds exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARDAP derivative 10 inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from chronic myeloid leukemia (CML) patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive KBM5-WT or its IM-resistant KBM5-T315I mutation...
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28501737/the-bcr-abl-tyrosine-kinase-inhibitor-nilotinib-stimulates-expression-of-il-1%C3%AE-in-vascular-endothelium-in-association-with-downregulation-of-mir-3p
#9
Masumi Sukegawa, Xiangmin Wang, Chie Nishioka, Bin Pan, Kailin Xu, Hiroshi Ohkawara, Yoichi Hamasaki, Masayuki Mita, Kenichi Nakamura, Masatoshi Okamoto, Hiromi Shimura, Masatsugu Ohta, Takayuki Ikezoe
BCR/ABL tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis for in dividuals with chronic myeloid leukemia (CML). However, many patients treated with TKIs suffer from TKI-related complications. In particular, vascular events such as peripheral artery occlusive disease have become aserious clinical problem for patients who receive the TKI, nilotinib. At present, the molecular mechanisms by which TKIs cause vascular endothelial cell insults remain unknown.This study explored the effects of the TKIs, imatinib, nilotinib and dasatinib, on vascular endothelial cells in vitro, and found that only nilotinib induced expression of interleukin-1β (IL-1β) by vascular endothelial cells...
May 5, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28499923/the-atypical-kinase-riok1-promotes-tumor-growth-and-invasive-behavior
#10
Florian Weinberg, Nadine Reischmann, Lisa Fauth, Sanaz Taromi, Justin Mastroianni, Martin Köhler, Sebastian Halbach, Andrea C Becker, Niantao Deng, Tatjana Schmitz, Franziska Maria Uhl, Nicola Herbener, Bianca Riedel, Fabian Beier, Alexander Swarbrick, Silke Lassmann, Jörn Dengjel, Robert Zeiser, Tilman Brummer
Despite being overexpressed in different tumor entities, RIO kinases are hardly characterized in mammalian cells. We investigated the role of these atypical kinases in different cancer cells. Using isogenic colon-, breast- and lung cancer cell lines, we demonstrate that knockdown of RIOK1, but not of RIOK2 or RIOK3, strongly impairs proliferation and invasiveness in conventional and 3D culture systems. Interestingly, these effects were mainly observed in RAS mutant cancer cells. In contrast, growth of RAS wildtype Caco-2 and Bcr-Abl-driven K562 cells is not affected by RIOK1 knockdown, suggesting a specific requirement for RIOK1 in the context of oncogenic RAS signaling...
April 12, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28497580/the-evaluation-of-the-relevance-of-thrombin-generation-and-procoagulant-activity-in-thrombotic-risk-assessment-in-bcr-abl-negative-myeloproliferative-neoplasm-patients
#11
H Baccouche, M Ben Jemaa, A Chakroun, S Chadi, S Mahjoub, I Sfar, Y Gorgi, N Ben Romdhane
INTRODUCTION: It has been recently suggested that microparticles (MP) play a role in the pathogenesis of thrombotic complications. This study aimed to assess the contribution of procoagulant activity expressed by circulating MP in thrombotic events in MPN patients. METHODS: Seventy-four MPN patients were enrolled in a trans-sectional study. The MP procoagulant activity was measured using two assays: (i) the thrombin generation (TG) assay used in different conditions with the addition of both tissue factor (TF) and phospholipids (PL) and with the addition of TF or PL alone and (ii) the PROCOAG-PPL assay...
May 12, 2017: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/28488190/computational-dissection-of-allosteric-inhibition-of-the-sh2-domain-of-bcr-abl-kinase-by-the-monobody-inhibitor-as25
#12
Mingfei Ji, Guodong Zheng, Xiaolong Li, Zhongqin Zhang, Guanqun Jv, Xiaowei Wang, Jialin Wang
The deregulated breakpoint cluster region (Bcr)-Abelson tyrosine kinase (Abl) fusion protein represents an attractive pharmacological target for the treatment of chronic myeloid leukemia (CML). The high affinity of monobody AS25 was designed to target the Src homology 2 (SH2) domain of Bcr-Abl, leading to allosteric inhibition of Bcr-Abl through formation of protein-protein interactions. An I164E mutation in the SH2 domain disrupts AS25 binding to the SH2 domain of Bcr-Abl. The detailed mechanisms, however, remain to be unresolved...
June 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28484463/immune-effector-recovery-in-chronic-myeloid-leukemia-and-treatment-free-remission
#13
REVIEW
Amy Hughes, Agnes S M Yong
Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28482729/treatment-of-chronic-myeloid-leukemia-assessing-risk-monitoring-response-and-optimizing-outcome
#14
Naranie Shanmuganathan, Devendra Keshaorao Hiwase, David Morrall Ross
Over the past two decades, tyrosine kinase inhibitors have become the foundation of chronic myeloid leukemia (CML) treatment. The choice between imatinib and newer tyrosine kinase inhibitors (TKIs) needs to be balanced against the known toxicity and efficacy data for each drug, the therapeutic goal being to maximize molecular response assessed by BCR-ABL RQ-PCR assay. There is accumulating evidence that the early achievement of molecular targets is a strong predictor of superior long-term outcomes. Early response assessment provides the opportunity to intervene early with the aim of ensuring an optimal response...
May 9, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28469859/drug-interaction-between-tacrolimus-and-nilotinib-in-a-patient-with-chronic-myeloid-leukemia-after-renal-transplant
#15
Takashi Onaka, Naoto Takahashi, Masatomo Miura, Akihito Yonezawa
Nilotinib, a BCR-ABL tyrosine kinase inhibitor, is a known inhibitor of CYP3A4 and could increase the concentration of drugs metabolized by CYP3A4. An immunosuppressive drug for nilotinib-treated patients following transplant should be administered with careful pharmacokinetic monitoring because of its interaction with nilotinib.
May 2017: Clinical Case Reports
https://www.readbyqxmd.com/read/28469513/bcr-abl-v280g-mutation-potential-role-in-imatinib-resistance-first-case-report
#16
Ana P Azevedo, Alice Reichert, Celina Afonso, Maria D Alberca, Purificação Tavares, Fernando Lima
INTRODUCTION: The identification of BCR-ABL expression as the defining leukemogenic event in chronic myeloid leukemia (CML) and the introduction of BCR-ABL tyrosine kinase inhibitors in 2001 have revolutionized disease management, leading to a reduction in mortality rates and accordingly an increase in the estimated prevalence of CML. CASE REPORT: Based on medical records and clinical follow-up, the authors present the case of a Philadelphia chromosome-positive CML patient who developed resistance to imatinib...
2017: Clinical Medicine Insights. Oncology
https://www.readbyqxmd.com/read/28468589/forced-expression-of-wnt-antagonists-sfrp1-and-wif1-sensitizes-chronic-myeloid-leukemia-cells-to-tyrosine-kinase-inhibitors
#17
Melek Pehlivan, Ceyda Caliskan, Zeynep Yuce, Hakkı Ogun Sercan
Chronic myeloid leukemia is a clonal myeloproliferative disorder that arises from the neoplastic transformation of the hematopoietic stem cell, in which the Wnt/β-catenin signaling pathway has been demonstrated to play an important role in disease progression. However, the role of Wnt signaling antagonists in therapy resistance and disease progression has not been fully investigated. We aimed to study the effects of Wnt/β-catenin pathway antagonists-secreted frizzled-related protein 1 and Wnt inhibitory factor 1-on resistance toward tyrosine kinase inhibitors in chronic myeloid leukemia...
May 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28464280/association-between-insurance-status-at-diagnosis-and-overall-survival-in-chronic-myeloid-leukemia-a-population-based-study
#18
Ashley M Perry, Andrew M Brunner, Tao Zou, Kristin L McGregor, Philip C Amrein, Gabriela S Hobbs, Karen K Ballen, Donna S Neuberg, Amir T Fathi
BACKGROUND: Chronic myeloid leukemia (CML) can be treated effectively with tyrosine kinase inhibitor therapy directed at BCR-ABL, but access to care, medication cost, and adherence may be barriers to treatment. This study was designed to determine whether the insurance status at diagnosis influences CML patient outcomes. METHODS: The Surveillance, Epidemiology, and End Results database was used to identify 5784 patients, aged 15 years or older, who were diagnosed with CML between 2007 and 2012 and whose insurance status was documented at diagnosis...
May 2, 2017: Cancer
https://www.readbyqxmd.com/read/28461114/mir-17-92-promotes-leukemogenesis-in-chronic-myeloid-leukemia-via-targeting-a20-and-activation-of-nf-%C3%AE%C2%BAb-signaling
#19
Qinghua Jia, Huiyan Sun, Fengjun Xiao, Yan Sai, Qingfang Li, Xiaoyan Zhang, Shuang Yang, Hengxiang Wang, Hua Wang, Yuefeng Yang, Chu-Tse Wu, Lisheng Wang
miR-17-92 cluster are overexpressed in hematological malignancies including chronic myeloid leukemia (CML). However, their roles and mechanisms that regulate BCR-ABL induced leukemogenesis remain unclear. In this study, we demonstrated that genomic depletion of miR-17-92 inhibited the BCR-ABL induced leukemogenesis by using a mouse model of transplantation of BCR-ABL transduced hematopoietic stem cells. Furthermore, we identified that miR-19b targeted A20 (TNFAIP3). A20 overexpression results in inactivation of NF-κB activity including decrease of phosphorylation of P65 and IκBα, leads to induce apoptosis and inhibit proliferation and cycle in CML CD34 (+) cells...
June 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28458002/in-silico-drug-repurposing-of-fda-approved-drugs-to-predict-new-inhibitors-for-drug-resistant-t315i-mutant-and-wild-type-bcr-abl1-a-virtual-screening-and-molecular-dynamics-study
#20
Farzin Sohraby, Milad Bagheri, Masoud Aliyar, Hassan Aryapour
The BCR-ABL fusion gene is one of the major causes of 95% of Chronic Myeloid Leukemia (CML). While, BCR-ABL protein is currently being used as a major target to treat CML. Although, current FDA-approved drugs such as; Imatinib and Nilotinib have stupendously improved the patients 5-year's survival rates, the drug resistance has dramatically reduced their effects. So, more accurate and effective alternative treatments are crucially needed. To address this issue, we screened the FDA-approved drugs by virtual screening and binding free energy calculations to identify new inhibitors for the wild-type and T315I gatekeeper mutant ABL1...
April 13, 2017: Journal of Molecular Graphics & Modelling
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