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https://www.readbyqxmd.com/read/28631564/indole-3-carbinol-induces-apoptosis-of-chronic-myelogenous-leukemia-cells-through-suppression-of-stat5-and-akt-signaling-pathways
#1
Majid Safa, Leila Jafari, Fatemeh Alikarami, Rima Manafi Shabestari, Ahmad Kazemi
Signal transducer and activator of transcription 5 and Akt pathways, implicated in signaling transduction downstream of BCR-ABL, play critical roles in the pathogenesis of chronic myeloid leukemia. Therefore, idenication of novel compounds that modulate the activity of such pathways could be a new approach in the treatment of chronic myeloid leukemia. Previous studies have demonstrated that indole-3-carbinol inhibits the proliferation and induces apoptosis of various tumor cells. However, its anticancer activity against chronic myeloid leukemia cells and the underlying mechanism remain unclear...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28623130/leukotriene-signaling-via-alox5-and-cysteinyl-leukotriene-receptor-1-is-dispensable-for-in%C3%A2-vitro-growth-of-cd34-cd38-stem-and-progenitor-cells-in-chronic-myeloid-leukemia
#2
Monika Dolinska, Alexandre Piccini, Wan Man Wong, Eleni Gelali, Anne-Sofie Johansson, Johannis Klang, Pingnan Xiao, Elham Yektaei-Karin, Ulla Olsson Strömberg, Satu Mustjoki, Leif Stenke, Marja Ekblom, Hong Qian
Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein in chronic myeloid leukemia (CML) are remarkably effective inducing deep molecular remission in most patients. However, they are less effective to eradicate the leukemic stem cells (LSC), resulting in disease persistence. Therefore, there is great need to develop novel therapeutic strategies to specifically target the LSC. In an experimental mouse CML model system, the leukotriene pathway, and specifically, the expression ALOX5, encoding 5-lipoxygenase (5-LO), has been reported as a critical regulator of the LSC...
June 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28623111/reversal-of-abcb1-mediated-efflux-by-imatinib-and-nilotinib-in-cells-expressing-various-transporter-levels
#3
Petr Mlejnek, Petr Kosztyu, Petr Dolezel, Susan E Bates, Eliska Ruzickova
Recently, it has been suggested that imatinib (IM) and nilotinib (NIL) could be studied beyond their original application, as inhibitors of the drug efflux pump ABCB1 (P-glycoprotein, MDR1). Since the reversal of ABCB1-mediated resistance has never been successfully demonstrated in the clinic, we addressed the question of whether IM and NIL may actually serve as efficient inhibitors of ABCB1. Here we define an efficient inhibitor as a compound that achieves full (90-100%) reversal of drug efflux at a concentration that does not exhibit significant off-target toxicity in vitro...
June 13, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28622336/a-knowledge-based-t2-statistic-to-perform-pathway-analysis-for-quantitative-proteomic-data
#4
En-Yu Lai, Yi-Hau Chen, Kun-Pin Wu
Approaches to identify significant pathways from high-throughput quantitative data have been developed in recent years. Still, the analysis of proteomic data stays difficult because of limited sample size. This limitation also leads to the practice of using a competitive null as common approach; which fundamentally implies genes or proteins as independent units. The independent assumption ignores the associations among biomolecules with similar functions or cellular localization, as well as the interactions among them manifested as changes in expression ratios...
June 16, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28612580/new-genetic-variation-in-bcr-gene-of-major-b3a2-breakpoint-bcr-abl-fusion-gene-in-patients-with-chronic-myelogenous-leukemia-in-yogyakarta-indonesia
#5
Tri Agusti Sholikah, Susanna Hilda Hutajulu, Dewi Sulistyawati, Sumartiningsih Aning, Sri Fatmawati, Anditta Syifarahmah, Kartika Widayati, Johan Kurnianda, Dewi Kartikawati Paramita
Background: Polymorphic bases in several exons of the BCR gene have been found in several studies of the BCR-ABL fusion gene . Most of the polymorphisms do not have any implications for the primary structure of the BCR-ABL protein. Nucleotide changes are often located in the area close to the fusion region, and therefore may influence primer annealing. Our previous work failed to amplify 15 of 200 samples from BCR-ABL positive chronic myelogenous leukemia (CML) patients using multiplex PCR, the standard method to detect BCR-ABL transcripts used in our institution...
May 1, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/28606225/-clinical-characteristics-and-prognostic-analysis-of-children-and-adolescents-over-10-years-of-age-with-acute-lymphoblastic-leukemia
#6
Jun Wu, Ai-Dong Lu, Le-Ping Zhang
OBJECTIVE: To explore the clinical characteristics and prognosis of children and adolescents over 10 years of age with acute lymphoblastic leukemia (ALL). METHODS: A total of 86 newly diagnosed ALL children and adolescents over 10 years of age (62 cases of B-ALL and 24 cases of T-ALL) were enrolled. Clinical characteristics, therapeutic effect and prognostic factors were retrospectively analyzed. Event-free survival (EFS) and overall survival (OS) rates were estimated by the Kaplan-Meier method...
June 2017: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
https://www.readbyqxmd.com/read/28601294/the-c-abl-inhibitor-nilotinib-as-a-potential-therapeutic-agent-for-chronic-cerebellar-ataxia
#7
Woo-Jin Lee, Jangsup Moon, Tae-Joon Kim, Jin-Sun Jun, Han Sang Lee, Young Jin Ryu, Soon-Tae Lee, Keun-Hwa Jung, Kyung-Il Park, Ki-Young Jung, Manho Kim, Sang Kun Lee, Kon Chu
Nilotinib is a potent inhibitor of tyrosine kinase BCR-ABL that penetrates the blood-brain barrier. To evaluate the effect of nilotinib in chronic cerebellar ataxia, twelve patients with chronic cerebellar ataxia nonresponsive to other treatment options (modified Rankin scale [mRS] scores: >2) and received nilotinib therapy (daily doses: 150-300mg) for >4 (range 5-16) weeks were reviewed. At follow-up, improved mRS scores were found in 7/12 (58.3%) patients and favorable mRS scores (≤2) were found in 6/12 (50...
August 15, 2017: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/28599273/targeting-bcr-abl-stem-progenitor-cells-and-bcr-abl-t315i-mutant-cells-by-effective-inhibition-of-the-bcr-abl-tyr177-grb2-complex
#8
Min Chen, Ali G Turhan, Hongxia Ding, Qingcong Lin, Kun Meng, Xiaoyan Jiang
Treatment of BCR-ABL+ human leukemia has been significantly improved by ABL tyrosine kinase inhibitors (TKIs), but they are not curative for most patients and relapses are frequently associated with BCR-ABL mutations, warranting new targets for improved treatments. We have now demonstrated that protein expression of human estrogen receptor alpha 36 (ERα36), an alternative splicing variant of human estrogen receptor alpha 66 (ERα66), is highly increased in TKI-insensitive CD34+ chronic myeloid leukemia (CML) cells and BCR-ABL-T315I mutant cells, and is abnormally localized in plasma membrane and cytoplasm...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28596663/novel-e8a2-bcr-abl-fusion-transcript-in-case-of-a-myeloproliferative-neoplasm
#9
Manoj Kumar Panigrahi, Dushyant Kumar, Anurag Mehta, Moushumi Suryavanshi, Dinesh Bhurani, Kandarpa Kumar Saikia
Main objective of this work was to confirm the occurrence of rare BCR-ABL fusion variant involving the a2 region of the ABL gene and e8 of BCR gene in a patient of Myeloproliferative neoplasm positive for t(9;22) translocation but negative for common major and minor breakpoint cluster regions. A patient with elevated white blood cell count was subjected to classical cytogenetics, FISH as well as RT-PCR testing using commercial kits as well as published primers and in house testing protocol. The translocation event in chromosome 9 and 22 could be successfully detected...
June 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28595903/shc004-221a1-a-novel-tyrosine-kinase-potently-inhibits-t315i-mutant-bcr-abl-in-chronic-myeloid-leukemia
#10
Duowei Wang, Yan Zheng, Jiaying Li, Hongxi Wu, Xianjing Li, Ying Tang, Yang Liu, Jiani Li, Rui Sun, Youli Zhou, Jihong Sun, Yong Yang
Although judicious use of tyrosine kinase inhibitors that target BCR-ABL constitutes an effective strategy for the control of chronic myeloid leukemia (CML), drug resistance is observed due to kinase domain mutations, among which a major one is BCR-ABL(T315I). In this study, we identified SHC004-221A1 as a potent inhibitor of T315I and other BCR-ABL mutants. Biochemical assays demonstrated that SHC004-221A1 has an inhibitory effect on all selected BCR-ABL mutants. In vitro studies showed that SHC004-221A1 inhibited the proliferation of tumor cell lines carrying native and T315I mutant BCR-ABL...
June 5, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28588176/evaluation-of-bcr-abl-gene-rearrangement-among-bangladeshi-chronic-myeloid-leukaemia-patients
#11
T F Dipta, A Datta, A Tarif, M A Mottalib, A M Yunus, M A Muttalib, S Choudhury, M A Islam
Chronic Myeloid Leukaemia (CML) is a clonal myeloproloferative disorder. Presence of molecular translocation t (9; 22) in CML patients can be confirmed by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). Among haematological malignancies CML is the commonest leukaemia of adults in Asia. Despite this, there are very few studies published from Bangladesh, documenting the frequency of bcr-abl fusion transcripts. So, we would like to perform this observational study to evaluate bcr-abl fusion transcripts and demographic status among RT-PCR positive chronic phase CML patients at BIRDEM & other two centers of Dhaka city, Bangladesh where patients admitted from different districts of Bangladesh in the period of January 2010 to June 2012...
April 2017: Mymensingh Medical Journal: MMJ
https://www.readbyqxmd.com/read/28576876/targeting-chronic-myeloid-leukemia-stem-cells-with-the-hypoxia-inducible-factor-inhibitor-acriflavine
#12
Giulia Cheloni, Michele Tanturli, Ignazia Tusa, Ngoc Ho DeSouza, Yi Shan, Antonella Gozzini, Fréderic Mazurier, Elisabetta Rovida, Shaoguang Li, Persio Dello Sbarba
Chronic myeloid leukemia (CML) is a hematopoietic stem cell (HSC)-driven neoplasia characterized by the expression of the constitutively-active tyrosine kinase BCR/Abl. CML therapy based on tyrosine kinase inhibitors (TKi) is highly effective in inducing remission but not in targeting leukemia stem cells (LSC), which sustain minimal residual disease and are responsible for CML relapse following discontinuation of treatment. The identification of molecules capable to target LSC appears therefore of primary importance to aim at CML eradication...
June 2, 2017: Blood
https://www.readbyqxmd.com/read/28573218/effect-of-thai-saraphi-flower-extracts-on-wt1-and-bcr-abl-protein-expression-in-leukemic-cell-lines
#13
Rungkarn Sangkaruk, Methee Rungrojsakul, Singkome Tima, Songyot Anuchapreeda
BACKGROUND: Saraphi (Mammea siamensis) is a Thai traditional herb. In this study, the cytotoxic effects of crude ethanolic and fractional extracts including hexane, ethyl acetate, and methanol fractions from M. siamensis flowers were investigated in order to determine their effect on WT1 expression in Molt4 and K562 cells and Bcr/Abl expression in K562 cells. MATERIALS AND METHODS: The flowers of M. siamensis were extracted using ethanol. The ethanol flower extract was further fractionated with hexane, ethyl acetate, and methanol...
2017: African Journal of Traditional, Complementary, and Alternative Medicines: AJTCAM
https://www.readbyqxmd.com/read/28569734/ablation-of-pi3k-blocks-bcr-abl-leukemogenesis-in-mice-and-a-dual-pi3k-mtor-inhibitor-prevents-expansion-of-human-bcr-abl-leukemia-cells
#14
Michael G Kharas, Matthew R Janes, Vanessa M Scarfone, Michael B Lilly, Zachary A Knight, Kevan M Shokat, David A Fruman
No abstract text is available yet for this article.
June 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28559287/occult-myeloproliferative-neoplasms-not-so-occult-any-more
#15
Dhauna Karam, Veena Iyer, Bharat Agrawal
Non-cirrhotic, non-malignant portal vein thrombosis (PVT) is commonly secondary to inherited or acquired prothrombotic states. However, even after extensive workup, 25% of patients with PVT have no apparent prothrombotic aetiology identified (idiopathic PVT). Inherited conditions include factor V Leiden, PT mutation and protein C/S/AT deficiency. Acquired conditions include APS, PNH and BCR-ABL 1-negative myeloproliferative neoplasms (MPN). BCR-ABL-1 negative MPNs are the most frequent underlying prothrombotic risk factor for PVT (15%-30%)...
May 30, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28557248/ponatinib-induced-widespread-ichthyosiform-eruption
#16
F Derlino, S Barruscotti, P Zappasodi, V Brazzelli, C Vassallo
Ponatinib is a new potent third-generation tyrosine kinase inhibitor (TKI), developed for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukaemia (ALL) resistant to first (imatinib) and second generation (dasatinib and nilotinib) TK-inhibitors. Aimed at wild type and mutant BCR-ABL, ponatinib demonstrates significant anti-leukemic activity and holds much promise in treating other malignancies, including gastrointestinal stromal tumors (GIST)(1;2). This article is protected by copyright...
May 30, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28556926/emergence-of-mplw515-mutation-in-a-patient-with-calr-deletion-evidence-of-secondary-acquisition-of-mpl-mutation-in-the-calr-clone
#17
Nicolas Partouche, Carole Conejero, Quentin Barathon, Julien Moroch, Michel Tulliez, Catherine Cordonnier, Stephane Giraudier
Myeloproliferative neoplasms are characterized by transduction pathway recognized as mutually exclusive molecular abnormalities such as BCR-ABL translocation, JAK2V617F or JAK2 exon 12 mutations, MPL w515, and CALR mutations. However, in some rare cases, associations of such mutations are found in 1 patient. This can be related to 2 pathologies (at least 2 different clones harboring 2 mutations) or associated mutations in 1 clone. We describe here such an association of CALR and MPL mutations in a patient harboring the second mutation in a subclone during the phenotypic evolution of the myeloproliferative neoplasms...
May 29, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28556300/development-of-protein-degradation-inducers-of-oncogenic-bcr-abl-protein-by-conjugation-of-abl-kinase-inhibitors-and-iap-ligands
#18
Norihito Shibata, Naoki Miyamoto, Katsunori Nagai, Kenichiro Shimokawa, Tomoya Sameshima, Nobumichi Ohoka, Takayuki Hattori, Yasuhiro Imaeda, Hiroshi Nara, Nobuo Cho, Mikihiko Naito
Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase such as imatinib and dasatinib exhibit remarkable therapeutic effects, though emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to down-regulate the BCR-ABL protein. We have devised a protein knockdown system by hybrid molecules named SNIPERs (Specific and Non-genetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers), which is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR-ABL protein has been developed recently...
May 26, 2017: Cancer Science
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
#19
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
#20
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 attention as a therapeutic drug target for cancer and infectious diseases. However, EPHA2 research and EPHA2-based therapies have been hampered by the lack of selective small-molecule inhibitors. Herein we report 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...
June 21, 2017: ChemMedChem
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