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https://www.readbyqxmd.com/read/28719608/cholesterol-esterification-inhibition-and-imatinib-treatment-synergistically-inhibit-growth-of-bcr-abl-mutation-independent-resistant-chronic-myelogenous-leukemia
#1
Shovik Bandyopadhyay, Junjie Li, Elie Traer, Jeffrey W Tyner, Amy Zhou, Stephen T Oh, Ji-Xin Cheng
Since the advent of tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, and dasatinib, chronic myelogenous leukemia (CML) prognosis has improved greatly. However, ~30-40% of patients develop resistance to imatinib therapy. Although most resistance is caused by mutations in the BCR-ABL kinase domain, 50-85% of these patients develop resistance in the absence of new mutations. In these cases, targeting other pathways may be needed to regain clinical response. Using label-free Raman spectromicroscopy, we evaluated a number of leukemia cell lines and discovered an aberrant accumulation of cholesteryl ester (CE) in CML, which was found to be a result of BCR-ABL kinase activity...
2017: PloS One
https://www.readbyqxmd.com/read/28715941/moderate-anemia-at-diagnosis-is-an-independent-prognostic-marker-of-the-eutos-sokal-and-hasford-scores-for-survival-and-treatment-response-in-chronic-phase-chronic-myeloid-leukemia-patients-with-frontline-imatinib
#2
Po-Shen Ko, Yuan-Bin Yu, Yao-Chung Liu, Yi-Tsui Wu, Man-Hsin Hung, Jyh-Pyng Gau, Chia-Jen Liu, Liang-Tsai Hsiao, Po-Min Chen, Tzeon-Jye Chiou, Chun-Yu Liu, Jin-Hwang Liu
OBJECTIVES: We aimed to examine the prognostic value of anemia for the diagnosis of chronic myeloid leukemia in the chronic phase (CML-CP) receiving imatinib. METHODS: One hundred fifty-four CML-CP patients were enrolled. The influences of moderate anemia with hemoglobin (Hb) < 10 g/dl, four scoring systems and the early molecular response at three months (BCR-ABL ≤ 10%; 3M-EMR) on the achievement of a deep molecular response (DMR, MR4.5), progression-free survival (PFS), event-free survival (EFS) and overall survival (OS) were compared...
July 18, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28706179/nilotinib-induced-recurrent-gastric-polyps-case-report-and-review-of-literature
#3
Nancy Kassem, Omar M Ismail, Halima Elomri, Mohamad A Yassin
BACKGROUND Tyrosine kinase inhibitors (TKIs) are currently an important targeted drug class in the treatment of chronic myeloid leukemia (CML). Imatinib was the first approved TKI for CML in 2001. Nilotinib is a second-generation TKI, approved in 2007; it inhibits BCR-ABL, PDGFR, and c-KIT, and is 30 times more potent than imatinib. Tyrosine kinase enzymes are expressed in multiple tissues and are involved in several signaling pathways; they have been shown to have several off-target side effects. CASE REPORT We report a case of an elderly male with CML and no history of gastrointestinal diseases, treated with nilotinib, and developed recurrent gastric polyps after three years of treatment...
July 14, 2017: American Journal of Case Reports
https://www.readbyqxmd.com/read/28704165/specific-monoclonal-antibody-against-bcr-abl-out-of-frame-alternative-proteins-as-diagnostic-tool-in-chronic-myelogenous-leukemia-patients
#4
Claudia Casnici, Katia Crotta, Gisella Volpe, Cristina Panuzzo, Donatella Lattuada, Giulia Mesiano, Giuseppe Saglio, Ornella Marelli
More recently, alternative splicing of specific genes are investigated for their therapeutic potential. In particular, we reported the existence of BCR-ABL alternative splicing isoforms, in about 80% of Philadelphia-positive patients, which lead to the expression of aberrant proteins. These fusion proteins are characterized by an orphan initial and correct Bcr portion attached to a 112 amino acid sequence, arising from the impairment in the reading frame (reading of ABL exon 4 and 5). We demonstrated that these Abl-out-of-frame (OOF) isoforms could have an immunological role with therapeutic implications...
July 13, 2017: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
https://www.readbyqxmd.com/read/28702412/megakaryocytic-morphology-in-janus-kinase-2-v617f-positive-myeloproliferative-neoplasm
#5
Shuchi Ghai, Sharada Rai
CONTEXT: Alterations in megakaryocyte morphology are the hallmark of myeloproliferative neoplasms (MPNs). These neoplasm are also associated with Janus kinase 2 (JAK2) V617F mutation in nearly 95% patients with polycythemia vera (PV), 40% patients of essential thrombocythemia (ET) and 50% patients of myelofibrosis (MF). The utility of megakaryocyte morphology in these disorders in correlation with JAK2 V617F remains unresolved. AIMS: The aim of the study was to assess the morphology of megakaryocytes in bone marrow aspirates (BMAs) and bone marrow biopsies of patients of BCR-ABL negative MPNs with JAK2 V617F mutation...
April 2017: South Asian Journal of Cancer
https://www.readbyqxmd.com/read/28698847/evaluation-of-a-new-flow-cytometry-based-method-for-detection-of-bcr-abl1-fusion-protein-in-chronic-myeloid-leukemia
#6
Swati Dasgupta, Ujjal K Ray, Arpita Ghosh Mitra, Deboshree M Bhattacharyya, Ashis Mukhopadhyay, Priyabrata Das, Sudeshna Gangopadhyay, Sudip Roy, Soma Mukhopadhyay
BACKGROUND: Philadelphia chromosome, a hallmark of chronic myeloid leukemia (CML), plays a key role in disease pathogenesis. It reflects a balanced reciprocal translocation between long arms of chromosomes 9 and 22 involving BCR and ABL1 genes, respectively. An accurate and reliable detection of BCR-ABL fusion gene is necessary for the diagnosis and monitoring of CML. Previously, many technologies, most of which are laborious and time consuming, have been developed to detect BCR-ABL chimeric gene or chromosome...
June 2017: Blood Research
https://www.readbyqxmd.com/read/28695168/living-with-the-effects-of-cutaneous-toxicities-induced-by-treatment
#7
REVIEW
Andreas Charalambous
The introduction of targeted therapies in cancer treatment was accompanied with promising results including tumor control and patients survival benefits. However, these drugs just like their predecessors were associated with systemic side effects, including frequent and various cutaneous effects. Targeted therapies such as epidermal growth factor receptor, vascular endothelial growth factor receptor, kit, platelet-derived growth factor receptor, and BCR-ABL inhibitors as well as mammalian target of rapamycin inhibitors can induce cutaneous toxicities of varying severity...
July 2017: Asia-Pacific Journal of Oncology Nursing
https://www.readbyqxmd.com/read/28687223/how-to-prevent-relapse-after-allogeneic-hematopoietic-stem-cell-transplantation-in-patients-with-acute-leukemia-and-myelodysplastic-syndrome
#8
REVIEW
N Yafour, F Beckerich, C E Bulabois, P Chevallier, E Daguindau, C Dumesnil, T Guillaume, A Huynh, S Masouridi Levrat, A L Menard, C Pautas, X Poiré, A Ravinet, M Michallet, A Bazarbachi
Disease relapse remains the first cause of mortality of hematological malignancies after allogeneic hematopoietic stem cell transplantation (allo-HCT). The risk of recurrence is elevated in acute myeloid leukemia (AML) patients with high-risk cytogenetic or molecular abnormalities, as well as when allo-HCT is performed in patients with refractory hematological malignancies or with persistent molecular or radiological (PET-CT scan) residual disease. For high risk AML and myelodysplasia (MDS), a post transplant maintenance strategy is possible, using hypomethylating agents or tyrosine kinase inhibitors (TKI) anti-FLT3 when the target is present...
July 4, 2017: Current Research in Translational Medicine
https://www.readbyqxmd.com/read/28684771/the-src-family-kinase-inhibitor-dasatinib-delays-pain-related-behaviour-and-conserves-bone-in-a-rat-model-of-cancer-induced-bone-pain
#9
Camilla Kristine Appel, Simone Gallego-Pedersen, Line Andersen, Sophie Blancheflor Kristensen, Ming Ding, Sarah Falk, Manasi Sayilekshmy, Charlotte Gabel-Jensen, Anne-Marie Heegaard
Pain is a severe and debilitating complication of metastatic bone cancer. Current analgesics do not provide sufficient pain relief for all patients, creating a great need for new treatment options. The Src kinase, a non-receptor protein tyrosine kinase, is implicated in processes involved in cancer-induced bone pain, including cancer growth, osteoclastic bone degradation and nociceptive signalling. Here we investigate the role of dasatinib, an oral Src kinase family and Bcr-Abl tyrosine kinase inhibitor, in an animal model of cancer-induced bone pain...
July 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28682311/platinum-pyrithione-induces-apoptosis-in-chronic-myeloid-leukemia-cells-resistant-to-imatinib-via-dub-inhibition-dependent-caspase-activation-and-bcr-abl-downregulation
#10
Xiaoying Lan, Chong Zhao, Xin Chen, Peiquan Zhang, Dan Zang, Jinjie Wu, Jinghong Chen, Huidan Long, Li Yang, Hongbiao Huang, Xuejun Wang, Xianping Shi, Jinbao Liu
Chronic myelogenous leukemia (CML) is characterized by the chimeric tyrosine kinase Bcr-Abl. T315I Bcr-Abl is the most notorious point mutation to elicit acquired resistance to imatinib (IM), leading to poor prognosis. Therefore, it is urgent to search for additional approaches and targeting strategies to overcome IM resistance. We recently reported that platinum pyrithione (PtPT) potently inhibits the ubiquitin-proteasome system (UPS) via targeting the 26 S proteasome-associated deubiquitinases (DUBs), without effecting on the 20 S proteasome...
July 6, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28681927/pathological-role-of-a-point-mutation-t315i-in-bcr-abl1-protein-a-computational-insight
#11
Vidya Rajendran, Chandrasekhar Gopalakrishnan, Rao Sethumadhavan
BCR-ABL protein is one of the most potent target to treat chronic myeloid leukemia (CML). Apart from other mutations, T315I is especially challenging as it confers resistance to all first- and second-generation tyrosine kinase inhibitors. So, a thorough study of altered behaviour upon mutation is crucially needed. To understand the resistance mechanism of mutant BCR-ABL protein, we organized a long-term molecular dynamics simulation (500 ns) and performed the detailed comparative conformational analysis. We found that due to mutation at 315(th) position (threonine to isoleucine), original structures deviated from normal and attained a flexible conformation...
July 6, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28678742/chronic-myeloid-leukemia-progenitor-cells-require-autophagy-when-leaving-hypoxia-induced-quiescence
#12
Angela Ianniciello, Amélie Guitart, Pierre-Yves Dumas, Claire Drullion, Arnaud Villacreces, Yan Peytour, Jean Chevaleyre, Philippe Brunet de la Grange, Isabelle Vigon, Vanessa Desplat, Muriel Priault, Persio Dello Sbarba, Zoran Ivanovic, François-Xavier Mahon, Jean-Max Pasquet
Albeit tyrosine kinase inhibitors anti-Abl used in Chronic Myeloid Leukemia (CML) block the deregulated activity of the Bcr-Abl tyrosine kinase and induce remission in 90% of patients, they do not eradicate immature hematopoietic compartments of leukemic stem cells. To elucidate if autophagy is important for stem cell survival and/or proliferation, we used culture in low oxygen concentration (0.1% O2 for 7 days) followed back by non-restricted O2 supply (normoxic culture) to mimic stem cell proliferation and commitment...
June 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28673389/tyrosine-kinase-inhibitor-treatment-for-newly-diagnosed-chronic-myeloid-leukemia
#13
REVIEW
Jerald P Radich, Michael J Mauro
Chronic myeloid leukemia (CML) is a myeloproliferative disorder that accounts for approximately 10% of new cases of leukemia. The introduction of tyrosine kinase inhibitors has led to a reduction in mortalities. Thus, the estimated prevalence of CML is increasing. The National Comprehensive Cancer Network and the European Leukemia Net guidelines incorporate frequent molecular monitoring of the fusion BCR-ABL transcript to ensure that patients reach and keep treatment milestones. Most patients with CML are diagnosed in the chronic phase, and approximately 10% to 30% of these patients will at some time in their course meet definition criteria of resistance to imatinib...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28673388/targeting-aberrant-signaling-in-myeloid-malignancies-promise-versus-reality
#14
REVIEW
Rob Sellar, Julie-Aurore Losman
Clonal myeloid disorders are characterized by genetic alterations that activate cytokine signaling pathways and stimulate cell proliferation. These activated signaling pathways have been extensively studied as potential therapeutic targets, and tyrosine kinase inhibitors have indeed had extraordinary success in treating BCR/ABL-positive chronic myeloiud leukemia. However, although inhibitors of other activated kinases have been developed that perform well in preclinical studies, the therapeutic efficacy of these drugs in patients has been unimpressive...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28669127/ensemble-based-virtual-screening-identification-of-a-potential-allosteric-inhibitor-of-bcr-abl
#15
Vivek Kumar Singh, Mohane Selvaraj Coumar
Ensemble-based virtual screening using different conformations of a target protein is gaining popularity, as it can leverage information from target flexibility for effective lead identification. In this paper, molecular dynamics simulation followed by RMSD-based clustering was employed to generate and choose distinct conformations of Bcr-Abl. Three representative structures from the most-populated clusters along with the crystal structure conformation (PDBID: 3K5V) were used to perform docking-based virtual screening of 14,400 compounds (in the Maybridge database) in order to identify potential allosteric site binders...
July 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28657677/effects-of-pimozide-derivatives-on-pstat5-in-k562-cells
#16
Riccardo Rondanin, Daniele Simoni, Martina Maccesi, Romeo Romagnoli, Stefania Grimaudo, Rosaria Maria Pipitone, Maria Meli, Antonio Cascio, Manlio Tolomeo
STAT5 is a transcription factor, component of the STAT family of signalling proteins. STAT-5 is involved in many types of cancer, including chronic myelogenous leukemia (CML), where this protein is found constitutively activated as a consequence of the BCR-ABL expression. Recently, literature has reported that neuroleptic drug pimozide can act as inhibitor of STAT5 phosphorylation and is capable to induce apoptosis in CML cells in vitro. Our group has synthesized simple derivatives of pimozide, with cytotoxic activity and able to reduce the levels of phosphorylated STAT5...
June 28, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28654842/haploidentical-hematopoietic-stem-cell-transplantation-for-pediatric-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-in-the-imatinib-era
#17
Huan Chen, Kai-Yan Liu, Lan-Ping Xu, Yu-Hong Chen, Xiao-Hui Zhang, Yu Wang, Ya-Zhen Qin, Yan-Rong Liu, Yue-Yun Lai, Xiao-Jun Huang
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains an important curative option for children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who have a poor response to chemotherapy plus imatinib. For such children, if there are no matched related or unrelated donors, alternative donor transplantation may be a choice. The role of haploidentical donor (HID) HSCT in pediatric patients with Ph+ ALL has not been reported. The study population included pediatric patients with Ph+ ALL who underwent HID-HSCT...
June 1, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28652370/small-mitochondrial-arf-smarf-protein-corrects-p53-independent-developmental-defects-of-arf-tumor-suppressor-deficient-mice
#18
Jolieke G van Oosterwijk, Chunliang Li, Xue Yang, Joseph T Opferman, Charles J Sherr
The mouse p19(Arf) (human p14(ARF)) tumor suppressor protein, encoded in part from an alternative reading frame of the Ink4a (Cdkn2a) gene, inhibits the Mdm2 E3 ubiquitin ligase to activate p53. Arf is not expressed in most normal tissues of young mice but is induced by high thresholds of aberrant hyperproliferative signals, thereby activating p53 in incipient tumor cells that have experienced oncogene activation. The single Arf mRNA encodes two distinct polypeptides, including full-length p19(Arf) and N-terminally truncated and unstable p15(smArf) ("small mitochondrial Arf") initiated from an internal in-frame AUG codon specifying methionine-45...
June 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28641626/-clinical-significance-of-minimal-residual-disease-in-risk-stratification-and-prognosis-of-childhood-b-lineage-acute-lymphoblastic-leukemia
#19
Fen-Yan An, Shu-Hong Zhang, Ling-Jun Kong, Ying Liang, Ji-Xin Xu, Hai-Long He, Yi-Huai Chai, Wen-Li Zhao
OBJECTIVE: To explore clinical significance of monitoring the level of minimal residual disease (MRD) at different time point in the risk stratification and prognosis of Childhood B-lineage Acute Lymphoblastic Leukemia. METHODS: Three hundred and eighty cases of children's B-ALL from Augest 2008 to January 2013 in our hospital were enrolled in this study. MRD levels were detected at day 15, day 33 and week 12 after initial chemotherapy. The event-free survival(EFS) and overall survival (OS) were measured on the basis of MRD levels at different stages of chemotherapy and were compared by Kaplan Meier analyses...
June 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28639894/deregulated-expression-of-cdc6-as-bcr-abl-dependent-survival-factor-in-chronic-myeloid-leukemia-cells
#20
Jia-Hua Zhang, Yan-Li He, Rui Zhu, Wen Du, Jun-Hua Xiao
Chronic myeloid leukemia is characterized by the presence of the reciprocal translocation t(9;22) and the BCR/ABL oncogene. The BCR/ABL oncogene activates multiple signaling pathways and involves the dysregulation of oncogenes during the progression of chronic myeloid leukemia. The cell division cycle protein 6, an essential regulator of DNA replication, is elevated in some human cancer cells. However, the expression of cell division cycle protein 6 in chronic myeloid leukemia and the underlying regulatory mechanism remain to be elucidated...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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