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TKI CML

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https://www.readbyqxmd.com/read/28103766/long-term-exposure-to-imatinib-mesylate-downregulates-hippo-pathway-and-activates-yap-in-a-model-of-chronic-myelogenous-leukemia
#1
Anna Chorzalska, Javier Flores Kim, Karim Roder, Alexander Tepper, Nagib Ahsan, R Shyama Prasad Rao, Adam J Olszewski, Xiaoqing Yu, Dmitry Terentyev, John Morgan, Diana O Treaba, Ting Zhao, Olin Liang, Philip Gruppuso, Patrycja Dubielecka
Despite the success of tyrosine kinase inhibitor (TKI) therapy in chronic myelogenous leukemia (CML), leukemic stem/progenitor cells remain detectable even in the state of deep molecular remission. Mechanisms that allow them to persist despite continued kinase inhibition remain unclear. We have previously shown that prolonged exposure to imatinib mesylate results in dysregulation of Akt/Erk 1/2 signaling, upregulation of miR-181a, enhanced adhesiveness, and resistance to high imatinib mesylate. In order to characterize the molecular basis and reversibility of those effects, we applied gene and protein expression analysis, quantitative phosphoproteomic, and direct miR-181a inhibition to our cellular model of CML cells subjected to prolonged exposure to imatinib mesylate...
January 19, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28099274/can-any-patients-with-chronic-myeloid-leukemia-outside-of-a-clinical-trial-have-their-tyrosine-kinase-inhibitor-discontinued
#2
Michael J Mauro
PURPOSE OF REVIEW: This article critically appraises the state of treatment-free remission as a strategy for patients with chronic myeloid leukemia (CML) in deep remission after therapy with tyrosine kinase inhibitors (TKIs). RECENT FINDINGS: Approximately half of patients with CML defined fairly narrowly by trial criteria - TKI sensitive, in deep molecular remission for a defined period - can successfully maintain protective levels of response after TKI cessation...
January 17, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28079885/mirna182-regulates-percentage-of-myeloid-and-erythroid-cells-in-chronic-myeloid-leukemia
#3
Deepak Arya, Sasikala P Sachithanandan, Cecil Ross, Dasaradhi Palakodeti, Shang Li, Sudhir Krishna
The deregulation of lineage control programs is often associated with the progression of haematological malignancies. The molecular regulators of lineage choices in the context of tyrosine kinase inhibitor (TKI) resistance remain poorly understood in chronic myeloid leukemia (CML). To find a potential molecular regulator contributing to lineage distribution and TKI resistance, we undertook an RNA-sequencing approach for identifying microRNAs (miRNAs). Following an unbiased screen, elevated miRNA182-5p levels were detected in Bcr-Abl-inhibited K562 cells (CML blast crisis cell line) and in a panel of CML patients...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28074067/expression-of-the-ctla-4-ligand-cd86-on-plasmacytoid-dendritic-cells-pdc-predicts-risk-of-disease-recurrence-after-treatment-discontinuation-in-cml
#4
C Schütz, S Inselmann, S Sausslele, C T Dietz, M C Müller, E Eigendorff, C A Brendel, S K Metzelder, T H Brümmendorf, C Waller, J Dengler, M E Goebeler, R Herbst, G Freunek, S Hanzel, T Illmer, Y Wang, T Lange, F Finkernagel, R Hehlmann, M Huber, A Neubauer, A Hochhaus, J Guilhot, F X Mahon, M Pfirrmann, A Burchert
It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86(+)pDC frequencies than normal donors (P<0·0024), whereas TFR patients had consistently low CD86(+)pDC (n=12)...
January 11, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28052354/evaluation-of-long-term-chronic-myeloid-leukemia-treatment-practices-with-tyrosine-kinase-inhibitors-in-a-national-cohort-of-veterans
#5
Eugene D Kreys, Christopher R Frei, Sarah M Villarreal, Mary J Bollinger, Xavier Jones, Jim M Koeller
STUDY OBJECTIVE: To evaluate nationwide chronic myeloid leukemia treatment practices over an extended period and across multiple lines of tyrosine kinase inhibitor (TKI) therapy with imatinib, dasatinib, and nilotinib. DESIGN: Retrospective cohort study. DATA SOURCE: Veterans Health Administration (VHA) national database. PATIENTS: A total of 2,873 VHA beneficiaries aged 18-89 years who had at least one encounter at any of the approximately 150 VHA hospitals and 800 VHA clinics, had a diagnosis code for chronic myeloid leukemia, and filled at least one prescription for imatinib, nilotinib, or dasatinib between October 1, 2001, and September 30, 2010...
January 4, 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28049640/cml-patients-with-deep-molecular-responses-to-tki-have-restored-immune-effectors-decreased-pd-1-and-immune-suppressors
#6
Amy Hughes, Jade Clarson, Carine Tang, Ljiljana Vidovic, Deborah L White, Timothy P Hughes, Agnes S M Yong
Immunological control may contribute to achievement of deep molecular response in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitor (TKI) therapy and may promote treatment free remission (TFR). We investigated effector and suppressor immune responses in CML patients at diagnosis (n=21), on TKI (imatinib, nilotinib, dasatinib) prior to achieving major molecular response (pre-MMR, BCR-ABL1 >0.1%, n=8), MMR (BCR-ABL1 ≤0.1%, n=20), molecular response(4.5) (MR(4.5), BCR-ABL1 ≤0.0032%, n=16) and sustained TFR (BCR-ABL1 undetectable following cessation of TKI therapy, n=13)...
January 3, 2017: Blood
https://www.readbyqxmd.com/read/28024517/-role-of-bone-marrow-mesenchymal-stem-cells-in-resistance-of-chronic-myeloid-leukemia-to-tyrosine-kinase-inhibitors-review
#7
Xiao-Yan Zhang, Qian Wan, Li-Jun Fang, Jian Li
Chronic myeloid leukemia (CML) is a disease originated from malignant hematopoietic stem cell disorder. In CML, mesenchymal stem cells(MSC) have been changed in the bone marrow microenvironment, which can protect the leukemia cells from apoptosis induced by tyrosine kinase inhibitors (TKI) and lead to the resistance to TKI by the secretion of soluble factors, involvement in cell-cell adhesion, and so on. This review mainly focuses on the changes of the bone marrow mesenchymal stem cells in CML, as well as the role and mechanism of MSC in the CML resistance of TKI...
December 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28024513/-a-new-goal-for-tyrosine-kinase-inhibitor-therapy-in-chronic-myeloid-leukemia-treatment-free-remission-review
#8
Lan Yang, Bian-Hong Wang, Xiang-Shu Jin, Yu Jing, Li Yu
Tyrosine kinase inhibitor (TKI) therapy significantly improved the prognosis and outcome of patients with chronic myeloid leukemia(CML). Long-term therapy of TKI drugs was often accompanied with financial burden and the rise of chronic adverse effects. At present, the treatment-free remission (TFR) has been gradually regarded as the new ultimate aim to the patients with long-term CML. In clinical trials, the patients with the therapy of imatinib stopping TKI treatment after acquired deep molecular reaction still maintained remission...
December 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28011678/enhanced-targeting-of-cml-stem-and-progenitor-cells-by-inhibition-of-porcupine-acyltransferase-in-combination-with-tki
#9
Puneet Agarwal, Bin Zhang, Yinwei Ho, Amy Cook, Ling Li, Fady M Mikhail, Youzhen Wang, Margaret E McLaughlin, Ravi Bhatia
Tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) has limited efficacy against leukemia stem cells (LSC) responsible for disease propagation, and most CML patients require continued TKI treatment to maintain remission. LSC maintenance is related, at least in part, to signals from the bone marrow microenvironment (BMM). Our previous studies have shown that Wnt signaling from the BMM contributes to preservation of CML LSC following TKI treatment. Secretion of Wnt ligands requires their modification by the O-acyl transferase Porcupine (PORCN)...
December 23, 2016: Blood
https://www.readbyqxmd.com/read/28009456/the-impact-of-socioeconomic-factors-on-treatment-choice-and-mortality-in-chronic-myeloid-leukaemia
#10
Gunnar Larfors, Fredrik Sandin, Johan Richter, Anders Själander, Leif Stenke, Mats Lambe, Martin Höglund
PURPOSE: To evaluate the influence of socioeconomic variables on treatment selection and survival of patients with chronic myeloid leukaemia (CML). METHODS: Using information available in population-based Swedish registries we evaluated indices of health, education and economy from the 980 patients in the Swedish CML register diagnosed between 2002 and 2012. Apart from internal comparisons, five age-, gender- and region-matched control subjects per patient served as control cohort...
December 23, 2016: European Journal of Haematology
https://www.readbyqxmd.com/read/28006933/nilotinib-induces-er-stress-and-cell-death-in-h9c2-cells
#11
D Lekes, I Szadvari, O Krizanova, K Lopusna, I Rezuchova, M Novakova, Z Novakova, T Parak, P Babula
Tyrosine kinases inhibitors (TKi) represent a relatively novel class of anticancer drugs that target cellular pathways overexpressed in certain types of malignancies, such as chronic myeloid leukaemia (CML). Nilotinib, ponatinib and imatinib exhibit cardiotoxic and vascular effects. In this study, we focused on possible cardiotoxicity of nilotinib using H9c2 cells as a suitable cell model. We studied role of endoplasmic reticulum (ER) stress and apoptosis in nilotinib toxicity using a complex approach. Nilotinib impaired mitochondrial function and induced formation of ROS under clinically relevant concentrations...
December 21, 2016: Physiological Research
https://www.readbyqxmd.com/read/27999193/the-novel-anticancer-agent-jnj-26854165-is-active-in-chronic-myeloid-leukemic-cells-with-unmutated-bcr-abl-and-t315i-mutant-bcr-abl-through-promoting-proteosomal-degradation-of-bcr-abl-proteins
#12
Liangshun You, Hui Liu, Jian Huang, Wanzhuo Xie, Jueying Wei, Xiujin Ye, Wenbin Qian
Chronic myeloid leukemia (CML) is a clonal malignant disease caused by the expression of BCR/ABL. MDM2 (human homolog of the murine double minute-2) inhibitors such as Nutlin-3 have been shown to induce apoptosis in a p53-dependent manner in CML cells and sensitize cells to Imatinib. Here, we demonstrate that JNJ-26854165, an inhibitor of MDM2, inhibits proliferation and triggers cell death in a p53-independent manner in various BCR/ABL-expressing cells, which include primary leukemic cells from patients with CML blast crisis and cells expressing the Imatinib-resistant T315I BCR/ABL mutant...
December 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27998234/factors-associated-with-tyrosine-kinase-inhibitor-initiation-and-adherence-among-medicare-beneficiaries-with-chronic-myeloid-leukemia
#13
Aaron N Winn, Nancy L Keating, Stacie B Dusetzina
Purpose There is substantial concern surrounding affordability of orally administered anticancer therapies, particularly for Medicare beneficiaries. We examined rates of initiation and adherence to tyrosine kinase inhibitors (TKIs) among Medicare beneficiaries with chronic myeloid leukemia (CML) with and without cost-sharing subsidies. We selected TKIs given their effectiveness and strong indication for use among patients diagnosed with CML. Patients and Methods Using SEER-Medicare data, we identified individuals diagnosed with CML from 2007 to 2011...
December 20, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27995875/-patient-reported-outcome-of-tyrosine-kinase-inhibitor-related-side-effects-and-their-impact-on-daily-life-in-chinese-patients-with-chronic-myeloid-leukemia-in-the-chronic-phase
#14
L Yu, H B Wang, Q Jiang
Objective: To explore the impact of patient reported outcome of tyrosine kinase inhibitor (TKI) related side effects on daily life in Chinese patients with chronic myeloid leukemia (CML) in the chronic phase (CP). Methods: From May to November in 2014, anonymous questionnaires were distributed to adult CML patients who were receiving TKI treatment in China. The impact of TKI-related side effects on daily life were assessed by the score of 1 (no impact) to 5 (high impact) from patient self-report. Results: Data from 731 respondents in the CP who reported the score of the impact of TKI-related side effects on daily life were collected...
November 14, 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/27995032/successful-pregnancy-and-delivery-in-a-patient-with-chronic-myeloid-leukemia-a-case-report-and-review-of-the-literature
#15
Weiwei Sheng, Naitong Sun
INTRODUCTION: Complications associated with chronic myeloid leukemia (CML) during pregnancy are rare, and management is challenging because very limited data are available on this patient group. CASE DESCRIPTION: We herein report a successful pregnancy and delivery in a patient diagnosed with CML. The patient was treated with imatinib (400 mg/day) as a first-line therapy. However, she became pregnant while she was in complete hematological remission and had a complete cytogenetic response...
2016: SpringerPlus
https://www.readbyqxmd.com/read/27980759/extensive-intracranial-arterial-stenoses-in-conjunction-with-the-use-of-tyrosine-kinase-inhibitor-nilotinib
#16
Ruham Alshiekh-Nasany, Awss Zidan, Carmen Martinez
New-generation tyrosine kinase inhibitors (TKI) are promising agents for the treatment of chronic myeloid leukemia (CML), but the linkage to vascular diseases warrants a special attention from treating physicians, as it may carry major morbidity and mortality.
December 2016: Clinical Case Reports
https://www.readbyqxmd.com/read/27979961/rt-qpcr-and-rt-digital-pcr-a-comparison-of-different-platforms-for-the-evaluation-of-residual-disease-in-chronic-myeloid-leukemia
#17
Mary Alikian, Alexandra S Whale, Susanna Akiki, Kim Piechocki, Celia Torrado, Thet Myint, Simon Cowen, Michael Griffiths, Alistair G Reid, Jane Apperley, Helen White, Jim F Huggett, Letizia Foroni
BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the cornerstone of successful clinical management of patients with chronic myeloid leukemia (CML). Quantitative monitoring of the percentage of the BCR, RhoGEF, and GTPase activating protein-ABL proto-oncogene 1, non-receptor tyrosine kinase fusion transcript BCR-ABL1(IS) (%BCR-ABL1(IS)) by reverse transcription-quantitative PCR (RT-qPCR) is the gold standard strategy for evaluating patient response to TKIs and classification into prognostic subgroups...
December 15, 2016: Clinical Chemistry
https://www.readbyqxmd.com/read/27973186/imatinib-discontinuation-and-tki-switching-patterns-in-the-retrospective-and-prospective-cohorts-in-simplicity-a-study-of-chronic-phase-chronic-myeloid-leukemia-cp-cml-patients-pts-in-routine-clinical-practice
#18
T Zyczynski, J Khoury, S Goldberg, M Mauro, M Michallet, R Paquette, A Foreman, M Subar, M Turner, M Manley Daumont, R Hehlmann, B Simonsson
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27971690/modelling-the-economic-impact-of-implementing-treatment-free-remission-tfr-in-philadelphia-ph-chronic-myelogenous-leukemia-in-chronic-phase-cml-cp-patients-treated-in-first-line-1l-with-the-tyrosine-kinase-inhibitors-tki-imatinib-and-nilotinib
#19
E Sauvage, J Duco, S Nizard, S Arroum, F Mahon, P Kuizenga, J Ricci
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27957861/codelivery-of-ponatinib-and-sar302503-by-active-bone-targeted-polymeric-micelles-for-the-treatment-of-therapy-resistant-chronic-myeloid-leukemia
#20
Chao-Feng Mu, Yang Xiong, Xue Bai, Yun-Jie Sheng, Jiajun Cui
Point mutations in the BCR-ABL1 domain and primitive chronic myelogenous leukemia (CML) cells existing in the bone marrow environment insensitive to tyrosine kinase inhibitors (TKIs) have become two major challenges in the CML therapy. In this study, combined TKI ponatinib and JAK2 inhibitor SAR302503 short-term treatment effectively suppressed growth and promoted apoptosis of BaF3/T315I cells in cytokine-containing medium in vitro. SAR302503 prevented cytokine-dependent resistance to ponatinib via inhibition of JAK2/STAT5 phosphorylation...
January 3, 2017: Molecular Pharmaceutics
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