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https://www.readbyqxmd.com/read/28944397/chronic-myeloid-leukemia-the-promise-of-tyrosine-kinase-inhibitor-discontinuation
#1
REVIEW
Ravi Kishore Narra, Kathryn E Flynn, Ehab Atallah
Some believe that tyrosine kinase inhibitor (TKI) therapy is as close to perfect as it gets in oncologic therapy. Patients diagnosed with chronic myeloid leukemia (CML) are treated with a daily oral therapy, through which most achieve remission. TKI therapy is not associated with classic chemotherapy side effects, and most patients are able to resume their normal activities of daily living. Moreover, recent data has demonstrated that CML does not affect the life expectancy of patients whose disease is well controlled with a TKI...
September 25, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28943878/triplebody-mediates-increased-anti-leukemic-reactivity-of-il-2-activated-donor-natural-killer-nk-cells-and-impairs-viability-of-their-cd33-expressing-nk-subset
#2
Stephan Kloess, Alessa Ede Valverde da Silva, Olaf Oberschmidt, Tanja Gardlowski, Nadine Matthies, Maulik Vyas, Lubomir Arseniev, Michael Heuser, Elke Pogge von Strandmann, Ulrike Köhl
Natural killer cells (NK) are essential for the elimination of resistant acute myeloid and acute lymphoblastic leukemia (AML and ALL) cells. NK cell-based immunotherapies have already successfully entered for clinical trials, but limitations due to immune escape mechanisms were identified. Therefore, we extended our established NK cell protocol by integration of the previously investigated powerful trispecific immunoligand ULBP2-aCD19-aCD33 [the so-called triplebodies (TBs)] to improve the anti-leukemic specificity of activated NK cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28942350/refractory-macrocytic-anemias-in-patients-with-clonal-hematopoietic-disorders-and-isolated-mutations-of-the-spliceosome-gene-zrsr2
#3
Roger A Fleischman, Shannon S Stockton, Christopher R Cogle
Although mutations in RNA splicing genes occur frequently in patients with clonal cytopenias of unknown significance (CCUS) and myelodysplastic syndromes (MDS), very often additional common myeloid gene driver mutations are present at diagnosis. Thus, the clinical significance of isolated mutations in the most commonly mutated RNA splicing genes remains unknown. Here we report five unusual patients with an isolated mutation causing a loss of function of ZRSR2, a protein required for recognition of a functional 3' splice site...
September 8, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28942039/comparative-effect-of-imatinib-and-ponatinib-on-autophagy-and-mirnome-in-chronic-myeloid-leukemia
#4
Cagla Kayabasi, Tugce Balci Okcanoglu, Besra Ozmen Yelken, Aycan Asik, Sunde Yilmaz Susluer, Cigir Biray Avci, Guray Saydam, Cumhur Gunduz
BCR-ABL tyrosine kinase inhibitors (TKIs) are selective therapies for the patients with Chronic Myeloid Leukemia (CML). Imatinib and ponatinib have remarkable long-term efficacy on a major molecular response. Although TKI related induction of cytotoxicity and apoptosis have been clearly investigated in molecular levels, their comparative effect on autophagy and miRNome are largely unknown. This study aimed to investigate the involvement of alterations of miRNA expressions in CML progression, and how imatinib and ponatinib affect this process, by comparing CML, imatinib-resistant CML and leukemia stem cells (LSC)...
September 20, 2017: Gene
https://www.readbyqxmd.com/read/28941052/the-spectrum-of-dnmt3a-variants-in-tatton-brown-rahman-syndrome-overlaps-with-that-in-hematologic-malignancies
#5
Wei Shen, Jennifer M Heeley, Colleen M Carlston, Rocio Acuna-Hidalgo, Willy M Nillesen, Karin M Dent, Ganka V Douglas, Kara L Levine, Pinar Bayrak-Toydemir, Carlo L Marcelis, Marwan Shinawi, John C Carey
De novo, germline variants in DNMT3A cause Tatton-Brown-Rahman syndrome (TBRS). This condition is characterized by overgrowth, distinctive facial appearance, and intellectual disability. Somatic DNMT3A variants frequently occur in hematologic malignances, particularly acute myeloid leukemia. The Arg882 residue is the most common site of somatic DNMT3A variants, and has also been altered in patients with TBRS. Here we present three additional patients with this disorder attributed to DNMT3A germline variants that disrupt the Arg882 codon, suggesting that this codon may be a germline mutation hotspot in this disorder...
September 21, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28940816/clinical-impact-of-kmt2c-and-spry4-expression-levels-in-intensively-treated-younger-adult-acute-myeloid-leukemia-patients
#6
Sabine Kayser, Maximilian Feszler, Julia Krzykalla, Matthias Schick, Michael Kramer, Axel Benner, Felicitas Thol, Uwe Platzbecker, Carsten Müller-Tidow, Anthony D Ho, Gerhard Ehninger, Michael Heuser, Richard F Schlenk, Christian Thiede, Christoph Röllig, Alwin Krämer
OBJECTIVE: To evaluate the prognostic impact of gene expression levels (ELs) of two tumor suppressor genes, sprouty 4 (SPRY4, located on 5q) and lysine methyltransferase 2C (KMT2C, located on 7q) in correlation to clinical characteristics and genetic abnormalities assessed at initial diagnosis in acute myeloid leukemia (AML). METHOD: Gene expression levels were measured on cDNA by RT-qPCR from diagnostic bone marrow samples of 275 intensively treated adult AML patients (median age, 48 years)...
September 22, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28940295/comparing-leukapheresis-protocols-for-an-aml-patient-with-symptomatic-leukostasis
#7
Abigail Cline, Ryan Jajosky, James Shikle, Roni Bollag
BACKGROUND: Acute myeloid leukemia (AML) is a malignancy characterized by rapid clonal proliferation of myeloid precursors, which can result in hyperleukocytosis. Leukapheresis can be used to rapidly reduce the white blood cell count (WBC). However, the only FDA cleared device for WBC depletion, the COBE Spectra, will no longer be supported by the manufacturer in 2017, and there are few studies comparing different methods of leukapheresis. CASE REPORT: A 68-year-old African American female was admitted to the hospital for relapse of her AML...
September 22, 2017: Journal of Clinical Apheresis
https://www.readbyqxmd.com/read/28939746/phase-iii-clinical-trial-rerise-study-results-of-efficacy-and-safety-of-radotinib-compared-with-imatinib-in-newly-diagnosed-chronic-phase-chronic-myeloid-leukemia
#8
Jae Yong Kwak, Sung-Hyun Kim, Suk Joong Oh, Dae Young Zang, Hawk Kim, Jeong-A Kim, Young Rok Do, Hyeoung-Joon Kim, Joon Seong Park, Chul Won Choi, Won-Sik Lee, Yeung-Chul Mun, Jee Hyun Kong, Joo-Seop Chung, Ho Jin Shin, Dae-Young Kim, Jinny Park, Chul Won Jung, Udomask Bunworasate, Narcisa Sonia Comia, Saengsuree Jootar, Harryanto Reksodiputro, Priscilla B Caguioa, Sung-Eun Lee, Dong-Wook Kim
PURPOSE: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for CML-CP in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. METHODS: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily (bid) radotinib doses, or imatinib daily (qd). The primary endpoint was major molecular response (MMR) by 12 months...
September 22, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28939454/outcome-and-minimal-residual-disease-monitoring-in-t-16-21-acute-myeloid-leukemia-patients-receiving-allogeneic-hematologic-stem-cell-transplantation
#9
Ya-Zhen Qin, Yao Chen, Lan-Ping Xu, Yu Wang, Xiao-Hui Zhang, Huan Chen, Xiao-Su Zhao, Kai-Yan Liu, Xiao-Jun Huang
Patients with t(16;21) acute myeloid leukemia (AML) who receive chemotherapy have poor outcomes. The treatment efficacy of allogeneic hematologic stem cell transplantation (allo-HSCT) must be identified, and the usefulness of minimal residual disease (MRD) monitoring requires evaluation. Fourteen t(16;21) AML patients consecutively receiving allo-HSCT at our institute were included in this study. The TLS-ERG transcript levels were serially monitored for a median of 15 (3-51) months after allo-HSCT. Eight patients relapsed, 7 patients died from relapse-related causes, and 1 patient died from a non-relapse-related cause...
September 19, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28939453/bone-marrow-wt1-levels-in-allogeneic-hematopoietic-stem-cell-transplant-hct-for-acute-myeloid-leukemia-and-myelodysplasia-clinically-relevant-time-points-and-100-copies-threshold-value
#10
Josep F Nomdedéu, Albert Esquirol, Maite Carricondo, Marta Pratcorona, Montserrat Hoyos, Ana Garrido, Miguel Rubio, Elena Bussaglia, Irene García-Cadenas, Camino Estivill, Salut Brunet, Rodrigo Martino, Jorge Sierra
The outcome of allogeneic hematopoietic stem cell transplant (HCT) in patients with myeloid malignancies is better in those without minimal residual disease (MRD) than in those with MRD+ as assessed by multiparametric flow cytometry (MPFC). WT1 quantitation has also been used to assess the probability of relapse in acute myeloid leukemia treated with chemotherapy. We analyzed the clinical value of normalized bone marrow WT1 levels as a measure of the expanded myeloid progenitor compartment in a consecutive series of 193 adult patients with myeloid malignancies who underwent HCT...
September 19, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28939105/protein-kinase-c-eta-regulates-mcl-1-level-via-erk1
#11
Deepanwita Pal, Alakananda Basu
Protein kinase C (PKC)-eta (PKCη) is a member of the novel category of PKC family. It is overexpressed in breast cancer and was shown to inhibit apoptosis and contribute to chemoresistance. Since the anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) plays an important role in breast cancer cell survival and chemoresistance, we investigated if PKCη regulates Mcl-1 level. Silencing of PKCη decreased Mcl-1 in several breast cancer cells, including MCF-7 and T47D cells. PKCη depletion had no effect on MCL1 mRNA but the decrease in Mcl-1 by PKCη knockdown was blocked by proteasomal inhibitors, such as MG132 and lactacystin...
September 19, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28938529/defining-a-therapeutic-window-for-kinase-inhibitors-in-leukemia-to-avoid-neutropenia
#12
Kate McArthur, Akshay A D'Cruz, David Segal, Kurt Lackovic, Andrew F Wilks, Joanne A O'Donnell, Cameron J Nowell, Motti Gerlic, David C S Huang, Christopher J Burns, Ben A Croker
Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28937371/npm1-and-flt3-mutations-in-acute-myeloid-leukemia-with-normal-karyotype-indian-perspective
#13
Sudha Sazawal, Neha Singh, Sonal Jain, Sunita Chhikara, Rekha Chaubey, Jina Bhattacharyya, Kandarpa Kr Saikia, Manoranjan Mahapatra, Renu Saxena
BACKGROUND: FLT3-ITD and NPM1 mutations are considered to be the major determinants of the patient response to therapy and outcome. The primary aim of this study was to establish the correlation between these molecular mutations and the clinico-hematologic parameters as well as the prognostic outcome of the Indian acute myeloid leukemia (AML) patients. MATERIALS AND METHODS: This prospective study involved newly diagnosed nonpromyelocytic AML patients who had undergone complete diagnostic workup, including immunophenotyping, conventional cytogenetics and molecular analysis for NPM1 and FLT3-ITD mutation by reverse transcriptase polymerase chain reaction at presentation...
July 2017: Indian Journal of Pathology & Microbiology
https://www.readbyqxmd.com/read/28935992/distinct-clinical-and-biological-implications-of-various-dnmt3a-mutations-in-myeloid-neoplasms
#14
S K Balasubramanian, M Aly, Y Nagata, T Bat, B P Przychodzen, C M Hirsch, V Adema, V Visconte, T Kuzmanovic, T Radivoyevitch, A Nazha, S Mukherjee, M A Sekeres, J P Maciejewski
Leukemia accepted article preview online, 22 September 2017. doi:10.1038/leu.2017.295.
September 22, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28935849/acute-myeloid-leukemia-with-mutated-nucleophosmin-1-an-immunogenic-aml-subtype-and-potential-candidate-for-immune-checkpoint-inhibition
#15
Jochen Greiner, Susanne Hofmann, Michael Schmitt, Marlies Götz, Markus Wiesneth, Hubert Schrezenmeier, Donald Bunjes, Hartmut Döhner, Lars Bullinger
"-".
September 21, 2017: Haematologica
https://www.readbyqxmd.com/read/28935132/acute-leukemia-patients-needs-qualitative-findings-and-opportunities-for-early-palliative-care
#16
Nathan A Boucher, Kimberly S Johnson, Thomas W LeBlanc
BACKGROUND AND OBJECTIVE: Patients with acute leukemias likely have needs that palliative care can respond to, yet little is known about specific challenges they face, particularly during active treatment. We examined acute myeloid leukemia (AML) patients' expressed challenges and supports following intensive induction chemotherapy. We aimed to understand opportunities for palliative care interventions in this population. METHODS: A qualitative study of AML patients with high-risk disease at Duke University Hospital, Durham, NC...
September 18, 2017: Journal of Pain and Symptom Management
https://www.readbyqxmd.com/read/28934678/establishment-of-cell-line-with-nk-nkt-phenotype-from-myeloid-nk-cell-acute-leukemia
#17
A Darji, N Desai, R Modi, B Khamar, S Rajkumar
Acute Myeloid Leukemia (AML) is the most common malignancy in adults with a 5-year survival rate of 27% of the total affected population. For effective treatment and new drug discovery, cell lines are considered as a very important tool. Here we report an establishment of a continuous human cell line AML-004 with a hypo-diploid chromosome 44 and presence of both NK/NKT phenotypes. The cell line was isolated from the blood sample of myeloid NK cell acute leukemia patients and extensively characterized by flow cytometery, morphology, and cytogentic analysis...
September 13, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28933777/generation-and-use-of-a-humanized-bone-marrow-ossicle-niche-for-hematopoietic-xenotransplantation-into-mice
#18
Andreas Reinisch, David Cruz Hernandez, Katharina Schallmoser, Ravindra Majeti
Xenotransplantation is frequently used to study normal and malignant hematopoiesis of human cells. However, conventional mouse xenotransplantation models lack essential human-specific bone-marrow (BM)-microenvironment-derived survival, proliferation, and self-renewal signals for engraftment of normal and malignant blood cells. As a consequence, many human leukemias and other hematologic disorders do not robustly engraft in these conventional models. Here, we describe a complete workflow for the generation of humanized ossicles with an accessible BM microenvironment that faithfully recapitulates normal BM niche morphology and function...
October 2017: Nature Protocols
https://www.readbyqxmd.com/read/28933735/clinical-outcomes-and-co-occurring-mutations-in-patients-with-runx1-mutated-acute-myeloid-leukemia
#19
Maliha Khan, Jorge Cortes, Tapan Kadia, Kiran Naqvi, Mark Brandt, Sherry Pierce, Keyur P Patel, Gautam Borthakur, Farhad Ravandi, Marina Konopleva, Steven Kornblau, Hagop Kantarjian, Kapil Bhalla, Courtney D DiNardo
(1) Runt-related transcription factor 1 (RUNX1) mutations in acute myeloid leukemia (AML) are often associated with worse prognosis. We assessed co-occurring mutations, response to therapy, and clinical outcomes in patients with and without mutant RUNX1 (mRUNX1); (2) We analyzed 328 AML patients, including 177 patients younger than 65 years who received intensive chemotherapy and 151 patients >65 years who received hypomethylating agents. RUNX1 and co-existing mutations were identified using next-generation sequencing; (3) RUNX1 mutations were identified in 5...
July 26, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28933312/characterization-of-imatinib-resistant-cml-leukemic-stem-initiating-cells-and-their-sensitivity-to-cbp-catenin-antagonists
#20
Yi Zhao, Kaijin Wu, Yongfeng Wu, Elizabeth Melendez, Goar Smbatyan, David Massiello, Michael Kahn
The development of the tyrosine kinase inhibitor Imatinib (IM) represents a milestone breakthrough in CML (Chronic Myeloid Leukemia) treatment. However, it is not curative and patients develop IM resistance. IM resistance has been previously correlated with the emergence of drug-resistant LIC/LSC (Leukemia Initiating Cell/Leukemia Stem Cell) and increased nuclear catenin levels and enhanced Wnt signaling. It has been demonstrated previously that drug resistant CML LIC/LSC can be safely eliminated both in vitro and in vivo via disruption of the CBP/catenin interaction, utilizing the highly biochemically selective small molecule CBP/catenin antagonist ICG-001...
September 19, 2017: Current Molecular Pharmacology
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