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https://www.readbyqxmd.com/read/29351208/preservation-method-and-phosphate-buffered-saline-washing-affect-the-acute-myeloid-leukemia-proteome
#1
Rebecca Wangen, Elise Aasebø, Andrea Trentani, Stein-Ove Døskeland, Øystein Bruserud, Frode Selheim, Maria Hernandez-Valladares
Acute myeloid leukemia (AML) primary cells can be isolated from peripheral blood, suspended with media containing bovine serum and cryoprotectant, and stored in liquid nitrogen before being processed for proteomic analysis by mass spectrometry (MS). The presence of bovine serum and human blood proteins in AML samples can hamper the identifications of proteins, and thereby reduce the proteome coverage of the study. Herein, we have established the effect of phosphate buffered saline (PBS) washing on AML patient samples stored in media...
January 19, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29348817/a-mitochondrial-targeted-purine-based-hsp90-antagonist-for-leukemia-therapy
#2
Kelly G Bryant, Young Chan Chae, Rogelio L Martinez, John C Gordon, Khaled M Elokely, Andrew V Kossenkov, Steven Grant, Wayne E Childers, Magid Abou-Gharbia, Dario C Altieri
Reprogramming of mitochondrial functions sustains tumor growth and may provide therapeutic opportunities. Here, we targeted the protein folding environment in mitochondria by coupling a purine-based inhibitor of the molecular chaperone Heat Shock Protein-90 (Hsp90), PU-H71 to the mitochondrial-targeting moiety, triphenylphosphonium (TPP). Binding of PU-H71-TPP to ADP-Hsp90, Hsp90 co-chaperone complex or mitochondrial Hsp90 homolog, TRAP1 involved hydrogen bonds, π-π stacking, cation-π contacts and hydrophobic interactions with the surrounding amino acids in the active site...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348812/design-and-synthesis-of-isoquinolidinobenzodiazepine-dimers-a-novel-class-of-antibody-drug-conjugate-payload
#3
Sean W Smith, Vasu Jammalamadaka, Dmitry Borkin, Jianyu Zhu, Sylvia J Degrado, Jennifer Lu, Jianqing Huang, Ying-Ping Jiang, Nareshkumar Jain, Jagath R Junutula
Antibody-drug conjugates (ADCs) represent an important class of emerging cancer therapeutics. Recent ADC development efforts highlighted the use of pyrrolobenzodiazepine (PBD) dimer payload for the treatment of several cancers. We identified the isoquinolidinobenzodiazepine (IQB) payload (D211), a new class of PBD dimer family of DNA damaging payloads. We have successfully synthesized all three IQB stereoisomers, experimentally showed that the purified (S,S)-D211 isomer is functionally more active than (R,R)-D221 and (S,R)-D231 isomers by >50,000-fold and ∼200-fold, respectively...
January 11, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29348128/pevonedistat-a-first-in-class-nedd8-activating-enzyme-nae-inhibitor-combined-with-azacitidine-in-patients-with-aml
#4
Ronan T Swords, Steven Coutre, Michael B Maris, Joshua F Zeidner, James M Foran, Jose Cruz, Harry P Erba, Jesus G Berdeja, Wayne Tam, Saran Vardhanabhuti, Iwona Pawlikowska-Dobler, Hélène M Faessel, Ajeeta B Dash, Farhad Sedarati, Bruce J Dezube, Douglas V Faller, Michael R Savona
Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study (NCT01814826) of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naïve AML, unfit for standard induction therapy, received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5, combined with fixed-dose AZA (75 mg/m2 IV/SC) on days 1-5, 8, and 9, every 28 days...
January 18, 2018: Blood
https://www.readbyqxmd.com/read/29346763/derepression-of-the-iroquois-homeodomain-transcription-factor-gene-irx3-confers-differentiation-block-in-acute-leukemia
#5
Tim D D Somerville, Fabrizio Simeoni, John A Chadwick, Emma L Williams, Gary J Spencer, Katalin Boros, Christopher Wirth, Eleni Tholouli, Richard J Byers, Tim C P Somervaille
The Iroquois homeodomain transcription factor gene IRX3 is expressed in the developing nervous system, limb buds, and heart, and transcript levels specify obesity risk in humans. We now report a functional role for IRX3 in human acute leukemia. Although transcript levels are very low in normal human bone marrow cells, high IRX3 expression is found in ∼30% of patients with acute myeloid leukemia (AML), ∼50% with T-acute lymphoblastic leukemia, and ∼20% with B-acute lymphoblastic leukemia, frequently in association with high-level HOXA gene expression...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29346508/oroxylin-a%C3%AF-a-natural-compound-mitigates-the-negative-effects-of-tnf%C3%AE-treated-acute-myelogenous-leukemia-cells
#6
Hui Li, Na Lu, Xiaoxuan Yu, Xiao Liu, Po Hu, Yu Zhu, Le Shen, Jingyan Xu, Zhiyu Li, Qinglong Guo, Hui Hui
Tumor necrosis factor alpha (TNFα) is a complicated cytokine which is involved in proliferation and differentiation of acute myelogenous leukemia (AML) cells through a poorly understood mechanism. Mechanistic studies indicate that TNFα induced binding of PI3K subunit p85α to N-terminal truncated nuclear receptor RXRα (tRXRα) proteins, and activated AKT. The activated PI3K/AKT pathway negatively regulated differentiation of AML cells through the up-regulation of c-Myc. In addition, TNFα also induced activation of nuclear factor κB (NF-κB), a nuclear transcription factor which was shown to promote cell proliferation...
January 13, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29346478/differentiation-syndrome-associated-with-enasidenib-a-selective-inhibitor-of-mutant-isocitrate-dehydrogenase-2-analysis-of-a-phase-1-2-study
#7
Amir T Fathi, Courtney D DiNardo, Irina Kline, Laurie Kenvin, Ira Gupta, Eyal C Attar, Eytan M Stein, Stephane de Botton
Importance: Enasidenib mesylate, a mutant isocitrate dehydrogenase 2 (IDH2) protein inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by the US Food and Drug Administration for use in relapsed/refractory (R/R) mutant IDH2 acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity...
January 18, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29345570/the-role-of-ampk-mtor-modulators-in-therapy-of-acute-myeloid-leukemia
#8
Dora Visnjic, Vilma Dembitz, Hrvoje Lalic
Differentiation therapy of acute promyelocytic leukemia with all-trans retinoic acid represents the most successful pharmacological therapy of acute myeloid leukemia (AML). Numerous studies demonstrate that drugs that inhibit mechanistic target of rapamycin (mTOR) and activate AMP-kinase (AMPK) have beneficial effects in promoting differentiation and blocking proliferation of AML. Most of these drugs are already in use for other purposes; rapalogs as immunosuppressants, biguanides as oral antidiabetics, and 5-amino-4-imidazolecarboxamide ribonucleoside (AICAr, acadesine) as an exercise mimetic...
January 16, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29345422/cantharidic-acid-induces-apoptosis-of-human-leukemic-hl-60-cells-via-c-jun-n-terminal-kinase-regulated-caspase-8-9-3-activation-pathway
#9
Shih-Chung Wang, Jyh-Ming Chow, Ming-Hsien Chien, Chiao-Wen Lin, Hui-Yu Chen, Pei-Ching Hsiao, Shun-Fa Yang
Cantharidin, a natural toxin from blister beetles, has shown potent anticancer activities on many solid tumor cells. Recently, cantharidin and its analogue, norcantharidin, were also shown to suppress nonsolid tumors such as chronic myeloid leukemia, acute myeloid leukemia (AML), and leukemic stem cells. However, there is no available information to address the effects of cantharidic acid (CAC), a hydrolysis product of cantharidin, on human AML cells. The present study showed that CAC, at a range of concentrations (0-20 μM), concentration-dependently inhibited cell proliferation in the HL-60 AML cell line...
January 18, 2018: Environmental Toxicology
https://www.readbyqxmd.com/read/29345177/prognostic-significance-of-cathepsin-l-expression-in-pediatric-acute-myeloid-leukemia
#10
Garima Pandey, Sameer Bakhshi, Bhaskar Thakur, Prerna Jain, Shyam S Chauhan
Overexpression of cathepsin L (CTSL), an endolysosomal cysteine protease, is associated with inferior survival of patients with various human malignancies. We evaluated the expression/activity of CTSL in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) of 103 pediatric acute myeloid leukemia (AML) patients to assess its prognostic significance in this malignancy. Thirty-five healthy siblings of patients served as controls. Our results revealed significantly higher CTSL activity (p < ...
January 18, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29345176/bone-marrow-vegfc-expression-is-associated-with-multilineage-dysplasia-and-several-prognostic-markers-in-adult-acute-myeloid-leukemia-but-not-with-survival
#11
Vicent Guillem, Marisa Calabuig, Salut Brunet, Jordi Esteve, Lourdes Escoda, David Gallardo, Josep-Maria Ribera, María Paz Queipo de Llano, Montserrat Arnan, Carme Pedro, María Luz Amigo, Josep M Martí-Tutusaus, Antoni García-Guiñón, Joan Bargay, Antonia Sampol, Olga Salamero, Llorenç Font, Carme Talarn, Montserrat Hoyos, Marina Díaz-Beyá, Ana Garrido, Blanca Navarro, Josep Nomdédeu, Jordi Sierra, Mar Tormo
Vascular endothelial growth factor C (VEGFC) stimulates leukemia cell proliferation and survival, and promotes angiogenesis. We studied VEGFC expression in bone marrow samples from 353 adult acute myeloid leukemia (AML) patients and its relationship with several clinical, cytogenetic, and molecular variables. We also studied the expression of 84 genes involved in VEGF signaling in 24 patients. We found that VEGFC expression was higher in AML patients with myelodysplasia-related changes (AML-MRC) than in patients with non-AML-MRC...
January 18, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29344807/inhibition-of-bone-resorption-by-bisphosphonates-interferes-with-orthodontically-induced-midpalatal-suture-expansion-in-mice
#12
Till Koehne, Bärbel Kahl-Nieke, Michael Amling, Heike Korbmacher-Steiner
OBJECTIVES: Craniofacial sutures are important growth sites for skull development and are sensitive to mechanical stress. In order to determine the role of bone resorption in stress-mediated sutural bone growth, midpalatal suture expansion was performed in mice receiving alendronate, an anti-resorptive bisphosphonate. MATERIALS AND METHODS: The midpalatal sutures of 8-week-old C57BL/6 mice were expanded by orthodontic wires over the period of 2 weeks. Mice with maxillary expansion without drug treatment as well as untreated animals served as controls...
January 18, 2018: Clinical Oral Investigations
https://www.readbyqxmd.com/read/29344730/skeletal-dissemination-in-paget-s-disease-of-the-spine
#13
REVIEW
Tim Rolvien, Sebastian Butscheidt, Jozef Zustin, Michael Amling
PURPOSE: Paget's disease of bone (PDB) is a common skeletal disorder that is associated with locally increased bone turnover, skeletal deformity and pain. We report a case of skeletal dissemination in PDB of the spine. METHODS: Case report. RESULTS: A 46-year-old former professional athlete suffered from disseminated PDB throughout the spine and hips after various surgical interventions including spondylodesis, bone grafting and bone morphogenetic protein (rhBMP-2) administration...
January 17, 2018: European Spine Journal
https://www.readbyqxmd.com/read/29344207/novel-homobarringtonie-containing-therapy-for-the-treatment-of-patients-with-primary-acute-myeloid-leukemia-that-are-resistant-to-conventional-therapy
#14
Jingsong He, Li Li, Jingjing Zhu, Weiyan Zheng, Wenjun Wu, Yanlong Zheng, Xiujin Ye
The current study investigated the efficacy and safety of a novel treatment regime consisting of homobarringtonie, cytosine arabinoside and etoposide (HCE) for the treatment of primary acute myeloid leukemia (AML). In the present study, 141 patients diagnosed with AML were divided into the HCE (n=47) and the conventional AML therapy, consisting of idamycin combined with cytarabine (IA; n=94), treatment groups. The measured patient outcome parameters were the emission and response rates, as well as medication-induced adverse events, with a median follow-up time of 28 months...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29344183/a-patient-with-chronic-myeloid-leukemia-and-situs-inversus-totalis-a-case-report
#15
Yunxia Sun, Xiaoli Li, Lijun Li, Huan Liu, Qian Xu, Bei Liu
In the present study, a case of chronic myeloid leukemia (CML) with complete situs inversus in a 68-year-old female patient was reported. The patient presented with general weakness, abdominal distension and tenderness in the right hypochondrium. A chest X-ray revealed a right-sided heart. Ultrasonography revealed situs inversus totalis. A bone marrow smear demonstrated CML in the accelerated phase. Imatinib mesylate was subsequently administered; the patient stopped taking imatinib mesylate following discharge from the hospital...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29344132/aberrant-nlrp3-inflammasome-associated-with-aryl-hydrocarbon-receptor-potentially-contributes-to-the-imbalance-of-t-helper-cells-in-patients-with-acute-myeloid-leukemia
#16
Yan Jia, Chen Zhang, Mingqiang Hua, Min Wang, Ping Chen, Daoxin Ma
Acute myeloid leukemia (AML) is a hematological malignancy in which the immune response serves a pivotal role in progression. Aryl hydrocarbon receptor (AHR) is involved in the modulation of the immune system, particularly in the differentiation of T-helper cell (Th) subsets. Although the NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been implicated as essential in the pathogenesis of autoimmune and inflammatory diseases, the role it serves in the development of AML remains unknown. Therefore, in order to identify and describe the possible roles of AHR, as well as NLRP3 inflammasome, in the pathogenesis of AML and their relationship with Th subsets (Th1 Th22), the present study investigated the mRNA expression levels of AHR and NLRP3 inflammasome molecules in the peripheral blood and bone marrow...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29344131/a-novel-variant-translocation-1-9-p22-q34-resulting-in-a-dek-nup214-fusion-gene-in-a-patient-with-acute-myeloid-leukemia-a-case-report
#17
Qishan Hao, Qi Zhang, Chengwen Li, Shuning Wei, Qinghua Li, Yang Song, Yingchang Mi
The present case report describes a 46-year-old female patient diagnosed with M4 acute myeloid leukemia (AML), accompanied with a t(1;9)(p22;q34) chromosomal abnormality. Transcriptome sequencing identified a DEK proto-oncogene (DEK)/nucleoporin (NUP)214 fusion gene, which results from the t(6;9)(p23;q34) chromosomal translocation. Polymerase chain reaction analysis and fluorescence in situ hybridization were used to verify the existence of the DEK/NUP214 fusion gene. Few patients with AML with the t(6;9)(p23;q34) chromosomal translocation have been reported to have other chromosomal or karyotype changes...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29344112/zgdhu-1-for-cancer-therapy
#18
Jinlin Liu, Liannv Qiu, Jun Xia, Sufeng Chen, Xiping Yu, Yonglie Zhou
N,N'-di-(m-methylphenyl)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1) is a novel tetrazine derivative that was initially designed and produced by Professor W.X. Hu, and which has been reported by our group to exhibit antitumor activity. Accumulating evidence suggests that the anticancer mechanisms of ZGDHu-1 may be involved indifferent biological activities, particularly in acute myeloid leukemia (AML) cells. At a high concentration, ZGDHu-1 has been demonstrated to inhibit the proliferation of the leukemia cells by arresting the cell cycle at the G2/M phase, and by inducing cell apoptosis via inducing the accumulation of reactive oxygen species, the translocation of phosphatidylserine across the plasma membrane and the loss of mitochondrial membrane potential...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29344089/bone-marrow-failure-may-be-caused-by-chromosome-anomalies-exerting-effects-on-runx1t1-gene
#19
R Valli, L Vinti, A Frattini, M Fabbri, G Montalbano, C Olivieri, A Minelli, F Locatelli, F Pasquali, E Maserati
Background: The majority of the cases of bone marrow failure syndromes/aplastic anaemias (BMFS/AA) are non-hereditary and considered idiopathic (80-85%). The peripheral blood picture is variable, with anaemia, neutropenia and/or thrombocytopenia, and the patients with idiopathic BMFS/AA may have a risk of transformation into a myelodysplastic syndrome (MDS) and/or an acute myeloid leukaemia (AML), as ascertained for all inherited BMFS. We already reported four patients with different forms of BMFS/AA with chromosome anomalies as primary etiologic event: the chromosome changes exerted an effect on specific genes, namely RUNX1, MPL, and FLI1, leading to the disease...
2018: Molecular Cytogenetics
https://www.readbyqxmd.com/read/29343975/spotlight-on-midostaurin-in-the-treatment-of-flt3-mutated-acute-myeloid-leukemia-and-systemic-mastocytosis-design-development-and-potential-place-in-therapy
#20
REVIEW
Ellen Weisberg, Martin Sattler, Paul W Manley, James D Griffin
The Fms-like tyrosine kinase-3 (FLT3; fetal liver kinase-2; human stem cell tyrosine kinase-1; CD135) is a class III receptor tyrosine kinase that is normally involved in regulating the proliferation, differentiation, and survival of both hematopoietic cells and dendritic cells. Mutations leading it to be constitutively activated make it an oncogenic driver in ~30% of acute myeloid leukemia (AML) patients where it is associated with poor prognosis. The prevalence of oncogenic FLT3 and the dependency on its constitutively activated kinase activity for leukemia growth make this protein an attractive target for therapeutic intervention...
2018: OncoTargets and Therapy
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