UMLS:C0023467 - FACTA Search

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Query: UMLS:C0023467 (acute myeloid leukemia)
35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activating mutations of FLT3 have been detected in patients with acute myeloid leukemia (AML). Two distinct types of FLT3 mutations are most common: internal tandem duplication (ITD) of sequences coding for the juxtamembrane domain and point mutations at codon 835 (Asp835) within the kinase domain. Both types of mutations constitutively activate the tyrosine kinase activity of FLT3 in experimental systems and result in factor-independent proliferation of Ba/F3 and 32D cells. Recently, novel mutations within the activation loop were identified in patients with AML: deletion of isoleucine 836 (Ile836del) and an exchange of isoleucine 836 to methionine plus an arginine insertion (Ile836Met+Arg). To examine whether the Ile836 mutations result in constitutive activation of the FLT3 receptor, we introduced both mutant FLT3 cDNAs transiently into HEK 293 cells. Both mutant FLT3 receptors were constitutively autophosphorylated in the absence of ligand and kinase activity led to constitutive activation of downstream signaling cascades as determined by activation of the STAT5 (signal transducer and activator of transcription 5) pathway. When stably expressed in the growth factor-dependent cell lines Ba/F3 and 32D, both deletion and insertion mutants led to factor-independent proliferation, indicating that both mutants have transforming capabilities. We then examined the sensitivity of the FLT3 ITD, FLT3 Asp835Tyr, and the novel FLT3 receptor mutants toward the kinase inhibitors AG1296, PKC412, and SU5614. We show that these FLT3 kinase inhibitors have distinct inhibitory potencies against different activating FLT3 receptor mutants. These results suggest that it may be useful to determine the exact kind of FLT3 mutation when applying receptor kinase inhibitors in clinical trials.
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PMID:Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. 1266 39

Background. Patients scheduled for myocardial perfusion imaging are often taking several antianginal drugs. There is presently no consensus concerning a regimen of discontinuation before either rest or pharmacologic stress myocardial perfusion imaging. Whether antianginal treatment affects diagnostic sensitivity and specificity is not well documented. Methods and Results. The effect of the three most commonly used antianginal drugs (nitroglycerin, 400 micro g [NTG]; metoprolol, 50 mg [MET]; and amlodipine, 5 mg [AML]) on myocardial perfusion was tested in 49 patients (age, 63 +/- 8 years; 43 men) allocated prospectively to one of the treatments (NTG, n = 25; MET, n = 14; and AML, n = 10). All patients had documented coronary artery disease and were scheduled for elective percutaneous coronary intervention. Patients were studied once on treatment and once off treatment with an interval of 1 to 3 weeks. For NTG, the measurements were performed on the same day with an interval of 1 hour. The MET and AML groups were also studied during dipyridamole-induced hyperemia (0.56 mg. kg(-1). min(-1) for 4 minutes). So that a quantitative value of myocardial perfusion in milliliters per gram per minute could be obtained, myocardial perfusion was quantified with nitrogen 13 ammonia positron emission tomography as an average of the midventricular perfusion in each of the 3 vascular territories. NTG treatment increased the overall resting perfusion (0.75 +/- 0.18 vs 0.86 +/- 0.22, P <.05), whereas resting perfusion was reduced after MET treatment (0.92 +/- 0.14 vs 0.82 +/- 0.17, P <.05). AML treatment did not alter resting perfusion (0.87 +/- 0.22 vs 0.87 +/- 0.23, P = NS). Dipyridamole-induced hyperemia was reduced after treatment with MET (2.02 +/- 0.66 vs l.57 +/- 0.52, P <.001), whereas the hyperemic response was unchanged after treatment with AML (1.54 +/- 0.49 vs 1.86 +/- 0.91, P = NS). Conclusions. Antianginal medication can alter both resting and hyperemic myocardial perfusion and might affect the ability to detect flow-limiting stenosis. NTG increases perfusion, MET reduces perfusion, and AML does not affect perfusion. Larger-scale trials are warranted to establish a consensus for optimal antianginal medication for patients undergoing perfusion imaging.
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PMID:Effect of antianginal medication on resting myocardial perfusion and pharmacologically induced hyperemia. 1273 68

BAY 43-9006 is a kinase inhibitor that induces apoptosis in a variety of tumor cells. Here we report that treatment with BAY 43-9006 results in marked cytochrome c and AIF release into the cytosol, caspase-9, -8, -7, and -3 activation, and apoptosis in human leukemia cells (U937, Jurkat, and K562). Pronounced apoptosis was also observed in blasts from patients with acute myeloid leukemia. These events were accompanied by ERK1/2 inactivation and caspase-independent down-regulation of Mcl-1. Inducible expression of a constitutively active MEK1 construct did not prevent Mcl-1 down-regulation, suggesting that this event is not related to MEK/ERK pathway inactivation. Furthermore, BAY 43-9006 did not induce major changes in Mcl-1 mRNA levels monitored by real-time PCR or Mcl-1 promoter activity demonstrated by luciferase reporter assays, but it did enhance Mcl-1 down-regulation in actinomycin D-treated cells. Inhibition of protein synthesis by cycloheximide or proteasome function with MG132 and pulse-chase studies with [35S]methionine demonstrated that BAY 43-9006 did not diminish Mcl-1 protein stability, nor did it enhance Mcl-1 ubiquitination, but instead markedly attenuated Mcl-1 translation in association with the rapid and potent dephosphorylation of the eIF4E translation initiation factor. Finally, ectopic expression of Mcl-1 in leukemic cells markedly inhibited BAY 43-9006-mediated cytochrome c cytosolic release, caspase-9, -7, and -3 activation, as well as cell death, indicating that Mcl-1 operates upstream of cytochrome c release and caspase activation. Together, these findings demonstrate that BAY 43-9006 mediates cell death in human leukemia cells, at least in part, through down-regulation of Mcl-1 via inhibition of translation.
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PMID:Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. 1610 13

Feeding mice a methionine and choline-deficient (MCD) diet serves as an experimental animal model for nonalcoholic steatohepatitis (NASH). In the present study we examined the effect of exposing AML-12 hepatocytes to MCD culture medium in regard to mechanisms of steatosis and alanine amino-transferase (ALT) release. Cells exposed to MCD medium developed significant and progressive steatosis from 6 to 24 h and also had significantly increased loss of ALT into the medium at 18 and 24 hours of incubation. No increased oxidative injury or cell death was observed. Osteopontin (OPN) mRNA in cells and protein expression in medium were significantly increased during 6-24 hours of incubation. MCD medium treatment also resulted in activation of PI3-kinase by 30 minutes and its downstream target p-Akt within 1hour of incubation. Steatosis was associated with increased expression of microsomal triglyceride transfer protein (MTTP) mRNA and increased ALT release with over expression of ALT mRNA, all of which were completely prevented by inhibition of PI3-kinase (LY294002). Blocking OPN signaling by treating with anti-OPN or anti-beta3-integrin antibody prevented the increased ALT release while only partially prevented the increased ALT mRNA expression, but had no effect on either steatosis or MTTP expression. In conclusion, incubation of cultured hepatocytes with MCD medium results in cellular steatosis and OPN dependent ALT release. PI3-kinase plays a central role in signaling the MCD medium-induced steatosis and increased OPN expression, whereas OPN appears to play a role in signaling hepatocyte ALT release but not steatosis.
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PMID:Roles of phosphatidylinositol 3-kinase and osteopontin in steatosis and aminotransferase release by hepatocytes treated with methionine-choline-deficient medium. 1643 72

An increasing body of evidence suggests that cytokines may play a role in the pathogenesis of cardiovascular diseases. Immunopharmacological studies provide new information on immunomodulating activity of some drugs, including their effect on the level of pro-inflammatory cytokines. The aim of the present study was to find out whether amlodipine and atenolol, drugs applied in the treatment of arterial hypertension, can modulate lipopolysaccharide (LPS)-induced pro-inflammatory cytokine level (TNF-alpha, IL-1, IL-6) in spontaneously hypertensive rats (SHR). The experiments were performed on 4 groups of animals as follows: WKY + MET(control Wistar-Kyoto normotensive rats), SHR + MET(control hypertensive rats), SHR + AML(hypertensive rats receiving amlodipine), SHR + AT (hypertensive rats receiving atenolol). Control rats received 1% solution of methylcellulose (1 ml/kg) by a gavage. Amlodipine and atenolol were administered by a gavage at doses of 15 mg/kg and 25 mg/kg, respectively. Arterial blood pressure was measured in conscious rats, using the tail-cuff method. Serum tumor necrosis factor alpha (TNF)-alpha, interleukin (IL)-1 and IL-6 concentrations were measured with enzyme-linked immunosorbent assay kits. Additionally, lipid levels were evaluated. The present data provide the evidence that amlodipine and atenolol act as immunomodulators of pro-inflammatory cytokines in SHR. Amlodipine decreased TNF-alpha, increased IL-6 and did not affect IL-1 level. Atenolol did not influence TNF-alpha and IL-1, but raised IL-6 in SHR. Additionally, amlodipine decreased total cholesterol level without changing HDL cholesterol level whereas atenolol did not influence lipid levels. The identification of additional immunomodulating properties of hypotensive drugs may be important for better understanding of their mechanisms of action.
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PMID:Influence of amlodipine and atenolol on lipopolysaccharide (LPS)-induced serum concentrations of TNF-alpha, IL-1, IL-6 in spontaneously hypertensive rats (SHR). 1708 63

A 31-year-old female with acute myelocytic leukemia was admitted to our hospital in June 2004. She had complications of brain abscess at the WBC nadir after the second course of induction therapy. However,because the platelet count was low, neurosurgical procedures, including craniotomy/abscess resection, or abscess drainage, were not performed, and we could not detect bacteria or fungus as the cause of brain abscess. Combination therapy with meropenem trihydrate and fosfluconazole was effective. Thereafter, she underwent related peripheral blood stem cell transplantation, and has had no recurrence of brain abscess. Brain abscess during chemotherapy for patients with acute leukemia is commonly due to fungus,particularly Aspergillus, which has a very high fatality rate. Therefore, the treatment of brain abscess without the detection of bacteria and fungus requires combination therapy with antifungal agents and antibiotics. In this case, methionine-positron emission tomography was useful for the evaluation of therapeutic effectiveness for brain abscess.
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PMID:[Improved outcome in brain abscess during induction in acute myelocytic leukemia]. 1749 59

Abnormal dietary intake of macronutrients is implicated in the development of obesity and fatty liver disease. Steatosis develops in cultured hepatocytes exposed to medium containing either a high concentration of long chain free fatty acids (HFFA) or medium deficient in methionine and choline (MCD). This study examined the mitochondrial reactive oxygen species (ROS)-dependent regulation of the phosphoinositol (PI) 3-kinase pathway in steatosis induced by exposure of AML-12 mouse hepatocytes to MCD or HFFA medium. Exposure to either MCD or HFFA medium resulted in increased production of superoxide anions and H(2)O(2), transduction of the PI 3-kinase pathway and steatosis. Inhibition of PI 3-kinase with LY294002 prevented steatosis. Pharmacologically inhibiting electron transport chain complex III production of ROS prevented activation of PI 3-kinase during macronutrient perturbation, whereas pharmacologically promoting electron transport chain complex III ROS production activated PI 3-kinase independent of nutrient input. The data suggest that H(2)O(2) is the ROS species involved in signal transduction; promoting the rapid conversion of superoxide to H(2)O(2) does not inhibit PI 3-kinase pathway activation during nutrient perturbation, and exogenous H(2)O(2) activates it independent of nutrient input. In addition to transducing PI 3-kinase, the ROS-dependent signal cascade amplifies the PI 3-kinase signal by maintaining phosphatase and tensin homolog in its inactive phosphorylated state. Knockdown of phosphatase and tensin homolog by small interfering RNA independently activated the PI 3-kinase pathway. Our findings suggest a common path for response to altered nutrition involving mitochondrial ROS-dependent PI 3-kinase pathway regulation, leading to steatosis.
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PMID:Mitochondrial reactive oxygen species signal hepatocyte steatosis by regulating the phosphatidylinositol 3-kinase cell survival pathway. 1754 Jul 68

Hepatic oxidative stress plays a critical role in metabolic forms of steatohepatitis. Phyllanthus urinaria, an herbal medicine, has been reported to have potential antioxidant properties. We tested the effects of P. urinaria on nutritional steatohepatitis both in vitro and in vivo. Immortalized normal hepatocytes (AML-12) or primary hepatocytes were exposed to control, the methionine-and-choline-deficient (MCD) culture medium, in the presence or absence of P. urinaria for 24 hours. Hepatocyte triglyceride, release of alanine aminotransferase, lipoperoxides, and reactive oxygen species production were determined. Age-matched C57BL/6 and db/db mice were fed control or MCD diet for 10 days with or without P. urinaria. Hepatic steatosis, necroinflammation, triglycerides, and lipid peroxide levels were determined. Hepatic expression of inflammatory factors and lipid regulatory mediators were assayed. P. urinaria reduced steatosis and alanine aminotransferase (ALT) levels in culture of hepatocytes in a dose-dependent manner. Phyllanthus prevented MCD-induced hepatic fat accumulation and steatohepatitis in mice. This effect was associated with repressed levels of hepatic lipid peroxides, reduced expression of cytochrome P450-2E1, pro-inflammatory tumor necrosis factor alpha, interleukin-6, dampened activation of inflammatory c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-kappaB), increased expression of lipolytic cytochrome P450 (Cyp4a10), and suppressed transcriptional activity of lipogenic CCAAT/enhancer binding protein beta (C/EBPbeta). Hepatic acyl co-enzyme A oxidase that regulated hepatic beta-oxidation of fatty acid and other lipid regulators were not affected by P. urinaria. In conclusion, P. urinaria effectively alleviated the steatohepatitis induced by the MCD, probably through dampening oxidative stress, ameliorating inflammation, and decreasing lipid accumulation.
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PMID:Phyllanthus urinaria ameliorates the severity of nutritional steatohepatitis both in vitro and in vivo. 1815 36

To determine whether aberrantly activated tyrosine kinases other than FLT3 and c-KIT contribute to acute myeloid leukemia (AML) pathogenesis, we used high-throughput (HT) DNA sequence ana-lysis to screen exons encoding the activation loop and juxtamembrane domains of 85 tyrosine kinase genes in 188 AML patients without FLT3 or c-KIT mutations. The screen identified 30 nonsynonymous sequence variations in 22 different kinases not previously reported in single-nucleotide polymorphism (SNP) databases. These included a novel FLT3 activating allele and a previously described activating mutation in MET (METT1010I). The majority of novel sequence variants were stably expressed in factor-dependent Ba/F3 cells. Apart from one FLT3 allele, none of the novel variants showed constitutive phosphorylation by immunoblot analysis and none transformed Ba/F3 cells to factor-independent growth. These findings indicate the majority of these alleles are not potent tyrosine kinase activators in this cellular context and that a significant proportion of nonsynonymous sequence variants identified in HT DNA sequencing screens may not have functional significance. Although some sequence variants may represent SNPs, these data are consistent with recent reports that a significant fraction of such sequence variants are "passenger" rather than "driver" alleles and underscore the importance of functional assessment of candidate disease alleles.
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PMID:High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. 1844 Dec 44

The relationship between mitochondria gene mutation and hematological malignancies has been focusing on as a key point in recent studies. This study was aimed to investigate whether in patients with myelodysplastic syndrome (MDS) exists mitochoudria cytochrome oxidase COI and COII gene mutations different from normal tissues and to analyze whether these mutations are "hot spot" mutations. Eighteen MDS patients aged from 20 to 70 years old were brought into this study, including 2 of RA, 3 of RCMD, 7 of RAEB, 5 of AML (transformation from MDS), and 1 of MDS/MPD. The total DNA was extracted both from bone marrow cells and buccal cells of the same patients. A pair of primers was designed to amplify a fragment with 528 base pair (7181 - 7709) by PCR technique, which contained high frequency mutation area of cytochrome oxidase COI and COII gene based on the literature reports. The PCR products were purified and sequenced as bidirection to confirm if there is any mutation. The results of sequence of COI and COII gene from MDS patient bone marrow cells were compared with both the standard sequence from GenBank and the sequence from MDS patient buccal cells. The results showed that 3 single nucleotide changes in 528 bp cytochrome oxidase gene fragment from 18 MDS patients were confirmed. They were 7674 T-->C, 7353 A-->G, and an insert mutation of G at 7702. The former two mutations caused isoleucine-->methionine, and methionine-->viline. The 7702G ins was only confirmed with marrow cells in a patient, and caused a frame shift, which suggested that the mutation might be related to MDS cells. It is concluded that some of "hot spots" of mtDNA mutation in cytochrome oxidase (COI, COII) gene from our MDS patients are failed to be confirmed, but 3 new mutations on this gene are found, which suggested that mitochondria DNA mutations in MDS patients still have much complexity and heterogeneity, mtDNA mutation may be a prophase or an accompany phenomenon of this disease.
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PMID:[Mutation of mitochondria cytochrome oxidase gene in patients with myelodysplastic syndrome]. 1871 66

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