In acute myeloid leukemia (AML) with complex aberrant karyotype, a loss of one TP53 allele is frequently observed. We analyzed the incidence of TP53 mutations and deletions in 107 AML with complex aberrant karyotype. In 50 of 57 cases showing a loss of one TP53 allele, a TP53 mutation was detected in the remaining allele. In addition, in 33 of 50 cases with two TP53 copies, a TP53 mutation was found. Therefore, the frequency of TP53 mutations in AML with complex aberrant karyotype was 78%. In a second step, we analyzed TP53 mutations in a cohort of AML comprising different cytogenetic subgroups. TP53 mutations were detected in 33 of 235 cases (14%). Coincidences with other molecular mutations were rare. We confirmed a high incidence of TP53 mutations in AML with a complex aberrant karyotype (29/42, 69%) IntroductionThe TP53 gene is the most frequently mutated gene in human tumors identified so far.1 In contrast, the reported TP53 mutation rate in acute myeloid leukemia (AML) is low.2-5 However, in AML with complex aberrant karyotype, a loss of the short arm of chromosome 17 is frequently observed, where the TP53 gene is located. 6 In a previous series, we showed a loss of one copy of the TP53 gene in 66 of 125 cases with AML and a complex aberrant karyotype (52.8%) by fluorescence in situ hybridization (FISH). 7 According to the classical tumor suppressor gene model, it can be assumed that mutations in the remaining allele are frequent. Therefore, the aim of this study was to determine the frequency of TP53 deletions and mutations in AML with a complex aberrant karyotype. In addition, we evaluated a cohort of AML representing all frequent cytogenetic subgroups for their respective frequency of TP53 mutations and analyzed the relation to other molecular genetic aberrations. Patients and methods PatientsAfter the informed written consent was obtained, bone marrow or peripheral blood samples, which were referred to our laboratory were analyzed with chromosome banding analysis, interphase FISH and for molecular mutations. Two different cohorts were analyzed: (1) 107 cases with AML and a complex aberrant karyotype defined as showing three or more clonal abnormalities but no balanced rearrangement leading to a leukemia-specific fusion gene; (2) 235 AML cases (214 de novo AML, 13 therapy-related AML (t-AML) and eight AML evolving from a myelodysplastic syndrome (s-AML)) comprising cases of all frequent cytogenetic categories (Table 1). Metaphase cytogeneticsCultivation and chromosome preparation was carried out as described elsewhere. In each case with a complex aberrant karyotype, results of G-banding analysis were confirmed by 24-color FISH. Chromosomes were classified according to the International System for Human Cytogenetic Nomenclature (ISCN, 1995). 8 Fluorescence in situ hybridizationInterphase FISH with a probe for the TP53 gene (ABBOTT, Wiesbaden, Germany) was performed in all cases with a complex aberrant karyotype as described previously. 7 TP53 mutation analysis TP53 mutation analysis was carried out u...
The poor prognosis of chronic lymphocytic leukemia (CLL) patients with del (17p) is well established. We analyzed whether mutation of TP53 on the remaining allele adds to the poor prognosis or whether even TP53 mutation alone may be an adverse prognostic factor. We analyzed TP53 mutations in 193 CLL patients by denaturing high performance liquid chromatography in combination with direct DNA sequencing and a TP53 resequencing research microarray. Mutations were correlated to chromosomal aberrations defined by interphase fluorescent in situ hybridization and chromosome banding analyses and to the clinical course of patients. TP53 mutations were detected in 13.5% (26 of 193) of samples, whereas the incidence of del (17p) was 9.3% (18 of 193). TP53 mutations were significantly associated with del (17p) (concordance 94%, P<0.001) and complex cytogenetic abnormalities (concordance 50%, P<0.001). Among 147 patients whose clinical data were available, patients with TP53 abnormalities (n=20) had a significantly decreased time to treatment compared to patients without TP53 aberration (P<0.001). Median time to treatment was short in patients with isolated TP53 mutation (n=6, 2.0 months) and in those with del (17p) (n=14, 21.3 months) as compared to patients without TP53 aberration (n=127, 64.9 months, P<0.001). In multivariate Cox regression analysis, VH status, TP53 mutations and also isolated TP53 mutations independently predicted rapid disease progression.
If high sodium intake is involved in the pathogenesis of essential hypertension, the effects of changing the sodium intake should be demonstrable in the susceptible part of the normotensive population. Therefore, we have investigated the effects of moderate salt restriction in 52 young normotensive subjects with and without a family history of hypertension; 22 (42%) responded to moderate salt restriction (200 to 50 mmol/day) over 2 weeks, with a significant fall in blood pressure shown by continuous automatic blood pressure recordings. Accordingly, these subjects were classified as salt-sensitive, and the remainder as salt-resistant. Compared to salt-resistant subjects, salt-sensitive subjects showed a 2.5-fold higher incidence of a positive family history of hypertension (p less than 0.01), and a significantly higher blood pressure and lower salivary sodium concentration during the usual high sodium diet. Although there were no differences in Na,K-ATPase activity and in Na-K cotransport of erythrocytes, the pressor response to infused norepinephrine in salt-sensitive subjects was double that of salt-resistant subjects independent of the diet and this was linked to indirect evidence for enhanced proximal tubular sodium reabsorption. On the usual high sodium diet, 40% of the normal population may be salt-sensitive and prone to develop hypertension. Hypersensitivity to catecholamines (genetically determined?) may be the cause of salt sensitivity. A low sodium concentration in saliva deserves further study as a simple screening test to identify salt-sensitive subjects.
L-Theanine, an amino acid in green tea, is suggested to improve cognition and mood. Therefore, L-theanine is available as a supplement and is now used as an ingredient in functional drinks. Because data on the metabolic fate of L-theanine from human studies are lacking, we investigated the kinetics of L-theanine uptake and its metabolites, ethylamine and glutamic acid, in healthy participants. Within a randomized crossover study, 12 participants ingested a bolus of 100 mg L-theanine via capsules or green tea. On further occasions, 3 participants received 50 and 200 mg L-theanine via capsules. Blood and urine were collected before and up to 24 h postconsumption to determine the concentrations of L-theanine, proteinogenic amino acids, and ethylamine in plasma, erythrocytes, and urine by HPLC. L-Theanine increased in plasma, erythrocytes, and urine with comparable results after both treatments. The maximum plasma concentration of L-theanine occurred 0.8 h after intake of 100 mg L-theanine via capsules (24.3 ± 5.7 μmol/L) and tea (26.5 ± 5.2 μmol/L), respectively. The AUC of L-theanine in plasma increased dose dependently after intake of 50, 100, and 200 mg L-theanine via capsules. Moreover, ethylamine and glutamic acid increased in plasma and were excreted by urine after intake of capsules and tea. In conclusion, L-theanine is rapidly absorbed and seems to be hydrolyzed to ethylamine and glutamic acid. A minor part of L-theanine is retained in erythrocytes. Kinetics and urinary excretion of L-theanine, ethylamine, and glutamic acid are comparable after both treatments. Thus, functional effects of L-theanine intake may result from L-theanine, ethylamine, or glutamic acid.
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