Citations

Abstract High BAALC expression levels are associated with poor outcome in cytogenetically normal acute myeloid leukemia (CN-AML) patients. Recently, miR-3151 was discovered in intron 1 of BAALC. To evaluate the prognostic significance of miR-3151 expression levels and to gain insight into the biologic and prognostic interplay between miR-3151 and its host, miR-3151 and BAALC expression were measured in pretreatment blood of 179 CN-AML patients. Gene-expression profiling and miRNA-expression profiling were performed using microarrays. High miR-3151 expression was associated with shorter disease-free and overall survival, whereas high BAALC expression predicted failure of complete remission and shorter overall survival. Patients exhibiting high expression of both miR-3151 and BAALC had worse outcome than patients expressing low levels of either gene or both genes. In gene-expression profiling, high miR-3151 expressers showed down-regulation of genes involved in transcriptional regulation, posttranslational modification, and cancer pathways. Two genes, FBXL20 and USP40, were validated as direct miR-3151 targets. The results of the present study show that high expression of miR-3151 is an independent prognosticator for poor outcome in CN-AML and affects different outcome end points than its host gene, BAALC. The combination of both markers identified a patient subset with the poorest outcome. This interplay between an intronic miR and its host may have important biologic implications.

Purpose To determine the frequency of DNMT3A mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in primary cytogenetically normal acute myeloid leukemia (CN-AML). Patients and Methods Four hundred fifteen previously untreated adults were analyzed for DNMT3A mutations and established prognostic gene mutations and expression markers. Gene- and microRNA-expression profiles were derived using microarrays. Results Younger (< 60 years; n = 181) and older (≥ 60 years; n = 234) patients had similar frequencies of DNMT3A mutations (35.3% v 33.3%). Missense mutations affecting arginine codon 882 (R882-DNMT3A) were more common (n = 92; 62%) than those affecting other codons (non–R882-DNMT3A). DNMT3A-mutated patients did not differ regarding complete remission rate, but had shorter disease-free survival (DFS; P = .03) and, by trend, overall survival (OS; P = .07) than DNMT3A–wild-type patients. In multivariable analyses, DNMT3A mutations remained associated with shorter DFS (P = .01), but not with shorter OS. When analyzed separately, the two DNMT3A mutation types had different significance by age group. Younger patients with non–R882-DNMT3A mutations had shorter DFS (P = .002) and OS (P = .02), whereas older patients with R882-DNMT3A mutations had shorter DFS (P = .005) and OS (P = .002) after adjustment for other clinical and molecular prognosticators. Gene- and microRNA-expression signatures did not accurately predict DNMT3A mutational status. Conclusion DNMT3A mutations are frequent in CN-AML, and their clinical significance seems to be age dependent. DNMT3A-R882 mutations are associated with adverse prognosis in older patients, and non–R882-DNMT3A mutations are associated with adverse prognosis in younger patients. Low accuracy of gene- and microRNA-expression signatures in predicting DNMT3A mutation status suggested that the role of these mutations in AML remains to be elucidated.

Abstract The associations of mutations in the enhancer of trithorax and polycomb family gene ASXL1 with pretreatment patient characteristics, outcomes, and gene-/microRNA-expression profiles in primary cytogenetically normal acute myeloid leukemia (CN-AML) are unknown. We analyzed 423 adult patients for ASXL1 mutations, other prognostic gene mutations, and gene-/microRNA-expression profiles. ASXL1 mutations were 5 times more common in older (≥ 60 years) patients (16.2%) than those younger than 60 years (3.2%; P < .001). Among older patients, ASXL1 mutations associated with wild-type NPM1 (P < .001), absence of FLT3-internal tandem duplications (P = .002), mutated CEBPA (P = .01), and with inferior complete remission (CR) rate (P = .04), disease-free survival (DFS; P = .03), overall survival (OS; P = .006), and event-free survival (EFS; P = .002). Within the European LeukemiaNet (ELN) genetic categories of older CN-AML, ASXL1 mutations associated with inferior CR rate (P = .02), OS (P < .001), and EFS (P < .001) among ELN Favorable, but not among ELN Intermediate-I patients. Multivariable analyses confirmed associations of ASXL1 mutations with unfavorable CR rate (P = .03), DFS (P < .001), OS (P < .001), and EFS (P < .001) among ELN Favorable patients. We identified an ASXL1 mutation-associated gene-expression signature, but no microRNA-expression signature. This first study of ASXL1 mutations in primary CN-AML demonstrates that ASXL1mutated older patients, particularly within the ELN Favorable group, have unfavorable outcomes and may be candidates for experimental treatment approaches.

It has previously been shown that acoustic ray paths in range-dependent ocean models exhibit chaotic behavior. Most of the investigations into the ray chaos phenomenon have been primarily numerical in nature. The objective of this report is to study theoretically the existence of ray chaos in a parabolic ray system with an analytically prescribed sound-speed model consisting of a double-channel profile perturbed by a typical periodic range-dependent disturbance. The perturbed Hamiltonian ray system is studied analytically via Melnikov’s method. It is shown that, under certain conditions, ray trajectories in some regions of the Poincaré section are equivalent to trajectories of the horseshoe map no matter how small the corresponding perturbation is. These conditions are sufficient for ray chaos and easily satisfied, thus explaining why double-channel propagation is very likely to exhibit chaotic behavior. [Work supported by CA43920 NIH.]

Earlier studies [P. J. Westervelt, J. Acoust. Soc. Am. 29, 199–203, 934–935 (1957)] of the mutual nonlinear interaction of two plane waves of sound with each other are extended to include the viscous effect. The viscous effect is considered both from the equations of motion and the equation of state of the medium. An analytical solution to the lowest order scattering process is obtained if the viscous effect of second order and higher can be neglected. In fact, it is shown that the scattered density ρs of two interacting plane waves having the frequencies ω1 and ω2, respectively, satisfies the following equation: ⧠2vρs=⧠2v{c0−2E12+[(2cosθ +B/A)/2ω1ω2 (1−cosθ)]∇2W12 +[DB(c20ω1ω2)−1 / 4A ×(1−cosθ)2]∇2(∂W12/∂t)+[DB(3+cosθ)/2Ac40 (1−cosθ)](∂V12/∂t)}, where E12, V12, and W12 are, respectively, the total, potential, and special defined energy densities, D is the sound diffusivity, B and A are nonlinearity parameters, θ is the intersecting angle, and ⧠2v is a modified d’Alembertian operator. [Work supported by CA43920 NIH.]

Earlier studies [P. J. Westervelt, J. Acoust. Soc. Am. 29, 199–203, 934–935 (1957)] of the mutual nonlinear interaction of two plane waves of sound with each other are extended to include the viscous effect. The viscous effect is considered both from the equations of motion and the equation of state of the medium. An analytical solution to the lowest-order scattering process is obtained if the viscous effect of second order and higher can be neglected.

Acoustic radiation pressure exerted by an arbitrary acoustic wave in a three-dimensional lossy medium is calculated by extending an indirect approach developed by Chu and Apfel [B-T. Chu and R. E. Apfel, ‘‘Acoustic radiation pressure produced by a beam of sound,’’ J. Acoust. Soc. Am. 72, 1673–1687 (1982)]. Without appealing to the detailed solutions of equations governing fluid motion, a general analytic expression for the radiation pressure in lossy media with arbitrary waves is obtained. When an infinite lossy medium is considered, the expression states that the radiation pressure, to the lowest order of approximation (i.e., second order), is equal to corresponding total energy density. For a special class of confined spaces, the expression leads to a rather general formula for the radiation pressure, in which the radiation pressure is given in terms of various energy densities in the field. Furthermore, a relationship among these energy densities is generalized to the case of lossy media, which enables one to compute the radiation pressure in the class of spaces with the knowledge of the first-order perturbation solution only.

Theories on acoustic radiation pressure associated with plane acoustic waves and lossless media have been examined extensively. The radiation pressure produced by a non-plane wave in a lossy unbounded medium was analyzed. The distinction between Lagrangian and Eulerian pressure was used to clarify the understanding of radiation pressure. The radiation pressure exerted on a perfectly absorbing pointwise target by an arbitrary acoustic wave in an unbounded lossy medium was then considered. By using an indirect approach developed in Chu and Apfel [B.-T. Chu and R. E. Apfel, 1673–1687 (1982)], the radiation pressure was analyzed without appealing to the detailed solutions of the governing fluid dynamic equations. It was shown that even in lossy media with arbitrary waves, the radiation pressure experienced by a pointwise target is equal to the Langevin pressure which is the time average energy density at that point. The radiation pressure exerted on a specific target by an arbitrary acoustic wave in an infinite lossy medium was studied and a concise theoretical result was obtained. [The work was supported by grants CA 43920 and HL 41046 from the National Institutes of Health.]

It has been shown that acoustic ray paths in range-dependent ocean models exhibit chaotic behavior. Most of the investigations into the ray chaos phenomenon have been primarily numerical in nature. Analytical derivation of sufficient conditions for chaos in acoustic systems has been restricted to inherently discrete problems. This article reports a theoretical study of the existence of ray chaos in a class of continuous parabolic ray systems. This class of ray systems is indexed by a family of analytically prescribed double-channel sound-speed profiles perturbed by periodic range-dependent disturbances. The perturbed Hamiltonian ray systems are studied analytically via the Melnikov method. It is shown that, under certain conditions, ray trajectories of the systems are equivalent to trajectories of a classic chaotic system known as the horseshoe map when the perturbation is periodic and small. These conditions are sufficient for ray chaos and easily satisfied, thus explaining why double-channel propagation is very likely to exhibit chaotic behavior.