bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Multitargeted Receptor Tyrosine Kinase Inhibitor Linifanib (ABT-869) Induces Apoptosis through an Akt and Glycogen Synthase Kinase 3β–Dependent Pathway
Authors: Hernandez-Davies Jenny E. , Zape Joan P. , Landaw Elliot M. , Tan Xiaolin , Presnell Ajia , Griffith Diana , Heinrich Michael C. , Glaser Keith B. , Sakamoto Kathleen M. 
Published: April 2011

Abstract
The FMS-like receptor tyrosine kinase 3 (FLT3) plays an important role in controlling differentiation and proliferation of hematopoietic cells. Activating mutations in FLT3 occur in patients with acute myeloid leukemia (AML; 15%–35%), resulting in abnormal cell proliferation. Furthermore, both adult and pediatric patients with AML harboring the FLT3 internal tandem duplication (ITD) mutation have a poor prognosis. Several inhibitors have been developed to target mutant FLT3 for the treatment of AML, yet the molecular pathways affected by drug inhibition of the mutated FLT3 receptor alone have not been characterized as yet. Linifanib (ABT-869) is a multitargeted tyrosine kinase receptor inhibitor that suppresses FLT3 signaling. In this article, we show that treatment with linifanib inhibits proliferation and induces apoptosis in ITD mutant cells in vitro and in vivo. We show that treatment with linifanib reduces phosphorylation of Akt and glycogen synthase kinase 3β (GSK3β). In addition, we show that inhibition of GSK3β decreases linifanib-induced apoptosis. This study shows the importance of GSK3 as a potential target for AML therapy, particularly in patients with FLT3 ITD mutations. Mol Cancer Ther; 10(6); 949–59. ©2011 AACR.
Overexpression of Mitotic Centromere–Associated Kinesin Stimulates Microtubule Detachment and Confers Resistance to Paclitaxel
Authors: Ganguly Anutosh , Yang Hailing , Cabral Fernando 
Published: April 2011

Abstract
Numerous studies have implicated mutations in tubulin or the overexpression of specific tubulin genes in resistance to microtubule-targeted drugs. Much less is known about the role of accessory proteins that modulate microtubule behavior in the genesis of drug resistance. Here, we examine mitotic centromere–associated kinesin (MCAK), a member of the kinesin family of microtubule motor proteins that has the ability to stimulate microtubule depolymerization, and show that overexpressing the protein confers resistance to paclitaxel and epothilone A, but increases sensitivity to colcemid. Cells transfected with FLAG-tagged MCAK cDNA using a tet-off–regulated expression system had a disrupted microtubule cytoskeleton and were able to survive a toxic concentration of paclitaxel in the absence, but not in the presence of tetracycline, showing that drug resistance was caused by ectopic MCAK production. Moreover, a population that was heterogeneous with respect to FLAG-MCAK expression became enriched with cells that produced the ectopic protein when it was placed under paclitaxel selection. Similar to previously isolated mutants with altered tubulin, paclitaxel resistant cells resulting from MCAK overexpression were found to have decreased microtubule polymer and a seven-fold increase in the frequency of microtubule detachment from centrosomes. These data are consistent with a model for paclitaxel resistance that is based on stability of the attachment of microtubules to their nucleating centers, and they implicate MCAK in the mechanism of microtubule detachment. Mol Cancer Ther; 10(6); 929–37. ©2011 AACR.
A Coactivator Role of CARM1 in the Dysregulation of β-Catenin Activity in Colorectal Cancer Cell Growth and Gene Expression
Authors: Ou Chen-Yin , LaBonte Melissa J. , Manegold Philipp C. , So Alex Yick-Lun , Ianculescu Irina , Gerke Daniel S. , Yamamoto Keith R. , Ladner Robert D. , Kahn Michael , Kim Jeong Hoon , Stallcup Michael R. 
Published: April 2011

Abstract
Aberrant activation of Wnt/β-catenin signaling, resulting in the expression of Wnt-regulated oncogenes, is recognized as a critical factor in the etiology of colorectal cancer. Occupancy of β-catenin at promoters of Wnt target genes drives transcription, but the mechanism of β-catenin action remains poorly understood. Here, we show that CARM1 (coactivator-associated arginine methyltransferase 1) interacts with β-catenin and positively modulates β-catenin–mediated gene expression. In colorectal cancer cells with constitutively high Wnt/β-catenin activity, depletion of CARM1 inhibits expression of endogenous Wnt/β-catenin target genes and suppresses clonal survival and anchorage-independent growth. We also identified a colorectal cancer cell line (RKO) with a low basal level of β-catenin, which is dramatically elevated by treatment with Wnt3a. Wnt3a also increased the expression of a subset of endogenous Wnt target genes, and CARM1 was required for the Wnt-induced expression of these target genes and the accompanying dimethylation of arginine 17 of histone H3. Depletion of β-catenin from RKO cells diminished the Wnt-induced occupancy of CARM1 on a Wnt target gene, indicating that CARM1 is recruited to Wnt target genes through its interaction with β-catenin and contributes to transcriptional activation by mediating events (including histone H3 methylation) that are downstream from the actions of β-catenin. Therefore, CARM1 is an important positive modulator of Wnt/β-catenin transcription and neoplastic transformation, and may thereby represent a novel target for therapeutic intervention in cancers involving aberrantly activated Wnt/β-catenin signaling. Mol Cancer Res; 9(5); 660–70. ©2011 AACR.
FOXD3 Regulates Migration Properties and Rnd3 Expression in Melanoma Cells
Authors: Katiyar Pragati , Aplin Andrew E. 
Published: April 2011

Abstract
Forkhead transcription factor, Foxd3, plays a critical role during development by controlling the lineage specification of neural crest cells. Notably, Foxd3 is highly expressed during the wave of neural crest cell migration that forms peripheral neurons and glial cells but is downregulated prior to migration of cells that give rise to the melanocytic lineage. Melanoma is the deadliest form of skin cancer and is derived from melanocytes. Recently, we showed that FOXD3 expression is elevated following the targeted inhibition of the B-RAF–MEK (MAP/ERK kinase)–ERK (extracellular signal-regulated kinase)1/2 pathway in mutant B-RAF melanoma cells. Because melanoma cells are highly migratory and invasive in a B-RAF–dependent manner, we explored the role of FOXD3 in these processes. In this study, we show that ectopic FOXD3 expression inhibits the migration, invasion, and spheroid outgrowth of mutant B-RAF melanoma cells. Upregulation of FOXD3 expression following inhibition of B-RAF and MEK correlates with the downregulation of Rnd3, a Rho GTPase and inhibitor of RhoA–ROCK signaling. Indeed, expression of FOXD3 alone was sufficient to downregulate Rnd3 expression at the mRNA and protein levels. Mechanistically, FOXD3 was found to be recruited to the Rnd3 promoter. Inhibition of ROCK partially restored migration in FOXD3-expressing cells. These data show that FOXD3 expression downregulates migration and invasion in melanoma cells and Rnd3, a target known to be involved in these properties. Mol Cancer Res; 9(5); 545–52. ©2011 AACR.
Functional Inactivation of Endogenous MDM2 and CHIP by HSP90 Causes Aberrant Stabilization of Mutant p53 in Human Cancer Cells
Authors: Li Dun , Marchenko Natalia D. , Schulz Ramona , Fischer Victoria , Velasco-Hernandez Talia , Talos Flaminia , Moll Ute M. 
Published: April 2011

Abstract
The tight control of wild-type p53 by mainly MDM2 in normal cells is permanently lost in tumors harboring mutant p53, which exhibit dramatic constitutive p53 hyperstabilization that far exceeds that of wild-type p53 tumors. Importantly, mutant p53 hyperstabilization is critical for oncogenic gain of function of mutant p53 in vivo. Current insight into the mechanism of this dysregulation is fragmentary and largely derived from ectopically constructed cell systems. Importantly, mutant p53 knock-in mice established that normal mutant p53 tissues have sufficient enzymatic reserves in MDM2 and other E3 ligases to maintain full control of mutant p53. We find that in human cancer cells, endogenous mutant p53, despite its ability to interact with MDM2, suffers from a profound lack of ubiquitination as the root of its degradation defect. In contrast to wild-type p53, the many mutant p53 proteins which are conformationally aberrant are engaged in complexes with the HSP90 chaperone machinery to prevent its aggregation. In contrast to wild-type p53 cancer cells, we show that in mutant p53 cancer cells, this HSP90 interaction blocks the endogenous MDM2 and CHIP (carboxy-terminus of Hsp70-interacting protein) E3 ligase activity. Interference with HSP90 either by RNA interference against HSF1, the transcriptional regulator of the HSP90 pathway, or by direct knockdown of Hsp90 protein or by pharmacologic inhibition of Hsp90 activity with 17AAG (17-allylamino-17-demethoxygeldanamycin) destroys the complex, liberates mutant p53, and reactivates endogenous MDM2 and CHIP to degrade mutant p53. Of note, 17AAG induces a stronger viability loss in mutant p53 than in wild-type p53 cancer cells. Our data support the rationale that suppression of mutant p53 levels in vivo in established cancers might achieve clinically significant effects. Mol Cancer Res; 9(5); 577–88. ©2011 AACR.
Mesoscale Controls on the Mountainside Snow Line
Authors: Minder Justin R. , Durran Dale R. , Roe Gerard H. 
Published: April 2011

Abstract
Observations show that on a mountainside the boundary between snow and rain, the snow line, is often located at an elevation hundreds of meters below its elevation in the free air upwind. The processes responsible for this mesoscale lowering of the snow line are examined in semi-idealized simulations with a mesoscale numerical model and in simpler theoretical models. Spatial variations in latent cooling from melting precipitation, in adiabatic cooling from vertical motion, and in the melting distance of frozen hydrometeors are all shown to make important contributions. The magnitude of the snow line drop, and the relative importance of the responsible processes, depends on properties of the incoming flow and terrain geometry. Results suggest that the depression of the snow line increases with increasing temperature, a relationship that, if present in nature, could act to buffer mountain hydroclimates against the impacts of climate warming. The simulated melting distance, and hence the snow line, depends substantially on the choice of microphysical parameterization, pointing to an important source of uncertainty in simulations of mountain snowfall.
The Effect of Mesh Resolution on Convective Boundary Layer Statistics and Structures Generated by Large-Eddy Simulation
Authors: Sullivan Peter P. , Patton Edward G. 
Published: April 2011

Abstract
A massively parallel large-eddy simulation (LES) code for planetary boundary layers (PBLs) that utilizes pseudospectral differencing in horizontal planes and solves an elliptic pressure equation is described. As an application, this code is used to examine the numerical convergence of the three-dimensional time-dependent simulations of a weakly sheared daytime convective PBL on meshes varying from 323 to 10243 grid points. Based on the variation of the second-order statistics, energy spectra, and entrainment statistics, LES solutions converge provided there is adequate separation between the energy-containing eddies and those near the filter cutoff scale. For the convective PBL studied, the majority of the low-order moment statistics (means, variances, and fluxes) become grid independent when the ratio zi/(CsΔf) &gt; 310, where zi is the boundary layer height, Δf is the filter cutoff scale, and Cs is the Smagorinsky constant. In this regime, the spectra show clear Kolmogorov inertial subrange scaling. The bulk entrainment rate determined from the time variation of the boundary layer height we = dzi/dt is a sensitive measure of the LES solution convergence; we becomes grid independent when the vertical grid resolution is able to capture both the mean structure of the overlying inversion and the turbulence. For all mesh resolutions used, the vertical temperature flux profile varies linearly over the interior of the boundary layer and the minimum temperature flux is approximately −0.2 of the surface heat flux. Thus, these metrics are inadequate measures of solution convergence. The variation of the vertical velocity skewness and third-order moments expose the LES’s sensitivity to grid resolution.
Impacts of Idealized Air–Sea Coupling on Madden–Julian Oscillation Structure in the Superparameterized CAM
Authors: Benedict James J. , Randall David A. 
Published: April 2011

AbstractAir–sea interactions and their impact on intraseasonal convective organization are investigated by comparing two 5-yr simulations from the superparameterized Community Atmosphere Model version 3.0 (SP-CAM). The first is forced using prescribed sea surface temperatures (SSTs). The second is identical except that a simplified oceanic mixed-layer model is used to predict tropical SST anomalies that are coupled to the atmosphere. This partially coupled simulation allows SSTs to respond to anomalous surface fluxes.Implementation of the idealized slab ocean model in the SP-CAM results in significant changes to intraseasonal convective variability and organization. The more realistic treatment of air–sea interactions in the coupled simulation improves many aspects of tropical convection on intraseasonal scales, from the relationships between precipitation and SSTs to the space–time structure and propagation of the Madden–Julian oscillation (MJO). This improvement is associated with a more realistic convergence structure and longitudinal gradient of SST relative to MJO deep convection. In the uncoupled SP-CAM, SST is roughly in phase with the MJO convective center and the development of the Kelvin wave response and boundary layer convergence east of the convective center is relatively weak. In the coupled SP-CAM, maxima in SST lead maxima in MJO convection by cycle. Coupling produces warmer SSTs, a stronger Kelvin wave response, enhanced low-level convergence, and increased convective heating ahead (east) of the MJO convective center. Convective development east of the MJO precipitation center is more favorable in the coupled versus the uncoupled version, resulting in more realistic organization and clearer eastward propagation of the MJO in the coupled SP-CAM.
Can Wind Lidars Measure Turbulence?
Authors: Sathe A. , Mann J. , Gottschall J. , Courtney M. S. 
Published: April 2011

AbstractModeling of the systematic errors in the second-order moments of wind speeds measured by continuous-wave (ZephIR) and pulsed (WindCube) lidars is presented. These lidars use the conical scanning technique to measure the velocity field. The model captures the effect of volume illumination and conical scanning. The predictions are compared with the measurements from the ZephIR, WindCube, and sonic anemometers at a flat terrain test site under different atmospheric stability conditions. The sonic measurements are used at several heights on a meteorological mast in combination with lidars that are placed on the ground. Results show that the systematic errors are up to 90% for the vertical velocity variance, whereas they are up to 70% for the horizontal velocity variance. For the ZephIR, the systematic errors increase with height, whereas for the WindCube, they decrease with height. The systematic errors also vary with atmospheric stability and are low for unstable conditions. In general, for both lidars, the model agrees well with the measurements at all heights and under different atmospheric stability conditions. For the ZephIR, the model results are improved when an additional low-pass filter for the 3-s scan is also modeled. It is concluded that with the current measurement configuration, these lidars cannot be used to measure turbulence precisely.
The Madden–Julian Oscillation’s Influence on African Easterly Waves and Downstream Tropical Cyclogenesis
Authors: Ventrice Michael J. , Thorncroft Chris D. , Roundy Paul E. 
Published: April 2011

The influence of the Madden–Julian oscillation (MJO) over tropical Africa and Atlantic is explored during the Northern Hemisphere summer months. The MJO is assessed by using real-time multivariate MJO (RMM) indices. These indices divide the active convective signal of the MJO into 8 phases. Convection associated with the MJO is enhanced over tropical Africa during RMM phases 8, 1, and 2. Convection becomes suppressed over tropical Africa during the subsequent RMM phases (phases 3–7). African convective signals are associated with westward-propagating equatorial Rossby waves. The MJO modulates African easterly wave (AEW) activity. AEW activity is locally enhanced during RMM phases 1–3 and suppressed during RMM phases 6–8. Enhanced AEW activity occurs during periods of enhanced convection over tropical Africa, consistent with stronger or more frequent triggering of AEWs as well as more growth associated with latent heat release. Enhanced AEW activity occurs during the low-level westerly wind phase of the MJO, which increases the cyclonic shear on the equatorward side of the AEJ, increasing its instability. Atlantic tropical cyclogenesis frequency varies coherently with the MJO. RMM phases 1–3 show the greatest frequency of tropical cyclogenesis events whereas phases 7 and 8 show the least. RMM phase 2 is also the most likely phase to be associated with a train of three or more tropical cyclones over the tropical Atlantic. This observed evolution of tropical cyclogenesis frequency varies coherently with variations in AEW activity and the large-scale environment.
Cloud Modeling Tests of the ULTIMATE–MACHO Scalar Advection Scheme
Authors: Yamaguchi Takanobu , Randall David A. , Khairoutdinov Marat F. 
Published: April 2011

AbstractNumerical diffusion can be minimized using fine grid spacing and/or higher-order numerical schemes. In this study, the authors focus on higher-order scalar advection schemes and their effects on simulated cloud fields. A monotonic multidimensional odd-order conservative advection scheme has been implemented, following the approach of Leonard. It has been tested in simulations of idealized scalar fields advected by simple prescribed motion, as well as turbulence fields; large-eddy simulations of turbulent stratocumulus clouds; and simulations of deep convective clouds. New third-, fifth-, and seventh-order schemes are compared with the second-order scheme originally used in the model. For the deep cumulus case, a high-resolution large-eddy simulation with the same domain size is used as a benchmark.The fifth-order scheme shows much less numerical diffusion than the lower-order scheme. The additional improvement with the seventh-order scheme is minor. The higher-order scheme generally produces simulated cloud fields similar to those obtained with a lower-order scheme with a finer grid spacing. This effect is especially noticeable for the updraft-core statistics of the deep cumulus simulation, as compared with the benchmark simulation. The fifth-order scheme with coarse horizontal resolution produces results close to those of the benchmark simulation. Compared to a high-resolution simulation with the low-order scheme, the numerical cost of the fifth-order simulation is smaller than a factor of 10.
Extremal Dependence Indices: Improved Verification Measures for Deterministic Forecasts of Rare Binary Events
Authors: Ferro Christopher A. T. , Stephenson David B. 
Published: April 2011

Abstract
Verifying forecasts of rare events is challenging, in part because traditional performance measures degenerate to trivial values as events become rarer. The extreme dependency score was proposed recently as a nondegenerating measure for the quality of deterministic forecasts of rare binary events. This measure has some undesirable properties, including being both easy to hedge and dependent on the base rate. A symmetric extreme dependency score was also proposed recently, but this too is dependent on the base rate. These two scores and their properties are reviewed and the meanings of several properties, such as base-rate dependence and complement symmetry that have caused confusion are clarified. Two modified versions of the extreme dependency score, the extremal dependence index, and the symmetric extremal dependence index, are then proposed and are shown to overcome all of its shortcomings. The new measures are nondegenerating, base-rate independent, asymptotically equitable, harder to hedge, and have regular isopleths that correspond to symmetric and asymmetric relative operating characteristic curves.
How Are Adherent People More Likely to Think? A Meta-Analysis of Health Beliefs and Diabetes Self-Care
Authors: Gherman Amfiana , Schnur Julie , Montgomery Guy , Sassu Raluca , Veresiu Ioan , David Daniel 
Published: April 2011

Purpose Diabetes is increasingly prevalent, and nonadherence with diabetes treatment regimens is associated with physical and social costs. Psychological predictors of adherence have been investigated in the literature, including cognitive factors. The present meta-analysis was conducted to investigate the association between beliefs related to diabetes and adherence to diabetes regimens. Methods Studies that measured both (a) beliefs, perceptions, or cognitions about diabetes and (b) the relationship between such cognitive factors and blood glucose levels or other adherence behaviors were included. This research focused on adults with any type of diabetes, reaching a final sample of 48 studies. The effect size r was calculated for all types of beliefs and outcomes. Results The types of beliefs most strongly associated with adherence were self-efficacy, perceiving a positive relationship with physician, and beliefs about the personal consequences of adherence. A few limitations of this meta-analysis are that studies were only retrieved through databases and other sources were not searched, only articles in English were included, and only adult participants were included. Conclusions People who are more adherent have a higher level of confidence in their ability to follow medical recommendations, expect more meaningful positive consequences for adherence, and perceive a more positive relationship with their health care provider. Educators and clinicians could use cognitive restructuring techniques to facilitate these types of beliefs and perceptions in people with diabetes.
The Pluralism Debate in Heterodox Economics
Authors: Lee Frederic S. 
Published: April 2011

The discourse in the pluralism debate in heterodox economics concludes that contested inquiry does not exist in economics and that heterodox economics is not an alternative to mainstream economics. This article responds to this claim and concludes pluralism is about promoting the right to have distinctly different theories and contested inquiry in economics. JEL classification: B40, B50
Pluralism, Heterodoxy, and the Rhetoric of Distinction
Authors: Mearman Andrew 
Published: April 2011

The paper addresses the arguments made by Frederic Lee on heterodoxy and pluralism. It argues that the definitions of mainstream and heterodox, and consequently the differences between them, are highly problematic. Specifically it challenges Lee’s characterizations of mainstream and heterodox economics as noncomparable. Attempts to contrast them starkly are part of a rhetoric of distinction which may be problematic. Thus, Lee’s concept of intellectual pluralism may be weaker than it seems, because it is based on distinction and its tolerance, rather than an embrace of diversity. Further, both theoretical and intellectual pluralism may be based on wider epistemological and ontological grounds and thus Lee’s distinction between them may also be problematic. Sheila Dow’s structured pluralism may be a more productive way of embracing difference. JEL classification: B40, B5