bluuebunny/crossref_metadata_2025 huggingface dataset:
ON A HYPERBOLIC–PARABOLIC SYSTEM MODELING CHEMOTAXIS
Authors: LI DONG , LI TONG , ZHAO KUN
Published: March 2011

We investigate local/global existence, blowup criterion and long-time behavior of classical solutions for a hyperbolic–parabolic system derived from the Keller–Segel model describing chemotaxis. It is shown that local smooth solution blows up if and only if the accumulation of the L∞ norm of the solution reaches infinity within the lifespan. Our blowup criteria are consistent with the chemotaxis phenomenon that the movement of cells (bacteria) is driven by the gradient of the chemical concentration.

Furthermore, we study the long-time dynamics when the initial data is sufficiently close to a constant positive steady state. By using a new Fourier method adapted to the linear flow, it is shown that the smooth solution exists for all time and converges exponentially to the constant steady state with a frequency-dependent decay rate as time goes to infinity.
AN EFFICIENT NUMERICAL METHOD FOR CAVITATION IN NONLINEAR ELASTICITY
Authors: XU XIANMIN , HENAO DUVAN
Published: March 2011

This paper is concerned with the numerical computation of cavitation in nonlinear elasticity. The Crouzeix–Raviart nonconforming finite element method is shown to prevent the degeneration of the mesh provoked by the conventional finite element approximation of this problem. Upon the addition of a suitable stabilizing term to the elastic energy, the method is used to solve cavitation problems in both radially symmetric and non-radially symmetric settings. While the radially symmetric examples serve to illustrate the efficiency of the method, and for validation purposes, the experiments with non-centered and multiple cavities (carried out for the first time) yield novel observations of situations potentially leading to void coalescence.
CONSOLIDATING A HEURISTIC FOR INCREMENTAL DECISION TREE LEARNING THROUGH ASYMPTOTIC ANALYSIS
Authors: KALLES DIMITRIS , PAPAGELIS ATHANASIOS , STAMATIOU YANNIS C.
Published: March 2011

This paper addresses stability issues in incremental induction of decision trees. Stability problems arise when an induction algorithm must revise a decision tree very often and oscillations between similar concepts decrease learning speed. We review a heuristic that solves this problem and subsequently employ asymptotic analysis to approximate the basic parameters related to the estimation of computational effort in incremental learning of decision trees. We then use these approximations to simplify the heuristic, we deliver insight into its amortizing behavior and argue how they can also speed-up its execution and enhance its applicability, also providing experimental evidence to support these claims.
CREATING CONTEXT-AWARE COLLABORATIVE WORKING ENVIRONMENTS
Authors: MARTÍNEZ-CARRERAS M. ANTONIA , MUÑOZ ANDRÉS , BOTÍA JUAN , GÓMEZ-SKARMETA ANTONIO F.
Published: March 2011

Context-aware systems are intended for providing services adapted to the needs of people, by taking into account their state and the information related to their environment. One alternative to represent this context information resides in the use of Semantic Web ontologies. They provide a formal vocabulary which allows to easily express and share knowledge. Additionally, several types of automatic knowledge manipulation and reasoning processes become available thanks to the formal features of such ontologies. The inclusion of context information through ontologies in Collaborative Working Environments (CWEs) may bring important benefits to team work inside an organization, such as an automatic selection between different collaborative services according to the team members' preferences and their current state. This paper describes the design and implementation of a context-reasoning system which has been integrated into a CWE architecture to take advantage of context-awareness.
DIFFERENT ANESTHESIA IN RAT INDUCES DISTINCT INTER-STRUCTURE BRAIN DYNAMIC DETECTED BY HIGUCHI FRACTAL DIMENSION
Authors: SPASIC SLADJANA , KESIC SRDJAN , KALAUZI ALEKSANDAR , SAPONJIC JASNA
Published: March 2011

The complexity, entropy and other non-linear measures of the electroencephalogram (EEG), such as Higuchi fractal dimension (FD), have been recently proposed as the measures of anesthesia depth and sedation. We hypothesized that during unconciousness in rats induced by the general anesthetics with opposite mechanism of action, behaviorally and poligraphically controlled as appropriately achieved stable anesthesia, we can detect distinct inter-structure brain dynamic using mean FDs. We used the surrogate data test for nonlinearity in order to establish the existence of nonlinear dynamics, and to justify the use of FD as a nonlinear measure in the time series analysis. The surrogate data of predefined probability distribution and autocorrelation properties have been generated using the algorithm of statically transformed autoregressive process (STAP). FD then is applied to quantify EEG signal complexity at the cortical, hippocampal and pontine level during stable general anesthesia (ketamine/xylazine or nembutal anesthesia).

Our study showed for the first time that global neuronal inhibition caused by different mechanisms of anesthetic action induced distinct brain inter-structure complexity gradient in Sprague Dawley rats. EEG signal complexities were higher at cortical and hippocampal level in ketamine/xylazine vs. nembutal anesthesia, with the dominance of hippocampal complexity. In nembutal anesthesia the complexity dominance moved to pontine level, and ponto-hippocampo-cortical decreasing complexity gradient was established. This study has proved the Higuchi fractal dimension as a valuable tool for measuring the anesthesia induced inter-structure EEG complexity.
OPTIMAL EXERCISE OF AN EXECUTIVE STOCK OPTION BY AN INSIDER
Authors: MONOYIOS MICHAEL , NG ANDREW
Published: March 2011

We consider an optimal stopping problem arising in connection with the exercise of an executive stock option by an agent with inside information. The agent is assumed to have noisy information on the terminal value of the stock, does not trade the stock or outside securities, and maximises the expected discounted payoff over all stopping times with regard to an enlarged filtration which includes the inside information. This leads to a stopping problem governed by a time-inhomogeneous diffusion and a call-type reward. We establish conditions under which the option value exhibits time decay, and derive the smooth fit condition for the solution to the free boundary problem governing the maximum expected reward, and derive the early exercise decomposition of the value function. The resulting integral equation for the unknown exercise boundary is solved numerically and this shows that the insider may exercise the option before maturity, in situations when an agent without the privileged information may not. Hence we show that early exercise may arise due to the agent having inside information on the future stock price.
ON THE PENALTY FUNCTION AND ON CONTINUITY PROPERTIES OF RISK MEASURES
Authors: FRITTELLI MARCO , GIANIN EMANUELA ROSAZZA
Published: March 2011

We discuss two issues about risk measures: we first point out an alternative interpretation of the penalty function in the dual representation of a risk measure; then we analyze the continuity properties of comonotone convex risk measures. In particular, due to the loss of convexity, local and global continuity are no more equivalent and many implications true for convex risk measures do not hold any more.
WHAT I LEARNED FROM BRITTON CHANCE
Authors: MASTERS BARRY R.
Published: March 2011

In this personal and reflective article, I honor the memory of Britton Chance and explain how his mentorship during my tenure at the Johnson Research Foundation greatly impacted my scientific career. I emphasize the critical role of mentors on the development of scientists and present some wonderful and remarkable attributes that characterized Britton Chance's scientific and personal style.
英国高技术移民政策的变迁与华人新移民的回应
Authors: 姚丽云
Published: March 2011

本文主要阐述英国20世纪90年代以来高技术移民政策的演变过程，以及中国高技术移民对政策的反应。围绕英国高技术移民项目与工作签证制度的沿革，移民政策的变化对高技术移民产生显著的影响。另一方面，这些高技术移民的反应及应对策略，对于移民政策的再建构具有反向作用力。高技术移民政策的演变是政府与多方力量共同权衡的结果。高技术移民和移民输入国政府在跨国场域中的关系也在移民政策的互动中得以进一步展示。
Neotectonic constraints on the Gaxun Nur inland basin in north-central China, derived from remote sensing, geomorphology and geophysical analyses
Authors: Hartmann Kai , Wünnemann Bernd , Hölz Sebastian , Kraetschell Anna , Zhang Hucai
Published: March 2011

The endorheic Gaxun Nur Basin (GNB, local name: Ejina basin), which is located north of the Tibetan Plateau between the tectonic stress fields of the Qilian Shan and the Gobi-Tienshan, has evolved as a large inland basin filled with deltaic sediments during the past 250 ka. Here we present selected examples of geomorphological, sedimentological and geophysical evidence of tectonic activity and discuss a possible time frame of selected occurrences.

We used medium-scale geomorphological mapping supported by analyses of Landsat ETM images, Corona images and an Aster Digital Terrain Model (Aster-DTM), combined with field surveys, dated sediment sections, and geophysical investigations using electromagnetic methods.

The spatio-temporal distribution of radiocarbon-dated lake sediments within the northern GNB indicates a non-even distribution of neotectonic activity with west–east increasing amplitude of subsidence rates from 0.8–1.1 m/ka in the western part and more than three times higher rates in the eastern part.

Our data indicate that tectonic has strongly amplified climate-induced environmental changes and may be regarded as an example of non-climatic pulses affecting lake-hydrology and basin development.
Rock type, precipitation, and the steepness of Himalayan threshold hillslopes
Authors: Korup Oliver , Weidinger Johannes T.
Published: March 2011

Studies on the dynamic coupling between tectonics, climate, and erosion at the margins of the Tibetan Plateau entail the notion of widely occurring threshold hillslopes along the southern Himalayan front. Here we show that differences in major lithological units are sufficient to explain trends in topographical relief and mean slope gradients across the eastern Nepal Himalaya. This lithological control is manifest in modal slope gradients that serve as proxies of peak rock-mass strength, and remain strikingly invariant per rock type on both sides of the Main Central Thrust (MCT) despite comparably high amounts of monsoon precipitation. We infer that lithology rather precipitation patterns plays an important though hitherto largely neglected role in modulating threshold hillslope steepness. A nonlinear relationship between mean slope gradients and relief further indicates that significant steepening of threshold hillslopes through relief increases is more readily facilitated in low-relief terrain. Most evidence of large (>10
8
m
3
) bedrock landslides in the Himalaya clusters where topographical relief >2 km, and slope gradients are above average. This provides the mechanism necessary for rapidly lowering drainage divides and limiting hillslope heights, were the steepness of threshold hillslopes to decline via relief destruction.
Promoter characterization and role of CRE in the basal transcription of the rat SNAT2 gene
Authors: Ortiz Victor , Alemán Gabriela , Escamilla-Del-Arenal Martín , Recillas-Targa Félix , Torres Nimbe , Tovar Armando R.
Published: March 2011

Small neutral amino acid transporter 2 (SNAT2) is the most abundant and ubiquitous transporter for zwitterionic short-chain amino acids. The activity of this amino acid transporter is stimulated in vivo or in vitro by glucagon or cAMP analogs. However, it is not known whether the increase in activity at the protein level is due to an increase in SNAT2 gene transcription. Thus, the aim of the present work was to study whether cAMP was able to stimulate SNAT2 gene expression and to localize and characterize the presence of cAMP response elements (CRE) in the promoter that controls the expression of the rat SNAT2 gene. We found that consumption of a high-protein diet that increased serum glucagon concentration or the administration of glucagon or incubation of hepatocytes with forskolin increased the SNAT2 mRNA level. We then isolated the 5′ regulatory region of the SNAT2 gene and determined that the transcriptional start site was located 970 bp upstream of the translation start codon. We identified two potential CRE sites located at −354 and −48 bp. Our results, using deletion analysis of the 5′ regulatory region of the SNAT2 gene, revealed that the CRE site located at −48 bp was fully responsible for SNAT2 regulation by cAMP. This evidence was strongly supported by mutation of the CRE site and EMSA and ChIP analysis. Alignment of rat, mouse, and human sequences revealed that this CRE site is highly conserved among species, indicating its essential role in the regulation of SNAT2 gene expression.
Exercise training does not correct abnormal cardiac glycogen accumulation in thedb/dbmouse model of type 2 diabetes
Authors: Shearer Jane , Ross Karen D. , Hughey Curtis C. , Johnsen Virginia L. , Hittel Dustin S. , Severson David L.
Published: March 2011

Substrate imbalance is a well-recognized feature of diabetic cardiomyopathy. Insulin resistance effectively limits carbohydrate oxidation, resulting in abnormal cardiac glycogen accumulation. Aims of the present study were to 1) characterize the role of glycogen-associated proteins involved in excessive glycogen accumulation in type 2 diabetic hearts and 2) determine if exercise training can attenuate abnormal cardiac glycogen accumulation. Control ( db+) and genetically diabetic ( db/db) C57BL/KsJ-leprdb/leprdbmice were subjected to sedentary or treadmill exercise regimens. Exercise training consisted of high-intensity/short-duration (10 days) and low-intensity/long-duration (6 wk) protocols. Glycogen levels were elevated by 35–50% in db/db hearts . Exercise training further increased (2- to 3-fold) glycogen levels in db/db hearts. Analysis of soluble and insoluble glycogen pools revealed no differential accumulation of one glycogen subspecies. Phosphorylation (Ser640) of glycogen synthase, an indicator of enzymatic fractional activity, was greater in db/db mice subjected to sedentary and exercise regimens. Elevated glycogen levels were accompanied by decreased phosphorylation (Thr172) of 5′-AMP-activated kinase and phosphorylation (Ser79) of its downstream substrate acetyl-CoA carboxylase. Glycogen concentration was not associated with increases in other glycogen-associated proteins, including malin and laforin. Novel observations show that exercise training does not correct diabetes-induced elevations in cardiac glycogen but, rather, precipitates further accumulation.
Exaggerated sympathetic mediated responses to behavioral or pharmacological challenges following antenatal betamethasone exposure
Authors: Shaltout Hossam A. , Chappell Mark C. , Rose James C. , Diz Debra I.
Published: March 2011

Glucocorticoid administration to women at risk for preterm delivery is standard practice to enhance neonatal survival. However, antenatal betamethasone exposure (β-exposure) increases mean arterial pressure (MAP) in adult sheep (1.8 yr old) and results in impaired baroreflex sensitivity (BRS) for control of heart rate (HR). In the current studies we tested the hypothesis that enhanced sympathetic nervous system and hypothalamo-pituitary-adrenal (HPA) axis-mediated responses are evident at an early age in β-exposed sheep. Pregnant ewes were administered betamethasone (0.17 mg/kg twice over 24 h) or vehicle (Veh-control) on the 80th day of gestation, and offspring were delivered at full term. Female β-exposed and control offspring instrumented at age 42 ± 3 days for conscious continuous recording of MAP and HR had similar resting values at baseline. However, BRS was ∼45% lower in β-exposed offspring. β-Exposed lambs allowed to suckle for 10 min had a greater elevation in MAP than Veh-control lambs (19 ± 1 vs 12 ± 2 mmHg; n = 4–5, P < 0.05). MAP was reduced by 20% from baseline via sodium nitroprusside infusion (SNP) over 10 min, which triggered a rebound increase in MAP only in β-exposed lambs. HR increased with the reduction in MAP during SNP infusion in Veh-control lambs, whereas there was no change in HR with the reduction in MAP in β-exposed lambs. Combined vasopressin-CRF injection caused greater increases in MAP in the β-exposed lambs. Cortisol and ACTH responses were higher in response to SNP hypotension in the β-exposed lambs. The data reveal enhanced sympathetic and HPA axis responses associated with impaired BRS preceding differences in resting MAP in preweanling female lambs exposed in utero to glucocorticoids. The consequences of these alterations at an early age include eventual development of higher blood pressure in this ovine model of fetal programming.
High-fat diet induces an initial adaptation of mitochondrial bioenergetics in the kidney despite evident oxidative stress and mitochondrial ROS production
Authors: Ruggiero Christine , Ehrenshaft Marilyn , Cleland Ellen , Stadler Krisztian
Published: March 2011

Obesity and metabolic syndrome are associated with an increased risk for several diabetic complications, including diabetic nephropathy and chronic kidney diseases. Oxidative stress and mitochondrial dysfunction are often proposed mechanisms in various organs in obesity models, but limited data are available on the kidney. Here, we fed a lard-based high-fat diet to mice to investigate structural changes, cellular and subcellular oxidative stress and redox status, and mitochondrial biogenesis and function in the kidney. The diet induced characteristic changes, including glomerular hypertrophy, fibrosis, and interstitial scarring, which were accompanied by a proinflammatory transition. We demonstrate evidence for oxidative stress in the kidney through 3-nitrotyrosine and protein radical formation on high-fat diet with a contribution from iNOS and NOX-4 as well as increased generation of mitochondrial oxidants on carbohydrate- and lipid-based substrates. The increased H2O2emission in the mitochondria suggests altered redox balance and mitochondrial ROS generation, contributing to the overall oxidative stress. No major derailments were observed in respiratory function or biogenesis, indicating preserved and initially improved bioenergetic parameters and energy production. We suggest that, regardless of the oxidative stress events, the kidney developed an adaptation to maintain normal respiratory function as a possible response to an increased lipid overload. These findings provide new insights into the complex role of oxidative stress and mitochondrial redox status in the pathogenesis of the kidney in obesity and indicate that early oxidative stress-related changes, but not mitochondrial bioenergetic dysfunction, may contribute to the pathogenesis and development of obesity-linked chronic kidney diseases.
Noninvasive assessment of vascular structure and function in conscious rats based on in vivo imaging of the albino iris
Authors: Stauss Harald M. , Rarick Kevin R. , Leick Katie M. , Burkle Jason W. , Rotella Diane L. , Anderson Michael G.
Published: March 2011

Experimental techniques allowing longitudinal studies of vascular disease progression or treatment effects are not readily available for most animal models. Thus, most existing studies are destined to either study individual time points or use large cohorts of animals. Here we describe a noninvasive technique for studying vascular disease that is based on in vivo imaging of the long posterior ciliary artery (LPCA) in the iris of albino rats. Using a slit-lamp biomicroscope, images of the LPCA were taken weekly in conscious normotensive Wistar Kyoto rats (WKY, n = 10) and spontaneously hypertensive rats (SHR, n = 10) for 10 wk. Using imaging software, we found that lumen diameter was significantly smaller and the wall-to-lumen (W/L) ratio larger in SHR than in WKY. Wall thickness was not different. Blood pressure correlated with the W/L ratio. Histology of the abdominal aorta also revealed a smaller lumen diameter and greater W/L ratio in SHR compared with WKY. Corneal application of the muscarinic receptor agonist pilocarpine elicited a dose-dependent vasodilation of the LPCA that could be antagonized by inhibition of nitric oxide synthase, suggesting that the pilocarpine response is mainly mediated by endothelium-derived nitric oxide. Consistent with endothelial dysfunction in SHR, pilocarpine-induced vasodilation was greater in WKY rats than in SHR. These findings indicate that in vivo imaging of the LPCA allows assessment of several structural and functional vascular parameters in conscious rats and that the LPCA responds to disease insults and pharmacologic treatments in a fashion that will make it a useful model for further studies.
Enzymatically Modified Low-Density Lipoprotein Is Recognized by C1q and Activates the Classical Complement Pathway
Authors: Arlaud Gérard J. , Biro Adrienn , Ling Wai Li
Published: March 2011

Several studies suggest that the complement system is involved in atherogenesis. To further investigate this question, we have studied the ability of native and modified forms of LDL to bind and activate C1, the complex protease that triggers the classical pathway of complement. Unlike native LDL, oxidized (oxLDL) and enzymatically modified (E-LDL) derivatives were both recognized by the C1q subunit of C1, but only E-LDL particles, obtained by sequential treatment with a protease and then with cholesterol esterase, had the ability to trigger C1 activation. Further investigations revealed that C1q recognizes a lipid component of E-LDL. Several approaches, including reconstitution of model lipid vesicles, cosedimentation, and electron microscopy analyses, provided evidence that C1 binding to E-LDL particles is mediated by the C1q globular domain, which senses unesterified fatty acids generated by cholesterol esterase. The potential implications of these findings in atherogenesis are discussed.
Extending Spatial Interaction Models with Agents for Understanding Relationships in a Dynamic Retail Market
Authors: Birkin Mark , Heppenstall Alison
Published: March 2011

For many years, effective model‐based representations of the dynamics and evolution of urban spatial structure have proved elusive. While some progress has been made through the deployment of spatial interaction models, these approaches have been limited by the difficulty of representing behavioural mechanisms and processes. In this paper, it is demonstrated that evolutionary models grounded in the principles of spatial interaction are compatible with the more novel approaches of agent‐based modelling. The incorporation of agents provides a much more flexible means for the representation of behavioural mechanisms. The paper illustrates the way in which three more complicated situations can be handled through the fusion of spatial interaction and agent modelling perspectives. These situations comprise discontinuous evolution (in which structural adjustment takes place in discrete steps, and not as a continuously smooth process); nonequilibrium dynamics (in which the underlying system parameters continue to evolve through time); the incorporation of new decision variables (which we illustrate through the addition of land rents into the model). The conclusion of the paper is that the combination of spatial interaction and agent‐based modelling methods provides encouraging prospects for the social simulation of real urban systems.
Weyl‐Titchmarsh Theory for Time Scale Symplectic Systems on Half Line
Authors: Šimon Hilscher Roman , Zemánek Petr
Published: March 2011

We develop the Weyl‐Titchmarsh theory for time scale symplectic systems. We introduce the M(λ)‐function, study its properties, construct the corresponding Weyl disk and Weyl circle, and establish their geometric structure including the formulas for their center and matrix radii. Similar properties are then derived for the limiting Weyl disk. We discuss the notions of the system being in the limit point or limit circle case and prove several characterizations of the system in the limit point case and one condition for the limit circle case. We also define the Green function for the associated nonhomogeneous system and use its properties for deriving further results for the original system in the limit point or limit circle case. Our work directly generalizes the corresponding discrete time theory obtained recently by S. Clark and P. Zemánek (2010). It also unifies the results in many other papers on the Weyl‐Titchmarsh theory for linear Hamiltonian differential, difference, and dynamic systems when the spectral parameter appears in the second equation. Some of our results are new even in the case of the second‐order Sturm‐Liouville equations on time scales.
Classification of Normal Sequences
Authors: Đoković Dragomir Ž.
Published: March 2011

Base sequencesBS(m,n)are quadruples(A;B;C;D)of{±1}-sequences, withAandBof lengthmandCandDof lengthn, such that the sum of their nonperiodic autocorrelation functions is aδ-function. Normal sequencesNS(n)are base sequences(A;B;C;D)∈BS(n,n)such thatA=B. We introduce a definition of equivalence for normal sequencesNS(n)and construct a canonical form. By using this canonical form, we have enumerated the equivalence classes ofNS(n)forn≤40.
PrLZ Protects Prostate Cancer Cells from Apoptosis Induced by Androgen Deprivation via the Activation of Stat3/Bcl-2 Pathway
Authors: Zhang Dong , He Dalin , Xue Yan , Wang Ruoxiang , Wu Kaijie , Xie Hongjun , Zeng Jin , Wang Xinyang , Zhau Haiyen E. , Chung Leland W.K. , Chang Luke S. , Li Lei
Published: March 2011

PrLZ/PC-1 is a newly identified, prostate-specific and androgen-inducible gene. Our previous study showed that PrLZ can enhance the proliferation and invasive capability of LNCaP cells, contributing to the development of prostate cancer. However, its potential role in androgen-independent processes remains elusive. In this study, we showed that PrLZ enhanced in vitro growth and colony formation of prostate cancer cells on androgen deprivation as well as tumorigenicity in castrated nude mice. In addition, PrLZ stabilized mitochondrial transmembrane potential, prevented release of cytochrome c from mitochondria to cytoplasm, and inhibited intrinsic apoptosis induced by androgen depletion. Mechanistically, PrLZ elevated the phosphorylation of Akt and Stat3 and upregulated Bcl-2 expression. Our data indicate that PrLZ protects prostate cancer cells from apoptosis and promotes tumor progression following androgen deprivation. In summary, we propose that PrLZ is a novel antiapoptotic gene that is specifically activated in prostate cancer cells escaping androgen deprivation may offer an appealing therapeutic target to prevent or treat advanced prostate malignancy. Cancer Res; 71(6); 2193–202. ©2011 AACR.
CAMTA1, a 1p36 Tumor Suppressor Candidate, Inhibits Growth and Activates Differentiation Programs in Neuroblastoma Cells
Authors: Henrich Kai-Oliver , Bauer Tobias , Schulte Johannes , Ehemann Volker , Deubzer Hedwig , Gogolin Sina , Muth Daniel , Fischer Matthias , Benner Axel , König Rainer , Schwab Manfred , Westermann Frank
Published: March 2011

A distal portion of human chromosome 1p is often deleted in neuroblastomas and other cancers and it is generally assumed that this region harbors one or more tumor suppressor genes. In neuroblastoma, a 261 kb region at 1p36.3 that encompasses the smallest region of consistent deletion pinpoints the locus for calmodulin binding transcription activator 1 (CAMTA1). Low CAMTA1 expression is an independent predictor of poor outcome in multivariate survival analysis, but its potential functionality in neuroblastoma has not been explored. In this study, we used inducible cell models to analyze the impact of CAMTA1 on neuroblastoma biology. In neuroblastoma cells that expressed little endogenous CAMTA1, its ectopic expression slowed cell proliferation, increasing the relative proportion of cells in G1/G0 phases of the cell cycle, inhibited anchorage-independent colony formation, and suppressed the growth of tumor xenografts. CAMTA1 also induced neurite-like processes and markers of neuronal differentiation in neuroblastoma cells. Further, retinoic acid and other differentiation- inducing stimuli upregulated CAMTA1 expression in neuroblastoma cells. Transciptome analysis revealed 683 genes regulated on CAMTA1 induction and gene ontology analysis identified genes consistent with CAMTA1-induced phenotypes, with a significant enrichment for genes involved in neuronal function and differentiation. Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma. Cancer Res; 71(8); 3142–51. ©2011 AACR.
Overexpression of a Novel Activator of PAK4, the CDK5 Kinase–Associated Protein CDK5RAP3, Promotes Hepatocellular Carcinoma Metastasis
Authors: Mak Grace Wing-Yan , Chan Mandy Man-Lok , Leong Veronica Yee-Law , Lee Joyce Man-Fong , Yau Tai-On , Ng Irene Oi-Lin , Ching Yick-Pang
Published: March 2011

The CDK5 kinase regulatory subunit-associated protein 3 (CDK5RAP3 or C53/LZAP) regulates apoptosis induced by genotoxic stress. Although CDK5RAP3 has been implicated in cancer progression, its exact role in carcinogenesis is not well established. In this article, we report that CDK5RAP3 has an important prometastatic function in hepatocarcinogenesis. An examination of human hepatocellular carcinoma (HCC) samples revealed at least twofold overexpression of CDK5RAP3 transcripts in 58% (39/67) of HCC specimens when compared with corresponding nontumorous livers. CDK5RAP3 overexpression was associated with more aggressive biological behavior. In HCC cell lines, stable overexpression of CDK5RAP3 promoted, and small interfering RNA–mediated knockdown inhibited, tumorigenic activity and metastatic potential. We found that overexpression of CDK5RAP3 and p21-activated protein kinase 4 (PAK4) correlated in human HCCs, and that CDK5RAP3 was a novel binding partner of PAK4, and this binding enhanced PAK4 activity. siRNA-mediated knockdown of PAK4 in CDK5RAP3-expressing HCC cells reversed the enhanced cell invasiveness mediated by CDK5RAP3 overexpression, implying that PAK4 is essential for CDK5RAP3 function. Taken together, our findings reveal that CDK5RAP3 is widely overexpressed in HCC and that overexpression of CDK5RAP3 promotes HCC metastasis through PAK4 activation. Cancer Res; 71(8); 2949–58. ©2011 AACR.
Cdk2 is Required for Breast Cancer Mediated by the Low-Molecular-Weight Isoform of Cyclin E
Authors: Akli Said , Van Pelt Carolyn S. , Bui Tuyen , Meijer Laurent , Keyomarsi Khandan
Published: March 2011

Cyclin E activates Cdk2, controls centrosome duplication, and regulates histone gene transcription. Cyclin E is deregulated in cancer and appears as low-molecular-weight (LMW) isoforms that correlate strongly with decreased survival in breast cancer patients. Transgenic mice overexpressing LMW-cyclin E have increased incidence of mammary tumors and distant metastasis when compared with mice that had full-length cyclin E. To specifically test the requirement for Cdk2 in LMW-cyclin E–mediated mammary tumorigenesis, we generated transgenic mice, which expressed LMW-cyclin E in a Cdk2-deficient background. We found that mammary gland development proceeds relatively normally in these animals, indicating that Cdk2 kinase activity is largely dispensable for this process. However, Cdk2-deficient mice were completely resistant to LMW-cyclin E–mediated mammary tumors. Cdk2 wild-type or heterozygous mice succumbed to mammary tumors with mean latencies of 16 and 19.5 months, respectively, but Cdk2 nullizygous littermates did not display tumors through 24 months. Similarly, continuous administration of two different Cdk inhibitors significantly delayed LMW-cyclin E–induced mammary tumor progression. Triple transgenic mice generated in a p53 heterozygous background also displayed no tumors. Finally, we found that Cdk2 silencing induced cell death in LMW-overexpressing breast cancer cell lines, but not in cell lines lacking LMW expression. Our findings establish a requirement for Cdk2 in LMW-cyclin E–mediated mammary tumorigenesis, arguing that human breast tumors overexpressing LMW-cyclin E are prime candidates for anti-Cdk2 therapy. Cancer Res; 71(9); 3377–86. ©2011 AACR.
Molecular Karyotypes of Hodgkin and Reed–Sternberg Cells at Disease Onset Reveal Distinct Copy Number Alterations in Chemosensitive versus Refractory Hodgkin Lymphoma
Authors: Slovak Marilyn L. , Bedell Victoria , Hsu Ya-Hsuan , Estrine Dolores B. , Nowak Norma J. , Delioukina Maria L. , Weiss Lawrence M. , Smith David D. , Forman Stephen J.
Published: March 2011

Purpose: To determine the recurring DNA copy number alterations (CNA) in classical Hodgkin lymphoma (HL) by microarray-based comparative genomic hybridization (aCGH) using laser capture microdissected CD30+ Hodgkin and Reed–Sternberg (HRS) cells.

Experimental Design: Archived tissues from 27 CD30+ HL plus control samples were analyzed by DNA microarrays. The HL molecular karyotypes were compared with the genomic profiles of germinal center B cells and treatment outcome (chemotherapy responsive vs. primary refractory disease).

Results: Gains and losses observed in more than 35% of HL samples were localized to 22 and 12 chromosomal regions, respectively. Frequent gains (>65%) were associated with growth and proliferation, NF-κB activation, cell-cycle control, apoptosis, and immune and lymphoid development. Frequent losses (>40%) observed encompassed tumor suppressor genes (SPRY1, NELL1, and ID4, inhibitor of DNA binding 4), transcriptional repressors (TXNIP, thioredoxin interacting protein), SKP2 (S-phase kinase-associated protein 2; ubiquitin ligase component), and an antagonist of NF-κB activation (PPARGC1A). In comparison to the germinal center profiles, the most frequent imbalances in HL were losses in 5p13 (AMACR, GDNF, and SKP2), and gains in 7q36 (SHH, sonic hedgehog homolog) and 9q34 (ABL1, CDK9, LCN2, and PTGES). Gains (>35%) in the HL chemoresponsive patients housed genes known to regulate T-cell trafficking or NF-κB activation (CCL22, CX3CL1, CCL17, DOK4, and IL10), whereas the refractory samples showed frequent loss of 4q27 (interleukin; IL21/IL2) and 17p12, and gain of 19q13.3 (BCL3/RELB).

Conclusion: We identified nonrandom CNAs in the molecular karyotypes of classical HL. Several recurring genetic lesions correlated with disease outcome. These findings may be useful prognostic markers in the counseling and management of patients and for the development of novel therapeutic approaches in primary refractory HL. Clin Cancer Res; 17(10); 3443–54. ©2011 AACR.
The Histone Methyltransferase and Putative Oncoprotein MMSET Is Overexpressed in a Large Variety of Human Tumors
Authors: Hudlebusch Heidi Rye , Santoni-Rugiu Eric , Simon Ronald , Ralfkiær Elisabeth , Rossing Henrik Holm , Johansen Jens Vilstrup , Jørgensen Mette , Sauter Guido , Helin Kristian
Published: March 2011

Purpose: Multiple myeloma SET (Suppressor of variegation, Enhancer of zeste, and Trithorax) domain (MMSET) is a histone lysine methyltransferase deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation and poor prognosis. With the aim of understanding, if MMSET can be involved in other types of cancer we investigated the expression of MMSET protein in different types of human tumors.

Experimental Design: A monoclonal antibody against MMSET was developed and immunohistochemical staining of tissue microarrays (TMA) containing a large number of tumor samples (n = 3774) and corresponding normal tissues (n = 904) was carried out. Further validations of MMSET expression were carried out on independent, tumor-specific sets of TMAs for urinary bladder (n = 1293) and colon cancer (n = 1206) with corresponding clinicopathological data and long-term follow-up.

Results: MMSET protein was highly expressed in different tumor types compared to normal counterparts. Particular frequent and/or high MMSET expression was found in carcinomas of the gastrointestinal tract (stomach, colon, anal canal), small cell lung carcinoma, tumors of the urinary bladder, female genitals, and skin. In bladder cancer, MMSET expression correlated with tumor aggressiveness. In contrast, MMSET expression was associated with good prognostic factors in colon cancer and was more pronounced in early stages of colon carcinogenesis (dysplasias) than in adenocarcinomas. However, colon cancer patients with high MMSET levels showed a worse 5-year survival.

Conclusions: Our data suggest that MMSET has a broader role in cancer than previously anticipated, and further analysis might qualify it as a prognostic marker and a target for the development of therapy against several types of cancer. Clin Cancer Res; 17(9); 2919–33. ©2011 AACR.
Synergistic Effect between Erlotinib and MEK Inhibitors in KRAS Wild-Type Human Pancreatic Cancer Cells
Authors: Diep Caroline H. , Munoz Ruben M. , Choudhary Ashish , Von Hoff Daniel D. , Han Haiyong
Published: March 2011

Purpose: The combination of erlotinib and gemcitabine has shown a small but statistically significant survival advantage when compared with gemcitabine alone in patients with advanced pancreatic cancer. However, the overall survival rate with the erlotinib and gemcitabine combination is still low. In this study, we sought to identify gene targets that, when inhibited, would enhance the activity of epidermal growth factor receptor (EGFR)-targeted therapies in pancreatic cancer cells.

Experimental Design: A high-throughput RNA interference (RNAi) screen was carried out to identify candidate genes. Selected gene hits were further confirmed and mechanisms of action were further investigated using various assays.

Results: Six gene hits from siRNA screening were confirmed to significantly sensitize BxPC-3 pancreatic cancer cells to erlotinib. One of the hits, mitogen-activated protein kinase (MAPK) 1, was selected for further mechanistic studies. Combination treatments of erlotinib and two MAP kinase kinase (MEK) inhibitors, RDEA119 and AZD6244, showed significant synergistic effect for both combinations (RDEA119–erlotinib and AZD6244–erlotinib) compared with the corresponding single drug treatments in pancreatic cancer cell lines with wild-type KRAS (BxPC-3 and Hs 700T) but not in cell lines with mutant KRAS (MIA PaCa-2 and PANC-1). The enhanced antitumor activity of the combination treatment was further verified in the BxPC-3 and MIA PaCa-2 mouse xenograft model. Examination of the MAPK signaling pathway by Western blotting indicated effective inhibition of the EGFR signaling by the drug combination in KRAS wild-type cells but not in KRAS mutant cells.

Conclusions: Overall, our results suggest that combination therapy of an EGFR and MEK inhibitors may have enhanced efficacy in patients with pancreatic cancer. Clin Cancer Res; 17(9); 2744–56. ©2011 AACR.
Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps
Authors: Takayama Tetsuji , Nagashima Hiroyuki , Maeda Masahiro , Nojiri Shuichi , Hirayama Michiaki , Nakano Yoichiro , Takahashi Yasuo , Sato Yasushi , Sekikawa Hitoshi , Mori Mitsuru , Sonoda Tomoko , Kimura Tetsuo , Kato Junji , Niitsu Yoshiro
Published: March 2011

Purpose: On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer.

Experimental design: Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted.

Results: ACF number at 2 months was significantly suppressed in the sulindac group (P = 0.0075), but not in the etodolac group (P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly (P = 0.02) and marginally (P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed.

Conclusions: ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer. Clin Cancer Res; 17(11); 3803–11. ©2011 AACR.
Global Gene Expression Profiling and Validation in Esophageal Squamous Cell Carcinoma and Its Association with Clinical Phenotypes
Authors: Su Hua , Hu Nan , Yang Howard H. , Wang Chaoyu , Takikita Mikiko , Wang Quan-Hong , Giffen Carol , Clifford Robert , Hewitt Stephen M. , Shou Jian-Zhong , Goldstein Alisa M. , Lee Maxwell P. , Taylor Philip R.
Published: March 2011

Purpose: Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with poor prognosis. Understanding molecular changes in ESCC will enable identification of molecular subtypes and provide potential targets for early detection and therapy.

Experimental Design: We followed up a previous array study with additional discovery and confirmatory studies in new ESCC cases by using alternative methods. We profiled global gene expression for discovery and confirmation, and validated selected dysregulated genes with additional RNA and protein studies.

Results: A total of 159 genes showed differences with extreme statistical significance (P < E-15) and 2-fold differences or more in magnitude (tumor/normal RNA expression ratio, N = 53 cases), including 116 upregulated and 43 downregulated genes. Of 41 genes dysregulated in our prior array study, all but one showed the same fold change directional pattern in new array studies, including 29 with 2-fold changes or more. Alternative RNA expression methods validated array results: more than two thirds of 51 new cases examined by real-time PCR (RT-PCR) showed 2-fold differences or more for all seven genes assessed. Immunohistochemical protein expression results in 275 cases which were concordant with RNA for five of six genes.

Conclusion: We identified an expanded panel of genes dysregulated in ESCC and confirmed previously identified differentially expressed genes. Microarray-based gene expression results were confirmed by RT-PCR and protein expression studies. These dysregulated genes will facilitate molecular categorization of tumor subtypes and identification of their risk factors, and serve as potential targets for early detection, outcome prediction, and therapy. Clin Cancer Res; 17(9); 2955–66. ©2011 AACR.
Intra–Lymph Node Prime-Boost Vaccination against Melan A and Tyrosinase for the Treatment of Metastatic Melanoma: Results of a Phase 1 Clinical Trial
Authors: Ribas Antoni , Weber Jeffrey S. , Chmielowski Bartosz , Comin-Anduix Begonya , Lu David , Douek Michael , Ragavendra Nagesh , Raman Steve , Seja Elizabeth , Rosario Darlene , Miles Sabrina , Diamond David C. , Qiu Zhiyong , Obrocea Mihail , Bot Adrian
Published: March 2011

Purpose: The goal of this study was to test the safety and activity of a therapeutic vaccine, MKC1106-MT, in patients with metastatic melanoma.

Experimental Design: MKC1106-MT comprises a plasmid (pMEL-TYR) and two peptides (E-MEL and E-TYR), corresponding to Melan A and tyrosinase, administered by intra–lymph node injection in a prime-boost sequence. All 18 patients were HLA-A*0201 positive and received a fixed priming dose of plasmid and a low or a high peptide dose. Enumeration of antigen-specific T cells was done prior to and throughout the treatment. Patients who did not exhibit disease progression remained on study and could receive up to eight cycles of treatment.

Results: The MKC1106-MT regimen was well tolerated and resulted in an overall immune response rate of 50%. The treatment showed disease control, defined as stable disease that lasted for 8 weeks or more in 6 of 18 (33%) of the patients: 14% and 46% in the low and high peptide dose, respectively. Interestingly, four patients, all with tumor burden largely confined to lymph nodes and Melan A–specific T cells at baseline, showed durable disease control associated with radiologic evidence of tumor regression. There was no noticeable correlation between the expansion of antigen-specific T cells in blood and the clinical outcome; yet, there was evidence of active tumor-infiltrating lymphocytes (TIL) in two regressing lesions.

Conclusions: MKC1106-MT showed immunogenicity and evidence of disease control in a defined patient population. These findings support further development of this investigational agent and the concept of therapeutic vaccination in metastatic melanoma. Clin Cancer Res; 17(9); 2987–96. ©2011 AACR.
Flavor Perception in Human Infants: Development and Functional Significance
Authors: Beauchamp Gary K. , Mennella Julie A.
Published: March 2011

Background: Foods people consume impact on their health in many ways. In particular, excess intake of salty, sweet and fatty foods and inadequate intake of fruits and vegetables have been related to many diseases including diabetes, hypertension, cardiovascular disease and some cancers. The flavor of a food determines its acceptability and modulates intake. It is thus critical to understand the factors that influence flavor preferences in humans. Aim: To outline several of the important factors that shape flavor preferences in humans. Methods: We review a series of studies, mainly from our laboratories, on the important role of early experiences with flavors on subsequent flavor preference and food intake. Results and Conclusions: Some taste preferences and aversions (e.g. liking for sweet, salty and umami; disliking for bitter) are innately organized, although early experiences can modify their expression. In utero events may impact on later taste and flavor preferences and modulate intake of nutrients. Both before and after birth, humans are exposed to a bewildering variety of flavors that influence subsequent liking and choice. Fetuses are exposed to flavors in amniotic fluid modulating preferences later in life and flavor learning continues after birth. Experience with flavors that are bitter, sour or have umami characteristics, as well as volatile flavors such as carrot and garlic, occurs through flavorings in breast milk, infant formula and early foods. These early experiences mold long-term food and flavor preferences which can impact upon later health.
Duodenal Chemosensing and Mucosal Defenses
Authors: Akiba Yasutada , Kaunitz Jonathan D.
Published: March 2011

The duodenal mucosa is exposed to endogenous and exogenous chemicals, including acid, CO2, bile acids and nutrients. Mucosal chemical sensors are necessary to exert physiological responses such as secretion, digestion, absorption, and motility. We propose a mucosal chemosensing system by which luminal chemicals are sensed via mucosal acid sensors and G-protein-coupled receptors. Luminal acid/CO2 sensing consists of ecto- and cytosolic carbonic anhydrases, epithelial ion transporters, and acid sensors expressed on the afferent nerves in the duodenum. Furthermore, a luminal L-glutamate signal is mediated via mucosal L-glutamate receptors, including metabotropic glutamate receptors and taste receptor 1 family heterodimers, with activation of afferent nerves and cyclooxygenase, whereas luminal Ca2+ is differently sensed via the calcium-sensing receptor in the duodenum. Recent studies also show the involvement of enteroendocrine G-protein-coupled receptors in bile acid and fatty acid sensing in the duodenum. These luminal chemosensors help activate mucosal defense mechanisms in or- der to maintain the mucosal integrity and physiological responses. Stimulation of luminal chemosensing in the duodenal mucosa may prevent mucosal injury, affect nutrient metabolism, and modulate sensory nerve activity.