bluuebunny/crossref_metadata_2025 huggingface dataset:
SUPERINTEGRABLE HAMILTONIAN SYSTEMS WITH NONCOMPACT INVARIANT SUBMANIFOLDS: KEPLER SYSTEM
Authors: SARDANASHVILY G.
Published: January 2010

The Mishchenko–Fomenko theorem on superintegrable Hamiltonian systems is generalized to superintegrable Hamiltonian systems with noncompact invariant submanifolds. It is formulated in the case of globally superintegrable Hamiltonian systems which admit global generalized action-angle coordinates. The well known Kepler system falls into two different globally superintegrable systems with compact and noncompact invariant submanifolds.
Activity of Neurons in Monkey Globus Pallidus During Oculomotor Behavior Compared With That in Substantia Nigra Pars Reticulata
Authors: Shin SooYoon , Sommer Marc A.
Published: January 2010

The basal ganglia are a subcortical assembly of nuclei involved in many aspects of behavior. Three of the nuclei have high firing rates and inhibitory influences: the substantia nigra pars reticulata (SNr), globus pallidus interna (GPi), and globus pallidus externa (GPe). The SNr contains a wide range of visual, cognitive, and motor signals that have been shown to contribute to saccadic eye movements. Our hypothesis was that GPe and GPi neurons carry similarly diverse signals during saccadic behavior. We recorded from GPe, GPi, and SNr neurons in monkeys that made memory-guided saccades and found that neurons in all three structures had increases or decreases in activity synchronized with saccade generation, visual stimulation, or reward. Comparing GPe neurons with GPi neurons, we found relatively more visual-related activity in GPe and more reward-related activity in GPi. Comparing both pallidal samples with the SNr, we found a greater resemblance between GPe and SNr neurons than that between GPi and SNr neurons. As expected from a known inhibitory projection from GPe to SNr, there was a general reversal of sign in activity modulations between the structures: bursts of activity were relatively more common in GPe and pauses more common in SNr. We analyzed the response fields of neurons in all three structures and found relatively narrow and lateralized fields early in trials (during visual and saccadic events) followed by a broadening later in trials (during reward). Our data reinforce an emerging, new consensus that the GPe and GPi, in addition to the SNr, contribute to oculomotor behavior.
Receptive Field Mosaics of Retinal Ganglion Cells Are Established Without Visual Experience
Authors: Anishchenko Anastacia , Greschner Martin , Elstrott Justin , Sher Alexander , Litke Alan M. , Feller Marla B. , Chichilnisky E. J.
Published: January 2010

A characteristic feature of adult retina is mosaic organization: a spatial arrangement of cells of each morphological and functional type that produces uniform sampling of visual space. How the mosaics of visual receptive fields emerge in the retina during development is not fully understood. Here we use a large-scale multielectrode array to determine the mosaic organization of retinal ganglion cells (RGCs) in rats around the time of eye opening and in the adult. At the time of eye opening, we were able to reliably distinguish two types of ON RGCs and two types of OFF RGCs in rat retina based on their light response and intrinsic firing properties. Although the light responses of individual cells were not yet mature at this age, each of the identified functional RGC types formed a receptive field mosaic, where the spacing of the receptive field centers and the overlap of the receptive field extents were similar to those observed in the retinas of adult rats. These findings suggest that, although the light response properties of RGCs may need vision to reach full maturity, extensive visual experience is not required for individual RGC types to form a regular sensory map of visual space.
Superoxide scavenging and Akt inhibition in myocardium ameliorate pressure overload-induced NF-κB activation and cardiac hypertrophy
Authors: Hingtgen Shawn D. , Li Zhenbo , Kutschke William , Tian Xin , Sharma Ram V. , Davisson Robin L.
Published: January 2010

Recent studies from our laboratory and others have shown that increases in cytoplasmic superoxide (O2·−) levels and Akt activation play a key role in agonist-stimulated NF-κB activation and cardiomyocyte hypertrophy in vitro. In this study, we tested the hypothesis that adenovirus (Ad)-mediated intramyocardial gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD) or a dominant-negative form of Akt (AdDNAkt) in mice would attenuate pressure overload-induced increases in activation of the redox-sensitive transcription factor NF-κB and cardiac hypertrophy. Adult C57BL/6 mice were subjected to thoracic aortic banding (TAB) or sham surgery, and intramyocardial injections of viral vectors (AdCu/ZnSOD, AdDNAkt, or control) were performed. There was robust transgene expression in the heart, which peaked 6–7 days after injection and then declined to undetectable levels by 12–14 days. In mice injected with AdBgL II, TAB caused a significant increase in O2·− generation and cardiac mass at 1 wk, and these responses were markedly attenuated by AdCu/ZnSOD. In addition, TAB induced time-dependent activation of NF-κB in the myocardium as measured longitudinally by in vivo bioluminescent imaging of NF-κB-dependent luciferase expression. This was also abolished by intracardiac AdCu/ZnSOD or AdDNAkt, but not the control vector. The inhibition of Akt and O2·−-mediated NF-κB activation in TAB hearts was associated with an attenuation of cardiac hypertrophy. Since a direct cause-and-effect relationship between NF-κB activation and cardiomyocyte hypertrophy has been established previously, our data support the hypothesis that increased O2·− generation and Akt activation are key signaling intermediates in pressure overload-induced activation of NF-κB and cardiac hypertrophy.
Heat shock response of killifish (Fundulus heteroclitus): candidate gene and heterologous microarray approaches
Authors: Healy Timothy M. , Tymchuk Wendy E. , Osborne Edward J. , Schulte Patricia M.
Published: January 2010

Northern and southern subspecies of the Atlantic killifish, Fundulus heteroclitus, differ in maximal thermal tolerance. To determine whether these subspecies also differ in their heat shock response (HSR), we exposed 20°C acclimated killifish to a 2 h heat shock at 34°C and examined gene expression in fish from both subspecies during heat shock and recovery using real-time quantitative PCR and a heterologous cDNA microarray designed for salmonid fishes. The heat shock proteins Hsp70-1, hsp27, and hsp30 were upregulated to a greater extent in the high temperature-tolerant southern subspecies than in the less tolerant northern subspecies, whereas hsp70-2 (which showed the largest upregulation of all the heat shock proteins) in both gill and muscle and hsp90α in muscle was upregulated to a greater extent in northern than in southern fish. These data demonstrate that differences in the HSR between subspecies cannot be due to changes in a single global regulator but must occur via gene-specific mechanisms. They also suggest that the role, if any, of hsps in establishing thermal tolerance is complex and varies from gene to gene. Heterologous microarray hybridization provided interpretable gene expression signatures, detecting differential regulation of genes known to be involved in the heat shock response in other species. Under control conditions, a variety of genes were differentially expressed in muscle between subspecies that suggest differences in muscle fiber type and could relate to previously observed differences between subspecies in the thermal sensitivity of swimming performance and metabolism.
Policy Iteration for Continuous‐Time Average Reward Markov Decision Processes in Polish Spaces
Authors: Zhu Quanxin , Yang Xinsong , Huang Chuangxia
Published: January 2010

We study the policy iteration algorithm (PIA) for continuous‐time jump Markov decision processes in general state and action spaces. The corresponding transition rates are allowed to be unbounded, and the reward rates may have neither upper nor lower bounds. The criterion that we are concerned with is expected average reward. We propose a set of conditions under which we first establish the average reward optimality equation and present the PIA. Then under two slightly different sets of conditions we show that the PIA yields the optimal (maximum) reward, an average optimal stationary policy, and a solution to the average reward optimality equation.
Systematic Investigation of Gettering Effects on 4th Row Element Impurities in Si by Dopant Atoms
Authors: Sueoka Koji , Kamimura Ken , Shiba Seiji
Published: January 2010

The gettering of 4th row element impurities (K, Ca, 3d transition metals, and Zn) in Si crystals by dopant atoms was systematically investigated by first‐principles calculation through evaluation of the diffusion barrier and the binding energy. The dopant atoms considered include p‐type dopants (B), n‐type dopants (P, As, Sb), or light elements (C, O). It was found that (1) the diffusion barrier of impurity atoms decreases with an increase in their atomic number up to Ni, (2) B atom becomes an efficient gettering center for metals except for Ni, (3) most of the metals except for Fe and Co cannot be gettered by n‐type dopants, and (4) C and O atoms alone do not become efficient gettering centers for the metals used in actual LSI processes. The vacancy Vc and n‐type dopant complexes (PVc, AsVc, SbVc) can be efficient gettering centers for Cu in n/n+ epitaxial wafers.
Land-Jump Performance in Patients with Juvenile Idiopathic Arthritis (JIA): A Comparison to Matched Controls
Authors: Ford Kevin R. , Myer Gregory D. , Melson Paula G. , Darnell Shannon C. , Brunner Hermine I. , Hewett Timothy E.
Published: January 2010

Objective. The purpose of this study was to determine if high functioning children with Juvenile Idiopathic Arthritis (JIA) with minimal disease activity have different biomechanics during high loading tasks compared to controls. Patients were included if they had minimal inflammation documented in one or both knees. Methods. The subject groups consisted of eleven patients with JIA and eleven sex, age, height, and weight matched controls. Sagittal plane kinematic and kinetics were calculated during a drop vertical jump maneuver. The Child Health Assessment Questionnaire (CHAQ) was collected on each patient with JIA. Results. The subjects with JIA had increased knee () and hip flexion () compared to control subjects. Subjects with JIA also demonstrated decreased knee extensor moments during take-off () and ankle plantar flexor moments during landing () and take-off (). In the JIA group, increased hip extensor moments were predictive of increased disability (, ).Conclusions. Patients with JIA may demonstrate underlying biomechanical deviations compared to controls. In addition, biomechanical assessment of hip extensor mechanics during dynamic tasks may provide an objective assessment tool to determine overall function in patients with JIA.
Impacts of the Replacement of Native Woodland with Exotic Pine Plantations on Leaf-Litter Invertebrate Assemblages: A Test of a Novel Framework
Authors: Murray Brad R. , Baker Andrew C. , Robson Tessa C.
Published: January 2010

We present an empirical comparison of invertebrate community structure between areas of undisturbed native eucalypt woodland and areas that have been cleared and replaced with plantations of exotic radiata pine (Pinus radiata). Implementation of a novel conceptual framework revealed that both insect (in autumn) and arachnid (in winter) assemblages demonstrated inhibition in response to the pine plantations. Species richness declines occurred in several taxonomic Orders (e.g., Hymenoptera, Blattodea, Acari) without compensated increases in other Orders in plantations. This was, however, a seasonal response, with shifts between inhibition and equivalency observed in both insects and arachnids across autumn and winter sampling periods. Equivalency responses were characterized by relatively similar levels of species richness in plantation and native habitats for several Orders (e.g., Coleoptera, Collembola, Psocoptera, Araneae). We propose testable hypotheses for the observed seasonal shifts between inhibition and equivalency that focus on diminished resource availability and the damp, moist conditions found in the plantations. Given the compelling evidence for seasonal shifts between categories, we recommend that seasonal patterns should be considered a critical component of further assemblage-level investigations of this novel framework for invasion ecology.
Combined Magnetohydrodynamic and Geometric Optimization of a Hypersonic Inlet
Authors: Subbarao Kamesh , Goss Jennifer D.
Published: January 2010

This paper considers
the numerical optimization of a double ramp
scramjet inlet using magnetohydrodynamic (MHD)
effects together with inlet ramp angle changes.
The parameter being optimized is the mass
capture at the throat of the inlet, such that
spillage effects for less than design Mach
numbers are reduced. The control parameters for
the optimization include the MHD effects in
conjunction with ramp angle changes. To enhance
the MHD effects different ionization scenarios
depending upon the alignment of the magnetic
field are considered. The flow solution is based
on the Advection Upstream Splitting Method
(AUSM) that accounts for the MHD source terms as
well. A numerical
Broyden‐Flecher‐Goldfarb‐Shanno‐ (BFGS‐) based
procedure is utilized to optimize the inlet mass
capture. Numerical validation results compared
to published results in the literature as well
as the outcome of the optimization procedure are
summarized to illustrate the efficacy of the
approach.
Hypercholesterolaemic Serum Increases the Permeability of Endothelial Cells through Zonula Occludens‐1 with Phosphatidylinositol 3‐Kinase Signaling Pathway
Authors: Bian Chang , Xu Geng , Wang Jianan , Ma Ji , Xiang MeiXiang , Chen Peng
Published: January 2010

Purpose. Hypercholesterolemia and tight junctions play important roles in atherosclerosis. But the relationship between these two factors is unclear. In the present study, we investigated whether hypercholesterolemic serum could change the permeability of endothelial cells through altering expression and/or distribution of tight junction protein zonula occludens‐1 (ZO‐1). Phosphatidylinositol 3‐kinase (PI3K) signaling pathway was also examined. Materials and Methods. Cultured endothelial cells were treated with different concentration levels of hypercholesterolemic serum. The expression and distribution of ZO‐1, the permeability of cultured cells and the involvement of PI3K signaling pathway were measured by various methods. Results. In the present study, we found that hypercholesterolemic serum could not change the expression of ZO‐1 either in mRNA or protein level. However, hypercholesterolemic serum could change the distribution of ZO‐1 in cultured endothelial cells, and increase the permeability with a dose‐dependent manner. When PI3K specific inhibitor wortmannin was used, the effects induced by hypercholesterolemic serum could be partly reversed. The role of PI3K signaling pathway was further confirmed by PI3K activity assay. Conclusions. Our results suggested that although hypercholesterolemic serum could not change the expression of ZO‐1, it could change the distribution and increase the permeability in endothelial cells through PI3K signaling pathway.
Adsorption of Pb(II) and Cd(II) by Squid Ommastrephes bartrami Melanin
Authors: Chen Shiguo , Xue Changhu , Wang Jingfeng , Feng Hui , Wang Yuming , Ma Qin , Wang Dongfeng
Published: January 2010

The adsorption of Cd(II) and Pb(II) by squid melanin was investigated. At a metal ion concentration of 2 mM/L, the biosorption efficiency of melanin reached 95% for Cd(II) and Pb(II). The maximum content of bound Cd(II) and Pb(II) was 0.93 mM/g and 0.65 mM/g, respectively. Temperature had no obvious effect on the adsorption of the metals, and in a pH range of 4.0–7.0, the adsorption yield was high and stable. Macrosalts such as NaCl, MgCl2, and CaCl2 had no obvious effect on the binding of Pb(II) but greatly diminished the adsorption of Cd(II), which indicated that different functional groups in squid melanin are responsible for their adsorption. IR analysis of metal ion‐enriched squid melanin demonstrated that the possible functional groups responsible for metal binding were phenolic hydroxyl (OH), carboxyl (COOH), and amine groups (NH). This study reports a new material for the removal of heavy metals from low‐strength wastewater.
A New Caspase‐8 Isoform Caspase‐8s Increased Sensitivity to Apoptosis in Jurkat Cells
Authors: Xu Zhifang , Tang Kejing , Wang Min , Rao Qing , Liu Bolin , Wang Jianxiang
Published: January 2010

Caspase‐8 is a key initiator of death receptor‐induced apoptosis. Here we report a novel short isoform of caspase‐8 (caspase‐8s), which encodes the first (Death Effector Domain) DED and part of the second DED, missing the C‐terminal caspase domain. In vivo binding assays showed that transfected caspase‐8s bound to (Fas‐associated death domain protein) FADD, the adaptor protein in (death‐induced signal complex) DISC. To investigate the potential effects of caspase‐8s on cell apoptosis, Jurkat cells were stably transfected with caspase‐8s. Overexpression of caspase‐8s increased sensitivity to the apoptotic stimuli, Fas‐agonistic antibody CH11. These results suggest that caspase‐8s may act as a promoter of apoptosis through binding to FADD and is involved in the regulation of apoptosis. In addition, the results also indicate that the first DED was an important structure mediating combination between caspase‐8 and FADD.
Signal‐Based Performance Evaluation of Dereverberation Algorithms
Authors: Naylor Patrick A. , Gaubitch Nikolay D. , Habets Emanuël A. P.
Published: January 2010

We address the measurement of reverberation in terms of the (DRR) in
the context of the assessment of dereverberation algorithms for which we wish to quantify the level of reverberation before and after processing. The DRR is normally calculated from the impulse response of the reverberating system. However, several important dereverberation algorithms involve nonlinear and/or time‐varying processing and therefore their effect cannot conveniently be represented in terms of modifications to the impulse response of the reverberating system. In such cases, we show that a good estimate of DRR can be obtained from the input/output signals alone using the Signal‐to‐Reverberant Ratio (SRR) only if the source signal is spectrally white and correctly normalized. We study alternative normalization schemes and conclude by showing a least squares optimal normalization procedure for estimating DRR using signal‐based SRR measurement. Simulation results illustrate the accuracy of DRR estimation using SRR.
Ghrelin and Metabolic Surgery
Authors: Pournaras Dimitrios J. , le Roux Carel W.
Published: January 2010

Metabolic surgery is the most effective treatment for morbid obesity. Ghrelin has been implicated to play a role in the success of these procedures. Furthermore, these operations have been used to study the gut-brain axis. This article explores this interaction, reviewing the available data on changes in ghrelin levels after different surgical procedures.
Extended Composite Right/Left‐Handed Transmission Line and Dual‐Band Reactance Transformation
Authors: Zhang Yuming , Spielman Barry
Published: January 2010

An extended composite right/left‐handed transmission line is introduced, and its dual‐band bandpass filter characteristics are explored. Novel reactance transformations, derived from this transmission line, are formulated to transform a low‐pass prototype filter into a dual‐band bandpass filter with arbitrary dual pass bands, well‐defined in‐band attenuation ripples, and high out‐of‐band rejection. The physical insight into such a dual‐band bandpass filter is provided with a dispersion analysis. The transformations are verified by simulated results for dual‐band bandpass filters.
Performance Enhancement of UWB Material Characterization and Object Recognition for Security Robots
Authors: Salman Rahmi , Schultze Thorsten , Willms Ingolf
Published: January 2010

By means of UWB Radar sensors the tasks of material characterisation and object recognition can be performed on the basis of a previous imaging of the whole environment. A UWB version of the microwave ellipsometry method is applied for estimating the permittivity of homogenous objects. The object recognition task is performed using bistatic sensor nodes on the basis of Radar measurements. The simulation‐based performance evaluations show a very robust behavior due to suitable preprocessing of Radar data. The applications comprise the detection of fire sources, the detection of metallic object hidden under clothing, and the recognition of building structures.
High‐Performance Region‐of‐Interest Image Error Concealment with Hiding Technique
Authors: Hsia Shih-Chang , Wang Szu-Hong , Chen Ming-Huei
Published: January 2010

Recently region‐of‐interest (ROI) based image coding is a popular topic. Since ROI area contains much more important information for an image, it must be prevented from error decoding while suffering from channel lost or unexpected attack. This paper presents an efficient error concealment method to recover ROI information with a hiding technique. Based on the progressive transformation, the low‐frequency components of ROI are encoded to disperse its information into the high‐frequency bank of original image. The capability of protection is carried out with extracting the ROI coefficients from the damaged image without increasing extra information. Simulation results show that the proposed method can efficiently reconstruct the ROI image when ROI bit‐stream occurs errors, and the measurement of PSNR result outperforms the conventional error concealment techniques by 2 to 5 dB.
X‐Parameter Measurement of Pulse‐Compression Nonlinear Transmission Lines
Authors: Li Ming , Amaya Rony E. , Harrison Robert G. , Tarr N. Garry
Published: January 2010

X‐parameters provide a powerful and eminently practical solution for interoperable measurement, modeling, and simulation of nonlinear microwave and RF components. Using X‐parameters to do large‐signal measurements has been brought into the spotlight. This paper introduces a new X‐parameter application: measuring large‐signal behaviour of pulse‐compression nonlinear transmission lines (NLTLs). A specially configured Nonlinear Vector Network Analyzer (NVNA) was used to measure the X‐parameters in the frequency‐domain, and then the measured data was transformed into a nonlinear time‐domain waveform. The results show both rise‐time and fall‐time reduction (double‐edge compression) as expected and indicate that this newly developed X‐parameter method implemented with an NVNA could correctly predict NLTLs′ pulse‐compression performance.
Image Superresolution Based on Locally Adaptive Mixed‐Norm
Authors: Omer Osama A. , Tanaka Toshihisa
Published: January 2010

In a typical superresolution algorithm, fusion error modeling, including registration error and additive noise, has a great influence on the performance of the super‐resolution algorithms. In this letter, we show that the quality of the reconstructed high‐resolution image can be increased by exploiting proper model for the fusion error. To properly model the fusion error, we propose to minimize a cost function that consists of locally and adaptively weighted L1‐ and L2‐norms considering the error model. Binary weights are used so as to adaptively select L1‐ or L2‐norm, based on the local errors. Simulation results demonstrate that proposed algorithm can overcome disadvantages of using either L1‐ or L2‐norm.
A Novel GPS Antijamming Receiver Based on Noncircularity
Authors: Xian-Ning Chen , Wan Qun , Wan-Lin Yang
Published: January 2010

We present a novel antijamming global position system (GPS) receiver that relies on the unique noncircularity of the GPS signal. Since the GPS signal is BPSK modulated, it is a noncircular signal while most interferers are circular signals. The proposed receiver utilizes this circular difference property to excise interferences while preserve the GPS signals. It is shown that the proposed receiver is a blind receiver that does not require any angular information of the satellites.
Forced Oscillations of Half‐Linear Elliptic Equations via Picone‐Type Inequality
Authors: Yoshida Norio
Published: January 2010

Picone‐type inequality is established for a class of half‐linear elliptic
equations with forcing term, and oscillation results are derived on the
basis of the Picone‐type inequality. Our approach is to reduce the multi‐dimensional
oscillation problems to one‐dimensional oscillation problems
for ordinary half‐linear differential equations.
How to Model the Near‐to‐the‐Carrier Regime and the Lower Knee Frequency of Real RF Oscillators
Authors: Chorti Arsenia
Published: January 2010

Numerous empirical data demonstrate that real noisy RF oscillators are affected by power‐law phase noise. However, until recently, the robust analytic modeling of the deep‐into‐the‐carrier spectral regime of RF oscillators was intangible due to the infinities involved in the relevant power‐law regions. In this letter we demonstrate how recent advances in oscillator spectral modeling can be applied to extrapolate the near‐to‐the‐carrier regime as well as estimate the oscillator lower knee frequency of transition between the deep‐into‐the‐carrier regime and the power‐law regions of real RF oscillators.
The Small Heat Shock Protein HSP25/27 (HspB1) Is Abundant in Cultured Astrocytes and Associated with Astrocytic Pathology in Progressive Supranuclear Palsy and Corticobasal Degeneration
Authors: Schwarz Lisa , Vollmer Grit , Richter-Landsberg Christiane
Published: January 2010

Filamentous tau-positive protein inclusions in neurons and glia are prominent features of a number of neurodegenerative disorders termed tauopathies. These inclusions are further characterized by the presence of heat shock proteins (HSPs). The group of small HSPs, namely, HSP27 andαB-crystallin, interact with the cytoskeleton, bind to nonnative proteins, and prevent their aggregation after stress. To further investigate their contribution to neurodegenerative diseases, we have analyzed the association of HSP27 with pathological lesions of tauopathies. Microarray and immunoblot analysis revealed that HSP27 is enhanced at the mRNA and protein levels in affected brains, and that it is associated with astrocytic pathology. The upregulation of HSP27 in tauopathies with gial pathology implies distinct mechanisms for glial and neuronal cells. This was sustained by cell culture studies, demonstrating that the small HSPs are specifically and prominently expressed in unstressed astrocytes and not in neurons and in neurons remained at a rather low level even after stress situations.
PAPR Reduction Performance by Active Constellation Extension for Diversity MIMO‐OFDM Systems
Authors: Tsiligkaridis Theodoros , Jones Douglas L.
Published: January 2010

The V‐BLAST wireless communication architecture, space‐time block code (STBC), and space‐frequency block code (SFBC) techniques are strong candidates for achieving very high data rates in 4G broadband wireless communications. This paper extends the efficient Active Constellation Extension Smart Gradient‐Project (ACE‐SGP) peak‐to‐average power (PAPR) reduction method to STBC, SFBC, and V‐BLAST systems. Simulation results show 4.19 and 3.57 dB of PAPR reduction for the Alamouti STBC and SFBC, respectively.
Hybrid TOA/AOA Approximate Maximum Likelihood Mobile Localization
Authors: Zhaounia Mohamed , Adnan Landolsi Mohamed , Bouallegue Ridha
Published: January 2010

This letter deals with a hybrid time‐of‐arrival/angle‐of‐arrival (TOA/AOA) approximate maximum likelihood (AML) wireless location algorithm. Thanks to the use of both TOA/AOA measurements, the proposed technique can rely on two base stations (BS) only and achieves better performance compared to the original approximate maximum likelihood (AML) method. The use of two BSs is an important advantage in wireless cellular communication systems because it avoids hearability problems and reduces network signaling burden. Simulation results show that, for certain scenarios, the proposed hybrid TOA/AOA AML with two BSs can outperform the AML with up to six BSs.
Nek4 Status Differentially Alters Sensitivity to Distinct Microtubule Poisons
Authors: Doles Jason , Hemann Michael T.
Published: January 2010

Microtubule poisons are widely used in cancer treatment, but the factors determining the relative efficacy of different drugs in this class remain obscure. In this study, we identified the NIMA kinase Nek4 in a genetic screen for mediators of the response to Taxol, a chemotherapeutic agent that stabilizes microtubules. After Taxol treatment, Nek4 promoted microtubule outgrowth, whereas Nek4 deficiency impaired G2-M arrest and decreased formation of mitotic-like asters. In contrast, Nek4 deficiency sensitized cells to vincristine, which destabilizes microtubules. Therefore, Nek4 deficiency may either antagonize or agonize the effects of microtubule poisons, depending on how they affect microtubule polymerization. Of note, Nek4 gene maps to a commonly deleted locus in non-small cell lung cancer. Thus, Nek4 deletion in this disease may rationalize the use of particular types of microtubule poisons for lung cancer therapy. Cancer Res; 70(3); 1033–41
Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors
Authors: Edgar Kyle A. , Wallin Jeffrey J. , Berry Megan , Lee Leslie B. , Prior Wei Wei , Sampath Deepak , Friedman Lori S. , Belvin Marcia
Published: January 2010

Therapeutic inhibitors are being developed against the phosphoinositide 3-kinase (PI3K) pathway, the deregulation of which drives tumor growth and survival in many cancers. There are eight PI3Ks in mammals divided into three classes. Class IA PI3Ks (p110α, p110β, and p110δ) are critical for cell growth and survival, with the p110α isoform implicated as the most important in carcinomas. In this study, we examined the effects of small-molecule inhibitors of class IA PI3Ks to explore the contributions of different isoforms in cancer cells. Similar responses were seen in cancer cells with wild-type or activated mutant PI3K genes treated with p110α/δ or p110α/β/δ inhibitors in cell viability assays. In contrast, PTEN-negative cell lines tended to be less responsive (4-fold overall) to an inhibitor of p110α/δ versus p110α/β/δ. Combining a p110α/δ inhibitor with a p110β inhibitor resulted in comparable potency to the p110α/β/δ inhibitor. The disparity in efficacy was confirmed in vivo. Pharmacodynamic biomarker analysis revealed that an inhibitor with insufficient potency against the p110β isoform was less effective at inhibiting the PI3K pathway in PTEN-negative tumor xenografts. Our results imply that patients with PTEN-negative tumors may preferentially benefit from treatment with a class I PI3K inhibitor that is capable of inhibiting the p110β isoform. Cancer Res; 70(3); 1164–72
NF-κB, and not MYCN, Regulates MHC Class I and Endoplasmic Reticulum Aminopeptidases in Human Neuroblastoma Cells
Authors: Forloni Matteo , Albini Sonia , Limongi Maria Zaira , Cifaldi Loredana , Boldrini Renata , Nicotra Maria Rita , Giannini Giuseppe , Natali Pier Giorgio , Giacomini Patrizio , Fruci Doriana
Published: January 2010

Neuroblastoma (NB) is the most common solid extracranial cancer of childhood. Amplification and overexpression of the MYCN oncogene characterize the most aggressive forms and are believed to severely downregulate MHC class I molecules by transcriptional inhibition of the p50 NF-κB subunit. In this study, we found that in human NB cell lines, high MYCN expression is not responsible for low MHC class I expression because neither transfection-mediated overexpression nor small interfering RNA suppression of MYCN affects MHC class I and p50 levels. Furthermore, we identified NF-κB as the immediate upstream regulator of MHC class I because the p65 NF-κB subunit binds MHC class I promoter in chromatin immunoprecipitation experiments, and MHC class I expression is enhanced by p65 transfection and reduced by (a) the chemical NF-κB inhibitor sulfasalazine, (b) a dominant-negative IKBα gene, and (c) p65 silencing. Moreover, we showed that the endoplasmic reticulum aminopeptidases ERAP1 and ERAP2, which generate MHC class I binding peptides, are regulated by NF-κB, contain functional NF-κB–binding elements in their promoters, and mimic MHC class I molecules in the expression pattern. Consistent with these findings, nuclear p65 was detected in NB cells that express MHC class I molecules in human NB specimens. Thus, the coordinated downregulation of MHC class I, ERAP1, and ERAP2 in aggressive NB cells is attributable to a low transcriptional availability of NF-κB, possibly due to an unknown suppressor other than MYCN. Cancer Res; 70(3); 916–24
Exon-Based Clustering of Murine Breast Tumor Transcriptomes Reveals Alternative Exons Whose Expression Is Associated with Metastasis
Authors: Dutertre Martin , Lacroix-Triki Magali , Driouch Keltouma , de la Grange Pierre , Gratadou Lise , Beck Samantha , Millevoi Stefania , Tazi Jamal , Lidereau Rosette , Vagner Stephan , Auboeuf Didier
Published: January 2010

In the field of bioinformatics, exon profiling is a developing area of disease-associated transcriptome analysis. In this study, we performed a microarray-based transcriptome analysis at the single exon level in mouse 4T1 primary mammary tumors with different metastatic capabilities. A novel bioinformatics platform was developed that identified 679 genes with differentially expressed exons in 4T1 tumors, many of which were involved in cell morphology and movement. Of 152 alternative exons tested by reverse transcription-PCR, 97 were validated as differentially expressed in primary tumors with different metastatic capability. This analysis revealed candidate progression genes, hinting at variations in protein functions by alternate exon usage. In a parallel effort, we developed a novel exon-based clustering analysis and identified alternative exons in tumor transcriptomes that were associated with dissemination of primary tumor cells to sites of pulmonary metastasis. This analysis also revealed that the splicing events identified by comparing primary tumors were not aberrant events. Lastly, we found that a subset of differentially spliced variant transcripts identified in the murine model was associated with poor prognosis in a large clinical cohort of patients with breast cancer. Our findings illustrate the utility of exon profiling to define novel theranostic markers for study in cancer progression and metastasis. Cancer Res; 70(3); 896–905
Effects of Acute versus Chronic Hypoxia on DNA Damage Responses and Genomic Instability
Authors: Pires Isabel M. , Bencokova Zuzana , Milani Manuela , Folkes Lisa K. , Li Ji-Liang , Stratford Mike R. , Harris Adrian L. , Hammond Ester M.
Published: January 2010

Questions exist concerning the effects of acute versus chronic hypoxic conditions on DNA replication and genomic stability that may influence tumorigenesis. Severe hypoxia causes replication arrest independent of S-phase checkpoint, DNA damage response, or transformation status. Arrests occur during both the initiation and elongation phases of DNA replication, correlated with a rapid decrease in available deoxynucleotide triphosphates. With fluctuating oxygen tensions in tumors, arrested hypoxic cells may undergo rapid reperfusion and reoxygenation that leads to reoxygenation-induced DNA damage. In cells subjected to chronic hypoxia, we found that replicative restart was inhibited along with numerous replication factors, including MCM6 and RPA, the latter of which limits the hypoxia-induced DNA damage response. In contrast, in cells where replicative restart occurred, it was accompanied by extensive reoxygenation-induced DNA damage and compromised DNA repair. We found that cells reoxygenated after acute hypoxia underwent rapid p53-dependent apoptosis. Our findings suggest that cells lacking functional p53 are more susceptible to genomic instability and potentially tumorigenesis if they experience reoxygenation after acute exposure to hypoxia. Cancer Res; 70(3); 925–35
Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity
Authors: Pavet Valeria , Beyrath Julien , Pardin Christophe , Morizot Alexandre , Lechner Marie-Charlotte , Briand Jean-Paul , Wendland Miriam , Maison Wolfgang , Fournel Sylvie , Micheau Olivier , Guichard Gilles , Gronemeyer Hinrich
Published: January 2010

Ongoing clinical trials are exploring anticancer approaches based on signaling by TRAIL, a ligand for the cell death receptors DR4 and DR5. In this study, we report on the selective apoptotic effects of multivalent DR5 binding peptides (TRAILmim/DR5) on cancer cells in vitro and in vivo. Surface plasmon resonance revealed up to several thousand-fold increased affinities of TRAILmim/DR5-receptor complexes on generation of divalent and trivalent molecules, the latter of which was achieved with a conformationally restricted adamantane core. Notably, only multivalent molecules triggered a substantial DR5-dependent apoptotic response in vitro. In tumor models derived from human embryonic kidney cells or primary foreskin fibroblasts, TRAILmim/DR5 peptides exerted a cancer cell–selective action that could synergize with resveratrol in a manner independent of p53. In a xenograft model of human colon cancer, a divalent TRAILmim/DR5 peptide inhibited tumor growth. Our results offer a proof-of-principle for the development of synthetic small molecules to trigger the TRAIL apoptosis pathway for cancer therapy. Cancer Res; 70(3); 1101–10
Pancreatic Cancer Risk and ABO Blood Group Alleles: Results from the Pancreatic Cancer Cohort Consortium
Authors: Wolpin Brian M. , Kraft Peter , Gross Myron , Helzlsouer Kathy , Bueno-de-Mesquita H. Bas , Steplowski Emily , Stolzenberg-Solomon Rachael Z. , Arslan Alan A. , Jacobs Eric J. , LaCroix Andrea , Petersen Gloria , Zheng Wei , Albanes Demetrius , Allen Naomi E. , Amundadottir Laufey , Anderson Garnet , Boutron-Ruault Marie-Christine , Buring Julie E. , Canzian Federico , Chanock Stephen J. , Clipp Sandra , Gaziano John Michael , Giovannucci Edward L. , Hallmans Göran , Hankinson Susan E. , Hoover Robert N. , Hunter David J. , Hutchinson Amy , Jacobs Kevin , Kooperberg Charles , Lynch Shannon M. , Mendelsohn Julie B. , Michaud Dominique S. , Overvad Kim , Patel Alpa V. , Rajkovic Aleksandar , Sanchéz Maria-José , Shu Xiao-Ou , Slimani Nadia , Thomas Gilles , Tobias Geoffrey S. , Trichopoulos Dimitrios , Vineis Paolo , Virtamo Jarmo , Wactawski-Wende Jean , Yu Kai , Zeleniuch-Jacquotte Anne , Hartge Patricia , Fuchs Charles S.
Published: January 2010

A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18–1.62], 1.47 (95% CI, 1.07–2.02), and 1.53 (95% CI, 1.21–1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13–1.58) and 1.61 (95% CI, 1.22–2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14–1.85) and 2.42 (1.28–4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03–3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk. Cancer Res; 70(3); 1015–23
RETRACTED: Variable Inhibition of Thrombospondin 1 against Liver and Lung Metastases through Differential Activation of Metalloproteinase ADAMTS1
Authors: Lee Yoon-Jin , Koch Moritz , Karl Daniel , Torres-Collado Antoni X. , Fernando Namali T. , Rothrock Courtney , Kuruppu Darshini , Ryeom Sandra , Iruela-Arispe M. Luisa , Yoon Sam S.
Published: January 2010

Metastasis relies on angiogenesis for tumor expansion. Tumor angiogenesis is restrained by a variety of endogenous inhibitors, including thrombospondin 1 (TSP1). The principal antiangiogenic activity of TSP1 resides in a domain containing three TSP1 repeats (3TSR), and TSP1 cleavage is regulated, in part, by the metalloproteinase ADAMTS1. In this study, we examined the role of TSP1 and ADAMTS1 in controlling metastatic disease in the liver and lung. TSP1 overexpression inhibited metastatic growth of colon or renal carcinoma cells in liver but not lung. Metastatic melanoma in liver grew more rapidly in Tsp1-null mice compared with controls, whereas in lung grew similarly in Tsp1-null mice or controls. Recombinant TSP1 was cleaved more efficiently in lysates from liver than lung. ADAMTS1 inhibition by neutralizing antibody, small interfering RNA, or genetic deletion abrogated cleavage activity. To confirm that lack of cleavage of TSP1 ablated its antiangiogenic function in the lung, we generated colon cancer cells stably secreting only the 3TSR domain and found that they inhibited formation of both liver and lung metastases. Collectively, our results indicate that the antiangiogenic activity of TSP1 is differentially regulated by ADAMTS1 in the liver and lung, emphasizing the concept that regulation of angiogenesis is varied in different tissue environments. Cancer Res; 70(3); 948–56
Targeting Vascular Endothelial Growth Factor Receptor in Thyroid Cancer: The Intracellular and Extracellular Implications
Authors: Keefe Stephen M. , Cohen Marc A. , Brose Marcia S.
Published: January 2010

Our understanding of the molecular pathophysiology of differentiated thyroid cancer (DTC) has developed considerably over the last 10 years. Aberrant signaling through B-Raf and Akt has been implicated in the tumorigenesis of DTC. Moreover, these highly vascular tumors have proven to be sensitive to the inhibition of vascular endothelial growth factor receptor (VEGFR-2). It is likely that the multikinase inhibitors, sorafenib, sunitinib, axitinib, and motesanib, whose targets include VEGFR-2, exert their effects primarily through inhibition of endothelial cells. However, as VEGFR-2 is expressed on DTC cells, these compounds may have direct antitumor action. This review will discuss the key signaling pathways involved in thyroid cancer and their implications for targeted therapy. Clin Cancer Res; 16(3); 778–83
IGFBP2 and IGFBP3 Protein Expressions in Human Breast Cancer: Association with Hormonal Factors and Obesity
Authors: Probst-Hensch Nicole M. , Steiner Julia H.B. , Schraml Peter , Varga Zsuzsanna , Zürrer-Härdi Ursina , Storz Martina , Korol Dimitri , Fehr Mathias K. , Fink Daniel , Pestalozzi Bernhard C. , Lütolf Urs M. , Theurillat Jean-Philippe , Moch Holger
Published: January 2010

Purpose: The insulin-like growth factor (IGF) signaling system is involved in breast cancer initiation and progression. The prognostic relevance of tumor expression patterns of IGFI-related proteins remains poorly understood. This study associates the expression of selected IGF proteins with breast tumor and patient characteristics.

Experimental Design: IGFI, IGFI receptor, IGF-binding protein (IGFBP)2, and IGFBP3 expression was measured in 855 primary breast carcinomas by immunohistochemistry using tissue microarrays. We investigated the association of tumor and nodal stage, grade, hormone receptor status, HER2 gene amplification, menopausal status, body mass index, and survival with IGF protein expression.

Results: In contrast to IGFI, the expression of IGFI receptor, IGFBP2, and IGFBP3 was associated with estrogen receptor status. In addition, IGFBP3 was positively correlated with body mass index and premenopausal status. Importantly, IGFBP2 was an independent and positive predictor of overall survival (hazard ratio, 0.48; 95% confidence interval, 0.24-0.95; P = 0.04). There was a weak suggestion for IGFBP2 and overweight to modify each other's effect on survival.

Conclusions: According to these results, which need confirmation in larger patient series, the prognostic relevance of IGFBP2 and IGFBP3 protein expressions in breast cancer may depend on the hormonal context and body weight. Clin Cancer Res; 16(3); 1025–32
Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibition Results in Biphasic Alteration of Epidermal Homeostasis with Keratinocytic Apoptosis and Pigmentation Disorders
Authors: Schad Karin , Baumann Conzett Katrin , Zipser Marie C. , Enderlin Valérie , Kamarashev Jivko , French Lars E. , Dummer Reinhard
Published: January 2010

Purpose: Raf/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway is constitutively activated in melanoma. AZD6244 blocks MEK1/2, inhibiting ERK phosphorylation. We focus on associated cutaneous toxicity and we attempt to understand the underlying pathophysiology and design treatment strategies.

Experimental Design: Dermatologic conditions of 22 patients with unresectable melanoma stage III/IV in a phase II trial were evaluated. Thirteen patients received AZD6244 initially, and nine patients were treated with AZD6244 following tumor progression with temozolomide. Biopsies were compared with matched controls in normal skin. Immunohistochemistry was performed. Half-side treatment of acute skin toxicity compared therapeutic options.

Results: Nineteen of 22 (86%) AZD6244-treated patients presented with cutaneous eruptions. Seventeen patients (77%) developed acute papulopustular rash. Chronic skin changes included xerosis, paronychia, and fissured fingertips, resembling cutaneous toxicity of epidermal growth factor receptor inhibition. In addition, we observed reduced pigmentation of hair and skin. Histology of acute skin lesions revealed a significant increase of apoptotic keratinocytes (P = 0.0008), focal neutrophilic infiltrates, destruction of the adnexal structures by neutrophils, and reduced cytokeratins. A significant proliferation shift from basal to suprabasal keratinocytes was shown in acute and chronic lesions. The number and viability of melanocytes was not affected. Corticosteroids plus antibacterial topical therapy ameliorate acute skin toxicity.

Conclusions: AZD6244-associated skin reactions partly overlap with those observed upon epidermal growth factor receptor inhibition. Additionally, pigmentation of skin and hair is affected. The interruption of the MEK signaling pathway results in an acute keratinocyte stress response with disturbed epidermal homeostasis, inflammation, and tissue damage. Chronic adaptation controls inflammatory tissue damage but leads to cutaneous malfunctions that explain chronic skin toxicity. Clin Cancer Res; 16(3); 1058–64