bluuebunny/crossref_metadata_2025 huggingface dataset:
EXTRAORDINARY MAGNETORESISTANCE IN HYBRID SEMICONDUCTOR-METAL SYSTEMS
Authors: HEWETT T. H. , KUSMARTSEV F. V.
Published: September 2009

We show that extraordinary magnetoresistance (EMR) arises in systems consisting of two components; a semiconducting ring with a metallic inclusion embedded. The important aspect of this discovery is that the system must have a quasi-two-dimensional character. Using the same materials and geometries for the samples as in experiments by Solin et al.1,2, we show that such systems indeed exhibit a huge magnetoresistance. The magnetoresistance arises due to the switching of electrical current paths passing through the metallic inclusion. Diagrams illustrating the flow of the current density within the samples are utilised in discussion of the mechanism responsible for the magnetoresistance effect. Extensions are then suggested which may be applicable to the silver chalcogenides. Our theory offers an excellent description and explanation of experiments where a huge magnetoresistance has been discovered2,3.
ACOUSTIC BAND GAP FORMATION IN TWO-DIMENSIONAL LOCALLY RESONANT SONIC CRYSTALS COMPRISED OF HELMHOLTZ RESONATORS
Authors: CHALMERS L. , ELFORD D. P. , KUSMARTSEV F. V. , SWALLOWE G. M.
Published: September 2009

We present a new type of sonic crystal technology offering a novel method of achieving broad acoustic band gaps. The proposed design of a locally resonating sonic crystal (LRSC) is constructed from "C"-shaped Helmholtz resonators as opposed to traditional solid scattering units. This unique construction enables a two band gap system to be generated in which the first — a Bragg type band gap, arises due to the periodic nature of the crystal, whilst the second gap results from resonance of the air column within the resonators. The position of this secondary band gap is found to be dependent upon the dimensions of the resonating cavity.

The band gap formation is investigated theoretically using finite element methods, and confirmed through experimental testing. It is noted that the resonance band gaps detected cover a much broader frequency range (in the order of kHz) than has been achieved to date. In addition the possibility of overlapping such a wide band gap with the characteristic Bragg gap generated by the structure itself could yield gaps of even greater range.

A design of sonic crystal is proposed, that comprises of several resonators with differing cavity sizes. Such a structure generates multiple resonance gaps corresponding to the various resonator sizes, which may be overlapped to form yet larger band gaps.

This multiple resonance gap system can occur in two configurations. Firstly a simple mixed array can be created by alternating resonator sizes in the array and secondly using a system coined the Matryoshka (Russian doll) array in which the resonators are distributed inside one another.

The proposed designs of LRSC's offer a real potential for acoustic shielding using sonic crystals, as both the size and position of the band gaps generated can be controlled. This is an application which has been suggested and investigated for several years with little progress. Furthermore the frequency region attenuated by resonance is unrelated to the crystals lattice constant, providing yet more flexibility in the design of such devices.
DISORDERED SUPERCONDUCTORS: A SIMPLE MODEL MANIFESTING PSEUDOGAP AND BCS-BEC CROSSOVER
Authors: DEY POULUMI , BASU SAURABH
Published: September 2009

The effect of random on-site disorder on s-wave (BCS) superconductors described by a two dimensional negative-U Hubbard model is studied using Bogoliubov-de Gennes (BdG) method. The mean field pairing amplitudes become spatially inhomogeneous at large values of disorder where the system breaks up into superconducting islands with large pairing amplitudes, separated by insulating strips. The amplitude fluctuations are correctly accounted for via BdG calculations, however it misses phase fluctuations which are inherent to low dimensions. The phase fluctuations affect superconducting properties strongly, and the effect is more pronounced in the limit of large disorder. We provide a close estimate of the actual transition temperature, Tcby incorporating phase fluctuations about the inhomogeneous BdG state. This is obtained by relating the jump in renormalized Ds(obtained from a self consistent Harmonic approximation on a phase-only Hamiltonian) at the Kosterlitz-Thouless (KT) transition and the KT transition temperature, TKTobtained from Ds(T) = (2/π)TKTas temperature tends to TKTfrom below. This yields opening of a large region sandwiched between [Formula: see text] (obtained by the vanishing of [Formula: see text]) and TKTwhere there is no phase coherence between the pairs, however amplitude correlations continue to exist, reminiscent of a pseudogap phase in high-Tcsuperconductors which is marked by short ranged preformed pairs without any definite phase relation between them. Further, the appearance of the superconducting islands from a homogeneous phase indicates the evolution of a system consisting of large and overlapping pairs to one that contains short and tightly bound pairs - a scenario termed as BCS-BEC crossover. We have investigated in details the crossover phenomenon as a function of disorder and confirmed it's existence at small values of electron concentration, however, absent at larger densities.
SUPERCONDUCTIVITY, SPIN AND CHARGE DENSITY STRUCTURES IN ONE AND TWO-DIMENSIONAL SELF-CONSISTENT MODELS
Authors: MATVEENKO S. I.
Published: September 2009

We review some analytical results of our studies of the charge- and spin density modulations (CDW and SDW) in a one- and two-dimensional electron systems. Self-consistent solutions of Bogoliubov- de Gennes equations for spin-charge solitonic superstructure and superconducting state are obtained in the framework of one and two-dimensional extended Hubbard models. Possible correspondence of the theory with experimental data on stripe phase in high Tc cuprates is discussed. We found various solutions for the two-dimensional self-consistent model of superconductors with dx2-y2 symmetry of the order parameter, taking into account spin and charge distributions. Analytical solutions for spin-charge density wave phases in the absence of the superconductivity ("stripe" and "checkerboard" structures) are presented. Analytical solutions for coexisting superconductivity and stripe-phase modulations in the cores of the Abrikosov's vortices are also found.
TERAHERTZ BLOCH OSCILLATOR WITH SUPPRESSED ELECTRIC DOMAINS: EFFECT OF ELASTIC SCATTERING
Authors: HYART TIMO , ALEKSEEV KIRILL N. , LEPPÄNEN AHTI , THUNEBERG ERKKI V.
Published: September 2009

We theoretically consider the amplification of THz radiation in a superlattice Bloch oscillator. The main dilemma in the realization of THz Bloch oscillator is finding operational conditions which allow simultaneously to achieve gain at THz frequencies and to avoid destructive space-charge instabilities. A possible solution to this dilemma is the extended Limited Space-Charge Accumulation scheme of Kroemer (H. Kroemer, cond-mat/0009311). Within the semiclassical miniband transport approach we extend its range of applicability by considering a difference in the relaxation times for electron velocity and electron energy. The kinetics of electrons and fields establishing a stationary signal in the oscillator is also discussed.
ELECTROSTATIC FIELD IN SUPERCONDUCTORS IV: THEORY OF GINZBURG-LANDAU TYPE
Authors: LIPAVSKÝ PAVEL , KOLÁČEK JAN
Published: September 2009

Bardeen's extension of the Ginzburg-Landau theory to low temperatures is modified so that along with magnetic properties it also covers the electrostatic field.
ON WIDE DIAMETER OF CAYLEY GRAPHS
Authors: JIA KEVIN E. , ZHANG ALICIA Q.
Published: September 2009

Because of its applications in network theory, the wide diameter of graphs has been studied extensively in recent years. It is still an open problem to compute the wide diameter of Cayley graphs. This paper investigates the wide diameter of Cayley graphs of ℤm, the cyclic group of residue classes modulo m. It is proved that the k-wide diameter of the Cayley graph Cay (Zm, A) generated by a k-element set A is d + 1 for k = 2 and ≤ d + 1 for k = 3, where d is the diameter of Cay (ℤm, A).
FAULT DIAMETER OF HYPERCUBES WITH HYBRID NODE AND LINK FAULTS
Authors: KUNG TZU-LIANG , LIN CHENG-KUAN , LIANG TYNE , HSU LI-YEN , TAN JIMMY J. M.
Published: September 2009

In this paper we study the fault diameter of the n-dimensional hypercube (or n-cube for short), Qn, for n ≥ 3. Let F be a set of hybrid node-faults and/or link-faults in Qn such that every node of Qn is still connected to at least one fault-free node by a fault-free link. Then we compute the exact diameter of Qn - F for |F| ≤ 2n - 3. As an immediate consequence, our result improves upon those presented by S. Latifi (1993), in which only node-faults were addressed.
Regulation of Midgut Growth, Development, and Metamorphosis
Authors: Hakim Raziel S. , Baldwin Kate , Smagghe Guy
Published: September 2009

The insect midgut is an important site of entry for pathogens and insect control agents. This review focuses on recent information related to midgut epithelial growth, metamorphosis, and repair as a defense against pathogens. The roles of stem cell mitogens and differentiation factors are described. Included is a discussion of apoptosis and autophagy in the yellow body. Sloughing, also described, protects the midgut from virus infections and bacterial toxins through death and replacement of affected cells. The mechanisms by which the repair process reduces the effectiveness of pest control strategies are discussed. Primary tissue culture methods also are described, and their value in understanding the mechanisms by which biologically based insecticides work is discussed.
Applications of Holography in Fluid Mechanics and Particle Dynamics
Authors: Katz Joseph , Sheng Jian
Published: September 2009

The quantification of three-dimensional (3D) flow structures and particle dynamics is crucial for unveiling complex interactions in turbulent flows. This review summarizes recent advances in volumetric particle detection and 3D flow velocimetry involving holography. We introduce the fundamental principle of holography and discuss the debilitating depth-of-focus problem, along with methods that have been implemented to circumvent it. The focus of this review is on recent advances in the development of in-line digital holography in general, and digital holographic microscopy in particular. A mathematical background for the numerical reconstruction of digital holograms is followed by a summary of recently introduced 3D particle tracking and velocity measurement techniques. The review concludes with sample applications, including 3D velocity measurements that fully resolve the flow in the inner part of a turbulent boundary layer, the diffusion of oil droplets in high–Reynolds number turbulence, and predator-prey interactions among swimming microorganisms in dense suspensions, as well as oceanic and atmospheric field experiments.
Lattice-Boltzmann Method for Complex Flows
Authors: Aidun Cyrus K. , Clausen Jonathan R.
Published: September 2009

With its roots in kinetic theory and the cellular automaton concept, the lattice-Boltzmann (LB) equation can be used to obtain continuum flow quantities from simple and local update rules based on particle interactions. The simplicity of formulation and its versatility explain the rapid expansion of the LB method to applications in complex and multiscale flows. We review many significant developments over the past decade with specific examples. Some of the most active developments include the entropic LB method and the application of the LB method to turbulent flow, multiphase flow, and deformable particle and fiber suspensions. Hybrid methods based on the combination of the Eulerian lattice with a Lagrangian grid system for the simulation of moving deformable boundaries show promise for more efficient applications to a broader class of problems. We also discuss higher-order boundary conditions and the simulation of microchannel flow with finite Knudsen number. Additionally, the remarkable scalability of the LB method for parallel processing is shown with examples. Teraflop simulations with the LB method are routine, and there is no doubt that this method will be one of the first candidates for petaflop computational fluid dynamics in the near future.
Dielectric Barrier Discharge Plasma Actuators for Flow Control
Authors: Corke Thomas C. , Enloe C. Lon , Wilkinson Stephen P.
Published: September 2009

The term plasma actuator has now been a part of the fluid dynamics flow-control vernacular for more than a decade. A particular type of plasma actuator that has gained wide use is based on a single–dielectric barrier discharge (SDBD) mechanism that has desirable features for use in air at atmospheric pressures. For these actuators, the mechanism of flow control is through a generated body-force vector field that couples with the momentum in the external flow. The body force can be derived from first principles, and the effect of plasma actuators can be easily incorporated into flow solvers so that their placement and operation can be optimized. They have been used in a wide range of internal and external flow applications. Although initially considered useful only at low speeds, plasma actuators are effective in a number of applications at high subsonic, transonic, and supersonic Mach numbers, owing largely to more optimized actuator designs that were developed through better understanding and modeling of the actuator physics. New applications continue to appear through a growing number of programs in the United States, Germany, France, England, the Netherlands, Russia, Australia, Japan, and China. This review provides an overview of the physics and modeling of SDBD plasma actuators. It highlights some of the capabilities of plasma actuators through examples from experiments and simulations.
Identifying Drivers of Catalytic Activity through Systematic Surface Modification of Cathode Materials
Authors: Wachsman E. D. , Kan Cynthia
Published: September 2009

To systematically study the effect of surface composition on the catalytic activity for oxygen exchange, strontium doped lanthanum manganite (LSM) powder was infiltrated with various metal nitrate solutions (La, Sr, Co, Fe) and then calcined to deposit the resultant metal oxide on the surface of the powder. The elements chosen for LSM infiltration were selected because they are the metal constituents of strontium doped cobalt ferrite (LSCF), which is initially a much more active cathode material. Results from LSM show a stronger effect from the addition of B site elements, thus LSCF was correspondingly infiltrated with manganese. By comparing the different surfaces, a better understanding of the underlying drivers of catalytic activity is gained. Two key properties for good catalytic activity are recognized: ionic conductivity and active metal sites on the surface which serve as either redox centers or adsorption sites.
Chemical and Electrochemical Properties of Cathode Material in SOFCs under Cr Poisoning Conditions
Authors: Komatsu Takeshi , Chiba Reiichi , Orui Himeko , Nozawa Kazuhiko , Yoshida Yoshiteru , Yokoo Masayuki , Hayashi Katsuya , Arakawa Masayasu , Arai Hajime , Sato Kazunori
Published: September 2009

This paper discusses on the Cr poisoning that occurs in solid oxide fuel cells with metallic alloy separators. The results of a series of experimental, including an analysis of cathodic overvoltage with loading time at a constant current density, observation of the cathode microstructure, and an experiment of chemical compatibility of the cathode material against Cr oxide, are presented. LNF cathodes are more stable against Cr poisoning than LSCF and LSM cathodes. Cr adhesives were observed near the cathode layer for all measured cells in the presence of the alloy. Furthermore, LNF was less reactive with Cr oxide than LSCF and LSM. The results of electrochemical measurements under the Cr poisoning condition agree with that of the chemical properties of the cathode material against Cr oxide.
ITM Ceramic Membrane Technology to Produce Synthesis Gas
Authors: Miller Christopher , Abrardo Joseph , Carolan Michael , Chen Jack , Minford Eric , Waldron William , Repasky John
Published: September 2009

Air Products and its partners are developing Ion Transport Membrane (ITM) technology for the production of synthesis gas, a mixture of hydrogen and carbon monoxide. The ITM Syngas process is a breakthrough technology that combines air separation and high-temperature synthesis gas generation processes into a single ceramic membrane reactor, with significant savings in the capital cost of synthesis gas production. Because synthesis gas is a feedstock for a range of different processes, ITM Syngas represents a technology platform that has numerous applications, such as hydrogen, clean fuels and chemicals. ITM ceramic membranes are fabricated from non-porous, mixed-metal oxides and operate with exceptionally high oxygen flux and selectivity when exposed to an oxygen chemical potential gradient at high temperatures. Significant advances have been made in developing and scaling up the ITM Syngas technology. This paper describes the development of commercial-size ceramic membranes and the ITM Syngas reactor system. Recent laboratory and pilot unit test results will also be discussed.
Synthesis and Na+ Conduction Properties of Phosphosilicate Glass-Ceramics in the Y-Nd Mixed System
Authors: Okura Toshinori , Saimaru Mitsugu , Monma Hideki
Published: September 2009

The glass-ceramics of the phosphorus containing Na5RSi4O12 (N5)-type (R=rare earth) Na+ superionic conductors in the Y-Nd mixed system Na2O-Y2O3-Nd2O3-P2O5-SiO2 (NaYNdPSi) were prepared by crystallization of glasses with the composition formula Na3+3x-yYzNd1-x-zPySi3-yO9. The optimum conditions for crystallization were discussed with reference to the conduction properties and the preparation of N5-type glass-ceramic NaYNdPSi. The ionic conductivity of the glass-ceramic Na3.9Y0.1Nd0.5P0.3Si2.7O9 was 1.6×10-2 S/cm at 300{degree sign}C.
A regulatory role of LPCAT1 in the synthesis of inflammatory lipids, PAF and LPC, in the retina of diabetic mice
Authors: Cheng Long , Han Xiao , Shi Yuguang
Published: September 2009

Platelet-activating factor (PAF) and lysophosphatidylcholine (LPC) are potent inflammatory lipids. Elevated levels of PAF and LPC are associated with the onset of diabetic retinopathy and neurodegeneration. However, the molecular mechanisms underlying such defects remain elusive. LPCAT1 is a newly reported lysophospholipid acyltransferase implicated in the anti-inflammatory response by its role in conversion of LPC to PC. Intriguingly, the LPCAT1 enzyme also catalyzes the synthesis of PAF from lyso-PAF with use of acetyl-CoA as a substrate. The present studies investigated regulatory roles of LPCAT1 in the synthesis of inflammatory lipids during the onset of diabetes. Our work shows that LPCAT1 plays an important role in the inactivation of PAF by catalyzing the synthesis of alkyl-PC, an inactivated form of PAF with use of acyl-CoA and lyso-PAF as substrates. In support of a role of LPCAT1 in anti-inflammatory responses in diabetic retinopathy, LPCAT1 is most abundantly expressed in the retina. Moreover, LPCAT1 mRNA levels and acyltransferase activity toward lyso-PAF and LPC were significantly downregulated in retina and brain tissues in response to the onset of diabetes in Ins2 Akita and db/db mice, mouse models of type 1 and type 2 diabetes, respectively. Conversely, treatment of db/db mice with rosiglitazone, an antidiabetes compound, significantly upregulated LPCAT1 mRNA levels concurrently with increased acyltransferase activity in the retina and brain. Collectively, these findings identified a novel regulatory role of LPCAT1 in catalyzing the inactivation of inflammatory lipids in the retina of diabetic mice.
A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model
Authors: Basu Hirak S. , Thompson Todd A. , Church Dawn R. , Clower Cynthia C. , Mehraein-Ghomi Farideh , Amlong Corey A. , Martin Christopher T. , Woster Patrick M. , Lindstrom Mary J. , Wilding George
Published: September 2009

High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiologic factor in prostate cancer (CaP) occurrence, recurrence, and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase, the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells, as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data show that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays CaP progression. [Cancer Res 2009;69(19):7689–95]
Comparative Analyses of Chromosome Alterations in Soft-Tissue Metastases within and across Patients with Castration-Resistant Prostate Cancer
Authors: Holcomb Ilona N. , Young Janet M. , Coleman Ilsa M. , Salari Keyan , Grove Douglas I. , Hsu Li , True Lawrence D. , Roudier Martine P. , Morrissey Colm M. , Higano Celestia S. , Nelson Peter S. , Vessella Robert L. , Trask Barbara J.
Published: September 2009

Androgen deprivation is the mainstay of therapy for progressive prostate cancer. Despite initial and dramatic tumor inhibition, most men eventually fail therapy and die of metastatic castration-resistant (CR) disease. Here, we characterize the profound degree of genomic alteration found in CR tumors using array comparative genomic hybridization (array CGH), gene expression arrays, and fluorescence in situ hybridization (FISH). Bycluster analysis, we show that the similarity of the genomic profiles from primary and metastatic tumors is driven by the patient. Using data adjusted for this similarity, we identify numerous high-frequency alterations in the CR tumors, such as 8p loss and chromosome 7 and 8q gain. By integrating array CGH and expression array data, we reveal genes whose correlated values suggest they are relevant to prostate cancer biology. We find alterations that are significantly associated with the metastases of specific organ sites, and others with CR tumors versus the tumors of patients with localized prostate cancer not treated with androgen deprivation. Within the high-frequency sites of loss in CR metastases, we find an overrepresentation of genes involved in cellular lipid metabolism, including PTEN. Finally, using FISH, we verify the presence of a gene fusion between TMPRSS2 and ERG suggested by chromosome 21 deletions detected by array CGH. We find the fusion in 54% of our CR tumors, and 81% of the fusion-positive tumors contain cells with multiple copies of the fusion. Our investigation lays the foundation for a better understanding of and possible therapeutic targets for CR disease, the poorly responsive and final stage of prostate cancer. [Cancer Res 2009;69(19):7793–802]
Epidermal Growth Factor Receptor Variant III–Induced Glioma Invasion Is Mediated through Myristoylated Alanine-Rich Protein Kinase C Substrate Overexpression
Authors: Micallef Johann , Taccone Michael , Mukherjee Joydeep , Croul Sidney , Busby Jennifer , Moran Michael F. , Guha Abhijit
Published: September 2009

Glioblastoma multiforme (GBM) is the most common and most malignant adult brain tumor. A characteristic of GBM is their highly invasive nature, making complete surgical resection impossible. The most common gain-of-function alteration in GBM is amplification, overexpression, and mutations of the epidermal growth factor receptor (EGFR). The constitutively activated mutant EGFR variant III (EGFRvIII), found in ∼20% of GBM, confers proliferative and invasive advantage. The signaling cascades downstream of aberrant EGFR activation contributing to the invasive phenotype are not completely understood. Here, we show myristoylated alanine-rich protein kinase C substrate (MARCKS), previously implicated in cell adhesion and motility, contributes to EGFR-mediated invasion of human GBM cells. EGFRvIII-expressing or EGF-stimulated human GBM cells increased expression, phosphorylation, and cytosolic translocation of MARCKS in a protein kinase C-α–dependent manner. Down-regulation of MARCKS expression with small interfering RNA in GBM cells expressing EGFRvIII led to decreased cell adhesion, spreading, and invasion. Elucidation of mechanisms that promote EGFRvIII-mediated tumorigenesis in GBM, such as MARCKS, provides additional understanding and potential biological targets against this currently terminal human cancer. [Cancer Res 2009;69(19):7548–56]
MYC Activity Mitigates Response to Rapamycin in Prostate Cancer through Eukaryotic Initiation Factor 4E–Binding Protein 1–Mediated Inhibition of Autophagy
Authors: Balakumaran Bala S. , Porrello Alessandro , Hsu David S. , Glover Wayne , Foye Adam , Leung Janet Y. , Sullivan Beth A. , Hahn William C. , Loda Massimo , Febbo Phillip G.
Published: September 2009

Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E–binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy. [Cancer Res 2009;69(19):7803–10]
Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-β–Induced Cell Death through Impairing Up-regulation of the NADPH Oxidase NOX4
Authors: Caja Laia , Sancho Patricia , Bertran Esther , Iglesias-Serret Daniel , Gil Joan , Fabregat Isabel
Published: September 2009

Transforming growth factor-β (TGF-β) induces apoptosis in hepatocytes, being considered a liver tumor suppressor. However, many human hepatocellular carcinoma (HCC) cells escape from its proapoptotic effects, gaining response to this cytokine in terms of malignancy. We have recently reported that the apoptosis induced by TGF-β in hepatocytes requires up-regulation of the NADPH oxidase NOX4, which mediates reactive oxygen species (ROS) production. TGF-β–induced NOX4 expression is inhibited by antiapoptotic signals, such as the phosphatydilinositol-3-phosphate kinase or the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. The aim of the present work was to analyze whether resistance to TGF-β–induced apoptosis in HCC cells is related to the impairment of NOX4 up-regulation due to overactivation of survival signals. Results indicate that inhibition of the MAPK/ERK kinase (MEK)/ERK pathway in HepG2 cells, which are refractory to the proapoptotic effects of TGF-β, sensitizes them to cell death through a mitochondrial-dependent mechanism, coincident with increased levels of BIM and BMF, decreased levels of BCL-XL and MCL1, and BAX/BAK activation. Regulation of BMF, BCL-XL, and MCL1 occurs at the mRNA level, whereas BIM regulation occurs post-transcriptionally. ROS production and glutathione depletion are only observed in cells treated with TGF-β and PD98059, which correlates with NOX4 up-regulation. Targeting knockdown of NOX4 impairs ROS increase and all the mitochondrial-dependent apoptotic features by a mechanism that is upstream from the regulation of BIM, BMF, BCL-XL, and MCL1 levels. In conclusion, overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-β–induced cell death through impairing NOX4 up-regulation, which is required for an efficient mitochondrial-dependent apoptosis. [Cancer Res 2009;69(19):7595–602]
Down-regulation of c-FLIP Enhances Death of Cancer Cells by Smac Mimetic Compound
Authors: Cheung Herman H. , Mahoney Douglas J. , LaCasse Eric C. , Korneluk Robert G.
Published: September 2009

Smac mimetic compounds (SMC) are novel small molecules being developed for cancer therapy. The mechanism of SMC-induced sensitivity in cancer cells depends on autocrine release of tumor necrosis factor α (TNFα); however, potential mechanisms of resistance remain unknown. Here, we investigated the molecular profile and cytotoxic responsiveness of a diverse panel of 51 cancer cell lines to combinations of a dimeric SMC (AEG40730), death ligand TNFα, and tumor necrosis factor-related apoptosis-inducing ligand. Synergy was seen in combination with death receptor agonists in some cells, although single-agent activity was limited to a fewsensitive lines. Unexpectedly, the majority of cell lines resistant to combinations of SMC-AEG40730 and death ligands expressed caspase-8, FADD, RIP1, and ligand receptors necessary for apoptosis execution. Furthermore, TNFα-mediated ubiquitination of RIP1 was repressed by SMC-AEG40730 treatment, leading to the formation of the proapoptosis complex II. However, in resistant cancer cells, SMC-AEG40730 repressed TNFα-mediated c-jun-NH2-kinase activation and the levels of caspase-8 inhibitor c-FLIP were persistently elevated, in contrast to SMC-responsive cancer cells. Importantly, the silencing of c-FLIP restored SMC sensitivity in previously resistant cancer cells by allowing ligand-mediated activation of caspase-8 and caspase-3 to proceed. Together, these results provide mechanistic insight into the action of SMCs, demonstrating that the deciphering of the relevant molecular signature in cancer cells leads to the prediction of cancer cell responsiveness to SMC treatment. Furthermore, a majority of resistant cancer cells were sensitized to SMC-AEG40730 and TNFα by down-regulating c-FLIP, suggesting novel approaches in the use of SMCs and c-FLIP antagonists in treating cancer. [Cancer Res 2009;69(19):7729–38]
Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters
Authors: Hu Shuiying , Chen Zhaoyuan , Franke Ryan , Orwick Shelley , Zhao Ming , Rudek Michelle A. , Sparreboom Alex , Baker Sharyn D.
Published: September 2009

Purpose: To compare side-by-side the uptake of sorafenib and sunitinib in vitro by human uptake solute carriers of the SLC22A and SLCO families, the transport by and inhibition of efflux ATP-binding cassette (ABC) transporters, and the role of ABCB1 in the plasma pharmacokinetics and brain penetration of these agents.

Experimental Design: Uptake of [3H]sorafenib or [3H]sunitinib was assessed in Xenopus laevis oocytes or mammalian cells transfected with cDNAs coding for human OATP1A2, OATP1B1, OATP1B3, OCT1, OAT2, OAT3, OCTN1, or OCTN2. Efflux and inhibition experiments were conducted in cells transfected with human ABCB1, ABCG2, ABCC2, or ABCC4. In vivo pharmacokinetic studies were done in knockout mice lacking Abcb1-type transporters.

Results: Intracellular uptake was not appreciably affected by any of the studied solute carriers and was minute relative to the respective prototypical substrates. Sorafenib and sunitinib showed concentration-dependent (1 and 10 μmol/L), low to moderate affinity for ABCB1 but were not affected by the other ABC transporters. Both agents inhibited all tested ABC transporters. The absence of Abcb1 had no affect on plasma pharmacokinetics, but brain penetration was moderately increased by 1.9- and 2.9-fold for sorafenib and sunitinib, respectively, in knockout animals versus controls.

Conclusions: Unlike other tyrosine kinase inhibitors, sorafenib and sunitinib do not appear to rely on active transport to enter the cell nor are they high-affinity substrates for ABC efflux transporters. Based on these characteristics, these two drugs may be less susceptible to transporter-mediated alterations in systemic exposure and transporter-related resistance mechanisms. (Clin Cancer Res 2009;15(19):6062–9)
CXCL13 and CXCL12 in Central Nervous System Lymphoma Patients
Authors: Fischer Lars , Korfel Agnieszka , Pfeiffer Sebastian , Kiewe Philipp , Volk Hans-Dieter , Cakiroglu Hüsniye , Widmann Thomas , Thiel Eckhard
Published: September 2009

Purpose: Homing of malignant lymphocytes to the central nervous system (CNS) may play a role in the pathogenesis of CNS lymphoma. In this study, we evaluated the chemokines CXCL12 and CXCL13 in the cerebrospinal fluid (CSF) and serum of patients with CNS lymphoma.

Experimental Design: Samples from 30 patients with CNS lymphoma (23 with primary and 7 with secondary CNS lymphoma; all B-cell lymphoma) and 40 controls (10 patients with other CNS malignancies and 30 without a malignant CNS disease) were examined. CXCL12 and CXCL13 concentrations were measured using enzyme-linked immunosorbent assays. The grade of blood-brain barrier disruption was estimated by the CSF/serum albumin ratio.

Results: CNS lymphoma patients and controls did not differ in CXCL12 serum and CSF levels. Serum levels of CXCL13 were generally low. CXCL13 CSF levels, however, were significantly higher in CNS lymphoma patients as compared with controls (P < 0.0001). Chemokine levels in CSF and serum did not correlate. In CNS lymphoma, CXCL13 concentration in CSF correlated with the degree of blood-brain barrier disruption (R = 0.66; P = 0.003). Elevated CSF levels of CXCL12 and CXCL13 measured in seven CNS lymphoma patients during therapy decreased in five patients who responded to chemotherapy and increased in two with lymphoma progression.

Conclusions: Our results suggest a production of CXCL13 within the CNS of CNS lymphoma patients, which decreases with response to therapy. Thus, CXCL13 may represent a marker for further diagnostic and prognostic studies. (Clin Cancer Res 2009;15(19):5968–73)
Interstitial Fluid Pressure as a Prognostic Factor in Cervical Cancer Following Radiation Therapy
Authors: Yeo Seung-Gu , Kim Jun-Sang , Cho Moon-June , Kim Ki-Hwan , Kim Jae-Sung
Published: September 2009

Purpose: To investigate tumor interstitial fluid pressure as a prognostic factor for recurrence-free survival in patients with cervical cancer following radiation therapy.

Experimental Design: Tumor interstitial fluid pressure was measured in 55 cervical cancer patients who received radiation therapy between August 1998 and September 2002. Interstitial fluid pressure measurements were made before radiation therapy (pre–radiation therapy interstitial fluid pressure) and after a median of 28.8 Gy in 16 fractions (range, 25.2-30.6 Gy in 14-17 fractions) of radiation therapy (mid–radiation therapy interstitial fluid pressure), using a modified wick-in-needle technique. Median follow-up was 74 months (range, 2-118 months). The Kaplan-Meier method with the log-rank test and Cox's proportional hazard model were used in univariate and multivariate analyses, respectively, of prognostic factors for recurrence-free survival.

Results: Median pre–radiation therapy and mid–radiation therapy interstitial fluid pressure were 29.0 mm Hg (range, 4.0-93.9 mm Hg) and 20.0 mm Hg (range, −1.2 to 29.6 mm Hg), respectively (P = 0.001). Pre–radiation therapy interstitial fluid pressure was significantly higher in adenocarcinomas than squamous cell carcinomas (P = 0.028). Significant reduction of interstitial fluid pressure was noted only in patients with complete responses (P = 0.002), and mid–radiation therapy interstitial fluid pressure was significantly lower in patients with complete responses (P = 0.036). In the multivariate analysis including interstitial fluid pressures and clinical variables, pre–radiation therapy interstitial fluid pressure was an independent prognostic factor for local and distant recurrence-free survival (P = 0.001 and 0.027, respectively).

Conclusions: Mid–radiation therapy interstitial fluid pressure measurement may be useful in predicting radiation therapy responses, and pre–radiation therapy interstitial fluid pressure was a significant prognostic factor for local and distant relapse-free survival in patients with cervical cancer after radiation therapy. (Clin Cancer Res 2009;15(19):6201–7)
A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors
Authors: Rini Brian I. , Garcia Jorge A. , Cooney Matthew M. , Elson Paul , Tyler Allison , Beatty Kristi , Bokar Joseph , Mekhail Tarek , Bukowski R.M. , Budd G. Thomas , Triozzi Pierre , Borden Ernest , Ivy Percy , Chen Helen X. , Dowlati Afshin , Dreicer Robert
Published: September 2009

Purpose: Bevacizumab is an antibody against vascular endothelial growth factor; sunitinib is an inhibitor of vascular endothelial growth factor and related receptors. The safety and maximum tolerated dose of sunitinib plus bevacizumab was assessed in this phase I trial.

Experimental Design: Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level, 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level, 5 mg/kg) on days 1, 15, and 29 of a 42-day cycle. Dose-limiting toxicities during the first 6-week cycle were used to determine the maximum tolerated dose.

Results: Thirty-eight patients were enrolled. Patients received a median of 3 cycles of treatment (range, 1-17+). There was one dose-limiting toxicity (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed Response Evaluation Criteria in Solid Tumors–defined partial response (18%; 95% confidence interval, 8-34%). Nineteen of the 32 patients with a postbaseline scan (59%) had at least some reduction in overall tumor burden (median, 32%; range, 3-73%).

Conclusions: The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Antitumor activity was observed across multiple solid tumors. (Clin Cancer Res 2009;15(19):6277–83)
Jekyll and Hyde and Me: Age-Graded Differences in Conceptions of Self-Unity
Authors: Proulx Travis , Chandler Michael J.
Published: September 2009

This research details the changing ways in which young people of different ages differently warrant the conviction that, notwithstanding evidence of good and bad behaviours, selves can be understood as unified across the various roles and contexts that they occupy. Canadian adolescents and young adults were asked to explain the apparent disunity of self implied by good and bad behaviours manifested by the fictional character Dr. Jekyll and Mr. Hyde, themselves and familiar others. Age-graded differences were observed, where young people described themselves as increasingly multiplicitous and context dependent as they grew older. This developmental trajectory is understood to represent an emerging desire to imagine one’s good behaviours as internally motivated, and one’s bad behaviours as externally provoked.
The Social and the Psychological: Structure and Context in Intellectual Development
Authors: Psaltis Charis , Duveen Gerard , Perret-Clermont Anne-Nelly
Published: September 2009

This paper discusses the distinct meanings of internalization and interiorization as ways of rendering intelligible the social constitution of the psychological in a line of research that started with Piaget and extended into a post-Piagetian reformulation of intelligence in successive generations of studies of the relations between social interaction and cognitive development. While the same clarity cannot be found in Vygotsky’s work, the emphasis on the cultural embeddedness of cognitive activity in contemporary cultural psychology has also been a significant influence on the evolution of this work. This paper proposes a further integration of these perspectives by developing the idea of operativity-in-context as a means of retaining the advantages of Piaget’s structural analysis of cognition whilst recognizing the situational and cultural constraints on cognitive functioning.
Which Neuromuscular or Cognitive Test Is the Optimal Screening Tool to Predict Falls in Frail Community-Dwelling Older People?
Authors: Shimada Hiroyuki , Suzukawa Megumi , Tiedemann Anne , Kobayashi Kumiko , Yoshida Hideyo , Suzuki Takao
Published: September 2009

Background: The use of falls risk screening tools may aid in targeting fall prevention interventions in older individuals most likely to benefit. Objective: To determine the optimal physical or cognitive test to screen for falls risk in frail older people. Methods: This prospective cohort study involved recruitment from 213 day-care centers in Japan. The feasibility study included 3,340 ambulatory individuals aged 65 years or older enrolled in the Tsukui Ordered Useful Care for Health (TOUCH) program. The external validation study included a subsample of 455 individuals who completed all tests. Physical tests included grip strength (GS), chair stand test (CST), one-leg standing test (OLS), functional reach test (FRT), tandem walking test (TWT), 6-meter walking speed at a comfortable pace (CWS) and at maximum pace (MWS), and timed up-and-go test (TUG). The mental status questionnaire (MSQ) was used to measure cognitive function. The incidence of falls during 1 year was investigated by self-report or an interview with the participant’s family and care staff. Results: The most practicable tests were the GS and MSQ, which could be administered to more than 90% of the participants regardless of the activities of daily living status. The FRT and TWT had lower feasibility than other lower limb function tests. During the 1-year retrospective analysis of falls, 99 (21.8%) of the 455 validation study participants had fallen at least once. Fallers showed significantly poorer performance than non-fallers in the OLS (p = 0.003), TWT (p = 0.001), CWS (p = 0.013), MWS (p = 0.007), and TUG (p = 0.011). The OLS, CWS, and MWS remained significantly associated with falls when performance cut-points were determined. Logistic regression analysis revealed that the TWT was a significant and independent, yet weak predictor of falls. A weighting system which considered feasibility and validity scored the CWS (at a cut-point of 0.7 m/s) as the best test to predict risk of falls. Conclusion: Clinical tests of neuromuscular function can predict risk of falls in frail older people. When feasibility and validity were considered, the CWS was the best test for use as a screening tool in frail older people, however, these preliminary results require confirmation in further research.
Identification of Factors Influencing the Decision-to-Delivery Interval in Emergency Caesarean Sections
Authors: Chauleur C. , Collet F. , Furtos C. , Nourrissat A. , Seffert P. , Chauvin F.
Published: September 2009

Background: In a life-threatening context, the American College of Obstetrics and Gynecology and the Royal College of Obstetrics and Gynaecology recommend a maximum delay of 30 min between the decision to perform an emergency caesarean and the infant’s birth. Our objectives were to estimate the rate of prolonged intervals and identify the factors influencing the decision-to-delivery interval. Methods: All women who had given birth at Saint-Etienne University Hospital by a non-prophylactic caesarean section between September 1 and November 1, 2007 were included in a prospective cohort study. A linear regression analysis was performed to identify the factors influencing the decision-to-delivery interval. Results: 68 women were included in the study. Regardless of the degree of emergency, the decision-to-delivery interval exceeded the recommended interval in 50% of the cases. In extremely urgent caesarean sections, the optimal interval of 15 min was exceeded in 85.7% of cases. We found that two factors contributed to delayed patient care: urgent and extremely urgent caesareans and hospitalization in a pathological pregnancy unit. This delay leads to more paediatric reanimations. Conclusion: This study highlights the difficulty to reach the recommended target interval. One solution is to improve the identification of the degree of urgency and the communication between the various members of the healthcare team.
Noninvasive Assessment of Cerebral Perfusion and Oxygenation in Acute Ischemic Stroke by Near-Infrared Spectroscopy
Authors: Terborg Christoph , Gröschel Klaus , Petrovitch Alexander , Ringer Thomas , Schnaudigel Sonja , Witte Otto W. , Kastrup Andreas
Published: September 2009

Background: In acute stroke patients, there is a need for noninvasive measurement to monitor blood flow-based therapies. We investigated the utility of near-infrared spectroscopy (NIRS) to determine cerebral perfusion in these patients. Methods: Eleven patients were investigated within 1.4 ± 2.2 days after onset of an ischemic middle cerebral artery infarction by monitoring the kinetics of an intravenous bolus of indocyanine green (ICG). For ICG kinetics, bolus peak time, time to peak (TTP = time between 0 and 100% ICG maximum), maximum ICG concentration, rise time (time between 10 and 90% ICG maximum), slope (maximum ICG/TTP), and blood flow index (BFI = maximum ICG/rise time) were obtained. Perfusion-weighted MRI (PWI) and NIRS measurements were performed within 24 h, and the interhemispherical differences of TTP values were compared. Results: Stroke patients showed an increased bolus peak time (p < 0.02), TTP (p < 0.01), and rise time (p < 0.01), whereas slope (p < 0.01) and BFI (p < 0.01) were diminished at the site of infarction as compared to the unaffected hemisphere. The interhemispherical differences of TTP as measured by PWI and NIRS were closely correlated (r = 0.86). Conclusions: Noninvasive measurements of cerebral ICG kinetics by NIRS provide a useful means of detecting cerebral perfusion deficits in patients with acute stroke, which correlate well with those obtained by PWI.