bluuebunny/crossref_metadata_2025 huggingface dataset:
Bound electron g-factor measurement by double-resonance spectroscopy on a fine-structure transitionThis paper was presented at the International Conference on Precision Physics of Simple Atomic Systems, held at École de Physique, les Houches, France, 30 May  – 4 June, 2010.
Authors: von Lindenfels David , Brantjes Nicolaas P.M. , Birkl Gerhard , Quint Wolfgang , Shabaev Vladimir M. , Vogel Manuel
Published: January 2011

Precise determination of bound-electron g-factors in highly charged ions provides stringent tests for state of the art theoretical calculations. The scope reaches from relativistic electron-correlation effects on the one hand to bound-state QED terms on the other. Besides, the investigation can contribute to the determination of the fine-structure constant α. In a first approach with boron-like ions of spinless nuclei (e.g., 40Ar13+ and 40Ca15+), we will excite the 22P1/2 – 22P3/2 fine-structure transition with laser radiation and probe microwave transitions between Zeeman sublevels. From this laser-microwave double-resonance technique the g-factor can be determined on a ppb level of accuracy. We have prepared a cryogenic trap assembly with a creation trap and a spectroscopy trap — a half-open compensated cylindrical Penning trap. Argon gas will be injected through a remotely controlled valve, working at cryogenic temperature and in the field of a superconducting magnet. Ions are produced by electron impact ionization and transferred to the spectroscopy trap. In the future, the trap will be connected to the HITRAP facility at GSI, and the method will be applied to hyperfine-structure transitions of hydrogen-like heavy ions to measure electronic and nuclear magnetic moments. We present important techniques employed in the experiment.
Progress at NIST in measuring the D-lines of Li isotopes using an optical frequency synthesizerThis paper was presented at the International Conference on Precision Physics of Simple Atomic Systems, held at École de Physique, les Houches, France, 30 May – 4 June, 2010.
Authors: Simien Clayton E. , Brewer Samuel M. , Tan Joseph N. , Gillaspy John D. , Sansonetti Craig J.
Published: January 2011

Precise spectroscopic experiments with light atoms can provide information about nuclear properties that are very difficult to obtain in electron scattering experiments. For example, relative nuclear radii of low-Z isotopes can be determined accurately from isotope shifts. Theory has attained sufficient accuracy to study exotic, short-lived halo nuclei by interpreting precise spectroscopic measurements. However, serious inconsistencies remain in the measured isotope shifts for the D1 and D2 lines of the stable isotopes (6Li and 7Li). The latest experiments, within the last decade, are in strong disagreement with each other and with theory. We report on the progress of a new experiment at the National Institute of Standards and Technology (NIST) to measure these lithium D lines using an optical frequency comb. A preliminary result for the splitting isotope shift (SIS) is presented.
Towards a first observation of magneto-electric directional anisotropy and linear birefringence in gasesThis paper was presented at the International Conference on Precision Physics of Simple Atomic Systems, held at École de Physique, les Houches, France, 30 May – 4 June, 2010.
Authors: Robilliard C. , Bailly G.
Published: January 2011

In this contribution to PSAS 2010, we report on recent progress on an experiment aimed at measuring small optical directional anisotropies by frequency metrology in a high-finesse ring cavity. We focus on our first experimental goal, the measurement of magneto-electric effects in gases. After a review of the expected effects in our set-up, we present the apparatus and the measurement procedure, showing that we already have the necessary sensitivity to start novel experiments.
Particle dark matter in the galactic halo: recent results from DAMA/LIBRAThis paper was presented at the International Conference on Precision Physics of Simple Atomic Systems, held at École de Physique, les Houches, France, 30 May – 4 June, 2010.
Authors: Bernabei R. , Belli P. , Montecchia F. , Nozzoli F. , Cappella F. , d’Angelo A. , Incicchitti A. , Prosperi D. , Cerulli R. , Dai C. J. , He H. L. , Ma X. H. , Sheng X. D. , Wang R. G. , Ye Z. P.
Published: January 2011

The DAMA/LIBRA experiment has a sensitive mass of about 250 kg highly radiopure NaI(Tl). It is running at the Gran Sasso National Laboratory of the INFN in Italy and is mainly devoted to the investigation of dark matter (DM) particles in the galactic halo by exploiting the model-independent DM annual modulation signature. The present DAMA/LIBRA and the former DAMA/NaI experiments (the first generation experiment having an exposed mass of about 100 kg) have thus far cumulatively released the results of data collected over 13 annual cycles (total exposure: 1.17 t year). They give model-independent evidence of the presence of DM particles in the galactic halo on the basis of the investigated DM signature at 8.9 σ C.L. for the cumulative exposure. The main aspects of the obtained results are summarized and some comments are addressed.
Advances towards a new measurement of the 1S–2S transition of positroniumThis paper was presented at the International Conference on Precision Physics of Simple Atomic Systems, held at École de Physique, les Houches, France, 30 May – 4 June, 2010.
Authors: Crivelli P. , Cesar C. L. , Gendotti U.
Published: January 2011

In this paper, a new experiment is presented to measure the 1S–2S transition of positronium, the bound state of an electron and a positron. The goal is to improve the current accuracy by a factor of 5 to reach a precision of the order of 0.6 ppb, to check recent QED calculations. This accuracy is challenging, but it seems well within reach in view of the technological advances that have occurred during the last two decades. We will present the details of the experimental set-up, the advances in the production of positronium, the developments of the laser system, and as well our new experimental technique for the detection of Ps in the 2S state.
Preparatory measurements for a test of time dilation in the ESRThis paper was presented at the International Conference on Precision Physics of Simple Atomic Systems, held at École de Physique, les Houches, France, 30 May – 4 June, 2010.
Authors: Botermann B. , Novotny C. , Bing D. , Geppert C. , Gwinner G. , Hänsch T. W. , Huber G. , Karpuk S. , Kühl T. , Nörtershäuser W. , Reinhardt S. , Saathoff G. , Schwalm D. , Stöhlker T. , Wolf A.
Published: January 2011

We present preparatory measurements for an improved test of time dilation at the experimental storage ring (ESR) at GSI in Darmstadt. A unique combination of particle accelerator experiments and laser spectroscopy is used to perform this test with the highest precision. 7Li+ ions are accelerated to 34% of the speed of light at the GSI Helmholtzzentrum für Schwerionenforschung and stored in the experimental storage ring. The forward and backward Doppler shifts of an electric dipole transition of these ions are measured with laser spectroscopy techniques. From these Doppler shifts, both the ion velocity β = ν/c and the time dilation factor [Formula: see text] can be derived for testing Special Relativity. Two laser systems have been developed to drive the 3S1→3P2 transition in 7Li+. Moreover, a detector system composed of photomultipliers, both to monitor the exact laser ion beam overlap as well as to optimize fluorescence detection, has been set up and tested. We investigate optical-optical double-resonance spectroscopy on a closed Λ-type three-level system to overcome Doppler broadening. A residual, broadened fluorescence background caused by velocity-changing processes in the ion beam is identified, and a background subtraction scheme implemented. At the present stage the experimental sensitivity, although already comparable with previous measurements on slower ion beams at the TSR storage ring that led to [Formula: see text] < 8.4 × 10–8, suffer from a poor signal-to-noise ratio. Modifications of the ion source as well as the detection system are discussed that promise to improve the sensitivity by one order of magnitude.
MALMQUIST INDICES OF PRE- AND POST-DEREGULATION PRODUCTIVITY, EFFICIENCY AND TECHNOLOGICAL CHANGE IN THE SINGAPOREAN BANKING SECTOR
Authors: LEE BOON L. , WORTHINGTON ANDREW C. , LEONG WAI HO
Published: January 2011

By the end of the 1990s, the Singaporean government had recognised the need to open up its banking sector so as to remain competitive in the global economy. The Monetary Authority of Singapore (MAS) thus began deregulation of the banking sector in 1999 to strengthen the competitiveness of local banks relative to their foreign competitors through mergers. This paper employs a nonparametric Malmquist productivity index to provide measure of productivity, technological change and efficiency gains over the period 1995–2005. The findings reveal some total factor productivity growth associated with deregulation and scale efficiency improvement largely from mergers amongst the local banks.
DO MACROECONOMIC CONDITIONS MATTER FOR AGRICULTURE? THE INDIAN EXPERIENCE
Authors: BHIDE SHASHANKA , VANI B. P. , RAJEEV MEENAKSHI
Published: January 2011

Macroeconomic instability, characterised by high inflation, fragile foreign exchange positions and high rates of interest, increases uncertainty and hence slows down economic growth. While this is generally accepted, the usual perception about the agricultural sector, particularly in India, is that it is immune to general macroeconomic shocks. In this paper, we examine this perception using a vector autoregressive model. The findings show that the agricultural sector is not insulated from macroeconomic shocks.
REAL SHOCK OR NOMINAL SHOCK? EXCHANGE RATE MOVEMENTS IN CAMBODIA AND LAO PDR
Authors: OK SEIHA , KAKINAKA MAKOTO , MIYAMOTO HIROAKI
Published: January 2011

This paper studies sources of fluctuations in real and nominal US dollar exchange rates in Cambodia and Lao PDR by decomposing them into the components induced by real and nominal factors. These shocks affecting real and nominal exchange rates are identified by using a structural vector autoregression (SVAR) model with the long-run neutrality restriction of Blanchard and Quah (1989). The empirical analysis demonstrates that real shocks in direction of depreciation lead to real and nominal depreciation, while nominal shocks induce long-run nominal depreciation but real appreciation in the short-run. Several economic implications are also discussed.
THE PROFITS OF FIRMS AND COUNTERVAILING DUTIES IN VERTICALLY RELATED MARKETS
Authors: WANG YU-TER
Published: January 2011

This paper studies the relationship between the profits of firms and countervailing duties in vertically related markets characterized by oligopolies. It is shown that a countervailing duty equal to the foreign export subsidy is required to neutralize the impact of foreign export subsidies on the profits of domestic firms. The domestic country has an incentive to impose a countervailing duty on foreign final goods even though foreign governments only subsidize exports of intermediate goods. In addition, foreign exporting firms may benefit from a countervailing duty more than a foreign export subsidy.
PAIR PRODUCTION OF FUNDAMENTAL UNSTABLE PARTICLES IN MODIFIED PERTURBATION THEORY IN NNLO
Authors: NEKRASOV M. L.
Published: January 2011

We consider pair production and decay of fundamental unstable particles in the framework of a modified perturbation theory (MPT) treating resonant contributions in the sense of distributions. The cross-section of the process is calculated within the NNLO of the MPT in a model that admits exact solution. Universal massless-particles contributions are taken into consideration. A comparison of the outcomes with the exact solution demonstrates excellent convergence of the MPT series at the energies near and above the maximum of the cross-section.
SPECTRA OF DISC AREA OPERATOR FOR TWISTED ACCELERATION-ENLARGED NEWTON–HOOKE SPACETIMES
Authors: DASZKIEWICZ MARCIN
Published: January 2011

The time-dependent spectra of disc area operator for twisted acceleration-enlarged Newton–Hooke spacetimes are derived. It is demonstrated that the corresponding area quanta are expanding or oscillating in time.
ON THE CLASSES OF COPULAS AND QUASI-COPULAS WITH A GIVEN DIAGONAL SECTION
Authors: DURANTE FABRIZIO , FERNÁNDEZ-SÁNCHEZ JUAN
Published: January 2011

Let [Formula: see text] and [Formula: see text] be, respectively, the classes of all copulas and quasi-copulas whose diagonal section is δ. We determine under which conditions on δ we have: (a) both [Formula: see text] and [Formula: see text] consist of a singleton; (b) [Formula: see text]. Moreover, a simple construction of copulas with a given convex diagonal section is introduced.
A PDL APPROACH FOR QUALITATIVE VELOCITY
Authors: BURRIEZA A. , MUÑOZ-VELASCO E. , OJEDA-ACIEGO M.
Published: January 2011

We introduce the syntax, semantics, and an axiom system for a PDL-based extension of the logic for order of magnitude qualitative reasoning, developed in order to deal with the concept of qualitative velocity, which together with qualitative distance and orientation, are important notions in order to represent spatial reasoning for moving objects, such as robots. The main advantages of using a PDL-based approach are, on the one hand, all the well-known advantages of using logic in AI, and, on the other hand, the possibility of constructing complex relations from simpler ones, the flexibility for using different levels of granularity, its possible extension by adding other spatial components, and the use of a language close to programming languages.
MULTIPLE POSITIVE PERIODIC SOLUTIONS TO m-LAYER PERIODIC LOTKA–VOLTERRA NETWORK-LIKE MULTIDIRECTIONAL FOOD-CHAIN WITH HARVESTING TERMS
Authors: LI YONGKUN , ZHAO KAIHONG
Published: January 2011

An m-layer peiodic Lotka–Volterra network-like multidirectional food-chain with harvesting terms is proposed in this paper. By applying Mawhin's continuation theorem of coincidence degree theory and some skills of the inequalities, sufficient conditions which guarantee the existence of [Formula: see text] positive periodic solutions of the system are obtained. An example is given to illustrate the effectiveness of our results.
VeryGene: linking tissue-specific genes to diseases, drugs, and beyond for knowledge discovery
Authors: Yang Xiaoqin , Ye Yun , Wang Guiping , Huang Hong , Yu Dekuang , Liang Shuang
Published: January 2011

In addition to many other genes, tissue-specific genes (TSGs) represent a set of genes of great importance for human physiology. However, the links among TSGs, diseases, and potential therapeutic agents are often missing, hidden, or too scattered to find. There is a need to establish a knowledgebase for researchers to share this and additional information in order to speed up discovery and clinical practice. As an initiative toward systems biology, the VeryGene web server was developed to fill this gap. A significant effort has been made to integrate TSGs from two large-scale data analyses with respective information on subcellular localization, Gene Ontology, Reactome, KEGG pathway, Mouse Genome Informatics (MGI) Mammalian Phenotype, disease association, and targeting drugs. The current release carefully selected 3,960 annotated TSGs derived from 127 normal human tissues and cell types, including 5,672 gene-disease and 2,171 drug-target relationships. In addition to being a specialized source for TSGs, VeryGene can be used as a discovery tool by generating novel inferences. Some inherently useful but hidden relations among genes, diseases, drugs, and other important aspects can be inferred to form testable hypotheses. VeryGene is available online at http://www.verygene.com .
Functional proteomic analysis reveals sex-dependent differences in structural and energy-producing myocardial proteins in rat model of alcoholic cardiomyopathy
Authors: Fogle Rachel L. , Hollenbeak Christopher S. , Stanley Bruce A. , Vary Thomas C. , Kimball Scot R. , Lynch Christopher J.
Published: January 2011

Long-term ethanol exposure leads to a sexually dimorphic response in both the susceptibility to cardiac pathology (protective effect of the female heart) and the expression of selected myocardial proteins. The purpose of the present study was to use proteomics to examine the effect of chronic alcohol consumption on a broader array of cardiac proteins and how these were affected between the sexes. Male and female rats were maintained for 18 wk on a 40% ethanol-containing diet in which alcohol was provided in drinking water and agar blocks. Differences in the content of specific cardiac proteins in isopycnic centrifugal fractions were determined using mass spectrometry on iTRAQ-labeled tryptic fragments. A random effects model of meta-analysis was developed to combine the results from multiple iTRAQ experiments. Analysis of a network of proteins involved in cardiovascular system development and function showed that troponins were oppositely regulated by alcohol exposure in females (upregulated) vs. males (downregulated), and this effect was validated by Western blot analysis. Pathway analysis also revealed that alcohol-consuming males showed increased expression of proteins involved in various steps of oxidative phosphorylation including complexes I, III, IV, and V, whereas females showed no change or decreased content. One implication from these findings is that females may be protected from the toxic effects of alcohol due to their ability to maintain contractile function, maintain efficiency of force generation, and minimize oxidative stress. However, the alcohol-induced insult may lead to increased production of reactive oxygen species and structural abnormalities in male myocardium.
Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer
Authors: Fasano Alessio
Published: January 2011

The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a “leaky gut” in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs.
Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal
Authors: Schotten Ulrich , Verheule Sander , Kirchhof Paulus , Goette Andreas
Published: January 2011

Atrial fibrillation (AF) is an arrhythmia that can occur as the result of numerous different pathophysiological processes in the atria. Some aspects of the morphological and electrophysiological alterations promoting AF have been studied extensively in animal models. Atrial tachycardia or AF itself shortens atrial refractoriness and causes loss of atrial contractility. Aging, neurohumoral activation, and chronic atrial stretch due to structural heart disease activate a variety of signaling pathways leading to histological changes in the atria including myocyte hypertrophy, fibroblast proliferation, and complex alterations of the extracellular matrix including tissue fibrosis. These changes in electrical, contractile, and structural properties of the atria have been called “atrial remodeling.” The resulting electrophysiological substrate is characterized by shortening of atrial refractoriness and reentrant wavelength or by local conduction heterogeneities caused by disruption of electrical interconnections between muscle bundles. Under these conditions, ectopic activity originating from the pulmonary veins or other sites is more likely to occur and to trigger longer episodes of AF. Many of these alterations also occur in patients with or at risk for AF, although the direct demonstration of these mechanisms is sometimes challenging. The diversity of etiological factors and electrophysiological mechanisms promoting AF in humans hampers the development of more effective therapy of AF. This review aims to give a translational overview on the biological basis of atrial remodeling and the proarrhythmic mechanisms involved in the fibrillation process. We pay attention to translation of pathophysiological insights gained from in vitro experiments and animal models to patients. Also, suggestions for future research objectives and therapeutical implications are discussed.
Regulation of Blood Pressure and Salt Homeostasis by Endothelin
Authors: Kohan Donald E. , Rossi Noreen F. , Inscho Edward W. , Pollock David M.
Published: January 2011

Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.
Some Normal Criteria about Shared Values with Their Multiplicity Zeros
Authors: Qi Jianming , Zhu Taiying
Published: January 2011

Let ℱ be a family of meromorphic functions in the domain
D, all of whose zeros are multiple. Let n  (n ≥ 2) be an integer and let a, b be two nonzero finite complex numbers. If f + a(f′) n and g + a(g′) n share b in D for every pair of functions f, g ∈ ℱ, then ℱ is normal in D.
A Case Study of User-Centred Design in Four Swiss RUP Projects
Authors: Vukelja Ljiljana , Opwis Klaus , Müller Lothar
Published: January 2011

We analysed four Rational Unified Process (RUP) projects in Switzerland that identified themselves as following a user-centred approach. Grounded theory served for analysis of 12 interviews with software developers, project managers, and UI specialists. For each professional group we analysed their work context, motivations, work practices, and strategies used to overcome the obstacles to user-centred design. Results show that end users did not participate in the projects. Instead of working directly with end users, participants used data from marketing research or consulted colleagues from other departments. Prototypes played an important role. We suggest the following remedies: (1) developing methods for easy integration of existing company knowledge about products with usability features, (2) professionalising UI design by educating project stakeholders in standard UI design, (3) creating an approved pool of company's personas for UI specialists' work, and (4) educating customers on their right to get good user interfaces.
Convergence of a Sequence of Sets in a Hadamard Space and the Shrinking Projection Method for a Real Hilbert Ball
Authors: Kimura Yasunori
Published: January 2011

We propose a new concept of set convergence in a Hadamard space and obtain its equivalent condition by using the notion of metric projections. Applying this result, we also prove a convergence theorem for an iterative scheme by the shrinking projection method in a real Hilbert ball.
Functions on the Plane as Combinations of Powers of Distances to Points
Authors: Martinez-Morales Jose L.
Published: January 2011

Some real functions on the plane can be expressed as a linear combination of powers of distances to certain points.
Effect of Hydrogen Peroxide on the Antibacterial Substantivity of Chlorhexidine
Authors: Shahriari Shahriar , Mohammadi Zahed , Mokhtari Mohammadi Mehdi , Yousefi Rasoul
Published: January 2011

The purpose of thisin vitrostudy was to assess the effect of hydrogen peroxide on the antibacterial substantivity of chlorhexidine (CHX). Seventy-five dentine tubes prepared from human maxillary central and lateral incisor teeth were used. After contamination withEnterococcus faecalisfor 14 days, the specimens were divided into five groups as follows: CHX, H2O2, CHX + H2O2, infected dentine tubes (positive control), and sterile dentine tubes (negative control). Dentine chips were collected with round burs into tryptic soy broth, and after culturing, the number of colony-forming units (CFU) was counted. The number of CFU was minimum in the first cultures in all experimental groups, and the results obtained were significantly different from each other at any time period (). At the first culture, the number of CFU in the CHX + H2O2group was lower than other two groups. At the other experimental periods, the CHX group showed the most effective antibacterial action (). Hydrogen peroxide group showed the worst result at all periods. In each group, the number of CFU increased significantly by time lapse (). In conclusion, H2O2had no additive effect on the residual antibacterial activity of CHX.
Enhanced Cryptography by Multiple Chaotic Dynamics
Authors: Chen Jianyong , Zhou Junwei , Wong Kwok-Wo , Ji Zhen
Published: January 2011

A potential security vulnerability of embedding compression in a chaos‐based cryptography is studied. Furthermore, a scheme for improving its security is proposed. This correspondence considers the use of multiple chaotic dynamics and drive chaotic trajectory by both plaintext sequence and initial values of a chaotic map. Chaotic trajectory is used for encryption that is never reused for different plaintext. This makes that scheme naturally resist chosen plaintext attack and cipher text‐only attack. Its strong security is justified by the key space, key sensitivity, and tests of random number sequences. The results show that the security of the proposed scheme is stronger than the latest algorithm especially in resisting chosen plaintext attack, while its performance is not sacrificed.
Suitability of Various Low-Power Testing Techniques for IP Core-Based SoC: A Survey
Authors: Mehta Usha , Dasgupta Kankar , Devashrayee Niranjan
Published: January 2011

Test power is the major issue for current generation
VLSI testing. It has become the biggest concern for today's SoC.
While reducing the design efforts, the modular design approach
in SoC (i.e., use of IP cores in SoC) has further exaggerated
the test power issue. It is not easy to select an effective low-power testing strategy from a large pool of diverse available
techniques. To find the proper solutions for test power reduction
strategy for IP core-based SoC, in this paper, starting
from the terminology and models for power consumption during
test, the state of the art in low-power testing is presented. The
paper contains the detailed survey on various power reduction
techniques proposed for all aspects of testing like external testing,
Built-In Self-Test techniques, and the advances in DFT techniques
emphasizing low power. Further, all the available low-power
testing techniques are strongly analyzed for their suitability to IP
core-based SoC.
Notch3 Activation Promotes Invasive Glioma Formation in a Tissue Site-Specific Manner
Authors: Pierfelice Tarran J. , Schreck Karisa C. , Dang Louis , Asnaghi Laura , Gaiano Nicholas , Eberhart Charles G.
Published: January 2011

Although Notch signaling has been widely implicated in neoplastic growth, direct evidence for in vivo initiation of neoplasia by the pathway in murine models has been limited to tumors of lymphoid, breast, and choroid plexus cells. To examine tumorigenic potential in the eye and brain, we injected retroviruses encoding activated forms of Notch1, Notch2, or Notch3 into embryonic mice. Interestingly, the majority of animals infected with active Notch3 developed proliferative lesions comprised of pigmented ocular choroid cells, retinal and optic nerve glia, and lens epithelium. Notch3-induced lesions in the choroid, retina, and optic nerve were capable of invading adjacent tissues, suggesting that they were malignant tumors. Although Notch3 activation induced choroidal tumors in up to 67% of eyes, Notch1 or Notch2 activation never resulted in such tumors. Active forms of Notch1 and Notch2 did generate a few small proliferative glial nodules in the retina and optic nerve, whereas Notch3 was 10-fold more efficient at generating growths, many of which were large invasive gliomas. Expression of active Notch1/Notch3 chimeric receptors implicated the RBPjk-association molecule and transactivation domains of Notch3 in generating choroidal and glial tumors, respectively. In contrast to our findings in the optic nerve and retina, introduction of active Notch receptors, including Notch3, into the brain never caused glial tumors. Our results highlight the differential ability of Notch receptor paralogs to initiate malignant tumor formation, and suggest that glial precursors of the optic nerve, but not the brain, are susceptible to transformation by Notch3. Cancer Res; 71(3); 1115–25. ©2011 AACR.
Alpha- versus Beta-Particle Radiopeptide Therapy in a Human Prostate Cancer Model (213Bi-DOTA-PESIN and 213Bi-AMBA versus177Lu-DOTA-PESIN)
Authors: Wild Damian , Frischknecht Michael , Zhang Hanwen , Morgenstern Alfred , Bruchertseifer Frank , Boisclair Julie , Provencher-Bolliger Anne , Reubi Jean-Claude , Maecke Helmut R.
Published: January 2011

Recurrent prostate cancer presents a challenge to conventional treatment, particularly so to address micrometastatic and small-volume disease. Use of α-radionuclide therapy is considered as a highly effective treatment in such applications due to the shorter range and exquisite cytotoxicity of α-particles as compared with β-particles. 213Bi is considered an α-emitter with high clinical potential, due to its short half-life (45.6 minutes) being well matched for use in peptide-receptor radionuclide α-therapy; however, there is limited knowledge available within this context of use. In this study, two novel 213Bi-labeled peptides, DOTA-PEG4-bombesin (DOTA-PESIN) and DO3A-CH2CO-8-aminooctanoyl-Q-W-A-V-G-H-L-M-NH2 (AMBA), were compared with 177Lu (β-emitter)-labeled DOTA-PESIN in a human androgen-independent prostate carcinoma xenograft model (PC-3 tumor). Animals were injected with 177Lu-DOTA-PESIN, 213Bi-DOTA-PESIN, or 213Bi-AMBA to determine the maximum tolerated dose (MTD), biodistribution, and dosimetry of each agent; controls were left untreated or were given nonradioactive 175Lu-DOTA-PESIN. The MTD of 213Bi-DOTA-PESIN and 213Bi-AMBA was 25 MBq (0.68 mCi) whereas 177Lu-DOTA-PESIN showed an MTD of 112 MBq (3 mCi). At these dose levels, 213Bi-DOTA-PESIN and 213Bi-AMBA were significantly more effective than 177Lu-DOTA-PESIN. At the same time, 177Lu-DOTA-PESIN showed minimal, 213Bi-DOTA-PESIN slight, and 213Bi-AMBA marked kidney damage 20 to 30 weeks posttreatment. These preclinical data indicate that α-therapy with 213Bi-DOTA-PESIN or 213Bi-AMBA is more efficacious than β-therapy. Furthermore, 213Bi-DOTA-PESIN has a better safety profile than 213Bi-AMBA, and represents a possible new approach for use in peptide-receptor radionuclide α-therapy treating recurrent prostate cancer. Cancer Res; 71(3); 1009–18. ©2011 AACR.
Deoxycytidine Kinase Modulates the Impact of the ABC Transporter ABCG2 on Clofarabine Cytotoxicity
Authors: Nagai Shinjiro , Takenaka Kazumasa , Nachagari Deepa , Rose Charles , Domoney Kali , Sun Daxi , Sparreboom Alex , Schuetz John D.
Published: January 2011

Purine nucleoside antimetabolites, such as clofarabine, are effective antileukemic agents. However, their effectiveness depends on an initial activation step in which they are monophosphorylated by deoxycytidine kinase (dCK). Some purine nucleoside antimetabolites and their monophosphate derivatives are exported by the ABC transporter ABCG2. Because clofarabine is a dCK substrate, and we show substantial variation in dCK and ABCG2 in myeloid leukemia, we hypothesized that the activity of dCK may modulate ABCG2-mediated resistance to clofarabine by regulating the formation of clofarabine monophosphate. We show that ABCG2 influence on clofarabine cytotoxicity was markedly influenced by dCK activity. When dCK expression was reduced by siRNA, clofarabine cytotoxicity was strongly reduced by enhanced ABCG2-mediated efflux. Conversely, dCK overexpression blunted ABCG2-mediated efflux of clofarabine by increasing the formation of clofarabine nucleotides. The use of an ABCG2 inhibitor confirmed that ABCG2 export of clofarabine is maximal when dCK levels are minimal. Analysis of intracellular clofarabine metabolites suggested that ABCG2 exported clofarabine more readily than clofarabine monophosphate. That ABCG2 primarily effluxes clofarabine, but not chlorfarabine-monophosphate, was confirmed by HPLC analysis of drug exported from ABCG2-overexpressing cells. Because the level and function of dCK and ABCG2 vary substantially among other types of cancer, these findings have important implications not only for clofarabine therapy but for purine nucleoside therapy in general. Therefore, we propose that addition of ABCG2 inhibitors would effectively increase the antitumor efficacy of purine nucleosides by blocking drug efflux that may be a significant mode of resistance when dCK levels are low. Cancer Res; 71(5); 1781–91. ©2011 AACR.
Dual IGF-I/II–Neutralizing Antibody MEDI-573 Potently Inhibits IGF Signaling and Tumor Growth
Authors: Gao Jin , Chesebrough Jon W. , Cartlidge Susan A. , Ricketts Sally-Ann , Incognito Leonard , Veldman-Jones Margaret , Blakey David C. , Tabrizi Mohammad , Jallal Bahija , Trail Pamela A. , Coats Steven , Bosslet Klaus , Chang Yong S.
Published: January 2011

Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). The role of the IGF-1R pathway in promoting tumor growth and survival is well documented. Overexpression of IGF-II and IR-A is reported in multiple types of cancer and is proposed as a potential mechanism for cancer cells to develop resistance to IGF-1R–targeting therapy. MEDI-573 is a fully human antibody that neutralizes both IGF-I and IGF-II and inhibits IGF signaling through both the IGF-1R and IR-A pathways. Here, we show that MEDI-573 blocks the binding of IGF-I and IGF-II to IGF-1R or IR-A, leading to the inhibition of IGF-induced signaling pathways and cell proliferation. MEDI-573 significantly inhibited the in vivo growth of IGF-I– or IGF-II–driven tumors. Pharmacodynamic analysis demonstrated inhibition of IGF-1R phosphorylation in tumors in mice dosed with MEDI-573, indicating that the antitumor activity is mediated via inhibition of IGF-1R signaling pathways. Finally, MEDI-573 significantly decreased 18F-fluorodeoxyglucose (18F-FDG) uptake in IGF-driven tumor models, highlighting the potential utility of 18F-FDG-PET as a noninvasive pharmacodynamic readout for evaluating the use of MEDI-573 in the clinic. Taken together, these results demonstrate that the inhibition of IGF-I and IGF-II ligands by MEDI-573 results in potent antitumor activity and offers an effective approach to selectively target both the IGF-1R and IR-A signaling pathways. Cancer Res; 71(3); 1029–40. ©2011 AACR.
Prediction and Genetic Demonstration of a Role for Activator E2Fs in Myc-Induced Tumors
Authors: Fujiwara Kenichiro , Yuwanita Inez , Hollern Daniel P. , Andrechek Eran R.
Published: January 2011

Advances in genomic signatures have begun to dissect breast cancer heterogeneity and application of these signatures will allow the prediction of which pathways are important in tumor development. Here we used genomic signatures to predict involvement of specific E2F transcription factors in Myc-induced tumors. We genetically tested this prediction by interbreeding Myc transgenics with mice lacking various activator E2F alleles. Tumor latency decreased in the E2F1 mutant background and significantly increased in both the E2F2 and E2F3 mutants. Investigating the mechanism behind these changes revealed a reduction in apoptosis in the E2F1 knockout strain. E2F2 and E2F3 mutant backgrounds alleviated Myc proliferative effects on the pregnant mammary gland, reducing the susceptible tumor target population. Gene expression data from tumors revealed that the E2F2 knockout background resulted in fewer tumors with EMT, corresponding with a reduction in probability of Ras activation. In human breast cancer we found that a low probability of E2F2 pathway activation was associated with increased relapse-free survival time. Together these data illustrate the predictive utility of genomic signatures in deciphering the heterogeneity within breast cancer and illustrate the unique genetic requirements for individual E2Fs in mediating tumorigenesis in both mouse models and human breast cancer. Cancer Res; 71(5); 1924–32. ©2011 AACR.
GSK1120212 (JTP-74057) Is an Inhibitor of MEK Activity and Activation with Favorable Pharmacokinetic Properties for Sustained In Vivo Pathway Inhibition
Authors: Gilmartin Aidan G. , Bleam Maureen R. , Groy Arthur , Moss Katherine G. , Minthorn Elisabeth A. , Kulkarni Swarupa G. , Rominger Cynthia M. , Erskine Symon , Fisher Kelly E. , Yang Jingsong , Zappacosta Francesca , Annan Roland , Sutton David , Laquerre Sylvie G.
Published: January 2011

Purpose: Despite their preclinical promise, previous MEK inhibitors have shown little benefit for patients. This likely reflects the narrow therapeutic window for MEK inhibitors due to the essential role of the P42/44 MAPK pathway in many nontumor tissues. GSK1120212 is a potent and selective allosteric inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes with promising antitumor activity in a phase I clinical trial (ASCO 2010). Our studies characterize GSK1120212' enzymatic, cellular, and in vivo activities, describing its unusually long circulating half-life.

Experimental Design: Enzymatic studies were conducted to determine GSK1120212 inhibition of recombinant MEK, following or preceding RAF kinase activation. Cellular studies examined GSK1120212 inhibition of ERK1 and 2 phosphorylation (p-ERK1/2) as well as MEK1/2 phosphorylation and activation. Further studies explored the sensitivity of cancer cell lines, and drug pharmacokinetics and efficacy in multiple tumor xenograft models.

Results: In enzymatic and cellular studies, GSK1120212 inhibits MEK1/2 kinase activity and prevents Raf-dependent MEK phosphorylation (S217 for MEK1), producing prolonged p-ERK1/2 inhibition. Potent cell growth inhibition was evident in most tumor lines with mutant BRAF or Ras. In xenografted tumor models, GSK1120212 orally dosed once daily had a long circulating half-life and sustained suppression of p-ERK1/2 for more than 24 hours; GSK1120212 also reduced tumor Ki67, increased p27Kip1/CDKN1B, and caused tumor growth inhibition in multiple tumor models. The largest antitumor effect was among tumors harboring mutant BRAF or Ras.

Conclusions: GSK1120212 combines high potency, selectivity, and long circulating half-life, offering promise for successfully targeting the narrow therapeutic window anticipated for clinical MEK inhibitors. Clin Cancer Res; 17(5); 989–1000. ©2011 AACR.
An Antibody–Drug Conjugate Targeting the Endothelin B Receptor for the Treatment of Melanoma
Authors: Asundi Jyoti , Reed Chae , Arca Jennifer , McCutcheon Krista , Ferrando Ronald , Clark Suzanna , Luis Elizabeth , Tien Janet , Firestein Ron , Polakis Paul
Published: January 2011

Purpose: To identify and evaluate targets amenable to antibody therapy in melanoma.

Experimental Design: We searched for mRNA transcripts coding for cell-surface proteins with expression patterns similar to that of the melanoma oncogene MITF. One such candidate, the endothelin B receptor (EDNBR), was first analyzed for a functional contribution to tumor growth by conditional induction of shRNA. Second, antibodies were raised to the receptor, conjugated with monomethyl auristatin E, and tested for efficacy against melanoma tumor models generated from cell lines.

Results: Conditional knockdown of the receptor in tumor xenograft models resulted in only a modest impact on tumor growth. A monoclonal antibody reactive with the N-terminal tail of EDNBR was found to internalize rapidly into melanoma cells. When conjugated with monomethyl auristatin E, the antibody–drug conjugate (ADC) showed remarkable efficacy against human melanoma cell lines and xenograft tumor models that was commensurate with levels of receptor expression. Comparative immunohistochemistry revealed a range of EDNBR expression across a panel of human melanomas, with the majority expressing levels equivalent to or greater than that in the models responsive to the ADC.

Conclusion: An ADC targeting the EDNBR is highly efficacious in preclinical models of melanoma. Clin Cancer Res; 17(5); 965–75. ©2011 AACR.
Why Family Caregivers Choose to Institutionalize a Loved One with Dementia: A Singapore Perspective
Authors: Tew Chee Wee , Tan Li Feng , Luo Nan , Ng Wai Yee , Yap Philip
Published: January 2011

Aim: To examine factors associated with family caregivers’ choice of care setting (own home vs. nursing home) for their relatives with dementia. Methods: Cross-sectional study involving caregivers recruited from a tertiary hospital dementia clinic and the local Alzheimer’s association. Caregivers completed a questionnaire containing demographics of the person with dementia (PWD) and caregiver, their choice of care setting and the following scales: Gain in Alzheimer Care Instrument, General Health Questionnaire, Short Sense of Competence Questionnaire, Revised Memory and Behavioral Problems Checklist and Zarit Burden Interview. Multiple logistic regression was performed to identify significant variables associated with the outcome of interest. Results: The final sample comprised 266 caregivers, the majority of whom were Chinese, female and children of PWD. Most (85.7%) preferred care at home, only 38 (14.3%) chose institutionalization. Four factors were associated with choice of nursing home: caregiver working (OR = 6.363, 2.120–19.086), no domestic maid (OR = 3.27, 1.458–7.331), lower caregiver gain (OR = 0.935, 0.882–0.992) and behavioral problems in PWD (OR = 1.011, 1.005–1.018). Conclusion: Strategies to minimize institutionalization must first address the provision of a dedicated caregiver at home. Consequently, interventions to help caregivers cope with behavioral problems in PWD and enhance caregiver gain are relevant.
Recognition, Attitudes and Causal Beliefs regarding Dementia in Italian, Greek and Chinese Australians
Authors: Low Lee-Fay , Anstey Kaarin Jane , Lackersteen Steven Malcolm , Camit Michael , Harrison Fleur , Draper Brian , Brodaty Henry
Published: January 2011

Background/Aim: To investigate recognition, attitudes and causal beliefs regarding dementia in Italian, Greek and Chinese Australians in comparison with 3rd generation Australians. Little is known about dementia literacy in these racial and ethnic minority groups. Methods: A cross-sectional telephone survey was conducted of 350 Italian, 414 Greek, 437 Chinese and 500 3rd generation Australians randomly selected from the telephone directory. Results: Third generation participants (85%) were more likely to recognize dementia symptoms in a vignette in comparison to Italian (61%), Greek (58%) and Chinese (72%) participants. Overall, the racial and ethnic minority groups had more negative attitudes about persons with dementia. The racial and ethnic minority groups were more likely to suggest old age and psychosocial risk factors caused dementia, whereas 3rd generation Australians were more likely to suggest brain disease. Differences between ethnic minority and 3rd generation groups remained after controlling for sociodemographic variables. There were differences between Italian, Greek and Chinese participants on markers of acculturation associated with knowledge and beliefs within each group. Conclusions: Racial and ethnic minority groups have poor dementia literacy in comparison to 3rd generation Australians. There is a need for dementia education targeted to and tailored for these groups.
Interethnic Differences in Dementia Epidemiology: Global and Asia-Pacific Perspectives
Authors: Venketasubramanian N. , Sahadevan S. , Kua E.H. , Chen C.P.L. , Ng T.-P.
Published: January 2011

The burden of dementia will continue to rise globally, particularly in developing countries, many of which lie in the Asia-Pacific region. It was initially thought that both prevalence and incidence of dementia showed little geographic variation. More recent work has suggested differences: migrant populations attain rates between their homelands and adopted countries, and higher rates have been found in African Americans and Hispanics compared to Caucasian Whites, and also among native Australians. The only interethnic studies in the Asia-Pacific region were performed in Singapore, which showed lower standardized prevalence among ethnic Chinese compared to ethnic Malays and Indians, independent of vascular risk factors. There was conflicting information about the relative frequencies of Alzheimer’s disease and vascular dementia between ethnic groups in Singapore. More research, with careful attention to potential cultural confounders, is needed to further explore and better understand interethnic differences in dementia epidemiology.