bluuebunny/crossref_metadata_2025 huggingface dataset:
New and innovative process to construct testable component with systematic approach
Authors: Gill Nasib Singh , Tomar Pradeep
Published: February 2011

In Component-Based Software Development (CBSD), component testability and testing, is an important capability, which supports productivity and quality assurance. CBSD is increasingly being used to reduce the cost and time of software development. Therefore testability and testing of components is one of the most important factors in determining the quality and reusability of components in CBSD. Testability is an important quality indicator of Component-Based Systems (CBS). This paper introduces an innovative process for building testable components. In this paper we first discuss testability, the impact of inadequate testing and testing infrastructure which affect component quality.
Object constraint language (OCL)
Authors: Pandey R. K.
Published: February 2011

OCL was introduced as a part of UML in 1997 as a business modeling language by IBM. Ever since its inception, the actual use of OCL in the industry has been almost negligible, even amongst the business application development community, for which it was specifically created. But now with the inception of MDA and related OMG standards the role of OCL is changing. UML 2.0 has introduced new concepts and refined some other including OCL in a way that UML 2.0 is now almost software architectures conformant too. This paper makes an investigation into the recent developments and explores the role of OCL in the current scenario and its future applications.
Software reusability assessment using soft computing techniques
Authors: Singh Yogesh , Bhatia Pradeep Kumar , Sangwan Omprakash
Published: February 2011

Software reuse, widely used now a days, is the development of software using some existing software components. In this paper we have proposed a model based on four parameters: Changeability, Interface Complexity, Understandability of Software and Documentation Quality for accessing software reusability levels using soft computing techniques viz. Fuzzy Logic, Neural Network and Neuro-Fuzzy. The proposed model using Neuro-Fuzzy technique is trained well and predicts satisfactory results with MARE 22% (21% for validation set 2) and MRE 0.007% (0.04 for validation set 2) when compared with other soft computing techniques.
Generating composite behavior of embedded software components based on UML behavioral model and process algebra
Authors: Kim Jinhyun , Choi Jin-Young , Kang Inhye , Lee Insup
Published: February 2011

This paper defines formally the composite behavior of two main embedded software components; application software and platform. The two typical embedded software components interact with one another continuously to achieve the purpose of system, but they have different computation characteristics; application software is oriented to data-flow for implementing software's functionalities, whereas the platform is oriented to control-ow for the control of software's executions. Hence, it is not easy to represent those capabilities in one behavioral model to analyze their composite behaviors. Thus, this paper presents a formal modeling framework, in which application software and platforms are defined in appropriate specification language suited to their own characteristics, and their behaviors in models are composed to capture their interactive and composite behaviors in their composite executions. In particular, we focus here on defining their composite behaviors in formal way.
Modeling a distributed intrusion detection system using collaborative building blocks
Authors: Gunawan Linda Ariani , Vogel Michael , Kraemer Frank Alexander , Schmerl Sebastian , Slåtten Vidar , Herrmann Peter , König Hartmut
Published: February 2011

Developing complex distributed systems is a non-trivial task. It is even more difficult when the systems need to dynamically reconfigure the distributed functionalities or tasks. Not only do we need to deal with the application-specific functionalities that are intricate, but we also have to handle the complex logic of coordinating the distribution and relocation of tasks. In this paper, we model an intrusion detection system that distributes its analysis units to a number of hosts and assigns fine-grained analysis tasks to these hosts in order to cope with the rapid increase of audit data from today's IT systems. The system is further capable to react to overload situations and to shift tasks to other hosts. To develop this complex system, we apply the model-based engineering method SPACE. In particular, we show that the collaborative specification style of the method can significantly reduce the development effort. Also, the formal semantics of SPACE ensures the correctness of important design properties.
A product information management system as a workbench for quantifier elimination computations with QEPCAD
Authors: Arnon Dennis S.
Published: February 2011

We report on the use of a Product Information Management system as a convenient front end for invoking and monitoring Quantifier Elimination computations by the QEPCAD program, and for user-friendly storage and analysis of accumulated outputs.
Cache friendly sparse matrix-vector multiplication
Authors: Haque Sardar Anisul , Hossain Shahadat , Maza M. Moreno
Published: February 2011

Sparse matrix-vector multiplication or SpMxV is an important kernel in scientific computing. For example, in the conjugate gradient method, where SpMxV is the main computational step. Though the total number of arithmetic operations in SpMxV is fixed, reducing the probability of cache misses per operation is still a challenging area of research. In this work, we present a new column ordering algorithm for sparse matrices. We analyze the cache complexity of SpMxV when A is ordered by our technique. The numerical experiments, with very large test matrices, clearly demonstrate the performance gains rendered by our proposed technique.
VarInt
Authors: Hellström Christian
Published: February 2011

Geometric numerical integration refers to a class of numerical integration algorithms that preserve the differential geometric structure that defines the evolution of dynamical systems. For simulations over relatively short time spans, as compared to the intrinsic time scales, standard (non-geometric) integrators are often advantageous, as they include adaptive and multistep methods, which can be both accurate and fast. Extended computations require a different, geometric approach, as non-geometric methods tend to generate or dissipate energy artificially due to the fact that they do not respect the fundamental geometry of the phase flow, which means that at some point the errors dominate.

It is common to create geometric numerical integrators based on either previous knowledge of classes of non-geometric numerical integrators, from which specific instances can be derived that are geometric, or truncated series solutions to the Hamilton--Jacobi equation for (canonical) transformations near the identity. Unfortunately, the actual calculations for higher-order geometric numerical algorithms are generally quite involved.

There is, however, an alternative strategy that avoids many of the difficulties inherent in the design of higher-order versions of these geometric numerical integrators. It relies on the discretization of the action functional, from which one derives the numerical algorithms in a straightforward manner. These so-called variational integrators preserve the differential geometric structure automatically; all conserved quantities are preserved infinitesimally, too.

An easy-to-use and freely available package named VarInt is presented that enables one to generate and analyse new variational integrators systematically to arbitrary order with Maple. All VarInt requires from the user is the action and a quadrature formula to approximate it. One can either select one of the built-in quadrature rules, or one supplies it manually. With VarInt it is now possible to venture beyond the standard geometric numerical integrators, without the need for an advanced appreciation of the mathematical details. Several numerical examples, obtained with a basic numerical analysis tool in VarInt, demonstrate the superior performance of new variational integrators for certain classes of dynamical systems.

VarInt is ideally suited for researchers and engineers who wish to design, study, test and/or analyse new geometric numerical integration algorithms without the hassle of laborious computations. All algorithms can be tuned to the required level of specificness of the problem at hand due to Maples symbolic capabilities and its code optimization procedures. In addition, VarInt can be of value in the classroom, as a tool to assist in increasing the understanding of variational integrators.
An implementation of the method of brackets for symbolic integration
Authors: Kohl Karen T.
Published: February 2011

In spite of being a classical problem, the current techniques available for Symbolic Integration are not sufficient to evaluate a variety of integrals coming from Mathematical Physics, such as Bessel functions. The Method of Brackets [2, 3], a heuristic process appearing in the evaluation of Feynman diagrams, can be used to evaluate symbolically a large class of single or multiple integrals. It represents an extension of the so-called Ramanujan Master Theorem [1]. The first implementation of the Method of Brackets has been written by the author in the open-source computer algebra system Sage. This implementation allows experimentation with representations of the integrand, which can affect output and efficiency. An algorithm that chooses the best representation of the integrand is being developed.
Heuristics for cannon's algorithm with an application to lyons sporadic group
Authors: Saouter Yannick
Published: February 2011

This article is devoted to describing heuristics to improve the efficiency of Cannon's algorithm. As an application, the method is used to derive a new presentation for the Lyons sporadic group.
Computing floating-point Gröbner bases accurately
Authors: Sasaki Tateaki , Kako Fujio
Published: February 2011

We propose a new method for floating-point Gröbner basis computation. The idea is to improve the accuracies of the coefficients of polynomials of intermediate bases computed by our previous method, by reducing coefficient matrices by Gaussian elimination.
Solving linear recurrence equations
Authors: Cha Yongjae , van Hoeij Mark , Levy Giles
Published: February 2011

The software is an implementation of the algorithms in [1], [2], and [3]. The main algorithm from [3] is implemented with additional base equations beyond what appear in [3] and is incorporated into [4]. Common to each algorithm is a transformation from a base equation to the input using transformations that preserve order and homogeneity (referred to as gt-transformations).
GENOM3CK
Authors: Hodorog Mădălina , Mourrain Bernard , Schicho Josef
Published: February 2011

We report on a library for computing the genus of a plane complex algebraic curve using knot theory. The library also computes other type of information about the curve, such as for instance: the set of singularities of the curve, the topological type (algebraic link) of each singularity, the Alexander polynomial of each algebraic link, the delta-invariant of each singularity, etc. Using the algebraic geometric modeler called Axel [1], we integrate symbolic, numeric and graphical capabilities into a single library, which we call GENOM3CK [3].
Polynomial homotopy continuation with PHCpack
Authors: Verschelde Jan
Published: February 2011

PHCpack is a software package to solve polynomial systems via homotopy continuation methods. In the last twenty years (since the start of the development of PHCpack), the notion of solving a polynomial system by PHCpack evolved from approximating all isolated complex solutions for systems with as many equations as variables into providing tools for a numerical irreducible decomposition. This document provides the outline for a software demonstration highlighting recent additions to the software, such as accepting polynomials with negative exponents and sweeping for real points that lie isolated on complex solution curves.
Ubiquity symposium: Natural Computation
Authors: Gelenbe Erol
Published: February 2011

In this twelfth piece to the Ubiquity symposium discussing What is computation? Erol Gelenbe reviews computation in natural systems, focusing mainly on biology and citing examples of the computation that is inherent in chemistry, natural selection, gene regulatory networks, and neuronal systems. --Editor
Three-Dimensional Topological Insulators
Authors: Hasan M. Zahid , Moore Joel E.
Published: February 2011

Topological insulators in three dimensions are nonmagnetic insulators that possess metallic surface states (SSs) as a consequence of the nontrivial topology of electronic wavefunctions in the bulk of the material. They are the first known examples of topological order in bulk solids. We review the basic phenomena and experimental history, starting with the observation of topological insulator behavior in BixSb1−x by angle and spin-resolved photoemission spectroscopy (spin-ARPES) and continuing through measurements on other materials and by other probes. A self-contained introduction to the single-particle theory is then given, followed by the many-particle definition of a topological insulator as a material with quantized magnetoelectric polarizability. The last section reviews recent work on strongly correlated topological insulators and new effects that arise from the proximity effect between a topological insulator and a superconductor. Although this article is not intended to be a comprehensive review of what is already a rather large field, we hope that it serves as a useful introduction, summary of recent progress, and guideline to future directions.
Energy Conversion in Photosynthesis: A Paradigm for Solar Fuel Production
Authors: Moore Gary F. , Brudvig Gary W.
Published: February 2011

Solar energy has the capacity to fulfill global human energy demands in an environmentally and socially responsible manner, provided efficient, low-cost systems can be developed for its capture, conversion, and storage. Toward these ends, a molecular-based understanding of the fundamental principles and mechanistic details of energy conversion in photosynthesis is indispensable. This review addresses aspects of photosynthesis that may prove auspicious to emerging technologies. Conversely, areas in which human ingenuity may offer innovative solutions, resulting in enhanced energy storage efficiencies in artificial photosynthetic constructs, are considered. Emphasis is placed on photoelectrochemical systems that utilize water as a source of electrons for the production of solar fuels.
Hybrid Solid-State Qubits: The Powerful Role of Electron Spins
Authors: Morton John J.L. , Lovett Brendon W.
Published: February 2011

We review progress on the use of electron spins to store and process quantum information, with particular focus on the ability of the electron spin to interact with multiple quantum degrees of freedom. We examine the benefits of hybrid quantum bits (qubits) in the solid state that are based on coupling electron spins to nuclear spins, electron charge, optical photons, and superconducting qubits. These benefits include the coherent storage of qubits for times exceeding seconds; fast qubit manipulation; single qubit measurement; and scalable methods for entangling spatially separated, matter-based qubits. In this way, the key strengths of different physical qubit implementations are brought together, laying the foundation for practical solid-state quantum technologies.
Characterizing Structure Through Shape Matching and Applications to Self-Assembly
Authors: Keys Aaron S. , Iacovella Christopher R. , Glotzer Sharon C.
Published: February 2011

Structural quantities such as order parameters and correlation functions are often employed to gain insight into the physical behavior and properties of condensed matter systems. Although standard quantities for characterizing structure exist, often they are insufficient for treating problems in the emerging field of nano- and microscale self-assembly, wherein the structures encountered may be complex and unusual. The computer science field of shape matching offers a robust solution to this problem by defining diverse methods for quantifying the similarity between arbitrarily complex shapes. Most order parameters and correlation functions used in condensed matter apply a specific measure of structural similarity within the context of a broader scheme. By substituting shape matching quantities for traditional quantities, we retain the essence of the broader scheme, but extend its applicability to more complex structures. Here we review some standard shape-matching techniques and discuss how they might be used to create highly flexible structural metrics for diverse systems such as self-assembled matter. We provide three proof-of-concept example problems applying shape-matching methods to identifying local and global structures and tracking structural transitions in complex assembled systems. The shape-matching methods reviewed here are applicable to a wide range of condensed matter systems, both simulated and experimental, provided particle positions are known or can be accurately imaged.
Reflections on My Career in Condensed Matter Physics
Authors: Dresselhaus Mildred S.
Published: February 2011

I present some personal views on the field of condensed matter physics (CMP), primarily as a long-time practitioner, but also as a physicist who has had the opportunity to play broader roles in scientific affairs. I comment on how CMP has evolved in the past half century, and express my optimism for its future.
Quantum Turbulence
Authors: Paoletti Matthew S. , Lathrop Daniel P.
Published: February 2011

We examine developments in the study of quantum turbulence with a special focus on clearly defining many of the terms used in the field. We critically review the diverse theoretical, computational, and experimental approaches from the point of view of experimental observers. Similarities and differences between the general properties of classical and quantum turbulence are elucidated. The dynamics and interactions of quantized vortices and their role in quantum turbulence are discussed with particular emphasis on reconnection and vortex ring collapse. A stark distinction between the velocity statistics of quantum and classical turbulence is exhibited and used to highlight a potential analogy between quantum turbulence and magnetohydrodynamic (MHD) turbulence in astrophysical plasmas. Although much of this review pertains to superfluid 4He (He II), the underlying science is broadly applicable to other quantum fluids such as 3He-B, type-II superconductors, Bose-Einstein condensates, Weinberg-Salam fields, and grand-unified-theory (GUT) Higgs fields.
The Quantum Spin Hall Effect
Authors: Maciejko Joseph , Hughes Taylor L. , Zhang Shou-Cheng
Published: February 2011

Most quantum states of condensed matter are classified by the symmetries they break. For example, crystalline solids break translational symmetry, and ferromagnets break rotational symmetry. By contrast, topological states of matter evade traditional symmetry-breaking classification schemes, and they signal the existence of a fundamentally different organizational principle of quantum matter. The integer and fractional quantum Hall effects were the first topological states to be discovered in the 1980s, but they exist only in the presence of large magnetic fields. The search for topological states of matter that do not require magnetic fields for their observation led to the theoretical prediction in 2006 and experimental observation in 2007 of the so-called quantum spin Hall effect in HgTe quantum wells, a new topological state of quantum matter. In this article, we review the theoretical foundations and experimental discovery of the quantum spin Hall effect.
Unconventional Quantum Criticality in Heavy-Fermion Compounds
Authors: Stockert O. , Steglich F.
Published: February 2011

We review magnetic quantum-critical points (QPCs) in heavy-fermion compounds separating at zero temperature: an antiferromagnetically ordered state and a nonordered ground state. At the magnetic instability, the Fermi-liquid (FL) description valid for normal metals breaks down, giving rise to unusual, non-Fermi-liquid (NFL) low-temperature behavior. After a short introduction to phase transitions and to T = 0 phase transitions in general as well as to the physics of heavy-fermion systems, the two main theoretical scenarios describing the physics at QPCs in these systems are presented, the conventional spin-density-wave (SDW) scenario and the unconventional Kondo-breakdown scenario. Whereas for the conventional scenario experimental data for CeCu2Si2 and Ce1−xLaxRu2Si2 are discussed only briefly, we focus in more detail on the unusual behavior of CeCu6−xAux and YbRh2Si2 at their respective QPCs and show that these systems are best described within the unconventional scenario.
Characterization of the reproductive effects of the anorexigenic VGF-derived peptide TLQP-21: in vivo and in vitro studies in male rats
Authors: Pinilla Leonor , Pineda Rafael , Gaytán Francisco , Romero Magdalena , García-Galiano David , Sánchez-Garrido Miguel A. , Ruiz-Pino Francisco , Tena-Sempere Manuel , Aguilar Enrique
Published: February 2011

VGF (nonacronymic) is a 68-kDa protein encoded by the homonymous gene, which is expressed abundantly at the hypothalamus and has been involved in the control of metabolism and body weight homeostasis. Different active peptide fragments are generated from VGF, including TLQP-21. Circumstantial evidence has suggested that VGF might also participate in the control of reproduction. Yet its mechanisms of action and the eventual role of specific VGF-derived peptides on the hypothalamic-pituitary-gonadal (HPG) axis remain unknown. Herein we report a series of studies on the reproductive effects of TLQP-21 as evaluated in male rats by a combination of in vivo and in vitro analyses. Central administration of TLQP-21 induced acute gonadotropin responses in pubertal and adult male rats, likely via stimulation of GnRH secretion, as documented by static incubations of hypothalamic tissue. In addition, in pubertal (but not adult) males, TLQP-21 stimulated LH secretion directly at the pituitary level. Repeated central administration of TLQP-21 to pubertal males subjected to chronic undernutrition was able to ameliorate the hypogonadotropic state induced by food deprivation. In contrast, chronic administration of TLQP-21 to fed males at puberty resulted in partial desensitization and puberty delay. Finally, in adult (but not pubertal) males, TLQP-21 enhanced hCG-stimulated testosterone secretion by testicular tissue in vitro. In summary, our data are the first to document a complex and multifaceted mode of action of TLQP-21 at different levels of the male HPG axis with predominant stimulatory effects, thus providing a tenable basis for the (direct) reproductive role of this VGF-derived peptide.
Rottlerin Inhibits Lonicera japonica‐Induced Photokilling in Human Lung Cancer Cells through Cytoskeleton‐Related Signaling Cascade
Authors: You Bang-Jau , Wu Yang-Chang , Bao Bo-Ying , Wu Chi-Yu , Yang Ya-Win , Chang Yu-Hao , Lee Hong-Zin
Published: February 2011

This study demonstrated that many apoptotic signaling pathways, such as Rho family, PKC family, MAP kinase family, and mitochondria‐mediated apoptotic pathway, were triggered by Lonicera japonica extracts and irradiation in CH27 cells. Rottlerin, a PKCδ
‐selective inhibitor, reversed the photoactivated Lonicera japonica extract‐induced decrease in PKCδ protein expression and change in cell morphology in this study. In addition, rottlerin inhibited the photoactivated Lonicera japonica‐induced decrease in protein expression of Ras, ERK, p38, PKCα, and PKCε, which are the kinases of prosurvival signaling pathway. We also demonstrated that pretreatment with rottlerin prevented actin microfilaments and microtubules from damage during the photoactivated Lonicera japonica‐induced CH27 cell death. Furthermore, the promotion of the cytoskeleton‐related signaling cascade following rottlerin by upregulation of cytoskeleton‐related mediators (p38, HSP27, FAK, paxillin, and tubulin) and molecules of downstream of F‐actin (mitochondria‐mediated apoptosis pathway) reduces CH27 cell death, indicating that cytoskeleton is the potential target in the photoactivated Lonicera japonicaextract‐induced photokilling of CH27 cells.
A New Hybrid Algorithm for a System of Mixed Equilibrium Problems, Fixed Point Problems for Nonexpansive Semigroup, and Variational Inclusion Problem
Authors: Jitpeera Thanyarat , Kumam Poom
Published: February 2011

The purpose of this paper is to consider a shrinking projection method for finding the common element of the set of common fixed points for nonexpansive semigroups, the set of common fixed points for an infinite family of a "Equation missing"-strict pseudocontraction, the set of solutions of a system of mixed equilibrium problems, and the set of solutions of the variational inclusion problem. Strong convergence of the sequences generated by the proposed iterative scheme is obtained. The results presented in this paper extend and improve some well-known results in the literature.
Synthesis, Characterization, and Magnetic and Thermal Studies on Some Metal(II) Thiophenyl Schiff Base Complexes
Authors: Osowole Aderoju Amoke
Published: February 2011

4-(Thiophen-3-yl)-aniline undergoes condensation with o-vanillin to form an ONS donor Schiff base, 2-methoxy-6-[(4-thiophene-3-yl-phenylimino)-methyl]-phenol, which forms complexes of the type [ML2]xH2O (where M = Mn, Co, Ni, Cu, Zn, Pd). These complexes are characterized by elemental analysis, 1H nmr, electronic, mass, and IR spectroscopies and conductance measurements. The electronic, IR and CHN data are supportive of a 4-coordinate tetrahedral geometry for Mn(II), Co(II), Ni(II), and Zn(II) complexes and square-planar geometry for Cu(II) and Pd(II) complexes, with the chromophores N2O2. The magnetic data reveals that the complexes are magnetically dilute and mononuclear with exception of the Cu(II) complex, which exhibits some anti-ferromagnetisms. The complexes are air-stable solids, and none is an electrolyte in nitro methane.
Gas-Phase Growth of Heterostructures of Carbon Nanotubes and Bimetallic Nanowires
Authors: Kim Whi Dong , Park Jung Min , Ahn Ji Young , Kim Soo Hyung
Published: February 2011

A simple, inexpensive, and viable method for growing multiple heterostructured carbon nanotubes (CNTs) over the entire surface of Ni-Al bimetallic nanowires (NWs) in the gas phase was developed. Polymer-templated bimetallic nitrate NWs were produced by electrospinning in the first step, and subsequent calcination resulted in the formation of bimetallic oxide NWs by thermal decomposition. In the second step, free-floating bimetallic NWs were produced by spray pyrolysis in an environment containing hydrogen gas as a reducing gas. These NWs were continuously introduced into a thermal CVD reactor in order to grow CNTs in the gas phase. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Raman spectrometry analyses revealed that the catalytic Ni sites exposed in the non-catalytic Al matrix over the entire surface of the bimetallic NWs were seeded to radially grow highly graphitized CNTs, which resembled “foxtail” structures. The grown CNTs were found to have a relatively uniform diameter of approximately10±2 nm and 10 to 15 walls with a hollow core. The average length of the gas-phase-grown CNTs can be controlled between 100 and 1000 nm by adjusting the residence time of the free-floating bimetallic NWs in the thermal CVD reactor.
Generalized Derivations and Bilocal Jordan Derivations of Nest Algebras
Authors: Yan Dangui , Zhang Chengchang
Published: February 2011

Let H be a complex Hilbert space and B(H) the collection of all linear bounded operators, 𝔄 is the closed subspace lattice including 0 an H, then 𝔄 is a nest, accordingly alg 𝔄 = {T ∈ B(H) : TN⊆N,   ∀ N ∈ 𝔄} is a nest algebra. It will be shown that of nest algebra, generalized derivations are generalized inner derivations, and bilocal Jordan derivations are inner derivations.
A Review on Composite Liposomal Technologies for Specialized Drug Delivery
Authors: Mufamadi Maluta S. , Pillay Viness , Choonara Yahya E. , Du Toit Lisa C. , Modi Girish , Naidoo Dinesh , Ndesendo Valence M. K.
Published: February 2011

The combination of liposomes with polymeric scaffolds could revolutionize the current state of drug delivery technology. Although liposomes have been extensively studied as a promising drug delivery model for bioactive compounds, there still remain major drawbacks for widespread pharmaceutical application. Two approaches for overcoming the factors related to the suboptimal efficacy of liposomes in drug delivery have been suggested. The first entails modifying the liposome surface with functional moieties, while the second involves integration of pre-encapsulated drug-loaded liposomes within depot polymeric scaffolds. This attempts to provide ingenious solutions to the limitations of conventional liposomes such as short plasma half-lives, toxicity, stability, and poor control of drug release over prolonged periods. This review delineates the key advances in composite technologies that merge the concepts of depot polymeric scaffolds with liposome technology to overcome the limitations of conventional liposomes for pharmaceutical applications.
MRE11 Deficiency Increases Sensitivity to Poly(ADP-ribose) Polymerase Inhibition in Microsatellite Unstable Colorectal Cancers
Authors: Vilar Eduardo , Bartnik Catherine M. , Stenzel Stephanie L. , Raskin Leon , Ahn Jaeil , Moreno Victor , Mukherjee Bhramar , Iniesta Maria D. , Morgan Meredith A. , Rennert Gad , Gruber Stephen B.
Published: February 2011

Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in the double strand break (DSB) repair gene MRE11. We assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in MRE11 may sensitize CRC cells to poly(ADP-ribose) polymerase (PARP-1) inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP-1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between MRE11 expression levels and cytotoxicity to ABT-888 at 10 μM was observed (R2 = 0.915, P < 0.001). Using two experimental approaches, including short hairpin RNA knocking down MRE11 in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant MRE11, we experimentally tried to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug–response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in MRE11 show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs. Cancer Res; 71(7); 2632–42. ©2011 AACR.
The Efficacy of Radiotherapy Relies upon Induction of Type I Interferon–Dependent Innate and Adaptive Immunity
Authors: Burnette Byron C. , Liang Hua , Lee Youjin , Chlewicki Lukasz , Khodarev Nikolai N. , Weichselbaum Ralph R. , Fu Yang-Xin , Auh Sogyong L.
Published: February 2011

The most widely held explanation for the efficacy of local radiotherapy (RT) is based on direct cytotoxicity to cancer cells through the induction of lethal DNA damage. Recent studies have shown that local ablative radiation of established tumors can lead to increased T-cell priming and T-cell–dependent tumor regression, but the underlying mechanism remains unclear. Here, we describe an essential role for type I IFN in local RT-mediated tumor control. We show that ablative RT increases intratumoral production of IFN-β and, more surprisingly, the antitumor effect of RT is abolished in type I IFN nonresponsive hosts. Furthermore, the major target of RT-induced type I IFN is the hematopoietic compartment. RT drastically enhances the cross-priming capacity of tumor-infiltrating dendritic cells (TIDC) from wild-type mice but not type I IFN receptor–deficient mice. The enhanced cross-priming ability of TIDCs after RT was dependent on autocrine production of type I IFNs. By using adenoviral-mediated expression of IFN-β, we show that delivery of exogenous IFN-β into the tumor tissue in the absence of RT is also sufficient to selectively expand antigen-specific T cells leading to complete tumor regression. Our study reveals that local high-dose RT can trigger production of type I IFN that initiates a cascading innate and adaptive immune attack on the tumor. Cancer Res; 71(7); 2488–96. ©2011 AACR.
Lactate Influx through the Endothelial Cell Monocarboxylate Transporter MCT1 Supports an NF-κB/IL-8 Pathway that Drives Tumor Angiogenesis
Authors: Végran Frédérique , Boidot Romain , Michiels Carine , Sonveaux Pierre , Feron Olivier
Published: February 2011

Lactate generated from pyruvate fuels production of intracellular NAD+ as an end result of the glycolytic process in tumors. Elevated lactate concentration represents a good indicator of the metabolic adaptation of tumors and is actually correlated to clinical outcome in a variety of human cancers. In this study, we investigated whether lactate could directly modulate the endothelial phenotype and thereby tumor vascular morphogenesis and perfusion. We found that lactate could enter endothelial cells through the monocarboxylate transporter MCT-1, trigger the phosphorylation/degradation of IκBα, and then stimulate an autocrine NF-κB/IL-8 (CXCL8) pathway driving cell migration and tube formation. These effects were prevented by 2-oxoglutarate and reactive oxygen species (ROS) inhibitors, pointing to a role for prolyl-hydroxylase and ROS in the integration of lactate signaling in endothelial cells. PHD2 silencing in endothelial cells recapitulated the proangiogenic effects of lactate, whereas a blocking IL-8 antibody or IL-8–targeting siRNA prevented them. Finally, we documented in mouse xenograft models of human colorectal and breast cancer that lactate release from tumor cells through the MCT4 (and not MCT1) transporter is sufficient to stimulate IL-8–dependent angiogenesis and tumor growth. In conclusion, our findings establish a signaling role for lactate in endothelial cells and they identify the lactate/NF-κB/IL-8 pathway as an important link between tumor metabolism and angiogenesis. Cancer Res; 71(7); 2550–60. ©2011 AACR.
Can a Metastatic Gene Expression Profile Outperform Tumor Size as a Predictor of Occult Lymph Node Metastasis in Oral Cancer Patients?
Authors: Méndez Eduardo , Lohavanichbutr Pawadee , Fan Wenhong , Houck John R. , Rue Tessa C. , Doody David R. , Futran Neal D. , Upton Melissa P. , Yueh Bevan , Zhao Lue Ping , Schwartz Stephen M. , Chen Chu
Published: February 2011

Purpose: To determine the differential gene expression between oral squamous cell carcinoma (OSCC) with and without metastasis to cervical lymph nodes and to assess prediction of nodal metastasis by using molecular features.

Experimental Design: We used Affymetrix U133 2.0 plus arrays to compare the tumor genome-wide gene expression of 73 node-positive OSCCs with 40 node-negative OSCCs (≥18 months). Multivariate linear regression was used to estimate the association between gene expression and nodal metastasis. Stepwise logistic regression and receiver operating characteristics (ROC) analysis were used to generate predictive models and to compare these with models by using tumor size alone.

Results: We identified five genes differentially expressed between node-positive and node-negative OSCCs after adjusting for tumor size and human papillomavirus status: REEP1, RNF145, CTONG2002744, MYO5A, and FBXO32. Stepwise regression identified a four-gene model (MYO5A, RFN145, FBXO32, and CTONG2002744) as the most predictive of nodal metastasis. A leave-one-out ROC analysis revealed that our model had a higher area under the curve (AUC) for identifying occult nodal metastasis compared with that of a model by tumor size alone (respective AUC: 0.85 and 0.61; P = 0.011). A model combining tumor size and gene expression did not further improve the prediction of occult metastasis. Independent validation using 31 metastatic and 13 nonmetastatic cases revealed a significant underexpression of CTONG2002744 (P = 0.0004).

Conclusions: These results suggest that our gene expression markers of OSCC metastasis hold promise for improving current clinical practice. Confirmation by others and functional studies of CTONG2002744 is warranted. Clin Cancer Res; 17(8); 2466–73. ©2011 AACR.
EGFRL858R Mutation and Polymorphisms of Genes Related to Estrogen Biosynthesis and Metabolism in Never-Smoking Female Lung Adenocarcinoma Patients
Authors: Yang Shi-Yi , Yang Tsung-Ying , Chen Kun-Chieh , Li Yao-Jen , Hsu Kuo-Hsuan , Tsai Chi-Rne , Chen Chih-Yi , Hsu Chung-Ping , Hsia Jiun-Yi , Chuang Cheng-Yen , Tsai Ying-Huang , Chen Kuan-Yu , Huang Ming-Shyan , Su Wu-Chou , Chen Yuh-Min , Hsiung Chao A. , Shen Chen-Yang , Chang Gee-Chen , Yang Pan-Chyr , Chen Chien-Jen
Published: February 2011

Purpose: To assess whether polymorphisms of genes related to estrogen biosynthesis and metabolism are associated with EGFR mutations.

Experimental Design: We studied 617 patients with lung adenocarcinoma, including 302 never-smoking women. On the basis of multiple candidate genes approach, the effects of polymorphisms of CYP17, CYP19A1, ERα, and COMT in association with the occurrence of EGFR mutations were evaluated using logistic regression analysis.

Results: In female never-smokers, significant associations with EGFR L858R mutation were found for the tetranucleotide (TTTA)n repeats in CYP19A1 (odds ratio, 2.6; 95%CI, 1.2–5.7 for 1 or 2 alleles with (TTTA)n repeats >7 compared with both alleles with (TTTA)n repeats ≤7), and the rs2234693 in ERα (OR, 2.1; 95% CI, 1.1–4.0 for C/T and C/C genotypes compared with T/T genotype). The C/C genotype (vs. T/T genotype) of ERα was significantly associated with EGFR L858R mutation (OR, 3.0; 95% CI, 1.1–8.1), in-frame deletion (OR, 2.9; 95% CI, 1.1–7.6) and other mutations (OR, 4.3; 95% CI, 1.3–14.0). The genotype of COMT rs4680 was significantly associated with EGFR L858R mutation in female and male never-smokers showing OR's (95% CI) of 1.8 (1.0–3.2) and 3.6 (1.1–11.3), respectively, for genotypes G/A and G/G compared with genotype A/A. The number of risk alleles of CYP17, CYP19A1, ERα, and COMT was associated with an increasing OR of EGFR L858R mutation in female never-smokers (P = 0.0002 for trend).

Conclusions: The L858R mutation of EGFR is associated with polymorphisms of genes related to estrogen biosynthesis and metabolism in never-smoking female lung adenocarcinoma patients. Clin Cancer Res; 17(8); 2149–58. ©2011 AACR.
Pharmacokinetics of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors: the Role of Alpha-1-Acid Glycoprotein Binding
Authors: Graham Richard A. , Lum Bert L. , Cheeti Sravanthi , Jin Jin Yan , Jorga Karin , Von Hoff Daniel D. , Rudin Charles M. , Reddy Josina C. , Low Jennifer A. , LoRusso Patricia M.
Published: February 2011

Purpose: In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC-0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics.

Experimental Design: Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points. Total and unbound (dialyzed) GDC-0449 plasma concentrations were assessed by liquid chromatography/tandem mass spectrometry, binding kinetics by surface plasmon resonance–based microsensor, and AAG levels by ELISA.

Results: A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R2 = 0.73). In several patients, GDC-0449 levels varied with fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. In vitro, GDC-0449 binds AAG strongly and reversibly (KD = 13 μmol/L) and human serum albumin less strongly (KD = 120 μmol/L). Simulations from a derived mechanistic PK model suggest that GDC-0449 pharmacokinetics are mediated by AAG binding, solubility-limited absorption, and slow metabolic elimination.

Conclusions: GDC-0449 levels strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low, unbound drug levels, different from previously reported AAG-binding drugs. This PK profile is due to high-affinity, reversible binding to AAG and binding to albumin, in addition to solubility-limited absorption and slow metabolic elimination properties. Clin Cancer Res; 17(8); 2512–20. ©2011 AACR.
Proton Pump Inhibitor Dose-Related Healing Rate of Artificial Ulcers after Endoscopic Submucosal Dissection: A Prospective Randomized Controlled Trial
Authors: Kawano Seiji , Okada Hiroyuki , Kawahara Yoshiro , Hori Keisuke , Tanioka Daisuke , Tsuzuki Takao , Inoue Masafumi , Yagi Satoru , Takenaka Ryuta , Yamamoto Kazuhide
Published: February 2011

Background/Aims: Two studies have reported on the superiority of a proton pump inhibitor (PPI) compared with a histamine-2-receptor antagonist for the treatment of artificial ulcers after endoscopic submucosal dissection (ESD), but the optimal dose of PPI remains to be defined. The aim of this study was to evaluate the possibility of reducing the dose of PPI. The authors thus compared 30 mg (standard-dose) and 15 mg (half-dose) lansoprazole in terms of ulcer healing, prevention of bleeding and quality of life. Methods: 91 patients with gastric mucosal neoplasm were enrolled. All patients who underwent ESD were administered lansoprazole 30 mg daily during the first week, after which they were randomly assigned to either the standard-dose or half-dose group. Results: One patient in each group developed hematemesis. The stage of ulcers, ulcer reduction ratios and scores on the Gastrointestinal Symptom Rating Scale did not differ at 28 and 56 days. The costs of PPI for the half-dose group and standard-dose group were 7,326.5 and 11,698.4 JPY, respectively, i.e. a difference of 471.9 JPY. Conclusions: A reduced dose of PPI after 1 week of ESD was equivalent in treatment performance to the standard dose and cheaper.
Steroid and Ursodesoxycholic Acid Combination Therapy in Severe Drug-Induced Liver Injury
Authors: Wree Alexander , Dechêne Alexander , Herzer Kerstin , Hilgard Phillip , Syn Wing-Kin , Gerken Guido , Canbay Ali
Published: February 2011

Background: Drug-induced liver injury (DILI) is the leading cause of acute severe liver disease in Western countries. Treatment strategies for DILI are still not well defined. Aim: We studied the safety and outcomes of steroid/ursodesoxycholic acid (UDCA) combination therapy in DILI patients. Patients, Materials and Methods: 15 consecutive patients with severe DILI were analyzed for clinical, biochemical and histological data. Nine patients were treated with a steroid step-down therapy with reduction of the daily dose over several weeks; 6 patients received a steroid pulse therapy for 3 days. UDCA was administered for several weeks in both groups. Results: Patients without histological signs of preexistent liver damage (n = 10) showed the most favorable clinical course. Bilirubin and serum transaminases dropped to <50% of peak values within 2 weeks, and normalized within 4–8 weeks. In contrast, patients with positive autoimmune antibodies (anti-nuclear antibodies and/or soluble liver antigen) and/or histological features of chronic hepatitis (n = 3) exhibited a slower reduction in bilirubin and serum transaminase levels. These patients were given immunosuppressants (steroids, azathioprine) for a further 6 months. Conclusion: Treatment of severe DILI with corticosteroids (both pulse and step-down therapy) and UDCA appears to be safe, and leads to a more rapid reduction in bilirubin and transaminases after DILI.
Bupivacaine Induces Reactive Oxygen Species Production via Activation of the AMP-Activated Protein Kinase-Dependent Pathway
Authors: Lu Jun , Xu Shi Yuan , Zhang Qing Guo , Lei Hong Yi
Published: February 2011

Aims: It was our aim to investigate whether AMP-activated protein kinase (AMPK) mediates the considerable increase in reactive oxygen species (ROS) and cell apoptosis induced by bupivacaine in the human neuroblastoma cell line SH-SY5Y. Methods: The recombinant plasmids pGPU6/GFP/Neo-shRNA AMPKα2 and pEGFP-N1-AMPKα2 were constructed and transfected into the SH-SY5Y cell line. The expression of AMPKα2 was determined by RT-PCR and Western blot after transfection. The SH-SY5Y cells transfected with recombinant plasmid were exposed to 1 mmol/l bupivacaine. Cell viability, intracellular ROS and apoptosis were determined. Results: The plasmid pEGFP-N1-AMPKα2 can upregulate the expression of AMPKα2, and the pGPU6/GFP/Neo-shRNA AMPKα2 can downregulate the expression of AMPKα2 in cells. Inhibition of AMPKα2 expression attenuated ROS production and cell apoptosis, and overexpression of AMPKα2 promoted ROS production and cell apoptosis after bupivacaine treatment. Conclusion: AMPK probably mediated ROS production and cell apoptosis induced by bupivacaine.
Correlation between Serum Immunoglobulin G and Hearing Threshold among Elderly Subjects with Age-Related Hearing Loss
Authors: Lasisi Akeem Olawale , Fehintola Fatai A. , Yusuf Oyindamola Bidemi , Olayemi Oladapo O.
Published: February 2011

Background and Purpose: This study was based on the hypothesis that suboptimal immune response and low serum immunoglobulin G (IgG) may predispose to age-related hearing loss (ARHL), and the objective was to determine the serum levels of IgG and hearing thresholds of apparently healthy elderly subjects and assess their correlation. Method: This prospective study involved 126 participants ≧60 years old who were found to be free of any medical conditions. Pure-tone averages for both the speech (500–2,000 Hz) and high frequencies (3,000–8,000 Hz) and serum IgG levels were determined. Using 30 dB as cut-off for hearing loss, the correlation with serum IgG was assessed. Results: There were 59 males and 67 females with a mean age ± SD of 67.0 ± 2.7 years. Speech frequency hearing loss was seen in 30.2%, while high-frequency hearing loss accounted for 74.6%. In the speech frequencies, the mean ± SD of serum IgG among subjects with normal hearing was 11.3 ± 3.9 g/l, while among those with hearing loss it was 8.3 ± 3.3 g/l (p = 0.01). In the high frequencies, the mean ± SD values of serum IgG among the subjects with normal hearing was 11.1 ± 2.3 g/l, while among those with hearing loss it was 8.7 ± 1.9 g/l (p = 0.01). Conclusion: Low serum IgG may be a contributory factor to the development of ARHL among the elderly. However, a longitudinal study involving intervention with immunoglobulin supplementation may further confirm this role.