bluuebunny/crossref_metadata_2025 huggingface dataset:
FAST COMPUTATION OF GEOMETRIC MOMENTS AND INVARIANTS USING SCHLICK'S APPROXIMATION
Authors: MUKUNDAN R.
Published: January 2009

Geometric moments have been used in several applications in the field of Computer Vision. Many techniques for fast computation of geometric moments have therefore been proposed in the recent past, but these algorithms mainly rely on properties of the moment integral such as piecewise differentiability and separability. This paper explores an alternative approach to approximating the moment kernel itself in order to get a notable improvement in computational speed. Using Schlick's approximation for the normalized kernel of geometric moments, the computational overhead could be significantly reduced and numerical stability increased. The paper also analyses the properties of the modified moment functions, and shows that the proposed method could be effectively used in all applications where normalized Cartesian moment kernels are used. Several experimental results showing the invariant characteristics of the modified moments are also presented.
ANALYSIS OF SOLUTION FOR SUPERVISED GRAPH EMBEDDING
Authors: YOU QUBO , ZHENG NANNING , GAO LING , DU SHAOYI , WU YANG
Published: January 2009

Recently, Graph Embedding Framework has been proposed for feature extraction. However, it is still an open issue on how to compute robust discriminant transformation for this purpose. In this paper, we show that supervised graph embedding algorithms share a general criterion. Based on the analysis of this criterion, we propose a general solution, called General Solution for Supervised Graph Embedding (GSSGE), for extracting the robust discriminant transformation of Supervised Graph Embedding. Then, we analyze the superiority of our algorithm over traditional algorithms. Extensive experiments on both artificial and real-world data are performed to demonstrate the effectiveness and robustness of our proposed GSSGE.
SEMANTIC-PARSING BASED ON SEMANTIC UNITS THEORY — A NEW APPROACH TO NATURAL LANGUAGES PROCESSING
Authors: GAO XIAOYU , YUE HU , LI L. , GAO QINGSHI
Published: January 2009

The syntax of different natural languages are different, hence the parsing of different natural languages are also different, thus leadings to structures of their parsing-trees being different. The reason that the sentences in different natural languages can be translated to each other is that they have the same meaning. This paper discusses a new sentence parsing, called semantic-parsing, based on semantic units theory. It is a new theory where a sentence of a natural language is not regarded as of words and phrases arranged linearly; rather it is expected to consist of semantic units with or without type-parameters. This is a new parsing approach where the syntax-parsing-tree and semantic-parsing-tree are isomorphic. It is also a new approach in which the structure-trees of the sentences in all different natural languages can correspond.
EFFECTIVE AND AUTOMATIC CALIBRATION USING CONCENTRIC CIRCLES
Authors: WANG LIANG , YAO HONGXUN , CHENG H. D.
Published: January 2009

In this paper, we present an effective, flexible and completely automated camera calibration approach using only one pair of concentric circles. This approach utilizes the characteristics of concentric circles' tangent lines to locate the center of these circles, and finds the geometric constraints for calibration based on the orthogonality formed by a point on the circle and the two intersected points of the circle with the line through the center of the circle. The entire process requires no conic equation fitting and no metric measurement of the test pattern, which is very flexible to implement.
TWO-STAGE LEXICON REDUCTION FOR OFFLINE ARABIC HANDWRITTEN WORD RECOGNITION
Authors: MOZAFFARI SAEED , FAEZ KARIM , MÄRGNER VOLKER , EL ABED HAIKAL
Published: January 2009

Given large number of words to be recognized, a two-stage strategy for eliminating unlikely candidates before recognition can be a reasonable and powerful approach for increasing the recognition speed. A holistic lexicon reduction technique for offline handwritten Arabic word recognition is proposed in this paper. The principle of this technique involves the extraction of dots and subwords from the cursive Arabic word image to describe its shape. In the first stage of reduction, the number of subwords in the input word is estimated. Then in the second stage, the word descriptor, based on the dots information, is used while taking into account only the candidates selected in the first stage. Experimental results on IFN/ENIT database, consisting of 26,459 cursive Arabic word images, show a lexicon reduction of 92.5% with accuracy of 74%.
DO GALACTIC GLOBULAR CLUSTERS CONTRIBUTE TO MICROLENSING EVENTS?
Authors: DE LUCA FABIANA , JETZER PHILIPPE
Published: January 2009

In this paper, we perform an analysis of the large set of microlensing events detected so far toward the galactic center, with the purpose of investigating whether some of the dark lenses are located in galactic globular clusters. We found that in four cases some events might have occurred due to lenses located in the globular clusters themselves. We also give a rough estimate for the average lens mass of the subset of events being highly aligned with galactic globular-cluster centers and find that, under reasonable assumptions, the deflectors could possibly be either brown dwarfs, M-stars, or stellar remnants.
COSMOLOGICAL MODEL SELECTION: STATISTICS AND PHYSICS
Authors: LINDER ERIC V. , MIQUEL RAMON
Published: January 2009

Interpretation of cosmological data to determine the number and values of parameters describing the universe must not rely solely on statistics but involve physical insight. When statistical techniques such as "model selection" or "integrated survey optimization" blindly apply Occam's Razor, this can lead to painful results. Sensitivity to prior probabilities and to the number of models compared can lead to "prior selection" rather than robust model selection. A concrete example demonstrates that information criteria can in fact misinform over a large region of parameter space.
Suppression of Intrinsic Delay Variation in FPGAs using Multiple Configurations
Authors: Matsumoto Yohei , Hioki Masakazu , Kawanami Takashi , Koike Hanpei , Tsutsumi Toshiyuki , Nakagawa Tadashi , Sekigawa Toshihiro
Published: January 2009

A new method for improving the timing yield of
field-programmable gate array (FPGA) devices affected by intrinsic
within-die variation is proposed. The timing variation is reduced
by selecting an appropriate configuration for each chip from a set
of independent configurations, the critical paths of which do not
share the same circuit resources on the FPGA. In this article, the
actual method used to generate independent multiple configurations
by simply repeating the routing phase is shown, along with the
results of Monte Carlo simulation with 10,000 samples. One
simulation result showed that the standard deviations of maximum
critical path delays are reduced by 28% and 49% for 10% and 30%
V
th
variations (
σ/ μ
), respectively,
with 10 independent configurations. Therefore, the proposed method
is especially effective for larger V
th
variation and is
expected to be useful for suppressing the performance variation of
FPGAs due to the future increase of parameter variation. Another
simulation result showed that the effectiveness of the proposed
technique was saturated at the use of 10 or more configurations
because of the degradation of the quality of the configurations.
Therefore, the use of 10 or fewer configurations is reasonable.
A Desktop Computer with a Reconfigurable Pentium®
Authors: Lu Shih-Lien L. , Yiannacouras Peter , Suh Taeweon , Kassa Rolf , Konow Michael
Published: January 2009

Advancements in reconfigurable technologies, specifically FPGAs, have yielded faster, more power-efficient reconfigurable devices with enormous capacities. In our work, we provide testament to the impressive capacity of recent FPGAs by hosting a complete Pentium
®
in a single FPGA chip. In addition we demonstrate how FPGAs can be used for microprocessor design space exploration while overcoming the tension between simulation speed, model accuracy, and model completeness found in traditional software simulator environments. Specifically, we perform preliminary experimentation/prototyping with an original Socket 7 based desktop processor system with typical hardware peripherals running modern operating systems such as Fedora Core 4 and Windows XP; however we have inserted a Xilinx Virtex-4 in place of the processor that should sit in the motherboard and have used the Virtex-4 to host a complete version of the Pentium
®
microprocessor (which consumes less than half its resources). We can therefore apply architectural changes to the processor and evaluate their effects on the complete desktop system. We use this FPGA-based emulation system to conduct preliminary architectural experiments including growing the branch target buffer and the level 1 caches. In addition, we experimented with interfacing hardware accelerators such as DES and AES engines which resulted in a 27x speedup.
Designing Efficient Input Interconnect Blocks for LUT Clusters Using Counting and Entropy
Authors: Feng Wenyi , Kaptanoglu Sinan
Published: January 2009

In a cluster-based FPGA, the interconnect from external routing tracks and cluster feedbacks to the LUT inputs consumes significant area, and no consensus has emerged among different implementations (e.g., 1-level or 2-level). In this paper, we model this interconnect as a unified input interconnect block (IIB). We identify three types of IIBs and develop general combinatorial techniques to count the number of distinct functional configurations for them. We use entropy, defined as the logarithm of this count, to estimate an IIB's routing flexibility. This enables us to analytically evaluate different IIBs without the customary time-consuming place and route experiments. We show that both depopulated 1-level IIBs and VPR-style 2-level IIBs achieve high routing flexibility but lack area efficiency. We propose a novel class of highly efficient, yet still simple, IIBs that use substantially fewer switches with only a small degradation in routing flexibility. Experimental results verify the routability of these IIBs, and confirm that entropy is a good predictor of routability.
Merged Dictionary Code Compression for FPGA Implementation of Custom Microcoded PEs
Authors: Gorjiara Bita , Reshadi Mehrdad , Gajski Daniel
Published: January 2009

Horizontal Microcoded Architecture (HMA) is a paradigm for designing programmable high-performance processing elements (PEs). However, it suffers from large code size, which can be addressed by compression. In this article, we study the code size of one of the new HMA-based technologies called No-Instruction-Set Computer (NISC). We show that NISC code size can be several times larger than a typical RISC processor, and we propose several low-overhead dictionary-based code compression techniques to reduce its code size. Our compression algorithm leverages the knowledge of “don't care” values in the control words and can reduce the code size by 3.3 times, on average. Despite such good results, as shown in this article, these compression techniques lead to poor FPGA implementations because they require many on-chip RAMs. To address this issue, we introduce an FPGA-aware dictionary-based technique that uses the dual-port feature of on-chip RAMs to reduce the number of utilized block RAMs by half. Additionally, we propose cascading two-levels of dictionaries for code size and block RAM reduction of large programs. For an MP3 application, a merged, cascaded, three-dictionary implementation reduces the number of utilized block RAMs by 4.3 times (76%) compared to a NISC without compression. This corresponds to 20% additional savings over the best single level dictionary-based compression.
Keeping Up with Technology
Authors: Edwards Alistair D. N.
Published: January 2009

This is a personal response to rereading the Glinert and York [1992] article “Computers and People with Disabilities.” Comparing the world of assistive technology as it was in 1992 and as it now appears is instructive in terms of the things which have changed --- and those which have not. The technology has certainly developed. This applies both to the mainstream and to the assistive technology which aims to make the mainstream accessible. So, in 1992, the GUI was a threat to visually impaired computer users; now there are powerful screen readers available. Yet what does not appear to have changed much is the fact that assistive technologies continue to lag behind the mainstream, constantly having to “catch up.” Also, while there has been some increase in awareness of the need for accessibility, there is still scope for that awareness to be translated into action.
Semantic fitting and reconstruction
Authors: Ullrich Torsten , Settgast Volker , Fellner Dieter W.
Published: January 2009

The current methods to describe the shape of three-dimensional objects can be classified into two groups: methods following the
composition of primitives
approach and descriptions based on
procedural shape representations
. As a 3D acquisition device returns an agglomeration of elementary objects (e.g. a laser scanner returns points), the model acquisition pipeline always starts with a composition of primitives. Due to the semantic information carried with a generative description, a procedural model provides valuable metadata that make up the basis for digital library services: retrieval, indexing, and searching.

An important challenge in computer graphics in the field of cultural heritage is to build a bridge between the generative and the explicit geometry description combining both worlds—the accuracy and systematics of generative models with the realism and the irregularity of real-world data. A first step towards a semantically enriched data description is a reconstruction algorithm based on decreasing exponential fitting. This approach is robust towards outliers and multiple dataset mixtures. It does not need a preceding segmentation and is able to fit a generative shape template to a point cloud identifying the parameters of a shape.
Data fusion
Authors: Bleiholder Jens , Naumann Felix
Published: January 2009

The development of the Internet in recent years has made it possible and useful to access many different information systems anywhere in the world to obtain information. While there is much research on the integration of heterogeneous information systems, most commercial systems stop short of the actual integration of available data. Data fusion is the process of fusing multiple records representing the same real-world object into a single, consistent, and clean representation.

This article places data fusion into the greater context of data integration, precisely defines the goals of data fusion, namely, complete, concise, and consistent data, and highlights the challenges of data fusion, namely, uncertain and conflicting data values. We give an overview and classification of different ways of fusing data and present several techniques based on standard and advanced operators of the relational algebra and SQL. Finally, the article features a comprehensive survey of data integration systems from academia and industry, showing if and how data fusion is performed in each.
A review of overview+detail, zooming, and focus+context interfaces
Authors: Cockburn Andy , Karlson Amy , Bederson Benjamin B.
Published: January 2009

There are many interface schemes that allow users to work at, and move between, focused and contextual views of a dataset. We review and categorize these schemes according to the interface mechanisms used to separate and blend views. The four approaches are overview+detail, which uses a spatial separation between focused and contextual views; zooming, which uses a temporal separation; focus+context, which minimizes the seam between views by displaying the focus within the context; and cue-based techniques which selectively highlight or suppress items within the information space. Critical features of these categories, and empirical evidence of their success, are discussed. The aim is to provide a succinct summary of the state-of-the-art, to illuminate both successful and unsuccessful interface strategies, and to identify potentially fruitful areas for further work.
Cross-disciplinary perspectives on meta-learning for algorithm selection
Authors: Smith-Miles Kate A.
Published: January 2009

The algorithm selection problem [Rice 1976] seeks to answer the question:Which algorithm is likely to perform best for my problem?Recognizing the problem as a learning task in the early 1990's, the machine learning community has developed the field of meta-learning, focused on learning about learning algorithm performance on classification problems. But there has been only limited generalization of these ideas beyond classification, and many related attempts have been made in other disciplines (such as AI and operations research) to tackle the algorithm selection problem in different ways, introducing different terminology, and overlooking the similarities of approaches. In this sense, there is much to be gained from a greater awareness of developments in meta-learning, and how these ideas can be generalized to learn about the behaviors of other (nonlearning) algorithms. In this article we present a unified framework for considering the algorithm selection problem as a learning problem, and use this framework to tie together the crossdisciplinary developments in tackling the algorithm selection problem. We discuss the generalization of meta-learning concepts to algorithms focused on tasks including sorting, forecasting, constraint satisfaction, and optimization, and the extension of these ideas to bioinformatics, cryptography, and other fields.
ACM DocEng 2008 recap
Authors: Simske Steven , Pellan Benoit , Shilman Michael
Published: January 2009

Welcome to São Paulo! This year's ACM-sponsored Document Engineering Symposium (DocEng 2008) was the first to be held in South America (and the Southern Hemisphere, come to that). In a year of firsts, this year's DocEng was the first to feature a Best Paper Award that brought a healthy competition amongst 5 deserving candidates during the conference and concluded these three days with an incredible suspense!
"Contextual annotation framework using ontology based contextual annotation service" by Thanyalak Maneewatthana, with Jessica Rubart as author
Authors: Maneewatthana Thanyalak , Rubart Jessica
Published: January 2009

Thanyalak Maneewatthana received her PhD from the University of Southampton, UK. The title of her thesis is "Contextual Annotation Framework using Ontology Based Contextual Annotation Service". She currently works at National Statistical Office, Thailand. Her research interests include semantic web technologies, knowledge management, service-oriented architecture.
Mining frequent cross-graph quasi-cliques
Authors: Jiang Daxin , Pei Jian
Published: January 2009

Joint mining of multiple datasets can often discover interesting, novel, and reliable patterns which cannot be obtained solely from any single source. For example, in bioinformatics, jointly mining multiple gene expression datasets obtained by different labs or during various biological processes may overcome the heavy noise in the data. Moreover, by joint mining of gene expression data and protein-protein interaction data, we may discover clusters of genes which show coherent expression patterns and also produce interacting proteins. Such clusters may be potential pathways.

In this article, we investigate a novel data mining problem,
mining frequent cross-graph quasi-cliques
, which is generalized from several interesting applications in bioinformatics, cross-market customer segmentation, social network analysis, and Web mining. In a graph, a set of vertices
S
is a γ-quasi-clique (0 < γ ≤ 1) if each vertex
v
in
S
directly connects to at least γ ⋅ (|
S
| − 1) other vertices in
S
. Given a set of graphs
G
1
, …,

G
n

and parameter
min_sup
(0 <
min_sup
≤ 1), a set of vertices
S
is a frequent cross-graph quasi-clique if
S
is a γ-quasi-clique in at least
min_sup
⋅
n
graphs, and there does not exist a proper superset of
S
having the property.

We build a general model, show why the complete set of frequent cross-graph quasi-cliques cannot be found by previous data mining methods, and study the complexity of the problem. While the problem is difficult, we develop practical algorithms which exploit several interesting and effective techniques and heuristics to efficaciously mine frequent cross-graph quasi-cliques. A systematic performance study is reported on both synthetic and real data sets. We demonstrate some interesting and meaningful frequent cross-graph quasi-cliques in bioinformatics. The experimental results also show that our algorithms are efficient and scalable.
Debugging Devices
Authors: Neville-Neil George
Published: January 2009

I suggest taking a very sharp knife and cutting the board traces at random until the thing either works, or smells funny! I gather you’re not asking the same question that led me to use the word changeineer in another column. I figure you have an actually malfunctioning piece of hardware and that you’ve already sent three previous versions back to the manufacturer, complete with nasty letters containing veiled references to legal action should they continue to send you broken products.
CTO Roundtable: Storage Part II
Authors: Creeger Mache
Published: January 2009

The following conversation is the second installment of a CTO roundtable featuring seven world-class experts on storage technologies. This series of CTO forums focuses on the near-term challenges and opportunities facing the commercial computing community. Overseen by the ACM Professions Board, the goal of the series is to provide IT managers with access to expert advice to help inform their decisions when investing in new architectures and technologies.
Review of "Pro LINQ Object Relational Mapping in C# 2008 by Vijay Mehta," Apress, 2008, $49.99, ISBN: 9781590599655
Authors: Naugler David
Published: January 2009

Review of "Pro LINQ Object Relational Mapping in C# 2008 by Vijay Mehta," Apress, 2008, $49.99, ISBN: 9781590599655
Review of "The Rails Way by Obie Fernandez," Addison-Wesley Professional, 2007, $49.99, ISBN: 9780321445612
Authors: Bellin David
Published: January 2009

Review of "The Rails Way by Obie Fernandez," Addison-Wesley Professional, 2007, $49.99, ISBN: 9780321445612
Does Efficiency Shape the Territorial Structure of Government?
Authors: Hooghe Liesbet , Marks Gary
Published: January 2009

This article asks three questions. Why is government organized across multiple levels? Does efficiency determine the level at which decisions are made? Does efficiency frame how policy problems are bundled in jurisdictions? Rather than examine how government structure may or may not lead to efficient outcomes, this article considers how efficiency constrains government. The purpose here is to probe fundamental commonalities of government structure which are usually taken for granted because they exist in an otherwise fluctuating political universe.
Niacin stimulates adiponectin secretion through the GPR109A receptor
Authors: Plaisance Eric P. , Lukasova Martina , Offermanns Stefan , Zhang Youyan , Cao Guoqing , Judd Robert L.
Published: January 2009

Niacin (nicotinic acid) has recently been shown to increase serum adiponectin concentrations in men with the metabolic syndrome. However, little is known about the mechanism(s) by which niacin regulates the intracellular trafficking and secretion of adiponectin. Since niacin appears to exert its effects on lipolysis through receptor (GPR109A)-dependent and -independent pathways, the purpose of this investigation was to examine the role of the recently identified GPR109A receptor in adiponectin secretion. Initial in vivo studies in rats demonstrated that niacin (30 mg/kg po) acutely increases serum adiponectin concentrations, whereas it decreases NEFAs. Further in vitro studies demonstrated an increase in adiponectin secretion and a decrease in lipolysis in primary adipocytes following treatment with niacin or β-hydroxybutyrate (an endogenous ligand of the GPR109A receptor), but these effects were blocked when adipocytes were pretreated with pertussis toxin. Niacin had no effect on adiponectin secretion or lipolysis in 3T3-L1 adipocytes, which have limited cell surface expression of the GPR109A receptor. To further substantiate these in vitro findings, wild-type and GPR109A receptor knockout mice were administered a single dose of niacin or placebo, and serum was obtained for the determination of adiponectin and NEFA concentrations. Serum adiponectin concentrations increased and serum NEFAs decreased in the wild-type mice within 10 min following niacin administration. However, niacin administration had no effect on adiponectin and NEFA concentrations in the GPR109A receptor knockout mice. These results demonstrate that the GPR109A receptor plays an important role in the dual regulation of adiponectin secretion and lipolysis.
Ecological Characterization of the Colonic Microbiota of Normal and Diarrheic Dogs
Authors: Bell Julia A. , Kopper Jamie J. , Turnbull Judy A. , Barbu Nicholas I. , Murphy Alice J. , Mansfield Linda S.
Published: January 2009

We used terminal restriction fragment polymorphism (T-RFLP) analysis to assess (1) stability of the fecal microbiota in dogs living in environments characterized by varying degrees of exposure to factors that might alter the microbiota and (2) changes in the microbiota associated with acute episodes of diarrhea. Results showed that the healthy canine GI tract harbors potential enteric pathogens. Dogs living in an environment providing minimal exposure to factors that might alter the microbiota had similar microbiotas; the microbiotas of dogs kept in more variable environments were more variable. Substantial changes in the microbiota occurred during diarrheic episodes, including increased levels ofClostridium perfringens, Enterococcus faecalis, andEnterococcus faecium. When diet and medications of a dog having a previously stable microbiota were changed repeatedly, the microbiota also changed repeatedly. Temporal trend analysis showed directional changes in the microbiota after perturbation, a return to the starting condition, and then fluctuating changes over time.
Effects of CNT Diameter on the Uniaxial Stress‐Strain Behavior of CNT/Epoxy Composites
Authors: Yu N. , Chang Y. W.
Published: January 2009

The present work studies the effects of the diameter of carbon nanotube (CNT) as well as CNT weight fraction on the uniaxial stress‐strain behavior, stiffness, and strength of CNT‐reinforced epoxy‐matrix composites. The experimental results show that average Young′s moduli of 5 wt%‐CNT/epoxy composites with a CNT diameter D < 20 nm and D = 40 ~ 60 nm are 4.56 GPa and 4.36 GPa, and the average tensile strengths are 52.89 MPa and 46.80 MPa, respectively, which corresponds to a percentage increase of 61.1%, 54.1%, 106%, and 82.3%, respectively. Two micromechanics models are employed and the predicted Young′s moduli are benchmarked with the experimental data of MWCNT‐reinforced epoxy‐matrix composites.
Recurrence of Mitotically Active Cellular Fibroma of the Ovary
Authors: Bucella Dario , Limbosch Jean-Frédéric , Buxant Frédéric , Simon Philippe , Fayt Isabelle , Anaf Vincent , Noël Jean-Christophe
Published: January 2009

Background. 10% of ovarian fibromatous tumours typically exhibit increased cellularity, mitotic activity, and less frequently nuclear atypia. Therefore, the classification within the group of fibromatous tumours may represent some difficulties, thus, one or several of these features should appear.Case. We introduce the clinical and pathologic features based on one case of recurrence of a mitotically active cellular ovarian fibroma (MACF) in the pararectal fossa. This recurrence took place six years after primary surgery. Macroscopically, the tumour was firm, fibrous, well delimited, yellow-white without gross necrosis. On microscopic examination, it was composed of a densely cellular proliferation of fibrolastic-like cells with bland nuclear features and arranged in a fascicular pattern. There was no sign of significant atypia or necrosis.Conclusion. Recently, this case is the first report of a recurrence of MACF, following primary surgery with no tumoral rupture or surgical difficulty. The clinical outcome of ovarian cellular fibromas (CFs) and MACFs is typically uneventful. This case, however, strongly suggests maintaining a long-term clinical follow-up even though the principal tumour was surgically treated without tumour rupture or in the absence of adherence or any surgical difficulty.
Experimental Observation of Oscillating Wave Propagation on Switch Lines for Generation of Continuous Electromagnetic Waves
Authors: Narahara Koichi , Yokota Akihiro
Published: January 2009

We report the experimental observation of the generation of continuous electrical waves in a
switch line, which is a transmission line periodically loaded with electronic switches. The oscillating
motions of a wave front have been experimentally demonstrated in a line with discrete Esaki diodes
employed as switches, when a rising step‐pulse signal was passed through the line.
PP2A regulates ionizing radiation–induced apoptosis through Ser46 phosphorylation of p53
Authors: Mi Jun , Bolesta Elzbieta , Brautigan David L. , Larner James M.
Published: January 2009

In response to ionizing radiation, p53 plays a critical role in regulating DNA repair and apoptosis. Among multiple phosphorylation sites, evidence suggests that Ser46 promotes apoptotic cell death through mitochondrial outer membrane permeabilization (MOMP) and subsequent activation of the caspase 7–PARP pathway. Therefore, we investigated which phosphatase regulates Ser46 after ionizing radiation, reasoning that the responsible phosphatase should be a target for radiosensitization. We determined that both inhibition of PP2A by the cell-permeable inhibitor calyculin A and knockdown of PP2A by RNAi (a) enhanced Ser46 phosphorylation in p53 and (b) induced coincident caspase 7 and PARP cleavage in response to ionizing radiation. Furthermore, mutation of p53 Ser46 to Ala attenuated ionizing radiation–induced apoptotic signaling. Consequently, we concluded that PP2A regulates ionizing radiation–induced apoptotic signaling through dephosphorylation of p53 Ser46. [Mol Cancer Ther 2009;8(1):135–40]
Differential effects of the vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 on tumor angiogenesis and tumor lymphangiogenesis
Authors: Schomber Tibor , Zumsteg Adrian , Strittmatter Karin , Crnic Ivana , Antoniadis Helena , Littlewood-Evans Amanda , Wood Jeanette , Christofori Gerhard
Published: January 2009

Halting tumor growth by interfering with tumor-induced angiogenesis is an attractive therapeutic approach. Such treatments include humanized antibodies blocking the activity of vascular endothelial growth factor (VEGF)-A (bevacizumab), soluble VEGF receptor (VEGFR) constructs (VEGF-Trap), or small-molecule inhibitors of VEGFR signaling, including PTK787/ZK222584 (PTK/ZK), sorafenib, and sunitinib. PTK/ZK has been shown previously to specifically block VEGF-induced phosphorylation of VEGFR-1, -2 and -3 and thereby to inhibit endothelial cell proliferation, differentiation, and tumor angiogenesis. We have investigated the effect of PTK/ZK on tumor angiogenesis and tumor lymphangiogenesis using the Rip1Tag2 transgenic mouse model of pancreatic β cell carcinogenesis. In Rip1Tag2 mice, tumor angiogenesis is predominantly mediated by VEGF-A, and as expected, PTK/ZK efficiently impaired tumor blood vessel angiogenesis and tumor growth. Double-transgenic Rip1Tag2;Rip1VEGF-C and Rip1Tag2;Rip1VEGF-D mice not only exhibit VEGF-A-dependent blood vessel angiogenesis but also tumor lymphangiogenesis induced by the transgenic expression of VEGF-C or -D. In these mouse models, PTK/ZK also repressed tumor blood vessel angiogenesis and tumor growth yet failed to affect tumor lymphangiogenesis and lymphogenic metastasis. Adenoviral delivery of soluble VEGFR-3 also did not prevent tumor lymphangiogenesis in these mice. In contrast, spontaneous tumor lymphangiogenesis, as observed by the stochastic expression of VEGF-C and -D in tumors of neural cell adhesion molecule-deficient Rip1Tag2 mice, was repressed by PTK/ZK and soluble VEGFR-3. The results indicate that the time of onset and the levels of VEGF-C/D expression may be critical variables in efficiently repressing tumor lymphangiogenesis and that pathways other than VEGFR signaling may be involved in tumor lymphangiogenesis. [Mol Cancer Ther 2009;8(1):55–63]
In vivo target-specific activatable near-infrared optical labeling of humanized monoclonal antibodies
Authors: Ogawa Mikako , Regino Celeste A.S. , Choyke Peter L. , Kobayashi Hisataka
Published: January 2009

Imaging with labeled monoclonal antibodies may be useful in detecting, staging, and monitoring tumors. Despite their high affinity and specificity, a critical limitation of antibody imaging is the high background signal due to prolonged clearance from the blood, which reduces the tumor-to-background ratio. To address this problem, we developed a molecular imaging probe consisting of multiple self-quenching fluorophores [Cy5.5 or Alexa Fluor 680 (Alexa680)] conjugated to a monoclonal antibody (trastuzumab) to synthesize Tra-Cy5.5(SQ) or Tra-Alexa680(SQ), respectively. This agent only becomes fluorescently “active” after cellular internalization but is quenched in the unbound state leading to high tumor-to-background ratios. The in vitro quenching capacity for both conjugates was ∼9-fold. In vivo imaging experiments were done in mice bearing both 3T3/HER-2+ and BALB/3T3/ZsGreen/HER-2− xenografts. Tra-Alexa680(SQ) produced specific enhancement in the 3T3/HER-2+ tumors but not in the HER-2− control tumors. However, Tra-Cy5.5(SQ) produced nonspecific enhancement in both 3T3/HER-2+ and control tumors. In conclusion, whereas Cy5.5-conjugates produced nonspecific results as well as rapid liver accumulation, conjugating multiple Alexa680 molecules to a single monoclonal antibody resulted in a near-infrared optical agent that activated within specific target tumors with high tumor-to-background ratio with considerable potential for clinical translation. [Mol Cancer Ther 2009;8(1):232–9]
Pulmonary Valve Replacement in Tetralogy of Fallot
Authors: Harrild David M. , Berul Charles I. , Cecchin Frank , Geva Tal , Gauvreau Kimberlee , Pigula Frank , Walsh Edward P.
Published: January 2009

Background—

Pulmonary valve replacement (PVR) in repaired tetralogy of Fallot (TOF) reduces pulmonary regurgitation and decreases right ventricular (RV) dilation, but its long-term impact on ventricular tachycardia (VT) and mortality is unknown. This study aimed to determine the incidence of death and VT in TOF after PVR and to test the hypothesis that PVR leads to improvement in these outcomes.

Methods and Results—

A total of 98 patients with TOF and late PVR for RV dilation were identified. Matched control subjects were identified for 77 of these patients; control subjects had TOF with RV dilation but no PVR. Matching was done by age (±2 years) and baseline QRS duration (±30 ms). No significant differences were found in age, QRS duration, type or decade of initial repair, age at TOF repair, or presence of pre-PVR VT between the 2 groups; limited echocardiographic and magnetic resonance imaging data showed no difference in left ventricular function but more RV dilation among PVR patients than control subjects. In the PVR group, 13 events occurred over 272 patient-years. No significant change in QRS duration was seen for any group. Overall 5- and 10-year freedom from death, VT, or both was 80% and 41%, respectively. In the matched comparison, no significant differences were seen in VT, death, or combined VT and/or death (
P
=0.32,
P
=0.06 [nearly favoring controls], and
P
=0.21).

Conclusions—

This cohort experienced either VT or death every 20 patient-years. In a matched comparison with a similar TOF group, late PVR for symptomatic pulmonary regurgitation/RV dilation did not reduce the incidence of VT or death.
Impact of a Prescription Copayment Increase on Lipid-Lowering Medication Adherence in Veterans
Authors: Doshi Jalpa A. , Zhu Jingsan , Lee Bruce Y. , Kimmel Stephen E. , Volpp Kevin G.
Published: January 2009

Background—

In February 2002, the Department of Veterans Affairs (VA) increased copayments from $2 to $7 per 30-day drug supply of each medication for many veterans. We examined the impact of the copayment increase on lipid-lowering medication adherence.

Methods and Results—

This quasiexperimental study used electronic records of 5604 veterans receiving care at the Philadelphia VA Medical Center from November 1999 to April 2004. The all copayment group included veterans subject to copayments for all drugs with no annual cap. Veterans subject to copayments for drugs only if indicated for a non–service-connected condition with an annual cap of $840 for out-of-pocket costs made up the some copayment group. Veterans who remained copayment exempt formed a natural control group (no copayment group). Patients were identified as adherent if the proportion of days covered with lipid-lowering medications was ≥80%. Patients were identified as having a continuous gap if they had at least 1 continuous episode with no lipid-lowering medications for ≥90 days. A difference-in-difference approach compared changes in lipid-lowering medication adherence during the 24 months before and after copayment increase among veterans subject to the copayment change with those who were not. Adherence declined in all 3 groups after the copayment increase. However, the percentage of patients who were adherent (proportion of days covered ≥80%) declined significantly more in the all copayment (−19.2%) and some copayment (−19.3%) groups relative to the exempt group (−11.9%). The incidence of a continuous gap increased significantly at twice the rate in both copayment groups (all copayment group, 24.6%; some copayment group, 24.1%) as the exempt group (11.7%). Compared with the exempt group, the odds of having a continuous gap in the after relative to the before period were significantly higher in both the all copayment group (odds ratio, 3.04; 95% confidence interval, 2.29 to 4.03) and the some copayment group (odds ratio, 1.85; 95% confidence interval, 1.43 to 2.40). Similar results were seen in subgroups of patients at high risk for coronary heart disease, high medication users, and elderly veterans.

Conclusion—

The copayment increase adversely affected lipid-lowering medication adherence among veterans, including those at high coronary heart disease risk.
Anti-Chlamydial Antibiotic Therapy for Symptom Improvement in Peripheral Artery Disease
Authors: Jaff Michael R. , Dale Rita A. , Creager Mark A. , Lipicky Raymond John , Constant John , Campbell Lee Ann , Hiatt William R.
Published: January 2009

Background—

A potentially strong association exists between
Chlamydia pneumoniae
and atherosclerosis, but the clinical benefits of antibiotic therapy have not been demonstrated. Preliminary studies of antibiotic therapy in peripheral artery disease have shown a decreased need for revascularization and improved walking ability. The objective of this phase-III trial was to assess the effect of a potent anti-Chlamydial agent, rifalazil, on peak walking time in patients with symptomatic peripheral artery disease.

Methods and Results—

Patients with intermittent claudication secondary to peripheral artery disease who were seropositive for
C pneumoniae
were randomized to 25 mg rifalazil once weekly for 8 weeks or matching placebo. Two hundred ninety-seven patients were enrolled from 3 countries and were followed up for 1 year. The mean±SD ankle brachial index at baseline was 0.63±0.16. The primary end point, change from baseline in log peak walking time on a graded treadmill, was assessed 180 days after randomization. Secondary end points included changes in claudication onset time and quality of life, assessed with the Walking Impairment Questionnaire and the Short Form Medical Outcomes 36. No benefit of rifalazil therapy was found in the primary or any secondary end point among this cohort of patients with peripheral artery disease. The group treated with rifalazil improved their peak walking times by 23% (95% confidence interval, 15 to 31) from baseline to day 180, whereas the placebo group improved by 18% (95% confidence interval, 11 to 26;
P
=0.38). Peak walking time, claudication onset time, Walking Impairment Questionnaire, and Short Form Medical Outcomes 36 showed no treatment-by-time interaction during the 360-day study period. Thirty-two adjudicated cardiovascular events occurred, 16 in each treatment group.

Conclusions—

Rifalazil did not improve exercise performance or quality of life in patients with intermittent claudication. No safety concerns were identified. Given the very small effect size, it is unlikely that larger studies would demonstrate a symptomatic benefit of this therapy in peripheral artery disease.
Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice
Authors: Pokreisz Peter , Vandenwijngaert Sara , Bito Virginie , Van den Bergh An , Lenaerts Ilse , Busch Cornelius , Marsboom Glenn , Gheysens Olivier , Vermeersch Pieter , Biesmans Liesbeth , Liu Xiaoshun , Gillijns Hilde , Pellens Marijke , Van Lommel Alfons , Buys Emmanuel , Schoonjans Luc , Vanhaecke Johan , Verbeken Erik , Sipido Karin , Herijgers Paul , Bloch Kenneth D. , Janssens Stefan P.
Published: January 2009

Background—

Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction in transgenic mice with cardiomyocyte-specific overexpression of PDE5 (PDE5-TG).

Methods and Results—

Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes, predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening, and calcium handling in isolated cardiomyocytes and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates. Ten days after myocardial infarction, LV cGMP levels had increased to a greater extent in wild-type mice than in PDE5-TG mice (
P
<0.05). Ten weeks after myocardial infarction, LV end-systolic and end-diastolic volumes were larger in PDE5-TG than in wild-type mice (57±5 versus 39±4 and 65±6 versus 48±4 μL, respectively;
P
<0.01 for both). LV systolic dysfunction and diastolic dysfunction were more marked in PDE5-TG than in wild-type mice, associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium.

Conclusions—

Increased PDE5 expression predisposes mice to adverse LV remodeling after myocardial infarction. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.
Endothelin-Stimulated Human B-Type Natriuretic Peptide Gene Expression Is Mediated by Yin Yang 1 in Association With Histone Deacetylase 2
Authors: Glenn Denis J. , Wang Feng , Chen Songcang , Nishimoto Minobu , Gardner David G.
Published: January 2009

Increased B-type natriuretic peptide (BNP) gene expression is regarded as one of the hallmarks of cardiac myocyte hypertrophy. Here we demonstrate that both basal- and endothelin-1–dependent stimulation of human (h) BNP gene transcription requires the presence of an intact Yin Yang 1 (YY1) binding site positioned at −62 bp relative to the transcription start site. Mutation of this site reduced both basal and stimulated hBNP promoter activity. This site was shown to bind YY1 both in vitro and within the context of the intact cell. The latter interaction increased after endothelin-1 treatment. Exposure to endothelin-1 also resulted in increased nuclear localization of YY1 and a reduction in acetylation of the YY1 protein. Overexpression of wild-type YY1 increased both basal and endothelin-stimulated hBNP promoter activity, whereas a carboxy-terminal deletion mutant of YY1 was devoid of activity. Treatment with the histone deacetylase inhibitor trichostatin A resulted in decreased hBNP reporter activity. YY1 was shown to associate with histone deacetylase 2, and histone deacetylase 2 was shown to associate directly with the hBNP promoter in the intact cell. Collectively these findings demonstrate that YY1 plays an important role in regulating the transcriptional activity of the hBNP gene promoter. These data suggest a model in which YY1 activates hBNP transcription through interaction with histone deacetylase 2.
Effect of Birth Parameters on Retinal Vascular Caliber
Authors: Sun Cong , Ponsonby Anne-Louise , Wong Tien Y. , Brown Shayne A. , Kearns Lisa S. , Cochrane Jenny , MacKinnon Jane R. , Ruddle Jonathan B. , Hewitt Alex W. , Liew Gerald , Dwyer Terence , Scurrah Katrina , Mackey David A.
Published: January 2009

Recent studies reported an association between smaller birth size and narrower retinal vascular caliber, but it remains unclear whether this association is attributed to confounding by shared environment or genetic factors. At a mean age of 9.3 years, 266 twins (49 monozygotic and 84 dizygotic pairs) in the Twins Eye Study in Tasmania underwent an ophthalmic examination including retinal photography. Retinal vascular caliber was measured using a validated protocol. The majority of these twins were also in the Tasmanian Infant Health Study, which prospectively collected data on birth parameters and antenatal maternal factors. We conducted the main analysis using linear mixed models, accounting for birth set clustering. Both the within-pair (−9.73; 95% CI: −14.68 to −4.77 μm per 5-cm decrease in birth length) and between-pair associations (−7.15; 95% CI: −11.54 to −3.01) with retinal arteriolar caliber were significant and of similar magnitude (difference in effect,
P
=0.61), after adjusting for age, sex, maternal smoking, mean arterial blood pressure, and other confounders. These associations remained within dizygotic and monozygotic pairs. Analyses of head circumference and retinal arteriolar caliber were similar to those of birth length (within-pair regression coefficient: −2.41; 95% CI: −5.09 to 0.28; between-pair regression coefficient: −2.60; 95% CI: −5.00 to −0.19). For birth weight, only a between-pair association was evident (−7.28; 95% CI: −13.07 to −1.48). This study demonstrates a consistent association between smaller birth size and narrower retinal arterioles in twins. The independent effect of shorter birth length on retinal arteriolar caliber supports a role for twin-specific supply line factors affecting fetal growth on vascular structure.