bluuebunny/crossref_metadata_2025 huggingface dataset:
An XML-Based Model Representation for Model Management, Transformation and Exchange
Authors: Johansson Bjo¨rn , Larsson Jonas , Sethson Magnus , Krus Peter
Published: May 2008

Modeling and simulation in engineering design has traditionally been domain-specific and tool-centered. Due to limitations in computer speed and simulation software, only limited problems could be analyzed thus resulting in simulation within only one domain using one specific tool. When products become more complex and integrated, it is necessary to study the interactions between sub-systems from different domains. The domains could be e.g. mechanics, electronics or hydraulics. Such integrated analysis is difficult to undertake since the tools used in each domain have their own representation of the models, only focusing on the specific task for that tool. Less often is the tool providing a general base for representing models. In the paper, a model representation based on the eXtensible Markup Language, XML, is proposed as a bridge for transformation between different model representations. It is at the same time a model repository that many tools can make use of. The dynamic behavior can be specified both implicitly and explicitly enabling transformations to specific simulation tools or standalone simulators. The content of the XML-document is presented and it is discussed how transformations can be accomplished in a straightforward fashion using standard tools for XML. Furthermore, the importance of that the model can be developed and extended throughout the whole product development process is discussed. This requires an extensible, model-centric environment, where it is possible to access the model with more than one tool. The presented XML-document for simulation models is designed with such a model-centric environment in mind. The main purpose of this paper is to introduce the reader to the tools and standards that are useful in creating a flexible solution for product modeling. By using the proposed concept, models can be created and then be accessed by arbitrary tools and at any point in the design process.
Modeling in the Physical Domain: An Optimization-Based Approach
Authors: Ye Yong , Youcef-Toumi Kamal
Published: May 2008

With the increasing complexity of dynamic systems, model reduction has become an attractive research topic. A very useful type of reduced models is obtained by removing as many physical components as possible from the original model, known as model reduction in the physical domain. Many results have been achieved in this area during past decades. Nonetheless, the newest developments in engineering practice as well as in theoretical research have brought about further challenges and opportunities. This paper expands the scope of model reduction in physical domain, and proposes a criterion based on the H∞ norm of certain error model is proposed. The model reduction problem is then formulated as an optimization problem with bilinear matrix inequality (BMI) constraints, which can be solved with various processes. Several examples are presented to illustrate the use of the proposed model reduction scheme.
A Model Accuracy and Validation Algorithm
Authors: Sendur Polat , Stein Jeffrey L. , Peng Huei , Louca Loucas S.
Published: May 2008

Dynamic models of physical systems with physically meaningful states and parameters have become increasingly important, for design, control and even procurement decisions. The successful use of models in these contexts requires that the models be of sufficient quality. However, while algorithms have been developed to help formulate and integrate physical system models, as well as to generate minimum complexity physical system models, algorithms to assess the “quality” of dynamic system models have not been produced. This is true even if the attributes of model are limited to accuracy and validity. The objective of this paper is to introduce a new methodology that systematically quantifies the accuracy of a predicted system response and determines the validity of the physical system model used to predict the system response. The accuracy and validity of the model are evaluated using statistical properties of measured system response. The new algorithm is called Accuracy & Validation Algorithm for Simulation (AVASIM), and is a time-domain perspective comparing the model’s time trajectories at user-defined points of interest as well as over the entire simulation horizon. To illustrate AVASIM, the quality of a handling model of a DaimlerChrysler Grand Cherokee is compared to the measurements obtained from that vehicle subjected to known steering inputs. Results demonstrate that the accuracy and validity of the Grand Cherokee model can be systematically assessed using the proposed methodology, and, thus, AVASIM appears to be a powerful tool for assessing the quality of system models.
Optimization of Threshold Values for Estimators Based on Single-Bit Quantized Sensors Using Genetic Algorithms
Authors: Unnikrishnan Nishant , Mahajan Ajay , Mengoulis Antonios , Viswanathan R.
Published: May 2008

The paper considers the problem of signal parameter estimation using a collection of distributed sensors called a sensor pack. Each sensor quantizes its data to one-bit information and sends it to a fusion processor for the estimation of the parameter. Estimation of a constant signal in additive noise is considered. Estimators are formulated based on one-bit sensor data and their mean squared error (MSE) performances are evaluated through simulation studies. It is shown that selecting certain threshold values for quantizing the sensor outputs can lower the MSE. Genetic algorithms are used to find the optimal threshold values for the sensors. Results from this study show that robust estimation of parameter is possible by using a moderately large number of one-bit quantized sensor data. This work has significance in applications that demand high reliability in sensor networks in spite of sensor failures, limited sensor dynamic range, resolution, bandwidth for data transmission or even data storage.
Fundamental Evaluation of Thermal Crack Resistance for Wheel Fracture Prevention
Authors: Sakamoto Haruo
Published: May 2008

This paper presents a method for the thermal crack evaluation of railroad wheel materials and the results. The research investigated the basic thermal crack resistance as a low cycle fatigue behavior in terms of Δεt-Ni and da/dN-ΔK. In order to be able to evaluate such material characteristics in service by experimentation, reproducible conditions such as similar stress-strain, temperature rise, and damage morphology are required. The methods proposed in the past for high temperature low cycle fatigue or thermal shock such as Coffin’s and Manson’s methods do not provide the above conditions at the same time for thermal cracks in railroad wheels. The material design to avoid such thermal damages has not yet been established. Therefore, a simple brake tester with a special device for measuring radial deflection converted into strain was designed and manufactured. The relations of Δεt-Ni and da/dN-ΔK, which have not been clarified for thermal crack behavior in railroad wheels, were obtained for wheel materials by experiment using this new device. To predict the life of a wheel, one must know the real service conditions from field measurements. Once the histogram of the initial brake speed, intensity of brake application, and number of brakings from the initial speed is obtained, the histogram can be converted into the relation of strain range and number of cycles. The calculation of cycles for crack origination and propagation is possible based on the experimental results on Δεt-Ni and da/dN-ΔK. From the material data of fracture toughness and possible residual stress value in the field, the critical crack length for wheel fracture can be then estimated, and the life from the cycles to the critical length is estimated. This method will provide the appropriate maintenance schedule to prevent wheel fracture.
Joint Role of Industry, Technology and Society in Modal Shift
Authors: Latorre Robert
Published: May 2008

Over 150 years ago engineers dealt with the technological development of heavy industry and its organization to meet society needs. During the past 25 years the issue of reducing environmental impact from technology has opened new engineering challenges. One is the modal shift from trucks on roads to trucks being loaded on coastal ships. Industry, technology and society has created a number of possibilities for realizing the modal shift. The pressure of economics is forcing the industry to seek cost reduction while the technology of high speed marine transport is developing to the point where a number of high speed ships can be utilized. Finally the social concerns of the environment and air pollution is impacting the expansion of current truck operations. The presentation shows the modal shift offers both economic benefits as well as reduction of the environmental impact.
Manipulation of Bio-Particles in Microelectrode Structures by Means of Non-Uniform AC Electric Fields
Authors: Castellanos Antonio , Ramos Antonio , Gonza´lez Antonio , Morgan Hywel , Green Nicolas
Published: May 2008

Non-uniform ac electric fields induce movement of polarizable particles. This phenomenon, known as dielectrophoresis, is useful to manipulate bioparticles. High electric fields when used in bio-separation systems give rise to fluid motion, which in turn results in a viscous drag on the particle. These fields generate heat, leading to volume forces in the liquid. Gradients in conductivity and permittivity rise to electrothermal forces; gradients in mass density to buoyancy. Also non-uniform ac electric fields produce forces on the induced charges in the diffuse double layer on the electrodes, and the resulting steady fluid motion has been termed ac electroosmosis. The effects of Brownian motion and diffusion are also discussed in this context. The orders of magnitude of the various forces experienced by a submicrometre particle in a model electrode system are calculated. The results are compared with experiments and the relative influence of each type of force is described.
Integration of a Signal Processing and Control ASIC With the JPL Micro-Gyroscope
Authors: Chen Yen-Cheng , M’Closkey Robert , Tran Tuan , Blaes Brent
Published: May 2008

This paper describes the integration of a vibratory rate sensor—the JPL microgyro—with a special purpose control ASIC developed at UCLA. The digital ASIC has a flexible control architecture that can be customized for individual sensors. We describe this process for one sensor prototype and include experimental results demonstrating the efficacy of the ASIC.
Liquid Metal Stream Junction Defects in Aluminum Lost Foam Casting
Authors: Bakhtiyarov Sayavur I. , Overfelt Ruel A. , Suryawanshi Amit
Published: May 2008

The purpose of this work is to study fold defects in gravity and counter gravity lost foam casting processes, and to determine the process parameters which will improve the casting properties. The experiments are focused on the time and spatial dependent aspects of mold filling in frame shape styrofoam patterns.
Self-Calibrating Sensor for Measuring Density Through Stainless Steel Pipeline Wall
Authors: Greenwood Margaret S. , Bamberger Judith A.
Published: May 2008

An ultrasonic instrument to measure the density of a liquid or slurry [1,2] through the stainless steel (SS) pipeline wall is described. By using multiple reflections of the ultrasound within the SS wall, the acoustic impedance (defined as the product of the density of the liquid and the velocity of sound in the liquid) is determined. Thus, the wall is part of the measurement system. The density is obtained by coupling the acoustic impedance measurement with a velocity of sound measurement. Since methods for measuring the time-of-flight (TOF) are well known, the research presented here will focus on the measurement of the acoustic impedance. The self-calibrating feature is very important because the measurement of the acoustic impedance is independent of changes in the pulser voltage. The objective is to develop an ultrasonic sensor that (1) can be attached permanently to a pipeline wall, possibly as a spool piece inserted into the line and (2) can clamp onto an existing pipeline wall and be movable to another location. The self-calibrating feature is very important because the signal strength is sensitive to the pressure on the clamp-on sensor. A sensor for immersion into a tank could also be developed. A U.S. Patent application has been filed.
Coat Thickness in Wire-Coating Process With Corrugated Die
Authors: Huynh B. Phuoc
Published: May 2008

Effects of die wall corrugation on coat thickness t in the wire-coating process are investigated numerically, using non-isothermal viscous fluids of a Newtonian type as coating material and a finite element method. Corrugation is assumed to be in the form of sine waves near die exit. It can be seen that shorter wavelength or larger wave amplitude depresses t, whereas higher Nahme-Griffith number Na increases it; however, the changes in t are only very small. t is also depressed slightly when die wall’s exit angle θ is large and negative; but in general it is insensitive to variation in θ when this is small. That t is only slightly affected by Na and θ is in stark contrast to extrudate’s swelling behaviour in simple extrusion through annular dies under comparable conditions. Furthermore, wire speed does not affect t over the ranges of Na value considered here. One interesting aspect relating to isothermal smooth-wall situation is that the ratio t/ΔR, ΔR being annular gap size, is nearly constant and equal to 0.5, independent of wire radius ratio Rwire/Rdie. This constancy is in contrast to the variation in coat thickness that results from a pure drag flow in the annulus.
An Analytical Study of Pedestrian Headform Impacts Using a Dual Asymmetrical Triangle Function
Authors: Cheng Ching-Shan , Wang J. T.
Published: May 2008

Child headform and adult headform impacting the bonnet (hood) of a passenger vehicle are two of the four types of tests conducted by EuroNCAP to rate the pedestrian protection performance of new vehicles. The present work focuses on the dual-peak acceleration pulses of the headform often observed in the tests. A dual asymmetrical triangle function is chosen to model the pulse. Using the analytical function, the kinematical equations of the headform, and the explicit equations for calculating the maximum displacement, rebound time and Head Injury Criterion (HIC) value are derived. A parametric study is conducted to investigate how the wave shape affects the HIC value. Several important characteristics of the dual-peak pulses, including the headform rebound time and the maximum headform displacement, are identified. A spreadsheet tool has also been developed using the dual asymmetrical triangle function to relate the headform kinematics to the mechanical property of the bonnet.
Rare provisional entity: primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma in a young woman
Authors: Csomor J , Bognár Á , Benedek S , Sinkó J , Fekete S , Krenács L , Matolcsy A , Reiniger L
Published: May 2008

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma is a rare and provisional entity, characterised by cutaneous involvement and aggressive clinical behaviour. The case is here presented of a young woman with concurrent cutaneous and systemic involvement. Despite multi-agent chemotherapy, only partial remission could be achieved, and the patient died from therapy-resistant respiratory and circulatory failure. This case report is intended to add to the data collected on this rare entity, with only about 20 cases as yet described.
Adenomatoid tumour of the liver
Authors: Nagata S , Aishima S , Fukuzawa K , Takagi H , Yonemasu H , Iwashita Y , Kinoshita T , Wakasugi K
Published: May 2008

An unusual primary adenomatoid tumour arising in the normal liver is described. Hepatectomy was performed, and the patient is alive and free of disease 1 year postsurgery. Grossly, the tumour showed a haemorrhagic cut surface with numerous microcystic structures. Histological examination revealed cystic or angiomatoid spaces of various sizes lined by cuboidal, low-columnar, or flattened epithelioid cells with vacuolated cytoplasm and round to oval nuclei. The epithelioid cells were entirely supported by proliferated capillaries and arteries together with collagenous stroma. Immunohistochemical studies showed that the epithelioid cells were strongly positive for a broad spectrum of cytokeratins (AE1/AE3, CAM5.2, epithelial membrane antigen and cytokeratin 7) and mesothelial markers (calretinin, Wilms’ tumour 1 and D2-40). These cells were negative for Hep par-1, carcinoembryonic antigen, neural cell adhesion molecule, CD34, CD31 and HMB45. Atypically, abundant capillaries were observed; however, the cystic proliferation of epithelioid cells with vacuoles and immunohistochemical profile of the epithelioid element were consistent with hepatic adenomatoid tumour.
Loss of basal cell keratin 14 reflects increased risk of recurrence in surgically resected sinonasal inverted papilloma
Authors: Gunia S , Liebe D , Koch S
Published: May 2008

Aims:

To evaluate selected markers in terms of their possible relation to the development of recurrence in microsurgically resected sinonasal inverted papilloma (SIP) in order to advance understanding of the mechanisms pathogenetically involved, and to identify novel biomarkers for individual risk assessment in SIP.

Methods:

Retrospective computerised database analysis and thorough review of medical charts was performed in order to identify all patients with newly diagnosed SIP who underwent microinvasive endonasal surgery at the HELIOS Klinikum Bad Saarow and at the Klinikum Hoyerswerda (Germany) between 1985 and 2005, yielding a total of 73 patients with newly diagnosed SIP. Among these, 22 patients (30.1%) developed recurrence during follow-up. Recurrent SIP were also microsurgically resected. Therefore, archival paraffin-wax-embedded tissues comprising a total of 95 SIP were immunostained for a panel of selected antigens (Ki67/CK5/CK14/E-cadherin/CD56) functionally involved in cellular adhesion structures or in proliferative activity. Adjacent non-papillomatous sinonasal mucosa was available in all cases and served as normal controls.

Results:

Increased proliferative activity (Ki67) and loss of basal cell keratin 14 (CK14) expression were related to the development of recurrence in microsurgically resected SIP.

Conclusion:

These findings might advance understanding of the pathogenesis behind the development of recurrence in microsurgically resected SIP by focusing on so far neglected alterations of cell-matrix connections at the epithelial-stromal interface in SIP, and might hint at CK14 representing a possible novel biomarker for individual risk assessment in microsurgically resected SIP.
ON PRODUCTION OF DIRECT PHOTONS AND NEUTRAL PIONS IN RHIC EXPERIMENTS AT $\sqrt{s_{NN}}=200~{\rm GeV}$
Authors: GUPTAROY P. , SAU GOUTAM , BISWAS S. K. , BHATTACHARYYA S.
Published: May 2008

In continuation of our previous works, we attempt here to understand the nature of data on direct photon and neutral pion production in the latest RHIC experiments at [Formula: see text] for all the different interactions studied therein from the viewpoint of a nonstandard outlook and approach as described in Refs. 4 and 5 here. It is found that the proposed model could account for the data-sets with a fair degree of success.
ANOMALOUS SINGLE PRODUCTION OF THE FOURTH GENERATION CHARGED LEPTONS AT FUTURE ep COLLIDERS
Authors: ÇİFTÇİ A. K. , ÇİFTÇİ R. , DURAN YILDIZ H. , SULTANSOY S.
Published: May 2008

Possible single productions of the fourth standard model family charged leptons via anomalous interactions at the future ep colliders are studied. Signatures of such anomalous processes and backgrounds are discussed in detail.
DUALITY TRANSFORMATION OF NON-ABELIAN TENSOR GAUGE FIELDS
Authors: GUTTENBERG SEBASTIAN , SAVVIDY GEORGE
Published: May 2008

For non-Abelian tensor gauge fields, we found an alternative form of duality transformation which maps the Lagrangian forms into each other and has the property that the direct and the inverse transformations coincide.
Linkage Disequilibrium and Association Mapping
Authors: Weir B.S.
Published: May 2008

Linkage disequilibrium refers to the association between alleles at different loci. The standard definition applies to two alleles in the same gamete, and it can be regarded as the covariance of indicator variables for the states of those two alleles. The corresponding correlation coefficient ρ is the parameter that arises naturally in discussions of tests of association between markers and genetic diseases. A general treatment of association tests makes use of the additive and nonadditive components of variance for the disease gene. In almost all expressions that describe the behavior of association tests, additive variance components are modified by the squared correlation coefficient ρ 2 and the nonadditive variance components by ρ4, suggesting that nonadditive components have less influence than additive components on association tests.
Positive Selection in the Human Genome: From Genome Scans to Biological Significance
Authors: Kelley Joanna L. , Swanson Willie J.
Published: May 2008

Here we review the evidence for positive selection in the human genome and its role in human evolution and population differentiation. In recent years, there has been a dramatic increase in the use of genome-wide scans to identify adaptively evolving loci in the human genome. Attention is now turning to understanding the biological relevance and adaptive significance of the regions identified as being subject to recent positive selection. Examples of adaptively evolving loci are discussed, specifically LCT and FOXP2. Comprehensive studies of these loci also provide information about the functional relevance of the selected alleles. We discuss current studies examining the role of positive selection in shaping copy number variation and noncoding genomic regions and highlight challenges presented by the study of positive selection in the human genome.
Reliability, robustness, and reproducibility in mouse behavioral phenotyping: a cross-laboratory study
Authors: Mandillo Silvia , Tucci Valter , Hölter Sabine M. , Meziane Hamid , Banchaabouchi Mumna Al , Kallnik Magdalena , Lad Heena V. , Nolan Patrick M. , Ouagazzal Abdel-Mouttalib , Coghill Emma L. , Gale Karin , Golini Elisabetta , Jacquot Sylvie , Krezel Wojtek , Parker Andy , Riet Fabrice , Schneider Ilka , Marazziti Daniela , Auwerx Johan , Brown Steve D. M. , Chambon Pierre , Rosenthal Nadia , Tocchini-Valentini Glauco , Wurst Wolfgang
Published: May 2008

Establishing standard operating procedures (SOPs) as tools for the analysis of behavioral phenotypes is fundamental to mouse functional genomics. It is essential that the tests designed provide reliable measures of the process under investigation but most importantly that these are reproducible across both time and laboratories. For this reason, we devised and tested a set of SOPs to investigate mouse behavior. Five research centers were involved across France, Germany, Italy, and the UK in this study, as part of the EUMORPHIA program. All the procedures underwent a cross-validation experimental study to investigate the robustness of the designed protocols. Four inbred reference strains (C57BL/6J, C3HeB/FeJ, BALB/cByJ, 129S2/SvPas), reflecting their use as common background strains in mutagenesis programs, were analyzed to validate these tests. We demonstrate that the operating procedures employed, which includes open field, SHIRPA, grip-strength, rotarod, Y-maze, prepulse inhibition of acoustic startle response, and tail flick tests, generated reproducible results between laboratories for a number of the test output parameters. However, we also identified several uncontrolled variables that constitute confounding factors in behavioral phenotyping. The EUMORPHIA SOPs described here are an important start-point for the ongoing development of increasingly robust phenotyping platforms and their application in large-scale, multicentre mouse phenotyping programs.
HMGA2 Participates in Transformation in Human Lung Cancer
Authors: Di Cello Francescopaolo , Hillion Joelle , Hristov Alexandra , Wood Lisa J. , Mukherjee Mita , Schuldenfrei Andrew , Kowalski Jeanne , Bhattacharya Raka , Ashfaq Raheela , Resar Linda M.S.
Published: May 2008

Although previous studies have established a prominent role for HMGA1 (formerly HMG-I/Y) in aggressive human cancers, the role of HMGA2 (formerly HMGI-C) in malignant transformation has not been clearly defined. The HMGA gene family includes HMGA1, which encodes the HMGA1a and HMGA1b protein isoforms, and HMGA2, which encodes HMGA2. These chromatin-binding proteins function in transcriptional regulation and recent studies also suggest a role in cellular senescence. HMGA1 proteins also appear to participate in cell cycle regulation and malignant transformation, whereas HMGA2 has been implicated primarily in the pathogenesis of benign, mesenchymal tumors. Here, we show that overexpression of HMGA2 leads to a transformed phenotype in cultured lung cells derived from normal tissue. Conversely, inhibiting HMGA2 expression blocks the transformed phenotype in metastatic human non–small cell lung cancer cells. Moreover, we show that HMGA2 mRNA and protein are overexpressed in primary human lung cancers compared with normal tissue or indolent tumors. In addition, there is a statistically significant correlation between HMGA2 protein staining by immunohistochemical analysis and tumor grade (P < 0.001). Our results indicate that HMGA2 is an oncogene important in the pathogenesis of human lung cancer. Although additional studies with animal models are needed, these findings suggest that targeting HMGA2 could be therapeutically beneficial in lung cancer and other cancers characterized by increased HMGA2 expression. (Mol Cancer Res 2008;6(5):743–50)
Interferon Regulatory Factors IRF5 and IRF7 Inhibit Growth and Induce Senescence in Immortal Li-Fraumeni Fibroblasts
Authors: Li Qunfang , Tang Lin , Roberts Paul Christopher , Kraniak Janice M. , Fridman Aviva Levine , Kulaeva Olga I. , Tehrani Omid S. , Tainsky Michael A.
Published: May 2008

Cellular immortalization is one of the prerequisite steps in carcinogenesis. By gene expression profiling, we have found that genes in the interferon (IFN) pathway were dysregulated during the spontaneous cellular immortalization of fibroblasts from Li-Fraumeni syndrome (LFS) patients with germ-line mutations in p53. IFN signaling pathway genes were down-regulated by epigenetic silencing during immortalization, and some of these same IFN-regulated genes were activated during replicative senescence. Bisulfite sequencing of the promoter regions of two IFN regulatory transcription factors (IRF5 and IRF7) revealed that IRF7, but not IRF5, was epigenetically silenced by methylation of CpG islands in immortal LFS cells. The induction of IRF7 gene by IFNα in immortal LFS cells was potentiated by pretreatment with the demethylation agent 5-aza-2′-deoxycytidine. Overexpression of IRF5 and IRF7 revealed that they can act either alone or in tandem to activate other IFN-regulated genes. In addition, they serve to inhibit the proliferation rate and induce a senescence-related phenotype in immortal LFS cells. Furthermore, polyinosinic:polycytidylic acid treatment of the IRF-overexpressing cells showed a more rapid induction of several IFN-regulated genes. We conclude that the epigenetic inactivation of the IFN pathway plays a critical role in cellular immortalization, and the reactivation of IFN-regulated genes by transcription factors IRF5 and/or IRF7 is sufficient to induce cellular senescence. The IFN pathway may provide valuable molecular targets for therapeutic interventions at early stages of cancer development. (Mol Cancer Res 2008;6(5):770–84)
Transforming Growth Factor-β1, Transforming Growth Factor-β2, and Transforming Growth Factor-β3 Enhance Ovarian Cancer Metastatic Potential by Inducing a Smad3-Dependent Epithelial-to-Mesenchymal Transition
Authors: Do Thuy-Vy , Kubba Lena A. , Du Hongyan , Sturgis Charles D. , Woodruff Teresa K.
Published: May 2008

Transforming growth factor-β (TGF-β) is thought to play a role in the pathobiological progression of ovarian cancer because this peptide hormone is overexpressed in cancer tissue, plasma, and peritoneal fluid. In the current study, we investigated the role of the TGF-β/Smad3 pathway in ovarian cancer metastasis by regulation of an epithelial-to-mesenchymal transition. When cancer cells were cultured on plastic, TGF-β1, TGF-β2, and TGF-β3 induced pro–matrix metalloproteinase (MMP) secretion, loss of cell-cell junctions, down-regulation of E-cadherin, up-regulation of N-cadherin, and acquisition of a fibroblastoid phenotype, consistent with an epithelial-to-mesenchymal transition. Furthermore, Smad3 small interfering RNA transfection inhibited TGF-β–mediated changes to a fibroblastic morphology, but not MMP secretion. When cancer cells were cultured on a three-dimensional collagen matrix, TGF-β1, TGF-β2, and TGF-β3 stimulated both pro-MMP and active MMP secretion and invasion. Smad3 small interfering RNA transfection of cells cultured on a collagen matrix abrogated TGF-β–stimulated invasion and MMP secretion. Analysis of Smad3 nuclear expression in microarrays of serous benign tumors, borderline tumors, and cystadenocarcinoma revealed that Smad3 expression could be used to distinguish benign and borderline tumors from carcinoma (P = 0.006). Higher Smad3 expression also correlated with poor survival (P = 0.031). Furthermore, a direct relationship exists between Smad3 nuclear expression and expression of the mesenchymal marker N-cadherin in cancer patients (P = 0.0057). Collectively, these results implicate an important role for the TGF-β/Smad3 pathway in mediating ovarian oncogenesis by enhancing metastatic potential. (Mol Cancer Res 2008;6(5):695–705)
Inhibition of Histone Deacetylases Promotes Ubiquitin-Dependent Proteasomal Degradation of DNA Methyltransferase 1 in Human Breast Cancer Cells
Authors: Zhou Qun , Agoston Agoston T. , Atadja Peter , Nelson William G. , Davidson Nancy E.
Published: May 2008

Histone deacetylases (HDAC) play a critical role in chromatin modification and gene expression. Recent evidence indicates that HDACs can also regulate functions of nonhistone proteins by catalyzing the removal of acetylated lysine residues. Here, we show that the HDAC inhibitor LBH589 down-regulates DNA methyltransferase 1 (DNMT1) protein expression in the nucleus of human breast cancer cells. Cotreatment with the proteasomal inhibitor MG-132 abolishes the ability of LBH589 to reduce DNMT1, suggesting that the proteasomal pathway mediates DNMT1 degradation on HDAC inhibition. Deletion of the NH2-terminal 120 amino acids of DNMT1 diminishes LBH589-induced ubiquitination, indicating that this domain is essential for its proteasomal degradation. DNMT1 recruits the molecular chaperone heat shock protein 90 (Hsp90) to form a chaperone complex. Treatment with LBH589 induces hyperacetylation of Hsp90, thereby inhibiting the association of DNMT1 with Hsp90 and promoting ubiquitination of DNMT1. In addition, inactivation of HDAC1 activity by small interfering RNA and MS-275 is associated with Hsp90 acetylation in conjunction with reduction of DNMT1 protein expression. We conclude that the stability of DNMT1 is maintained in part through its association with Hsp90. Disruption of Hsp90 function by HDAC inhibition is a unique mechanism that mediates the ubiquitin-proteasome pathway for DNMT1 degradation. Our studies suggest a new role for HDAC1 and identify a novel mechanism of action for the HDAC inhibitors as down-regulators of DNMT1. (Mol Cancer Res 2008;6(5):873–83)
Gene Expression Changes in an Animal Melanoma Model Correlate with Aggressiveness of Human Melanoma Metastases
Authors: Xu Lei , Shen Steven S. , Hoshida Yujin , Subramanian Aravind , Ross Ken , Brunet Jean-Philippe , Wagner Stephan N. , Ramaswamy Sridhar , Mesirov Jill P. , Hynes Richard O.
Published: May 2008

Metastasis is the deadliest phase of cancer progression. Experimental models using immunodeficient mice have been used to gain insights into the mechanisms of metastasis. We report here the identification of a “metastasis aggressiveness gene expression signature” derived using human melanoma cells selected based on their metastatic potentials in a xenotransplant metastasis model. Comparison with expression data from human melanoma patients shows that this metastasis gene signature correlates with the aggressiveness of melanoma metastases in human patients. Many genes encoding secreted and membrane proteins are included in the signature, suggesting the importance of tumor-microenvironment interactions during metastasis. (Mol Cancer Res 2008;6(5):760–9)
Impairment of the DNA Repair and Growth Arrest Pathways by p53R2 Silencing Enhances DNA Damage–Induced Apoptosis in a p53-Dependent Manner in Prostate Cancer Cells
Authors: Devlin Hong-Lin , Mack Phillip C. , Burich Rebekah A. , Gumerlock Paul H. , Kung Hsing-Jien , Mudryj Maria , deVere White Ralph W.
Published: May 2008

p53R2 is a p53-inducible ribonucleotide reductase that contributes to DNA repair by supplying deoxynucleotide triphosphate pools in response to DNA damage. In this study, we found that p53R2 was overexpressed in prostate tumor cell lines compared with immortalized prostatic epithelial cells and that the protein was induced upon DNA damage. We investigated the effects of p53R2 silencing on DNA damage in LNCaP cells (wild-type p53). Silencing p53R2 potentiated the apoptotic effects of ionizing radiation and doxorubicin treatment as shown by increased sub-G1 content and decreased colony formation. This sensitizing effect was specific to DNA-damaging agents. Comet assay and γ-H2AX phosphorylation status showed that the decreased p53R2 levels inhibited DNA repair. Silencing p53R2 also reduced the levels of p21WAF1/CIP1 at the posttranscriptional level, suggesting links between the p53-dependent DNA repair and cell cycle arrest pathways. Using LNCaP sublines stably expressing dominant-negative mutant p53, we found that the sensitizing effect of p53R2 silencing is mediated by p53-dependent apoptosis pathways. In the LNCaP sublines (R273H, R248W, and G245S) that have defects in inducing p53-dependent apoptosis, p53R2 silencing did not potentiate DNA damage–induced apoptosis, whereas p53R2 silencing was effective in a LNCaP subline (P151S) which retains the ability to induce p53-dependent apoptosis. This study shows that p53R2 is a potential therapeutic target that could be used to enhance the effectiveness of ionizing radiation or DNA-damaging chemotherapy in a subset of patients with prostate cancer. (Mol Cancer Res 2008;6(5):808–18)
Growth Factor Regulation of Estrogen Receptor Coregulator PELP1 Functions via Protein Kinase A Pathway
Authors: Nagpal Jatin K. , Nair Sujit , Chakravarty Dimple , Rajhans Rajib , Pothana Saikumar , Brann Darrell W. , Tekmal Rajeshwar Rao , Vadlamudi Ratna K.
Published: May 2008

PELP1 (proline-rich, glutamic acid–rich, and leucine-rich protein-1) is a potential proto-oncogene that functions as a coregulator of estrogen receptor (ER), and its expression is deregulated during breast cancer progression. Emerging evidence suggests growth factor signaling crosstalk with ER as one possible mechanism by which breast tumors acquire resistance to therapy. In this study, we examined mechanisms by which growth factors modulate PELP1 functions, leading to activation of ER. Using in vivo labeling assays, we have found that growth factors promote phosphorylation of PELP1. Utilizing a panel of substrate-specific phosphorylated antibodies, we discovered that growth factor stimulation promotes phosphorylation of PELP1 that is recognized by a protein kinase A (PKA) substrate–specific antibody. Accordingly, growth factor–mediated PELP1 phosphorylation was effectively blocked by PKA-specific inhibitor H89. Utilizing purified PKA enzyme and in vitro kinase assays, we obtained evidence of direct PELP1 phosphorylation by PKA. Using deletion and mutational analysis, we identified PELP1 domains that are phosphorylated by PKA. Interestingly, site-directed mutagenesis of the putative PKA site in PELP1 compromised growth factor–induced activation and subnuclear localization of PELP1 and also affected PELP1-mediated transactivation function. Utilizing MCF-7 cells expressing a PELP1 mutant that cannot be phosphorylated by PKA, we provide mechanistic insights by which growth factor signaling regulates ER transactivation in a PELP1-dependent manner. Collectively, these findings suggest that growth factor signals promote phosphorylation of ER coactivator PELP1 via PKA pathway, and such modification may have functional implications in breast tumors with deregulated growth factor signaling. (Mol Cancer Res 2008;6(5):851–61)
TLS-ERG Leukemia Fusion Protein Deregulates Cyclin-Dependent Kinase 1 and Blocks Terminal Differentiation of Myeloid Progenitor Cells
Authors: Pan Jing , Zou Junhui , Wu Daniel Y. , Roberson Rachael S. , Hennings Leah J. , Ma Xiaoyun , Yared Marwan , Blackburn Michael L. , Chansky Howard A. , Yang Liu
Published: May 2008

TLS-ERG fusion protein is derived from the t(16;21) translocation found in human myeloid leukemia. Here, we show that retroviral transduction of TLS-ERG confers a growth advantage to L-G myeloid progenitor cells and blocks terminal differentiation. We found that the level of cyclin-dependent kinase 1 (Cdk1) protein was significantly decreased in controls but unchanged in TLS-ERG–expressing cells after granulocyte colony-stimulating factor treatment or interleukin-3 withdrawal. Injection of TLS-ERG–expressing L-G cells induced rapid development of a leukemia-like disease in syngeneic mice. Through site-directed mutagenesis, we showed that transformation and deregulation of Cdk1 by TLS-ERG require an intact ets DNA-binding domain within the fusion protein. Interestingly, treatment of TLS-ERG–expressing L-G cells with 5-aza-2′-deoxycytidine (Decitabine) or trichostatin A resulted in down-regulation of Cdk1 and induction of terminal differentiation. To investigate whether Cdk1 deregulation is indeed responsible for transformation by TLS-ERG, we constructed lentiviral vectors for delivery of Cdk1 mutants and small interfering RNA (siRNA). Both dominant-negative inhibition and siRNA knockdown of Cdk1 were able to restore the ability of TLS-ERG–expressing L-G cells to undergo terminal differentiation. In addition, siRNA knockdown of Cdk1 in YNH-1 cells derived from a t(16;21) acute myelogenous leukemia patient also resulted in terminal differentiation. As restoration of terminal myeloid differentiation to TLS-ERG cells is dependent on cell cycle arrest, our findings suggest an important role for Cdk1 in cellular transformation and may be useful in the search for new treatments of TLS-ERG–associated myeloid leukemia. (Mol Cancer Res 2008;6(5):862–72)
A Functional Screen Identifies miR-34a as a Candidate Neuroblastoma Tumor Suppressor Gene
Authors: Cole Kristina A. , Attiyeh Edward F. , Mosse Yael P. , Laquaglia Michael J. , Diskin Sharon J. , Brodeur Garrett M. , Maris John M.
Published: May 2008

MicroRNAs are small noncoding RNAs that have critical roles in regulating a number of cellular functions through transcriptional silencing. They have been implicated as oncogenes and tumor suppressor genes (oncomirs) in several human neoplasms. We used an integrated genomics and functional screening strategy to identify potential oncomirs in the pediatric neoplasm neuroblastoma. We first identified microRNAs that map within chromosomal regions that we and others have defined as frequently deleted (1p36, 3p22, and 11q23-24) or gained (17q23) in high-risk neuroblastoma. We then transiently transfected microRNA precursor mimics or inhibitors into a panel of six neuroblastoma cell lines that we characterized for these genomic aberrations. The majority of transfections showed no phenotypic effect, but the miR-34a (1p36) and miR-34c (11q23) mimics showed dramatic growth inhibition in cell lines with 1p36 hemizygous deletion. In contrast, there was no growth inhibition by these mimics in cell lines without 1p36 deletions. Quantitative reverse transcription-PCR showed a perfect correlation of absent miR-34a expression in cell lines with a 1p36 aberration and phenotypic effect after mimetic add-back. Expression of miR-34a was also decreased in primary tumors (n = 54) with 1p36 deletion (P = 0.009), but no mutations were discovered in resequencing of the miR-34a locus in 30 neuroblastoma cell lines. Flow cytometric time series analyses showed that the likely mechanism of miR-34a growth inhibition is through cell cycle arrest followed by apoptosis. BCL2 and MYCN were identified as miR-34a targets and likely mediators of the tumor suppressor phenotypic effect. These data support miR-34a as a tumor suppressor gene in human neuroblastoma. (Mol Cancer Res 2008;6(5):735–42)
The Biphasic Role of the Hypoxia-Inducible Factor Prolyl-4-Hydroxylase, PHD2, in Modulating Tumor-Forming Potential
Authors: Lee KangAe , Lynd Jeremy D. , O'Reilly Sandra , Kiupel Matti , McCormick J. Justin , LaPres John J.
Published: May 2008

Hypoxia is a common feature of solid tumors. The cellular response to hypoxic stress is controlled by a family of prolyl hydroxylases (PHD) and the transcription factor hypoxia-inducible factor 1 (HIF1). To investigate the relationship between PHD and HIF1 activity and cellular transformation, we characterized the expression levels of PHD isoforms across a lineage of cell strains with varying transformed characteristics. We found that PHD2 is the primary functional isoform in these cells and its levels are inversely correlated to tumor-forming potential. When PHD2 levels were altered with RNA interference in nontumorigenic fibroblasts, we found that small decreases can lead to malignant transformation, whereas severe decreases do not. Consistent with these results, direct inhibition of PHD2 was also shown to influence tumor-forming potential. Furthermore, we found that overexpression of PHD2 in malignant fibroblasts leads to loss of the tumorigenic phenotype. These changes correlated with HIF1α activity, glycolytic rates, vascular endothelial growth factor expression, and the ability to grow under hypoxic stress. These findings support a biphasic model for the relationship between PHD2 activity and malignant transformation. (Mol Cancer Res 2008;6(5):829–42)
Zebrafish as a Cancer Model
Authors: Feitsma Harma , Cuppen Edwin
Published: May 2008

The zebrafish has developed into an important model organism for biomedical research over the last decades. Although the main focus of zebrafish research has traditionally been on developmental biology, keeping and observing zebrafish in the lab led to the identification of diseases similar to humans, such as cancer, which subsequently became a subject for study. As a result, about 50 articles have been published since 2000 in which zebrafish were used as a cancer model. Strategies used include carcinogenic treatments, transplantation of mammalian cancer cells, forward genetic screens for proliferation or genomic instability, reverse genetic target-selected mutagenesis to inactivate known tumor suppressor genes, and the generation of transgenics to express human oncogenes. Zebrafish have been found to develop almost any tumor type known from human, with similar morphology and, according to gene expression array studies, comparable signaling pathways. However, tumor incidences are relatively low, albeit highly comparable between different mutants, and tumors develop late in life. In addition, tumor spectra are sometimes different when compared with mice and humans. Nevertheless, the zebrafish model has created its own niche in cancer research, complementing existing models with its specific experimental advantages and characteristics. Examples of these are imaging of tumor progression in living fish by fluorescence, treatment with chemical compounds, and screening possibilities not only for chemical modifiers but also for genetic enhancers and suppressors. This review aims to provide a comprehensive overview of the state of the art of zebrafish as a model in cancer research. (Mol Cancer Res 2008;6(5):685–94)
Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas
Authors: Brantley Emily C. , Benveniste Etty N.
Published: May 2008

Glioblastoma is the most common and severe primary brain tumor in adults. Its aggressive and infiltrative nature renders the current therapeutics of surgical resection, radiation, and chemotherapy relatively ineffective. Accordingly, recent research has focused on the elucidation of various signal transduction pathways in glioblastoma, particularly aberrant activation. This review focuses on the signal transducer and activator of transcription-3 (STAT-3) signal transduction pathway in the context of this devastating tumor. STAT-3 is aberrantly activated in human glioblastoma tissues, and this activation is implicated in controlling critical cellular events thought to be involved in gliomagenesis, such as cell cycle progression, apoptosis, angiogenesis, and immune evasion. There are no reports of gain-of-function mutations in glioblastoma; rather, the activation of STAT-3 is thought to be a consequence of either dysregulation of upstream kinases or loss of endogenous inhibitors. This review provides detailed insight into the multiple mechanisms of STAT-3 activation in glioblastoma, as well as describing endogenous and chemical inhibitors of this pathway and their clinical significance. In glioblastoma, STAT-3 acts a molecular hub to link extracellular signals to transcriptional control of proliferation, cell cycle progression, and immune evasion. Because STAT-3 plays this central role in glioblastoma signal transduction, it has significant potential as a therapeutic target. (Mol Cancer Res 2008;6(5):675–84)
The Fibroblast Growth Factor–Inducible 14 Receptor Is Highly Expressed in HER2-Positive Breast Tumors and Regulates Breast Cancer Cell Invasive Capacity
Authors: Willis Amanda L. , Tran Nhan L. , Chatigny Julie M. , Charlton Nichole , Vu Hong , Brown Sharron A.N. , Black Michael A. , McDonough Wendy S. , Fortin Shannon P. , Niska Joshua R. , Winkles Jeffrey A. , Cunliffe Heather E.
Published: May 2008

Genomic characterization is beginning to define a molecular taxonomy for breast cancer; however, the molecular basis of invasion and metastasis remains poorly understood. We report a pivotal role for the fibroblast growth factor–inducible 14 (Fn14) receptor in this process. We examined whether Fn14 and its ligand tumor necrosis factor–like weak inducer of apoptosis (TWEAK) were expressed in breast tumors and whether deregulation of Fn14 levels affected malignant behavior of breast cancer cell lines. Analysis of TWEAK and Fn14 in publicly available gene expression data indicated that high Fn14 expression levels significantly correlated with several poor prognostic indicators (P < 0.05). Fn14 expression was highest in the HER2-positive/estrogen receptor–negative (HER2+/ER−) intrinsic subtype (P = 0.0008). An association between Fn14 and HER2 expression in breast tumors was confirmed by immunohistochemistry. Fn14 levels were elevated in invasive, ER− breast cancer cell lines. Overexpression of Fn14 in weakly invasive MCF7 and T47D cells resulted in a marked induction of invasion and activation of nuclear factor-κB (NF-κB) signaling. Ectopic expression of Fn14tCT, a Fn14 deletion mutant that cannot activate NF-κB signaling, was not able to induce invasion. Moreover, ectopic expression of Fn14tCT in highly invasive MDA-MB-231 cells reduced their invasive capability. RNA interference–mediated inhibition of Fn14 expression in both MDA-MB-231 and MDA-MB-436 cells reduced invasion. Expression profiling of the Fn14-depleted cells revealed deregulation of NF-κB activity. Our findings support a role for Fn14-mediated NF-κB pathway activation in breast tumor invasion and metastasis. (Mol Cancer Res 2008;6(5):725–34)