bluuebunny/crossref_metadata_2025 huggingface dataset:
ACTIVITY MINING: FROM ACTIVITIES TO ACTIONS
Authors: CAO LONGBING , ZHAO YANCHANG , ZHANG CHENGQI , ZHANG HUAIFENG
Published: June 2008

Activity data accumulated in real life, such as terrorist activities and governmental customer contacts, present special structural and semantic complexities. Activity data may lead to or be associated with significant business impacts, and result in important actions and decision making leading to business advantage. For instance, a series of terrorist activities may trigger a disaster to society, and large amounts of fraudulent activities in social security programs may result in huge government customer debt. Uncovering these activities or activity sequences can greatly evidence and/or enhance corresponding actions in business decisions. However, mining such data challenges the existing KDD research in aspects such as unbalanced data distribution and impact-targeted pattern mining. This paper investigates the characteristics and challenges of activity data, and the methodologies and tasks of activity mining based on case-study experience in the area of social security. Activity mining aims to discover high impact activity patterns in huge volumes of unbalanced activity transactions. Activity patterns identified can be used to prevent disastrous events or improve business decision making and processes. We illustrate the above issues and prospects in mining governmental customer contacts data to recover customer debt.
ROUGH SET-BASED DECISION TREE USING A CORE ATTRIBUTE
Authors: HAN SANG-WOOK , KIM JAE-YEARN
Published: June 2008

Decision trees are widely used in machine learning and artificial intelligence. In this paper, we extend previous research and present a new decision tree classification algorithm that uses a rough set theory to produce classification rules. Our algorithm is based on core attributes and on comparing the values of attributes between objects. Our experiments compared the performance of the Iterative Dichotomiser 3 (ID3) algorithm, C4.5, and the proposed decision tree algorithm to demonstrate its accuracy and ability to simplify rules.
FALSE FINANCIAL STATEMENTS: CHARACTERISTICS OF CHINA'S LISTED COMPANIES AND CART DETECTING APPROACH
Authors: BAI BELINNA , YEN JEROME , YANG XIAOGUANG
Published: June 2008

False Financial Statements (FFS) have long been a serious problem in China and other Asian countries, which significantly dampen the confidence of the investors. Regardless of listed companies or non-listed companies, the percentage of financial statements that contained false information is quite high, which is one of the major reasons why China stock markets moved in the opposite direction towards its wonderful economic growth over the past few years. The objective of this research is to introduce one statistical technique — Classification and Regression Tree (CART), to identify and predict the impacts of FFS. We survey financial statements manipulation tricks, FFS indicators and FFS detection techniques from both China and international perspective, and further look into ten listed companies with known FFS history in China; combining these findings, we propose key indicators to work with CART.

Our analysis includes 24 false financial reports, and 124 non-false financial reports. We use CART to develop two FFS detecting models: CART without industry benchmark and CART with industry benchmark. For supporting comparison, we also build a Logit regression which is a commonly used technique in FFS detecting. We find that CART is effective in distinguishing FFS from non-FFS. Both CART models achieve better accuracy in identifying fraud cases and making predictions than Logit regression does, and CART with industry benchmark is slightly better than CART without benchmark, but it does not always have superior performance. Our CART model also tries to capture the indicators and their combinations that could reflect firms with high possibility of FFS in China.
PRICING FOR END-TO-END ASSURED BANDWIDTH SERVICES
Authors: GUPTA APARNA , ZHANG LINGYI
Published: June 2008

The Internet today mostly offers a simple best-effort mode of service. The capabilities of the Internet will be significantly enhanced if it supports better QoS modes, especially when QoS is provided for end-to-end services. This enhancement requires both technological development and economic mechanisms to support better QoS service modes. In this article, we study a Multi-ISP Overlay Provider's (MOP's) pricing problem for delivering end-to-end services with expected bandwidth assurance. A categorization based pricing scheme is developed, where end-to-end bandwidth services are classified based on the provider's efforts in delivering the services. A nonlinear pricing based model is constructed that interacts with network management infrastructure, responds to customer demand and captures the MOP's contractual relationships with Internet Service Provider (ISP) networks used for creating the MOP's services.
WEB FARMING WITH CLICKSTREAM
Authors: HU JIA , ZHONG NING
Published: June 2008

In a commercial website or portal, Web information fusion is usually from the following two approaches, one is to integrate the Web content, structure, and usage data for surfing behavior analysis; the other is to integrate Web usage data with traditional customer, product, and transaction data for purchasing behavior analysis. In this paper, we propose a unified model based on Web farming technology for collecting clickstream logs in the whole user interaction process. We emphasize that collecting clickstream logs at the application layer will help to seamlessly integrate Web usage data with other customer-related data sources.

In this paper, we extend the Web log standard to modeling clickstream format and Web mining to Web farming from passively collecting data and analyzing the customer behavior to actively influence the customer's decision making. The proposed model can be developed as a common plugin for most existing commercial websites and portals.
Biology of trans-Translation
Authors: Keiler Kenneth C.
Published: June 2008

The trans-translation mechanism is a key component of multiple quality control pathways in bacteria that ensure proteins are synthesized with high fidelity in spite of challenges such as transcription errors, mRNA damage, and translational frameshifting. trans-Translation is performed by a ribonucleoprotein complex composed of tmRNA, a specialized RNA with properties of both a tRNA and an mRNA, and the small protein SmpB. tmRNA-SmpB interacts with translational complexes stalled at the 3′ end of an mRNA to release the stalled ribosomes and target the nascent polypeptides and mRNAs for degradation. In addition to quality control pathways, some genetic regulatory circuits use trans-translation to control gene expression. Diverse bacteria require trans-translation when they execute large changes in their genetic programs, including responding to stress, pathogenesis, and differentiation.
Sunlight‐Initiated Photochemistry: Excited Vibrational States of Atmospheric Chromophores
Authors: Vaida Veronica , Feierabend Karl J. , Rontu Nabilah , Takahashi Kaito
Published: June 2008

Atmospheric chemical reactions are often initiated by ultraviolet (UV) solar radiation since absorption in that wavelength range coincides to typical chemical bond energies. In this review, we present an alternative process by which chemical reactions occur with the excitation of vibrational levels in the ground electronic state by red solar photons. We focus on the O–H vibrational manifold which can be an atmospheric chromophore for driving vibrationally mediated overtone‐induced chemical reactions. Experimental and theoretical O–H intensities of several carboxylic acids, alcohols, and peroxides are presented. The importance of combination bands in spectra at chemically relevant energies is examined in the context of atmospheric photochemistry. Candidate systems for overtone‐initiated chemistry are provided, and their lowest energy barrier for reaction and the minimum quanta of O–H stretch required for reaction are calculated. We conclude with a discussion of the major pathways available for overtone‐induced reactions in the atmosphere.
Lipoperoxidation and Protein Oxidative Damage Exhibit Different Kinetics During Septic Shock
Authors: Andresen Max , Regueira Tomas , Bruhn Alejandro , Perez Druso , Strobel Pablo , Dougnac Alberto , Marshall Guillermo , Leighton Federico
Published: June 2008

Septic shock (SS)‐related multiorgan dysfunction has been associated with oxidative damage, but little is known about the temporal damage profile and its relationship to severity. The present work investigated prospectively 21 SS patients. Blood samples were obtained at diagnosis, 24, 72 hours, day 7, and at 3 months. At admission, thiobarbituric acid reactive substances (TBARSs), plasma protein carbonyls, plasma protein methionine sulfoxide (MS), ferric/reducing antioxidant power (FRAP), total red blood cell glutathione (RBCG), uric acid (UA), and bilirrubin levels were increased
(P < .05). Total radical—trapping antioxidant potential (TRAP) and vitamin‐E were similar to controls, and vitamin‐C was decreased (P < .05). During evolution, TBARS and RBCG increased (P < .001), vitamin‐E levels remained stable, whereas plasma protein carbonyls and MS, TRAP, vitamin‐C, reduced glutathione, and UA levels decreased
(P < .006). After 3 months, plasma protein carbonyls and MS persisted elevated. More severe patients exhibited higher TBARS, TRAP, FRAP, vitamin‐C, UA, and bilirrubin levels. Our results suggest early and persistent oxidative stress during septic shock and a correlation between increasing levels of lipoperoxidation and sepsis severity.
Photocatalyzed Degradation of a Pesticide Derivative Glyphosate in Aqueous Suspensions of Titanium Dioxide
Authors: Muneer Mohammad , Boxall Colin
Published: June 2008

The photocatalytic degradation of a herbicide derivative, glyphosate [(N‐phosphonomethyl) glycine] has been investigated in aqueous suspensions of titanium dioxide at different pH values. This compound was found to degrade more efficiently under alkaline pH, where no adsorption takes place on the surface of the catalyst in the dark. The main degradation route involves the cleavage of the P–C bond giving rise to sarcosine and glycine as the intermediate products formed during the photooxidation process.
Strengths and Pitfalls of Meta-Analysis Reports in Vesicoureteral Reflux
Authors: Afshar K. , MacNeily A. E.
Published: June 2008

There are many ongoing controversies surrounding vesicoureteral reflux (VUR). These include variable aspects of this common congenital anomaly. Lack of evidence-based recommendations has prolonged the debate. Systematic reviews (SRs) and meta-analysis (MA) are considered high-level evidence. The purpose of this review article is to summarize and critically appraise the available SR/MA pertaining to VUR. We also discuss the strength and pitfalls of SR/MA in general. A thorough literature search identified 9 SRs/MAs relevant to VUR. Both authors critically reviewed these articles for contents and methodological issues. There are many concerns about the quality of the studies included in these SRs. Clinical heterogeneity stemming from different patient selection criteria, interventions, and outcome definitions is a major issue. In spite of major advances in understanding different aspects of VUR in the last few decades, there is a paucity of randomized controlled trials in this field.
An Autonomic Nervous System Model Applied to the Analysis of Orthostatic Tests
Authors: Le Rolle Virginie , Hernández Alfredo I. , Richard Pierre-Yves , Carrault Guy
Published: June 2008

One of the clinical examinations performed to evaluate the autonomic nervous system (ANS) activity is the tilt test, which consists in studying the cardiovascular response to the change of a patient′s position from a supine to a head‐up position. The analysis of heart rate variability signals during tilt tests has been shown to be useful for risk stratification and diagnosis on different pathologies. However, the interpretation of such signals is a difficult task. The application of physiological models to assist the interpretation of these data has already been proposed in the literature, but this requires, as a previous step, the identification of patient‐specific model parameters. In this paper, a model‐based approach is proposed to reproduce individual heart rate signals acquired during tilt tests. A new physiological model adapted to this problem and coupling the ANS, the cardiovascular system (CVS), and global ventricular mechanics is presented. Evolutionary algorithms are used for the identification of patient‐specific parameters in order to reproduce heart rate signals obtained during tilt tests performed on eight healthy subjects and eight diabetic patients. The proposed approach is able to reproduce the main components of the observed heart rate signals and represents a first step toward a model‐based interpretation of these signals.
Extending the Root‐Locus Method to Fractional‐Order Systems
Authors: Merrikh-Bayat Farshad , Afshar Mahdi
Published: June 2008

The well‐known root‐locus method is developed for special subset of linear time‐invariant systems known as fractional‐order systems. Transfer functions of these systems are rational functions with polynomials of rational powers of the Laplace variable s. Such systems are defined on a Riemann surface because of their multivalued nature. A set of rules for plotting the root loci on the first Riemann sheet is presented. The important features of the classical root‐locus method such as asymptotes, roots condition on the real axis, and breakaway points are extended to fractional case. It is also shown that the proposed method can assess the closed‐loop stability of fractional‐order systems in the presence of a varying gain in the loop. Three illustrative examples are presented to confirm the effectiveness of the proposed algorithm.
Subordination and Superordination Results for a Class of Analytic Multivalent Functions
Authors: Goyal S. P. , Goswami Pranay , Silverman H.
Published: June 2008

We derive subordination and superordination results for a family of
normalized analytic functions in the open unit disk defined by integral operators. We
apply this to obtain sandwich results and generalizations of some known results.
Enhancement of Neocortical-Medial Temporal EEG Correlations during Non-REM Sleep
Authors: Axmacher Nikolai , Helmstaedter Christoph , Elger Christian E. , Fell Juergen
Published: June 2008

Interregional interactions of oscillatory activity are crucial for the integrated processing of multiple brain regions. However, while the EEG in virtually all brain structures passes through substantial modifications during sleep, it is still an open question whether interactions between neocortical and medial temporal EEG oscillations also depend on the state of alertness. Several previous studies in animals and humans suggest that hippocampal-neocortical interactions crucially depend on the state of alertness (i.e., waking state or sleep). Here, we analyzed scalp and intracranial EEG recordings during sleep and waking state in epilepsy patients undergoing presurgical evaluation. We found that the amplitudes of oscillations within the medial temporal lobe and the neocortex were more closely correlated during sleep, in particular during non-REM sleep, than during waking state. Possibly, the encoding of novel sensory inputs, which mainly occurs during waking state, requires that medial temporal dynamics are rather independent from neocortical dynamics, while the consolidation of memories during sleep may demand closer interactions between MTL and neocortex.
Peroxisome Proliferators‐Activated Receptor (PPAR) Modulators and Metabolic Disorders
Authors: Cho Min-Chul , Lee Kyoung , Paik Sang-Gi , Yoon Do-Young
Published: June 2008

Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator‐activated receptor (PPAR), which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (α,γ, andσ) are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators.
Structural Development Studies of Subtype‐Selective Ligands for Peroxisome Proliferator‐Activated Receptors (PPARs) Based on the 3,4‐Disubstituted Phenylpropanoic Acid Scaffold as a Versatile Template
Authors: Miyachi Hiroyuki , Hashimoto Yuichi
Published: June 2008

Improvements in our understanding of the functions of the nuclear receptor peroxisome proliferator‐activated receptor (PPAR) subtypes as pleiotropic regulators of biological responses, including lipid, lipoprotein, glucose homeostasis, inflammation, differentiation and proliferation of various cancer cells, and memory, have provided an opportunity to develop novel PPAR ligands with characteristic subtype selectivity. Such ligands are not only chemical tools to investigate the functions of PPARs, but also candidates for the treatment of PPAR‐mediated diseases, including metabolic syndrome, inflammation, dementia, and cancer. This minireview summarizes our work on the design, synthesis, and pharmacological evaluation of subtype‐selective PPAR agonists based on the use of 3,4‐disubstituted phenylpropanoic acid as a versatile template.
Field Effect on Crystal Phase of Silicon in Si/CeO2/SiO2 Structure
Authors: Milovzorov Dmitry E.
Published: June 2008

The structural, optical, and conductivity properties of silicon film deposited on cerium dioxide buffer layer were studied. The electronic structure of system consists of various defect levels inside band gap. The temperature spatial distribution plays a great role in silicon crystallization. The field destruction of crystal phase and its restoration, after annealing, were investigated.
Sensitive Label‐Free Biomolecular Detection Using Thin Silicon Waveguides
Authors: Densmore A. , Xu D.-X. , Janz S. , Waldron P. , Lapointe J. , Mischki T. , Lopinski G. , Delâge A. , Schmid J. H. , Cheben P.
Published: June 2008

We review our work developing optical waveguide‐based evanescent field sensors for the label‐free, specific detection of biological molecules. Using high‐index‐contrast silicon photonic wire waveguides of submicrometer dimension, we demonstrate ultracompact and highly sensitive molecular sensors compatible with commercial spotting apparatus and microfluidic‐based analyte delivery systems. We show that silicon photonic wire waveguides support optical modes with strong evanescent field at the waveguide surface, leading to strong interaction with surface bound molecules for sensitive response. Furthermore, we present new sensor geometries benefiting from the very small bend radii achievable with these high‐index‐contrast waveguides to extend the sensing path length, while maintaining compact size. We experimentally demonstrate the sensor performance by monitoring the adsorption of protein molecules on the waveguide surface and by tracking small refractive index changes of bulk solutions.
Versatile Bottom‐Up Approach to Nanostructured Functional Materials for Optoelectronic Applications
Authors: Macchi Giorgio , Meinardi Francesco , Valsesia Patrizia , Tubino Riccardo
Published: June 2008

A versatile strategy to load ordered mesoporous silica‐based materials with functional molecular building blocks in order to obtain host‐guest systems exhibiting specific functions is described. Optical microscope examination of the obtained material confirms that the addition of a chromophoric moiety to the reaction mixture is not detrimental in achieving the desired macroscopic morphology of the silica particles. A micro‐photoluminescence investigation of the obtained material gave strong evidence that both surfactant micelles and the porous oxide matrix preserve the spectral features of the included molecular species in a nonconventional chemical environment.
Collimated Magnetron Sputter Deposition for Mirror Coatings
Authors: Vickery Anette , Jensen Carsten P. , Christensen Finn E. , Steenstrup Mads Peter , Schønfeldt Troels
Published: June 2008

At the Danish National Space Center (DNSC), a planar magnetron sputtering chamber has been established as a research and production coating facility for curved X‐ray mirrors for hard X‐ray optics for astronomical X‐ray telescopes. In the following, we present experimental evidence that a collimation of the sputtered particles is an efficient way to suppress the interfacial roughness of the produced multilayer. We present two different types of collimation optimized for the production of low roughness curved mirrors and flat mirrors, respectively.
Matrix Metalloproteinase 9 Is a Mediator of Epidermal Growth Factor–Dependent E-Cadherin Loss in Ovarian Carcinoma Cells
Authors: Cowden Dahl Karen D. , Symowicz Jaime , Ning Yan , Gutierrez Elisa , Fishman David A. , Adley Brian P. , Stack M. Sharon , Hudson Laurie G.
Published: June 2008

Epidermal growth factor (EGF) receptor (EGFR) is frequently elevated in epithelial ovarian cancer, and E-cadherin expression is often reduced in advanced disease. In this study, we investigated a mechanism by which EGFR activation promotes disruption of adherens junctions through induction of matrix metalloproteinase 9 (MMP-9). We show that EGFR activation down-modulates E-cadherin, and broad spectrum MMP inhibition ameliorates EGF-stimulated junctional disruption and loss of E-cadherin protein. MMP-9 involvement in EGF-dependent down-regulation of E-cadherin was determined by siRNA specifically directed against MMP-9. Furthermore, treatment with recombinant MMP-9 or transient expression of MMP-9 is sufficient to reduce E-cadherin levels in differentiated ovarian tumor cells. Stable overexpression of MMP-9 led to a loss of E-cadherin and junctional integrity, and promoted a migratory and invasive phenotype. Thus, elevated MMP-9 protein expression is sufficient for junctional disruption and loss of E-cadherin in these cells. The associations between EGFR activation, MMP-9 expression, and E-cadherin were investigated in human ovarian tumors and paired peritoneal metastases wherein immunohistochemical staining for activated (phospho) EGFR and MMP-9 colocalized with regions of reduced E-cadherin. These data suggest that regulation of MMP-9 by EGFR may represent a novel mechanism for down-modulation of E-cadherin in ovarian cancer. [Cancer Res 2008;68(12):4606–13]
Human T-Cell Leukemia Virus I Tax Protein Sensitizes p53-Mutant Cells to DNA Damage
Authors: Mihaylova Valia T. , Green Allison M. , Khurgel Moshe , Semmes Oliver J. , Kupfer Gary M.
Published: June 2008

Mutations in p53 are a common cause of resistance of cancers to standard chemotherapy and, thus, treatment failure. Reports have shown that Tax, a human T-cell leukemia virus type I encoded protein that has been associated with genomic instability and perturbation of transcription and cell cycle, sensitizes HeLa cells to UV treatment. The extent to which Tax can sensitize cells and the mechanism by which it exerts its effect are unknown. In this study, we show that Tax sensitizes p53-mutant cells to a broad range of DNA-damaging agents, including mitomycin C, a bifunctional alkylator, etoposide, a topoisomerase II drug, and UV light, but not ionizing radiation, a double-strand break agent, or vinblastine, a tubulin poison. Tax caused hypersensitivity in all p53-deleted cell lines and several, but not all, mutant-expressed p53–containing cell lines, while unexpectedly being protective in p53 wild-type (wt) cells. The effect observed in p53-deleted lines could be reversed for this by transfection of wt p53. We also show that Tax activates a p53-independent proapoptotic program through decreased expression of the retinoblastoma protein and subsequent increased E2F1 expression. The expression of several proapoptotic proteins was also induced by Tax, including Puma and Noxa, culminating in a substantial increase in Bax dimerization. Our results show that Tax can sensitize p53-mutant cells to DNA damage while protecting p53 wt cells, a side benefit that might result in reduced toxicity in normal cells. Such studies hold the promise of a novel adjunctive therapy that could make cancer chemotherapy more effective. [Cancer Res 2008;68(12):4843–52]
Transmembrane Protein 18 Enhances the Tropism of Neural Stem Cells for Glioma Cells
Authors: Jurvansuu Jaana , Zhao Ying , Leung Doreen S.Y. , Boulaire Jerome , Yu Yuan Hong , Ahmed Sohail , Wang Shu
Published: June 2008

The failure of current glioma therapies is mainly due to the ability of the tumor cells to invade extensively the surrounding healthy brain tissue, hence escaping localized treatments. Neural stem cells (NSC) are able to home in on tumor foci at sites distant from the main tumor mass, possibly enabling treatment of scattered glioma clusters. To make the strategy more effective, we performed a cDNA expression library screening to identify the candidate genes that once overexpressed would enhance the tropism of NSCs for gliomas. Here, we show that a previously unannotated gene, the one encoding transmembrane protein 18 (TMEM18), is one such gene. Overexpression of TMEM18 was seen in the current study to provide NSCs and neural precursors an increased migration capacity toward glioblastoma cells in vitro and in the rat brain. Functional inactivation of the TMEM18 gene resulted in almost complete loss of the migration activity of these cells. Thus, TMEM18 is a novel cell migration modulator. Overexpression of this protein could be favorably used in NSC-based glioma therapy. [Cancer Res 2008;68(12):4614–22]
Underexpression of RhoH in Hairy Cell Leukemia
Authors: Galiègue-Zouitina Sylvie , Delestré Laure , Dupont Caroline , Troussard Xavier , Shelley Carl Simon
Published: June 2008

The cause of hairy cell leukemia (HCL) is unknown. Current treatments seem effective only for a limited period of time. In addition, a significant proportion of patients remain refractive to all treatment options. These considerations indicate the need to develop alternative therapeutic strategies for HCL. Here, we report that HCL is characterized by underexpression of RhoH. In vitro reconstitution of RhoH expression inhibits the aberrant adhesion and transendothelial migration that drives disease pathogenesis. In an in vivo model of HCL, RhoH reconstitution limits malignant progression and protects against mortality. These findings provide the proof of principle that RhoH reconstitution represents a potential new approach to the treatment of HCL. [Cancer Res 2008;68(12):4531–40]
Role of PELP1/MNAR Signaling in Ovarian Tumorigenesis
Authors: Dimple Chakravarty , Nair Sujit S. , Rajhans Rajib , Pitcheswara Perla R. , Liu Jinsong , Balasenthil Seetharaman , Le Xiao-Feng , Burow Matthew E. , Auersperg Nelly , Tekmal Rajeshwar Rao , Broaddus Russell R. , Vadlamudi Ratna K.
Published: June 2008

Emerging evidence suggests that nuclear receptor (NR) coregulators have potential to act as master genes and their deregulation can promote oncogenesis. Proline-, glutamic acid–, and leucine–rich protein-1 (PELP1/MNAR) is a novel NR coregulator. Its expression is deregulated in hormone-driven cancers. However, the role of PELP1/MNAR in ovarian cancer progression remains unknown. Analysis of serial analysis of gene expression data suggested deregulation of PELP1/MNAR expression in ovarian tumors. Western analysis of PELP1/MNAR in normal and serous ovarian tumor tissues showed 3- to 4-fold higher PELP1/MNAR expression in serous tumors compared with normal ovarian tissues. To examine the significance of PELP1/MNAR in ovarian cancer progression, we have generated model cells that overexpress PELP1/MNAR and ovarian cancer cells in which PELP1/MNAR expression is down-regulated by stable expression of PELP1/MNAR-specific shRNA. Down-regulation of PELP1/MNAR in cancerous ovarian model cells (OVCAR3) resulted in reduced proliferation, affected the magnitude of c-Src and protein kinase B (AKT) signaling, and reduced tumorigenic potential of ovarian cancer cells in a nude mouse model. PELP1/MNAR overexpression in nontumorigenic immortalized surface epithelial cells (IOSE cells) promoted constitutive activation of c-Src and AKT signaling pathways and promoted anchorage-independent growth. Immunohistochemical studies using human ovarian cancer tissue arrays (n = 123) showed that PELP1/MNAR is 2- to 3-fold overexpressed in 60% of ovarian tumors, and PELP1/MNAR deregulation occurs in all different types of ovarian cancer. Collectively, these results suggest that PELP1/MNAR signaling plays a role in ovarian cancer cell proliferation and survival, and that its expression is deregulated in ovarian carcinomas. [Cancer Res 2008;68(12):4902–9]
The Tyrosine Kinase Inhibitor Cediranib Blocks Ligand-Induced Vascular Endothelial Growth Factor Receptor-3 Activity and Lymphangiogenesis
Authors: Heckman Caroline A. , Holopainen Tanja , Wirzenius Maria , Keskitalo Salla , Jeltsch Michael , Ylä-Herttuala Seppo , Wedge Stephen R. , Jürgensmeier Juliane M. , Alitalo Kari
Published: June 2008

Solid tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer the potential to inhibit more than one kinase and impede tumor growth by multiple mechanisms. However, their potency toward individual targets can vary. Cediranib (RECENTIN; AZD2171) is an inhibitor of VEGF signaling that has been shown in experimental models to prevent VEGF-A–induced angiogenesis and primary tumor growth, yet the effects of cediranib on VEGF receptor (VEGFR)-3–mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of cediranib against VEGFR-3 and its associated signaling events compared with its activity against VEGFR-2, we used the receptor-specific ligands VEGF-E and VEGF-C156S. In human endothelial cells, cediranib inhibited VEGF-E–induced phosphorylation of VEGFR-2 and VEGF-C156S–induced phosphorylation of VEGFR-3 at concentrations of ≤1nmol/L and inhibited activation of downstream signaling molecules. Additionally, cediranib blocked VEGF-C156S–induced and VEGF-E–induced proliferation, survival, and migration of lymphatic and blood vascular endothelial cells. In vivo, cediranib (6 mg/kg/d) prevented angiogenesis and lymphangiogenesis induced by VEGF-E–expressing and VEGF-C156S–expressing adenoviruses, respectively. Cediranib (6 mg/kg/day) also blocked angiogenesis and lymphangiogenesis induced by adenoviruses expressing VEGF-A or VEGF-C and compromised the blood and lymphatic vasculatures of VEGF-C–expressing tumors. Cediranib may, therefore, be an effective means of preventing tumor progression, not only by inhibiting VEGFR-2 activity and angiogenesis, but also by concomitantly inhibiting VEGFR-3 activity and lymphangiogenesis. [Cancer Res 2008;68(12):4754–62]
Krüppel-like Factor 4 Induces p27Kip1 Expression in and Suppresses the Growth and Metastasis of Human Pancreatic Cancer Cells
Authors: Wei Daoyan , Kanai Masahsi , Jia Zhiliang , Le Xiangdong , Xie Keping
Published: June 2008

The zinc finger transcription factor Krüppel-like factor 4 (KLF4) has been implicated in both tumor suppression and progression. However, its function in pancreatic cancer has not been well characterized. Here, we show that pancreatic cancer cell lines expressed various levels of KLF4 RNA and protein. Ectopic expression of KLF4 by FG and BxPC-3 pancreatic cancer cells resulted in cell cycle arrest and marked inhibition of cell growth in vitro and attenuation of tumor growth and metastasis in an orthotopic mouse model. Overexpression of KLF4 also led to significant induction of p27Kip1 expression, at both the RNA and protein levels, in a dose- and time-dependent manner, indicating that KLF4 transcriptionally regulates the expression of p27Kip1. Chromatin immunoprecipitation assays consistently showed that KLF4 protein physically interacts with the p27Kip1 promoter. Promoter deletion and point mutation analyses indicated that a region between nucleotides −435 and −60 of the p27Kip1 promoter and intact of the three KLF4-binding sites within that region were required for the full induction of p27Kip1 promoter activity by KLF4. Our findings suggest that KLF4 transactivates p27Kip1 expression and inhibits the growth and metastasis of human pancreatic cancer. [Cancer Res 2008;68(12):4631–9]
Chloramphenicol Induces Abnormal Differentiation and Inhibits Apoptosis in Activated T Cells
Authors: Yuan Zeng-Rong , Shi Yufang
Published: June 2008

Chloramphenicol is a broad-spectrum antibiotic used for the treatment of many infectious diseases and has become one of the major seafood contaminants. Hematologic disorders such as aplastic anemia and leukemia induced by chloramphenicol are a major concern. However, the mechanism underlying chloramphenicol-induced leukemogenesis is not known. By investigating the effects of chloramphenicol on the activation of mouse T cells stimulated with anti-CD3 antibody or staphylococcal enterotoxin B, we found that chloramphenicol induces the differentiation of activated T cells into lymphoblastic leukemia-like cells, characterized by large cell size, multiploid nuclei, and expression of CD7, a maker for immature T cells and T-cell lymphocytic leukemia, thus phenotypically indicating differentiation toward leukemogenesis. High expression of cyclin B1, but not p53, c-myc, and CDC25A, was detected in chloramphenicol-treated activated T cells, which may relate to abnormal cell differentiation. Chloramphenicol inhibited the activation-induced cell death of mouse and human T-cell receptor–activated T cells by down-regulating the expression of Fas ligand. Our findings show that abnormal cell differentiation and inhibition of apoptosis may contribute to the development of leukemia associated with clinical applications of chloramphenicol. [Cancer Res 2008;68(12):4875–81]
Novel Steroid Receptor Phyto-Modulator Compound A Inhibits Growth and Survival of Prostate Cancer Cells
Authors: Yemelyanov Alexander , Czwornog Jennifer , Gera Lajos , Joshi Sonali , Chatterton Robert T. , Budunova Irina
Published: June 2008

Androgen receptor (AR)– and glucocorticoid receptor (GR)– mediated signaling play opposite roles in prostate tumorigenesis: AR promotes prostate carcinoma (PC) development, whereas GR acts as a tumor suppressor. Compound A (CpdA) is a stable analogue of an aziridine precursor from the African shrub Salsola tuberculatiformis Botschantzev. It was shown recently that, in model cells, CpdA inhibits AR function and strongly enhances anti-inflammatory function of GR. We determined the effects of CpdA in prostate cells with different AR/GR status: (a) RWPE-1 cells (ARlow/GRlow), (b) PC3 and DU145 cells (GR+/AR−), (c) LNCaP cells (GR−/AR+), and (d) LNCaP-GR cells expressing both receptors. Similar to steroid hormones, CpdA induces nuclear translocation of both receptors in prostate cells. Despite this, CpdA inhibits DNA-binding and transactivation potential of AR. In addition, CpdA inhibits GR-mediated transactivation but induces GR transrepression via inhibition of several transcription factors, including nuclear factor-κB, AP-1, Ets-1, Elk-1, SRF, CRE/ATF, and NFATc. CpdA strongly decreases growth and induces caspase-dependent apoptosis in highly malignant PC3 and DU145 cells and in other AR/GR-expressing PC cells. The cytostatic effect of CpdA is receptor dependent: down-regulation of GR or AR expression drastically attenuates CpdA-induced PC cell growth inhibition. Finally, virtual docking analysis indicates that CpdA shares binding cavities in AR and GR ligand-binding domains with corresponding hormones and forms hydrogen bonds (H-bond) with the same amino acids that are involved in H-bond formation during steroid binding. Overall, our data suggest that CpdA is a unique dual-target steroid receptor modulator that has a high potential for PC therapy. [Cancer Res 2008;68(12):4763–73]
Measles Virus Induces Oncolysis of Mesothelioma Cells and Allows Dendritic Cells to Cross-Prime Tumor-Specific CD8 Response
Authors: Gauvrit Anne , Brandler Samantha , Sapede-Peroz Carole , Boisgerault Nicolas , Tangy Frédéric , Gregoire Marc
Published: June 2008

Despite conventional medical and surgical treatments, malignant pleural mesothelioma (MPM) remains incurable. Oncovirotherapy (i.e., the use of replication-competent virus for cancer treatment) is currently explored in clinical trials. In this study, we investigated the antineoplastic potential of a new oncolytic viral agent, a live-attenuated measles virus (MV) strain derived from the Edmonston vaccine lineage (Schwarz strain). We evaluated both oncolytic activity and immunoadjuvant properties of the MV vaccine strain on mesothelioma tumor cells. Infectivity, syncytium formation, and cytolytic activity of MV were studied on a panel of mesothelioma cells derived from pleural effusions of MPM patients. We observed that MV infected preferentially MPM cell lines in comparison with nontransformed mesothelial cells, leading to an efficient killing of a significant fraction of tumor cells. A cytoreductive activity was also evidenced through formation of multinuclear cellular aggregates (syncytia). The susceptibility of MPM cell lines to measles infection was assessed by the analysis of cell surface expression of the MV vaccine receptor (CD46). We also evaluated whether MV infection of mesothelioma cells could elicit an autologous antitumor immune response. We showed that MV Schwarz strain induced apoptotic cell death of infected mesothelioma cells, which were efficiently phagocytosed by dendritic cells (DC). Loading of DCs with MV-infected MPM cells induced DC spontaneous maturation, as evidenced by the increased expression of MHC and costimulatory molecules along with the production of proinflammatory cytokines. Priming of autologous T cells by DCs loaded with MV-infected MPM cells led to a significant proliferation of tumor-specific CD8 T cells. Altogether, these data strongly support the potential of oncolytic MV as an efficient therapeutic agent for mesothelioma cancer. [Cancer Res 2008;68(12):4882–92]
Lack of Hypoxic Response in Uterine Leiomyomas despite Severe Tissue Hypoxia
Authors: Mayer Arnulf , Höckel Michael , Wree Alexander , Leo Cornelia , Horn Lars-Christian , Vaupel Peter
Published: June 2008

Hypoxia is now established as a key factor influencing the pathophysiology of malignant growth. Among other effects, hypoxia modulates the expression of a multitude of genes through the induction of hypoxia-inducible transcription factors. This differential gene expression favors angiogenesis, cell survival, an invasive/metastatic phenotype, and resistance to anticancer therapies. Because benign tumors do not exhibit these traits, one might expect these entities to be neither hypoxic nor to induce the genetic hypoxia response program. To test this hypothesis, an investigation of the oxygenation status of 17 leiomyomas and 1 leiomyosarcoma of the uterus using polarographic needle electrodes (Eppendorf pO2 sensor) and the expression of hypoxia-related markers in biopsy specimens of the same tumors was carried out. Marker expression in eight additional archival leiomyosarcomas was also assessed. Leiomyoma tissue was generally found to be severely hypoxic, with median oxygen (O2) partial pressure values ranging from 1 to 5 mm Hg. In contrast, none of the hypoxia-related markers hypoxia-inducible factor (HIF)–1α, HIF-2α, glucose transporter-1, or carbonic anhydrase IX were expressed in any leiomyoma. Larger intercapillary distances were correlated with a poorer oxygenation status. Conversely, the expression of hypoxia-related markers was abundant in the leiomyosarcomas and they also exhibited a high-turnover phenotype (significantly increased proliferation and apoptosis). Uterine leiomyoma might therefore represent a state of oxygen-limited proliferation. Malignancy in the same organ system is associated with growth and metabolism beyond tissue-inherent limitations leading to the induction of hypoxia-related markers, thereby contributing to a self-perpetuating aggressive phenotype. [Cancer Res 2008;68(12):4719–26]
Targeting the BAF57 SWI/SNF Subunit in Prostate Cancer: A Novel Platform to Control Androgen Receptor Activity
Authors: Link Kevin A. , Balasubramaniam Sucharitha , Sharma Ankur , Comstock Clay E.S. , Godoy-Tundidor Sonia , Powers Nathan , Cao Khanh H. , Haelens Annemie , Claessens Frank , Revelo Monica P. , Knudsen Karen E.
Published: June 2008

The androgen receptor (AR) is critical for disseminated prostate cancer proliferation and survival. AR activity is targeted either through prevention of ligand synthesis or through the use of antagonists that bind the COOH-terminal ligand-binding domain. Although initially effective, treatment fails due to restored AR activity in the presence of therapeutics. Thus, new means must be developed to target AR activity. The SWI/SNF chromatin remodeling complex is critical for AR transcriptional activity, and the BAF57 SWI/SNF subunit facilitates direct interaction with the receptor. Although selected SWI/SNF subunit expression is reduced in prostate cancer, we show that BAF57 is retained in human disease and is elevated in a subset of tumors. Functional analyses showed that BAF57 contributes uniquely to androgen-mediated stimulation of transcription without compromising the effectiveness of AR antagonists. Subsequent studies revealed that BAF57 is recruited to the AR DNA-binding domain/hinge region, which occurs concomitant with receptor activation. These data provided the basis for a novel inhibitor derived from BAF57 [BAF57 inhibitory peptide (BIPep)], which blocked AR residence on chromatin and resultant AR-dependent gene activation. Importantly, BIPep expression was sufficient to inhibit androgen-dependent prostate cancer cell proliferation in AR-positive cells. In summary, these data identify blockade of AR-BAF57 interaction as a novel means to target agonist-induced AR function in prostate cancer, and provide the first evidence that abrogation of SWI/SNF function can be developed as a point of therapeutic intervention in prostate cancer. [Cancer Res 2008;68(12):4551–8]
Vascular Endothelial Growth Factor (VEGF)-A165b Is a Weak In vitro Agonist for VEGF Receptor-2 Due to Lack of Coreceptor Binding and Deficient Regulation of Kinase Activity
Authors: Kawamura Harukiyo , Li Xiujuan , Harper Steven J. , Bates David O. , Claesson-Welsh Lena
Published: June 2008

Vascular endothelial growth factor (VEGF)-A165b is a COOH-terminal splice variant of VEGF-A that has been implicated in negative regulation of angiogenesis. We compared the properties of VEGF-A165b with those of VEGF-A121, VEGF-A145, and VEGF-A165. Induction of tyrosine phosphorylation sites in VEGFR-2 differed between the VEGF ligands as determined by tryptic phosphopeptide mapping and by use of phosphosite-specific antibodies. VEGF-A165b was considerably poorer in inducing phosphorylation of the positive regulatory site Y1052 in VEGFR-2. Whereas this did not affect activation of VEGFR-2 in vitro, we show that VEGF-A165b failed to induce vasculogenesis and sprouting angiogenesis in differentiating embryonic stem cells and vascularization of s.c. Matrigel plugs. In addition, the ability of the different VEGF ligands to induce angiogenesis correlated with their abilities to bind the VEGF coreceptor neuropilin 1 (NRP1). Our data indicate that loss of VEGFR-2/NRP1 complex formation and Y1052 phosphorylation contribute to the lack of angiogenic properties of VEGF-A165b. [Cancer Res 2008;68(12):4683–92]
Tissue Inhibitor of Metalloproteinase 3 Suppresses Tumor Angiogenesis in Matrix Metalloproteinase 2–Down-regulated Lung Cancer
Authors: Chetty Chandramu , Lakka Sajani S. , Bhoopathi Praveen , Kunigal Sateesh , Geiss Roger , Rao Jasti S.
Published: June 2008

Matrix metalloproteinase-2 (MMP-2) expression is often up-regulated in advanced cancers and known to play an important role in tumor angiogenesis. We previously showed that adenoviral-mediated delivery of siRNA for MMP-2 (Ad-MMP-2-Si) inhibited lung cancer growth, angiogenesis, and metastasis. In this study, we investigated the signaling mechanisms involved in Ad-MMP-2-Si–mediated inhibition of angiogenesis. Ad-MMP-2-Si treatment inhibited neovascularization in vivo as determined by mouse dorsal air sac model, and conditioned medium from Ad-MMP-2-Si–infected A549 lung cancer cells (Ad-MMP-2-Si-CM) inhibited endothelial tube formation in vitro. Ad-MMP-2-Si-CM decreased proliferation as determined by Ki-67 immunofluorescence and induced apoptosis in endothelial cells as determined by terminal deoxynucleotidyl-transferase–mediated dUTP nick-end labeling (TUNEL) assay. Furthermore, Ad-MMP-2-Si-CM inhibited AKT phosphorylation and induced phosphorylation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase in endothelial cells. Overexpression of constitutively active AKT reversed the Ad-MMP-2-Si-CM–mediated inhibition of tube formation and induction of ERK phosphorylation. Conversely, Ad-MMP-2-Si-CM induced tissue inhibitor of metalloproteinase (TIMP) 3 expression, and the interaction of vascular endothelial growth factor 2 and TIMP-3 was determined by coimmunoprecipitation experiments. TIMP-3 induction was mediated by ERK activation. In addition, electrophoretic mobility shift and chromatin immunoprecipitation assays show that Sp1 transcription factor mediated Ad-MMP-2-Si-CM–stimulated increase of TIMP-3. Vasculature destruction was confirmed with colocalization studies with TUNEL and an endothelial marker, CD31, in tumor sections of Ad-MMP-2-Si–treated mice. Our data collectively suggest that MMP-2 inhibition induces endothelial apoptosis in vivo and inhibits endothelial tube formation. These experiments provide the first evidence that inhibition of p-AKT and induction of p-ERK1/2 are crucial events in the induction of TIMP-3–mediated endothelial apoptosis in MMP-2 inhibited lung tumors. [Cancer Res 2008;68(12):4736–45]