bluuebunny/crossref_metadata_2025 huggingface dataset:
A life-cycle perspective on online community success
Authors: Iriberri Alicia , Leroy Gondy
Published: February 2009

Using the information systems lifecycle as a unifying framework, we review online communities research and propose a sequence for incorporating success conditions during initiation and development to increase their chances of becoming a successful community, one in which members participate actively and develop lasting relationships. Online communities evolve following distinctive lifecycle stages and recommendations for success are more or less relevant depending on the developmental stage of the online community. In addition, the goal of the online community under study determines the components to include in the development of a successful online community. Online community builders and researchers will benefit from this review of the conditions that help online communities succeed.
Web page classification
Authors: Qi Xiaoguang , Davison Brian D.
Published: February 2009

Classification of Web page content is essential to many tasks in Web information retrieval such as maintaining Web directories and focused crawling. The uncontrolled nature of Web content presents additional challenges to Web page classification as compared to traditional text classification, but the interconnected nature of hypertext also provides features that can assist the process.

As we review work in Web page classification, we note the importance of these Web-specific features and algorithms, describe state-of-the-art practices, and track the underlying assumptions behind the use of information from neighboring pages.
The spatial resolution of crossmodal attention
Authors: Gray Rob , Mohebbi Rayka , Tan Hong Z.
Published: February 2009

Previous research on crossmodal attentional orienting has reported speeded reaction times (RT) when the stimuli from the different modalities are in the same spatial location and slowed RTs when the stimuli are presented in very different locations (e.g., opposite sides of the body). However, little is known about what occurs for spatial interactions between these two extremes. We systematically varied the separation between cues and targets to quantify the spatial distribution of crossmodal attention. The orthogonal cueing paradigm [Spence et al. 1998] was used. Visual targets presented above or below the forearm were preceded by either vibrotactile cues presented on the forearm, auditory cues presented below the forearm, or visual cues presented on the forearm. The presentation of both unimodal and crossmodal cues led to a roughly monotonic increase in RT as a function of the cue-target separation. Unimodal visual cueing resulted in an attentional focus that was significantly narrower than that produced by crossmodal cues: the distribution of visual attention for visual cues had roughly half of the lateral extent of that produced by tactile cueing and roughly one fourth of the lateral extent as that produced by auditory cueing. This occurred when both seven (Experiment 1) and three (Experiment 2) cue locations were used suggesting that the effects are not primarily due to differences in the ability to localize the cues. These findings suggest that the location of tactile and auditory warning signals does not have to be controlled as precisely as the location of visual warning signals to facilitate a response to the critical visual event.
The geometry of linear higher-order recursion
Authors: Lago Ugo Dal
Published: February 2009

Imposing linearity and ramification constraints allows to weaken higher-order (primitive) recursion in such a way that the class of representable functions equals the class of polynomial-time computable functions, as the works by Leivant, Hofmann, and others show. This article shows that fine-tuning these two constraints leads to different expressive strengths, some of them lying well beyond polynomial time. This is done by introducing a new semantics, called algebraic context semantics. The framework stems from Gonthier's original work (itself a model of Girard's geometry of interaction) and turns out to be a versatile and powerful tool for the quantitative analysis of normalization in the lambda calculus with constants and higher-order recursion.
On the proof complexity of deep inference
Authors: Bruscoli Paola , Guglielmi Alessio
Published: February 2009

We obtain two results about the proof complexity of deep inference: (1) Deep-inference proof systems are as powerful as Frege ones, even when both are extended with the Tseitin extension rule or with the substitution rule; (2) there are analytic deep-inference proof systems that exhibit an exponential speedup over analytic Gentzen proof systems that they polynomially simulate.
The evolution of virtualization
Authors: Kroeker Kirk L.
Published: February 2009

Virtualization is moving out of the data center and making inroads with mobile computing, security, and software delivery.
InterviewAn interview with C.A.R. Hoare
Authors: Shustek Len , Hoare C.A.R.
Published: February 2009

C.A.R. Hoare, developer of the Quicksort algorithm and a lifelong contributor to the theory and design of programming languages, discusses the practical application of his theoretical ideas.
Learning and detecting emergent behavior in networks of cardiac myocytes
Authors: Grosu Radu , Smolka Scott A. , Corradini Flavio , Wasilewska Anita , Entcheva Emilia , Bartocci Ezio
Published: February 2009

We address the problem of specifying and detecting emergent behavior in networks of cardiac myocytes, spiral electric waves in particular, a precursor to atrial and ventricular fibrillation. To solve this problem we: (1) apply discrete mode abstraction to the cycle-linear hybrid automata (CLHA) we have recently developed for modeling the behavior of myocyte networks; (2) introduce the new concept of spatial superposition of CLHA modes; (3) develop a new spatial logic, based on spatial superposition, for specifying emergent behavior; (4) devise a new method for learning the formulae of this logic from the spatial patterns under investigation; and (5) apply bounded model checking to detect the onset of spiral waves. We have implemented our methodology as the EMERALD tool suite, a component of our EHA framework for specification, simulation, analysis, and control of excitable hybrid automata. We illustrate the effectiveness of our approach by applying EMERALD to the scalar electrical fields produced by our CELLEXCITE simulation environment for excitable-cell networks.
Strange ontologies in digital culture
Authors: Whitelaw Mitchell , Guglielmetti Mark , Innocent Troy
Published: February 2009

The concept of a “strange ontology” is articulated via the intersection of philosophical and computational definitions of ontology. Within digital media, each simulated world requires both; an ontology, to define its existence as data; and a subject, the player or user, who engages with the simulation. Glitches or interventions in these simulations create ontologies that are inconsistent with our lived experience, rendering them “strange.” We draw upon a range of works to illustrate this concept, including game art, social networking software, Guglielmetti's “Laboratories of though” and generative art. This article aims to define this concept and outlines a terrain for further investigation.
A Conversation with Van Jacobson
Authors: Stanik John
Published: February 2009

To those with even a passing interest in the history of the Internet and TCP/IP networking, Van Jacobson will be a familiar name. During his 25 years at Lawrence Berkeley National Laboratory and subsequent leadership positions at Cisco Systems and Packet Design, Jacobson has helped invent and develop some of the key technologies on which the Internet is based. He is most well known for his pioneering contributions to the TCP/IP networking stack, his seminal work on alleviating congestion on the Internet, his leadership in developing the MBone (multicast backbone), and his development of several widely used IP networking tools, such as trace-route, pathchar, and tcpdump.
A survey of platforms for mobile networks research
Authors: Oliver Earl
Published: February 2009

The use of smartphones is growing at an unprecedented rate and is projected to soon pass laptops as consumers' mobile platform of choice. The proliferation of these devices has created new opportunities for mobile researchers; however, when faced with hundreds of devices across nearly a dozen development platforms, selecting the ideal platform is often met with unanswered questions. In this paper I consider desirable characteristics of mobile platforms necessary for mobile networks research. Based on these characteristics, I assess five smartphone platforms: Android (Linux), BlackBerry, iPhone (Mac OS X), Symbian, and Windows Mobile. This survey is current as of December 2008. A living version of this survey is available at: http://blizzard.cs.uwaterloo.ca/eaoliver/platforms/.
Pioglitazone reduces inflammatory responses of human adipocytes to factors secreted by monocytes/macrophages
Authors: Permana Paska A. , Zhang Weiyang , Wabitsch Martin , Fischer-Posovszky Pamela , Duckworth William C. , Reaven Peter D.
Published: February 2009

Infiltration of monocyte-derived macrophages into adipose tissue may contribute to tissue and systemic inflammation and insulin resistance. We hypothesized that pioglitazone (Pio) could specifically reduce the inflammatory response of adipocytes to factors released by monocytes/macrophages. We show that macrophage factors (Mφ-factors) greatly increase expression levels of proinflammatory adipokines, chemokines, and adhesion molecules in human subcutaneous and visceral adipose tissue (SAT and VAT) as well as in adipocytes (up to several hundredfold of control). Compared with SAT, VAT showed enhanced basal and Mφ-factor-induced inflammatory responses. Mφ-factors also induced greater lipolysis in adipocytes, as assessed by concentrations of glycerol released from the cells (196 ± 13 vs. 56 ± 7 μM in control, P < 0.05). Pretreatment of adipose tissue or adipocytes with Pio reduced these responses to Mφ-factors (by 13–86%, P < 0.05) and prevented Mφ-factor suppression of adiponectin expression. Furthermore, Pio pretreatment of adipocytes and macrophages tended to further reduce inflammatory responses of adipocytes to Mφ-factors and monocyte adhesion to Mφ-factor-activated adipocytes. In support of these in vitro data, media conditioned by monocytes isolated from impaired glucose-tolerant subjects treated with Pio (compared with placebo) induced release of lower concentrations of proinflammatory adipokines and glycerol (100 ± 7 vs. 150 ± 15 μM, P < 0.05) from adipocytes. In summary, Pio decreases inflammatory responses in adipose tissue/cells induced by monocytes/macrophages by acting on either or both cell types. These beneficial effects of Pio may attenuate proinflammatory responses resulting from monocyte/macrophage infiltration into adipose tissue and suppress tissue inflammation resulting from the interaction between both cell types.
Regulation of light's action in the mammalian circadian clock: role of the extrasynaptic GABAA receptor
Authors: Ehlen J. Christopher , Paul Ketema N.
Published: February 2009

GABAA receptor agonists act in the suprachiasmatic nucleus (SCN) to reset circadian rhythms during the day but inhibit the ability of light to reset rhythms during the night. In the present study, we examined whether these paradoxical differences in the effect of GABAA receptor stimulation on the circadian system are mediated by separate GABAA receptor subtypes. 4,5,6,7-Tetrahydroisoxazolo[5,4- c]pyridin-3-ol (THIP), a GABAA receptor agonist, preferentially activates GABAA receptors in extrasynaptic locations. THIP, muscimol (a GABAA agonist), or vehicle were microinjected into the SCN region of Syrian hamsters free-running in constant darkness during the mid-subjective day, early subjective night, or late subjective night. The subjective night injections were followed by a light pulse or sham control. Behavioral phase shifts of wheel running rhythms and both Period1 ( Per1) and Per2 mRNA levels in the SCN were assessed. Animals that received THIP during the subjective day did not exhibit significant phase alterations. During the early and late subjective night, however, THIP abolished the phase-shifting effects of light and the ability of light to increase Per1 and Per2 mRNA levels. The ability of N-methyl-d-aspartic acid to phase-shift wheel running rhythms was also attenuated by THIP. Together these data demonstrate that THIP does not produce phase shifts during the subjective day, but does inhibit the ability of light to produce phase shifts. Thus, extrasynaptic GABAA receptors appear to play a role in regulating light input to the SCN, while a different population of GABAA receptors appears to be responsible for daytime effects of GABA.
Prolonged exercise training induces long-term enhancement of HSP70 expression in rat plantaris muscle
Authors: Ogata Tomonori , Oishi Yasuharu , Higashida Kazuhiko , Higuchi Mitsuru , Muraoka Isao
Published: February 2009

Skeletal muscle may develop adaptive molecular chaperone enhancements as a potential defense system through repeated daily exercise stimulation. The present study investigated whether prolonged exercise training alters the expression of molecular chaperone proteins for the long term in skeletal muscle. Mature male Wistar rats were subjected for 8 wk to either a single bout of acute intermittent treadmill running (30 m/min, 5 min × 4, 5° grade) or prolonged treadmill running training (15–40 m/min, 5 min × 4, 5–7° grade). Levels of five molecular chaperone proteins [heat shock protein (HSP)25, HSP60, glucose-regulated protein (GRP)78, HSP70, and heat shock cognate (HSC)70] were measured in response to acute exercise and prolonged training. HSP70 levels were increased 6 and 24 h after acute exercise, but expression returned to control level within 2 days. In contrast, prolonged training had a long-term effect on HSP70 expression. Levels of HSP70 were notably increased by 4.5-fold over control 2 days after prolonged training; the enhancement was maintained for at least 14 days after training ended. However, other molecular chaperone proteins did not show adaptive changes in response to prolonged training. In addition, HSP70 enhancement by prolonged exercise training was not accompanied by transcription of HSP70 mRNA. These findings demonstrate that prolonged training can induce long-term enhancement of HSP70 expression without change at the mRNA level in skeletal muscle.
Potential role of purinergic signaling in lithium-induced nephrogenic diabetes insipidus
Authors: Zhang Yue , Nelson Raoul D. , Carlson Noel G. , Kamerath Craig D. , Kohan Donald E. , Kishore Bellamkonda K.
Published: February 2009

Lithium (Li)-induced nephrogenic diabetes insipidus (NDI) has been attributed to the increased production of renal prostaglandin (PG)E2. Previously we reported that extracellular nucleotides (ATP/UTP), acting through P2y2 receptor in rat medullary collecting duct (mCD), produce and release PGE2. Hence we hypothesized that increased production of PGE2 in Li-induced NDI may be mediated by enhanced purinergic signaling in the mCD. Sprague-Dawley rats were fed either control or Li-added diet for 14 or 21 days. Li feeding resulted in marked polyuria and polydipsia associated with a decrease in aquaporin (AQP)2 protein abundance in inner medulla (∼20% of controls) and a twofold increase in urinary PGE2. When acutely challenged ex vivo with adenosine 5′- O-(3-thiotriphosphate) (ATPγS), UTP, or ADP, mCD of Li-fed rats showed significantly higher increases (50–130% over control diet-fed rats) in PGE2 production, indicating that more than one subtype of P2y receptor is involved. This was associated with a 3.4-fold increase in P2y4, but not P2y2, receptor mRNA expression in the inner medulla of Li-fed rats compared with control diet-fed rats. Confocal laser immunofluorescence microscopy revealed predominant localization of both P2y2 and P2y4 receptors in the mCD of control or Li diet-fed rats. Together, these data indicate that in Li-induced NDI 1) purinergic signaling in the mCD is sensitized with increased production of PGE2 and 2) P2y2 and/or P2y4 receptors may be involved in the enhanced purinergic signaling. Our study also reveals the potential beneficial effects of P2y receptor antagonists in the treatment and/or prevention of Li-induced NDI.
Identification and analysis of differentially expressed genes in immune tissues of Atlantic cod stimulated with formalin-killed, atypicalAeromonas salmonicida
Authors: Feng Charles Y. , Johnson Stewart C. , Hori Tiago S. , Rise Marlies , Hall Jennifer R. , Gamperl A. Kurt , Hubert Sophie , Kimball Jennifer , Bowman Sharen , Rise Matthew L.
Published: February 2009

Physiological changes, elicited in animal immune tissues by exposure to pathogens, may be studied using functional genomics approaches. We created and characterized reciprocal suppression subtractive hybridization (SSH) cDNA libraries to identify differentially expressed genes in spleen and head kidney tissues of Atlantic cod ( Gadus morhua) challenged with intraperitoneal injections of formalin-killed, atypical Aeromonas salmonicida. Of 4,154 ESTs from four cDNA libraries, 10 genes with immune-relevant functional annotations were selected for QPCR studies using individual fish templates to assess biological variability. Genes confirmed by QPCR as upregulated by A. salmonicida included interleukin-1β, interleukin-8, a small inducible cytokine, interferon regulatory factor 1 (IRF1), ferritin heavy subunit, cathelicidin, and hepcidin. This study is the first large-scale discovery of bacteria-responsive genes in cod and the first to demonstrate upregulation of IRF1 in fish immune tissues as a result of bacterial antigen stimulation. Given the importance of IRF1 in vertebrate immune responses to viral and bacterial pathogens, the full-length cDNA sequence of Atlantic cod IRF1 was obtained and compared with putative orthologous sequences from other organisms. Functional annotations of assembled SSH library ESTs showed that bacterial antigen stimulation caused changes in many biological processes including chemotaxis, regulation of apoptosis, antimicrobial peptide production, and iron homeostasis. Moreover, differences in spleen and head kidney gene expression responses to the bacterial antigens pointed to a potential role for the cod spleen in blood-borne pathogen clearance. Our data show that Atlantic cod immune tissue responses to bacterial antigens are similar to those seen in other fish species and higher vertebrates.
Analysis of High Birefringence of Four Types of Photonic Crystal Fiber by Combining Circular and Elliptical Air Holes in Fiber Cladding
Authors: Chau Yuan-Fong , Yeh Han-Hsuan , Tsai Din Ping
Published: February 2009

This paper presents a numerical study of high birefringence induced by four types (Type 1–4) of different sizes of elliptical air holes in photonic crystal fibers (PCFs). The numerical simulation is carried out by using the finite element method. The statistical correlations between the birefringence and the various parameters are obtained. Based on our results, the birefringence is found to be largely dependent on the variation of the normalized frequency, size ratio, effective area of the circular and elliptical air holes, and the ring number of cladding. Two of our suggested structures, Type 1 and Type 3, can considerably enhance the birefringence in PCFs leading to values as high as7.697×10−3and8.002×10−3, respectively, which are much higher than that obtained by a conventional step-index fiber.
Flexible Hardware-Based Stereo Matching
Authors: Ambrosch Karina , Kubinger Wilfried , Humenberger Martin , Steininger Andreas
Published: February 2009

To enable adaptive stereo vision for hardware-based embedded stereo vision systems, we propose a novel technique for implementing a flexible block size, disparity range, and frame rate. By reusing existing resources of a static architecture, rather than dynamic reconfiguration, our technique is compatible with application specific integrated circuit (ASIC) as well as field programmable gate array (FPGA) implementations. We present the corresponding block diagrams and their implementation in our hardware-based stereo matching architecture. Furthermore, we show the impact of flexible stereo matching on the generated disparity maps for the sum of absolute differences (SADs), rank, and census transform algorithms. Finally, we discuss the resource usage and achievable performance when synthesized for an Altera Stratix II FPGA.
The Coarse-Grained/Fine-Grained Logic Interface in FPGAs with Embedded Floating-Point Arithmetic Units
Authors: Yu Chi Wai , Lamoureux Julien , Wilton Steven J. E. , Leong Philip H. W. , Luk Wayne
Published: February 2009

This paper examines the interface between fine-grained and coarse-grained programmable logic in FPGAs. Specifically, it presents an empirical study that covers the location, pin arrangement, and interconnect between embedded floating point units (FPUs) and the fine-grained logic fabric in FPGAs. It also studies this interface in FPGAs which contain both FPUs and embedded memories. The results show that (1) FPUs should have a square aspect ratio; (2) they should be positioned near the center of the FPGA; (3) their I/O pins should be arranged around all four sides of the FPU; (4) embedded memory should be located between the FPUs; and (5) connecting higher I/O density coarse-grained blocks increases the demand for routing resources. The hybrid FPGAs with embedded memory required 12% wider channels than the case where embedded memory is not used.
In Situ Real‐Time Chemiluminescence Imaging of Reactive Oxygen Species Formation from Cardiomyocytes
Authors: Li Yunbo , Shen Haiou , Zhu Hong , Trush Michael A. , Jiang Ming , Wang Ge
Published: February 2009

We have applied the highly sensitive chemiluminescence (CL) imaging
technique to investigate the in situ ROS formation in cultured monolayers of rat H9c2 cardiomyocytes. Photon emission was detected via an innovative imaging system after incubation of H9c2 cells in culture with luminol and horseradish peroxidase (HRP), suggesting constitutive formation of ROS by the cardiomyocytes. Addition of benzo(a)pyrene‐1,6‐quinone
(BPQ) to cultured H9c2 cells resulted in a 4‐5‐fold increase in the formation of ROS, as detected by the CL imaging. Both constitutive and BPQ‐stimulated CL responses in cultured H9c2 cells were sustained for up to 1 hour. The CL responses were completely abolished in the presence of superoxide dismutase and catalase, suggesting the primary involvement of superoxide and hydrogen peroxide (H2O2). In contrast to BPQ‐mediated redox cycling, blockage of mitochondrial electron transport chain by either antimycin A or rotenone exerted marginal effects on the ROS formation by cultured H9c2 cells. Upregulation of cellular antioxidants for
detoxifying both superoxide and H2O2 by 3H‐1,2‐dithiole‐3‐thione resulted in marked inhibition of both constitutive and BPQ‐augmented ROS formation in cultured H9c2 cells. Taken together, we demonstrate the sensitive detection of ROS by CL imaging in cultured cardiomyocytes.
Acquired Jugular Vein Aneurysm
Authors: Hopsu Erkki , Tarkkanen Jussi , Vento Seija I. , Pitkäranta Anne
Published: February 2009

Venous malformations of the jugular veins are rare findings. Aneurysms and phlebectasias are the lesions most often reported. We report on an adult patient with an abruptly appearing large tumorous mass on the left side of the neck identified as a jugular vein aneurysm. Upon clinical examination with ultrasound, a lateral neck cyst was primarily suspected. Surgery revealed a saccular aneurysm in intimate connection with the internal jugular vein. Histology showed an organized hematoma inside the aneurysmal sac, which had a focally thinned muscular layer. The terminology and the treatment guidelines of venous dilatation lesions are discussed. For phlebectasias, conservative treatment is usually recommended, whereas for saccular aneurysms, surgical resection is the treatment of choice. While an exact classification based on etiology and pathophysiology is not possible, a more uniform taxonomy would clarify the guidelines for different therapeutic modalities for venous dilatation lesions.
Outpatient-Based Therapy of Oral Fludarabine and Subcutaneous Alemtuzumab for Asian Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia
Authors: Hwang William Y. K. , Dearden Claire , Loh Yvonne S. M. , Linn Yeh C. , Tien Sim L. , Teoh Gerrard K. H. , How Gee F. , Heng Kee K. , Goh Yeow T. , Lee Lai H.
Published: February 2009

Background. Intravenous alemtuzumab and fludarabine are effective in combination for the treatment of chronic lymphocytic leukemia (CLL), but require hospital visits for intravenous injection. We performed a pilot study to assess the safety and efficacy of outpatient-based oral fludarabine with subcutaneous alemtuzumab (OFSA) for the treatment of relapsed/refractory CLL.Results. Depending on their response, patients were given two to six 28-day cycles of subcutaneous alemtuzumab 30 mg on days 1,3, and 5 and oral fludarabine 40 mg/m2/day for 5 days. Median patient age was 74. The lymphocyte counts of all five patients fell after the 1st cycle of treatment and reached normal/low levels on completion of 2 to 6 cycles of therapy. Platelet counts and hemoglobin were unaffected. All five patients achieved complete hematological remission, while two attained minimal residual disease negativity on 4-color flow cytometry.Conclusions. Our OFSA regimen was effective in elderly Asian patients with relapsed/refractory CLL, and it should be investigated further.
Preparation and Characterization of NiO Nanoparticles by Anodic Arc Plasma Method
Authors: Qiao Hongxia , Wei Zhiqiang , Yang Hua , Zhu Lin , Yan Xiaoyan
Published: February 2009

NiO nanoparticles with average particle size of 25 nm were successfully prepared by anodic arc plasma method.
The composition, morphology, crystal microstructure, specific surface area, infrared spectra, and particle size distribution of product were analyzed by using X‐ray diffraction (XRD), transmission electron microscopy (TEM) and the corresponding
selected area electron diffraction (SAED), Fourier transform infrared (FTIR) spectrum, and Brunauer‐Emmett‐Teller (BET) N2 adsorption.
The experiment results show that the NiO nanoparticles are bcc structure with spherical shape and well dispersed, the particle size
distribution ranging from 15 to 45 nm with the average particle size is about 25 nm, and the specific surface area is 33 m2/g. The
infrared absorption band of NiO nanoparticles shows blue shifts compared with that of bulk NiO.
A Role for Stroma-Derived Annexin A1 as Mediator in the Control of Genetic Susceptibility to T-Cell Lymphoblastic Malignancies through Prostaglandin E2 Secretion
Authors: Santos Javier , González-Sánchez Laura , Matabuena-deYzaguirre María , Villa-Morales María , Cozar Patricia , López-Nieva Pilar , Fernández-Navarro Pablo , Fresno Manuel , Díaz-Muñoz Manuel D. , Guenet Jean-Louis , Montagutelli Xavier , Fernández-Piqueras José
Published: February 2009

Cancer susceptibility is essentially attributable to multiple low-penetrance genes. Using interspecific consomic and congenic mice between the tumor-resistant SEG/Pas and the tumor-sensitive C57BL/6J strains, a region on chromosome 19 involved in the genetic resistance to γ-irradiation–induced T-cell lymphomas (Tlyr1) has been identified. Through the development of nonoverlapping subcongenic strains, it has been further shown that Anxa1 may be a candidate resistance gene on the basis of its differential expression in thymus stroma cells after γ-radiation exposure. In addition, thymus stroma cells of thymic lymphomas exhibited a significant reduction in the expression levels of Anxa1. Interestingly, the activity of Anxa1 relies on prostaglandin E2 (PGE2) induction that brings about apoptosis in thymocytes. In fact, in vitro transfection experiments revealed that PGE2 production was enhanced when HEK 293 cells were transfected with full-length cDNAs of Anxa1, with PGE2 production in the cells transfected with the allele of the resistant strain (Anxa1Tyr) being higher than that in cells transfected with the allele of the susceptible strain (Anxa1Phe). Furthermore, the presence of this compound in the medium induced apoptosis of immature CD4+CD8+CD3low cells in a dose-dependent manner. These results improve our knowledge of the molecular mechanisms triggering T-cell lymphoblastic lymphoma development while highlighting the relevance of the stroma in controlling genetic susceptibility and the use of PGE2 as a new therapeutic approach in T-cell hematologic malignancies. [Cancer Res 2009;69(6):2577–87]
Design and Activity of a Murine and Humanized Anti-CEACAM6 Single-Chain Variable Fragment in the Treatment of Pancreatic Cancer
Authors: Riley Christopher J. , Engelhardt Kevin P. , Saldanha Jose W. , Qi Wenqing , Cooke Laurence S. , Zhu Yingting , Narayan Satya T. , Shakalya Kishore , Croce Kimiko Della , Georgiev Ivan G. , Nagle Raymond B. , Garewal Harinder , Von Hoff Daniel D. , Mahadevan Daruka
Published: February 2009

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease, with surgery being the only curative modality for localized disease, and gemcitabine with or without erlotinib remains the standard of therapy for unresectable or metastatic disease. CEACAM6 is overexpressed in human PDA independent of stage or grade and causes anoikis resistance when dysregulated. Because murine monoclonal antibody 13-1 possesses target-specific cytotoxicity in human PDA cell lines, we designed a humanized anti-CEACAM6 single-chain variable fragment (scFv) based on monoclonal antibody 13-1. PEGylation of the glycine-serine linker was used to enhance plasma half-life. These scFvs bound CEACAM6 with high affinity, exhibited cytotoxic activity, and induced dose-dependent poly(ADP-ribose) polymerase cleavage. Murine PDA xenograft models treated with humanized scFv alone elicited tumor growth inhibition, which was enhanced in combination with gemcitabine. Immunohistochemistry showed significant apoptosis, with inhibition of angiogenesis and proliferation, and preservation of the target. Collectively, our results have important implications for the development of novel antibody-based therapies against CEACAM6 in PDA. [Cancer Res 2009;69(5):1933–40]
miR-205 Exerts Tumor-Suppressive Functions in Human Prostate through Down-regulation of Protein Kinase Cε
Authors: Gandellini Paolo , Folini Marco , Longoni Nicole , Pennati Marzia , Binda Mara , Colecchia Maurizio , Salvioni Roberto , Supino Rosanna , Moretti Roberta , Limonta Patrizia , Valdagni Riccardo , Daidone Maria Grazia , Zaffaroni Nadia
Published: February 2009

Limited information is available concerning the expression and role of microRNAs in prostate cancer. In this study, we investigated the involvement of miR-205 in prostate carcinogenesis. Significantly lower miR-205 expression levels were found in cancer than in normal prostate cell lines as well as in tumor compared with matched normal prostate tissues, with a particularly pronounced reduction in carcinomas from patients with local-regionally disseminated disease. Restoring the expression of miR-205 in prostate cancer cells resulted in cell rearrangements consistent with a mesenchymal-to-epithelial transition, such as up-regulation of E-cadherin and reduction of cell locomotion and invasion, and in the down-regulation of several oncogenes known to be involved in disease progression (i.e., interleukin 6, caveolin-1, EZH2). Our evidence suggests that these events are driven by the concurrent repression of specific predicted miR-205 targets, namely N-chimaerin, ErbB3, E2F1, E2F5, ZEB2, and protein kinase Cε. Strikingly, the latter seemed to play a direct role in regulating epithelial-to-mesenchymal transition. In fact, its down-regulation led to a cell phenotype largely reminiscent of that of cells ectopically expressing miR-205. Overall, we showed for the first time that miR-205 exerts a tumor-suppressive effect in human prostate by counteracting epithelial-to-mesenchymal transition and reducing cell migration/invasion, at least in part through the down-regulation of protein kinase Cε. [Cancer Res 2009;69(6):2287–95]
IFNγ Promotes Papilloma Development by Up-regulating Th17-Associated Inflammation
Authors: Xiao Mingjie , Wang Chunhui , Zhang Jinhua , Li Zhiguang , Zhao Xueqiang , Qin Zhihai
Published: February 2009

IFNγ plays a crucial role in immunity against a variety of transplanted tumors and methylcholanthrene-mediated tumorigenesis in mice. However, it is not clear whether and how endogenous IFNγ influences 7,12-dimethylbenz(a)anthracene (DMBA)–induced and 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced papilloma development. We found here that IFNγ expression was markedly up-regulated shortly after DMBA/TPA application to the skin. Surprisingly, neutralizing IFNγ activity in vivo did not increase but rather decreased tumor development. Furthermore, IFNγ receptor–deficient mice were also more resistant to papilloma development than their counterparts were. IFNγ acted mainly in the promotion stage of papilloma development by enhancing TPA-induced leukocyte infiltration and epidermal hyperproliferation. The up-regulation of tumor necrosis factor α, interleukin (IL)-6, and transforming growth factor β was largely dependent on host IFNγ responsiveness. Remarkably, up-regulation of both IL-17 expression in the skin and T helper 17 (Th17) cell number in draining lymph nodes after DMBA/TPA treatment was dependent on IFNγ signaling. Depletion of IL-17 not only decreased the DMBA/TPA–induced inflammation and keratinocyte proliferation but also delayed papilloma development. These results show that IFNγ, under certain conditions, may promote tumor development by enhancing a Th17-associated inflammatory reaction. [Cancer Res 2009;69(5):2010–7]
Control of HIF-1α Expression by eIF2α Phosphorylation–Mediated Translational Repression
Authors: Zhu Keyi , Chan WaiKin , Heymach John , Wilkinson Miles , McConkey David J.
Published: February 2009

Hypoxia inducible factor 1α (HIF-1α) plays a central role in regulating tumor angiogenesis via its effects on vascular endothelial growth factor (VEGF) transcription, and its expression is regulated through proteasome-mediated degradation. Paradoxically, previous studies have shown that proteasome inhibitors (PI) block tumor angiogensis by reducing VEGF expression, but the mechanisms have not been identified. Here, we report that PIs down-regulated HIF-1α protein levels and blocked HIF-1α transcriptional activity in human prostate cancer cells. PIs induced phosphorylation of the translation initiation factor 2α (eIF2α), which caused general translational repression to inhibit HIF-1α expression. Furthermore, PIs induced HIF-1α accumulation in LNCaP-Pro5 cells depleted of eIF2α via siRNA transfection and in MEFs expressing a phosphorylation-deficient mutant form of eIF2α. Finally, PIs failed to induce eIF2α phosphorylation or translational attenuation in DU145 or 253JB-V cells, and, in these cells, PIs promoted HIF-1α accumulation. Our data established that PIs down-regulated HIF-1α expression in cells that display activation of the unfolded protein response by stimulating phosphorylation of eIF2α and inhibiting HIF-1α translation. [Cancer Res 2009;69(5):1836–43]
Resistance to Chemotherapy Is Associated with Fibroblast Growth Factor Receptor 4 Up-Regulation
Authors: Roidl Andreas , Berger Hans-Jürgen , Kumar Sushil , Bange Johannes , Knyazev Pjotr , Ullrich Axel
Published: February 2009

Purpose: Establishment of antiapoptotic signaling pathways in tumor cells is a major cause for the failure of chemotherapy against cancer. To investigate the underlying mechanisms, we developed an experimental approach that is based on the genetic plasticity of cancer cells and the selection for cell survival on treatment with chemotherapeutic agents.

Experimental Design: Gene expression changes of surviving cell clones were analyzed by macroarrays. Involvement of fibroblast growth factor receptor 4 (FGFR4) in antiapoptotic pathways was elucidated by apoptosis assays, small interfering RNA experiments, and an antagonistic antibody.

Results: We show that FGFR4 gene expression is up-regulated in doxorubicin-treated, apoptosis-resistant cancer cell clones. Ectopic expression of FGFR4 in cancer cells led to reduced apoptosis sensitivity on treatment with doxorubicin or cyclophosphamide, whereas knockdown of endogenous FGFR4 expression in breast cancer cell lines had the opposite effect. FGFR4 overexpression resulted in Bcl-xl up-regulation at both mRNA and protein levels. Knockdown of FGFR4 expression by small interfering RNA caused a decrease in phospho-extracellular signal-regulated kinase 1/2 levels and reduced Bcl-xl expression. Moreover, an antagonistic FGFR4 antibody suppressed the resistance of cancer cells with endogenous FGFR4 expression against apoptosis-inducing chemotherapeutic agents.

Conclusion: Based on these findings, we propose an antiapoptotic signaling pathway that is initiated by FGFR4 and regulating the expression of Bcl-xl through the mitogen-activated protein kinase cascade. Our findings are exemplary for a novel strategy toward the elucidation of diverse signaling pathways that define antiapoptotic potential in cancer cells. These observations open new avenues toward the diagnosis of chemoresistant tumors and therapies targeting FGFR4-overexpressing cancers.
High VEGFR-3–positive Circulating Lymphatic/Vascular Endothelial Progenitor Cell Level Is Associated with Poor Prognosis in Human Small Cell Lung Cancer
Authors: Bogos Krisztina , Renyi-Vamos Ferenc , Dobos Judit , Kenessey Istvan , Tovari Jozsef , Timar Jozsef , Strausz Janos , Ostoros Gyula , Klepetko Walter , Ankersmit Hendrik Jan , Lang Gyorgy , Hoda Mir AliReza , Nierlich Patrick , Dome Balazs
Published: February 2009

Purpose: The newly identified bone marrow–derived cell population, called lymphatic/vascular endothelial progenitor cells (LVEPC), has been shown to contribute to lymph capillary growth in experimental tumor systems. The clinical significance of these cells has not yet been investigated in a human malignancy. Our aim was to study whether peripheral blood circulating LVEPCs participate in the progression of human small cell lung cancer (SCLC).

Experimental Design: A total of 88 patients with limited-stage SCLC and 32 tumor-free control subjects were included. Peripheral blood circulating LVEPC labeled with CD34 and vascular endothelial growth factor receptor-3 (VEGFR3) antibodies and the serum levels of the key lymphangiogenic molecule VEGF-C were measured by flow cytometry and ELISA, respectively.

Results: CD34-positive/VEGFR3-positive LVEPC levels were significantly increased in patients (versus controls; P < 0.01), and there was also a significant relationship between LVEPC counts and lymph node metastasis (P < 0.01). High pretreatment circulating LVEPC numbers correlated with poor overall survival (P < 0.01). Although we observed significantly elevated VEGF-C concentrations in patients (versus controls; P < 0.01), there was no significant correlation between VEGF-C and LVEPC levels. Moreover, no significant differences in peripheral blood VEGF-C levels were seen between patients subgrouped by clinicopathologic variables including tumor and lymph node stages and survival.

Conclusions: Peripheral blood levels of bone marrow–derived LVEPCs are significantly increased in patients with SCLC and correlate with lymphatic involvement and prognosis. This is the first study that shows evidence of increased numbers of circulating LVEPC in patients with a malignant tumor.
Radiotherapy Decreases Vascular Density and Causes Hypoxia with Macrophage Aggregation in TRAMP-C1 Prostate Tumors
Authors: Chen Fang-Hsin , Chiang Chi-Shiun , Wang Chun-Chieh , Tsai Chien-Sheng , Jung Shih-Ming , Lee Chung-Chi , McBride William H. , Hong Ji-Hong
Published: February 2009

Purpose: To investigate how single or fractionated doses of radiation change the microenvironment in transgenic adenocarcinoma of the mouse prostate (TRAMP)-C1 tumors with respect to vascularity, hypoxia, and macrophage infiltrates.

Experimental Design: Murine prostate TRAMP-C1 tumors were grown in C57BL/6J mice to 4 mm tumor diameter and were irradiated with either 25 Gy in a single dose or 60 Gy in 15 fractions. Changes in vascularity, hypoxia, and macrophage infiltrates were assessed by immunohistochemistry and molecular assays.

Results: Tumor growth was delayed for 1 week after both radiation schedules. Tumor microvascular density (MVD) progressively decreased over a 3-week period to nadirs of 25% and 40% of unirradiated tumors for single or fractionated treatment, respectively. In accord with the decrease in MVDs, mRNA levels of endothelial markers, such as CD31, endoglin, and TIE, decreased over the same time period after irradiation. Central dilated vessels developed surrounded by avascularized hypoxic regions that became infiltrated with aggregates of CD68+ tumor-associated macrophages, reaching a maximum at 3 weeks after irradiation. Necrotic regions decreased and were more dispersed.

Conclusion: Irradiation of TRAMP-C1 tumors with either single or fractionated doses decreases MVD, leading to the development of disperse chronic hypoxic regions, which are infiltrated with CD68+ tumor-associated macrophages. Approaches to interfere in the development of these effects are promising strategies to enhance the efficacy of cancer radiotherapy.
Cellular folate status modulates the expression of BCRP and MRP multidrug transporters in cancer cell lines from different origins
Authors: Lemos Clara , Kathmann Ietje , Giovannetti Elisa , Beliën Jeroen A.M. , Scheffer George L. , Calhau Conceição , Jansen Gerrit , Peters Godefridus J.
Published: February 2009

As cellular folate levels seem to have a different effect on cancer cells from different origins, we extended our initial study to a broader panel of cancer cells. BCRP and MRP1-5 expression was determined in KB, OVCAR-3, IGROV-1, ZR75-1/R/MTX, SCC-11B, SCC-22B, and WiDr either grown in standard RPMI 1640 containing 2.3 μmol/L supraphysiologic concentration of folic acid [high folate (HF)] or adapted to more physiologic concentrations [1-5 nmol/L folic acid or leucovorin; low folate (LF)]. Compared with the HF counterparts, KB LF cells displayed 16.1-fold increased MRP3 and OVCAR-3 LF cells showed 4.8-fold increased MRP4 mRNA levels along with increased MRP3 and MRP4 protein expression, respectively. A marked increase on BCRP protein and mRNA expression was observed in WiDr LF cells. These cells acquired ∼2-fold resistance to mitoxantrone compared with the HF cell line, a phenotype that could be reverted by the BCRP inhibitor Ko143. Of note, WiDr cells expressed BCRP in the intracellular compartment, similarly to what we have described for Caco-2 cells. Our results provide further evidence for an important role of cellular folate status in the modulation of the expression of multidrug resistance transporters in cancer cells. We show that up-regulation of intracellularly localized BCRP in response to adaptation to LF conditions may be a common feature within a panel of colon cancer cell lines. Under these circumstances, folate supplementation might improve the efficacy of chemotherapeutic drugs by decreasing BCRP expression. [Mol Cancer Ther 2009;8(3):655–64]
p53 Deficiency Leads to Compensatory Up-Regulation of p16INK4a
Authors: Leong Wai Fook , Chau Jenny Fung Ling , Li Baojie
Published: February 2009

p53-p21-cyclin-dependent kinase and p16INK4a-cyclin-dependent kinase pathways have parallel functions in preventing tumorigenesis. In cancer patients, tumor suppressor p53 is frequently inactivated through mutations, whereas p16INK4a is silenced through promoter methylation. However, the interaction between these two pathways is less well understood. Here, we report that p53 controls p16INK4a expression in a unique way. p53 deficiency led to up-regulation of p16INK4a in primary mouse embryonic fibroblasts, osteoblasts, and various mouse organs, and an increase in the p16INK4a promoter activity, without affecting the half-life of p16INK4a. Reconstitution of p53, but not mutant p53, restored the proper expression of p16INK4a. These results indicate that p53 is necessary in repressing p16INK4a expression. However, up-regulation of p53 in response to genotoxic stress or nutlin-3 treatment did not down-regulate p16INK4a. p53 did not repress the p16INK4a promoter activity either. These findings suggest that p53 has a necessary but not sufficient role in repressing p16INK4a expression. p16INK4a elevation in p53−/− cells is, at least partially, mediated by Ets1, a known positive regulator of p16INK4a, as p53 deficiency up-regulated Ets1 through protein stabilization and knockdown of Ets1 down-regulated p16INK4a expression in p53−/− mouse embryonic fibroblasts. These studies uncover a compensatory mechanism for the loss of p53 and provide a basis for targeting both p53 and p16INK4a in cancer therapy. (Mol Cancer Res 2009;7(3):354–63)
Race, Genetic West African Ancestry, and Prostate Cancer Prediction by Prostate-Specific Antigen in Prospectively Screened High-Risk Men
Authors: Giri Veda N. , Egleston Brian , Ruth Karen , Uzzo Robert G. , Chen David Y.T. , Buyyounouski Mark , Raysor Susan , Hooker Stanley , Torres Jada Benn , Ramike Teniel , Mastalski Kathleen , Kim Taylor Y. , Kittles Rick
Published: February 2009

“Race-specific” prostate-specific antigen (PSA) needs evaluation in men at high risk for prostate cancer for optimizing early detection. Baseline PSA and longitudinal prediction for prostate cancer were examined by self-reported race and genetic West African (WA) ancestry in the Prostate Cancer Risk Assessment Program, a prospective high-risk cohort. Eligibility criteria were age 35 to 69 years, family history of prostate cancer, African American race, or BRCA1/2 mutations. Biopsies were done at low PSA values (<4.0 ng/mL). WA ancestry was discerned by genotyping 100 ancestry informative markers. Cox proportional hazards models evaluated baseline PSA, self-reported race, and genetic WA ancestry. Cox models were used for 3-year predictions for prostate cancer. Six hundred forty-six men (63% African American) were analyzed. Individual WA ancestry estimates varied widely among self-reported African American men. Race-specific differences in baseline PSA were not found by self-reported race or genetic WA ancestry. Among men with ≥1 follow-up visit (405 total, 54% African American), 3-year prediction for prostate cancer with a PSA of 1.5 to 4.0 ng/mL was higher in African American men with age in the model (P = 0.025) compared with European American men. Hazard ratios of PSA for prostate cancer were also higher by self-reported race (1.59 for African American versus 1.32 for European American, P = 0.04). There was a trend for increasing prediction for prostate cancer with increasing genetic WA ancestry. “Race-specific” PSA may need to be redefined as higher prediction for prostate cancer at any given PSA in African American men. Large-scale studies are needed to confirm if genetic WA ancestry explains these findings to make progress in personalizing prostate cancer early detection.