bluuebunny/crossref_metadata_2025 huggingface dataset:
RESPONSE OF SOFT CLAY STRATA AND CLAY-PILE-RAFT SYSTEMS TO SEISMIC SHAKING
Authors: BANERJEE SUBHADEEP , GOH SIANG HUAT , LEE FOOK HOU
Published: October 2007

The behavior of pile foundations under earthquake loading is an important factor affecting the performance of structures. Observations from past earthquakes have shown that piles in firm soils generally perform well, while the performance of piles in soft or liquefied ground can raise some questions. Centrifuge model tests were carried out at the National University of Singapore to investigate the response of pile-soil system under three different earthquake excitations. Some initial tests were done on kaolin clay beds to understand the pure clay behavior under repetitive earthquake shaking. Pile foundations comprising of solid steel, hollow steel and hollow steel pile filled with cement in-fill were then embedded in the kaolin clay beds to study the response of clay-pile system. Superstructural inertial loading on the foundation was modeled by fastening steel weight on top of the model raft. The model test results show that strain softening and stiffness degradation feature strongly in the behaviour of the clay. In uniform clay beds without piles, this is manifested as an increase in resonance periods of the surface response with level of shaking and with successive earthquakes. For the pile systems tested, the effect of the surrounding soft clay was primarily to impose an inertial loading onto the piles, thereby increasing the natural period of the piles over and above that of the pile foundation alone. There is also some evidence that the relative motion between piles and soil leads to aggravated softening of the soil around the pile, thereby lengthening its resonance period of the soil further. The centrifuge model tests were back-analyzed using the finite element code ABAQUS. The analysis shows that the simple non-linear hypoelastic soil model gave reasonably good agreement with the experimental observations. The engineering implication arising from this study so far is that, for the case of relatively short piles in soft clays, the ground surface motions may not be representative of the raft motion. Other than the very small earthquakes, the raft motion has a shorter resonance period than the surrounding soil.
Information fusion for wireless sensor networks
Authors: Nakamura Eduardo F. , Loureiro Antonio A. F. , Frery Alejandro C.
Published: September 2007

Wireless sensor networks produce a large amount of data that needs to be processed, delivered, and assessed according to the application objectives. The way these data are manipulated by the sensor nodes is a fundamental issue. Information fusion arises as a response to process data gathered by sensor nodes and benefits from their processing capability. By exploiting the synergy among the available data, information fusion techniques can reduce the amount of data traffic, filter noisy measurements, and make predictions and inferences about a monitored entity. In this work, we survey the current state-of-the-art of information fusion by presenting the known methods, algorithms, architectures, and models of information fusion, and discuss their applicability in the context of wireless sensor networks.
Scalable precision cache analysis for real-time software
Authors: Staschulat Jan , Ernst Rolf
Published: September 2007

Caches are needed to increase the processor performance, but the temporal behavior is difficult to predict, especially in embedded systems with preemptive scheduling. Current approaches use simplified assumptions or propose complex analysis algorithms to bound the cache-related preemption delay. In this paper, a scalable preemption delay analysis for associative instruction caches to control the analysis precision and the time-complexity is proposed. An accurate preemption delay calculation is integrated into a cache-aware schedulability analysis. The framework is evaluated in several experiments.
Robust implicit EDF
Authors: Crenshaw Tanya L. , Hoke Spencer , Tirumala Ajay , Caccamo Marco
Published: September 2007

Advances in wireless technology have brought us closer to extensive deployment of distributed real-time embedded systems connected through a wireless channel. The medium-access control (MAC) layer protocol is critical in providing a real-time guarantee. We have devised a real-time wireless MAC protocol, robust implicit earliest deadline first, or RI-EDF. Packets are transmitted according to EDF scheduling rules, offering a protocol that implicitly avoids contention. In the event of a packet loss or a node failure, every node has the opportunity to recover the schedule based on a static recovery priority, offering a protocol that is robust with no central point of failure. We demonstrate in simulations that RI-EDF provides better goodput and lower packet loss than existing protocols like 802.11 PCF and EDCF. In our implementation and distributed control test-bed, we show that RI-EDF provides better throughput than the TinyOS MAC-layer protocol. Overall, RI-EDF provides predictable temporal behavior with minimal impact on node failures, packet losses, and noise in the channel.
Static checking of dynamically generated queries in database applications
Authors: Wassermann Gary , Gould Carl , Su Zhendong , Devanbu Premkumar
Published: September 2007

Many data-intensive applications dynamically construct queries in response to client requests and execute them. Java servlets, for example, can create strings that represent SQL queries and then send the queries, using JDBC, to a database server for execution. The servlet programmer enjoys static checking via Java's strong type system. However, the Java type system does little to check for possible errors in the dynamically generated SQL query strings. Thus, a type error in a generated selection query (e.g., comparing a string attribute with an integer) can result in an SQL runtime exception. Currently, such defects must be rooted out through careful testing, or (worse) might be found by customers at runtime. In this article, we present a
sound
,
static
program analysis technique to verify that dynamically generated query strings do not contain type errors. We describe our analysis technique and provide soundness results for our static analysis algorithm. We also describe the details of a prototype tool based on the algorithm and present several illustrative defects found in senior software-engineering student-team projects, online tutorial examples, and a real-world purchase order system written by one of the authors.
Providing signed content on the Internet by synthesized animation
Authors: Kennaway J. R. , Glauert J. R. W. , Zwitserlood I.
Published: September 2007

Written information is often of limited accessibility to deaf people who use sign language. The eSign project was undertaken as a response to the need for technologies enabling efficient production and distribution over the Internet of sign language content. By using an avatar-independent scripting notation for signing gestures and a client-side web browser plug-in to translate this notation into motion data for an avatar, we achieve highly efficient delivery of signing, while avoiding the inflexibility of video or motion capture. Tests with members of the deaf community have indicated that the method can provide an acceptable quality of signing.
BrowserShield
Authors: Reis Charles , Dunagan John , Wang Helen J. , Dubrovsky Opher , Esmeir Saher
Published: September 2007

Vulnerability-driven filtering of network data can offer a fast and easy-to-deploy alternative or intermediary to software patching, as exemplified in Shield [Wang et al. 2004]. In this article, we take Shield's vision to a new domain, inspecting and cleansing not just static content, but also dynamic content. The dynamic content we target is the dynamic HTML in Web pages, which have become a popular vector for attacks. The key challenge in filtering dynamic HTML is that it is undecidable to statically determine whether an embedded script will exploit the browser at runtime. We avoid this undecidability problem by rewriting web pages and any embedded scripts into safe equivalents, inserting checks so that the filtering is done at runtime. The rewritten pages contain logic for recursively applying runtime checks to dynamically generated or modified web content, based on known vulnerabilities. We have built and evaluated
BrowserShield
, a general framework that performs this dynamic instrumentation of embedded scripts, and that admits policies for customized runtime actions like vulnerability-driven filtering. We also explore other applications on top of BrowserShield.
Model-directed Web transactions under constrained modalities
Authors: Sun Zan , Mahmud Jalal , Ramakrishnan I. V. , Mukherjee Saikat
Published: September 2007

Online transactions (e.g., buying a book on the Web) typically involve a number of steps spanning several pages. Conducting such transactions under constrained interaction modalities as exemplified by small screen handhelds or interactive speech interfaces—the primary mode of communication for visually impaired individuals—is a strenuous, fatigue-inducing activity. But usually one needs to browse only a small fragment of a Web page to perform a transactional step such as a form fillout, selecting an item from a search results list, and so on. We exploit this observation to develop an automata-based process model that delivers only the “relevant” page fragments at each transactional step, thereby reducing information overload on such narrow interaction bandwidths. We realize this model by coupling techniques from content analysis of Web documents, automata learning and statistical classification. The process model and associated techniques have been incorporated into Guide-O, a prototype system that facilitates online transactions using speech/keyboard interface (Guide-O-Speech), or with limited-display size handhelds (Guide-O-Mobile). Performance of Guide-O and its user experience are reported.
Cache architecture for on-demand streaming on the Web
Authors: Sharman Raj , Ramanna Shiva Shankar , Ramesh Ram , Gopal Ram
Published: September 2007

On-demand streaming from a remote server through best-effort Internet poses several challenges because of network losses and variable delays. The primary technique used to improve the quality of distributed content service is replication. In the context of the Internet, Web caching is the traditional mechanism that is used. In this article we develop a new staged delivery model for a distributed architecture in which video is streamed from remote servers to edge caches where the video is buffered and then streamed to the client through a last-mile connection. The model uses a novel revolving indexed cache buffer management mechanism at the edge cache and employs selective retransmissions of lost packets between the remote and edge cache for a best-effort recovery of the losses. The new Web cache buffer management scheme includes a dynamic adjustment of cache buffer parameters based on network conditions. In addition, performance of buffer management and retransmission policies at the edge cache is modeled and assessed using a probabilistic analysis of the streaming process as well as system simulations. The influence of different endogenous control parameters on the quality of stream received by the client is studied. Calibration curves on the QoS metrics for different network conditions have been obtained using simulations. Edge cache management can be done using these calibration curves. ISPs can make use of calibration curves to set the values of the endogenous control parameters for specific QoS in real-time streaming operations based on network conditions. A methodology to benchmark transmission characteristics using real-time traffic data is developed to enable effective decision making on edge cache buffer allocation and management strategies.
Interview with Peter J. Nürnberg
Authors: Atzenbeck Claus
Published: September 2007

Peter J. Nürnberg is a Managing Partner of Xtructure, LLC, a company founded in 2002 to provide network modeling and simulation tools. He received his M.S. (1994) and Ph.D. (1997) in Computer Science at Texas A&M University, working on hypermedia and structural computing infrastructures. He spent two years at the University of Aarhus, Denmark, before moving to Aalborg University Esbjerg, Dennmark. He also spent one year at Graz University of Technology, Austria. He has served as Chair of SIGWEB (2003-2006), Program Chair of ACM Hypertext 2006, General Chair ACM Hypertext 2000 and of ACM Digital Libraries 2000, and an Associate Editor of ACM Transactions on the Web.
Experiences in deploying a wireless mesh network testbed for traffic control
Authors: Lan Kun-chan , Wang Zhe , Hassan Mahbub , Moors Tim , Berriman Rodney , Libman Lavy , Ott Maximilian , Landfeldt Bjorn , Zaidi Zainab
Published: September 2007

Wireless mesh networks (WMN) have attracted considerable interest in recent years as a convenient, flexible and low-cost alternative to wired communication infrastructures in many contexts. However, the great majority of research on metropolitan-scale WMN has been centered around maximization of available bandwidth, suitable for non-real-time applications such as Internet access for the general public. On the other hand, the suitability of WMN for mission-critical infrastructure applications remains by and large unknown, as protocols typically employed in WMN are, for the most part, not designed for real-time communications. In this paper, we describe the Smart Transport and Roads Communications (STaRComm) project at National ICT Australia (NICTA), which sets a goal of designing a wireless mesh network architecture to solve the communication needs of the traffic control system in Sydney, Australia. This system, known as SCATS (Sydney Coordinated Adaptive Traffic System)and used in over 100 cities around the world, connects a hierarchy of several thousand devices -- from individual traffic light controllers to regional computers and the central Traffic Management Centre (TMC)-- and places stringent requirements on the reliability and latency of the data exchanges. We discuss our experience in the deployment of an initial testbed consisting of 7 mesh nodes placed at intersections with traffic lights, and share the results and insights learned from our measurements and initial trials in the process.
Efficient identification of uncongested internet links for topology downscaling
Authors: Papadopoulos Fragkiskos , Psounis Konstantinos
Published: September 2007

It has been recently suggested that uncongested links could be completely ignored when evaluating Internet's performance. In particular, based on the observation that only the congested links along the path of each flow introduce sizable queueing delays and dependencies among flows, it has been shown that one can infer the performance of the larger Internet by creating and observing a suitably scaled-down replica, consisting of the congested links only. Given that the majority of Internet links are uncongested, it has been demonstrated that this approach can be used to greatly simplify and expedite performance prediction.

However, an important open problem, directly related to the practicability of such an approach, is whether there exist efficient and scalable ways for identifying uncongested links, in large and complex Internet-like networks. Of course, such a question is not only very important for scaling down Internet's topology, but also in many other contexts, e.g. such as in traffic engineering and capacity planning.

In this paper we present simple rules that can be used to efficiently identify uncongested Internet links. In particular, we first identify scenarios under which one can easily deduce whether a link is uncongested by inspecting the network topology. Then, we identify scenarios in which this is not possible, and propose an efficient methodology, based on the large deviations theory and flow-level statistics, to approximate the queue length distribution,and in turn, to deduce the congestion level of a link. We also demonstrate how simple commonly used metrics, such as the link utilization, can be quite misleading in classifying an Internet link.
Extreme programming compared with Microsoft-style iterative development
Authors: Cusumano Michael A.
Published: September 2007

Highlighting the similarities---although they might be superficial in some cases---in software development practices.
ACM TOSEM
Authors: Notkin David
Published: September 2007

Reviewers are an essential - and voluntary - cornerstone of ACM TOSEM, as for every peer-reviewed publication. Sitting in the EIC seat has provided me, not surprisingly, with a firsthand look at many reviewers, many reviews, and many reactions to reviews by authors and associate editors alike.
Corticotropin-releasing hormone activates connexin 43 via activator protein-1 transcription factor in human myometrial smooth muscle cells
Authors: Wu Xiang , Shen Hong , Yu Ling , Peng Mei , Lai Wei-Si , Ding Yi-Ling
Published: September 2007

Corticotropin-releasing hormone (CRH) and connexin 43 (Cx43) play crucial roles in uterine contraction and the onset of labor. The aim of the present study was to investigate the regulatory effects of CRH on Cx43 expression in human myometrial smooth muscle cells (SMCs) and, potentially, its activation of the c-Fos/activator protein (AP)-1 signaling pathway. Human myometrial SMCs collected from nonpregnant women were treated with different concentrations of CRH. Transient transfection of AP-1 decoy oligodeoxynucleotide (ODN) was used to block AP-1 sites of Cx43. The transcriptional activity of AP-1 was detected by luciferase assay. Cx43 protein expression was visualized by immunofluorescence staining. mRNA and protein expression of c-Fos and Cx43 were demonstrated by real-time quantitative RT-PCR and Western blot, respectively. CRH facilitated Cx43 expression and enhanced AP-1 promoter activity in human uterine SMCs. After CRH treatment, Cx43 expression in the cytoplasm increased significantly. CRH significantly increased mRNA and protein expression of c-Fos and Cx43 in a dose-dependent manner ( P < 0.01). A transient transfection of AP-1 decoy ODN did not affect CRH regulation of c-Fos ( P > 0.05) but almost completely abolished CRH-induced enhancement of Cx43 expression ( P < 0.01). In human primary myometrial SMCs, CRH enhances Cx43 mRNA and protein expression through upregulation of c-Fos expression. Blockade of AP-1 sites to the Cx43 promoter can neutralize the CRH-induced upregulation of Cx43.
Adiponectin improves endothelial function in hyperlipidemic rats by reducing oxidative/nitrative stress and differential regulation of eNOS/iNOS activity
Authors: Li Rong , Wang Wen-Qing , Zhang Haifeng , Yang Xinchung , Fan Qian , Christopher Theodore A. , Lopez Bernard L. , Tao Ling , Goldstein Barry J. , Gao Feng , Ma Xin L.
Published: September 2007

Plasma adiponectin level is significantly reduced in patients with metabolic syndrome, and vascular dysfunction is an important pathological event in these patients. However, whether adiponectin may protect endothelial cells and attenuate endothelial dysfunction caused by metabolic disorders remains largely unknown. Adult rats were fed with a regular or a high-fat diet for 14 wk. The aorta was isolated, and vascular segments were incubated with vehicle or the globular domain of adiponectin (gAd; 2 μg/ml) for 4 h. The effect of gAd on endothelial function, nitric oxide (NO) and superoxide production, nitrotyrosine formation, gp91phox expression, and endothelial nitric oxide synthase (eNOS)/inducible NOS (iNOS) activity/expression was determined. Severe endothelial dysfunction (maximal vasorelaxation in response to ACh: 70.3 ± 3.3 vs. 95.2 ± 2.5% in control, P < 0.01) was observed in hyperlipidemic aortic segments, and treatment with gAd significantly improved endothelial function ( P < 0.01). Paradoxically, total NO production was significantly increased in hyperlipidemic vessels, and treatment with gAd slightly reduced, rather than increased, total NO production in these vessels. Treatment with gAd reduced (−78%, P < 0.01) superoxide production and peroxynitrite formation in hyperlipidemic vascular segments. Moreover, a moderate attenuation (−30%, P < 0.05) in gp91phox and iNOS overexpression in hyperlipidemic vessels was observed after gAd incubation. Treatment with gAd had no effect on eNOS expression but significantly increased eNOS phosphorylation ( P < 0.01). Most noticeably, treatment with gAd significantly enhanced eNOS (+83%) but reduced iNOS (−70%, P < 0.01) activity in hyperlipidemic vessels. Collectively, these results demonstrated that adiponectin protects the endothelium against hyperlipidemic injury by multiple mechanisms, including promoting eNOS activity, inhibiting iNOS activity, preserving bioactive NO, and attenuating oxidative/nitrative stress.
Glucagon-like peptide 2 has limited efficacy to increase nutrient absorption in fetal and preterm pigs
Authors: Sangild Per T. , Malo Christiane , Schmidt Mette , Petersen Yvette M. , Elnif Jan , Holst Jens J. , Buddington Randal K.
Published: September 2007

Exogenous glucagon-like peptide 2 (GLP-2) prevents intestinal atrophy and increases nutrient absorption in term newborn pigs receiving total parenteral nutrition (TPN). We tested the hypothesis that the immature intestine of fetuses and preterm neonates has a diminished nutrient absorption response to exogenous GLP-2. This was accomplished using catheterized fetal pigs infused for 6 days (87–91% of gestation) with GLP-2 (25 nmol·kg−1·day−1 iv; n = 7) or saline ( n = 7), and cesarean-delivered preterm pigs (92% of gestation) that received TPN with GLP-2 (25 nmol·kg−1·day−1 iv; n = 8) or saline ( n = 7) for 6 days after birth. Responses to GLP-2 were assessed by measuring intestinal dimensions, absorption of nutrients (glucose, leucine, lysine, proline) by intact tissues and brush border membrane vesicles, and abundance of sodium-glucose cotransporter mRNA. Infusion of GLP-2 increased circulating GLP-2 levels in fetuses, but did not increase intestinal mass or absorption of nutrients by intact tissues and brush border membrane vesicles, except for lysine. Administration of exogenous GLP-2 to preterm TPN-fed pigs similarly did not increase rates of nutrient absorption, yet nutrient absorption capacities of the entire small intestine tended to increase (+10–20%, P < 0.10) compared with TPN alone due to increased intestinal mass (+30%, P < 0.05). GLP-2 infusion did not increase sodium-glucose cotransporter-1 mRNA abundance in fetuses or postnatal preterm pigs. Hence, the efficacy of exogenous GLP-2 to improve nutrient absorption by the intestine of fetal and preterm pigs is limited compared with term pigs and more mature animals and humans.
Metabolic response of trained and untrained women during high-intensity intermittent cycle exercise
Authors: Trapp E. Gail , Chisholm Donald J. , Boutcher Stephen H.
Published: September 2007

The metabolic response to two different forms of high-intensity intermittent cycle exercise was investigated in young women. Subjects (8 trained and 8 untrained) performed two bouts of high-intensity intermittent exercise: short sprint (SS) (8-s sprint, 12-s recovery) and long sprint (LS) (24-s sprint, 36-s recovery) for 20 min on two separate occasions. Both workload and oxygen uptake were greater in the trained subjects but were not significantly different for SS and LS. Plasma glycerol concentrations significantly increased during exercise. Lactate concentrations rose over the 20 min and were higher for the trained women. Catecholamine concentration was also higher postexercise compared with preexercise for both groups. Both SS and LS produced similar metabolic response although both lactate and catecholamines were higher after the 24-s sprint. In conclusion, these results show that high-intensity intermittent exercise resulted in significant elevations in catecholamines that appear to be related to increased venous glycerol concentrations. The trained compared with the untrained women tended to show an earlier increase in plasma glycerol concentrations during high-intensity exercise.
Dynamics of Response to Perceptual Pop-Out Stimuli in Macaque V1
Authors: Smith Matthew A. , Kelly Ryan C. , Lee Tai Sing
Published: September 2007

Contextual modulation due to feature contrast between the receptive field and surrounding region has been reported for numerous stimuli in primary visual cortex. One type of this modulation, iso-orientation surround suppression, has been studied extensively. The degree to which surround suppression is related to other forms of contextual modulation remains unknown. We used shape-from-shading stimuli in a field of distractors to test the latency and magnitude of contextual modulation to a stimulus that cannot be distinguished with an orientation-selective mechanism. This stimulus configuration readily elicits perceptual pop-out in human observers and induces a long-latency contextual modulation response in neurons in macaque early visual cortex. We found that animals trained to detect the location of a pop-out stimulus were better at finding a sphere that appeared to be lit from below in the presence of distractors that were lit from above. Furthermore, neuronal responses were stronger and had shorter latency in the condition where behavioral performance was best. This asymmetry is compatible with earlier psychophysical findings in human observers. In the population of V1 neurons, the latency of the contextual modulation response is 145 ms on average (ranging from 70 to 230 ms). This is much longer than the latency for iso-orientation surround suppression, indicating that the underlying circuitry is distinct. Our results support the idea that a feature-specific feedback signal generates the pop-out responses we observe and suggest that V1 neurons actively participate in the computation of perceptual salience.
The Barrier Magnetic Separator for the Treatment of WeaklyMagnetic Ores: Laboratoryscale Investigations and Industrial Tests
Authors: Turkenich A. M. , Baranov U. D. , Ruditsky A. V.
Published: October 2007

The principle of action of the barrier separator for beneficiation of coarse weakly
magnetic ores is described. New data of laboratory‐scale investigations of beneficiation
of manganese ore and mineral sands are introduced. The results of tests in the
Volnogorsk State Mining and Metallurgical Plant (VSMMP) show high technological
effectiveness and reliability of the experimental separator.
SND1, a Component of RNA-Induced Silencing Complex, Is Up-regulated in Human Colon Cancers and Implicated in Early Stage Colon Carcinogenesis
Authors: Tsuchiya Naoto , Ochiai Masako , Nakashima Katsuhiko , Ubagai Tsuneyuki , Sugimura Takashi , Nakagama Hitoshi
Published: October 2007

Colon cancers have been shown to develop after accumulation of multiple genetic and epigenetic alterations with changes in global gene expression profiles, contributing to the establishment of widely diverse phenotypes. Transcriptional and posttranscriptional regulation of gene expression by small RNA species, such as the small interfering RNA and microRNA and the RNA-induced silencing complex (RISC), is currently drawing major interest with regard to cancer development. SND1, also called Tudor-SN and p100 and recently reported to be a component of RISC, is among the list of highly expressed genes in human colon cancers. In the present study, we showed remarkable up-regulation of SND1 mRNA in human colon cancer tissues, even in early-stage lesions, and also in colon cancer cell lines. When mouse Snd1 was stably overexpressed in IEC6 rat intestinal epithelial cells, contact inhibition was lost and cell growth was promoted, even after the cells became confluent. Intriguingly, IEC6 cells with high levels of Snd1 also showed an altered distribution of E-cadherin from the cell membrane to the cytoplasm, suggesting loss of cellular polarity. Furthermore, the adenomatous polyposis coli (Apc) protein was coincidentally down-regulated, with no significant changes in the Apc mRNA level. Immunohistochemical analysis using chemically induced colonic lesions developed in rats revealed overexpression of Snd1 not only in colon cancers but also in aberrant crypt foci, putative precancerous lesions of the colon. Up-regulation of SND1 may thus occur at a very early stage in colon carcinogenesis and contribute to the posttranscriptional regulation of key players in colon cancer development, including APC and β-catenin. [Cancer Res 2007;67(19):9568–76]
Epidermal Growth Factor Receptor Cooperates with Signal Transducer and Activator of Transcription 3 to Induce Epithelial-Mesenchymal Transition in Cancer Cells via Up-regulation of TWIST Gene Expression
Authors: Lo Hui-Wen , Hsu Sheng-Chieh , Xia Weiya , Cao Xinyu , Shih Jin-Yuan , Wei Yongkun , Abbruzzese James L. , Hortobagyi Gabriel N. , Hung Mien-Chie
Published: October 2007

Aberrant epidermal growth factor receptor (EGFR) signaling is a major cause of tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether deregulated EGFR pathway is involved in epithelial-mesenchymal transition (EMT), an early event that occurs during metastasis of cancers of an epithelial origin. Here, we show that EGF induces EGFR-expressing cancer cells to undergo a transition from the epithelial to the spindle-like mesenchymal morphology. EGF reduced E-cadherin expression and increased that of mesenchymal proteins. In search of a downstream mediator that may account for EGF-induced EMT, we focused on transcription repressors of E-cadherin, TWIST, SLUG, and Snail and found that cancer cells express high levels of TWIST and that EGF enhances its expression. EGF significantly increases TWIST transcripts and protein in EGFR-expressing lines. Forced expression of EGFR reactivates TWIST expression in EGFR-null cells. TWIST expression is suppressed by EGFR and Janus-activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) inhibitors, but not significantly by those targeting phosphoinositide-3 kinase and MEK/ERK. Furthermore, constitutively active STAT3 significantly activates the TWIST promoter, whereas the JAK/STAT3 inhibitor and dominant-negative STAT3 suppressed TWIST promoter. Deletion/mutation studies further show that a 26-bp promoter region contains putative STAT3 elements required for the EGF-responsiveness of the TWIST promoter. Chromatin immunoprecipitation assays further show that EGF induces binding of nuclear STAT3 to the TWIST promoter. Immunohistochemical analysis of 130 primary breast carcinomas indicates positive correlations between non-nuclear EGFR and TWIST and between phosphorylated STAT3 and TWIST. Together, we report here that EGF/EGFR signaling pathways induce cancer cell EMT via STAT3-mediated TWIST gene expression. [Cancer Res 2007;67(19):9066–76]
Peroxiredoxin 1 Interacts with Androgen Receptor and Enhances Its Transactivation
Authors: Park Soo-Yeon , Yu Xiaofei , Ip Clement , Mohler James L. , Bogner Paul N. , Park Young-Mee
Published: October 2007

Although hypoxia is accepted as an important microenvironmental factor influencing tumor progression and treatment response, it is usually regarded as a static global phenomenon. Consequently, less attention is given to the impact of dynamic changes in tumor oxygenation in regulating the behavior of cancer cells. Androgen receptor (AR) signaling plays a critical role in prostate cancer. We previously reported that hypoxia/reoxygenation, an in vitro condition used to mimic an unstable oxygenation climate in a tumor, stimulates AR activation. In the present study, we showed that peroxiredoxin 1 (Prx1), a member of the peroxiredoxin protein family, acts as a key mediator in this process. We found that the aggressive LN3, C4-2, and C4-2B prostate cancer cell lines derived from LNCaP possess constitutively elevated Prx1 compared with parental cells, and display greater AR activation in response to hypoxia/reoxygenation. Although the cell survival–enhancing property of Prx1 has traditionally been attributed to its antioxidant activity, the reactive oxygen species–scavenging activity of Prx1 was not essential for AR stimulation because Prx1 itself was oxidized and inactivated by hypoxia/reoxygenation. Increased AR transactivation was observed when wild-type Prx1 or mutant Prx1 (C52S) lacking antioxidant activity was introduced into LNCaP cells. Reciprocal immunoprecipitation, chromatin immunoprecipitation, and in vitro pull-down assays corroborated that Prx1 interacts with AR and enhances its transactivation. We also show that Prx1 is capable of sensitizing a ligand-stimulated AR. Based on the above information, we suggest that disrupting the interaction between Prx1 and AR may serve as a fruitful new target in the management of prostate cancer. [Cancer Res 2007;67(19):9294–303]
Do MDM2 SNP309 and TP53 R72P Interact in Breast Cancer Susceptibility? A Large Pooled Series from the Breast Cancer Association Consortium
Authors: Schmidt Marjanka K. , Reincke Scarlett , Broeks Annegien , Braaf Linde M. , Hogervorst Frans B.L. , Tollenaar Rob A.E.M. , Johnson Nichola , Fletcher Olivia , Peto Julian , Tommiska Johanna , Blomqvist Carl , Nevanlinna Heli A. , Healey Catherine S. , Dunning Alison M. , Pharoah Paul D.P. , Easton Douglas F. , Dörk Thilo , Van't Veer Laura J. ,   on behalf of the Breast Cancer Association Consortium
Published: October 2007

Association studies in large series of breast cancer patients can be used to identify single-nucleotide polymorphisms (SNP) contributing to breast cancer susceptibility. Previous studies have suggested associations between variants in TP53 (R72P) and MDM2 (SNP309) and cancer risk. Data from molecular studies suggest a functional interaction between these genes. We therefore investigated the effect of TP53 R72P and MDM2 SNP309 on breast cancer risk and age at onset of breast cancer in a pooled series of 5,191 cases and 3,834 controls from the Breast Cancer Association Consortium (BCAC). Breast cancer risk was not found to be associated with the combined variant alleles [odds ratio (OR), 1.00; 95% confidence interval (95% CI), 0.81–1.23]. Estimated ORs were 1.01 (95% CI, 0.93–1.09) per MDM2 SNP309 allele and 0.98 (95% CI, 0.91–1.04) for TP53 R72P. Although we did find evidence for a 4-year earlier age at onset for carriers of both variant alleles in one of the breast cancer patient series of the BCAC (the German series), we were not able to confirm this effect in the pooled analysis. Even so, carriers of both variant alleles did not have different risk estimates for bilateral or estrogen receptor–positive breast cancer. In conclusion, in this large collaborative study, we did not find an association of MDM2 SNP309 and TP53 R72P, separately or in interaction, with breast cancer. This suggests that any effect of these two variants would be very small and possibly confined to subgroups that were not assessed in our present study. [Cancer Res 2007;67(19):9584–90]
An Increased Expression of Cysteinyl Leukotriene 2 Receptor in Colorectal Adenocarcinomas Correlates with High Differentiation
Authors: Magnusson Cecilia , Ehrnström Roy , Olsen Jørgen , Sjölander Anita
Published: October 2007

Increased levels of inflammatory mediators such as cysteinyl leukotrienes (CysLT) have been found in and around tumors. These data, along with our previous observation that the G-protein–coupled receptor CysLT1R, which signals survival and proliferation, is up-regulated in colon cancer, suggest an important role for CysLT1R in tumor development. The objective of this study was to examine the expression and function of the low-affinity CysLT2 receptor (CysLT2R) in colon cancer. We found lower expression levels of CysLT2R compared with CysLT1R in cancer cell lines as well as clinical tumor material. Interestingly, CysLT2R, like CysLT1R, was found to be one of few G-protein–coupled receptors that are located both at the plasma membrane and the nuclear membrane. No effect of CysLT2R signaling on cell proliferation was observed, nor was there a correlation between CysLT2R and different proliferation markers such as Ki-67 and cyclooxygenase-2 in the tumor material. Instead, we found that activation of this receptor in colon cancer cells led to cellular differentiation similar to the effects of butyrate treatment. In accordance with this finding, we found that reduced expression of CysLT2R in colon cancer was associated with poor prognosis. We report the novel finding that CysLT2R signaling leads to terminal differentiation of colon carcinoma cells and growth inhibition, and that its expression is relatively high in less malignant forms of colon cancer. These data suggest that the balance between these two receptors is important for tumor progression and disease outcome. [Cancer Res 2007;67(19):9190–8]
MicroRNA-21 Knockdown Disrupts Glioma Growth In vivo and Displays Synergistic Cytotoxicity with Neural Precursor Cell–Delivered S-TRAIL in Human Gliomas
Authors: Corsten Maarten F. , Miranda Rafael , Kasmieh Randa , Krichevsky Anna M. , Weissleder Ralph , Shah Khalid
Published: October 2007

Despite the development of new glioma therapies that allow for tumor-targeted in situ delivery of cytotoxic drugs, tumor resistance to apoptosis remains a key impediment to effective treatment. Mounting evidence indicates that microRNAs (miRNA) might play a fundamental role in tumorigenesis, controlling cell proliferation and apoptosis. In gliomas, microRNA-21 (miR-21) levels have been reported to be elevated and their knockdown is associated with increased apoptotic activity. We hypothesized that suppression of miR-21 might sensitize gliomas for cytotoxic tumor therapy. With the use of locked nucleic acid (LNA)-antimiR-21 oligonucleotides, bimodal imaging vectors, and neural precursor cells (NPC) expressing a secretable variant of the cytotoxic agent tumor necrosis factor–related apoptosis inducing ligand (S-TRAIL), we show that the combined suppression of miR-21 and NPC-S-TRAIL leads to a synergistic increase in caspase activity and significantly decreased cell viability in human glioma cells in vitro. This phenomenon persists in vivo, as we observed complete eradication of LNA-antimiR-21–treated gliomas subjected to the presence of NPC-S-TRAIL in the murine brain. Our results reveal the efficacy of miR-21 antagonism in murine glioma models and implicate miR-21 as a target for therapeutic intervention. Furthermore, our findings provide the basis for developing combination therapies using miRNA modulation and cytotoxic tumor therapies. [Cancer Res 2007;67(19):8994–9000]
Targeting CCL2 with Systemic Delivery of Neutralizing Antibodies Induces Prostate Cancer Tumor RegressionIn vivo
Authors: Loberg Robert D. , Ying Chi , Craig Matt , Day Lashon L. , Sargent Erin , Neeley Chris , Wojno Kirk , Snyder Linda A. , Yan Li , Pienta Kenneth J.
Published: October 2007

The identification of novel tumor-interactive chemokines and the associated insights into the molecular and cellular basis of tumor-microenvironment interactions have continued to stimulate the development of targeted cancer therapeutics. Recently, we have identified monocyte chemoattractant protein 1 (MCP-1; CCL2) as a prominent regulator of prostate cancer growth and metastasis. Using neutralizing antibodies to human CCL2 (CNTO888) and the mouse homologue CCL2/JE (C1142), we show that treatment with anti-CCL2/JE antibody (2 mg/kg, twice weekly i.p.) attenuated PC-3Luc–mediated overall tumor burden in our in vivo model of prostate cancer metastasis by 96% at 5 weeks postintracardiac injection. Anti-CCL2 inhibition was not as effective as docetaxel (40 mg/kg, every week for 3 weeks) as a single agent, but inhibition of CCL2 in combination with docetaxel significantly reduced overall tumor burden compared with docetaxel alone, and induced tumor regression relative to initial tumor burden. These data suggest an interaction between tumor-derived chemokines and host-derived chemokines acting in cooperation to promote tumor cell survival, proliferation, and metastasis. [Cancer Res 2007;67(19):9417–24]
A New Central Scaffold for Metastasis: Parsing HEF1/Cas-L/NEDD9
Authors: O'Neill Geraldine M. , Seo Sachiko , Serebriiskii Ilya G. , Lessin Stuart R. , Golemis Erica A.
Published: October 2007

Greater understanding of metastasis is required to improve cancer treatment outcomes. Recently, changes in expression of the scaffold protein HEF1/CAS-L/NEDD9 were found to be a potent prometastatic stimulus in melanoma and other cancers. Mechanistic studies suggest diverse cellular roles of HEF1 and highlight its importance in the response to extracellular cues that drive invasion and metastasis. As a metastatic “hub” for signaling in cancer, HEF1 may provide a useful target for drug discovery efforts. [Cancer Res 2007;67(19):8975–9]
Egr-1 Mediates Hypoxia-Inducible Transcription of the NDRG1 Gene through an Overlapping Egr-1/Sp1 Binding Site in the Promoter
Authors: Zhang Ping , Tchou-Wong Kam-Meng , Costa Max
Published: October 2007

N-myc down-regulated gene 1 (NDRG1/Cap43) is inducible by a variety of environmental stressors, including hypoxia. The present study identified a cis-acting element mediating the transactivation of the NDRG1 gene in murine RAW264.7 macrophage cells treated with hypoxia or deferoxamine, an iron chelator mimicking hypoxia. Through a series of deletions of the promoter of NDRG1 luciferase constructs, a minimal cis-acting element conferring inducibility by hypoxia and deferoxamine was localized to an early growth response 1 (Egr-1) and Sp1 overlapping binding site. Electrophoretic mobility shift assay, antibody supershift assay, and mutations of the Egr-1 binding site confirmed the specific binding of Egr-1 protein to this Egr-1/Sp1 motif. In addition, hypoxia increased the level of Egr-1 protein that correlated with induction of NDRG1 expression at both RNA and protein levels. Transient transfection of the Egr-1 gene into HeLa cells also resulted in up-regulation of the NDRG1 mRNA. The role of Egr-1 was further verified by mutations in the Egr-1 binding site, which reduced promoter inducibility by hypoxia and deferoxamine. Furthermore, the induction of NDRG1 expression by hypoxia and deferoxamine was diminished by RNA interference knockdown of Egr-1 gene expression and in Egr-1−/− mouse embryonic fibroblasts (MEF) compared with Egr-1+/− MEFs. These results showed for the first time that Egr-1 regulates NDRG1 transcription through an overlapping Egr-1/Sp1 binding site that acts as a major site of positive regulation of the NDRG1 promoter by hypoxia signaling. [Cancer Res 2007;67(19):9125–33]
Cancer Resistance in Transgenic Mice Expressing the SAC Module of Par-4
Authors: Zhao Yanming , Burikhanov Ravshan , Qiu Shirley , Lele Subodh M. , Jennings C. Darrell , Bondada Subbarao , Spear Brett , Rangnekar Vivek M.
Published: October 2007

Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that induces apoptosis in cancer cells, but not in normal/immortalized cells. The cancer-specific proapoptotic action of Par-4 is encoded in its centrally located SAC domain. We report here the characterization of a novel mouse model with ubiquitous expression of the SAC domain. Although SAC transgenic mice displayed normal development and life span, they were resistant to the growth of spontaneous, as well as oncogene-induced, autochthonous tumors. Resistance to tumorigenesis was linked to inhibition of nuclear factor-κB activity and induction of apoptosis by the SAC domain. Collectively, our findings provide genetic evidence that the SAC domain of Par-4 confers cancer resistance in transgenic mice without compromising normal viability or aging, and may have therapeutic significance. [Cancer Res 2007;67(19):9276–85]
Meeting Report: Fifth Annual AACR Frontiers in Cancer Prevention Research
Authors: Hoque Ashraful , Parnes Howard L. , Stefanek Michael E. , Heymach John V. , Brown Powel H. , Lippman Scott M.
Published: September 2007

Addressing genetics, risk modeling, molecular targets for chemoprevention, clinical prevention trials, behavioral prevention research, public policy, and more, the Fifth Annual International Conference on Frontiers in Cancer Prevention Research, held in Boston, Massachusetts, in November 2006, added an outstanding new chapter to the landmark AACR Frontiers program for advancing the science and practice of cancer prevention throughout the world. [Cancer Res 2007;67(19):8989–93]
The Impact of Sex and Smoking Status on the Mutational Spectrum of Epidermal Growth Factor Receptor Gene in Non–small Cell Lung Cancer
Authors: Toyooka Shinichi , Matsuo Keitaro , Shigematsu Hisayuki , Kosaka Takayuki , Tokumo Masaki , Yatabe Yasushi , Ichihara Syuji , Inukai Michio , Suehisa Hiroshi , Soh Junichi , Kiura Katsuyuki , Fong Kwun M. , Lee Huei , Wistuba Ignacio I. , Gazdar Adi F. , Mitsudomi Tetsuya , Date Hiroshi
Published: October 2007

Purpose: Mutation of epidermal growth factor receptor (EGFR) gene has been reported to be present in non–small cell lung cancer (NSCLC) and significantly associated with female sex and never-smoking status. In this study, we extensively investigated the impact of sex and smoking on the EGFR mutation.

Experimental Design: We examined EGFR exons 18 to 21 status in 1,467 NSCLC patients by direct sequencing to study the impact of sex and smoking status on the EGFR mutational spectrum.

Results: Among 1,467 patients, 197 mutations were found at exon 19, 176 at exon 21, 21 at exon 18, and 24 at exon 20. To examine the independent effect of sex and smoking, the mutational status of each exon was compared between smokers and never smokers in each sex and between males and females stratified by smoking status. In females, exon 19 (P = 0.001) and exon 21 (P < 0.001) mutations were significantly less frequent in ever smokers compared with never smokers. In males, exon 19 (P < 0.001), exon 21 (P < 0.001), and exon 18 (P = 0.003) mutations were significantly less frequent in ever smokers compared with never smokers. In analysis stratified by smoking, there was no difference in sex among never smokers. However, exon 19 mutations were significantly less frequent in males compared with females among ever smokers (P = 0.003). In addition, the interactive effect of male sex and ever smoking status significantly decreased the frequency of exon 19 mutations (P = 0.047) when female never smoker was set as a reference.

Conclusion: Both sex and smoking status could influence the EGFR mutational spectrum. Our findings suggest that individual EGFR exons may have differing susceptibilities for mutagenesis.