bluuebunny/crossref_metadata_2025 huggingface dataset:
ANALYTIC PRICING OF CONTINGENT CLAIMS UNDER THE REAL-WORLD MEASURE
Authors: MILLER SHANE M. , PLATEN ECKHARD
Published: February 2009

This article derives a series of analytic formulae for various contingent claims under the real-world probability measure using the stylised minimal market model (SMMM). This model provides realistic dynamics for the growth optimal portfolio (GOP) as a well-diversified equity index. It captures both leptokurtic returns with correct tail properties and the leverage effect. Under the SMMM, the discounted GOP takes the form of a time-transformed squared Bessel process of dimension four. From this property, one finds that the SMMM possesses a special and interesting relationship to non-central chi-square random variables with zero degrees of freedom. The analytic formulae derived under the SMMM include options on the GOP, options on exchange prices and options on zero-coupon bonds. For options on zero-coupon bonds, analytic prices facilitate efficient calculation of interest rate caps and floors.
THE PREVALENCE OF ENTREPRENEURIAL ORIENTATION IN A DEVELOPING COUNTRY: JUXTAPOSITIONS WITH FIRM SUCCESS AND SOUTH AFRICA'S INNOVATION INDEX
Authors: URBAN BORIS
Published: February 2009

The study investigates the prevalence of entrepreneurial orientation (EO) amongst diverse South African firms (n = 315) in a multicultural environment. Through literary investigations innovation as an important predictor of competitiveness is emphasized and EO is validated as a multidimensional construct, acknowledging that in addition to individual and firm differences, forces operating within cultural contexts also influence levels of EO. Based on global competitiveness indices, the country level innovation index is interpreted in the context of a developing country. By addressing methodological concerns of sample representativeness and firm size, survey data is obtained at the firm level and analyzed using correlational analysis. The findings indicate that EO is positively associated with overall firm performance and the overall significance of the study emerges when links with South Africa's innovation levels are made.
New palaeomagnetic data from the Mahabaleshwar Plateau, Deccan Flood Basalt Province, India: implications for the volcanostratigraphic architecture of continental flood basalt provinces
Authors: Jay Anne E. , Niocaill Conall Mac , Widdowson Mike , Self Stephen , Turner William
Published: February 2009

New magnetostratigraphic data from seven Western Ghats sections in the Deccan Volcanic Province are presented. These are combined with an established geochemically defined stratigraphy, and volcanological logs, to provide a correlated, chronological eruptive framework. We identify two magnetic polarities in five of the sections, and these are assigned to chrons 29r and 29n. Importantly, the reversal boundary represents an identifiable isochronous surface within the volcanic pile. This surface occurs at different elevations, as does the altitude of the geochemically defined formation boundary (i.e. Ambenali–Mahabaleshwar Fms), which defines a second isochronous surface. Inspection reveals significant differences in the number and thickness of lava units preserved between these two surfaces. This indicates that there was significant local topography (
c
. 80 m) across Deccan Volcanic Province lava fields during their development; an interpretation consistent with topographies observed across modern and historical examples (e.g. Hawaii, Iceland). These data also indicate that the geochemical stratigraphies of continental flood basalt provinces can mask local and sub-regional detail in lava stacking patterns when applied at smaller spatial scales (<10
2
–10
4
m). Finally, transitional (R–N) directions preserved in some eruptive units place constraints upon the rates of eruption, and indicate
c
. 2 ka periods of volcanic repose.
Detrital zircon age constraints on the provenance of sandstones on Hatton Bank and Edoras Bank, NE Atlantic
Authors: Morton Andrew C. , Hitchen Kenneth , Fanning C. Mark , Yaxley Greg , Johnson Howard , Ritchie J.Derek
Published: February 2009

U–Pb dating of detrital zircons shows that the provenance of Cretaceous–Palaeogene sandstones on Hatton and Edoras banks (SW Rockall Plateau) comprises magmatic rocks dated at
c
. 1800 Ma and
c
. 1750 Ma, respectively. Their depositional setting, first-cycle mineralogy and unimodal detrital zircon populations suggest that these sandstones are of local origin. The zircon age data are therefore considered to provide constraints on these poorly understood areas of the Rockall Plateau. The U–Pb dates are directly comparable with U–Pb zircon crystallization ages from granitoid rocks reported from the Ketilidian Belt of southern Greenland and from the Rhinns Complex of western Britain. Hf isotopic data from the Edoras Bank sample are consistent with derivation from a juvenile Palaeoproterozoic block. In conjunction with previously reported Sm–Nd T
dm
model ages from the Ketilidian Belt, Rockall Bank and the Rhinns Complex, these data extend the known distribution of a large juvenile Palaeoproterozoic terrane spanning the southern NE Atlantic. In contrast, Hf isotopic data from the Hatton Bank sample imply a large contribution from Archaean crust. The zircon population from Edoras Bank also contains sparse Mesoproterozoic grains, providing evidence for the presence of volumetrically minor Grenville-age intrusions in the southern part of the Rockall Plateau.
The record of tectonic denudation and erosion in an emerging orogen: an apatite fission-track study of the Sierra Nevada, southern Spain
Authors: Clark S.J.P. , Dempster T.J.
Published: February 2009

Apatite fission-track analysis of rocks from the Sierra Nevada basement, southern Spain reveals a detailed record of Neogene denudation. This is combined with evidence of the accumulation of clastic sedimentary rocks in the adjacent Granada Basin to provide a comprehensive record of the denudation of the emerging mountain block. Fission-track ages of
c
. 9–10 and 4 Ma obtained from the basement reveal periods of rapid cooling linked to tectonic denudation of the metamorphic core. The first major pulse of erosion from the Sierra Nevada produced proximal conglomerates in the marine basin and is constrained at
c
. 7 Ma using Sr-isotope stratigraphy. No major signal of rapid cooling is preserved by the fission-track systems in the basement block associated with this event. Apatite fission-track data from the conglomerates show young ages and short track lengths indicative of reheating. Modelling of the data suggests that heating occurred at around 4 Ma and is linked to movement of hot fluids through the basin. The ability of thermochronometers to record erosional events during the early stages of orogenesis is critically examined and we suggest that in young rising mountain blocks surface processes are incapable of keeping pace with rock uplift, and denudation principally occurs via tectonic processes.
Alcatraz
Authors: Liang Zhenkai , Sun Weiqing , Venkatakrishnan V. N. , Sekar R.
Published: February 2009

In this article, we present an approach for realizing a
safe execution environment (SEE)
that enables users to “try out” new software (or configuration changes to existing software) without the fear of damaging the system in any manner. A key property of our SEE is that it faithfully reproduces the behavior of applications, as if they were running natively on the underlying (host) operating system. This is accomplished via
one-way isolation:
processes running within the SEE are given read-access to the environment provided by the host OS, but their write operations are prevented from escaping outside the SEE. As a result, SEE processes cannot impact the behavior of host OS processes, or the integrity of data on the host OS. SEEs support a wide range of tasks, including: study of malicious code, controlled execution of untrusted software, experimentation with software configuration changes, testing of software patches, and so on. It provides a convenient way for users to inspect system changes made within the SEE. If these changes are not accepted, they can be rolled back at the click of a button. Otherwise, the changes can be committed so as to become visible outside the SEE. We provide consistency criteria that ensure semantic consistency of the committed results. We develop two different implementation approaches, one in
user-land
and the other in the
OS kernel
, for realizing a safe-execution environment. Our implementation results show that most software, including fairly complex server and client applications, can run successfully within our SEEs. It introduces low performance overheads, typically below 10 percent.
Single-value combinatorial auctions and algorithmic implementation in undominated strategies
Authors: Babaioff Moshe , Lavi Ron , Pavlov Elan
Published: February 2009

In this article, we are interested in general techniques for designing mechanisms that approximate the social welfare in the presence of selfish rational behavior. We demonstrate our results in the setting of Combinatorial Auctions (CA). Our first result is a general deterministic technique to decouple the algorithmic allocation problem from the strategic aspects, by a procedure that converts any
algorithm
to a dominant-strategy ascending
mechanism
. This technique works for any single value domain, in which each agent has the same value for each desired outcome, and this value is the only private information. In particular, for “single-value CAs”, where each player desires any one of several different bundles but has the same value for each of them, our technique converts any approximation algorithm to a dominant strategy mechanism that almost preserves the original approximation ratio. Our second result provides the first computationally efficient deterministic mechanism for the case of single-value multi-minded bidders (with private value and private desired bundles). The mechanism achieves an approximation to the social welfare which is close to the best possible in polynomial time (unless P=NP). This mechanism is an
algorithmic implementation in undominated strategies
, a notion that we define and justify, and is of independent interest.
Reduced malonyl-CoA content in recovery from exercise correlates with improved insulin-stimulated glucose uptake in human skeletal muscle
Authors: Frøsig Christian , Roepstorff Carsten , Brandt Nina , Maarbjerg Stine J. , Birk Jesper B. , Wojtaszewski Jørgen F. P. , Richter Erik A. , Kiens Bente
Published: February 2009

This study evaluated whether improved insulin-stimulated glucose uptake in recovery from acute exercise coincides with reduced malonyl-CoA (MCoA) content in human muscle. Furthermore, we investigated whether a high-fat diet [65 energy-% (Fat)] would alter the content of MCoA and insulin action compared with a high-carbohydrate diet [65 energy-% (CHO)]. After 4 days of isocaloric diet on two occasions (Fat/CHO), 12 male subjects performed 1 h of one-legged knee extensor exercise (∼80% peak workload). Four hours after exercise, insulin-stimulated glucose uptake was determined in both legs during a euglycemic-hyperinsulinemic clamp. Muscle biopsies were obtained in both legs before and after the clamp. Four hours after exercise, insulin-stimulated glucose uptake was improved (∼70%, P < 0.001) independent of diet composition and despite normal insulin-stimulated regulation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase, Akt, GSK-3, and glycogen synthase. Interestingly, exercise resulted in a sustained reduction (∼20%, P < 0.05) in MCoA content 4 h after exercise that correlated ( r = 0.65, P < 0.001) with improved insulin-stimulated glucose uptake. Four days of Fat diet resulted in an increased content of intramyocellular triacylglycerol ( P < 0.01) but did not influence muscle MCoA content or whole body insulin-stimulated glucose uptake. However, at the muscular level proximal insulin signaling and insulin-stimulated glucose uptake appeared to be compromised, although to a minor extent, by the Fat diet. Collectively, this study indicates that reduced muscle MCoA content in recovery from exercise may be part of the adaptive response leading to improved insulin action on glucose uptake after exercise in human muscle.
The Plastic Nature of the Vascular Wall: A Continuum of Remodeling Events Contributing to Control of Arteriolar Diameter and Structure
Authors: Martinez-Lemus Luis A. , Hill Michael A. , Meininger Gerald A.
Published: February 2009

The diameter of resistance arteries has a profound effect on the distribution of microvascular blood flow and the control of systemic blood pressure. Here, we review mechanisms that contribute to the regulation of resistance artery diameter, both acutely and chronically, their temporal characteristics, and their interdependence. Furthermore, we hypothesize the existence of a remodeling continuum that allows for the vascular wall to rapidly modify its structural characteristics, specifically through the re-positioning of vascular smooth muscle cells. Importantly, the concepts presented more closely link acute vasoregulatory responses with adaptive changes in vessel wall structure. These rapid structural adaptations provide resistance vessels the ability to maintain a desired diameter under presumed optimal energetic and mechanical conditions.
Positive Solutions for Third‐Order Nonlinear p‐Laplacian m‐Point Boundary Value Problems on Time Scales
Authors: Xu Fuyi
Published: February 2009

We study the following third‐order p‐Laplacian m‐point boundary value problems
on time scales: , t ∈ [0, T] T, βu(0) − γuΔ(0) = 0, , , where ϕp(s) is p‐Laplacian operator, that is, ϕp(s) = |s|p−2s, , 1/p + 1/q = 1,   0 < ξ1 < ⋯<ξm−2 < ρ(T). We obtain the existence of positive solutions by using fixed‐point theorem in
cones. The conclusions in this paper essentially extend and improve the known results.
Reaction of Chromium(III) with 3,4‐Dihydroxybenzoic Acid: Kinetics and Mechanism in Weak Acidic Aqueous Solutions
Authors: Zavitsanos Kimon , Tampouris Konstantinos , Petrou Athinoula L.
Published: February 2009

The interactions between chromium(III) and 3,4‐dihydroxybenzoic acid (3,4‐DHBA) were studied resulting in the formation of oxygen‐bonded complexes upon substitution of water molecules in the chromium(III) coordination sphere. The experimental results show that the reaction takes place in at least three stages, involving various intermediates. The first stage was found to be linearly dependent on ligand concentration , and the corresponding activation parameters were calculated as follows:  kJ mol−1,  J mol−1 K−1 (composite activation parameters) . The second and third stages, which are kinetically indistinguishable, do not depend on the concentrations of ligand and chromium(III), accounting for isomerization and chelation processes, respectively. The corresponding activation parameters are kJ mol−1,  J mol−1 K−1. The observed stages are proposed to proceed via interchange dissociative (Id, first stage) and associative (second and third stages) mechanisms. The reactions are accompanied by proton release, as is shown by the pH decrease.
Live Broadcasting of High Definition Audiovisual Content Using HDTV over Broadband IP Networks
Authors: Vegiris C. E. , Avdelidis K. A. , Dimoulas C. A. , Papanikolaou G. V.
Published: February 2009

The current paper focuses on validating an implementation of a state-of-the art audiovisual (AV) technologies setup for live broadcasting of cultural shows, via broadband Internet. The main objective of the work was to study, configure, and setup dedicated audio-video equipment for the processes of capturing, processing, and transmission of extended resolution and high fidelity AV content in order to increase realism and achieve maximum audience sensation. Internet2 and GEANT broadband telecommunication networks were selected as the most applicable technology to deliver such traffic workloads. Validation procedures were conducted in combination with metric-based quality of service (QoS) and quality of experience (QoE) evaluation experiments for the quantification and the perceptual interpretation of the quality achieved during content reproduction. The implemented system was successfully applied in real-world applications, such as the transmission of cultural events from Thessaloniki Concert Hall throughout Greece as well as the reproduction of Philadelphia Orchestra performances (USA) via Internet2 and GEANT backbones.
Homocysteine May Involve in the Pathogenesis of Behcet′s Disease by Inducing Inflammation
Authors: Kartal Durmazlar Selda Pelin , Akgul Ahmet , Eskioglu Fatma
Published: February 2009

Objective. Our aim was to evaluate the significance of homocysteine (Hcy) in Behcet′s disease (BD) and the association of elevated Hcy levels associated with the indices of inflammation in BD. Methods. Untreated 70 patients with BD and 33 healthy individuals were included into the study. Hcy, tumor necrosis alpha (TNF‐α), C‐reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were evaluated with respect to activity and specific individual clinical manifestations of the disease. Results. Hcy levels were found significantly elevated in active BD when compared to inactive BD and healthy controls. Hcy levels were found to have high correlation with the number of active clinical manifestations increased. A significant positive correlation was found between serum Hcy and TNF‐α levels, CRP, and ESR. Hcy was found to be the best predictor of TNF‐α among other parameters. Conclusion. Hcy may involve in the pathogenesis of BD by inducing inflammation.
Stream Execution on Embedded Wide-Issue Clustered VLIW Architectures
Authors: Yan Shan , Lin Bill
Published: February 2009

Very long instruction word- (VLIW-) based processors have become widely adopted as a basic building block in modern System-on-Chip designs. Advances in clustered VLIW architectures have extended the scalability of the VLIW architecture paradigm to a large number of functional units and very-wide-issue widths. A central challenge with wide-issue clustered VLIW architecture is the availability of programming and automated compiler methods that can fully utilize the available computational resources. Existing compilation approaches for clustered-VLIW architectures are based on extensions of previously developed scheduling algorithms that primarily focus on the maximization of instruction-level parallelism (ILP). However, many applications do not have sufficient ILP to fully utilize a large number of functional units. On the other hand, many applications in digital communications and multimedia processing exhibit enormous amounts of data-level parallelism (DLP). For these applications, the streaming programming paradigm has been developed to explicitly expose coarse-grained data-level parallelism as well as the locality of communication between coarse-grained computation kernels. In this paper, we investigate the mapping of stream programs to wide-issue clustered VLIW processors. Our work enables designers to leverage their existing investments in VLIW-based architecture platforms to harness the advantages of the stream programming paradigm.
FulminantClostridium difficileEnteritis after Proctocolectomy and Ileal Pouch-Anal Anastamosis
Authors: Boland Elena , Thompson Jon S.
Published: February 2009

Clostridium difficile(C. difficile) infection of the small bowel is very rare. The disease course is more severe than that ofC. difficilecolitis, and the mortality is high. We present a case ofC. difficileenteritis in a patient with with ileal pouch-anal anastamosis (IPAA), and review previous case reports in order to better characterize this unusual condition.
Epithelial Cell Gene Expression Induced by IntracellularStaphylococcus aureus
Authors: Li Xianglu , Fusco William G. , Seo Keun S. , Bayles Kenneth W. , Mosley Erin E. , McGuire Mark A. , Bohach Gregory A.
Published: February 2009

HEp-2 cell monolayers were cocultured with intracellularStaphylococcus aureus, and changes in gene expression were profiled using DNA microarrays. IntracellularS. aureusaffected genes involved in cellular stress responses, signal transduction, inflammation, apoptosis, fibrosis, and cholesterol biosynthesis. Transcription of stress response and signal transduction-related genes includingatf3, sgk, map2k1, map2k3, arhb, andarhewas increased. In addition, elevated transcription of proinflammatory genes was observed fortnfa, il1b, il6, il8, cxcl1, ccl20, cox2,andpai1. Genes involved in proapoptosis and fibrosis were also affected at transcriptional level by intracellularS. aureus. Notably, intracellularS. aureusinduced strong transcriptional down-regulation of several cholesterol biosynthesis genes. These results suggest that epithelial cells respond to intracellularS. aureusby inducing genes affecting immunity and in repairing damage caused by the organism, and are consistent with the possibility that the organism exploits an intracellular environment to subvert host immunity and promote colonization.
Trends in Finnish Public Orthodontic Care from the Professionals' Perspective
Authors: Pietilä Ilpo , Pietilä Terttu , Varrela Juha , Pirttiniemi Pertti , Alanen Pentti
Published: February 2009

The study maps out orthodontic care in Finnish municipal health centres in 2001, describes changes during the previous ten years reported by chief dental officers, and assesses the views of orthodontists on current public orthodontic services. The data were collected by questionnaires sent to all health centres and all orthodontists in Finland. Of all 0–18-year-olds, 11% were receiving orthodontic treatment with an appliance (range 2–43% among the health centres). The most frequently used appliances were headgear, quadhelix, and fixed appliances. Limited economic resources and the lack of orthodontic expertise were mentioned by the chief dental officers as factors decreasing the volume of services. The orthodontists mentioned the large regional variation and the lack of national guidelines as the most important aspects that should be improved on a national basis. To bring about improvement, they suggested increasing the number of specialist orthodontists and the delegation of orthodontic tasks to auxiliaries.
17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis
Authors: Nagasaki Shuji , Suzuki Takashi , Miki Yasuhiro , Akahira Jun-ichi , Kitada Kunio , Ishida Takanori , Handa Hiroshi , Ohuchi Noriaki , Sasano Hironobu
Published: February 2009

17β-Hydroxysteroid dehydrogenase type 12 (17β-HSD12) has been shown to be involved in elongation of very long chain fatty acid (VLCFA) as well as in biosynthesis of estradiol (E2). 17β-HSD12 expression was also reported in breast carcinomas but its functions have remained unknown. In this study, we examined the correlation between mRNA expression profiles determined by microarray analysis and tissue E2 concentrations obtained from 16 postmenopausal breast carcinoma cases. No significant correlations were detected between 17β-HSD12 expression and E2 concentration. We then immunolocalized this enzyme in 110 cases of invasive ductal carcinoma. 17β-HSD12 immunoreactivity in breast carcinoma cells was significantly associated with poor prognosis of the patients. We further examined the biological significance of 17β-HSD12 using cell-based studies. Small interfering RNA–mediated knockdown of 17β-HSD12 in SK-BR-3 (estrogen receptor–negative breast carcinoma cell line) resulted in significant growth inhibition, which was recovered by the addition of VLCFAs such as arachidonic acid. The status of 17β-HSD12 immunoreactivity was also correlated with adverse clinical outcome in cyclooxygenase 2 (COX2)–positive breast cancer patients but not in COX2-negative patients. Therefore, these findings indicated that 17β-HSD12 was not necessarily related to intratumoral E2 biosynthesis, at least in human breast carcinoma, but was rather correlated with production of VLCFAs such as arachidonic acid, which may subsequently be metabolized to prostaglandins by COX2 and result in tumor progression of the patients. [Cancer Res 2009;69(4):1392–9]
Identification of SULF2 as a Novel Transcriptional Target of p53 by Use of Integrated Genomic Analyses
Authors: Chau B. Nelson , Diaz Robert L. , Saunders Matthew A. , Cheng Chun , Chang Aaron N. , Warrener Paul , Bradshaw Jeffrey , Linsley Peter S. , Cleary Michele A.
Published: February 2009

Microarray analysis has been useful for identifying the targets of many transcription factors. However, gene expression changes in response to transcription factor perturbation reveal both direct transcriptional targets and secondary gene regulation. By integrating RNA interference, gene expression profiling, and chromatin immunoprecipitation technologies, we identified a set of 32 direct transcriptional targets of the tumor suppressor p53. Of these 32 genes, 11 are not currently associated with the core p53 pathway. From among these novel pathway members, we focused on understanding the connection between p53 and SULF2, which encodes an extracellular heparan sulfate 6-O-endosulfatase that modulates the binding of growth factors to their cognate receptors and that has been shown to function as a tumor suppressor. Genetic and pharmacologic perturbation of p53 directly influences SULF2 expression, and similar to silencing of TP53, RNA interference–mediated suppression of SULF2 results in an impaired senescence response of cells to genotoxic stress. Thus, our integrated genomic approach has led to the identification of a novel mediator of p53 network biology. [Cancer Res 2009;69(4):1368–74]
Identification of a Novel Pathway That Selectively Modulates Apoptosis of Breast Cancer Cells
Authors: Tinnikov Alexander A. , Yeung Kay T. , Das Sharmistha , Samuels Herbert H.
Published: February 2009

Expression of the nuclear receptor interacting factor 3 (NRIF3) coregulator in a wide variety of breast cancer cells selectively leads to rapid caspase-2–dependent apoptotic cell death. A novel death domain (DD1) was mapped to a 30–amino acid region of NRIF3. Because the cytotoxicity of NRIF3 and DD1 seems to be cell type–specific, these studies suggest that breast cancer cells contain a novel “death switch” that can be specifically modulated by NRIF3 or DD1. Using an MCF-7 cell cDNA library in a yeast two-hybrid screen, we cloned a factor that mediates apoptosis by DD1 and refer to this factor as DD1-interacting factor-1 (DIF-1). DIF-1 is a transcriptional repressor that mediates its effect through SirT1, and this repression is attenuated by the binding of NRIF3/DD1. DIF-1 expression rescues breast cancer cells from NRIF3/DD1-induced apoptosis. Small interfering RNA (siRNA) knockdown of DIF-1 selectively leads to apoptosis of breast cancer cells, further suggesting that DIF-1 plays a key role in NRIF3/DD1-mediated apoptosis. A protein kinase A inhibitor (H89) also elicits apoptosis of breast cancer cells but not of the other cell types examined, and DIF-1 also protects these cells from H89-mediated apoptosis. In addition, H89 incubation results in a rapid increase in NRIF3 levels and siRNA knockdown of NRIF3 protects breast cancer cells from H89-mediated apoptosis. Our results indicate that DIF-1 plays a key role in breast cancer cell survival and further characterizing this pathway may provide important insights into developing novel therapies to selectively target breast cancer cells for apoptosis. [Cancer Res 2009;69(4):1375–82]
An Activating β1 Integrin Mutation Increases the Conversion of Benign to Malignant Skin Tumors
Authors: Ferreira Manuela , Fujiwara Hironobu , Morita Kazumasa , Watt Fiona M.
Published: February 2009

Identifying the physiologic relevance of cancer-associated genetic polymorphisms is a major challenge. Several changes in the coding sequence of β integrin subunits have now been described in human tumors. One of these, T188Iβ1, was identified as a heterozygous mutation in a poorly differentiated squamous cell carcinoma (SCC) and shown to activate extracellular matrix adhesion and inhibit keratinocyte differentiation in vitro. To study its contribution to tumor development, we overexpressed the mutant or wild-type (WT) human β1 subunit in the basal layer of mouse epidermis using the keratin 14 promoter. The transgenic integrins were expressed at the cell surface and were functional, with the T188Iβ1 subunit promoting cell spreading to a greater extent than WTβ1. Epidermal proliferation and differentiation were unaffected and no expansion of the stem cell compartment was detected. During chemical carcinogenesis, both transgenes increased papilloma formation, but only the T188Iβ1 transgene stimulated the conversion of papillomas to SCCs. Papillomas bearing the mutation showed increased Erk activity and reduced differentiation. SCCs expressing T188Iβ1 were less well-differentiated than those expressing WTβ1. These observations establish that the expression of a genetic variant in the I-like domain of β1 integrins does not affect normal epidermal homeostasis, but increases tumor susceptibility and influences tumor type. [Cancer Res 2009;69(4):1334–42]
In vivo Off-Resonance Saturation Magnetic Resonance Imaging of αvβ3-Targeted Superparamagnetic Nanoparticles
Authors: Khemtong Chalermchai , Kessinger Chase W. , Ren Jimin , Bey Erik A. , Yang Su-Geun , Guthi Jagadeesh Setti , Boothman David A. , Sherry A. Dean , Gao Jinming
Published: February 2009

Magnetic resonance imaging is a powerful clinical imaging technique that allows for noninvasive tomographic visualization of anatomic structures with high spatial resolution and soft tissue contrast. However, its application in molecular imaging of cancer has been limited by the lack of sensitivity and detection accuracy in depicting the biochemical expression of these diseases. Here, we combine an ultrasensitive design of superparamagnetic polymeric micelles (SPPM) and an off-resonance saturation (ORS) method to enhance the imaging efficacy of tumor biomarkers in vivo. SPPM nanoparticles encoded with cyclic(RGDfK) were able to target the αvβ3-expressing microvasculature in A549 non–small cell lung tumor xenografts in mice. ORS greatly improved tumor detection accuracy over the conventional T2*-weighted method by its ability to turn “ON” the contrast of SPPM. This combination of ORS imaging with a tumor vasculature–targeted, ultrasensitive SPPM design offers new opportunities in molecular imaging of cancer. [Cancer Res 2009;69(4):1651–8]
Breast Cancer Metastasis Suppressor 1 Up-regulates miR-146, Which Suppresses Breast Cancer Metastasis
Authors: Hurst Douglas R. , Edmonds Mick D. , Scott Gary K. , Benz Christopher C. , Vaidya Kedar S. , Welch Danny R.
Published: February 2009

Breast cancer metastasis suppressor 1 (BRMS1) is a predominantly nuclear protein that differentially regulates expression of multiple genes, leading to suppression of metastasis without blocking orthotopic tumor growth in multiple human and murine cancer cells of diverse origins. We hypothesized that miR-146 may be involved in the ability of BRMS1 to supress metastasis because miR-146 expression is altered by BRMS1 and because BRMS1 and miR-146 are both associated with decreased signaling through the nuclear factor-κB pathway. BRMS1 significantly up-regulates miR-146a by 6- to 60-fold in metastatic MDA-MB-231 and MDA-MB-435 cells, respectively, and miR-146b by 40-fold in MDA-MB-435 as measured by real-time quantitative reverse transcription-PCR. Transduction of miR-146a or miR-146b into MDA-MB-231 down-regulated expression of epidermal growth factor receptor, inhibited invasion and migration in vitro, and suppressed experimental lung metastasis by 69% and 84%, respectively (mean ± SE: empty vector = 39 ± 6, miR-146a = 12 ± 1, miR-146b = 6 ± 1). These results further support the recent notion that modulating the levels of miR-146a or miR-146b could have a therapeutic potential to suppress breast cancer metastasis. [Cancer Res 2009;69(4):1279–83]
Distinct BRAF (V600E) and KRAS Mutations in High Microsatellite Instability Sporadic Colorectal Cancer in African Americans
Authors: Kumar Krishan , Brim Hassan , Giardiello Francis , Smoot Duane T. , Nouraie Mehdi , Lee Edward L. , Ashktorab Hassan
Published: February 2009

Purpose: Colorectal cancer develops through genetic, epigenetic, and environmental events that result in uncontrolled cell proliferation. Colorectal cancer incidence and mortality is higher in African Americans (AA) than in the general population. Here, we carried out a molecular analysis of sporadic colorectal cancer tumors from AAs to investigate possible explanations for the observed disparities.

Experimental Design: A total of 222 AA colorectal cancer tumors were analyzed for microsatellite instability (MSI) for protein expression of two DNA mismatch repair genes, MLH1 and MSH2, by immunohistochemistry; for the methylation silencing of MLH1, p16, APC, and APC2 promoters by methylation-specific PCR; and for point mutations in two oncogenes, KRAS and BRAF, by sequencing.

Results: In our sample, 19.8% of the AAs colorectal cancer tumors were MSI high (MSI-H) and did not associate with any of the clinicopathologic features, except tumor differentiation. Higher levels of inactive DNA mismatch repair proteins MLH1 (41%) and MSH2 (33%) were found by immunohistochemistry. Methylation-specific PCR analysis revealed a high level of methylation for MLH1 (66%), APC (53%), and APC2 (90%), but not for p16 (26%). BRAF mutations were only within the MSI-H tumors, whereas most (64%) of KRAS mutations were found within the non–MSI-H group.

Conclusions:MLH1, MSH2, and BRAF alterations are significantly associated with MSI-H phenotype, unlike APC, APC2 and KRAS alterations. The prominent role of DNA mismatch repair gene suppression in MSI-H and a distinctive role of BRAF and KRAS mutations with respect to MSI status are supported by this study.
Establishment and Characterization of a Model of Acquired Resistance to Epidermal Growth Factor Receptor Targeting Agents in Human Cancer Cells
Authors: Benavente Sergio , Huang Shyhmin , Armstrong Eric A. , Chi Alexander , Hsu Kun-Tai , Wheeler Deric L. , Harari Paul M.
Published: February 2009

Purpose: The epidermal growth factor receptor (EGFR) is recognized as a key mediator of proliferation and progression in many human tumors. A series of EGFR-specific inhibitors have recently gained Food and Drug Administration approval in oncology. These strategies of EGFR inhibition have shown major tumor regressions in approximately 10% to 20% of advanced cancer patients. Many tumors, however, eventually manifest resistance to treatment. Efforts to better understand the underlying mechanisms of acquired resistance to EGFR inhibitors, and potential strategies to overcome resistance, are greatly needed.

Experimental Design: To develop cell lines with acquired resistance to EGFR inhibitors we utilized the human head and neck squamous cell carcinoma tumor cell line SCC-1. Cells were treated with increasing concentrations of cetuximab, gefitinib, or erlotinib, and characterized for the molecular changes in the EGFR inhibitor–resistant lines relative to the EGFR inhibitor–sensitive lines.

Results: EGFR inhibitor–resistant lines were able to maintain their resistant phenotype in both drug-free medium and in athymic nude mouse xenografts. In addition, EGFR inhibitor–resistant lines showed a markedly increased proliferation rate. EGFR inhibitor–resistant lines had elevated levels of phosphorylated EGFR, mitogen-activated protein kinase, AKT, and signal transducer and activator of transcription 3, which were associated with reduced apoptotic capacity. Subsequent in vivo experiments indicated enhanced angiogenic potential in EGFR inhibitor–resistant lines. Finally, EGFR inhibitor–resistant lines showed cross-resistance to ionizing radiation.

Conclusions: We have developed EGFR inhibitor–resistant human head and neck squamous cell carcinoma cell lines. This model provides a valuable preclinical tool to investigate molecular mechanisms of acquired resistance to EGFR blockade.
The Expression of Three Genes in Primary Non–Small Cell Lung Cancer Is Associated with Metastatic Spread to the Brain
Authors: Grinberg-Rashi Helena , Ofek Efrat , Perelman Marina , Skarda Jozef , Yaron Pnina , Hajdúch Marián , Jacob-Hirsch Jasmin , Amariglio Ninette , Krupsky Meir , Simansky David A. , Ram Zvi , Pfeffer Raphael , Galernter Ilana , Steinberg David M. , Ben-Dov Issachar , Rechavi Gideon , Izraeli Shai
Published: February 2009

Purpose: Brain metastases affect 25% of patients with non–small cell lung cancer (NSCLC). We hypothesized that the expression of genes in primary NSCLC tumors could predict brain metastasis and be used for identification of high-risk patients, who may benefit from prophylactic therapy.

Experimental Design: The expression of 12 genes was measured by real-time quantitative reverse transcriptase PCR in 142 frozen NSCLC tissue samples. Univariate and multivariate Cox regression analysis was used to analyze the correlation between gene expression and the occurrence of brain metastasis. Immunohistochemistry on independent samples was used to verify the findings.

Results: A score based on the expression levels of three genes, CDH2 (N-cadherin), KIFC1, and FALZ, was highly predictive of brain metastasis in early and advanced lung cancer. The probability of remaining brain metastasis–free at 2 years after diagnosis was 90.0 ± 9.5% for patients with stage I/stage II tumors and low score compared with 62.7 ± 12% for patients with high score (P < 0.01). In patients with more advanced lung cancer, the brain metastasis–free survival at 24 months was 89% for patients with low score compared with only 37% in patients with high score (P < 0.02). These results were confirmed by immunohistochemical detection of N-cadherin in independent cohort of primary NSCLC.

Conclusions: The expression levels of three genes in primary NSCLC tumors may be used to identify patients at high risk for brain metastasis who may benefit from prophylactic therapy to the central nervous system.
Stem Cells and Tissue-Engineered Skin
Authors: Charruyer A. , Ghadially R.
Published: February 2009

Advances in tissue engineering of skin are needed for clinical applications (as in wound healing and gene therapy) for cutaneous and systemic diseases. In this paper we review the use of epidermal stem cells as a source of cells to improve tissue-engineered skin. We discuss the importance and limitations of epidermal stem cell isolation using biomarkers, in quest of a pure stem cell preparation, as well as the culture conditions necessary to maintain this purity as required for a qualitatively superior and long-lasting engineered skin. Finally, we review the advantages of using additional multipotent stem cell sources to functionally and cosmetically optimize the engineered tissue.
Tissue Engineering for Cutaneous Wounds: Selecting the Proper Time and Space for Growth Factors, Cells and the Extracellular Matrix
Authors: Macri L. , Clark R.A.F.
Published: February 2009

Currently, autografts are the best treatment to any substantial cutaneous injury, and their success is well known as a burn therapy. However, autografts have been less successful in the treatment of chronic ulcers, and are usually a last-resort therapy because of infection at the injured site, high surgical expense, additional morbidity and engraftment failure. In addition, patients with burns covering more than 50% of their skin have limited donor sites for autograft harvest. Therefore, there is a great need for a cost-effective, user-friendly, tissue-engineered construct (TEC) that can provide successful treatments to both acute and chronic wounds in a wider repertoire of patients, including diabetics and the elderly. One approach to the challenge is to create a substitute for skin in vitro that can integrate into the engraftment site in vivo. An alternative is to engineer a biocompatible, resorbable matrix that can recruit the proper, native tissue cells to the injured site and induce them to heal the wound without scarring. This chapter reviews the 3 essential components of cutaneous wound healing, that is, cells, extracellular matrix molecules and bioactive molecules, that must be considered for designing TECs to potentially enhance the healing process. In nature, a ‘dynamic reciprocity’ exists amongst cells and extracellular matrix that is mediated by bioactive molecules at the site of injury. Thus, it is important to examine the interplay of all 3 components when engineering a TEC. This chapter also includes examples of commercially available products to highlight how researchers have already begun to find success in tissue engineering.
The Effect of Speaking Rate onConsonant Vowel Coarticulation
Authors: Agwuele Augustine , Sussman Harvey M. , Lindblom Björn
Published: February 2009

In 2007 Lindblom et al. introduced a methodological tool to disentangle consonant-vowel (CV) coarticulation attributable to emphatic stress apart from the vowel expansion effects known to accompany the prosodic overlay. After empirically accounting for the altered vowel positions, they reported small but consistent increases in F2 transition onsets in emphatically produced CVs that could not be attributed to vowel context influences, and that differed across stop place. At issue is whether the findings of these authors can be replicated, but in the opposite direction, for CVs produced at fast speaking rates. A modified locus equation regression metric was similarly used to account for rate-induced vowel reduction effects in predicting frequencies of F2 transition onsets in rapid speech. Six American-English speakers produced [V1.CV2] sequences embedded in a carrier sentence, at three speaking tempos: normal, fast, and fastest. Significant differences were found between ‘predicted’ and ‘observed’ F2 onsets across stops, with alveolars and velars showing greater decreases in F2 onsets during more rapid speech than labials. The complementary findings are discussed relative to a unified view of anticipatory coarticulation in CV production across a continuum of hyperarticulated spectral expansion to hypoarticulated spectral reduction.
Tonal Contrasts and Initial Consonants: A Case Study of Tamang, a ‘Missing Link’ in Tonogenesis
Authors: Mazaudon Martine , Michaud Alexis
Published: February 2009

Tamang (Bodic division of Tibeto-Burman) is spoken at the edge of the East Asian ‘tone-prone’ zone, next to the almost tone-free Indian linguistic area, and is, chronologically, at the late end of the tone multiplication wave which has swept through East Asia in the course of the last two millennia. It can be regarded as a ‘missing link’ in tonogenesis: following the loss of voicing contrasts on syllable-initial consonants, Tamang has four tonal categories instead of its earlier two-tone system; the present state of the prosodic system is typologically transitional, in that these four tonal categories are realised by several cues which include fundamental frequency (F0), phonation type, and allophonic variation in the realisation of consonants. Acoustic and electroglottographic recordings of 131 words in two carrier sentences by 5 speakers were conducted (total number of target syllables analysed: n = 1,651). They allow for a description in terms of F0, glottal open quotient, duration, and realisation of consonants. The results confirm the diversity of cues to the four tonal categories, and show evidence of laxness on tones 3 and 4, i.e. on the two tones which originate diachronically in voiced initials. The discussion hinges on the phonological definition of tone.
The Risk of Gallbladder Stone Formation Is Increased in Patients with Predialysis Chronic Kidney Disease but Not Those Undergoing Chronic Hemodialysis Therapy
Authors: Kazama Junichiro James , Kazama Sakumi , Koda Ryo , Yamamoto Suguru , Narita Ichiei , Gejyo Fumitake
Published: February 2009

Background: It is unclear whether the prevalence of gallbladder stones (GBS) is higher in patients with chronic kidney disease (CKD). Methods: A total of 398 patients with CKD of each of the 5 disease stages [CKD1: 26; CKD2: 52; CKD3: 58; CKD4: 48; CKD5: 214, of whom 61 were predialysis and 153 were on dialysis (CKD5D)] were included in this study. Those in whom GBS were detected by ultrasonographic examination or who had a history of cholecystectomy owing to GBS were considered GBS patients. Results: In comparison to the GBS prevalence of 5.9% in the control group, that in CKD patients increased with the advancement of the disease stage (CKD1: 7.7%; CKD2: 15.4%; CKD3: 19.0%; CKD4: 20.8%; CKD5 predialysis: 21.3%; CKD5D: 22.9%). The prevalence was significantly greater in CKD5 patients than in the control group. CKD5 is a risk factor for GBS independent of age or sex. However, no significant relationship was found between the prevalence of GBS and the duration of hemodialysis therapy in CKD5D patients. Age was the only factor that was associated with GBS in predialysis CKD patients. Conclusion: The risk of GBS formation was high in predialysis CKD patients. Although the risk disappeared in CKD5D patients, the prevalence of GBS was still significantly higher than in the control population. Factors that promote GBS formation in predialysis CKD patients and/or that inhibit GBS formation in CKD5D patients remain unknown.
Professional Education and Training in Public Health Genomics: A Working Policy Developed on Behalf of the Public Health Genomics European Network
Authors: Burton H. , Adams M.
Published: February 2009

Public health genomics (PHG) is an area of public health that is vital if we are to ensure that scientific advances in genomics are effectively and responsibly translated into public and health policies. Education and training in PHG for relevant professionals in public health and wider health and public policy was thus identified in 2006 as a key issue by the Public Health Genomics European Network (PHGEN). This paper provides an outline of the educational needs and practical proposals for the development of PHG education based on a resourced educational network that will undertake work on competences, the identification and sharing of current educational resources, and the development of programs in a variety of media and settings including highly specialist resources for researchers or individuals specializing in this area of policy.
AMP-Activated Protein Kinase Deficiency Enhances Myocardial Ischemia/Reperfusion Injury but Has Minimal Effect on the Antioxidant/Antinitrative Protection of Adiponectin
Authors: Wang Yajing , Gao Erhe , Tao Ling , Lau Wayne Bond , Yuan Yuexin , Goldstein Barry J. , Lopez Bernard L. , Christopher Theodore A. , Tian Rong , Koch Walter , Ma Xin-Liang
Published: February 2009

Background—

Diabetes increases the morbidity/mortality of ischemic heart disease, but the underlying mechanisms are incompletely understood. Deficiency of both AMP-activated protein kinase (AMPK) and adiponectin occurs in diabetes, but whether AMPK is cardioprotective or a central mediator of adiponectin cardioprotection in vivo remains unknown.

Methods and Results—

Male adult mice with cardiomyocyte-specific overexpression of a mutant AMPKα
2
subunit (AMPK-DN) or wild-type (WT) littermates were subjected to in vivo myocardial ischemia/reperfusion (MI/R) and treated with vehicle or adiponectin. In comparison to WT, AMPK-DN mice subjected to MI/R endured greater cardiac injury (larger infarct size, more apoptosis, and poorer cardiac function) likely as a result of increased oxidative stress in these animals. Treatment of AMPK-DN mice with adiponectin failed to phosphorylate cardiac acetyl-CoA carboxylase as it did in WT mouse heart. However, a significant portion of the cardioprotection of adiponectin against MI/R injury was retained in AMPK-DN mice. Furthermore, treatment of AMPK-DN mice with adiponectin reduced MI/R-induced cardiac oxidative and nitrative stress to the same degree as that seen in WT mice. Finally, treating AMPK-DN cardiomyocytes with adiponectin reduced simulated MI/R-induced oxidative/nitrative stress and decreased cell death (
P
<0.01).

Conclusions—

Collectively, our results demonstrated that AMPK deficiency significantly increases MI/R injury in vivo but has minimal effect on the antioxidative/antinitrative protection of adiponectin.