bluuebunny/crossref_metadata_2025 huggingface dataset:
STRUCTURE AND PIEZOELECTRIC PROPERTIES OF (Bi0.5Na0.5)1-x-y-zBax(Bi0.5Li0.5)ySrzTiO3 LEAD-FREE CERAMICS
Authors: LIN DUNMIN , KWOK K. W.
Published: May 2010

Lead-free ( Bi 0.5 Na 0.5)1-x-y-z Ba x( Bi 0.5 Li 0.5)y Sr z TiO 3 ceramics were prepared by an ordinary sintering method and their structure and piezoelectric properties have been studied. X-ray diffraction patterns show that Ba 2+, Li + and Sr 2+ diffuse into the Bi 0.5 Na 0.5 TiO 3 lattices to form a solid solution with a pure perovskite structure and a morphotropic phase boundary (MPB) between rhombohedral and tetragonal phases is formed at 0.04 ≤ x ≤ 0.08 and z < 0.06. The content of Li + has no obvious influence on the crystal structure of the ceramics. The ceramics situated within the MPB exhibit a lower coercive field E c and a larger remanent polarization P r . Because of the formation of the MPB, lower E c and larger P r , the ceramics with x = 0.06, y = 0.075 - 0.125 and z = 0-0.02 possess improved piezoelectric properties. The optimum d33 (235 pC/N ) and k p (36.3%) are reached at x/y/z = 0.06/0.125/0.02 and 0.06/0.075/0.02, respectively. The deformed P–E loop is also observed near or above T d .
PROCESSING AND PROPERTIES OF Na0.5Bi0.5TiO3 PIEZOELECTRIC CERAMICS MODIFIED WITH La, Mn AND Fe
Authors: AKSEL ELENA , FORONDA HUMBERTO , CALHOUN KYLE A. , JONES JACOB L. , SCHAAB SILKE , GRANZOW TORSTEN
Published: May 2010

Although a great deal of work has been done to understand defect chemistry in "soft" and "hard" PZT-based materials, there is little understanding of how defect chemistry influences the properties of lead-free piezoelectric materials. This paper reports a systematic investigation of doping on the ferroelectric and piezoelectric properties in Na 0.5 Bi 0.5 TiO 3 (NBT)-based ceramics. NBT-based ceramics have been synthesized by traditional solid state routes using several different dopants including lanthanum, manganese, and iron in 1 mol%. The addition of iron and manganese lead to an increase in the coercive field (E c ), a decrease in the piezoelectric coefficient (d33), and an increase in the thermal depoling temperature (T depole ), similar to the behavior of "hard" PZT. Lanthanum, on the other hand, leads to a decrease in the E c , an increase in d33, and a decrease in T depole similar to that seen in "soft" PZT.
SINGLE GRAINS HOSTING TWO SPACE GROUPS — A TRANSMISSION ELECTRON MICROSCOPY STUDY OF A LEAD-FREE FERROELECTRIC
Authors: SCHMITT LJUBOMIRA ANA , KLEEBE HANS-JOACHIM
Published: May 2010

In this letter, conclusive experimental evidence is presented for the coexistence of two phases within individual grains in the system ( Bi 0.5 Na 0.5 TiO 3)0.91-( BaTiO 3)0.06-( K 0.5 Na 0.5 NbO 3)0.03. Electron diffraction data unequivocally reveal the presence of a rhombohedral and a tetragonal phase with space group R3c and P4bm, respectively, both on the nanoscale level. Superlattice reflections, observed in the corresponding selected area electron diffraction, were used to identify the rhombohedral and tetragonal phase present at different regions within one grain. It is thought that the rhombohedral phase acts as a nucleation site for the phase transformation monitored under applied electrical field. The coexistence of these two phases in conjunction with the triggered tetragonal to rhombohedral phase transformation rationalizes the high bipolar and unipolar strain recorded for this lead-free ferroelectric material.
DEFECT STRUCTURE OF COPPER DOPED POTASSIUM NIOBATE CERAMICS
Authors: ERÜNAL EBRU , EICHEL RÜDIGER-A. , KÖRBEL SABINE , ELSÄSSER CHRISTIAN , ACKER JÉRÔME , KUNGL HANS , HOFFMANN MICHAEL J.
Published: May 2010

The defect structure resulting from copper doping of potassium niobate ( KNbO3) ceramics was investigated by a combined analysis of electron paramagnetic resonance (EPR) spectroscopy and first-principles calculations based on density functional theory (DFT). The results indicate that under atmospheric oxygen partial pressure, Cu preferentially substitutes on the Nb sites where it can trap one or two oxygen vacancies. Correspondingly, for 0.25 mol% Cu doped KNbO3ceramics, two types of defect associates are formed — [Formula: see text] and [Formula: see text]. The association of Cu impurities and oxygen vacancies lowers the defect formation energy by 1.0 eV to 2.7 eV, depending on the Fermi level. Owing to the opposite charges of these two types of defects, overall charge neutrality is theoretically possible by mutual compensation of the defect associates, without formation of additional non-associated oxygen vacancies.
IN-SITU X-RAY DIFFRACTION STUDY OF FERROELECTRIC DOMAIN SWITCHING IN ORTHORHOMBIC NKN CERAMICS
Authors: HALL DAVID A. , AZOUGH FERIDOON , MIDDLETON-STEWART NICHOLA , CERNIK ROBERT J. , FREER ROBERT , MORI TSUTOMU , KUNGL HANS , CURFS CAROLINE
Published: May 2010

The family of perovskite ferroelectrics based on sodium potassium niobate (NKN) ceramics exhibit useful piezoelectric properties and show potential for the replacement of conventional lead based piezoceramics. In the present study, iron-doped NKN ceramics were prepared by a solid state reaction method. Ferroelectric hysteresis measurements indicated that a remanent polarization value approaching 0.4Cm-2 could be obtained by poling under a continuous AC electric field with amplitude of 3 MV m-1. X-ray diffraction (XRD) patterns of these materials were recorded in transmission during poling, using high energy synchrotron X-rays with a wavelength of 1.55 × 10-11m. Changes in crystallographic texture were observed during poling as a result of 90° and 60°/120° domain switching. The strain due to ferroelectric domain switching in orthorhombic NKN is described in terms of the differences in transformation strain between different domain variants, with reference to the high temperature cubic lattice.
FLEXOELECTRIC COMPOSITE — A NEW PROSPECT FOR LEAD-FREE PIEZOELECTRICS
Authors: CHU BAOJIN , ZHU WENYI , LI NAN , CROSS L. ERIC
Published: May 2010

Flexoelectricity describes the physical phenomenon of the generation of electric polarization from mechanical strain gradient in solid insulators. In common dielectric materials, the flexoelectric coefficient is trivially small ~10-10 C/m. In Ba(Sr,Ti)O 3 (BST) ceramics, flexoelectric coefficient up to 10-4 C/m was observed. Such high coefficient makes it possible to design high piezoelectric response flexoelectric composites. In this letter, we will demonstrate that the newly designed flexoelectric composites could have piezoelectric properties better than conventional piezoelectric materials.
Exercise training increases sarcolemmal and mitochondrial fatty acid transport proteins in human skeletal muscle
Authors: Talanian Jason L. , Holloway Graham P. , Snook Laelie A. , Heigenhauser George J. F. , Bonen Arend , Spriet Lawrence L.
Published: May 2010

Fatty acid oxidation is highly regulated in skeletal muscle and involves several sites of regulation, including the transport of fatty acids across both the plasma and mitochondrial membranes. Transport across these membranes is recognized to be primarily protein mediated, limited by the abundance of fatty acid transport proteins on the respective membranes. In recent years, evidence has shown that fatty acid transport proteins move in response to acute and chronic perturbations; however, in human skeletal muscle the localization of fatty acid transport proteins in response to training has not been examined. Therefore, we determined whether high-intensity interval training (HIIT) increased total skeletal muscle, sarcolemmal, and mitochondrial membrane fatty acid transport protein contents. Ten untrained females (22 ± 1 yr, 65 ± 2 kg; V̇o2peak: 2.8 ± 0.1 l/min) completed 6 wk of HIIT, and biopsies from the vastus lateralis muscle were taken before training, and following 2 and 6 wk of HIIT. Training significantly increased maximal oxygen uptake at 2 and 6 wk (3.1 ± 0.1, 3.3 ± 0.1 l/min). Training for 6 wk increased FAT/CD36 at the whole muscle (10%) and mitochondrial levels (51%) without alterations in sarcolemmal content. Whole muscle plasma membrane fatty acid binding protein (FABPpm) also increased (48%) after 6 wk of training, but in contrast to FAT/CD36, sarcolemmal FABPpm increased (23%), whereas mitochondrial FABPpm was unaltered. The changes on sarcolemmal and mitochondrial membranes occurred rapidly, since differences (≤2 wk) were not observed between 2 and 6 wk. This is the first study to demonstrate that exercise training increases fatty acid transport protein content in whole muscle (FAT/CD36 and FABPpm) and sarcolemmal (FABPpm) and mitochondrial (FAT/CD36) membranes in human skeletal muscle of females. These results suggest that increases in skeletal muscle fatty acid oxidation following training are related in part to changes in fatty acid transport protein content and localization.
Roles for miRNA-378/378* in adipocyte gene expression and lipogenesis
Authors: Gerin Isabelle , Bommer Guido T. , McCoin Colin S. , Sousa Kyle M. , Krishnan Venkatesh , MacDougald Ormond A.
Published: May 2010

In this study, we explored the roles of microRNAs in adipocyte differentiation and metabolism. We first knocked down Argonaute2 (Ago2), a key enzyme in the processing of micro-RNAs (miRNAs), to investigate a potential role for miRNAs in adipocyte differentiation and/or metabolism. Although we did not observe dramatic differences in adipogenesis between Ago2 knock-down and control 3T3-L1 cells, incorporation of [14C]glucose or acetate into triacylglycerol, and steady-state levels of triacyglycerol were all reduced, suggesting a role for miRNAs in adipocyte metabolism. To study roles of specific miRNAs in adipocyte biology, we screened for miRNAs that are differentially expressed between preadipocytes and adipocytes for the 3T3-L1 and ST2 cell lines. Distinct subsets of miRNAs decline or increase during adipocyte conversion, whereas most miRNAs are not regulated. One locus encoding two miRNAs, 378/378*, contained within the intron of PGC-1β is highly induced during adipogenesis. When overexpressed in ST2 mesenchymal precursor cells, miRNA378/378* increases the size of lipid droplets and incorporation of [14C]acetate into triacylglycerol. Although protein and mRNA expression levels of C/EBPα, C/EBPβ, C/EBPδ, and PPARγ1 are unchanged, microarray and quantitative RT-PCR analyses indicate that a set of lipogenic genes are upregulated, perhaps due to increased expression of PPARγ2. Knock-down of miRNA378 and/or miRNA378* decreases accumulation of triacylglycerol. Interestingly, we made the unexpected finding that miRNA378/378* specifically increases transcriptional activity of C/EBPα and C/EBPβ on adipocyte gene promoters.
MicroRNA signatures in peripheral blood mononuclear cells of chronic heart failure patients
Authors: Voellenkle Christine , van Rooij Jeroen , Cappuzzello Claudia , Greco Simona , Arcelli Diego , Di Vito Luca , Melillo Guido , Rigolini Roberta , Costa Elena , Crea Filippo , Capogrossi Maurizio C. , Napolitano Monica , Martelli Fabio
Published: May 2010

MicroRNAs (miRNAs) are noncoding RNAs that act as negative regulators of gene expression. Interestingly, specific alterations of miRNA expression have been found in failing hearts of different etiologies. The aim of this study was to identify the miRNA expression pattern of peripheral blood mononuclear cells (PBMCs) derived from chronic heart failure (CHF) patients affected by ischemic (ICM) and nonischemic dilated (NIDCM) cardiomyopathy. The expression profile of 257 miRNAs was assessed in 7 NIDCM patients, 8 ICM patients, and 9 control subjects by quantitative real-time PCR. Significantly modulated miRNAs were validated by using an independent set of 34 CHF patients (NIDCM = 19, ICM = 15) and 19 control subjects. Three miRNAs (miR-107, -139, and -142-5p) were downmodulated in both NIDCM and ICM patients versus control subjects. Other miRNAs were deregulated in only one of the CHF classes analyzed compared with control subjects: miR-142-3p and -29b were increased in NIDCM patients, while miR-125b and -497 were decreased in ICM patients. Bioinformatic analysis of miRNA predicted targets and of gene expression modifications associated with CHF in PBMCs indicated a significant impact of the miRNA signature on the transcriptome. Furthermore, miRNAs of both the NIDCM and the ICM signature shared predicted targets among CHF-modulated genes, suggesting potential additive or synergistic effects. The present study identified miRNAs specifically modulated in the PBMCs of NIDCM and ICM patients. Intriguingly, most of these miRNAs were previously reported as deregulated in human and/or mouse failing hearts. The identified miRNAs might have a potential diagnostic and/or prognostic use in CHF.
Comparative Global Gene Expression Profiles of Wild-TypeYersinia pestisCO92 and Its Braun Lipoprotein Mutant at Flea and Human Body Temperatures
Authors: Galindo Cristi L. , Sha Jian , Moen Scott T. , Agar Stacy L. , Kirtley Michelle L. , Foltz Sheri M. , McIver Lauren J. , Kozlova E. V. , Garner Harold R. , Chopra Ashok K.
Published: May 2010

Braun/murein lipoprotein (Lpp) is involved in inflammatory responses and septic shock. We previously characterized aΔlppmutant ofYersinia pestisCO92 and found that this mutant was defective in surviving in macrophages and was attenuated in a mouse inhalation model of plague when compared to the highly virulent wild-type (WT) bacterium. We performed global transcriptional profiling of WTY. pestisand itsΔlppmutant using microarrays. The organisms were cultured at 26 and 37 degrees Celsius to simulate the flea vector and mammalian host environments, respectively. Our data revealed vastly different effects oflppmutation on the transcriptomes ofY. pestisgrown at 37 versus26C. While the absence of Lpp resulted mainly in the downregulation of metabolic genes at26C, theY. pestis Δlppmutant cultured at37Cexhibited profound alterations in stress response and virulence genes, compared to WT bacteria. We investigated one of the stress-related genes (htrA) downregulated in theΔlppmutant relative to WTY. pestis. Indeed, complementation of theΔlppmutant with thehtrAgene restored intracellular survival of theY. pestis Δlppmutant. Our results support a role for Lpp inY. pestisadaptation to the host environment, possibly via transcriptional activation ofhtrA.
A Theoretical Argument Why the t-Copula Explains Credit Risk Contagion Better than the Gaussian Copula
Authors: Cossin Didier , Schellhorn Henry , Song Nan , Tungsong Satjaporn
Published: May 2010

One of the key questions in credit dependence modelling is the specfication of the copula function linking the marginals of default variables. Copulae functions are important because they allow to decouple statistical inference into two parts: inference of the marginals and inference of the dependence. This is particularly important in the area of credit risk where information on dependence is scant. Whereas the techniques to estimate the parameters of the copula function seem to be fairly well established, the choice of the copula function is still an open problem. We find out by simulation that the t-copula naturally arises from a structural model of credit risk, proposed by Cossin and Schellhorn (2007). If revenues are linked by a Gaussian copula, we demonstrate that the t-copula provides a better fit to simulations than does a Gaussian copula. This is done under various specfications of the marginals and various configurations of the network. Beyond its quantitative importance, this result is qualitatively intriguing. Student's t-copulae induce fatter (joint) tails than Gaussian copulae ceteris paribus. On the other hand observed credit spreads have generally fatter joint tails than the ones implied by the Gaussian distribution. We thus provide a new statistical explanation why (i) credit spreads have fat joint tails, and (ii) financial crises are amplified by network effects.
Autotaxin Promotes Cancer Invasion via the Lysophosphatidic Acid Receptor 4: Participation of the Cyclic AMP/EPAC/Rac1 Signaling Pathway in Invadopodia Formation
Authors: Harper Kelly , Arsenault Dominique , Boulay-Jean Stephanie , Lauzier Annie , Lucien Fabrice , Dubois Claire M.
Published: May 2010

The ability of cancer cells to invade and metastasize is the major cause of death in cancer patients. Autotaxin (ATX) is a secreted lysophospholipase whose level of expression within tumors correlates strongly with their aggressiveness and invasiveness. ATX is the major enzyme involved in the production of lysophosphatidic acid (LPA), a phospholipid that is known to act mostly through its three first characterized receptors (LPA1, LPA2, and LPA3). Tumor cell invasion across tissue boundaries and metastasis are dependent on the capacity of invasive cancer cells to breach the basement membrane. This process can be initiated by the formation of the actin-rich cell protrusions, invadopodia. In this study, we show that ATX is implicated in the formation of invadopodia in various cancer cells types and this effect is dependent on the production of LPA. We further provide evidence that LPA4 signaling in fibrosarcoma cells regulates invadopodia formation downstream of ATX, a process mediated through the activation of EPAC by cyclic AMP and subsequent Rac1 activation. Results using LPA4 shRNA support the requirement of the LPA4 receptor for cell invasion and in vivo metastasis formation. This work presents evidence that blocking the LPA receptor, LPA4, in fibrosarcoma cells could provide an additional tool to improve the efficacy of treatment of metastasis in patients. Because LPA receptors and ATX are currently being targeted in preclinical trials, the current findings should stimulate future studies to evaluate the expression pattern and clinical outcome of LPA4, together with other LPA receptors, in various cancer patients. Cancer Res; 70(11); 4634–43. ©2010 AACR.
Ubiquitin-Specific Protease 8 Links the PTEN-Akt-AIP4 Pathway to the Control of FLIPS Stability and TRAIL Sensitivity in Glioblastoma Multiforme
Authors: Panner Amith , Crane Courtney A. , Weng Changjiang , Feletti Alberto , Fang Shanna , Parsa Andrew T. , Pieper Russell O.
Published: May 2010

The antiapoptotic protein FLIPS is a key suppressor of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis in human glioblastoma multiforme (GBM) cells. We previously reported that a novel phosphatase and tensin homologue (PTEN)–Akt–atrophin-interacting protein 4 (AIP4) pathway regulates FLIPS ubiquitination and stability, although the means by which PTEN and Akt were linked to AIP4 activity were unclear. Here, we report that a second regulator of ubiquitin metabolism, the ubiquitin-specific protease 8 (USP8), is a downstream target of Akt, and that USP8 links Akt to AIP4 and the regulation of FLIPS stability and TRAIL resistance. In human GBM xenografts, levels of USP8 correlated inversely with pAkt levels, and genetic or pharmacologic manipulation of Akt regulated USP8 levels in an inverse manner. Overexpression of wild-type USP8, but not catalytically inactive USP8, increased FLIPS ubiquitination, decreased FLIPS half-life, decreased FLIPS steady-state levels, and decreased TRAIL resistance, whereas short interfering RNA (siRNA)–mediated suppression of USP8 levels had the opposite effect. Because high levels of the USP8 deubiquitinase correlated with high levels of FLIPS ubiquitination, USP8 seemed to control FLIPS ubiquitination through an intermediate target. Consistent with this idea, overexpression of wild-type USP8 decreased the ubiquitination of the FLIPS E3 ubiquitin ligase AIP4, an event previously shown to increase AIP4-FLIPS interaction, whereas siRNA-mediated suppression of USP8 increased AIP4 ubiquitination. Furthermore, the suppression of FLIPS levels by USP8 overexpression was reversed by the introduction of siRNA targeting AIP4. These results show that USP8, a downstream target of Akt, regulates the ability of AIP4 to control FLIPS stability and TRAIL sensitivity. Cancer Res; 70(12); 5046–53. ©2010 AACR.
Oncostatin M Renders Epithelial Cell Adhesion Molecule–Positive Liver Cancer Stem Cells Sensitive to 5-Fluorouracil by Inducing Hepatocytic Differentiation
Authors: Yamashita Taro , Honda Masao , Nio Kouki , Nakamoto Yasunari , Yamashita Tatsuya , Takamura Hiroyuki , Tani Takashi , Zen Yoh , Kaneko Shuichi
Published: May 2010

Recent evidence suggests that a certain type of hepatocellular carcinoma (HCC) is hierarchically organized by a subset of cells with stem cell features (cancer stem cells; CSC). Although normal stem cells and CSCs are considered to share similar self-renewal programs, it remains unclear whether differentiation programs are also maintained in CSCs and effectively used for tumor eradication. In this study, we investigated the effect of oncostatin M (OSM), an interleukin 6–related cytokine known to induce the differentiation of hepatoblasts into hepatocytes, on liver CSCs. OSM receptor expression was detected in the majority of epithelial cell adhesion molecule–positive (EpCAM+) HCC with stem/progenitor cell features. OSM treatment resulted in the induction of hepatocytic differentiation of EpCAM+ HCC cells by inducing signal transducer and activator of transcription 3 activation, as determined by a decrease in stemness-related gene expression, a decrease in EpCAM, α-fetoprotein and cytokeratin 19 protein expressions, and an increase in albumin protein expression. OSM-treated EpCAM+ HCC cells showed enhanced cell proliferation with expansion of the EpCAM-negative non-CSC population. Noticeably, combination of OSM treatment with the chemotherapeutic agent 5-fluorouracil (5-FU), which eradicates EpCAM-negative non-CSCs, dramatically increased the number of apoptotic cells in vitro and suppressed tumor growth in vivo compared with either saline control, OSM, or 5-FU treatment alone. Taken together, our data suggest that OSM could be effectively used for the differentiation and active cell division of dormant EpCAM+ liver CSCs, and the combination of OSM and conventional chemotherapy with 5-FU efficiently eliminates HCC by targeting both CSCs and non-CSCs. Cancer Res; 70(11); 4687–97. ©2010 AACR.
Clinical and Correlative Results of SWOG S0354: A Phase II Trial of CNTO328 (Siltuximab), a Monoclonal Antibody against Interleukin-6, in Chemotherapy-Pretreated Patients with Castration-Resistant Prostate Cancer
Authors: Dorff Tanya B. , Goldman Bryan , Pinski Jacek K. , Mack Philip C. , Lara Primo N. , Van Veldhuizen Peter J. , Quinn David I. , Vogelzang Nicholas J. , Thompson Ian M. , Hussain Maha H.A.
Published: May 2010

Purpose: Interleukin-6 (IL-6) facilitates cancer cell survival via pleotrophic effects. We conducted a multicenter phase II study of CNTO328 (siltuximab) as second-line therapy for men with castration-resistant prostate cancer.

Experimental Design: Eligible men had castration-resistant prostate cancer treated with one prior chemotherapy. Subjects were treated with 6 mg/kg CNTO328 i.v. every 2 weeks for 12 cycles. Response was assessed after every three cycles. Primary end point was prostate-specific antigen (PSA) response rate defined as a 50% reduction. Accrual was planned in two stages, with 20 eligible patients in the first stage and 40 overall. Plasma cytokines and growth factors were measured by Luminex.

Results: Fifty-three eligible subjects had all received prior taxane therapy. Two (3.8%; 95% CI, 0.5-13.0%) had PSA response. None of the 31 patients with measurable disease had a RECIST (Response Evaluation Criteria in Solid Tumors) response but 7 (23%) had stable disease. With median follow-up of 14.8 months, median progression-free survival was 1.6 months (95% CI, 1.6-1.7) and median overall survival was 11.6 months (95% CI, 7.5-19.0). Grade 3/4 toxicities included disseminated intravascular coagulation (1), central nervous system ischemia (1), elevated aspartate aminotransferase (1), gastritis/esophagitis (2), thrombocytopenia (2), pain (2), leukopenia (1), and neuropathy (2). Median baseline IL-6 levels were 12.5 pg/mL (interquartile range, 2.5-41.5). Patients with IL-6 >12.5 pg/mL had worse survival than those with levels <12.5 pg/mL (53% versus 94%; P = 0.02). After treatment, IL-6 levels were >250-fold higher. Thirty-two of 38 patients had a decline in C-reactive protein plasma levels at 6 weeks.

Conclusions: CNTO328 resulted in a PSA response rate of 3.8% and a RECIST stable disease rate of 23%. Declining C-reactive protein levels during treatment may reflect biological activity. Despite evidence of CNTO-mediated IL-6 inhibition, elevated baseline IL-6 levels portended a poor prognosis. Clin Cancer Res; 16(11); 3028–34. ©2010 AACR.
Effect of the Specific Src Family Kinase Inhibitor Saracatinib on Osteolytic Lesions Using the PC-3 Bone Model
Authors: Yang Joy C. , Bai Lanfang , Yap Stanley , Gao Allen C. , Kung Hsing-Jien , Evans Christopher P.
Published: May 2010

The hematogenous metastatic spread of prostate cancer is preferentially to bone and can result in significant patient morbidity. Although these metastatic lesions are typically osteoblastic, bone resorption is believed to have a prerequisite role in their development. Src kinase has been identified to contribute to prostate cancer tumor growth and metastasis. In addition, Src is also essential in bone metabolism, especially in bone resorption. We hypothesized that inhibiting Src activity with the specific Src family kinase inhibitor saracatinib (AZD0530) would inhibit tumor cell growth and osteoclast differentiation in the tumor-bone interface, thus providing a new approach for advanced prostate cancer. We found that saracatinib inhibited PC-3 cell growth and invasion in a dose-dependent manner. Phosphorylation of Src, focal adhesion kinase, and P38 kinases was inhibited by saracatinib at the submicromolar range. Saracatinib also inhibited the expression and secretion of invasion-related molecules interlukin-8, urokinase-type plasminogen activator, and matrix metalloprotease-9. Receptor activator of NF-κB ligand (RANKL)–induced osteoclastogenesis and signaling were inhibited by saracatinib in both macrophages and PC-3 cells. In in vivo studies, control mice developed more severe osteolytic lesions compared with the treatment group. Immunohistochemical and biochemical assays of bone metabolites confirmed that saracatinib preserved bone architecture in the presence of prostate cancer tumor cells. In summary, we have shown the inhibition of PC3 cell growth and invasion by saracatinib. Src inhibition also blocked the RANKL stimulatory pathway in osteoclasts and PC3 cells. The inhibition of Src thus targets multiple sites involved in prostate cancer bone metastasis, which may offer a therapeutic advantage in treating advanced prostate cancer. Mol Cancer Ther; 9(6); 1629–37. ©2010 AACR.
Effects of β-Carotene Supplementation on Molecular Markers of Lung Carcinogenesis in Male Smokers
Authors: Wright Margaret E. , Groshong Steve D. , Husgafvel-Pursiainen Kirsti , Genova Erin , Lucia M. Scott , Wolff Henrik , Virtamo Jarmo , Albanes Demetrius
Published: May 2010

Two primary prevention trials unexpectedly showed adverse effects of supplemental β-carotene on lung cancer incidence in cigarette smokers. To elucidate the molecular mechanisms that might underlie these effects, we studied the immunohistochemical expression of cytochrome P450 1A1, 1A2, and 2E1, retinoic acid receptor β, activated protein-1 elements, cyclin D1, and Ki67 in lung tumors and, when available, adjacent normal tissues obtained from incident cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Archival lung tissue was available from 52 men randomized to receive 20 mg of β-carotene per day and 30 men randomized to the placebo arm, all of whom were diagnosed with incident non–small-cell lung carcinoma during the course of the trial and subsequently underwent radical pulmonary resection. In normal-appearing bronchial epithelium, positive staining for cyclin D1 was observed in 23% of cases in the β-carotene group and 0% of cases in the placebo group (based on only 3 of 13 versus 0 of 11 cases staining positively, however; P = 0.04), with no differences in expression noted in lung tumor tissue (P = 0.48). There were no statistically significant differences in Ki67 expression in normal or cancerous lung tissue between intervention groups, although a small increase in staining in tumors was noted among cases in the β-carotene versus placebo group (88% versus 71% of cases stained positive, respectively; P = 0.13). Contrary to expectation, β-carotene supplementation had no apparent effect on retinoic acid receptor-β expression. These findings suggest that male smokers supplemented with β-carotene may have had an increased risk of lung cancer due to aberrant cell growth, although our results are based on a relatively small number of cases and require confirmation in other completed trials of β-carotene supplementation. Cancer Prev Res; 3(6); 745–52. ©2010 AACR.
Interleukin-6 as a Potential Indicator for Prevention of High-Risk Adenoma Recurrence by Dietary Flavonols in the Polyp Prevention Trial
Authors: Bobe Gerd , Albert Paul S. , Sansbury Leah B. , Lanza Elaine , Schatzkin Arthur , Colburn Nancy H. , Cross Amanda J.
Published: May 2010

Serum interleukin-6 (IL-6), a proinflammatory cytokine, is considered an indicator of inflammation and may be an indicator of colorectal carcinogenesis given that inflammation can promote carcinogenesis. Flavonols, which can be found in fruits and vegetables, may inhibit colorectal carcinogenesis partly by inhibiting inflammation. We estimated odds ratios and 95% confidence intervals (95% CI) to determine whether serum IL-6 was associated with colorectal adenoma recurrence and flavonol intake and thus may serve as a risk indicator and as a response indicator to dietary flavonols. Serum IL-6 concentrations at baseline, year 1, and year 3 were measured in 872 participants from the intervention arm of the Polyp Prevention Trial, a 4-year trial that examined the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence. Intake of flavonols, especially of isorhamnetin, kaempferol, and quercetin, was inversely associated with serum IL-6 concentrations (highest versus lowest flavonol intake quartile, 1.80 versus 2.20 pg/mL) and high-risk (OR, 0.51; 95% CI, 0.26-0.98) and advanced adenoma recurrence (OR, 0.17; 95% CI, 0.06-0.50). A decrease in IL-6 concentration during the trial was inversely associated with high-risk (OR, 0.44; 95% CI, 0.23-0.84) and advanced adenoma recurrence (OR, 0.47; 95% CI, 0.19-1.18). Individuals with above median flavonol intake and equal or below median IL-6 change after baseline had the lowest risk of recurrence of high-risk and advanced adenoma. Our results suggest that serum IL-6 may serve as a risk indicator and as a response indicator to dietary flavonols for colorectal cancer prevention. Cancer Prev Res; 3(6); 764–75. ©2010 AACR.
Uremia Aggravates Left Ventricular Remodeling after Myocardial Infarction
Authors: Dikow Ralf , Schmidt Ulrike , Kihm Lars P. , Schaier Matthias , Schwenger Vedat , Gross Marie-Luise , Katus Hugo A. , Zeier Martin , Hardt Stefan E.
Published: May 2010

Background: Renal failure is a well-established cardiovascular risk factor. We hypothesized that uremia negatively affects post-myocardial infarction (MI) remodeling and left ventricular (LV) function and examined the pathohistological correlations. Methods: Subtotally nephrectomized rats (SNX) and controls with MI only (MIC) were examined 1, 4 and 8 weeks after MI. MI size, ejection fraction (EF), cardiac fibrosis, vascular density and cardiomyocyte density were studied. Results: The extension of MI was 0.08 ± 0.02 in SNX versus 0.06 ± 0.02 in MIC rats (p < 0.031). Prior to MI, EF was comparable in SNX and MIC (74 ± 3 vs. 72 ± 2%, n.s.). Despite a relatively small infarct size EF in SNX decreased to 58 ± 4% 1 week after infarction and progressively worsened to 51 ± 4% after 8 weeks. In MIC animals EF only slightly decreased 1 week after MI (70 ± 3%) and remained unchanged at follow-up. In SNX animals LV end-diastolic diameter continuously increased following MI throughout the study period indicating accelerated remodeling. Furthermore, accelerated myocardial fibrosis was already notable 1 week after MI in SNX animals and the volume density of capillaries and cardiomyocytes was significantly lower in SNX rats. Conclusion: MI in experimental uremia is associated with progressive impairment of LV function, LV dilatation and accelerated myocardial fibrosis.
Progression of Chronic Kidney Disease: Adrenergic Genetic Influence on Glomerular Filtration Rate Decline in Hypertensive Nephrosclerosis
Authors: Chen Yuqing , Lipkowitz Michael S. , Salem Rany M. , Fung Maple M. , Bhatnagar Vibha , Mahata Manjula , Nievergelt Caroline M. , Rao Fangwen , Mahata Sushil K. , Schork Nicholas J. , Hicks Pamela J. , Bowden Donald W. , Freedman Barry I. , Brophy Victoria H. , O’Connor Daniel T. ,   for the AASK co-investigators
Published: May 2010

Background: African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease. Methods: We used the African-American Study of Kidney Disease to probe whether β2-adrenergic receptor (ADRB2) predicts glomerular filtration rate (GFR) decline rate. A total of 580 participants were included. Baseline GFR was 51.2 ± 0.5 ml/min/1.73 m2. Subjects were randomized in a 2 × 3 block design: to intensively lowered (MAP ≤92 mm Hg) versus ‘usual’ (MAP = 102–107 mm Hg) blood pressure goal groups, and also divided by three randomized antihypertensive drugs (ramipril, metoprolol, or amlodipine). We scored 4 SNPs at the ADRB2 locus. Results: Haplotypes at ADRB2 predicted chronic GFR decline rate, GFR declined more slowely in individuals with haplotype-1 (–804G→173T→16Gly→27GIn), and faster in those who carried haplotype-3 (–804G→173T→16Arg→27Gln). ADRB2 genotype interacted with antihypertensive drug class to influence GFR slope (p = 0.001–0.037). We extended our findings to an independent case/control sample of Black hypertensive ESRD, in which we found that variant Gly16Arg that tagged the GFR slope-determining ADRB2 haplotype also conferred risk for the ESRD trait in Blacks. Conclusions: The GFR decline/progression rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway.
Watermelon Profilin: Characterization of a Major Allergen as a Model for Plant-Derived Food Profilins
Authors: Cases Bárbara , Pastor-Vargas Carlos , Gil Dones Félix , Perez-Gordo Marina , Maroto Aroa S. , de las Heras Manuel , Vivanco Fernando , Cuesta-Herranz Javier
Published: May 2010

Background: Plant profilins have been reported as minor allergens. They are a well-known pan-allergen family responsible for cross-reactivity between plant-derived foods and pollens. Watermelon profilin has been reported to be a major allergen in watermelon (Citrullus lanatus).The aim of this study was to characterize recombinant watermelon profilin, confirming its reactivity for diagnostic purposes and the development of immunotherapy. Methods: Native profilin was purified from watermelon extract by affinity chromatography using poly-L-proline. Recombinant His-tagged profilin was produced in Pichia pastoris yeast using pPICZαA vector and purified by metal chelate affinity chromatography. ELISA and immunoblot were carried out with sera from 17 watermelon-allergic patients. Biological activity was tested by the basophil activation test. Results: Native profilin and recombinant profilin were purified and identified by mass spectrometry. Both show similar IgE reactivity in vitro and are biologically active. Conclusions: Similarities were found in the IgE-binding patterns and biological activity of recombinant profilin and native profilin. Recombinant profilin may be a powerful tool for specific diagnosis.
Natural Killer Cells in Allergic Rhinitis Patients and Nonatopic Controls
Authors: Mesdaghi Mehrnaz , Vodjgani Mohammad , Salehi Eisa , Hadjati Jamshid , Sarrafnejad Abdolfattah , Bidad Katayoon , Berjisian Farideh
Published: May 2010

Background: Allergic rhinitis (AR) is currently considered to be a worldwide problem. The role of type 2 cytokines in this disease has been established, and natural killer (NK) cells are possibly the source of cytokine secretions. This study was performed to confirm the existence of type 2 cytokine-secreting NK cells in AR patients and to determine their characteristics. Methods: Twenty AR patients and 20 healthy nonatopic controls were included. Peripheral blood mononuclear cells were separated from heparinized blood by density gradient centrifugation. NK cells were enriched and cultured for 72 h. Cytokine secretion was measured by ELISA, and cytotoxicity assay was carried out using the PKH2-labeled K562 cell line. Intracytoplasmic cytokine staining and an analysis of surface markers of NK cells were performed on freshly isolated peripheral blood mononuclear cells using flow cytometry. Results: Patients with AR had a higher percentage of NK cells compared to nonatopic subjects. The mean percentage of IL-4+ NK cells was significantly higher and that of IFN-γ+ NK cells was nonsignificantly lower in AR patients compared to healthy nonatopic controls. IL-13 secretion was also significantly higher in AR patients compared to nonatopic controls. While there was no difference between the case and the control groups with regard to the surface expression of CD40, CD45RO, and CD95, the expression of CD178 was significantly higher in the cases when compared to the controls. NK cell cytotoxicity was also significantly higher in AR patients compared to healthy controls. Conclusions: This study confirms the existence of type 2 cytokine-secreting NK cells in AR and shows their increased number and enhanced cytotoxicity compared to normal individuals.
Association between Sputum Natural Killer T Cells and Eosinophilic Airway Inflammation in Human Asthma
Authors: Koh Young-Il , Shim Jae-Uoong
Published: May 2010

Background: Natural killer T (NKT) cells play an essential role in the development of airway hyperresponsiveness (AHR) in murine asthma. However, their role in the pathogenesis of human asthma has not been defined. The present study investigated whether NKT cells were associated with AHR or airway inflammation in human asthma. Methods: We measured the number of NKT cells in peripheral blood and induced sputum obtained from 61 asthmatics, 10 patients with eosinophilic bronchitis (EB) and 17 controls. EB was used as a disease control model to investigate the mechanisms of AHR in asthma outside the influence of eosinophilic airway inflammation. The quantities of CD3+CD56+ NKT cells, 6B11+ NKT cells and Vα24+ NKT cells were measured by flow cytometry. Results: The measurement of NKT cells did not differ among the 3 groups in peripheral blood. However, in sputum, CD3+CD56+ NKT cells and Vα24+ NKT cells were significantly increased in patients with asthma and EB compared to controls, and 6B11+ NKT cells were also increased in patients with asthma and EB, although not significantly. There was no difference in the measurements of sputum NKT cells between asthmatics and patients with EB. Sputum Vα24+ NKT cells were inversely associated with the degree of AHR in asthmatics. Conclusions: Sputum NKT cells might play an important role in the pathogenesis of eosinophilic airway inflammation in human chronic stable asthma. However, functional studies on airway NKT cells are needed to elucidate the association between NKT cells and AHR.
Site of Ruptured Intracranial Saccular Aneurysms in Patients in Izumo City, Japan
Authors: Inagawa Tetsuji
Published: May 2010

Background and Purpose: A community-based study was conducted to estimate the site distribution of ruptured intracranial aneurysms and to evaluate clinical features related to aneurysm site. Methods: The author reviewed data from 358 patients with aneurysmal subarachnoid hemorrhage (SAH) treated between 1980 and 1998 in Izumo, Japan. In 291 of these patients, the sites of the ruptured aneurysms were confirmed. Results: The aneurysm arose from the anterior communicating artery (AcoA) in 101 patients, the distal anterior cerebral artery (ACA) in 24, the internal carotid artery (ICA) in 70, the middle cerebral artery (MCA) in 77, and the vertebrobasilar artery (VBA) in 19. Regardless of age, ACoA aneurysms were more frequent in men, whereas ICA aneurysms were more common in women. Intracerebral hemorrhage was more frequent in patients with MCA aneurysms, whereas intraventricular hemorrhage was more common in those with VBA, ACoA and distal ACA aneurysms. While the incidence of symptomatic vasospasm was not related to aneurysm site, the patients who died due to vasospasm harbored an ACoA or ICA aneurysm. The incidence of hydrocephalus was relatively high in patients with ACoA, ICA and VBA aneurysms, and low in those with MCA aneurysms. The overall outcome was best in patients with MCA aneurysms, followed by those with aneurysms of the ACA, including ACoA and distal ACA, ICA and VBA; these results were in good agreement with the admission grades. Conclusions: The roughly estimated proportions of the sites of aneurysm rupture were 40% for the ACA, including ACoA and distal ACA, 25% for the ICA, 25% for the MCA, and 10% for the VBA. The clinical features showed significant differences according to aneurysm site.
A Competing Risk Survival Analysis Model to Assess the Efficacy of Filling Carious Primary Teeth
Authors: Stephenson J. , Chadwick B.L. , Playle R.A. , Treasure E.T.
Published: May 2010

In recent years a strategy of selective, symptom-based intervention of carious primary teeth has been developed amongst some British general dental practitioners. Practice-based studies appear to provide evidence that policies of restoration of symptomless carious primary teeth do not confer any significant benefits above those associated with non-restorative care. However, results from these studies contrast with those of many clinical trials and prospective studies of primary molar restorations. In the current investigation, cohort study data from 5,168 carious primary molar teeth from 2,654 British children aged 4–5 years at baseline, augmented with Dental Practice Board treatment data, was utilised to assess the effect of restorative treatment on the likelihood of carious teeth subsequently progressing to either exfoliation or extraction. The effect of demographic and tooth level covariates on the fate of these teeth was also assessed. Multivariate multilevel parametric survival models were applied to the analysis of the carious-exfoliation and carious-extraction transitions to which the teeth were subject, assuming an underlying data hierarchy with teeth nested within individuals. Time of occurrence of caries affected survival experience, with teeth in which caries occurred later in life being associated with higher survival rates to extraction. Amongst filled teeth, later fillings were also associated with higher survival rates to extraction. Demographic and tooth level variables had a limited effect on survival experience. Treatment was found to be significantly associated with survival with respect to extraction, with survival rates of over 80% at 14 years, double those of untreated teeth.
Antioxidant Efficacy on Human Skin in vivo Investigated by UVA-Induced Chemiluminescence Decay Analysis via Induced Chemiluminescence of Human Skin
Authors: Jain A. , Rieger I. , Rohr M. , Schrader A.
Published: May 2010

Background/Aims: Exogenous factors (e.g. physical: UV irradiation; or chemical: hydrogen peroxide) and endogenous metabolic processes (e.g. cellular respiration, oxidative burst, etc.) generate oxidative stress in living tissues which are in balance with enzymatic antioxidative systems and ingested antioxidants under normal conditions. These complex biological reactions are accompanied by chemiluminescence (ultraweak photon emission). However, knowledge about the chemiluminescence decay characteristics of human skin and the modulatory influence of topically applied antioxidants is still scarce. Methods: Using ICL-S (induced chemiluminescence of human skin), a highly sensitive in vivo method, the decay characteristics of UVA-induced photon emission caused by different UVA doses were investigated in detail. In addition, modulatory properties of topical antioxidant pretreatment were examined for 2 weeks. Results: UVA-induced chemiluminescence signals were generally characterized by two distinct decay phases: an initial burst (0–5 s), contributing approximately 80% of the complete signal with an inverse dose-response relationship (UVA dose vs. chemiluminescence intensity), followed by a second decay phase (delayed chemiluminescence, 5–200 s) showing a direct correlation. Antioxidant pretreatment caused a reduction in signal intensity of approximately 50%, which was calculated by signal integration and confirmed using the modulation of the intersection point of decay curves resulting from irradiation with different UVA doses at constant intensity with and without treatment. Conclusion: In addition to the established UVA filter testing (independent from UVB filter content) on human skin in vivo, ICL-S is also a valuable tool for the efficacy testing of topically applied antioxidants under in vivo conditions in humans. The first rapid, but short, decay phase not only provides approximately 80% of the complete chemiluminescence signal, but is also essential for the investigation of antioxidant-mediated effects. Chemiluminescence signal modulations induced by UVA intensity reduction (e.g. UV filters in daily care products) can be clearly distinguished from antioxidant-mediated signal modulations. The probe head dimensions permit comprehensive in vivo testing in humans on practically every skin area (e.g. arms, legs, back, abdomen and face).
Nitinol Stent Implantation Versus Balloon Angioplasty for Lesions in the Superficial Femoral Artery and Proximal Popliteal Artery
Authors: Laird John R. , Katzen Barry T. , Scheinert Dierk , Lammer Johannes , Carpenter Jeffrey , Buchbinder Maurice , Dave Rajesh , Ansel Gary , Lansky Alexandra , Cristea Ecaterina , Collins Tyrone J. , Goldstein Jeffrey , Jaff Michael R. ,   for the RESILIENT Investigators
Published: May 2010

Background—

Controversy still exists regarding the best endovascular treatment strategy for patients with symptomatic disease of the superficial femoral artery. There are conflicting data regarding the benefits of superficial femoral artery stenting and the role of primary stenting compared with balloon angioplasty with provisional stent implantation.

Methods and Results—

A total of 206 patients from 24 centers in the United States and Europe with obstructive lesions of the superficial femoral artery and proximal popliteal artery and intermittent claudication were randomized to implantation of nitinol stents or percutaneous transluminal angioplasty. The mean total lesion length was 71 mm for the stent group and 64 mm for the angioplasty group. Acute lesion success (<30%residual stenosis) was superior for the stent group compared with the angioplasty group (95.8% versus 83.9%;
P
<0.01). Twenty-nine (40.3%) patients in the angioplasty group underwent bailout stenting because of a suboptimal angiographic result or flow-limiting dissection. Bailout stenting was treated as a target lesion revascularization and loss of primary patency in the final analysis. At 12 months, freedom from target lesion revascularization was 87.3% for the stent group compared with 45.1% for the angioplasty group (
P
<0.0001). Duplex ultrasound-derived primary patency at 12 months was better for the stent group (81.3% versus 36.7%;
P
<0.0001). Through 12 months, fractures occurred in 3.1% of stents implanted. No stent fractures resulted in loss of patency or target lesion revascularization.

Conclusions—

In this multicenter trial, primary implantation of a self-expanding nitinol stent for moderate-length lesions in the superficial femoral artery and proximal popliteal artery was associated with better acute angiographic results and improved patency compared with balloon angioplasty alone.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00673985.