bluuebunny/crossref_metadata_2025 huggingface dataset:
Yield strength ratios, critical strength ratios, and brittleness of sandy soils from laboratory tests
Authors: Sadrekarimi Abouzar , Olson Scott M.
Published: March 2011

In this study, we performed 26 undrained triaxial compression and 32 constant-volume ring shear tests on two clean sands and one silty sand. We then used these results to evaluate the critical states, and shear strength ratios mobilized at yield and at critical state. We obtained yield strength ratios that ranged from 0.16 to 0.32 and from 0.20 to 0.35 in triaxial compression and ring shear, respectively. Critical strength ratios mobilized prior to particle damage ranged from 0.01 to 0.26 in triaxial compression and from 0.04 to 0.22 in ring shear. Particle damage and shear displacement increased the slopes of the critical-state lines during ring shear testing, and consequently the critical strength ratios incorporating particle damage decreased from 0.02 to 0.12. In addition, specimen brittleness (before particle damage) increases with initial void ratio and state parameter and is affected by initial fabric and particle shape. However, particle damage and crushing considerably increases sand brittleness, making it essentially independent of initial void ratio. A unique relation is found between sand brittleness and critical strength ratio independent of sand type, mode of shear, fabric, and particle damage, which indicates an upper bound critical strength ratio of about 0.3 for mildly contractive sands.
Seepage, leaching, and embankment instability
Authors: Man Alex , Graham Jim , Blatz James
Published: March 2011

Water-retention dykes at a hydroelectric generating station in southeastern Manitoba experienced irregular instabilities over many years after they were heightened in the late 1940s. Samples from an unstable section of dyke showed considerable reductions in gypsum content and increased brittleness compared with those of neighbouring unloaded clay. The samples also showed that lowering the content of gypsum reduced the sizes of yield loci and the strains required for strain softening to occur. These observations and the time-dependent nature of the problem suggested that seepage from the forebay had leached naturally occurring cementation from the foundation clay and subsequently changed its behaviour. Stress–deformation modeling indicated the foundation clay had yielded during initial construction and again when the dykes were heightened. Seepage from the forebay occurred at different rates in different locations through the irregular sand–silt partings that are generally present in proglacial clays. Leaching and strain softening were therefore also irregular. Leaching led to reduction in the size of the yield loci and therefore increased the volume of soil that yielded under loading from the dyke. In slope-stability modeling, excess pore-water pressures arising from time-dependent brittleness were sufficient to cause instability of the dykes.
Mesure en continu de la raideur dynamique d’une voie ferrée
Authors: Hosseingholian Mohsen , Levacher Daniel , Khay Matoren
Published: March 2011

La structure supportant le trafic ferroviaire est un des éléments les plus importants pour assurer la stabilité géométrique de la voie et son bon fonctionnement à long terme. Des couches de sols de faible portance et instables peuvent provoquer sous l’effet de la circulation des trains, des défauts géométriques, accélérant ainsi la dégradation des constituants de la voie. La raideur est considérée comme un indicateur structurel pertinent de la voie. Sa détermination reste difficile et dépend de la méthode utilisée. Ainsi, une étude fut réalisée pour mettre au point une technique automatisée de mesure de la raideur de la voie. Cette technique consiste à mesurer la raideur en continu sous des charges à l’essieu définies. La méthode proposée permet de localiser précisément les sections de voie présentant de fortes variations de raideur. Les essais pour des voies classiques effectués avec un chargement par vérin hydrodynamique et le Portancemètre routier ont montré que la raideur d’une voie dépend fortement des paramètres de charge et de fréquence d’excitation. La technique utilisée permet de connaître le comportement de la structure selon la réponse du sol support. Enfin, les résultats obtenus ont permis de développer un nouvel outil de mesure en continu de la portance.
Luminescence and decay properties of the 1D2 level of Pr3+-doped YPO4
Authors: Collins J. , Bettinelli M. , Di Bartolo B.
Published: March 2011

This investigation reports on the spectroscopic properties of trivalent Pr in YPO4. In particular, we show how the luminescence from the 1D2 level depends on the polarization of the emission and on the temperature of the sample. We also report on the decay kinetics of the 1D2 level, which show the lifetime decreasing as temperature is increased. Our observed lifetime of 440 µs is at low temperature and is significantly longer than that reported by other workers. We explain the temperature dependence of the 1D2 emission by considering the population redistribution in the 1D2 level, without invoking the existence of multiphonon relaxation. Finally, we estimate the radiative decay rates of individual crystal field levels within the 1D2 manifold.
Effects of different dietary omega-6/3 polyunsaturated fatty acids ratios on infarct size and the limbic system after myocardial infarction
Authors: Rondeau I. , Picard S. , Bah T. M. , Roy L. , Godbout R. , Rousseau G.
Published: March 2011

Changes in dietary omega-6/3 polyunsaturated fatty acids (PUFA) ratios affect anti- and proinflammatory equilibrium. As reperfused myocardial infarction (MI) is an inflammatory pathology that alters the cell integrity of the myocardium but also of other tissues, such as the hippocampus and amygdala, attenuation of the inflammation could be helpful in maintaining cell integrity after MI. Therefore, we hypothesized that a decrease in the dietary omega-6/3 PUFA ratio, without altering the diet content in total fat, proteins, or carbohydrates, will result in a reduction of infarct size and a diminution of postreperfusion apoptosis observed in the amygdala and hippocampus. Male Sprague–Dawley rats were fed 1 of 3 diets containing different omega-6/3 PUFA ratios for 2 weeks (5:1; 1:1; 1:5). Then, myocardial ischemia was induced by left anterior descending coronary artery occlusion for 40 min, followed by reperfusion. Cardioprotective mechanisms were studied in the myocardium at 15 min of reperfusion, along with myocardial infarct size after 24 h of reperfusion. Apoptosis was evaluated in the hippocampus and the amygdala. We found that infarct size was significantly reduced by 32% in groups 1:5 and 1:1 vs. group 5:1. Akt activity was higher in groups 1:5 and 1:1 compared with group 5:1. Caspase-3 enzymatic activity doubled in area CA1 and the dentate gyrus (DG) in group 5:1 compared with groups 1:1 and 1:5. In addition, caspase-8 enzymatic activity was increased in the DG at 24 h, and caspase-9 was enhanced in CA1 at 24 h in group 5:1 vs. groups 1:1 and 1:5. These results demonstrate that the increase in the dietary omega-3 PUFA, at the expense of omega-6 PUFA, reduces infarct size and helps to inhibit apoptosis in the limbic system after MI.
Adenosine A2 receptors are involved in the activation of ATP-sensitive K+ currents during metabolic inhibition in guinea pig ventricular myocytes
Authors: Pan Sheng-Jun , Li Li-Rong
Published: March 2011

It has been hypothesized that an interaction among adenosine A1 receptors, protein kinase C (PKC) activation, and ATP-sensitive potassium channels (KATP) mediates ischemic preconditioning in experiments on different animal species. The purpose of this study was to determine if activation of KATP is functionally coupled to A1 receptors and (or) PKC activation during metabolic inhibition (MI) in guinea pig ventricular myocytes. Perforated-patch using nystatin and conventional whole-cell recording methods were used to observe the effects of adenosine and adenosine-receptor antagonists on the activation of KATP currents during MI induced by application of 2,4-dinitrophenol (DNP) and 2-deoxyglucose (2DG) without glucose, in the presence or absence of a PKC activator, phorbol 12-myristate 13-acetate (PMA). Adenosine accelerated the time course activation of KATP currents during MI under the intact intracellular condition or dialyzed condition with l mmol/L ATP in the pipette solution. The accelerated effect of adenosine activation of KATP under MI was not reversed by a nonselective Al adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (SPT), or a specific Al adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). However, the adenosine A2 receptor antagonist alloxazine reversed the time course activation of the KATP current under MI. An adenylate cyclase activator, forskolin, did not further abbreviate the time course activation of KATP with or without adenosine. Application of a PKC blocker, chelerythrine, reversed the time course activation of KATP by adenosine under MI. In addition, pretreatment with a PKC activator, PMA, had similar effects to adenosine, while adenosine did not further shorten the time required for activation of KATP currents during MI with PMA pretreatment. There is no direct evidence of activation of KATP currents by adenosine A1 receptor during metabolic inhibition under our experimental condition. However, adenosine A2 receptor activation is involved in the KATP channel activation in the guinea pig ventricular myocytes, of which effect is not mediated through the increase in intracellular cAMP. Adenosine seems to interact with PKC activation to open KATP during MI, but a possible link between the adenosine A2 receptor and PKC activation in this process needs further elucidation.
MODIFIED FUNCTION PROJECTIVE SYNCHRONIZATION OF CHAOTIC NEURAL NETWORKS WITH DELAYS BASED ON OBSERVER
Authors: CHEN LIPING , CHAI YI , WU RANCHAO
Published: March 2011

This paper deals with a new type of synchronization scheme for chaotic neural networks with delays, called modified function projective synchronization, in which chaotic neural networks synchronize up to a scaling function matrix. Based on the nonlinear state observer, a control scheme is derived through the placement technique by designing a state-observer of the derived system to synchronize chaotic neural networks up to a scaling function matrix. This technique, capable of adjusting the scaling function factor arbitrarily for the value of scaling function factor, has no effect on the controllability of error system. That overcomes some limitation in earlier literature. A chaotic cellular neural network and a chaotic Hopfield neural model are used as numerical examples to demonstrate the effectiveness of the proposed synchronization technique.
A NEW SYMMETRIC EIGHT-STEP PREDICTOR-CORRECTOR METHOD FOR THE NUMERICAL SOLUTION OF THE RADIAL SCHRÖDINGER EQUATION AND RELATED ORBITAL PROBLEMS
Authors: PANOPOULOS G. A. , ANASTASSI Z. A. , SIMOS T. E.
Published: March 2011

A new general multistep predictor-corrector (PC) pair form is introduced for the numerical integration of second-order initial-value problems. Using this form, a new symmetric eight-step predictor-corrector method with minimal phase-lag and algebraic order ten is also constructed. The new method is based on the multistep symmetric method of Quinlan–Tremaine,1with eight steps and 8th algebraic order and is constructed to solve numerically the radial time-independent Schrödinger equation. It can also be used to integrate related IVPs with oscillating solutions such as orbital problems. We compare the new method to some recently constructed optimized methods from the literature. We measure the efficiency of the methods and conclude that the new method with minimal phase-lag is the most efficient of all the compared methods and for all the problems solved.
SPECTRAL AND PHOTOCATALYTIC PROPERTIES OF HETEROSTRUCTURES WITH BISQUINOCYANINE DYE AND ZnO, ZrO2 AND SiO2
Authors: KOBASA IGOR , KONDRATYEVA IRYNA , HUSYAK NATALIYA
Published: March 2011

New heterostructures (HS) containing various oxides and a dye with two conjugated chromophores have been synthesized. Light absorption spectra have been recorded and interpreted for the dye in solution and in the HS. Photocatalytic activity (PA) of the HS has been determined using the test reaction of methylene blue (MB) photodegradation. PA values were found for various light spectrum zones.
ENGINEERING ORIENTATION IN BLOCK COPOLYMERS FOR APPLICATION TO PROSTHETIC HEART VALVES
Authors: STASIAK JOANNA , MOGGRIDGE GEOFF D. , ZAFFORA ADRIANO , PANDOLFI ANNA , COSTANTINO MARIA L.
Published: March 2011

This study demonstrates how the mechanical performance of polymeric material can be enhanced by morphology and phase orientation of block copolymers to achieve desired anisotropic mechanical properties. The material used was a new Kraton block copolymer consisting of styrene-isoprene-butadiene-styrene blocks having cylindrical morphology. We report a method of achieving long range uniaxial as well as biaxial orientation of block copolymer. Each microstructural organization results in a specific mechanical performance, which depends on the direction of the applied deformation. The method of tailoring mechanical properties by engineering microstructure may be successfully utilized to applications requiring anisotropic mechanical response, such as prosthetic heart valves.
MICROWAVE DIELECTRIC PROPERTIES AND RAMAN SPECTROSCOPY OF SCHEELITE SOLID SOLUTION [(Li0.5Bi0.5)1-xCax]MoO4 CERAMICS WITH ULTRA-LOW SINTERING TEMPERATURES
Authors: ZHOU DI , WANG HONG , WANG QIU-PING , WU XIN-GUANG , GUO JING , ZHANG GAO-QUN , SHUI LI , YAO XI , RANDALL CLIVE A. , PANG LI-XIA , LIU HAN-CHEN
Published: March 2011

A Scheelite solid solution was formed based on [( Li0.5Bi0.5 )1-x Ca x] MoO 4 ceramics and prepared via a solid state reaction method in the range 0.0 ≤ x ≤ 1.0. High performance microwave dielectric properties were obtained in the [(Li0.5Bi0.5)0.15Ca0.85]MoO4 ceramic sintered at 760°C with a relative permittivity of 14.1, a Qf value of 24,000 GHz (at 10.0 GHz), and a temperature coefficient value of +10.7 ppm/°C and the [(Li0.5Bi0.5)0.1Ca0.9]MoO4 ceramic sintered at 850°C with a relative permittivity of 12.7, a Qf value of 41,300 GHz (at 10.3 GHz), and a temperature coefficient value of -16.5 ppm/°C. X-ray diffraction, Raman spectroscopy and the classical damped oscillator model were applied to study the relationship between the microwave dielectric properties and structures.
MECHANISM OF ELECTRICAL CONDUCTION THROUGH SINGLE OLIGOTHIOPHENE MOLECULES
Authors: LEE SEE KEI , YAMADA RYO , TADA HIROKAZU , TANAKA SHOJI
Published: March 2011

The temperature dependence of electrical conductance of oligothiophene molecules with the length of 2.2 nm (5-mer), 5.6 nm (14-mer) and 6.7 nm (17-mer) was measured by break junction method with a scanning tunneling microscope to clarify the charge transport mechanisms. The conductance of 17-mer molecule increased exponentially with temperature whereas the conductance of 5-mer and 14-mer molecules did not change. These results indicate that the dominant charge transport mechanism changed from tunneling to thermally activated hopping at molecular length around 6.7 nm (17-mer).
SYNTHESIS AND LUMINESCENCE PROPERTIES OF ZnO:Eu3+ NANOWIRE ARRAYS VIA ELECTRODEPOSITED METHOD
Authors: ZHAO SHIHUA , YANG LEI , WANG LINGLING , YU BENHAI , CHEN YUXI , CUI YUTING
Published: March 2011

ZnO:Eu3+ nanowire arrays (NWAs) were prepared using anodic alumina membranes (AAMs) via an electrodeposited method. The XRD patterns, high resolution transmission electron microscopy (HRTEM) and infrared absorption spectra indicate that Eu3+ has entered ZnO crystal lattice. SEM images show that the as-prepared NWAs were embedded in Al2O3 nanotube arrays (NTAs) and the uniform diameters of those nanowires are about 80 nm. The Fourier Transform pattern of the HRTEM shows that the NWAs are single crystals with preferential growth direction along the [0001]. The PL spectra show that the ratio of relative emission intensity of 612 and 597 nm increases with the increase of dopant concentration of Eu3+ . There is no emission peak at 597 nm with the dopant concentration of 10% Eu3+ . The PL results also show that a new UV emission band centered at 306 nm appears.
Epithelial BMP signaling is required for proper specification of epithelial cell lineages and gastric endocrine cells
Authors: Maloum Faïza , Allaire Joannie M. , Gagné-Sansfaçon Jessica , Roy Evelyne , Belleville Karine , Sarret Philippe , Morisset Jean , Carrier Julie C. , Mishina Yuji , Kaestner Klaus H. , Perreault Nathalie
Published: March 2011

Bone morphogenetic protein (BMP) signaling within the gastrointestinal tract is complex. BMP ligands and their receptors are expressed in both epithelial and mesenchymal compartments, suggesting bidirectional signaling between these two entities. Despite an increasing interest in BMP signaling in gut physiology and pathologies, the distinct contribution of BMP signaling in the epithelium vs. the mesenchyme in gastrointestinal homeostasis remains to be established. We aimed to investigate the role of epithelial BMP signaling in gastric organogenesis, gland morphogenesis, and maintenance of epithelial cell functions. Using the Cre/loxP system, we generated a mouse model with an early deletion during development of BMP receptor 1A ( Bmpr1a) exclusively in the foregut endoderm. Bmpr1aΔGECmice showed no severe abnormalities in gastric organogenesis, gland epithelial proliferation, or morphogenesis, suggesting only a minor role for epithelial BMP signaling in these processes. However, early loss of BMP signaling in foregut endoderm did impact on gastric patterning, leading to an anteriorization of the stomach. In addition, numbers of parietal cells were reduced in Bmpr1aΔGECmice. Epithelial BMP deletion significantly increased the numbers of chromogranin A-, ghrelin-, somatostatin-, gastrin-, and serotonin-expressing gastric endocrine cells. Cancer never developed in young adult (<100 days) Bmpr1a-inactivated mice although a marker of spasmolytic polypeptide-expressing metaplasia was upregulated. Using this model, we have uncovered that BMP signaling negatively regulates the proliferation and commitment of endocrine precursor cells. Our data also indicate that loss of BMP signaling in epithelial gastric cells alone is not sufficient to induce gastric neoplasia.
Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor
Authors: Chumanevich Alexander A. , Causey Corey P. , Knuckley Bryan A. , Jones Justin E. , Poudyal Deepak , Chumanevich Alena P. , Davis Tia , Matesic Lydia E. , Thompson Paul R. , Hofseth Lorne J.
Published: March 2011

Inflammatory bowel diseases (IBDs), mainly Crohn's disease and ulcerative colitis, are dynamic, chronic inflammatory conditions that are associated with an increased colon cancer risk. Inflammatory cell apoptosis is a key mechanism for regulating IBD. Peptidylarginine deiminases (PADs) catalyze the posttranslational conversion of peptidylarginine to peptidylcitrulline in a calcium-dependent, irreversible reaction and mediate the effects of proinflammatory cytokines. Because PAD levels are elevated in mouse and human colitis, we hypothesized that a novel small-molecule inhibitor of the PADs, i.e., chloramidine (Cl-amidine), could suppress colitis in a dextran sulfate sodium mouse model. Results are consistent with this hypothesis, as demonstrated by the finding that Cl-amidine treatment, both prophylactic and after the onset of disease, reduced the clinical signs and symptoms of colitis, without any indication of toxic side effects. Interestingly, Cl-amidine drives apoptosis of inflammatory cells in vitro and in vivo, providing a mechanism by which Cl-amidine suppresses colitis. In total, these data help validate the PADs as therapeutic targets for the treatment of IBD and further suggest Cl-amidine as a candidate therapy for this disease.
The passive mechanical properties of the extensor digitorum longus muscle are compromised in 2- to 20-mo-old mdx mice
Authors: Hakim Chady H. , Grange Robert W. , Duan Dongsheng
Published: March 2011

Muscle rigidity and myotendinous junction (MTJ) deficiency contribute to immobilization in Duchenne muscular dystrophy (DMD), a lethal disease caused by the absence of dystrophin. However, little is known about the muscle passive properties and MTJ strength in a diseased muscle. Here, we hypothesize that dystrophin-deficient muscle pathology renders skeletal muscle stiffer and MTJ weaker. To test our hypothesis, we examined the passive properties of an intact noncontracting muscle-tendon unit in mdx mice, a mouse model for DMD. The extensor digitorum longus (EDL) muscle-tendon preparations of 2-, 6-, 14-, and 20-mo-old mdx and normal control mice were strained stepwisely from 110% to 160% of the muscle optimal length. The stress-strain response and failure position were analyzed. In support of our hypothesis, the mdx EDL preparation consistently developed higher stress before muscle failure. Postfailure stresses decreased dramatically in mdx but not normal preparations. Further, mdx showed a significantly faster stress relaxation rate. Consistent with stress-strain assay results, we observed significantly higher fibrosis in mdx muscle. In 2- and 6-mo-old mdx and 20-mo-old BL10 mice failure occurred within the muscle (2- to 14-mo-old BL10 preparations did not fail). Interestingly, in ≥14-mo-old mdx mice the failure site shifted toward the MTJ. Electron microscopy revealed substantial MTJ degeneration in aged but not young mdx mice. In summary, our results suggest that the passive properties of the EDL muscle and the strength of MTJ are compromised in mdx in an age-dependent manner. These findings offer new insights in studying DMD pathogenesis and developing novel therapies.
Metformin Decreases the Dose of Chemotherapy for Prolonging Tumor Remission in Mouse Xenografts Involving Multiple Cancer Cell Types
Authors: Iliopoulos Dimitrios , Hirsch Heather A. , Struhl Kevin
Published: March 2011

Metformin, the first-line drug for treating diabetes, selectively kills the chemotherapy resistant subpopulation of cancer stem cells (CSC) in genetically distinct types of breast cancer cell lines. In mouse xenografts, injection of metformin and the chemotherapeutic drug doxorubicin near the tumor is more effective than either drug alone in blocking tumor growth and preventing relapse. Here, we show that metformin is equally effective when given orally together with paclitaxel, carboplatin, and doxorubicin, indicating that metformin works together with a variety of standard chemotherapeutic agents. In addition, metformin has comparable effects on tumor regression and preventing relapse when combined with a four-fold reduced dose of doxorubicin that is not effective as a monotherapy. Finally, the combination of metformin and doxorubicin prevents relapse in xenografts generated with prostate and lung cancer cell lines. These observations provide further evidence for the CSC hypothesis for cancer relapse, an experimental rationale for using metformin as part of combinatorial therapy in a variety of clinical settings, and for reducing the chemotherapy dose in cancer patients. Cancer Res; 71(9); 3196–201. ©2011 AACR.
Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression
Authors: Hilvo Mika , Denkert Carsten , Lehtinen Laura , Müller Berit , Brockmöller Scarlet , Seppänen-Laakso Tuulikki , Budczies Jan , Bucher Elmar , Yetukuri Laxman , Castillo Sandra , Berg Emilia , Nygren Heli , Sysi-Aho Marko , Griffin Julian L. , Fiehn Oliver , Loibl Sibylle , Richter-Ehrenstein Christiane , Radke Cornelia , Hyötyläinen Tuulia , Kallioniemi Olli , Iljin Kristiina , Orešič Matej
Published: March 2011

Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many cancers. However, the precise molecular composition of lipids in tumors remains generally poorly characterized. The aim of the present study was to analyze the global lipid profiles of breast cancer, integrate the results to protein expression, and validate the findings by functional experiments. Comprehensive lipidomics was conducted in 267 human breast tissues using ultraperformance liquid chromatography/ mass spectrometry. The products of de novo fatty acid synthesis incorporated into membrane phospholipids, such as palmitate-containing phosphatidylcholines, were increased in tumors as compared with normal breast tissues. These lipids were associated with cancer progression and patient survival, as their concentration was highest in estrogen receptor–negative and grade 3 tumors. In silico transcriptomics database was utilized in investigating the expression of lipid metabolism related genes in breast cancer, and on the basis of these results, the expression of specific proteins was studied by immunohistochemistry. Immunohistochemical analyses showed that several genes regulating lipid metabolism were highly expressed in clinical breast cancer samples and supported also the lipidomics results. Gene silencing experiments with seven genes [ACACA (acetyl-CoA carboxylase α), ELOVL1 (elongation of very long chain fatty acid–like 1), FASN (fatty acid synthase), INSIG1 (insulin-induced gene 1), SCAP (sterol regulatory element–binding protein cleavage–activating protein), SCD (stearoyl-CoA desaturase), and THRSP (thyroid hormone–responsive protein)] indicated that silencing of multiple lipid metabolism–regulating genes reduced the lipidomic profiles and viability of the breast cancer cells. Taken together, our results imply that phospholipids may have diagnostic potential as well as that modulation of their metabolism may provide therapeutic opportunities in breast cancer treatment. Cancer Res; 71(9); 3236–45. ©2011 AACR.
Genz-644282, a Novel Non-Camptothecin Topoisomerase I Inhibitor for Cancer Treatment
Authors: Kurtzberg Leslie S. , Roth Stephanie , Krumbholz Roy , Crawford Jennifer , Bormann Christy , Dunham Sarah , Yao Min , Rouleau Cecile , Bagley Rebecca G. , Yu Xian-Jie , Wang Fei , Schmid Steven M. , LaVoie Edmond J. , Teicher Beverly A.
Published: March 2011

Purpose: Genz-644282 [8,9-dimethoxy-5-(2-N-methylaminoethyl)-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one] has emerged as a promising candidate for antitumor agents. This report describes the bone marrow colony-forming unit, granulocyte macrophage (CFU-GM) and tumor cell CFU activity of topoisomerase I (Top1) inhibitors, such as Genz-644282, topotecan, irinotecan/SN-38, and ARC-111, and examines their activity in several human tumor xenograft models.

Experimental Design: Colony-forming assays were conducted with mouse and human bone marrow and eight human tumor cell lines. In addition, 29 human tumor cell lines representing a range of histology and potential resistance mechanisms were assayed for sensitivity to Genz-644282 in a 72-hour exposure assay. The efficacy of Genz-644282 was compared with standard anticancer drugs (i.e., irinotecan, docetaxel, and dacarbazine) in human tumor xenografts of colon cancer, renal cell carcinoma, non–small cell lung cancer, and melanoma.

Results: Human bone marrow CFU-GM was more sensitive to the Top1 inhibitors than was mouse bone marrow CFU-GM. The ratio of mouse to human IC90 values was more than 10 for the camptothecins and less than 10 for Genz-644282, which had more potency as a cytotoxic agent toward human tumor cells in culture than the camptothecins in the colony-forming and 72-hour proliferation assays. Genz-644282 has superior or equal antitumor activity in the human tumor xenografts than the standard drug comparators.

Conclusions: On the basis of preclinical activity and safety, Genz-644282 was selected for development and is currently undergoing phase 1 clinical trial. Clin Cancer Res; 17(9); 2777–87. ©2011 AACR.
Ribavirin Treatment Effects on Breast Cancers Overexpressing eIF4E, a Biomarker with Prognostic Specificity for Luminal B-Type Breast Cancer
Authors: Pettersson Filippa , Yau Christina , Dobocan Monica C. , Culjkovic-Kraljacic Biljana , Retrouvay Hélène , Puckett Rachel , Flores Ludmila M. , Krop Ian E. , Rousseau Caroline , Cocolakis Eftihia , Borden Katherine L. B. , Benz Christopher C. , Miller Wilson H.
Published: March 2011

Purpose: We have evaluated the eukaryotic translation initiation factor 4E (eIF4E) as a potential biomarker and therapeutic target in breast cancer. eIF4E facilitates nuclear export and translation of specific, growth-stimulatory mRNAs and is frequently overexpressed in cancer.

Experimental Design: Breast cancer cells were treated with ribavirin, an inhibitor of eIF4E, and effects on cell proliferation and on known mRNA targets of eIF4E were determined. eIF4E expression was assessed, at the mRNA and protein level, in breast cancer cell lines and in skin biopsies from patients with metastatic disease. Additionally, pooled microarray data from 621 adjuvant untreated, node-negative breast cancers were analyzed for eIF4E expression levels and correlation with distant metastasis–free survival (DMFS), overall and within each intrinsic breast cancer subtype.

Results: At clinically relevant concentrations, ribavirin reduced cell proliferation and suppressed clonogenic potential, correlating with reduced mRNA export and protein expression of important eIF4E targets. This effect was suppressed by knockdown of eIF4E. Although eIF4E expression is elevated in all breast cancer cell lines, variability in ribavirin responsiveness was observed, indicating that other factors contribute to an eIF4E-dependent phenotype. Assessment of the prognostic value of high eIF4E mRNA in patient tumors found that significant discrimination between good and poor outcome groups was observed only in luminal B cases, suggesting that a specific molecular profile may predict response to eIF4E-targeted therapy.

Conclusions: Inhibition of eIF4E is a potential breast cancer therapeutic strategy that may be especially promising against specific molecular subtypes and in metastatic as well as primary tumors. Clin Cancer Res; 17(9); 2874–84. ©2011 AACR.
Radical Perineal Prostatectomy versus Radical Retropubic Prostatectomy after Previous Prostate Surgery: Surgical and Functional Outcomes
Authors: Imperatore Vittorio , Cantiello Francesco , Fusco Ferdinando , Iannuzzo Mariateresa , Di Meo Sergio , Imbimbo Ciro , Mirone Vincenzo
Published: March 2011

Purpose: We performed a retrospective review of our database to evaluate surgical and functional outcomes in men undergoing radical perineal prostatectomy (RPP) versus radical retropubic prostatectomy (RRP) after previous prostate surgery. Patients and Methods: A total of 616 men underwent RPP at our institution. A retrospective review of these patients showed that 59 had a history of previous surgical approach for benign prostatic hyperplasia. A second group of 59 match-paired prostate cancer patients with a history of previous prostate surgery, treated by RRP, were recruited in the our database and was used as control group. All patients were followed up at 3, 6 and 12 months and evaluated during an office evaluation with regard to urinary incontinence and erectile dysfunction. Results: Overall complete continence was achieved in 49 (83%), 51 (86.4%) and 55 (93.2%) RPP patients at 3, 6 and 12 months, respectively, versus 39 (66.1%), 42 (71.1%) and 47 (79.6%) RRP patients, respectively (p = 0.03, p = 0.04 and p = 0.03, respectively). No significant difference was reported between the two groups in the overall percentage of preserved normal erectile function. Conclusions: Radical prostatectomy in patients with previous prostate surgery should be performed with the transperineal rather than the retropubic approach.
The Beneficial Effects of Tadalafil on Renal Ischemia-Reperfusion Injury in Rats
Authors: Guzeloglu Mehmet , Yalcinkaya Fatih , Atmaca Soner , Bagriyanik Alper , Oktar Suleyman , Yuksel Oguz , Fansa Iyad , Hazan Eyup
Published: March 2011

Acute renal failure due to ischemia-reperfusion (I/R) injury is a common complication in cardiovascular surgery. We determined the influence of tadalafil on renal injury in a renal I/R model in rats. For this purpose, 21 male Wistar albino rats were separated into 3 groups: sham, placebo and tadalafil. A right nephrectomy was performed, and the left renal pedicles were occluded for 60 min and reperfused for 60 min in the placebo and tadalafil groups. A single dose of tadalafil (10 mg/kg) through an orogastric tube was administered to the tadalafil group. Tubular atrophy with acute inflammation in renal histology, total oxidant status (TOS) and total antioxidant status (TAS) were determined in tissue homogenates. Compared to the tadalafil group, tubular atrophy and acute inflammation was significant in the placebo group. TAS levels were significantly higher in the tadalafil group compared to the placebo (p = 0.01) and sham groups (p = 0.04). While TOS levels were significantly higher in the placebo group (p = 0.03), tadalafil did not significantly alter the TOS levels. The beneficial effects of tadalafil can be attributed to its protective effects on renal tubular cells and inhibition of leukocyte infiltration in renal tissue. We think that tadalafil treatment has an important role in reducing renal injury resulting from renal I/R.
Prostate Volume and Its Correlation with Histopathological Outcomes in Prostate Cancer
Authors: Sooriakumaran Prasanna , Srivastava Abhishek , Bhagat Dhristie , John Majnu , Grover Sonal , El-Douaihy Youssef , Rajan Sivaram , Leung Robert , Tewari Ashutosh
Published: March 2011

Introduction: There is a paucity of data investigating the relationship between histopathological variables of oncologic importance and prostate volume, and we aimed to investigate this. Patients and Methods: 2,207 consecutive patients who underwent robotic-assisted radical prostatectomy were studied. Preoperative demographic and both pre- and postoperative histopathological parameters were compared among the small (<40 cm3), intermediate (40–70 cm3), and large (>70 cm3) prostate groups. Results: Patients with smaller prostates were younger, had slightly lower BMIs, and lower prostate-specific antigen (PSA) levels than those with larger prostates (p < 0.001). They also had worse histopathological criteria (Gleason, core positivity, and maximum percent cancer) on preoperative biopsy and had worse radical specimen Gleason sums (p < 0.001), percent cancer (p < 0.001), and pathological stage (p = 0.016). 11.5% of the men in the small prostate group suffered a positive surgical margin (PSM) compared to 8.3 and 5.6% in the intermediate and large prostate groups, respectively (p = 0.008). Basilar, posterolateral, and multifocal PSMs were commoner in the small prostate group. Conclusions: Younger men have smaller prostates and worse preoperative histopathological parameters despite lower PSA values. Men with small prostates undergoing robotic-assisted radical prostatectomy have worse final Gleason sums, tumour volume, extraprostatic extension, and PSM rates than those with larger prostates.
Osteoblastoma of the Third Cervical Vertebra in a 16-Year-Old Boy: Case Report and Review of the Literature
Authors: Amirjamshidi Abbass , Abbassioun Kazem
Published: March 2011

Background/Subject: A rare case of osteoblastoma of the third cervical vertebra (C3) occurring in a 16-year-old adolescent is presented. He was admitted suffering from neck pain for more than 3 years. Method: Plain X-rays, technetium bone scanning, CT scan and MRI indicated an expansile, partially sclerotic lesion of the C3 involving the superior facet and pedicle on the right side. The lesion was excised through a posterior approach. Result: Even though the 18-month follow-up is still a very short interval in our case, the subject’s neck pain has resolved completely and there has been no sign of tumor recurrence in the recently taken imaging. There has been no clinical or radiologic sign of instability in the follow-up investigations. To the best of our knowledge, this is the third case of C3 osteoblastoma reported in the literature, highlighting the predilection of the reported cases to occur in 14- to 16-year-old boys. Conclusion: A full investigation is indicated in youngsters suffering from persisting neck pain and complete resection of the lesion can prevent recurrence and malignant transformation. Long-term follow-up is needed to declare a lifelong cure of the disease.
Sensory Innervation of the Nonspecialized Connective Tissues in the Low Back of the Rat
Authors: Corey Sarah M. , Vizzard Margaret A. , Badger Gary J. , Langevin Helene M.
Published: March 2011

Chronic musculoskeletal pain, including low back pain, is a worldwide debilitating condition; however, the mechanisms that underlie its development remain poorly understood. Pathological neuroplastic changes in the sensory innervation of connective tissue may contribute to the development of nonspecific chronic low back pain. Progress in understanding such potentially important abnormalities is hampered by limited knowledge of connective tissue’s normal sensory innervation. The goal of this study was to evaluate and quantify the sensory nerve fibers terminating within the nonspecialized connective tissues in the low back of the rat. With 3-dimensional reconstructions of thick (30–80 µm) tissue sections we have for the first time conclusively identified sensory nerve fiber terminations within the collagen matrix of connective tissue in the low back. Using dye labeling techniques with Fast Blue, presumptive dorsal root ganglia cells that innervate the low back were identified. Of the Fast Blue-labeled cells, 60–88% also expressed calcitonin gene-related peptide (CGRP) immunoreactivity. Based on the immunolabeling with CGRP and the approximate size of these nerve fibers (≤2 µm) we hypothesize that they are Aδ or C fibers and thus may play a role in the development of chronic pain.
Stimulatory Effect of Pigeon Milk Growth Factor on Protein and Nucleic Acid Synthesis in Neonate Mice
Authors: Shetty Sreerama , Hegde S.N.
Published: March 2011

Effect of subcutaneously administered pigeon milk-derived growth factor (PMGF) on protein and nucleic acid content of various body organs was studied in neonate mice. Although the body and organ weights of PMGF-treated mice did not differ from those of controls, the weight of testes was significantly higher in the former than the latter. The treated animals had significantly greater content of protein (in liver and skin), DNA (in liver, lung, stomach, duodenum, ileum and rectum) and RNA (in liver, stomach, ileum and skin). The protein/DNA ratio was lower in many organs of PMGF-treated mice. These results indicate that the biological properties of PMGF bear semblance to those of epidermal growth factor isolated from mouse salivary gland and human milk.
mTOR Complex 2 Activation by Reconstituted High-Density Lipoprotein Prevents Senescence in Circulating Angiogenic Cells
Authors: Guo Xianrong , Yu Miao , Kang Xiaomin , Yin Hongchao
Published: March 2011

Objective—

Circulating angiogenic cells (CACs) participate in neovascularization and arterial repair. Although high-density lipoprotein (HDL) is known to enhance the functional activity of CACs, the mechanisms underlying this regulation are poorly understood. Here, we examined the mechanism(s) by which reconstituted HDL (rHDL) affects CAC senescence.

Methods and Results—

CACs isolated from human peripheral blood and treated with rHDL displayed reduced senescence, as measured by acidic β-galactosidase staining. This protective effect was blocked by the mammalian target of rapamycin (mTOR) inhibitor (rapamycin). According to Western blot analysis and immunoprecipitation results, rHDL promoted mTOR phosphorylation, mTOR-rictor complex formation, and mTOR-rictor–dependent Akt activation, which were accompanied by increased nuclear translocation of human telomerase reverse transcriptase and enhanced nuclear telomerase activity. Suppression of rictor gene expression with a small interfering RNA blocked mTOR-rictor complex formation and Akt activation. The suppression also abolished the rHDL-induced inhibition of CAC senescence and promotion of nuclear telomerase activity. Treatment of aged mice with rHDL attenuated spleen-derived CAC senescence. In CACs isolated from rHDL-treated aged mice, the phosphorylated mTOR and Akt levels were significantly enhanced.

Conclusion—

rHDL stimulates sustained mTOR phosphorylation and mTOR-rictor complex formation and inhibits senescence onset in CACs through mTOR complex 2 pathway activation.
A Novel Role for Calpain in the Endothelial Dysfunction Induced by Activation of Angiotensin II Type 1 Receptor Signaling
Authors: Scalia Rosario , Gong Yulan , Berzins Brett , Freund Brin , Feather Danielle , Landesberg Gavin , Mishra Gourav
Published: March 2011

Rationale:

The cytosolic protease calpain has been recently implicated in the vascular remodeling of angiotensin II (Ang II) type 1 receptor (AT
1
R) signaling. The role of Ang II/AT
1
R/calpain signaling on endothelial function, an important and early determinant of vascular pathology, remains though totally unknown. Accordingly, we investigated the role of calpain in the endothelial dysfunction of Ang II.

Objective:

To demonstrate a mechanistic role for calpain in the endothelial dysfunction induced by Ang II/AT
1
R signaling. To establish endothelial-expressed calpains as an important target of AT
1
R signaling.

Methods and Results:

Subchronic administration of nonpressor doses of Ang II to rats and mice significantly increased vascular calpain activity via AT
1
R signaling. Intravital microscopy studies revealed that activation of vascular expressed calpains causes endothelial dysfunction with increased leukocyte–endothelium interactions and albumin permeability in the microcirculation. Western blot and immunohistochemistry studies confirmed that Ang II/AT
1
R signaling preferentially activates the constitutively expressed μ-calpain isoform and demonstrated a calpain-dependent degradation of IκBα, along with upregulation of nuclear factor κB–regulated endothelial cell adhesion molecules. These physiological and biochemical parameters were nearly normalized following inhibition of AT
1
R or calpain in vivo. RNA silencing studies in microvascular endothelial cells, along with knockout and transgenic mouse studies, further confirmed the role of μ-calpain in the endothelial adhesiveness induced by Ang II.

Conclusions:

This study uncovers a novel role for calpain in the endothelial dysfunction of Ang II/AT
1
R signaling and establishes the calpain system as a novel molecular target of the vascular protective action of renin–angiotensin system inhibition. Our results may have significant clinical implications in vascular disease.
Botulinum Toxin for the Upper Limb After Stroke (BoTULS) Trial
Authors: Shaw Lisa C. , Price Christopher I.M. , van Wijck Frederike M.J. , Shackley Phil , Steen Nick , Barnes Michael P. , Ford Gary A. , Graham Laura A. , Rodgers Helen
Published: March 2011

Background and Purpose—

Botulinum toxin is increasingly used to treat upper limb spasticity due to stroke, but its impact on arm function is unclear. We evaluated botulinum toxin for upper limb spasticity and function poststroke.

Methods—

Three hundred thirty-three patients with stroke with upper limb spasticity and reduced arm function participated in a multicenter randomized controlled trial. The intervention group received botulinum toxin type A injection(s) plus a 4-week therapy program. The control group received the therapy program alone. Repeat injection(s) and therapy were available at 3, 6, and 9 months. The primary outcome was upper limb function at 1 month (Action Research Arm Test). Secondary outcomes included measures of impairment, activity limitation, and pain at 1, 3, and 12 months. Outcome assessments were blinded and analysis was by intention to treat.

Results—

There was no significant difference in achievement of improved arm function (Action Research Arm Test) at 1 month (intervention group: 42 of 167 [25.1%], control group 30 of 154 [19.5%];
P
=0.232). Significant differences in favor of the intervention group were seen in muscle tone at 1 month; upper limb strength at 3 months; basic arm functional tasks (hand hygiene, facilitation of dressing) at 1, 3, and 12 months; and pain at 12 months.

Conclusions—

Botulinum toxin type A is unlikely to be useful for improving active upper limb function (eg, reaching and grasping) in the majority of patients with spasticity after stroke, but it may improve basic upper limb tasks (hand hygiene, facilitation of dressing) and pain.
Effect of Normobaric Oxygen Therapy in a Rat Model of Intracerebral Hemorrhage
Authors: Fujiwara Norio , Mandeville Emiri T. , Geng Xiaokun , Luo Yumin , Arai Ken , Wang Xiaoying , Ji Xunming , Singhal Aneesh B. , Lo Eng H.
Published: March 2011

Background and Purpose—

Normobaric oxygen (NBO) therapy may be neuroprotective in acute ischemic stroke. However, how NBO may affect intracerebral hemorrhage is unclear. We tested NBO in a rat model of striatal intracerebral hemorrhage.

Methods—

Intracerebral hemorrhage was induced by stereotactic injection of collagenase Type VII (0.5 U) into the right striatum of male Sprague-Dawley rats. One hour later, rats were randomized into controls (n=13) versus NBO treatment (n=13). NBO was applied for 2 hours. Hemorrhagic blood volume, brain water content, and neurological outcomes (forelimb placement test, forelimb asymmetry, neuroscore) were quantified at 72 hours. Experiments were repeated in a second independent laboratory to assess reproducibility in neurological outcomes (n=10 per group).

Results—

NBO did not worsen hemorrhage severity or brain edema. There were no significant differences in hemorrhagic blood volumes (control, 6.4±0.9 μL versus NBO, 7.0±2.1 μL;
P
=0.18) or brain water content (control, 81.9%±1.1% versus NBO, 81.6%±0.5%;
P
=0.58). NBO did not affect any of the neurological outcome tests in the primary or secondary studies.

Conclusions—

NBO therapy may not worsen outcomes in intracerebral hemorrhage.