bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Study of Mode II Fracture of Hybrid Composite and Metal-Wire Joints
Authors: Kwon Y. W. , Schultz W. A. , Loup D. C. , Rasmussen E. A.
Published: February 2011

In order to join a composite structure to a metallic structure, metal-wire mats were co-cured with composite laminas using the vacuum assisted resin transfer molding technique. Then, interface fracture toughness was measured for Mode II fracture for various lay-up and interface conditions. The study included interfaces of metal-wire to composite, composite to composite, and metal-wire to metal-wire. In addition, the lay-up orientations of metal-wire mats were varied between 0 deg and 90 deg. This study also examined the crack propagation from a composite to a metal/composite interface. During the test, the digital image correlation technique was applied to capture the strain field around the crack tip. The results suggested that a hybrid metal-wire/composite laminate would be effective to connect a composite structure to a metallic structure as long as some critical interface conditions were avoided.
Evaluation of Creep Strength Reduction Factors for Welded Joints of Grade 122 Steel
Authors: Takahashi Yukio , Tabuchi Masaaki
Published: February 2011

HCM12A (ASME Grade 122) is used for boiler components in thermal power plants because of its high creep strength. However, a type IV creep damage formed in the heat-affected zone can cause a considerable decrease in the creep strength of the weldment and a failure of large diameter piping due to this damage took place recently in a thermal power plant. In order to update the design method and develop life estimation method for this kind of piping system with axial weld, the creep rupture data of base metal and welded joints have been collected and analyzed by the Strength of High-Chromium Steel Committee in Japan. In the present paper, the creep rupture data of over 400 points for welded joint specimens of HCM12A offered from six Japanese organizations are analyzed. These data clearly indicate that the long-term creep strength of the welded joints becomes weaker than that of the base metal at above 600°C due to the type IV fracture in the fine grain heat-affected zone. After the discussions on the effects of product form, welding procedure, specimen sampling procedure, etc., on the creep strength, the master creep life equation for the welded joints is developed. The so-called region decomposition technique was adopted to fit the data in both high and low stress regimes with a reasonable accuracy. The creep strength reduction factor obtained from 100,000 h creep strength of the welded joints and the base metal is given as a function of temperature.
Electronic Consent Channels: Preserving Patient Privacy Without Handcuffing Researchers
Authors: Shelton Robert H.
Published: February 2011

By responding to patient privacy concerns, policy-makers, researchers, and information technology leaders can transform how we protect and use patient data.
Solubility in the KH2PO4-K2HPO4-K2H2P2O7-K3HP2O7-H2O system at 0 °C
Authors: Ebert Miroslav , Lukeš Ivan , Eysseltová Jitka , Nassler Jindřich , Mička Zdeněk
Published: February 2011

The solubility was studied in the KH2PO4-K2HPO4-K2H2P2O7-K3HP2O7-H2O system at 0 °C. The results are discussed in terms of their application to the preparation of multicomponent PK type liquid fertilizers.
Extraktion von Seltenerdelementen mit Imidodiphosphorsäuretetraphenylester
Authors: Herrmann Eckhard , Navrátil Oldřich , Nang Hoang ba , Smola Jiří , Friedrich Joachim , Příhoda Jiří , Dreyer Rolf , Chalkin Vladimir Alexeevič , Kulpe Siegfried
Published: February 2011

Der Tetraphenylester der Imidodiphosphorsäure ist eine einprotonige Säure (HA), die in Benzen dimer vorliegt. Der Exponent der Dimerisationskonstanten beträgt log Kd = 3,3(5), die Verteilungskonstante des Monomeren zwischen Benzen und 0,1 M Chloridlösungen = 13(2). Die Extraktion von schweren Seltenerdelementen (Ln) erfolgt aus salpetersalz und perchlorsauren Lösungen bei cH+ x 4 mol l-1 mit benzenischen Lösungen von HA unter Bildung der Chelatkomplexe LnA3, wobei A- als bidentater Ligand wirkt. Bei der Extraktion von La3+ erfolgt eine zusätzliche Koordination von HA. Ist die HClO4-Konzentration größer als 6 mol l-1, dominiert ein Solvatmechanismus. Bestimmt wurden außerdem die Trennfaktoren für die Lanthanoide.
Processing of ion-molecule beam scattering data: Framework of scattering diagrams and derived quantities
Authors: Friedrich Břetislav , Herman Zdeněk
Published: February 2011

The problem of processing data resulting from ion-molecule beam scattering experiments under single-collision conditions is treated from the point of view of the probability theory. The probability-interpreted quantities characterizing ion-molecule scattering are related to the total and differential cross-section of the process in question.
Analogues of the neuroleptic agent isobutaclamol: Stereoisomeric 3b,4,5,6,7,9,9a,10-octahydro-[1]benzothiepino[2,3,4-ed]pyrido[2,1-a]isoquinolin-5-ols and some related compounds
Authors: Šindelář Karel , Holubek Jiří , Ryska Miroslav , Svátek Emil , Dlabač Antonín , Valchář Martin , Protiva Miroslav
Published: February 2011

10,11-Dihydrodibenzo[b,f]thiepin-10-carbonitrile (XVI) was reduced with aluminium hydride to the primary amine XVII which was formylated with acetic formic anhydride. The formamide derivative was cyclized by the Bischler-Napieralski reaction to the condensed dihydroisoquinoline XX. Addition of methyl vinyl ketone to the hydrochloride of compound XX at 100 °C gave a mixture of the stereoisomeric 3b,4,5,6,7,9,9a,10-octahydro[1]benzothiepino[2,3,4-ed]pyrido[2,1-a]isoquinolin-5-ones (XIII) which was separated by chromatography to the major 3b,9a-cis isomer XIIIb and the minor 3b,9a-trans isomer XIIIa to which the configuration was assigned on the basis of analogy. Reactions of both ketones with tert-butylmagnesium chloride and isopropyllithium led to mixtures whose chromatographic separation afforded the tertiary alcohols XIa, XIb, XIIa and XIIb mostly in low yields. In most cases the main products were the secondary alcohols XIV and apparently also the pinacols XXIII, formed by reduction. An attempt at preparing similar [1]benzothiopyrano[2,3,4-ed]pyrido[1,2-a]isoquinoline derivatives was discontinued because of an anomalous result of cyclization of compound XXVII. Compound XIa, being a 15-thia analogue of isobutaclamol (VI) displayed a high affinity to dopamine receptors in striatum of the rat brain which confirms the correctness of the assignment of relative configuration on C(3b) and C(9a).
Cyclocondensation reactions of 4-R-benzylidene-4-phenylbenzoylacetonitriles with cycloalkanones
Authors: Marchalín Štefan , Kuthan Josef
Published: February 2011

Cyclocondensation of 4-R-benzylidene-4-phenylbenzoylacetonitriles I with cycloalkanones II in the presence of ammonium acetate gives 4-aryl-2-(4-biphenylyl)-3-cyanocycloalkeno[b]pyridines IV-VI. A detailed study of the reaction course of cyclohexanone (IIa) with the ketonitriles Ia-Ij has shown that the bicyclic 1,4-dihydropyridine derivatives III, which easily undergo oxidation with air oxygen, are the intermediates in the formation of the heteroaromatic compounds IV. A mechanism is suggested for the reaction, and the dependence is discussed between structure of the synthetized compounds III-VI and their spectral properties.
Metathesis of methyl 10-undecenoate
Authors: Balcar Hynek , Dosedlová Alena , Hanuš Vladimír , Petrusová Lidmila , Matyska Bohumír
Published: February 2011

The metathesis of methyl 10-undecenoate was studied using the WCl6 + (CH3)4Sn catalyst system. The rate of metathesis and the maximum degree of conversion are affected markedly by the reactions of the ester, and of the other oxygen compounds if present, with tungsten hexachloride. Introduction of an oxygen ligand to the central tungsten atom of the active centre increases the reactivity and stability of the latter, thus affecting positively the initial rate of the metathesis reaction. At the same time, however, the rate of the catalyst deactivation increasing concentration of the ester, whereupon the degree of the conversion decreases. As a result of competition of the two effects, a maximum appears in the dependence of the amount of the ester reacted on the ester-to-tungsten hexachloride ratio.
Preparation and synthetic utilization of 3-(adenin-9-yl)-2-hydroxyalkanoic acids and their derivatives
Authors: Holý Antonín
Published: February 2011

Condensation of adenine and its substituted derivatives with 1,1-dialkoxy-2-bromoalkanes afforded substituted 2-(adenin-9-yl)-1,1-dialkoxyalkanes I and IV. Acid hydrolysis of I or IV, followed by reaction with alkali metal cyanides and acid hydrolysis, gave substituted 3-(adenin-9-yl)-2-hydroxyalkanoic acids II, Vand VI. Methyl esters of these compounds (VIII) were converted into 3-(adenin-9-yl)alkane-1,2-diols IX by reduction with sodium borohydride. 3-(Adenin-9-yl)-2-methoxypropanoic acid (XVII) was obtained by oxidation of 9-(3-hydroxy-2-methoxypropyl)adenine (XVI) with sodium periodate; 4-(adenin-9-yl)-2-(S)-hydroxybutanoic acid (XXVII) was synthesized by oxidation of 9-(S)-(2-tetrahydropyranyloxy-4-hydroxybutyl)adenine (XXV), prepared from diethyl L-malate. Acid hydrolysis of XXV afforded 9-(S)-(2,4-dihydroxybutyl)adenine (XXVI). 4-(Adenin-9-yl)-3-hydroxypentanoic acid (XXIX) was obtained by reaction of malonic acid with 2-(adenin-9-yl)-1,1-diethoxypropane (IVa) in water.
Reaction of 2,2'-anhydro-1-(β-D-arabinofuranosyl)-6-azauracil, 4-chloropyrimidine and 6-chloropurine nucleosides with amino acids
Authors: Hřebabecký Hubert , Beránek Jiří
Published: February 2011

Reaction of cycloazauridine I with glycine and L-Lysine in water at pH 10 afforded the glycine derivative II and the Nε-lysine derivative III, respectively. An identical sample of III was prepared by reaction of Nα-formyl-L-lysine with I followed by deformylation of the formed IV. L-Arginine reacts with I in water to give the Nα-derivative V. Under analogous conditions, 6-chloro-9-β-D-ribofuranosylpurine and L-lysine afford the Nε derivative X. Reaction with Nα- and Nε-formyl-L-lysine at pH 10 leads to the Nε-ribosylpurinyl derivatives XI and XII which are deformylated with hydrochloric acid to compounds X and XIII. Benzyl glycinate reacts with 4-chloro-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)- and 4-chloro-1-(2,3,5-tri-O-benzoyl-β-D-arabinofuranosyl)pyrimidin-2(1H)-one in chloroform to give benzyl N-(1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrimidin-2(1H)-on-4-yl)glycinate (VI) and N-(1-(2,3,5-tri-O-benzoyl-β-D-arabinofuranosyl)pyrimidin-2(1H)-on-4-yl)glycinate (VIII). Their methanolysis with sodium methoxide afforded the free methyl glycinates VII and IX. The reaction of poly(L-lysine) with I and 6-chloro-9-β-D-ribofuranosylpurine was investigated.
MAGNETIC SHAPE MEMORY ALLOYS: THREE-DIMENSIONAL MODELING AND ANALYSIS
Authors: BESSOUD A.-L. , STEFANELLI U.
Published: February 2011

We present a three-dimensional phenomenological model for the magneto-mechanical behavior of magnetic shape memory materials such as Ni2MnGa . Moving from micromagnetic considerations, we advance to some thermodynamically consistent constitutive relations describing the magnetically-induced cubic-to-tetragonal martensitic transformation in a single crystal. We present an existence analysis for both the constitutive relation problem and the three-dimensional quasi-static evolution problem. Finally, we discuss the reduction of this model to some simpler one by means of a rigorous Γ-convergence analysis.
Microstructural Changes in LiNi0.8Co0.15Al0.05O2 Positive Electrode Material during the First Cycle
Authors: Zheng Shijian , Huang Rong , Makimura Yoshinari , Ukyo Yoshio , Fisher Craig A. J. , Hirayama Tsukasa , Ikuhara Yuichi
Published: February 2011

The microstructure of LiNi0.8Co0.15Al0.05O2 positive electrode material before and after the first cycle was investigated by scanning transmission electron microscopy (STEM) and electron energy loss spectroscopy (EELS). STEM and EELS analysis shows that, before cycling, there are very thin layers of material at grain boundaries that contain a small amount of transition metal ions (particularly Ni) on Li sites. After the first cycle, the thickness of some grain boundary layers increases significantly, accompanied by formation of microcracks at grain boundaries. Also, from the grain interior to the grain boundary, the structure gradually changes from an ordered layer structure (α-NaFeO2-type) to a partially ordered structure and then to a disordered rock-salt structure. We posit that these microstructural changes are primarily responsible for the irreversible capacity during the first cycle.
Congestive heart failure with preserved ejection fraction is associated with severely impaired dynamic Starling mechanism
Authors: Shibata Shigeki , Hastings Jeff L. , Prasad Anand , Fu Qi , Bhella Paul S. , Pacini Eric , Krainski Felix , Palmer M. Dean , Zhang Rong , Levine Benjamin D.
Published: February 2011

Sedentary aging leads to increased cardiovascular stiffening, which can be ameliorated by sufficient amounts of lifelong exercise training. An even more extreme form of cardiovascular stiffening can be seen in heart failure with preserved ejection fraction (HFpEF), which comprises ∼40∼50% of elderly patients diagnosed with congestive heart failure. There are two major interrelated hypotheses proposed to explain heart failure in these patients: 1) increased left ventricular (LV) diastolic stiffness and 2) increased arterial stiffening. The beat-to-beat dynamic Starling mechanism, which is impaired with healthy human aging, reflects the interaction between ventricular and arterial stiffness and thus may provide a link between these two mechanisms underlying HFpEF. Spectral transfer function analysis was applied between beat-to-beat changes in LV end-diastolic pressure (LVEDP; estimated from pulmonary artery diastolic pressure with a right heart catheter) and stroke volume (SV) index. The dynamic Starling mechanism (transfer function gain between LVEDP and the SV index) was impaired in HFpEF patients ( n = 10) compared with healthy age-matched controls ( n = 12) (HFpEF: 0.23 ± 0.10 ml·m−2·mmHg−1 and control: 0.37 ± 0.11 ml·m−2·mmHg−1, means ± SD, P = 0.008). There was also a markedly increased (3-fold) fluctuation of LV filling pressures (power spectral density of LVEDP) in HFpEF patients, which may predispose to pulmonary edema due to intermittent exposure to higher pulmonary capillary pressure (HFpEF: 12.2 ± 10.4 mmHg2 and control: 3.8 ± 2.9 mmHg2, P = 0.014). An impaired dynamic Starling mechanism, even more extreme than that observed with healthy aging, is associated with marked breath-by-breath LVEDP variability and may reflect advanced ventricular and arterial stiffness in HFpEF, possibly contributing to reduced forward output and pulmonary congestion.
Information transmission and detection thresholds in the vestibular nuclei: single neurons vs. population encoding
Authors: Massot Corentin , Chacron Maurice J. , Cullen Kathleen E.
Published: February 2011

Understanding how sensory neurons transmit information about relevant stimuli remains a major goal in neuroscience. Of particular relevance are the roles of neural variability and spike timing in neural coding. Peripheral vestibular afferents display differential variability that is correlated with the importance of spike timing; regular afferents display little variability and use a timing code to transmit information about sensory input. Irregular afferents, conversely, display greater variability and instead use a rate code. We studied how central neurons within the vestibular nuclei integrate information from both afferent classes by recording from a group of neurons termed vestibular only (VO) that are known to make contributions to vestibulospinal reflexes and project to higher-order centers. We found that, although individual central neurons had sensitivities that were greater than or equal to those of individual afferents, they transmitted less information. In addition, their velocity detection thresholds were significantly greater than those of individual afferents. This is because VO neurons display greater variability, which is detrimental to information transmission and signal detection. Combining activities from multiple VO neurons increased information transmission. However, the information rates were still much lower than those of equivalent afferent populations. Furthermore, combining responses from multiple VO neurons led to lower velocity detection threshold values approaching those measured from behavior (∼2.5 vs. 0.5–1°/s). Our results suggest that the detailed time course of vestibular stimuli encoded by afferents is not transmitted by VO neurons. Instead, they suggest that higher vestibular pathways must integrate information from central vestibular neuron populations to give rise to behaviorally observed detection thresholds.
Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention
Authors: Rubio-Aliaga Isabel , Roos Baukje de , Sailer Manuela , McLoughlin Gerard A. , Boekschoten Mark V. , van Erk Marjan , Bachmair Eva-Maria , van Schothorst Evert M. , Keijer Jaap , Coort Susan L. , Evelo Chris , Gibney Michael J. , Daniel Hannelore , Muller Michael , Kleemann Robert , Brennan Lorraine
Published: February 2011

Obesity frequently leads to insulin resistance and the development of hepatic steatosis. To characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from C57BL/6J mice obtained from two independent intervention trials. After 12 wk of high-fat feeding the animals became obese, hyperglycemic, and insulin resistant, had elevated levels of blood cholesterol and VLDL, and developed hepatic steatosis. Nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. The hepatic oxidative capacity and the lipid milieu were significantly altered, which may play a key role in the development of insulin resistance. Additionally, high choline levels were observed after the high-fat diet. Previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of one-carbon metabolism. The present results suggest that the coupling of high levels of choline and low levels of methionine plays an important role in the development of insulin resistance and liver steatosis. In conclusion, the complexities of the alterations induced by high-fat feeding are multifactorial, indicating that the interplay between several metabolic pathways is responsible for the pathological consequences.
Serotonin transporter, sex, and hypoxia: microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH
Authors: White Kevin , Loughlin Lynn , Maqbool Zakia , Nilsen Margaret , McClure John , Dempsie Yvonne , Baker Andrew H. , MacLean Margaret R.
Published: February 2011

Pulmonary arterial hypertension (PAH) is up to threefold more prevalent in women than men. Female mice overexpressing the serotonin transporter (SERT; SERT+ mice) exhibit PAH and exaggerated hypoxia-induced PAH, whereas male SERT+ mice remain unaffected. To further investigate these sex differences, microarray analysis was performed in the pulmonary arteries of normoxic and chronically hypoxic female and male SERT+ mice. Quantitative RT-PCR analysis was employed for validation of the microarray data. In relevant groups, immunoblotting was performed for genes of interest (CEBPβ, CYP1B1, and FOS). To translate clinical relevance to our findings, CEBPβ, CYP1B1, and FOS mRNA and protein expression was assessed in pulmonary artery smooth muscle cells (PASMCs) derived from idiopathic PAH (IPAH) patients and controls. In female SERT+ mice, multiple pathways with relevance to PAH were altered. This was also observed in chronically hypoxic female SERT+ mice. We selected 10 genes of interest for qRT-PCR analysis (FOS, CEBPβ, CYP1B1, MYL3, HAMP2, LTF, PLN, NPPA, UCP1, and C1S), and 100% concordance was reported. Protein expression of three selected genes, CEBPβ, CYP1B1, FOS, was also upregulated in female SERT+ mice. Serotonin and 17β-estradiol increased CEBPβ, CYP1B1, and FOS protein expression in PASMCs. In addition, CEBPβ, CYP1B1, and FOS mRNA and protein expression was also increased in PASMCs derived from IPAH patients. Here, we have identified a number of genes that may predispose female SERT+ mice to PAH, and these findings may also be relevant to human PAH.
Systems Biology: The Next Frontier for Bioinformatics
Authors: Likić Vladimir A. , McConville Malcolm J. , Lithgow Trevor , Bacic Antony
Published: February 2011

Biochemical systems biology augments more traditional disciplines, such as genomics, biochemistry and molecular biology, by championing (i) mathematical and computational modeling; (ii) the application of traditional engineering practices in the analysis of biochemical systems; and in the past decade increasingly (iii) the use of near-comprehensive data sets derived from ‘omics platform technologies, in particular “downstream” technologies relative to genome sequencing, including transcriptomics, proteomics and metabolomics. The future progress in understanding biological principles will increasingly depend on the development of temporal and spatial analytical techniques that will provide high-resolution data for systems analyses. To date, particularly successful were strategies involving (a) quantitative measurements of cellular components at the mRNA, protein and metabolite levels, as well asin vivometabolic reaction rates, (b) development of mathematical models that integrate biochemical knowledge with the information generated by high-throughput experiments, and (c) applications to microbial organisms. The inevitable role bioinformatics plays in modern systems biology puts mathematical and computational sciences as an equal partner to analytical and experimental biology. Furthermore, mathematical and computational models are expected to become increasingly prevalent representations of our knowledge about specific biochemical systems.
Implicative Ideals of BCK‐Algebras Based on the Fuzzy Sets and the Theory of Falling Shadows
Authors: Jun Young Bae , Kang Min Su , Park Chul Hwan
Published: February 2011

Based on the theory of falling shadows and fuzzy sets, the notion of a falling
fuzzy implicative ideal of a BCK‐algebra is introduced. Relations among
falling fuzzy ideals, falling fuzzy implicative ideals, falling fuzzy positive implicative
ideals, and falling fuzzy commutative ideals are given. Relations
between fuzzy implicative ideals and falling fuzzy implicative ideals are provided.
Prognosis and Outcome Predictors in Psychogenic Nonepileptic Seizures
Authors: Durrant Joseph , Rickards Hugh , Cavanna Andrea E.
Published: February 2011

It is estimated that one in five patients referred to specialist epilepsy clinics for refractory seizures have psychogenic nonepileptic seizures (PNES). Despite the high prevalence, little is known about the prognosis of patients with PNES. In this paper we set out to systematically assess published original studies on the prognosis and outcome predictors of patients with PNES. Our literature search across the databases Medline, PsycINFO, and EMBASE generated 18 original studies meeting the search criteria. Prognosis was found to be poor in adults, but good in children. Predictors of poor outcome included the presence of coexisting epilepsy or psychiatric comorbidities, violent seizure phenomenology, dependent lifestyle, and poor relationships. Overall, too much reliance is placed on seizure remission as an outcome measurement for patients with PNES, and the impact of many of the outcome predictors requires evaluation using larger studies with longer followup.
Effects of Gravity and Inlet/Outlet Location on a Two‐Phase Cocurrent Imbibition in Porous Media
Authors: El-Amin M. F. , Sun Shuyu
Published: February 2011

We introduce 2D numerical investigations of the problem of gravity and inlet/outlet location effects of water‐oil two‐phase cocurrent imbibition in a porous medium. Three different cases of side‐, top‐, and bottom‐inlet location are considered. Two‐dimensional computations are carried out using the finite element method. Intensive comparisons are done between considering and neglecting gravity effect on water saturation, pressures of water and oil as well as water velocity. Results are introduced either in curves or as 2D visualization graphs. The results indicate that the buoyancy effects due to gravity force take place depending on inlet location. So, the buoyancy force in the momentum equations of the co‐current imbibition model cannot be neglected as done by several previous studies. Also, we note that the 2D zero gravity model has a uniform flow and may be represented as 1D flow unlike the 2D nonzero gravity model showing a nonuniform flow.
A Generalized Hybrid Steepest-Descent Method for Variational Inequalities in Banach Spaces
Authors: Sahu D. R. , Wong N. C. , Yao J. C.
Published: February 2011

The hybrid steepest-descent method introduced by Yamada (2001) is an algorithmic solution to the variational inequality problem over the fixed point set of nonlinear mapping and applicable to a broad range of convexly constrained nonlinear inverse problems in real Hilbert spaces. Lehdili and Moudafi (1996) introduced the new prox-Tikhonov regularization method for proximal point algorithm to generate a strongly convergent sequence and established a convergence property for it by using the technique of variational distance in Hilbert spaces. In this paper, motivated by Yamada's hybrid steepest-descent and Lehdili and Moudafi's algorithms, a generalized hybrid steepest-descent algorithm for computing the solutions of the variational inequality problem over the common fixed point set of sequence of nonexpansive-type mappings in the framework of Banach space is proposed. The strong convergence for the proposed algorithm to the solution is guaranteed under some assumptions. Our strong convergence theorems extend and improve certain corresponding results in the recent literature.
Breast Schwannoma
Authors: Dialani Vandana , Hines Neely , Wang Yihong , Slanetz Priscilla
Published: February 2011

Schwannomas arise from Schwann cells of the peripheral nerve sheath. The most common locations include the head, neck, and extensor surfaces of the extremities. Intramammary schwannomas are very rare and account for only 2.6% of schwannomas. A review of the English literature reveals 27 such cases of breast schwannoma. In this paper we describe another such rare case.
Tumor Suppressor RARRES1 Interacts with Cytoplasmic Carboxypeptidase AGBL2 to Regulate the α-Tubulin Tyrosination Cycle
Authors: Sahab Ziad J. , Hall Michael D. , Me Sung You , Dakshanamurthy Sivanesan , Ji Yun , Kumar Deepak , Byers Stephen W.
Published: February 2011

Even though it is among the most commonly methylated loci in multiple cancers, the retinoic acid–induced tumor suppressor retinoic acid receptor responder 1 (RARRES1) has no known function. We now show that RARRES1 is lost in many cancer cells, particularly those with a mesenchymal phenotype, and is a transmembrane carboxypeptidase inhibitor that interacts with ATP/GTP binding protein-like 2 (AGBL2), a cytoplasmic carboxypeptidase. Knockdown of AGBL2 results in a failure of the cell to detyrosinate the C-terminal EEY region of α-tubulin and indicates that it is a candidate for the long sought-after tubulin tyrosine carboxypeptidase important in the regulation of microtubule dynamics. In contrast, knockdown of RARRES1 increases the level of detyrosinated α-tubulin consistent with a role as the cognate inhibitor of AGBL2. We conclude that RARRES1, its interacting partners AGBL2, Eg5/KIF11, another EEY-bearing protein (EB1), and the microtubule tyrosination cycle are important in tumorigenesis and identify a novel area for therapeutic intervention. Cancer Res; 71(4); 1219–28. ©2011 AACR.
HIF-1α Confers Aggressive Malignant Traits on Human Tumor Cells Independent of Its Canonical Transcriptional Function
Authors: Yoo Young-Gun , Christensen Jared , Huang L. Eric
Published: February 2011

Hypoxia is known to favor tumor survival and progression. Numerous studies have shown that hypoxia-inducible factor 1α (HIF-1α), an oxygen-sensitive transcription factor, is overexpressed in various types of human cancers and upregulates a battery of hypoxia-responsive genes for the growth and survival of cancer cells. Although tumor progression involves the acquisition of genetic and/or epigenetic changes that confer additional malignant traits, the underlying mechanisms of these changes remain obscure. We recently identified an alternative mechanism of HIF-1α function by which HIF-1α suppresses DNA repair by counteracting c-Myc transcriptional activity that maintains gene expression. Here, we show that this HIF-α–c-Myc pathway plays an essential role in mediating hypoxic effects on malignant progression via genetic alterations, resulting in the formation of malignant tumors with aggressive local invasion and epithelial–mesenchymal transition. We show an absolute requirement of the HIF-α–c-Myc pathway for malignant progression, whereas the canonical transcription function of HIF-1α alone is insufficient and seemingly dispensable. This study indicates that HIF-1α induction of genetic alteration is the underlying cause of tumor progression, especially by the hypoxic microenvironment. Cancer Res; 71(4); 1244–52. ©2011 AACR.
Small Molecule Kinase Inhibitor Screen Identifies Polo-Like Kinase 1 as a Target for Neuroblastoma Tumor-Initiating Cells
Authors: Grinshtein Natalie , Datti Alessandro , Fujitani Mayumi , Uehling David , Prakesch Michael , Isaac Methvin , Irwin Meredith S. , Wrana Jeffrey L. , Al-awar Rima , Kaplan David R.
Published: February 2011

Neuroblastoma (NB) is an often fatal pediatric tumor of neural crest origin. We previously isolated NB tumor-initiating cells (NB TIC) from bone marrow metastases that resemble cancer stem cells and form metastatic NB in immunodeficient animals with as few as ten cells. To identify signaling pathways important for the survival and self-renewal of NB TICs and potential therapeutic targets, we screened a small molecule library of 143 protein kinase inhibitors, including 33 in clinical trials. Cytostatic or cytotoxic drugs were identified that targeted PI3K (phosphoinositide 3-kinase)/Akt, PKC (protein kinase C), Aurora, ErbB2, Trk, and Polo-like kinase 1 (PLK1). Treatment with PLK1 siRNA or low nanomolar concentrations of BI 2536 or BI 6727, PLK1 inhibitors in clinical trials for adult malignancies, were cytotoxic to TICs whereas only micromolar concentrations of the inhibitors were cytotoxic for normal pediatric neural stem cells. Furthermore, BI 2536 significantly inhibited TIC tumor growth in a therapeutic xenograft model, both as a single agent and in combination with irinotecan, an active agent for relapsed NB. Our findings identify candidate kinases that regulate TIC growth and survival and suggest that PLK1 inhibitors are an attractive candidate therapy for metastatic NB. Cancer Res; 71(4); 1385–95. ©2011 AACR.
Replication and Functional Genomic Analyses of the Breast Cancer Susceptibility Locus at 6q25.1 Generalize Its Importance in Women of Chinese, Japanese, and European Ancestry
Authors: Cai Qiuyin , Wen Wanqing , Qu Shimian , Li Guoliang , Egan Kathleen M. , Chen Kexin , Deming Sandra L. , Shen Hongbing , Shen Chen-Yang , Gammon Marilie D. , Blot William J. , Matsuo Keitaro , Haiman Christopher A. , Khoo Ui Soon , Iwasaki Motoki , Santella Regina M. , Zhang Lina , Fair Alecia Malin , Hu Zhibin , Wu Pei-Ei , Signorello Lisa B. , Titus-Ernstoff Linda , Tajima Kazuo , Henderson Brian E. , Chan Kelvin Y.K. , Kasuga Yoshio , Newcomb Polly A. , Zheng Hong , Cui Yong , Wang Furu , Shieh Ya-Lan , Iwata Hiroji , Le Marchand Loic , Chan Sum Yin , Shrubsole Martha J. , Trentham-Dietz Amy , Tsugane Shoichiro , Garcia-Closas Montserrat , Long Jirong , Li Chun , Shi Jiajun , Huang Bo , Xiang Yong-Bing , Gao Yu-Tang , Lu Wei , Shu Xiao-Ou , Zheng Wei
Published: February 2011

We evaluated the generalizability of a single nucleotide polymorphism (SNP), rs2046210 (A/G allele), associated with breast cancer risk that was initially identified at 6q25.1 in a genome-wide association study conducted among Chinese women. In a pooled analysis of more than 31,000 women of East-Asian, European, and African ancestry, we found a positive association for rs2046210 and breast cancer risk in Chinese women [ORs (95% CI) = 1.30 (1.22–1.38) and 1.64 (1.50–1.80) for the AG and AA genotypes, respectively, P for trend = 1.54 × 10−30], Japanese women [ORs (95% CI) = 1.31 (1.13–1.52) and 1.37 (1.06–1.76), P for trend = 2.51 × 10−4], and European-ancestry American women [ORs (95% CI) = 1.07 (0.99–1.16) and 1.18 (1.04–1.34), P for trend = 0.0069]. No association with this SNP, however, was observed in African American women [ORs (95% CI) = 0.81 (0.63–1.06) and 0.85 (0.65–1.11) for the AG and AA genotypes, respectively, P for trend = 0.4027]. In vitro functional genomic studies identified a putative functional variant, rs6913578. This SNP is 1,440 bp downstream of rs2046210 and is in high linkage disequilibrium with rs2046210 in Chinese (r2 = 0.91) and European-ancestry (r2 = 0.83) populations, but not in Africans (r2 = 0.57). SNP rs6913578 was found to be associated with breast cancer risk in Chinese and European-ancestry American women. After adjusting for rs2046210, the association of rs6913578 with breast cancer risk in African Americans approached borderline significance. Results from this large consortium study confirmed the association of rs2046210 with breast cancer risk among women of Chinese, Japanese, and European ancestry. This association may be explained in part by a putatively functional variant (rs6913578) identified in the region. Cancer Res; 71(4); 1344–55. ©2011 AACR.
Pten in the Breast Tumor Microenvironment: Modeling Tumor–Stroma Coevolution
Authors: Wallace Julie A. , Li Fu , Leone Gustavo , Ostrowski Michael C.
Published: February 2011

Solid human tumors and their surrounding microenvironment are hypothesized to coevolve in a manner that promotes tumor growth, invasiveness, and spread. Mouse models of cancer have focused on genetic changes in the epithelial tumor cells and therefore have not robustly tested this hypothesis. We have recently developed a murine breast cancer model that ablates the PTEN tumor suppressor pathway in stromal fibroblasts. Remarkably, the model resembles human breast tumors both at morphologic and molecular levels. We propose that such models reflect subtypes of tumor–stromal coevolution relevant to human breast cancer, and will therefore be useful in defining the mechanisms that underpin tumor–stroma cross-talk. Additionally, these models should also aid in molecularly classifying human breast tumors on the basis of both the microenvironment subtypes they contain as well as on the tumor subtype. Cancer Res; 71(4); 1203–7. ©2011 AACR.
Knockdown of Oncogenic KRAS in Non–Small Cell Lung Cancers Suppresses Tumor Growth and Sensitizes Tumor Cells to Targeted Therapy
Authors: Sunaga Noriaki , Shames David S. , Girard Luc , Peyton Michael , Larsen Jill E. , Imai Hisao , Soh Junichi , Sato Mitsuo , Yanagitani Noriko , Kaira Kyoichi , Xie Yang , Gazdar Adi F. , Mori Masatomo , Minna John D.
Published: February 2011

Oncogenic KRAS is found in more than 25% of lung adenocarcinomas, the major histologic subtype of non–small cell lung cancer (NSCLC), and is an important target for drug development. To this end, we generated four NSCLC lines with stable knockdown selective for oncogenic KRAS. As expected, stable knockdown of oncogenic KRAS led to inhibition of in vitro and in vivo tumor growth in the KRAS-mutant NSCLC cells, but not in NSCLC cells that have wild-type KRAS (but mutant NRAS). Surprisingly, we did not see large-scale induction of cell death and the growth inhibitory effect was not complete. To further understand the ability of NSCLCs to grow despite selective removal of mutant KRAS expression, we conducted microarray expression profiling of NSCLC cell lines with or without mutant KRAS knockdown and isogenic human bronchial epithelial cell lines with and without oncogenic KRAS. We found that although the mitogen-activated protein kinase pathway is significantly downregulated after mutant KRAS knockdown, these NSCLCs showed increased levels of phospho-STAT3 and phospho–epidermal growth factor receptor, and variable changes in phospho-Akt. In addition, mutant KRAS knockdown sensitized the NSCLCs to p38 and EGFR inhibitors. Our findings suggest that targeting oncogenic KRAS by itself will not be sufficient treatment, but may offer possibilities of combining anti-KRAS strategies with other targeted drugs. Mol Cancer Ther; 10(2); 336–46. ©2011 AACR.
Atypical Protein Kinase Cι (PKCι) Promotes Metastasis of Esophageal Squamous Cell Carcinoma by Enhancing Resistance to Anoikis via PKCι-SKP2-AKT Pathway
Authors: Liu Shu-Guang , Wang Bo-Shi , Jiang Yan-Yi , Zhang Tong-Tong , Shi Zhi-Zhou , Yang Yang , Yang Yi-Ling , Wang Xiao-Chun , Lin De-Chen , Zhang Yu , Yang Hai , Cai Yan , Zhan Qi-Min , Wang Ming-Rong
Published: February 2011

Protein kinase Cι (PKCι) is an atypical PKC isoform and participates in multiple aspects of the transformed phenotype in human cancer cells. We previously reported that frequent amplification and overexpression of PKCι were correlated with lymph node metastasis in primary esophageal squamous cell carcinomas (ESCC). In the present study, short interfering RNA–mediated silencing of PKCι revealed that this enzyme was required for cell migration, invasion, and resistance to anoikis. In vivo experiments showed that PKCι suppression decreased tumor growth in esophageal cancer xenografts and lung metastases in nude mice. At the molecular level, knockdown of PKCι in suspended ESCC cells caused a decrease in S-phase kinase-associated protein 2 (SKP2) that had been reported to promote resistance to anoikis via the PI3K/AKT pathway. AKT phosphorylation was abolished after PKCι suppression, but AKT activation could be refreshed by PKCι upregulation, suggesting that PKCι enhanced cell resistance to anoikis via the PKCι-SKP2-PI3K/AKT pathway. Addition of the proteasome inhibitor MG132 prevented the decrease of SKP2 in PKCι silenced cells, and polyubiquitin-SKP2 was elevated after PKCι depletion, showing that PKCι might regulate the expression of SKP2 through the ubiquitin-proteasome pathway in suspended cells. Furthermore, overexpression of SKP2 in PKCι-downregulated cells restored cell resistance to anoikis. Most importantly, PKCι expression significantly correlated with SKP2 in 133 ESCC tissues (P = 0.031). Taken together, our data show that PKCι promotes tumorigenicity and metastasis of human esophageal cancer and that SKP2 is a candidate downstream effector of PKCι signaling in ESCC. Mol Cancer Res; 9(4); 390–402. ©2011 AACR.
Patient-Reported Side Effects of Intradetrusor Botulinum Toxin Type A for Idiopathic Overactive Bladder Syndrome
Authors: Bauer Ricarda M. , Gratzke Christian , Roosen Alexander , Hocaoglu Yasmin , Mayer Margit E. , Buchner Alexander , Stief Christian G. , May Florian
Published: February 2011

Objective: The aim of the study was a prospective assessment of patient-reported side effects in an open-label study after intradetrusor botulinum toxin injections for idiopathic overactive bladder (OAB). Patients and Methods: Botulinum toxin A injection was performed in 56 patients with idiopathic OAB. Patients were followed up for 6 months concerning side effects and patients’ satisfaction. Results: Different types of side effects were assessed such as dry mouth (19.6%), arm weakness (8.9%), eyelid weakness (8.9%), leg weakness (7.1%), torso weakness (5.4%), impaired vision (5.4%) and dysphagia (5.4%). In all cases, symptoms were mild and transient. Urological complications such as gross hematuria (17.9%), acute urinary retention (8.9%) and acute urinary tract infection (7.1%) were noticed. In all cases, acute urinary retention was transient and treated with temporary intermittent self-catheterization. There was no statistically significant correlation between dosage and observed side effects. Patients’ satisfaction rate was high (71.4%). Conclusion: Intradetrusor injection of botulinum toxin was associated with a high rate of neurourological side effects. In general, side effects were transient, mild and did not require special treatment.
Arytenoid Asymmetry in Relation to Posture, Neck Tension and Glottal Attack in Singers
Authors: Husseini Sami Tanbouzi , Ashkar Jihad , Halawi Akaber , Sibai Abla , Hamdan Abdul-Latif
Published: February 2011

Objectives: To look at the incidence of arytenoid asymmetry in a group of healthy singers and to investigate whether the asymmetry correlates with posture, neck tension and glottal attack. Materials and Method: The medical records and video recordings of 42 singers were reviewed retrospectively. Posture, neck tension and glottal attack were evaluated in relation to arytenoid asymmetry during adduction. Results: The number of singers was 42, with a male-to-female ratio of 2:1. The age range was 16–38 years, with a mean of 24 ± 4.13 years. The total prevalence of arytenoid asymmetry was 50%, with a predominance in males and on the right side. The most common asymmetry was that of the cuneiform cartilages, accounting for 40.5% of the total sample and 81% of the total asymmetries. There was no correlation between arytenoid asymmetry and either posture, neck tension or glottal attack (p = 0.343, 0.489 and 0.945, respectively). Conclusion: One out of 2 singers is likely to have arytenoid asymmetry during adduction. The presence of asymmetry does not correlate with posture, neck tension or glottal attack.
Observation of de Novo Bladder Dysfunction under Treatment with Her2-neu Antibodies
Authors: Hinkel Andreas , Strumberg Dirk , Noldus Joachim , Pannek Jürgen
Published: February 2011

Purpose: We diagnosed de novo bladder dysfunction in several breast cancer patients under cancer-specific therapy with trastuzumab. The goal of this retrospective analysis was to investigate whether bladder dysfunction is common in a larger population of breast cancer patients receiving trastuzumab therapy. Patients and Methods: We identified 93 patients who received at least two doses of trastuzumab at our institution in the years 2003–2006. 57 of those patients were still alive at the time of this analysis. We mailed a validated global questionnaire for the assessment of incontinence (King’s Health Questionnaire, KHQ) to them, additionally asking for bladder dysfunction observed under trastuzumab therapy. Results: 43 (75%) of the patients returned the questionnaire, 11 (25%) of them reporting severe de novo bladder dysfunction under therapy. Significant differences between symptomatic and asymptomatic patients were detected in all KHQ subscales. Previous conditions and surgeries as well as medications, especially hormonal therapy, were excluded as underlying causes. However, there were more patients under taxane-based chemotherapy in the symptomatic group. Conclusions: The epidermal growth factor receptor is involved in the cellular response to mechanical stretch in the urinary bladder. Based on our findings, we hypothesize that interfering with this pathway may well be the cause of symptomatic bladder dysfunction in patients under trastuzumab medication. A prospective study is required to further elucidate this hypothesis.
Time to Recurrence after Nephrectomy as a Predictor of Cancer-Specific Survival in Localized Clear-Cell Renal Cell Carcinoma
Authors: Rodriguez-Covarrubias Francisco , Gomez-Alvarado M. Olivia , Sotomayor Mariano , Castillejos-Molina Ricardo , Mendez-Probst Carlos E. , Gabilondo Fernando , Feria-Bernal Guillermo
Published: February 2011

Objective: To evaluate the prognostic impact of early recurrence (within 12 months) after surgery on cancer-specific survival (CSS) of patients with localized clear-cell renal cell carcinoma (ccRCC). Methods: Patients with surgically treated localized ccRCC were studied. Using the Kaplan-Meier method, we calculated CSS; by univariate and multivariate models we analyzed the association of early recurrence with cancer-related mortality. Results: We identified 259 patients with pT1–4/NX/0M0 ccRCC treated between February 1981 and September 2009; of 66 (25.5%) with disease recurrence, 29 (43.9%) had early relapse. Overall, 43 patients (16.6%) died from ccRCC. The 5- and 10-year CSS for those without, late and early recurrence was 98.5 and 96.5%, 53 and 39.8%, and 23 and 23%, respectively (p < 0.0001). In the multivariate Cox model, pT stage (p = 0.01) and early recurrence (p < 0.0001) independently predicted CSS. Conclusions: Recurrent disease after localized ccRCC confers a poor prognosis, especially if detected within 12 months after surgery. Thus, this criterion should be included as an independent risk factor for cancer-related mortality.
The Effect of Sunitinib on Immune Subsets in Metastatic Clear Cell Renal Cancer
Authors: Powles Thomas , Chowdhury Simon , Bower Mark , Saunders Nataile , Lim Louise , Shamash Jonathan , Sarwar Naveed , Sadev Anju , Peters John , Green James , Boleti Katia , Augwal Samir
Published: February 2011

Background: Sunitinib is standard first-line therapy for metastatic clear cell renal cancer (MCRC). It is associated with leucopenia; however, its effects on specific immune cell subsets are unclear. Alterations in immune cell subsets may contribute to tumour progression. Methods: Lymphocyte subsets (CD3, 4, 8, 19 and 56) were measured in 43 untreated MCRC patients who received sunitinib. The protocol included a structured treatment interruption of 5 weeks. Cell populations were measured at specific time points during sunitinib treatment and the treatment break. Results: Sunitinib was associated with significant declines in total leucocyte (–48%), neutrophil (–62%), CD3 total T cell (–31%) and CD4 counts (32%; p < 0.05). There was no significant change in CD19 B lymphocyte, CD8 or CD56 natural killer cells. During the sunitinib-free interval, all parameters recovered to baseline. No patients developed opportunistic infections or neutropenic sepsis. The level of specific immune subsets at presentation or occurrence of a fall in specific counts had an effect on progression-free survival (p > 0.05). Conclusions: Sunitinib is associated with reversible inhibition of specific lymphocyte subsets which has implications for the immunological control of MCRC and its use in combination with other agents. Despite suppressive effects, there was no evidence of predisposition to immune suppressive-related infection.