bluuebunny/crossref_metadata_2025 huggingface dataset:
Vibration measurements during foundation test installation at Vancouver International Airport
Authors: Bertok J. , Barron K. E.
Published: May 2010

This technical note describes a case history of vibration measurements made in connection with the extension of the Area Control Centre at Vancouver International Airport. Two test stone columns and two test piles were monitored during installation to ascertain whether either method would produce vibration levels disturbing to the existing building or the sensitive electronic equipment inside. It was found that the vibration levels from both foundation types were below the allowable levels for both the buildings and the sensitive electronic equipment. Key words: building foundation, piles, stone columns, installation, vibration, measurement, interpretation.
A failure criterion for stiff soils and rocks exhibiting softening
Authors: Yoshida N. , Morgenstern N. R. , Chan D. H.
Published: May 2010

A simple nonlinear failure criterion is proposed for geologic materials exhibiting time-dependent softening. It is expressed in terms of maximum and minimum principal stresses, uniaxial compression strength, and three strength parameters. These strength parameters can be easily determined from conventional strength tests such as the triaxial compression test. The application of the proposed failure criterion to experimental data taken from the literature shows that there is excellent agreement.The proposed failure criterion is used to describe the effect of softening observed in materials such as overconsolidated clays and soft rocks. The effect of softening can be represented in this failure criterion through a time-dependent reduction in the strength parameters. The variation in shear strength during softening is embraced from the initial strength to the fully softened condition. Key words: failure criterion, softening, time-dependent strength reduction.
Norman Wells pipeline permafrost and terrain monitoring: geothermal and geomorphic observations, 1984–1987
Authors: Burgess M. M. , Harry D. G.
Published: May 2010

A long-term permafrost and terrain research and monitoring program along the 869 km buried oil pipeline between Norman Wells, Northwest Territories, and Zama, Alberta, has been undertaken by the Geological Survey of Canada, in cooperation with the Department of Indian and Northern Affairs Canada. The two main program components are (1) the detailed quantification of changes in the geothermal regime and geomorphic conditions at instrumented monitoring sites and (2) general observations of terrain conditions and performance along the pipeline route. Pipeline operation commenced in April 1985. Observations during the first 2.5 years of pipeline operation indicate that, as expected, the pipe thermal regime and ground thermal regime have not yet stabilized in response to construction and operation. Warming trends in both mean annual pipe temperature and mean annual right-of-way ground temperature have occurred. Surface settlement in permafrost terrain is ongoing in the pipe trench as well as on the remainder of the right-of-way. Surface erosion has occurred, particularly at stream crossings and on low-angle slopes lacking erosion control structures. Key words: pipeline, permafrost, thermal regime, thaw settlement, surface erosion, instrumentation, Norman Wells, Mackenzie Valley, Canada.
Compressive strength and creep behavior of hydrate-consolidated sand
Authors: Cameron I. , Handa Y. P. , Baker T. H. W.
Published: May 2010

Cylindrical samples of sand consolidated with tetrahydrofuran hydrate were tested for their compressive strength and creep behavior under uniaxial compression. The samples were 15 cm in length and 7.5 cm in diameter and were tested at −10 °C. The results, when combined with our previous measurements on similar samples at −6 °C, show that the material becomes stronger by about 10% with decrease in temperature; otherwise, the slopes of the peak stress – strain rate curves are the same. These results are similar to those of sand consolidated with ice, except that in the latter case the increase in strength over the same temperature range is about 30%. Furthermore, the slope of the peak stress – strain rate curve for the hydrate-consolidated sand is almost zero, whereas for the ice-consolidated sand it is quite steep. Consequently, at strain rates below 10−5 s−1 the hydrate-consolidated sand is stronger, whereas at strain rates above 10−5 s−1 the ice-consolidated sand is the stronger material. Noticeable differences were also observed in the creep behavior of the hydrate- and ice-consolidated sands. At −10 °C, ice-consolidated sand failed in about 15 h under a stress of about 7 MPa, whereas hydrate-consolidated sand failed after 52.3 h under a stress of 12.2 MPa and some samples did not fail even after 540 h when subjected to a stress of 9.3 MPa. Key words: gas hydrates, ice, frozen sand, mechanical properties, compressive strength, creep behavior.
VISUAL AND AUDITORY CUES SIGNIFICANTLY REDUCE HUMAN'S INTRINSIC BIASES WHEN TASKED TO GENERATE A RANDOM NUMBER SEQUENCE
Authors: CRISOLOGO IRENE , BATAC RENE , LONGJAS ANTHONY , LEGARA ERIKA FILLE , MONTEROLA CHRISTOPHER
Published: May 2010

Humans are deemed ineffective in generating a seemingly random number sequence primarily because of inherent biases and fatigue. Here, we establish statistically that human-generated number sequence in the presence of visual cues considerably reduce one's tendency to be fixated to a certain group of numbers allowing the number distribution to be statistically uniform. We also show that a stitching procedure utilizing auditory cues significantly minimizes human's intrinsic biases towards doublet and sequential ordering of numbers. The article provides extensive experimentation and comprehensive pattern analysis of the sequences formed when humans are tasked to generate a random series using numbers "0" to "9." In the process, we develop a statistical framework for analyzing the apparent randomness of finite discrete sequences via numerical measurements.
FLOW OF EMOTIONAL MESSAGES IN ARTIFICIAL SOCIAL NETWORKS
Authors: CHMIEL ANNA , HOŁYST JANUSZ A.
Published: May 2010

Models of message flows in an artificial group of users communicating via the Internet are introduced and investigated using numerical simulations. We assumed that messages possess an emotional character with a positive valence and that the willingness to send the next affective message to a given person increases with the number of messages received from this person. As a result, the weights of links between group members evolve over time. Memory effects are introduced, taking into account that the preferential selection of message receivers depends on the communication intensity during the recent period only. We also model the phenomenon of secondary social sharing when the reception of an emotional e-mail triggers the distribution of several emotional e-mails to other people.
ISOMER SPECTRUM OFC30CLUSTER AND THE GROWTH DYNAMICS
Authors: GONG XIU-FANG , YANG GONG-XIAN , NING XI-JING , WANG YIN , LI PENG
Published: May 2010

We calculated the isomer spectrum of C30cluster by time-going-backward quasi-dynamics method and performed molecular dynamic simulations of the cluster growth in He buffer gas at 2500 K. Based on geometrical shapes, the isomers can be classified into closed cages, open cages, bowls, sheets and other irregular shapes. Although potential energies and free energies of the sheet isomers are much higher than those of the closed cage isomers, the dynamical simulations show that the sheet isomers rather than the cage isomers dominate in the resultant clusters at the simulation temperature and the most probable sheet isomer lies on the 47th level counted from the bottom one of the isomer spectrum.
MULTI-PHASE OSCILLATION IN RF CMOS LC OSCILLATORS COUPLED BY MUTUAL INDUCTORS
Authors: KAWANARI TOSHIHIRO , MORO SEIICHIRO
Published: May 2010

When the oscillators are coupled, coupling methods are very important and influence some factors, for example, increasing or decreasing of noise and whether multi-phase synchronization phenomena can be observed or not due to the number of oscillators and so on. In this paper, multi-phase synchronization phenomena which are generated in RF CMOS LC oscillators with mutual inductor couplings and the stability of various oscillatory modes in the proposed model are investigated. In the proposed system, multi-phase synchronization phenomena can be observed regardless of the number of oscillators in RF region due to setting up the sign of the mutual inductance properly, and the each oscillatory mode is stable.
PHASE MODEL REDUCTION AND SYNCHRONIZATION OF PERIODICALLY FORCED NONLINEAR OSCILLATORS
Authors: BONNIN MICHELE , CORINTO FERNANDO , GILLI MARCO
Published: May 2010

Phase models represent the ideal framework to investigate the synchronization of a nonlinear oscillator with an external forcing. While many researches focused the attention to their analysis, little work has been done about the reduction of a physical system to the corresponding phase model. In this paper we show how, resorting to averaging techniques, it is possible to obtain the phase model corresponding to a given set of state equations. As examples, we derive the phase equations and investigate the synchronization properties of two popular nonlinear oscillators.
MARKOV CHAIN MODELING AND ANALYSIS OF COMPLICATED PHENOMENA IN COUPLED CHAOTIC OSCILLATORS
Authors: NISHIO YOSHIFUMI , KOMATSU YUTA , UWATE YOKO , HASLER MARTIN
Published: May 2010

In this paper, we propose a Markov chain modeling of complicated phenomena observed from coupled chaotic oscillators. Once we obtain the transition probability matrix from computer simulation results, various statistical quantities can be easily calculated from the model. It is shown that various statistical quantities are easily calculated by using the Markov chain model. Various features derived from the Markov chain models of chaotic wandering of synchronization states and switching of clustering states are compared with those obtained from computer simulations of original circuit equations.
A LOW-VOLTAGE SCALABLE (1.8 V–0.75 V) CMOS FOLDED-CASCODE LC QUADRATURE VCO FOR RF RECEIVERS
Authors: REZAUL HASAN S. M.
Published: May 2010

This paper presents a scalable low voltage CMOS folded-cascode quadrature voltage controlled oscillator (QVCO) design for radio-frequency (RF) applications using the TSMC 0.18 μm 6M1P CMOS process technology. The simulated startup behavior of this proposed QVCO topology indicates that, the QVCO is free from bi-modal oscillation (frequency ambiguity). The QVCO provided extended voltage swing with the supply voltage scalable in the range of 1.8 V to 0.75 V. The QVCO operates in the frequency range of 4 GHz to 3 GHz (corresponding to supply voltage scaling in the range of 1.8 V to 0.75 V) with around 11.7% tuning range and low quadrature error. The QVCO had a power consumption under 10 mW within the specified supply voltage scaling range. Phase noise simulations using the Monte Carlo analysis provide an approximate phase noise estimate of ≈ -150 dBc/Hz at an offset of 600 KHz from the center frequency (@3.7 GHz) for operation using the 1.8 V supply voltage, using moderate inductor-Q values. Monte Carlo simulations were also carried out to determine the effects of the process, voltage and temperature variations.
HIGHER-ORDER CHAOTIC OSCILLATOR USING ACTIVE BESSEL FILTER
Authors: LINDBERG ERIK , MYKOLAITIS GYTIS , BUMELIENĖ SKAIDRA , PYRAGIENĖ TATJANA , TAMAŠEVIČIUS ARŪNAS , TAMAŠEVIČIŪTĖ ELENA , KIRVAITIS RAIMUNDAS
Published: May 2010

A higher-order oscillator, including a nonlinear unit and an 8th-order low-pass active Bessel filter is described. The Bessel unit plays the role of "three-in-one": a delay line, an amplifier and a filter. Results of hardware experiments and numerical simulation are presented. Depending on the parameters of the nonlinear unit the oscillator operates either in a one-scroll or two-scroll mode. Two positive Lyapunov exponents, found at larger values of the negative slopes of the nonlinear function, characterize the oscillations as hyperchaotic.
BOREPIN, BORANORBORNADIENE AND BORANORCARADIENE: SUBSTITUENT EFFECTS ON INTERCONVERSIONS AT THEORETICAL LEVELS
Authors: KASSAEE M. Z. , MUSAVI S. M. , MOTAMEDI E.
Published: May 2010

Density-functional B3LYP and ab initio HF calculations are used to study three isomeric systems including: borepin I, boranorbornadiene II, and boranorcaradiene III as well as their X-substituted analogues at two different positions ( X = F, Cl, Br, CH3, OCH3, CF3, CN , and NH2 ). Geometries, enthalpies, and energy barriers for two series of interconversions, IIIX → IX and IIIX → IIX, are calculated using 6-311G* basis set. The B3LYP calculated relative stability is in the order: I (0.00 kcal/mol) > II (23.33 kcal/mol) > III (39.07 kcal/mol). Except for NH2 , the electronic effects of the substituents are generally insignificant on the relative stability. At B3LYP, the gas-phase activation enthalpies for III → I and III → II interconversions are estimated to be very small (0.6 and 0.75 kcal/mol, respectively). The reverse conversions, I → III and II → III, have activation energies of 39.67 and 16.49 kcal/mol, respectively. These energies rule out the possibility of a rapid interconversion of the isomers in the gas phase. Again, none of the substituents, X, can change this situation. Two pathways are proposed for the possible [1, 3]-suprafacial sigmatropic shifts of IIIX → IIX. The partial aromatic characters of planar borepins are estimated using magnetic (NICS) and structural criteria (bond length alternation).
DFT STUDY ON SECOND-ORDER NONLINEAR OPTICAL PROPERTIES OF THE DERIVATIVES OF DISUBSTITUTED SEVEN-VERTEX COBALTACARBORANE METALLOCENYL
Authors: LIU XIAODONG , QIU YONGQING , SUN SHILING , LIU CHUNGUANG , SU ZHONGMIN
Published: May 2010

DFT B3LYP method was employed to calculate the second-order nonlinear optical (NLO) responses of the derivatives of disubstituted seven-vertex cobaltacarborane metallocenyl. The results show that cobaltacarborane metallocenyl plays a pushing/pulling role and a bridge role to transfer electron in these molecules. The five-membered ring of cyclopentadiene is more beneficial to increase second-order NLO response than the five-membered ring composed of two C atoms and three B atoms in cobaltacarborane. Moreover, the second-order NLO response is more powerful when one substituent containing electron donor group and one substituent containing electron acceptor group are located at meta position. Accordingly, among the nine models, model c2 is the optimum model with largest value of βtot. The calculation results also show that cobaltacarborane metallocenyl and ferrocene parts play the same roles to increase second-order NLO response. Thus, cobaltacarborane metallocenyl can be a promising second-order NLO material.
STEREODYNAMICS STUDY OF THE REACTION Cl(2p3/2) + C2D6 (v = 0, j = 0) → DCl + C2D5
Authors: LIU YUFANG , HE XIAOHU , GAO YALI , SUN JINFENG
Published: May 2010

The product angular momentum polarization of the Cl + C2D6 → DCl + C2D5 reaction is calculated via the quasiclassical trajectory (QCT) method at the collision energy of 0.25 eV. A new London–Eyring–Polanyi–Sato (LEPS) potential energy surface (PES) is used in this reaction. There is a "late" barrier and a "deep" well on this new LEPS PES. The four polarization-dependent "generalized" differential cross sections (PDDCSs) are presented in the center-of-mass frame. In the meantime, the distributions of P(ϕr), P(θr), and P(θr, ϕr) are calculated. The calculations are in good agreement with the experimental data. In addition, the rotational alignment factors [Formula: see text], [Formula: see text], and [Formula: see text] in the stationary-target frame (STF) are also calculated.
ON p-ADIC PROPERTIES OF TWISTED TRACES OF SINGULAR MODULI
Authors: LE DANIEL , MANBER SHELLY , SHAH SHRENIK
Published: May 2010

We prove that logarithmic derivatives of certain twisted Hilbert class polynomials are holomorphic modular forms modulo p of filtration p + 1. We derive p-adic information about twisted Hecke traces and Hilbert class polynomials. In this framework, we formulate a precise criterion for p-divisibility of class numbers of imaginary quadratic fields in terms of the existence of certain cusp forms modulo p. We explain the existence of infinite classes of congruent twisted Hecke traces with fixed discriminant in terms of the factorization of the associated Hilbert class polynomial modulo p. Finally, we provide a new proof of a theorem of Ogg classifying those p for which all supersingular j-invariants modulo p lie in Fp.
CLASSIFYING BRUMER'S QUINTIC POLYNOMIALS BY WEAK MORDELL–WEIL GROUPS
Authors: KIDA MASANARI , RIKUNA YŪICHI , SATO ATSUSHI
Published: May 2010

We develop a general classification theory for Brumer's dihedral quintic polynomials by means of Kummer theory arising from certain elliptic curves. We also give a similar theory for cubic polynomials.
WHY DO SOME COUNTRIES UNDERTAKE STRUCTURAL REFORMS WHEN OTHERS DO NOT?
Authors: HALLETT ANDREW HUGHES
Published: May 2010

It is widely accepted that structural, institutional and labour market reforms are essential for the development of the OECD and emerging market economies; and that argument has been incorporated into official policy in the EU as part of the Lisbon agenda. Yet there is little analysis in the economics literature of how these reforms should work, or of which reforms would be most effective. Similarly, there is no explanation of why policy makers extol the virtues of reform, but often fail to carry them out. Or why some countries embrace reform, but others in similar circumstances do not. To explain these differences we develop a general equilibrium model with imperfect competition, extended to include labour market imperfections and tax distortions. We find that fiscal constraints to be the principal reason that reforms do not get undertaken, though labour market regulation can be a serious complicating factor in certain cases. As a result, the reduction of tax distortions, rather than market or institutional reform, is usually the most effective type of reform. The implication is that we need models that combine different reform instruments and different distortions to analyse this kind of problem.
GLOBALISATION, INTERNATIONAL COMPETITIVENESS AND GROWTH: ADVANCED AND EMERGING MARKETS, LARGE AND SMALL COUNTRIES
Authors: SALVATORE DOMINICK
Published: May 2010

The past three decades have witnessed a rapid tendency toward globalisation in the world economy. A great deal of controversy exists, however, as to whether and to what extent globalisation has increased nations' international competitiveness and growth. After discussing the common characteristics of the rapidly growing economies and the meaning and importance of globalisation, this paper examines the relationship among globalisation, international competitiveness and growth during the most recent period of rapid globalisation for all the countries for which data exists as a group, and then separately for advanced and emerging markets, and for large and small countries.
Estimating changes in volume-weighted mean body temperature using thermometry with an individualized correction factor
Authors: Jay Ollie , DuCharme Michel B. , Webb Paul , Reardon Francis D. , Kenny Glen P.
Published: May 2010

This study investigated whether the estimation error of volume-weighted mean body temperature (ΔT̄b) using changes in core and skin temperature can be accounted for using personal and environmental parameters. Whole body calorimetry was used to directly measure ΔT̄b in an Experimental group (EG) of 36 participants (24 males, 12 females) and a Validation group (VG) of 20 (9 males, 11 females) throughout 90 min of cycle ergometry at 40°C, 30% relative humidity (RH) ( n = 9 EG, 5 VG); 30°C, 30% RH ( n = 9 EG, 5 VG); 30°C, 60% RH ( n = 9 EG, 5 VG); and 24°C, 30% RH ( n = 9 EG, 5 VG). The core of the two-compartment thermometry model was represented by rectal temperature and the shell by a 12-point mean skin temperature (ΔT̄sk). The estimation error (X0) between ΔT̄b from calorimetry and ΔT̄b from thermometry using core/shell weightings of 0.66/0.34, 0.79/0.21, and 0.90/0.10 was calculated after 30, 60, and 90 min of exercise, respectively. The association between X0 and the individual variation in metabolic heat production (M − W), body surface area (BSA), body fat percentage (%fat), and body surface area-to-mass ratio (BSA/BM) as well as differences in environmental conditions (Oxford index) in the EG data were assessed using stepwise linear regression. At all time points and with all core/shell weightings tested, M − W, BSA, and Oxford index independently correlated significantly with the residual variance in X0, but %fat and BSA/BM did not. The subsequent regression models were used to predict the thermometric estimation error (X0_pred) for each individual in the VG. The value estimated for X0_pred was then added to the ΔT̄b estimated using the two-compartment thermometry models yielding an adjusted estimation (ΔT̄b_adj) for the individuals in the VG. When comparing ΔT̄b_adj to the ΔT̄b derived from calorimetry in the VG, the best performing model used a core/shell weighting of 0.66/0.34 describing 74%, 84%, and 82% of the variation observed in ΔT̄b from calorimetry after 30, 60, and 90 min, respectively.
Computational analysis of gene regulation in animal sleep deprivation
Authors: Wang Haifang , Liu Yuting , Briesemann Marko , Yan Jun
Published: May 2010

Sleep is an animal behavior shared by a wide range of species, suggesting that it must serve fundamental functions. However, the functions and molecular mechanisms underlying sleep are largely unknown. Through a meta-analysis of all available short-term sleep deprivation (SD) microarray data in mouse brain, we identified 91 key mouse SD-affected genes and two RBM3 isoforms showing opposite changes of expression during SD. Although most of the key SD-affected genes showed consistent changes of expression during SD across brain subregions despite their heterogeneous basal expression levels, we also identified the genes whose SD responses strongly depend upon the brain subregion. A gene regulatory network was also constructed for these genes showing that cAMP-responsive element (CRE) is one of the key cis-regulatory elements controlling SD-affected genes. We observed that SD during an animal's normal sleeping time could significantly disturb the circadian oscillation of clock genes. Surprisingly, synaptogenesis markers were significantly underexpressed in SD mice, differing from the previous findings in rat and fly. Comparing SD microarray data in mouse, rat, sparrow, and fly, we identified Egr and Nr4a gene families as conserved SD-affected genes, thus shedding new light on the origin of sleep in animals.
Age-Related Differences in Stepping Response When Stepping onto a Known Soft Surface under Dual Task Conditions
Authors: Harada Nobuko , Okada Shuichi , Negoro Shinya
Published: May 2010

The purpose of this study was to investigate whether age-related differences in stepping response influence postural control when stepping onto a known soft surface under dual task conditions. Nine young and eleven older female adults participated. First, they stepped on a flat surface while grasping an empty cup (single task), and then they repeated the task while grasping a cup filled with water (dual task). For the second experiment, they stepped on a soft surface placed in front of them while performing the above tasks. The main result was that %DIP (initiation phase as a percentage of the total stepping task time) was significantly higher for older than for young adults during the dual task on the soft surface. In conclusion, caution due to previous experience may increase attentional demand during dual tasks and lengthen the time required for central nervous processing in order to avoid losing postural stability in older adults, resulting in reductions in step velocity and step length compared to those in young adults.
Clinical Use of Cinacalcet in MEN1 Hyperparathyroidism
Authors: Moyes V. J. , Monson J. P. , Chew S. L. , Akker S. A.
Published: May 2010

Background. Management of multiple-endocrine neoplasia type 1- (MEN1-) associated hyperparathyroidism is associated with high recurrence rates and high surgical morbidity due to multiple neck explorations. Cinacalcet, a calcimimetic agent licensed for the treatment of secondary hyperparathyroidism and parathyroid carcinoma, may provide a medical alternative for the management of these complex patients.Methods. A prospective audit was performed of eight patients; three males and five females, aged 20–38 at diagnosis. Two patients commenced cinacalcet as primary treatment and six had previous surgery. Six patients had complications of hyperparathyroidism: renal calculi, renal dysfunction, and reduced bone mineral density. All were commenced on cinacalcet 30 mg bd for MEN1 associated hyperparathyroidism; doses were subsequently reduced to 30 mg od in four patients.Results. Significant reductions were observed in serum calcium and PTH measurements. Serum calcium reduced by a median of 0.35 mmol/L ( Wilcoxon Signed Rank). Serum PTH levels decreased by a median of 5.05 pmol/L (). There was no change in urine calcium. Duration ranged from 10–35 months with maintenance of control. Cinacalcet was well tolerated by six patients; one experienced nausea and one experienced diarrhoea.Conclusion. Cinacalcet is an effective and well-tolerated medical treatment for the management of complex primary hyperparathyroidism.
Fibroblast Growth Factor Receptor Signaling Dramatically Accelerates Tumorigenesis and Enhances Oncoprotein Translation in the Mouse Mammary Tumor Virus–Wnt-1 Mouse Model of Breast Cancer
Authors: Pond Adam C. , Herschkowitz Jason I. , Schwertfeger Kathryn L. , Welm Bryan , Zhang Yiqun , York Brian , Cardiff Robert D. , Hilsenbeck Susan , Perou Charles M. , Creighton Chad J. , Lloyd Richard E. , Rosen Jeffrey M.
Published: May 2010

Fibroblast growth factor (FGF) cooperates with the Wnt/β-catenin pathway to promote mammary tumorigenesis. To investigate the mechanisms involved in FGF/Wnt cooperation, we genetically engineered a model of inducible FGF receptor (iFGFR) signaling in the context of the well-established mouse mammary tumor virus–Wnt-1 transgenic mouse. In the bigenic mice, iFGFR1 activation dramatically enhanced mammary tumorigenesis. Expression microarray analysis did not show transcriptional enhancement of Wnt/β-catenin target genes but instead showed a translational gene signature that also correlated with elevated FGFR1 and FGFR2 in human breast cancer data sets. Additionally, iFGFR1 activation enhanced recruitment of RNA to polysomes, resulting in a marked increase in protein expression of several different Wnt/β-catenin target genes. FGF pathway activation stimulated extracellular signal-regulated kinase and the phosphorylation of key translation regulators both in vivo in the mouse model and in vitro in a human breast cancer cell line. Our results suggest that cooperation of the FGF and Wnt pathways in mammary tumorigenesis is based on the activation of protein translational pathways that result in, but are not limited to, increased expression of Wnt/β-catenin target genes (at the level of protein translation). Further, they reveal protein translation initiation factors as potential therapeutic targets for human breast cancers with alterations in FGF signaling. Cancer Res; 70(12); 4868–79. ©2010 AACR.
MiR-199a-3p Regulates mTOR and c-Met to Influence the Doxorubicin Sensitivity of Human Hepatocarcinoma Cells
Authors: Fornari Francesca , Milazzo Maddalena , Chieco Pasquale , Negrini Massimo , Calin George Adrian , Grazi Gian Luca , Pollutri Daniela , Croce Carlo Maria , Bolondi Luigi , Gramantieri Laura
Published: May 2010

MicroRNAs (miRNA) have rapidly emerged as modulators of gene expression in cancer in which they may have great diagnostic and therapeutic import. MicroRNA-199a-3p (miR-199a-3p) is downregulated in several human malignancies including hepatocellular carcinoma (HCC). Here, we show that miR-199a-3p targets mammalian target of rapamycin (mTOR) and c-Met in HCC cells. Restoring attenuated levels of miR-199a-3p in HCC cells led to G1-phase cell cycle arrest, reduced invasive capability, enhanced susceptibility to hypoxia, and increased sensitivity to doxorubicin-induced apoptosis. These in vitro findings were confirmed by an analysis of human HCC tissues, which revealed an inverse correlation linking miR-199a-3p and mTOR as well as a shorter time to recurrence after HCC resection in patients with lower miR-199a-3p expression. These results suggest that tactics to regulate mTOR and c-Met by elevating levels of miR-199a-3p may have therapeutic benefits in highly lethal cancers such as HCC. Cancer Res; 70(12); 5184–93. ©2010 AACR.
A Dominant Mutant Allele of the ING4 Tumor Suppressor Found in Human Cancer Cells Exacerbates MYC-Initiated Mouse Mammary Tumorigenesis
Authors: Kim Suwon , Welm Alana L. , Bishop J. Michael
Published: May 2010

ING4 is a candidate tumor suppressor gene that is deleted in 10% to 20% of human breast cancers and is mutated in various human cancer cell lines. To evaluate whether ING4 has a tumor-suppressive role in breast tissue, we overexpressed it in mouse mammary glands using a transplant system. Ectopic expression of ING4 suppressed MYC-induced mammary hyperplasia, but not tumorigenesis. In the same model system, we show that a COOH-terminal truncation mutant of ING4 found in human cancer cells could act alone to induce abnormal gland structures resembling mammary hyperplasia, which did not progress to tumors. However, coexpression of the ING4 mutant with MYC increased the penetrance and metastasis of MYC-initiated mammary tumors, giving rise to tumors with more organized acinar structures. Similarly, in vitro expression of the ING4 mutant in MCF10A mammary epithelial cells reinforced tight junctional structures. Our results provide direct functional evidence that ING4 could suppress the early stages of breast cancer and that dominant mutant alleles of ING4 might contribute to malignant development. Cancer Res; 70(12); 5155–62. ©2010 AACR.
Cbl and Human Myeloid Neoplasms: The Cbl Oncogene Comes of Age
Authors: Kales Stephen C. , Ryan Philip E. , Nau Marion M. , Lipkowitz Stanley
Published: May 2010

Cbl was originally discovered in 1989 as the cellular homolog of the v-Cbl oncogene, the transforming gene of the Cas NS-1 murine retrovirus that causes myeloid leukemia and lymphomas in mice. Cbl is a member of a family of RING finger ubiquitin ligases that negatively regulate signaling by tyrosine kinases and that function as adaptor proteins to regulate signaling positively. Until the past 2 years, there was little evidence that Cbl proteins were involved in human malignancies. Recent publications have shown homozygous mutations in Cbl in human myeloid neoplasms. Although in vitro and animal transformation models suggested that mutant forms of Cbl acted as an oncogene, the cellular role suggested that the protein could serve as a tumor suppressor gene. The recent data begin to reconcile this paradox as the loss of ubiquitin ligase function (the tumor suppressor function) is coupled to the maintenance of the positive signaling function (the oncogene function). These data also provide insight into potential therapeutic approaches to myeloid disorders harboring Cbl mutations. Cancer Res; 70(12); 4789–94. ©2010 AACR.
Angiopoietin-2 Interferes with Anti-VEGFR2–Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas
Authors: Chae Sung-Suk , Kamoun Walid S. , Farrar Christian T. , Kirkpatrick Nathaniel D. , Niemeyer Elisabeth , de Graaf Annemarie M.A. , Sorensen A. Gregory , Munn Lance L. , Jain Rakesh K. , Fukumura Dai
Published: May 2010

Purpose: In brain tumors, cerebral edema is a significant source of morbidity and mortality. Recent studies have shown that inhibition of vascular endothelial growth factor (VEGF) signaling induces transient vascular normalization and reduces cerebral edema, resulting in a modest survival benefit in glioblastoma patients. During anti-VEGF treatment, circulating levels of angiopoietin (Ang)-2 remained high after an initial minor reduction. It is not known, however, whether Ang-2 can modulate anti-VEGF treatment of glioblastoma. Here, we used an orthotopic glioma model to test the hypothesis that Ang-2 is an additional target for improving the efficacy of current anti-VEGF therapies in glioma patients.

Experimental Design: To recapitulate high levels of Ang-2 in glioblastoma patients during anti-VEGF treatment, Ang-2 was ectopically expressed in U87 glioma cells. Animal survival and tumor growth were assessed to determine the effects of Ang-2 and anti–VEGF receptor 2 (VEGFR2) treatment. We also monitored morphologic and functional vascular changes using multiphoton laser scanning microscopy and immunohistochemistry.

Results: Ectopic expression of Ang-2 had no effect on vascular permeability, tumor growth, or survival, although it resulted in higher vascular density, with dilated vessels and reduced mural cell coverage. On the other hand, when combined with anti-VEGFR2 treatment, Ang-2 destabilized vessels without affecting vessel regression and compromised the survival benefit of VEGFR2 inhibition by increasing vascular permeability. VEGFR2 inhibition normalized tumor vasculature whereas ectopic expression of Ang-2 diminished the beneficial effects of VEGFR2 blockade by inhibiting vessel normalization.

Conclusion: Cancer treatment regimens combining anti-VEGF and anti-Ang-2 agents may be an effective strategy to improve the efficacy of current anti-VEGF therapies. Clin Cancer Res; 16(14); 3618–27. ©2010 AACR.
Development of Autoantibody Signatures as Novel Diagnostic Biomarkers of Non–Small Cell Lung Cancer
Authors: Wu Lingling , Chang Wenjun , Zhao Jinfeng , Yu Yongwei , Tan Xiaojie , Su Tong , Zhao Lijun , Huang Shengdong , Liu Shiyuan , Cao Guangwen
Published: May 2010

Purpose: To select autoantibody signatures as noninvasive biomarkers of non–small cell lung cancer (NSCLC).

Experimental Design: A phage cDNA expression library was constructed with fresh samples from 30 lung cancer patients and biopanned using serum pools of 10 NSCLC patients and 10 healthy controls. A six–phage peptide detector was discovered by two-step immunoscreenings and was validated in an independent set of 90 NSCLC patients and 90 matched healthy controls, 30 NSCLC patients with chemotherapy, and 12 chronic obstructive pulmonary disease (COPD) patients. The expression of a peptide target was validated by using immunohistochemistry. Factors affecting NSCLC-related death were evaluated by Cox regression analysis.

Results: Six phage peptide clones showing higher seroreactivity than others in 30 NSCLC patients were selected for diagnostic validation. The six–phage peptide detector was able to discriminate between NSCLC patients and healthy controls with a sensitivity and specificity of >92%, and had similar validity for indicating NSCLC at early stage. The seroreactivity of the six phage peptides was significantly higher in the NSCLC patients than in those with chemotherapy and the COPD patients, respectively. Of the six phage peptides, one encoded a peptide showing 100% homology to olfactomedin 1. Expression of olfactomedin 1 protein was significantly higher in lung adenocarcinoma than in lung cancer of other histologic types and normal lung tissues. The autoantibody signature was not associated with the prognosis of the NSCLC patients.

Conclusions: The six–phage peptide detector stands out as promising diagnostic biomarkers for NSCLC, unlikely for NSCLC relapse after chemotherapy. Olfactomedin 1 may be a novel target of lung adenocarcinoma. Clin Cancer Res; 16(14); 3760–8. ©2010 AACR.
Activated Phosphoinositide 3-Kinase/AKT Signaling Confers Resistance to Trastuzumab but not Lapatinib
Authors: O'Brien Neil A. , Browne Brigid C. , Chow Lucy , Wang Yuhua , Ginther Charles , Arboleda Jane , Duffy Michael J. , Crown John , O'Donovan Norma , Slamon Dennis J.
Published: May 2010

Trastuzumab and lapatinib provide clinical benefit to women with human epidermal growth factor receptor 2 (HER)–positive breast cancer. However, not all patients whose tumors contain the HER2 alteration respond. Consequently, there is an urgent need to identify new predictive factors for these agents. The aim of this study was to investigate the role of receptor tyrosine kinase signaling and phosphoinositide 3-kinase (PI3K)/AKT pathway activation in conferring resistance to trastuzumab and lapatinib. To address this question, we evaluated response to trastuzumab and lapatinib in a panel of 18 HER2-amplified cell lines, using both two- and three-dimensional culture. The SUM-225, HCC-1419, HCC-1954, UACC-893, HCC-1569, UACC-732, JIMT-1, and MDA-453 cell lines were found to be innately resistant to trastuzumab, whereas the MDA-361, MDA-453, HCC-1569, UACC-732, JIMT-1, HCC-202, and UACC-893 cells are innately lapatinib resistant. Lapatinib was active in de novo (SUM-225, HCC-1419, and HCC-1954) and in a BT-474 cell line with acquired resistance to trastuzumab. In these cells, trastuzumab had little effect on AKT phosphorylation, whereas lapatinib retained activity through the dephosphorylation of AKT. Increased phosphorylation of HER2, epidermal growth factor receptor, HER3, and insulin-like growth factor IR correlated with response to lapatinib but not trastuzumab. Loss of PTEN or the presence of activating mutations in PI3K marked resistance to trastuzumab, but lapatinib response was independent of these factors. Thus, increased activation of the PI3K/AKT pathway correlates with resistance to trastuzumab, which can be overcome by lapatinib. In conclusion, pharmacologic targeting of the PI3K/AKT pathway may provide benefit to HER2-positive breast cancer patients who are resistant to trastuzumab therapy. Mol Cancer Ther; 9(6); 1489–502. ©2010 AACR.
Oligodeoxyribozymes That Cleave β-Catenin Messenger RNA Inhibit Growth of Colon Cancer Cells via Reduction of β-Catenin Response Transcription
Authors: Choi Bo-Ra , Gwak Jungsug , Kwon Hyun-Mi , Oh Sangtaek , Kim Kwang Pyo , Choi Woo-Hyung , Cho Yo-Han , Kim Dong-Eun
Published: May 2010

Abnormal regulation of Wnt/β-catenin signaling followed by increased levels of the β-catenin protein have been identified in enhanced cellular proliferation and development of colon polyps and cancers. To inhibit β-catenin gene expression in colon cancer cells, RNA-cleaving oligodeoxyribozyme (DNAzyme) was employed to destroy the β-catenin mRNA. We designed a strategy to identify the cleavage sites in β-catenin RNA with a pool of random sequences from a DNAzyme library and identified four potential DNAzyme-working sites. DNAzymes were constructed for the selected target sites and were tested for the ability to cleave β-catenin RNA. When introduced into the cells, the selected DNAzymes decreased the expression of β-catenin significantly as well as its downstream gene, cyclin D1. Additionally, we designed short hairpin RNA that targets the same cleavage site for the selected DNAzyme. The designed short hairpin RNA also inhibited β-catenin gene expression in colon cancer cells. Our studies show that RNA-cleaving DNAzymes and RNA interference targeted to β-catenin significantly reduced β-catenin–dependent gene expression, resulting in inhibition of colon cancer cell growth. These results indicate that the functional antisense oligonucleotides directed against β-catenin might have potential as a therapeutic intervention to treat colon cancer. Mol Cancer Ther; 9(6); 1894–902. ©2010 AACR.
Successful Treatment of Castleman's Disease with Interleukin-1 Receptor Antagonist (Anakinra)
Authors: El-Osta Hazem , Janku Filip , Kurzrock Razelle
Published: May 2010

Castleman's disease (CD) is a very rare lymphoproliferative disorder whose underlying pathophysiology is not fully understood and for which no standard treatment exists. Because interleukin-1 (IL-1) might promote the production of interleukin-6 (IL-6), a key pathogenic factor for the disease, we hypothesized that blocking the interleukin-1 receptor would be a useful therapy for CD. We report the case of a 61-year-old woman with CD who had undergone multiple treatments, including cladribine, rituximab, steroids, etanercept, and anti-IL-6 monoclonal antibody, and whose disease was refractory to all of these treatments. She was started on the recombinant IL-1 receptor antagonist, Anakinra, at a subcutaneous dose of 100 mg daily. Within one week, her fatigue and anorexia markedly improved, and her laboratory abnormalities, including anemia, thrombocytosis, leukocytosis, and elevated markers of inflammation, all resolved. Our observation suggests that Anakinra may be an attractive therapeutic approach for refractory multicentric CD. Mol Cancer Ther; 9(6); 1485–8. ©2010 AACR.
The Deubiquitinating Enzyme USP26 Is a Regulator of Androgen Receptor Signaling
Authors: Dirac Annette M.G. , Bernards René
Published: May 2010

The androgen receptor (AR) is a member of the nuclear receptor superfamily and is essential for male sexual development and maturation, as well as prostate cancer development. Regulation of AR signaling activity depends on several posttranslational modifications, one of these being ubiquitination. We screened a short hairpin library targeting members of the deubiquitination enzyme family and identified the X-linked deubiquitination enzyme USP26 as a novel regulator of AR signaling. USP26 is a nuclear protein that binds to AR via three important nuclear receptor interaction motifs, and modulates AR ubiquitination, consequently influencing AR activity and stability. Our data suggest that USP26 assembles with AR and other cofactors in subnuclear foci, and serves to counteract hormone-induced AR ubiquitination, thereby contributing to the regulation of AR transcriptional activity. Mol Cancer Res; 8(6); 844–54. ©2010 AACR.
Identification of Genes Correlated with Early-Stage Bladder Cancer Progression
Authors: Stone Randolph , Sabichi Anita L. , Gill Jennifer , Lee I-ling , Adegboyega Patrick , Dai Michael S. , Loganantharaj Raja , Trutschl Marjan , Cvek Urska , Clifford John L.
Published: May 2010

Transitional cell carcinoma (TCC) of the bladder ranks fourth in incidence of all cancers in the developed world, yet the mechanisms of its origin and progression remain poorly understood. There are also few useful diagnostic or prognostic biomarkers for this disease. We have combined a transgenic mouse model for invasive bladder cancer (UPII-SV40Tag mice) with DNA microarray technology to determine molecular mechanisms involved in early TCC development and to identify new biomarkers for detection, diagnosis, and prognosis of TCC. We have identified genes that are differentially expressed between the bladders of UPII-SV40Tag mice and their age-matched wild-type littermates at 3, 6, 20, and 30 weeks of age. These are ages that correspond to premalignant, carcinoma in situ, and early-stage and later stage invasive TCC, respectively. Our preliminary analysis of the microarray data sets has revealed ∼1,900 unique genes differentially expressed (≥3-fold difference at one or more time points) between wild-type and UPII-SV40Tag urothelium during the time course of tumor development. Among these, there were a high proportion of cell cycle regulatory genes and a proliferation signaling genes that are more strongly expressed in the UPII-SV40Tag bladder urothelium. We show that several of the genes upregulated in UPII-SV40Tag urothelium, including RacGAP1, PCNA, and Hmmr, are expressed at high levels in superficial bladder TCC patient samples. These findings provide insight into the earliest events in the development of bladder TCC as well as identify several promising early-stage biomarkers. Cancer Prev Res; 3(6); 776–86. ©2010 AACR.
Polymorphism C in the Serotonin Transporter Gene in Depression-Free Elderly Patients with Vascular Dementia
Authors: Seripa Davide , Matera Maria Giovanna , D’Onofrio Grazia , Sancarlo Daniele , Bizzarro Alessandra , Cascavilla Leandro , Paris Francesco , Gravina Carolina , Bonghi Loriana , Capurso Cristiano , Solfrizzi Vincenzo , Daniele Antonio , Masullo Carlo , Panza Francesco , Pilotto Alberto
Published: May 2010

Background: Genotypes of the solute carrier family 6 (neurotransmitter transporter, serotonin) member 4 (SLC6A4) have been variously associated with depression, obsessive-compulsive disorder, memory impairment, and anxiety. Less clear are data regarding their association with severe dementia, in particular with vascular dementia (VaD). Aims: To evaluate the possible involvement of different SLC6A4 genotypes/haplotypes in VaD. Methods: The analysis of the 3 markers rs3813034, rs140701 and rs4795541 spanning the SLC6A4 locus was made in 541 consecutive patients clinically diagnosed as having VaD (n = 372) or no cognitive impairment (n = 169) attending a geriatric ward. A community-dwelling sample of 353 healthy subjects, as a reference for the genetic frequencies in the recruitment area, was also included in the study. All patients and subjects were free from any symptoms of depression, obsessive-compulsive disorder and anxiety. A complete neuroimaging documentation was available for all patients. Results: No important differences were observed in genotype distribution across the study groups. Similarly, no important differences were observed in haplotype distribution when a 3-point analysis was made. Conclusion: Our findings suggest that polymorphism C in the promoter region of the SLC6A4 gene plays a minor role, if any, in the pathogenesis of VaD.
Prevalence and Clinical Significance of Epileptiform EEG Discharges in a Large Memory Clinic Cohort
Authors: Liedorp Maarten , Stam Cornelis J. , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Scheltens Philip
Published: May 2010

Background: Although EEG is not considered as standard in memory clinics, evidence indicates that epileptiform discharges are of value in diagnosing cognitive complaints as epilepsy. Objective: To determine prevalence and significance of epileptiform discharges in a memory clinic. Methods: 1,674 consecutive patients underwent routine EEGs [mean age 66 years, diagnoses: Alzheimer disease (AD; n = 510), other dementia (n = 193), mild cognitive impairment (MCI; n = 225), subjective complaints (n = 368), and other disorders (n = 378)]. Database statistics, charts and EEG reports were reviewed. Results:Epileptiform discharges were present in 42 (3%) patients, of which 60% lacked clinical seizures. All discharges were focal and predominantly temporally localized. Epileptiform activity was not associated with a dementia diagnosis (2% in AD and 1% in other dementia vs. 2% in MCI, 2% in subjective complaints and 5% in other disorders, p = 0.07) or with lower Mini-Mental State Examination scores (p = 0.69). Two (diagnoses: AD, vascular dementia) of 20 patients with epileptiform activity without clinical seizures developed first seizures after 2 years. Conclusion: In a memory clinic cohort, epileptiform discharges are rare, nonspecific and indicate a moderate risk of first-ever seizures in demented patients. These findings should be taken into account when routinely evaluating memory clinic patients with EEG.