bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic effects of hyperoxic ventilation during shock
Authors: BITTERMAN HAIM
Published: January 2011

Decreased availability of oxygen to metabolizing cells is a major feature of circulatory shock that leads to tissue damage and multiple organ dysfunctions. A wish to alleviate tissue hypoxia underlies the common clinical use of hyperoxic ventilation in shock. Yet, this straightforward approach is met by skepticism that is based on the potential pro‐inflammatory effects of hyperoxia and the acknowledged roles of reactive oxygen species and oxidative stress in tissue injury. A steadily growing body of experimental data indicates that hyperoxia exerts an extensive profile of physiologic and pharmacologic effects that improve tissue oxygenation, exert anti‐inflammatory and antibacterial effects, augment tissue repair mechanisms, and may also decrease oxidative stress during shock. The currently available preclinical information on the benefits of early use of safe regimens of hyperoxic ventilation alone or in combination with other commonly employed modalities sets the stage for renewal of careful clinical evaluation of oxygen therapy in resuscitation of circulatory shock.
Theoretical and Interpretation Challenges to Using the Author Affiliation Index Method to Rank Journals
Authors: Agrawal Vijay K. , Agrawal Vipin , Rungtusanatham M.
Published: January 2011

We formally review the Author Affiliation Index (AAI) method as originally conceived by David Harless and Robert J. Reilly from the Economics Department at the Virginia Commonwealth University School of Business and as subsequently developed and interpreted by Gorman and Kanet in their 2005 article. Through this formal review, we first highlight and discuss two important informational inputs that can impact the stability of the AAI scores for journals in any given set of to‐be‐evaluated journals. We then identify and challenge interpretations related to these scores (one theoretical, one statistical) offered by Gorman and Kanet that result in misleading conclusions about journal quality and that may potentially motivate inappropriate editorial behavior. For important professional decisions of hiring, performance evaluation, promotion, and tenure, we conclude by cautioning against sole reliance on the AAI method for ranking journals and against exclusive interpretation of the score computed via the AAI method as an indicator of journal quality.
Linking Task Conditions to Physiology and Judgment Errors in RM Systems
Authors: Bendoly Elliot
Published: January 2011

In models of optimal decision making, assumptions about managerial behavior are often made with the hope that the prescriptions offered by these models will be effective in practice, even if actual behavior occasionally strays from these assumptions. However, recent revenue management (RM) research has demonstrated what appear to be systematic deviations from normative models of decision making. These deviations can even be observed in relatively simple RM contexts. We suggest that technical errors in capacity allocation decisions are linked to issues such as arousal and stress associated with state conditions of RM tasks. Our study goes beyond existing findings by considering behavioral phenomena in concurrent task settings, where the decision maker is faced with managing decisions for more than one product or service. Physiological measures of eye dilation and blink rate are used as markers of arousal and stress in subjects engaged in RM tasks. Our analysis shows that physiological responses are indeed associated with both the state conditions of RM tasks and the number of capacity blocks managed concurrently by an individual. Deviations from modeled decision making appear to be significantly dependent upon these physiological responses. We conclude with a discussion of implications for further research and practice.
Streptococcus anginosusl‐cysteine desulfhydrase gene expression is associated with abscess formation in BALB/c mice
Authors: Takahashi Y. , Yoshida A. , Nagata E. , Hoshino T. , Oho T. , Awano S. , Takehara T. , Ansai T.
Published: January 2011

Streptococcus anginosus, an anginosus group bacterium, is frequently isolated from odontogenic abscesses, and is the oral bacterium that is primarily responsible for producing hydrogen sulfide from l‐cysteine through the action of its l‐cysteine desulfhydrase (βC‐S lyase) enzyme. However, the relationship between its production of hydrogen sulfide and abscess formation has not been investigated. To elucidate the etiological role of hydrogen sulfide in abscess formation, we initially measured, using specific primers, expression of the lcd gene, which encodes βC‐S lyase, in the pus of abscesses that formed in BALB/c mice following subcutaneous injection of S. anginosus into the dorsa. Expression of lcd was >15‐fold higher when l‐cysteine was present than when it was absent. A mouse virulence assay revealed that the mean diameter of abscesses caused by S. anginosus FW73 plus l‐cysteine was greater than that of abscesses caused by S. anginosus FW73 in the absence of l‐cysteine. These findings demonstrate that the lcd gene of S. anginosus is upregulated in mouse abscesses and that hydrogen sulfide, the product of a reaction catalyzed by βC‐S lyase, plays an etiological role in odontogenic abscess formation.
Improved Discrete Ordinates Method for Ray Effects Mitigation
Authors: Huang Zhi-Feng , Zhou Huai-Chun , Hsu Pei-feng
Published: January 2011

A new and improved method based on the concept of discrete ordinates scheme with infinitely small weights (DOS+ISW) is developed for modeling radiative heat transfer in three-dimensional participating media. To demonstrate the effectiveness of the method in mitigating ray effects, the ray effects caused by (1) abrupt step changes in the boundary conditions and (2) the stepwise variation of the medium emissive power are considered. In this work, angular quadrature sets with large number of discrete ordinate directions are chosen to mitigate ray effects while at the same time keeping the computational time increase to a minimum. Comparing with the conventional discrete ordinates method, the difference is that intensities in these directions are calculated by DOS+ISW method. Intensity with fine directional resolution calculated by this method is validated by comparing with that of reverse Monte Carlo method. The large number of discrete ordinate directions used in the new method becomes computationally prohibitive in the conventional discrete ordinates method due to the increased computer memory and computation time requirements.
Global Spectral Methods in Gas Radiation: The Exact Limit of the SLW Model and Its Relationship to the ADF and FSK Methods
Authors: Solovjov V. P. , Webb B. W.
Published: January 2011

The exact form of the spectral line weighted-sum-of-gray-gases (SLW) model is developed as a limiting case of the classical SLW method when the number of gray gases in the classical model approaches infinity. Solutions of the exact SLW radiative transfer equation are obtained in the case of isothermal media. It is demonstrated that the accuracy of the exact SLW method is limited only by the accuracy of the absorption-line blackbody distribution function (ALBDF) correlations used for the characterization of the absorption spectrum. This work also theoretically and rigorously demonstrates for the first time the relationship among the SLW, absorption distribution function (ADF), and full spectrum k-distribution (FSK) models. The theoretical foundation is laid for the extension of the exact method in the case of nonisothermal media.
Twelve Degree of Freedom Baby Humanoid Head Using Shape Memory Alloy Actuators
Authors: Tadesse Yonas , Hong Dennis , Priya Shashank
Published: January 2011

A biped mountable robotic baby head was developed using a combination of Biometal fiber and Flexinol shape memory alloy actuators (SMAs). SMAs were embedded in the skull and connected to the elastomeric skin at control points. An engineered architecture of the skull was fabricated, which incorporates all the SMA wires with 35 routine pulleys, two firewire complementary metal-oxide semiconductor cameras that serve as eyes, and a battery powered microcontroller base driving circuit with a total dimension of 140×90×110 mm3. The driving circuit was designed such that it can be easily integrated with a biped and allows programming in real-time. This 12DOF head was mounted on the body of a 21DOF miniature bipedal robot, resulting in a humanoid robot with a total of 33DOFs. Characterization results on the face and associated design issues are described, which provides a pathway for developing a humanlike facial anatomy using wire-based muscles. Numerical simulation based on SIMULINK was conducted to assess the performance of the prototypic robotic face, mainly focusing on the jaw movement. The nonlinear dynamics model along with governing equations for SMA actuators containing transcendental and switching functions was solved numerically and a generalized SIMULINK model was developed. Issues related to the integration of the robotic head with a biped are discussed using the kinematic model.
Metamodel-Based Optimization for Problems With Expensive Objective and Constraint Functions
Authors: Kazemi Moslem , Wang G. Gary , Rahnamayan Shahryar , Gupta Kamal
Published: January 2011

Current metamodel-based design optimization methods rarely deal with problems of not only expensive objective functions but also expensive constraints. In this work, we propose a novel metamodel-based optimization method, which aims directly at reducing the number of evaluations for both objective function and constraints. The proposed method builds on existing mode pursuing sampling method and incorporates two intriguing strategies: (1) generating more sample points in the neighborhood of the promising regions, and (2) biasing the generation of sample points toward feasible regions determined by the constraints. The former is attained by a discriminative sampling strategy, which systematically generates more sample points in the neighborhood of the promising regions while statistically covering the entire space, and the latter is fulfilled by utilizing the information adaptively obtained about the constraints. As verified through a number of test benchmarks and design problems, the above two coupled strategies result in significantly low number of objective function evaluations and constraint checks and demonstrate superior performance compared with similar methods in the literature. To the best of our knowledge, this is the first metamodel-based global optimization method, which directly aims at reducing the number of evaluations for both objective function and constraints.
Trapping in GdSiO high-k films
Authors: Rao R. , Simoncini R. , Gottlob H. D. B. , Schmidt M. , Irrera F.
Published: January 2011

In this article, the authors systematically characterized TiN/GdSiO/SiO2/Si metal oxide semiconductor capacitors from the point of view of charge trapping. Charge trapping was investigated measuring the flatband voltage with the pulsed capacitance-voltage (C-V) technique, in condition of injection from gate and substrate. As a result, a bell shaped curve of the flatband shift versus trapping time was found, with a turn-around at 100–200 μs. This was explained as the concomitant of transient phenomena due to a charge of opposite polarity starting from the two different interfaces of the high-k film. This study was possible only because of the pulsed C-V technique. At long times, trapping has always shown a logarithmic trend and the kinetics of trapping is linearly dependent on the applied voltage. Finally, dc and pulsed stress were performed at voltages of interest for logic applications.
Rare-earth oxide/TiN gate stacks on high mobility strained silicon on insulator for fully depleted metal-oxide-semiconductor field-effect transistors
Authors: Özben E. Durğun , Lopes J. M. J. , Nichau A. , Lupták R. , Lenk S. , Besmehn A. , Bourdelle K. K. , Zhao Q. T. , Schubert J. , Mantl S.
Published: January 2011

We demonstrate the integration of TbScO3, LaScO3, and LaLuO3 as alternative gate oxides for fully depleted silicon on insulator (SOI) and strained SOI metal-oxide-semiconductor field-effect transistors (MOSFETs) with equivalent oxide thicknesses of 2.8, 2.4, and 1.55 nm, respectively. Silicate formation at the high-κ/Si interface was studied by x-ray photoelectron spectroscopy. Electrical investigations revealed good transistor performance with these novel gate oxides with permittivities in the range of 26–32 and TiN as a metal gate. Steep inverse subthreshold slopes of 72 mV/dec, high Ion/Ioff ratios over 108, and a low density of interface states of ≈5×1011 (eV cm2)−1 were achieved. MOSFETs on SOI substrates show good low field electron mobilities of 180, 183, and 188 cm2/V s for all investigated oxides. For devices on strained SOI the electron mobility was improved by a factor of 2. The measured mobilities are close to those of devices with HfO2 as gate dielectric, while offering better electrostatic control due to their higher permittivities.
Effect of gate capping configurations and silicon-on-insulator thickness with external stresses on partially depleted metal-oxide-semiconductor field-effect transistors
Authors: Chang Wen-Teng , Lin Jian-An , Wang Chih-Chung , Yeh Wen-Kuan
Published: January 2011

Silicon nitride gate capping by contact etch-stop layer (CESL) was used in this study to induce high and low tensile and compressive stresses on 50-, 70-, and 90-nm-thick silicon-on-insulator (SOI) n-/p-metal-oxide-semiconductor field-effect transistors. The devices with thicker SOI show a higher interface state, particularly the highly strained devices, although they exhibit higher transconductance. The transconductances of different CESL configurations are sensitive to the tSOI effect, but the transconductances of different tSOI are less sensitive to external compressive stress compared with those of CESL configurations. The CESL-induced compressive devices show higher piezoresistive coefficients than the tensile CESL devices, yielding an external stress of up to about 45.7 MPa for both longitudinal and transverse configurations. This probably results from nonlinear stress-strain relations on the CESL-induced strained channel.
SPATIALLY CHAOTIC BIFURCATIONS OF AN ELASTIC WEB OF LINKS
Authors: KOCSIS ATTILA , NÉMETH RÓBERT K. , KÁROLYI GYÖRGY
Published: January 2011

Spatially chaotic bifurcations of an elastic web of links are investigated. We numerically construct the global bifurcation diagrams uniquely describing the buckled states, and show that the exponential growth of the number of equilibrium branches with the size of the web indicates spatial chaos. The types of bifurcations from the trivial equilibrium branch are also determined, and we show that cusp catastrophes of any order can appear. This observation relates the buckling of the elastic web of links to the buckling of rods with finite shear and infinite bending and normal stiffness.
BIFURCATIONS IN A STOCHASTIC BUSINESS CYCLE MODEL
Authors: HUANG DONGWEI , WANG HONGLI , YI YINGFEI
Published: January 2011

We introduce a stochastic business cycle model and study the underlying stochastic Hopf bifurcations with respect to probability densities at different parameter values. Our analysis is based on the calculation of the largest Lyapunov exponent via multiplicative ergodic theorem and the theory of boundary analysis for quasi-nonintegrable Hamiltonian systems. Some numerical simulations of the model are performed.
DETERMINING THE CHARACTERISTICS OF A SELF-EXCITED OSCILLATION IN ROTOR/STATOR SYSTEMS FROM THE INTERACTION OF LINEAR AND NONLINEAR NORMAL MODES
Authors: JIANG JUN , WU ZHIQIANG
Published: January 2011

In this paper, the linear and nonlinear modes of the unforced coupled rotor/stator system from a general rotor/stator model, which accounts for both the dynamics of the rotor and the stator as well as the friction and the deformation at the contact surfaces, are derived. The bifurcations of the nonlinear normal modes are analyzed based on the constrained bifurcation theory with the linear normal modes as the constraints. Then, the existence boundaries and the backward whirl frequencies of dry friction backward whirl — a hazardous self-excited oscillation in rotor/stator systems — of this model are derived. It is found by analysis that many inherent characteristics of the dry friction backward whirl can be derived from the information of the interaction of the linear and the nonlinear normal modes of the coupled rotor/stator system, such as the number of existence regions and their position relationship, the minimal friction on the contact surfaces that may induce the self-excited oscillation, the upper limits of the backward whirl frequencies of the response, and more. This study has well demonstrated the dominant role of the interaction of the linear and the nonlinear normal modes in deciding the characteristics of some nonlinear dynamical behaviors.
Synthesis and fluorescence studies of porphyrin appended 1,3,4-oxadiazoles
Authors: Chandra Shekar K.P. , Mishra Bhupendra , Kumar Anil , Phukan S. , Mitra S. , Kumar Dalip
Published: January 2011

A modular synthetic approach for preparing a family of porphyrin appended 1,3,4-oxadiazoles 9 is described. The porphyrin hydrazides are reacted with aryl aldehydes in presence of Yb(OTf)3 as catalyst to give porphyrin hydrazones 8 which are then cyclized to porphyrin appended 1,3,4-oxadiazoles 9 using iodobenzene diacetate. Photophysical studies in CHCl3 solvent shows that the electronic structure of the porphyrin chromophore is not greatly perturbed by the incorporation of the oxadiazole group onto the meso-phenyl ring. Efficient quenching of porphyrin fluorescence was observed in 9g with a pyridinium moiety.
Surface Plasmon-Induced Band Gap in the Photocurrent Response of Organic Solar Cells
Authors: Sabat Ribal Georges , Santos Marcos Jose Leite , Rochon Paul
Published: January 2011

A 260 nm layer of organic bulk heterojunction blend of the polymer poly(3-hexylthiophene) (P3HT) and the fullerene [6,6]-phenyl C61-butyric (PCBM) was spin-coated in between aluminum and gold electrodes, respectively, on top of a laser inscribed azo polymer surface-relief diffraction grating. Angle-dependent surface plasmons (SPs) with a large band gap were observed in the normalized photocurrent by the P3HT-PCBM layer as a function of wavelength. The SP-induced photocurrents were also investigated as a function of the grating depth and spacing.
Optimization Shape of Variable Capacitance Micromotor Using Differential Evolution Algorithm
Authors: Ketabi A. , Navardi M. J.
Published: January 2011

A new method for optimum shape design of variable capacitance micromotor (VCM) using Differential Evolution (DE), a stochastic search algorithm, is presented. In this optimization exercise, the objective function aims to maximize torque value and minimize the torque ripple, where the geometric parameters are considered to be the variables. The optimization process is carried out using a combination of DE algorithm and FEM analysis. Fitness value is calculated by FEM analysis using COMSOL3.4, and the DE algorithm is realized by MATLAB7.4. The proposed method is applied to a VCM with 8 poles at the stator and 6 poles at the rotor. The results show that the optimized micromotor using DE algorithm had higher torque value and lower torque ripple, indicating the validity of this methodology for VCM design.
Effect of EDTA on the Growth Kinetics and Structural and Optical Properties of KDP Crystal
Authors: Rahman Anisur , Podder Jiban
Published: January 2011

The solubility of potassium dihydrogen phosphate (KDP) was determined for five different temperatures. Metastable zone width of aqueous solutions of KDP saturated at different temperatures was determined by nucleation method in pure form and adding a well-known chelating agent ethylenediaminetetraacetic acid (0.5 mol% EDTA). The induction period was measured, experiments were performed at selected degrees of supersaturation (), and the critical nucleation parameters like interfacial energy () were calculated, based on the classical theory of nucleation. The structural and optical properties of the grown crystals have been investigated. FTIR analysis has been carried out to characterize the grown crystals. Band gap has been calculated from transmission spectra.
Administration of a Decoction of Sucrose‐ and Polysaccharide‐RichRadix Astragali (Huang Qi) Ameliorated Insulin Resistance and Fatty Liver but Affected Beta‐Cell Function in Type 2 Diabetic Rats
Authors: Juan Yi-Chen , Kuo Yao-Haur , Chang Chia-Chuan , Zhang Li-Jie , Lin Yan-Yu , Hsu Chia-Yun , Liu Hui-Kang
Published: January 2011

The current investigation attempted to confirm the beneficial actions of a chemically characterized Radix Astragali decoction (AM‐W) against type 2 diabetic (T2D) Sprague‐Dawley (SD) rats. Using a case/control design, after 2 months of treatment with AM‐W (500 mg/kg, daily i.p.) in T2D rats therapeutic outcomes were compared. Sucrose and Astragalus polysaccharides (ASPs) were shown to exist in nearly equal proportions in AM‐W. Body weight loss, an improvement in insulin sensitivity, and an attenuation of fatty liver after AM‐W administration in T2D rats were evident. Surprisingly, blood sugar, beta‐cell function, and glucose tolerance in T2D rats did not improve with AM‐W treatment. Further investigation indicated the deleterious effects of the addition of sucrose (100 and 500 μg/mL) and APSs (500 μg/mL) on glucose‐stimulated insulin secretion and viability, respectively. In conclusion, a proper administration dosage and a reduction in the sucrose content are keys to maximizing the merits of this herb.
Antimetastatic Potentials of Dioscorea nipponica on Melanoma In Vitro and In Vivo
Authors: Ho Mao-Lin , Hsieh Yih-Shou , Chen Jia-Yuh , Chen Kuo-Shuen , Chen Jia-Jing , Kuo Wu-Hsien , Lin Shu-Jiuan , Chen Pei-Ni
Published: January 2011

Recent studies have revealed pleiotropic anticancer and antiproliferative capabilities of Dioscorea nipponica Makino whereas the effect of this plant on metastasis of cancer cells has not been clearly clarified. In the present study, we extracted Dioscorea nipponica Makino with methanol (DNE1), chloroform (DNE2), ethyl acetate (DNE3), n‐butanol (DNE4), and water (DNE5). We first demonstrate that DNE3 was found to be effective in reducing the lung metastases formation by about 99.5% as compared to vehicle‐treated control animals. When a nontoxic concentration of the extract was treated directly to highly metastatic murin melanoma cells (B16F10) and human melanoma cells (A2058) in vitro, it exerted a dose‐dependent inhibitory effect on the invasion (P < .001), motility (P < .001), secretion of MMPs (P < .001), and u‐PA (P < .001) of both cell lines. To investigate the possible mechanisms involved in these events, we performed western blot analysis to find that DNE inhibited phosphorylation of Akt. A treatment with DNE3 to B16F10 cells also inhibited the activation of NF‐κB and increased the expression of IkappaB. Taken together, these findings suggested that DNE3 could reduce the metastasis of melanoma cells, thereby constituting an adjuvant treatment for metastasis control.
Loss of the NHE2 Na+/H+ Exchanger in Mice Results in Dilation of Folliculo‐Stellate Cell Canaliculi
Authors: Miller Marian L. , Andringa Anastasia , Schultheis Patrick J. , Shull Gary E.
Published: January 2011

Genetic ablation of the NHE2 Na+/H+ exchanger causes gastric achlorhydria, absorptive defects in kidney and colon, and low fertility. Here we show that NHE2 is expressed in the pituitary, with the highest mRNA expression in pars distalis and lower expression in pars intermedia. In pars distalis of NHE2‐null mice, prominent cyst‐like dilatations of folliculo‐stellate (FS) cell canaliculi developed with age, and there were increased FS cell area, accumulation of lipid in FS cell cytoplasm, redundancies in FS cell basement membrane, and other changes. The expansion of the canaliculi indicates that NHE2 is a major absorptive Na+/H+ exchanger in the luminal membranes lining the extensive network of channels formed by FS cells, which may provide a means of intrapituitary communication. The results suggest that NHE2 contributes to homeostatic regulation of the volume and composition of the canalicular fluid and may counter the secretory activity of the CFTR Cl− channel, which is known to be expressed in pituitary.
The Self-Administered Patient Satisfaction Scale for Primary Hip and Knee Arthroplasty
Authors: Mahomed N. , Gandhi Rajiv , Daltroy Lawrence , Katz J. N.
Published: January 2011

Introduction. The objective of this study was to develop a short self-report questionnaire for evaluating patient satisfaction with the outcome of hip and knee replacement surgery. Methods. This scale consists of four items focusing on satisfaction with the extent of pain relief, improvement in ability to perform home or yard work, ability to perform recreational activities, and overall satisfaction with joint replacement. This instrument does not measure satisfaction with process of care. The responses are scored on a Likert scale, with the total score ranging from 25 to 100 per question. The instrument was tested on 1700 patients undergoing primary total hip and total knee replacement surgery, evaluated preoperatively, at 12 weeks, and one year postoperatively. Psychometric testing included internal consistency, measured with Cronbach's alpha, and convergent validity, measured by correlation with changes in measures of health status between the preoperative, 12-week, and one-year evaluations. Results. The internal consistency (reliability) of the scale, measured by the Cronbach's alpha, ranged from 0.86 to 0.92. The scale demonstrated substantial ceiling effects at 1 year. The scale scores correlated modestly with the absolute SF-36 PCS and WOMAC scores (ρ=0.56–0.63 and also with the WOMAC change scores (ρ=0.38–0.46) at both 12-week and 1-year followups. Conclusions. This instrument is valid and reliable for measuring patient satisfaction following primary hip and knee arthroplasty and could be further evaluated for use with other musculoskeletal interventions.
Development and Application of MCNP5 and KENO‐VI Monte Carlo Models for the Atucha‐2 PHWR Analysis
Authors: Pecchia M. , Parisi C. , D′Auria F. , Mazzantini O.
Published: January 2011

The geometrical complexity and the peculiarities of Atucha‐2 PHWR require the adoption of advanced Monte Carlo codes for performing realistic neutronic simulations. Core models of Atucha‐2 PHWR were developed using both MCNP5 and KENO‐VI codes. The developed models were applied for calculating reactor criticality states at beginning of life, reactor cell constants, and control rods volumes. The last two applications were relevant for performing successive three dimensional neutron kinetic analyses since it was necessary to correctly evaluate the effect of each oblique control rod in each cell discretizing the reactor. These corrective factors were then applied to the cell cross sections calculated by the two‐dimensional deterministic lattice physics code HELIOS. These results were implemented in the RELAP‐3D model to perform safety analyses for the licensing process.
Abstract A12: Differential micro-RNA expression in a multistage 5-fluorouracil resistant colon cancer model
Authors: Mader Robert M. , Wieser Matthias , Berger Walter , Kalipciyan Maria , Hackl Matthias , Steger Guenther G. , Grillari Johannes
Published: January 2011

Purpose: Among small non-coding RNAs, micro-RNAs have demonstrated a variety of essential functions under both physiological and pathological conditions such as cell cycle progression, oncogenic transformation and apoptosis. Thus, we hypothesized that micro-RNAs may play a major role in cellular stress adaptation.

Methods: To attain this aim, we evaluated a multi-stage colon cancer system with increasing degrees of resistance to the antimetabolite 5-fluorouracil by i) differential expression profiling (micro-RNA arrays) and ii) subsequent validation of the candidate RNAs by quantitative PCR.

Results: Among 15 differential expressed micro-RNAs in our model system, 9 were confirmed by qPCR and selected for further investigations. Noteworthy, for every level of drug resistance (low, intermediate, and high) specific micro-RNAs were identified indicating an individual response to escalating cytotoxic stress at the molecular level. With regard to micro-RNA functions, our findings point at an involvement - if not a regulatory function - of the recognized micro-RNAs in the following processes (data from the literature): doxorubicin resistance (miR-130a), survival signaling, DNA-oriented stress, and oncogenic properties (all miR-19), epithelial-mesenchymal transition (miR-141 and miR-200), as well as invasion and metastasis (miR-10b). Some of these features are currently under investigation by transfection of the corresponding micro-RNA precursors or antagomirs in the chemoresistant model in order to assess the contribution of the identified micro-RNAs to the resistance phenotype.

Conclusions: Previous work from our team has demonstrated the orchestrated response of cancer cells to xenobiotics at the molecular level by global gene expression profiling. The investigated subclones, derived from the metastatic colon cancer cell line CCL 227, were characterized by stage dependent mRNA regulations affecting vital cellular functions such as cytoskeleton, cell-cell communication, signal transduction, cell cycle control and apoptosis. Remarkably, different degrees of chemoresistance addressed different cellular mechanisms, thus providing to the cancer cell the necessary flexibility to adapt to different levels of stress. Likewise, micro-RNAs seem to follow a similar behavior with different micro-RNA patterns reflecting the development of resistance to 5-fluorouracil. As micro-RNAs are very likely to play a decisive role in the cellular response to therapeutic stress, their regulation might offer novel starting points to understand and to oppose drug resistance. This work has been supported by the “Initiative Krebsforschung”, Austria.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):A12
Abstract A13: Selective role of iNOS reveals its negative regulatory influence on the expression of TNFR1, NF-κB and other cell survival signaling events during a P19-induced apoptosis in HL-60 cells
Authors: Malik Fayaz
Published: January 2011

P19, a semi-synthetic analog of sesquiterpene lactone ‘Parthenin’, is a promising template to develop into novel anti-cancer leads. P19 induced robust cell death in human leukemia cell lines compared to normal cells when observed after 48h treatment with IC50 of 3.5 μM in HL-60 cells to that of 35 μM in human normal gingival fibroblast cells. Mechanistic studies into HL-60 cells death after 6 h exposure to 10 μM P19 were investigated. It killed cells by apoptosis consequent to robust generation of NO through enhanced expression of iNOS. N-acetyl-L-cysteine (NAC) and s-methyl isothiourea (sMIT) suppressed apoptosis equipotently by inhibiting endogenous NO formation. P19 disrupted mitochondrial functions by altering Bax/Bcl2 ratio, cytosolic Bid loss, Drp1 over expression, Bax and cytochrome c translocation leading predominantly to caspase-9 activation. P19 also translocated AIF from mitochondria to the nucleus which may further potentiate caspases-independent cell death, because pan caspase inhibitor offered incomplete protection. On the contrary, activation of caspase-8 was augmented with concomitant selective enhanced expression of apical death receptor DR4 rather than TNFR1 and FASR. Activation of pre-executioner caspases positively regulated the activation of caspase-3 leading to PARP-1 cleavage and therefore, DNA fragmentation. Down-regulation of activator TNFR1 and transactivator PARP-1 of NF-κB with attendant decreased expression of both the subunits p50 and p65 of NF-κB argue against the plausible involvement of NF-κB as a transcription factor in the induction of iNOS. Further, P19 potently inhibited pro-survival proteins pSTAT-3 and survivin that are overtly expressed in cancer cells. The multimodal proapoptotic features of P19 raises its potential usefulness as a promising anti-cancer therapeutic.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):A13
Abstract A16: Overexpression of activin A is associated with poor prognosis in patients with oral squamous cell carcinoma and promotes the proliferation, motility and invasion of oral cancer cells.
Authors: Chang Kai-Ping , Tsai Chi-Neu
Published: January 2011

Objective: Both activin A, a member of transforming growth factor superfamily, and its inhibitor follistatin have been shown to be overexpressed in various cancers. We examined the expression of activin A and follistatin in tissue and blood samples from patients with oral squamous cell carcinoma.

Methods: The study population comprises 92 patients with oral squamous cell carcinoma. activin A and follistatin levels in tissues and sera were examined by qRT-PCR, immunohistochemistry and ELISA, respectively. Effects of activin A on oral cancer cells were investigated by trans-well migration/invasion assays and RNA interference.

Results: Overexpression of immunohistochemically detected activin A was correlated with positive N stage, poor histological differentiation, and perineural invasion (P = 0.029, 0.002, and 0.014, respectively). Statistical significant correlations between activin A and FST were observed in both mRNA and immunohistochemical expression (Pearson's correlation r = 0.507, P = 0.008 and r = 0.354 and P = 0.0005, respectively). In survival analyses, patients with oral squamous cell carcinoma whose tumors overexpressed activin A had a worse prognosis for overall survival and disease-free survival (P = 0.009 and 0.007). However, expression of follistatin in tumor was not correlated with overall survival or disease-free survival. Serum activin A and follistatin levels in 111 untreated patients were neither significantly different from those of 91 control samples nor associated with any clinicopathological manifestations. In vitro suppression of activin A expression in OC3 cells using specific interfering RNA attenuated cell proliferation, migration, and invasiveness.

Conclusion: These findings suggest that activin A overexpression in oral squamous cell carcinomas is associated with patients survival and may contribute to tumor progression and metastasis.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):A16
Abstract A19: Targeting follicle stimulating hormone receptor in postmenopausal epithelial ovarian cancer
Authors: Bose Chinmay K. , Mukhopadhyay Ashis
Published: January 2011

Objectives: Recent studies have established expression of gonadotrphin receptor especially more important Follicle Stimulating hormone Receptor (FSHR) in ovarian surface epithelium (OSE), its benign and early malignant tumours. There is no explanation as yet for such unusual finding. Hence, an extensive search of concerned literatures is made to find out the probable cause of this aberrant expression.

Materials and Methods: A systematic review of reports from MEDLINE/PUBMED was performed from May ′02 to June ′05 on mechanism of FSHR expression in OSE and ovarian cancer. Many reports were collected from journal and additional reports were perused from the reference lists of retrieved articles.

Results: The neurotrophins (NT) including nerve growth factor (NGF) are a family of related growth factors that are of major importance in the regulation of neuronal survival and differentiation. In the ovary, they can help in follicular maturation and ovulation by inducing the FSH receptor (FSHR). NTs can be implicated as the cause of this aberrant expression of FSHR in OSE. This is because unlike other factors responsible for FSHR expression NT has central action and can lower serum FSH, as is found in such ovarian cancer.

Conclusion: NGF deregulates expression of FSHR in OSE and secretion of FSH from the pituitary. This phenomenon may hold the key to the hitherto unexplained carcinogenic process of sporadic epithelial ovarian cancer.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):A19
Abstract A22: Temozolomide upregulates B7-H1 in glioma cells and promotes immunoressistance against T cells
Authors: Irvin Dwain K. , Miyamoto Shinya , Black Keith , Rentsendorj Altanchimeg
Published: January 2011

Temozolomide is widely used as the first-line chemotherapeutic agent for malignant glioma. However, it can prolong the median survival and progression-free survival in glioblastoma patients by only a few months. Recently, it has been demonstrated that multiple human tumors express B7-H1 and B7-H4, immune inhibitory transmembrane glycoproteins, including glioblastoma. It has been suggested that tumor cells utilize these proteins as a potential mechanism of immunoressistance. Therefore, we sought to determine if glioma cells up-regulate B7-H1 and B7-H4 and promotes immunoressistance in glioma cells. We show by fluorescent activated cells sorting that T98G, human glioblastoma cell line, GBM157, GBM177, primary human glioblastoma cells, and GL26, murine glioma cell line, express both B7-H1 and B7-H4. We also demonstrate that both B7-H1 and B7-H4 were significantly up-regulated in surviving T98G, GBM157, and GL26 cells after 3-day temozolomide exposure. The standardized fluorescence index of B7-H1 protein after temozolomide (1000 mM) exposure significantly increased from 1.54 to 3.07 (p =0.0021) and that of B7-H4 significantly increased from 1.99 to 3.17 (p =0.0043) in surviving T98G cells. Real-time quantitative PCR also showed significant up-regulation in B7-H1 gene expression by 4.6 times (p < 0.0001) and in B7-H4 gene expression by 2.0 times (p = 0.0398) after 3-day temozolomide (1000mM) exposure in surviving T98G cells. In order to determine if up-regulation of B7-H1 promoted immunoressistance we co-culture surviving temozolamide exposed glioma cells with either CD4+ or CD8+ T-cells and determined secreted levels of IL-10 by enzyme-linked immunofluorescence assay and T-cell apoptosis, respectively. We show that CD4+ T-cells significantly up-regulate IL-10 secretion after co-culture with surviving temozolamide exposed glioma cells and that CD8+ T-cells apoptosis is also significantly increased as compared to control GL26 glioma cells. Taken together, these results suggest that up-regulation of B7-H1 and B7-H4 in glioma cells promotes glioma immunoressistance through the up-regulation of CD4+ T-cell IL-10 secretion and CD8+ T-cell apoptosis.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):A22
Abstract A24: Low mir-200c expression correlates with an aggressive, invasive, and chemoresistant phenotype of non-small cell lung cancer
Authors: Ceppi Paolo , Mudduluru Giridhar , Kumarswamy Regalla , Rapa Ida , Giorgio Scagliotti V. , Mauro Papotti , Heike Allgayer
Published: January 2011

The development of metastasis is the main reason for cancer-related death in non-small cell lung cancer (NSCLC). Initiation of metastasis involves an increase in cell motility mediated by the loss of cell-cell adhesion caused by E-cadherin repression, in a process commonly known as epithelial-to-mesenchymal transition (EMT). A central role for microRNA-200 family members in regulating EMT has been recently indicated, but data regarding the significance of their expression in lung tumors are still unavailable. The present study investigated the expression of mir-200c in a panel of NSCLC cell lines (n=9) and found a strong inverse correlation with cell invasive potential. Forced re-introduction of mir-200c into highly invasive/aggressive NSCLC cells induced a loss of mesenchymal phenotype, by restoring E-cadherin and reducing N-cadherin expression, and inhibited in vitro cell invasion as well as in vivo metastasis formation, as evaluated by chicken embryo metastasis assay. Moreover, mir-200c overexpression restored the sensitivity towards cisplatin and cetuximab, two chemotherapeutic agents widely used in the treatments of thoracic cancers, of the drug-resistant NCI-H1299 cells. Hyper-methylation of the promoter region was found to be the mechanism behind the loss of mir-200c in invasive cells, as evaluated by 5-aza-dC treatment and methylation specific PCR. In primary tumor specimens obtained from 45 consecutively resected NSCLC patients, mir-200c expression confirmed its role in malignant tumor progression, being significantly inversely associated with a poor grade of differentiation (p=0.01) and a higher propensity to lymph node metastases (p<0.01). In conclusion, these data indicate that loss of miR-200c expression plays an important role in the initiation of an aggressive, invasive, and chemoresistant phenotype. The determination of its expression in tumors can be used for the stratification of the patients to be treated with anti-metastatic therapy.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):A24
Abstract A28: The effects of combined treatment with NF-κB inhibitors and arsenic trioxide on leukemic cell lines
Authors: Stepnik Maciej , Smok-Pieniazek Anna , Komorowska Magdalena , Arkusz Joanna
Published: January 2011

Arsenic trioxide (ATO) induces growth inhibition and apoptosis in a wide variety of cancer cell lines. Some reports indicate that this effect can be enhanced by inhibiting the activity of transcription factor NF-κB.

The aim of our study was to evaluate the efficacy of combined treatment with ATO and selected NF-κB inhibitors (sulindac, parthenolide, BAY 11-7082, MG-132 and gliotoxin) in inducing cell death of five leukemic cell lines: EL-4 mouse thymoma, Jurkat, HL-60, K562 and HPB-ALL. The cytotoxicity of the chemicals was evaluated using 72-hrs WST-1 reduction assay and apoptosis was assessed with Annexin V-FITC/propidium iodide staining (FACS).

We observed that among the inhibitors tested, gliotoxin and MG-132 when used alone showed the highest cytotoxicity on all cell lines (effective concentrations less than 1 μM). Parthenolide and BAY11-7082 induced complete death of all cell lines at the concentration of 10 μM. All four inhibitors did not potentiated the effects of ATO used at 0.5 or 1 μM. Although sulindac was the least cytotoxic compound when used alone, it showed the highest potentiating effect on ATO induced cytotoxicity on all cell lines. The response of cells to the combination was rather diverse with Jurkat and HPB-ALL cells being the most sensitive. As a rule, all cell lines treated simultaneously with ATO (1 μM) and sulindac (100 μM) showed complete decrease in viability after 72 hrs. The results with annexin V/PI staining indicated apoptosis as the main cell death mechanism. This combination had much weaker effect on the viability of healthy blood lymphocytes.

The results of our study reveal an interesting cytotoxic effect of ATO with combination with sulindac on a panel of leukemic cell lines. The work was supported by the Polish State Committee for Scientific Research (grant No PB 2806/B/PO1/2007/33).

Citation Information: Clin Cancer Res 2010;16(7 Suppl):A28
Abstract A32: Pretargeted immunoPET of CEA-expressing in intraperitoneal human colonic tumor xenografts in nude mice
Authors: Schoffelen Rafke , Sharkey Robert M. , Franssen Gerben M. , Goldenberg David M. , McBride William J. , Rossi Edmund A. , Chang Chien-Hsing , Laverman Peter , Graaf Winette T.A. , Oyen Wim J.G. , Boerman Otto C.
Published: January 2011

Objective: Radiolabeled antibodies were being developed commercially for the detection of several cancer types. However, imaging with radiolabeled antibodies require a relatively long interval between injection and imaging acquisition for adequate contrast to develop. The pretargeting method is a 2-step method: a unlabeled bsMAb with affinity for the tumor and a small radiolabeled molecule is injected, followed by the a radiolabeled compound. This aims to optimize the imaging system by specific tumor accumulation and fast blood clearance of the radiopharmacon, which allows imaging within one hour. Short-lived positron emitting radionuclides, e.g. 68Ga (half life: 68 min) match the pharmacokinetics of the small molecule. In this study, pretargeted immunoPET with a bispecific monoclonal anti-carcinoembryonic antigen (CEA) x anti-histamine-succinyl-glycine (HSG) antibody, TF2, and a radiolabeled peptide, IMP288, was compared to 18F-FDG in detecting CEA-expressing tumors in nude mice.

Methods: Groups of five BALB/c nude mice were inoculated with CEA-expressing human colonic tumor cells intraperitoneally. One group received 5 MBq 18F-FDG intravenously (i.v.). Another group received TF2 and 5 MBq 68Ga-IMP288 i.v. 16 h later. After one hour PET/CT images were acquired. One day later this was repeated vice versa. Uptake of 68Ga-IMP288 or 18F-FDG in the tumors and other dissected tissues was determined.

Results: High, specific tumor uptake of 68Ga-IMP288 (23.4 ± 7.2% ID/g) was observed, with very low accretion in the normal tissues (intestines: 0.50 ± 0.19 % ID/g; liver: 1.83 ± 0.45 % ID/g). This resulted in high tumor-to-background ratios (e.g. tumor-to-intestines 57.5 ± 22.4) and in the clear visualization of the small intra-abdominal tumor lesions (1.5–5 mm), as soon as one hour after the injection of 68Ga-IMP288. 18F-FDG localized efficiently in the tumors (8.7 ± 3.1 % ID/g), but with physiological uptake in various normal tissues (intestines: 2.15 ± 0.61 % ID/g; liver: 2.78 ± 0.52 % ID/g). The low tumor-to-background ratio (e.g. tumor-to-intestines 4.0 ± 0.9) complicated the detection of the tumors.

Conclusions: This study indicated that pretargeted immunoPET with TF2 and 68Ga-IMP288 is a specific and sensitive method for detecting colon cancer.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):A32
Abstract A37: Correlation of EGFR ligand expression with response to classical or targeted therapies in non-small cell lung cancer xenografts
Authors: Fichtner Iduna , Rolff Jana , Rivera Maria , Merk Johannes
Published: January 2011

Increased levels of the epidermal growth factor receptor (EGFR) and its cognate ligands are common in non-small cell lung cancer (NSCLC) and correlate with a poor prognosis. In the last years targeted therapies against the EGFR were developed, but results of clinical trials were rather disappointing. The identification of biomarkers in NSCLC as predictive factors for an individualized therapy is urgently needed.

Twenty six xenografts were established from fresh surgical material from NSCLC patients and characterized with regard to their sensitivity to four cytostatics (Carboplatin, Etoposide, Paclitaxel, Gemcitabine) and two EGFR-inhibitors (Cetuximab, Erlotinib). The expression of EGFR and its ligands epidermal growth factor (EGF), transforming growth factor alpha (TGFα), epiregulin and amphiregulin were examined at mRNA and protein level.

Three ligands, which bind exclusively to EGFR (EGF, TGFα and amphiregulin) showed correlations to the mRNA expression of the receptor. Also the mRNA-levels of amphiregulin and epiregulin correlated with each other. The responsiveness towards Etoposide correlated negatively with the EGF-protein (r=-0.479, P<0.05) and with the EGFR-mRNA (r=-0.663, P<0.01) expression. This could mean that the expression of the EGFR-pathway related molecules is able to protect tumor cells from the induction of apoptosis through a cytostatic drug. The response rate to Gemcitabine showed a negative correlation with the TGFα-mRNA level (r=-0.525, P<0.01). Controversially, the amphiregulin-mRNA level correlated positively with the responsiveness to Gemcitabine (r=0.553, P<0.01). A high level of TGFα-mRNA correlated with the resistance to Erlotinib (r=-0.456, P<0.05). The epiregulin-mRNA level showed a positive correlation concerning the sensitivity towards Cetuximab (r=0.476, P<0.05). High EGFR levels seem to be indicative for the resistance to Erlotinib (r=0.636, P<0.05) in squamous cell carcinomas and for the sensitivity to Cetuximab (r=-0.888, P<0.05) in adenocarcinomas.

The results of the present study showed the role of the EGFR activated pathways in the dynamics of tumor progression in NSCLC on the one hand and reflect the high level of redundancy and interrelationships of the EGFR signalling pathway on the other hand. The patient-derived NSCLC models are suitable tools for the identification of biomarkers and their regulation mechanisms in a clinically related and standardized way.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):A37