bluuebunny/crossref_metadata_2025 huggingface dataset:
On experimental determination of the random-incidence response of microphones
Authors: Barrera-Figueroa Salvador , Rasmussen Knud , Jacobsen Finn
Published: May 2007

The random-incidence sensitivity of a microphone is defined as the ratio of the output voltage to the sound pressure that would exist at the position of the acoustic center of the microphone in the absence of the microphone in a sound field with incident plane waves coming from all directions. The random-incidence correction of a number of laboratory standard microphones has been determined experimentally. Although the measurement procedure seems to be straightforward, some practical and fundamental problems arise: (i) Reflections from the mounting rig contaminate the measured frequency response, and whereas some of these reflections can be removed using a time-selective technique, others coincide with the direct impulse response and consequently cannot be removed in the time domain and thus affect the accuracy of the estimate; (ii) the accuracy of the estimate is relying on the rotational symmetry of the microphone and depends on the angular resolution. The effect of the angular resolution has been compared with the analytical solution of the scattering and diffraction around a solid sphere. Numerical calculations supplement the experimental results. Although the procedure has only been applied to laboratory standard microphones, it is not restricted to such microphones and may be applied to other types of measurement microphones.
Analysis of the performance of a particle velocity sensor between two cylindrical obstructions
Authors: van Honschoten J. W. , Yntema D. R. , Svetovoy V. B. , Dijkstra M. , Wiegerink R. J. , Elwenspoek M.
Published: May 2007

The performance of an acoustic particle velocity sensor that is placed between two cylindrical objects has been analyzed both analytically and by means of finite volume simulations on fluid dynamics. The results are compared with acoustic experiments that show a large magnification of the output signal of the particle velocity sensor due to the mounting of the sensor between two cylinders. The influences of this construction consist of an attenuation of particle velocities at frequencies below a few hertz, whereas signals in the higher frequency range are amplified, up to approximately three times (10dB) in a frequency range between 50 and 1000Hz. The theoretical analysis is based on the derivation of the stream function for the situation of two long cylinders immersed in an oscillating incompressible viscous fluid, at low Reynolds numbers. The results lead to an improved insight into the effects of viscosity and fluid flow that play a role in acoustic measurements and open the way for further optimization of the sensitivity of the sensor.
Directional loudness and binaural summation for wideband and reverberant sounds
Authors: Sivonen Ville Pekka
Published: May 2007

In an earlier investigation [Sivonen and Ellermeier, J. Acoust. Soc. Am. 119, 2965–2980 (2006)], the effect of sound incidence angle on loudness was investigated for anechoic, narrowband sounds. In the present follow-up investigation, the effect of incidence angle on loudness was investigated using wideband sounds under anechoic conditions and narrowband sounds under reverberant conditions. Five listeners matched the loudness of a sound coming from five incidence angles in the horizontal plane to that of the same sound with frontal incidence. These directional loudness matches were obtained with an adaptive, two-alternative, two-interval, forced-choice procedure. The stimuli were presented to the listeners via individual binaural synthesis. The results show that loudness depends on sound incidence angle in both experiments. The wideband and reverberant sounds, however, yielded significantly smaller directional effects than had been obtained for the same listeners when anechoic, narrowband sounds were used. When modeling the binaural summation underlying the loudness matches, a power summation of the at-ear signals yielded good predictions for all types of stimuli investigated.
Comparison of measurements and predictions of sound propagation in a valley-slope configuration in an inhomogeneous atmosphere
Authors: Renterghem T. Van , Botteldooren D. , Lercher P.
Published: May 2007

Mountainous areas form a very specific context for sound propagation: There is a particular ground effect and meteorological conditions are often extreme. In this paper, detailed sound propagation calculations are compared to noise measurements accompanied by meteorological observations. The sound source considered is road traffic along the center axis of a valley. Noise levels were measured in two cross sections, at three locations each: one on the valley floor and two on the slopes, up to 166m above the source. For the numerical calculations, the rotated Green’s function parabolic equation method is used, taking into account the undulation of the terrain and an inhomogeneous atmosphere. Typical parameters of this method were optimized for computational efficiency. Predictions agree with measurements to within 3dBA up to propagation distances of 1km, in windless conditions. The calculations further show that the terrain profile is responsible for an increase in sound pressure level at distant, elevated points up to 30dBA compared to a flat ground situation. Complex temperature profiles account for level changes between −3dBA and +10dBA relative to a homogeneous atmosphere. This study shows that accurate sound level prediction in a valley-slope configuration requires detailed numerical calculations.
Nonlinear frequency-dependent attenuation in sandy sediments
Authors: Holmes J. D. , Carey W. M. , Dediu S. M. , Siegmann W. L.
Published: May 2007

This paper summarizes evidence of a nonlinear frequency dependence of attenuation for compressional waves in shallow-water waveguides with sandy sediment bottoms. Sediment attenuation is found consistent with α(f)=α(fo)∙(f∕fo)n, n≈1.8±0.2 at frequencies less than 1kHz in agreement with the theoretical expectation, (n=2), of Biot [J. Acoust. Soc. Am. 28(2), 168–178, 1956]. For frequencies less than 10kHz, the sediment layers, within meters of the water-sediment interface, appear to play a role in the attenuation that strongly depends on the power law. The accurate calculation of sound transmission in a shallow-water waveguide requires the depth-dependent sound speed, density, and frequency-dependent attenuation.
A Common Allele on Chromosome 9 Associated with Coronary Heart Disease
Authors: McPherson Ruth , Pertsemlidis Alexander , Kavaslar Nihan , Stewart Alexandre , Roberts Robert , Cox David R. , Hinds David A. , Pennacchio Len A. , Tybjaerg-Hansen Anne , Folsom Aaron R. , Boerwinkle Eric , Hobbs Helen H. , Cohen Jonathan C.
Published: May 2007

Coronary heart disease (CHD) is a major cause of death in Western countries. We used genome-wide association scanning to identify a 58-kilobase interval on chromosome 9p21 that was consistently associated with CHD in six independent samples (more than 23,000 participants) from four Caucasian populations. This interval, which is located near the
CDKN2A
and
CDKN2B
genes, contains no annotated genes and is not associated with established CHD risk factors such as plasma lipoproteins, hypertension, or diabetes. Homozygotes for the risk allele make up 20 to 25% of Caucasians and have a ∼30 to 40% increased risk of CHD.
On the application of
in situ
monazite chemical geochronology to constraining
P
–
T
–
t
histories in high-temperature (
>
850
°
C) polymetamorphic granulites from Prydz Bay, East Antarctica
Authors: Kelsey D.E. , Hand M. , Clark C. , Wilson C.J.L.
Published: May 2007

We present electron microprobe-based
in situ
(Th + U)–Pb monazite chemical age data from granulite-facies metapelites in Prydz Bay, East Antarctica. The monazite age data define two distinct age populations, Late Neoproterozoic to Early Palaeozoic (
c
. 570–520 Ma) and Neoproterozoic (
c
. 950–820 Ma), that confirm the polytectonic nature of Prydz Bay. Our data suggest that similarity in lineation orientation along the Prydz Bay coast is not sufficient to necessarily indicate time-equivalance. The minimum duration of Early Palaeozoic tectonism, spanning at least 60 Ma, is constrained from an Mg–Al-rich metapelite: monazite hosted by coarse-grained orthopyroxene defines the oldest Early Palaeozoic population, whereas cordierite + orthopyroxene symplectites define the youngest Early Palaeozoic population. The spatial distribution of monazites and their ages is correlatable with the inferred mineral assemblage evolution. We are able to characterize the evolution of Early Palaeozoic tectonism in quantitative
P
–
T
–
t
–mineral assemblage space, demonstrating that ultrahigh-temperature tectono-metamorphism in Prydz Bay is of Early Palaeozoic age. The survival of Neoproterozoic inheritance in Fe–Al-rich metapelites has implications for high Pb retentivity in monazite when chemical and kinetic conditions are favourable. The approach and logic applied herein are entirely and directly transferable to the interrogation of any other metamorphic terrane.
Electoral Laws as Political Consequences: Explaining the Origins and Change of Electoral Institutions
Authors: Benoit Kenneth
Published: May 2007

▪ Abstract  In this review article, I identify the key questions raised by the treatment of electoral systems not as causal influences on party systems but as effects or byproducts of party systems. Framing these questions in the context of the classic consequences-oriented study of electoral institutions, I first review the classic approach, which treats electoral systems as causes, and explore the potential implications when electoral systems are viewed instead as outcomes of party systems. I then survey a variety of principal explanations of the origins and change of electoral laws, followed by a focus on several of the more explicitly defined models of this process. I conclude by discussing—and contesting—the notion that except for exceptional founding episodes of institutional choice, electoral systems eventually stabilize as equilibrium institutions.
Framing Theory
Authors: Chong Dennis , Druckman James N.
Published: May 2007

▪ Abstract  We review the meaning of the concept of framing, approaches to studying framing, and the effects of framing on public opinion. After defining framing and framing effects, we articulate a method for identifying frames in communication and a psychological model for understanding how such frames affect public opinion. We also discuss the relationship between framing and priming, outline future research directions, and describe the normative implications of framing.
Experimental and Numerical Investigation of Reactant Flow in Flow Channels and Leakage Cross Flow through Gas Diffusion Layers in PEM fuel Cells
Authors: Park Jaewan , Li Xianguo
Published: May 2007

In a PEM fuel cell, reactant can leak or cross to the neighboring channels via the porous gas diffusion layer due to the pressure difference and short flow path. Such cross flow becomes significant for thin and long serpentine flow channels with thick gas diffusion layer. In this work, a numerical and experimental study has been carried out to investigate the cross flow in a PEM fuel cell. Experimental measurements revealed that the pressure drop in a PEM fuel cell is significantly lower than that without cross flow. Three- dimensional numerical simulation has been performed for wide ranges of flow rate, permeability and thickness of gas diffusion layer to analyze the effects of those parameters on the resultant cross flow and the pressure drop of the reactant streams. The effects of this phenomenon are also crucial for effective water removal from the porous electrode structure and must be reflected on the design and operation of PEM fuel cells.
Evaluation of Methanol Crossover through SPEEK/TPA/Y-zeolite Composite Membranes by Electrochemical Method
Authors: Zaidi Syed J. , Bello Mukhtar , Rahman Saleem
Published: May 2007

This research work reports the evaluation of methanol crossover through newly developed composite membranes prepared from inorganic proton conducting material (tungstophosphoric acid (TPA)/Y-zeolite) with sulfonated polyether ether ketone (SPEEK) polymer. The composite membranes were prepared by embedding different proportions (10-40 wt %) of conducting material (TPA/Y-zeolite) into SPEEK polymer matrix. Methanol crossover through these membranes was studied using potentiometric technique. It was found that membranes with low loading of inorganic conducting material show better reduction in methanol crossover. The membranes are thermally stable up to around 160 ºC. These membranes have potential to be considered for use in low power methanol fuel cells due to their low methanol crossover, adequate stability and low cost.
Preparation and Evaluation of Novel Pt-C Co-Sputtered Electrode for Methanol Oxidation
Authors: Umeda Minoru , Shibamine Masahiko , Tanaka Shohji , Uchida Isamu
Published: May 2007

This report describes a novel Pt-C electrode prepared by a co- sputtering technique for use as the anode catalyst of direct methanol fuel cells. The 0.3 µm-thick electrocatalyst layer was prepared on an Au foil substrate. The atomic ratio of the obtained catalyst was found to be C/Pt=0-0.44 by SEM-EDS analysis. Based on its X-ray photoelectron spectra, the co- sputtered carbon was suggested to affect the Pt electronic structure of the Pt-C electrodes. Cyclic voltammograms of the methanol oxidation measured at the Pt-C electrodes demonstrated that the electrocatalytic activity increased according to the increase in the C/Pt ratio up to 0.12, but then decreased from C/Pt=0.12-0.44. The activation enhancement was thought to be attributed to a change in the electronic structure of the co-sputtered Pt. The deactivation that appeared at C/Pt=0.12-0.44 was considered to be a result of the decrease in the number of bimolecular reaction sites, Pt- Pt, due to the insertion of a carbon molecule.
Chromium Reactions and Transport in Solid Oxide Fuel Cells
Authors: Cruse Terry A. , Ingram Brian J. , Liu Di-Jia , Krumpelt Michael
Published: May 2007

With solid oxide fuel cells operating at 800{degree sign}C or lower, metal alloy bipolar plates (interconnects) offer a number of advantages over ceramic interconnects. However, these alloys rely on the formation of a protective chromium based scale, either chromia or a manganese chromium spinel. As metallic bipolar plates have been explored, and used, over the last decade, a number of interactions have been observed between the bipolar plate and various cathode materials. This paper examines the interactions between E-Brite® and an LSM/YSZ composite active cathode. Tests examined direct contact of the E-Brite® with the cathode, and the effect of using gold foil as a physical barrier so only gas phase interactions were possible. Additionally, key observations on test fixture design and materials selection are discussed, which may shed light on why different researchers have observed a wide range of fuel cell degradation rates.
Anode-supported Planar-type SOFC Development at NTT
Authors: Sugita Satoshi , Arai Hajime , Yoshida Yoshiteru , Orui Himeko , Arakawa Masayasu
Published: May 2007

Anode-supported planer-type SOFCs are promising for clean power- generating system with high efficiency. We have developed a metallic separator, a sealing method and a cell-separator connecting method all of which are suitable for anode-supported planar-type cells. Using these technologies, we have achieved power density of up to 0.6W/cm2 and cell DC electric efficiency of 53% in LHV on both one- and three-cell stack units.
The Optimal Heat-up Strategy of Solid-Oxide Fuel Cells
Authors: Chen Ming H. , Jiang Tsung L.
Published: May 2007

A thermal-structure coupled simulation model has been developed and employed to evaluate the heat-up time of solid- oxide fuel cells and the associated thermal stress for various heat-up processes. Simulation results show that effects of the residual stress of the PEN structure on the evaluation of the thermal stress are significant. Noticeably, the dual-channel heating approach is found more favorable than the single- channel heating approach. Among the investigated heat-up processes, the dual-channel heating approach is the optimal heat-up strategy for the lowest thermal stress and a shorter heat-up time.
The Response of Hydrogen Sensor to Environment
Authors: Hu Cheng , Sun Colin , Shen Jun , Fan Lilian , Holland Robert M. , Kambo Perminder , Wong Darryl K. , Ng Chi W. , Comeault Chad , Chisholm John
Published: May 2007

In many hydrogen sensor applications, the ambient environment applies effects on sensor response. Some environmental parameters may cause significant function changes in sensor performance. These parameters include temperature, humidity, pressure and gas flow rate, among others. Calibration and compensation for these effects are thus needed to acquire meaningful and accurate results from sensor measurements. In this report, a custom-designed hydrogen sensor test station is described. The test station provides simultaneous and accurate control of gas composition, gas flow rate, temperature, humidity and pressure. The test procedures were designed to examine sensor response to the changes of these parameters. A number of hydrogen sensors of various types had been tested in a series of testing processes. The general behavior of these gas sensors was studied and gave a brief overview of hydrogen sensors in present market.
Low-Temperature Hydrogen Production from Steam Reforming Of Methane Using Electrically Activated Catalys
Authors: Zhang Jun Z. , Still Mark , Gaudet Gregory T.
Published: May 2007

A nano catalyst for steam reforming of methane has been prepared by using plasma technology developed at Nanoproducts Corperation. The catalyst was loaded on monolith support and reduced in hydrogen using an electric-activation method. The reduced catalyst showed a great ability for catalyzing methane steam reforming at low temperature.
Integrating Wind And Solar With Hydrogen Producing Fuel Cells
Authors: Hemmes Kas
Published: May 2007

The often proposed solution for the fluctuating wind energy supply is the conversion of the surplus of wind energy into hydrogen by means of electrolysis. In this paper a patented alternative is proposed consisting of the integration of wind turbines with internal reforming fuel-cells, capable of co- producing hydrogen and electricity from natural gas. Storage of hydrogen is not absolutely necessary, since the naturally available energy storage capacity of the gas field is effectively used. The flexibility of a fuel cell to vary electric output and/or simultanuously produce hydrogen from natural gas can be used very beneficial in an integrated windturbine fuel cell configuration. Flowsheet calculations have shown that the change in hydrogen output can be three times or more than the increase in electric input from wind energy at constant natural gas input and constant total electric power output, resulting in an apparent conversion efficiency of more than 300%.
Roles of muscarinic receptor subtypes in small intestinal motor dysfunction in acute radiation enteritis
Authors: Frisby Claudine L. , Fraser Robert J. , Schirmer Murray B. , Yeoh Eric K. , Blackshaw L. Ashley
Published: May 2007

Administration of abdominal radiotherapy results in small intestinal motor dysfunction. We have developed a rat radiation enteritis model that, after exposure in vivo, shows high-amplitude, long-duration (HALD) pressure waves in ex vivo ileal segments. These resemble in vivo dysmotility where giant contractions migrate both antegradely and retrogradely. Mediation of these motor patterns is unclear, although enteric neural components are implicated. After the induction of acute radiation enteritis in vivo, ileal segments were isolated and arterially perfused. TTX, hexamethonium, atropine, or the selective muscarinic antagonists pirenzepine (M1), methoctramine (M2), and 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP; M3) were added to the perfusate. The baseline mean rate per minute per channel of HALD pressure waves was 0.35 ± 0.047. This was significantly reduced by TTX (83.3%, P < 0.01), hexamethonium (90.3%, P < 0.03), and atropine (98.4%, P < 0.01). The HALD pressure wave mean rate per minute per channel was significantly reduced by pirenzepine (81.1%, P < 0.03), methoctramine (96.8%, P < 0.001), and 4-DAMP (93.1%, P < 0.03) compared with predrug baseline data. As an indicator of normal motility patterns, the frequency of low-amplitude, short-duration pressure waves was also assessed. The mean rate per minute per channel of 5.15 ± 0.98 was significantly increased by TTX (19%, P < 0.05) but significantly reduced by pirenzepine (35.1%, P < 0.02) and methoctramine (75%, P < 0.0003). However, the rate of small-amplitude pressure waves was not affected by hexamethonium, atropine, or the M3 antagonist 4-DAMP. The data indicate a role for neuronal mechanisms and the specific involvement of cholinergic receptors in generating dysmotility in acute radiation enteritis. The effect of selective M3 receptor antagonism suggests that M3 receptors may provide specific therapeutic targets in acute radiation enteritis.
High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes
Authors: Singh Vivek P. , Le Bao , Bhat Vadiraja B. , Baker Kenneth M. , Kumar Rajesh
Published: May 2007

The prevailing paradigm is that cardiac ANG II is synthesized in the extracellular space from components of the circulating and/or local renin-angiotensin system. The recent discovery of intracrine effects of ANG II led us to determine whether ANG II is synthesized intracellularly in neonatal rat ventricular myocytes (NRVM). NRVM, incubated in serum-free medium, were exposed to isoproterenol or high glucose in the absence or presence of candesartan, which was used to prevent angiotensin type 1 (AT1) receptor-mediated internalization of ANG II. ANG II was measured in cell lysates and the culture medium, which represented intra- and extracellularly synthesized ANG II, respectively. Isoproterenol increased ANG II concentration in cell lysates and medium of NRVM in the absence or presence of candesartan. High glucose markedly increased ANG II synthesis only in cell lysates in the absence and presence of candesartan. Western analysis showed increased intracellular levels of angiotensinogen, renin, and chymase in high-glucose-exposed cells. Confocal immunofluorocytometry confirmed the presence of ANG II in the cytoplasm and nucleus of high-glucose-exposed NRVM and along the actin filaments in isoproterenol-exposed cells. ANG II synthesis was dependent on renin and chymase in high-glucose-exposed cells and on renin and angiotensin-converting enzyme in isoproterenol-exposed cells. In summary, the site of ANG II synthesis, intracellular localization, and the synthetic pathway in NRVM are stimulus dependent. Significantly, NRVM synthesized and retained ANG II intracellularly, which redistributed to the nucleus under high-glucose conditions, suggesting a role for an intracrine mechanism in diabetic conditions.
Muscle metaboreflex-induced increases in cardiac sympathetic activity vasoconstrict the coronary vasculature
Authors: O'Leary Donal S. , Sala-Mercado Javier A. , Hammond Robert L. , Ansorge Eric J. , Kim Jong-Kyung , Rodriguez Jaime , Fano Dominic , Ichinose Masashi
Published: May 2007

Ischemia of active skeletal muscle evokes a powerful blood pressure-raising reflex termed the muscle metaboreflex (MMR). MMR activation increases cardiac sympathetic nerve activity, which increases heart rate, ventricular contractility, and cardiac output (CO). However, despite the marked increase in ventricular work, no coronary vasodilation occurs. Using conscious, chronically instrumented dogs, we observed MMR-induced changes in arterial pressure, CO, left circumflex coronary blood flow (CBF), and coronary vascular conductance (CVC) before and after α1-receptor blockade (prazosin, 100 μg/kg iv). MMR was activated during mild treadmill exercise by partially reducing hindlimb blood flow. In control experiments, MMR activation caused a substantial pressor response-mediated via increases in CO. Although CBF increased (+28.1 ± 3.7 ml/min; P < 0.05), CVC did not change (0.45 ± 0.05 vs. 0.47 ± 0.06 ml·min−1·mmHg−1, exercise vs. exercise with MMR activation, respectively; P > 0.05). Thus all of the increase in CBF was due to the increase in arterial pressure. In contrast, after prazosin, MMR activation caused a greater increase in CBF (+55.9 ± 17.1 ml/min; P < 0.05 vs. control) and CVC rose significantly (0.59 ± 0.08 vs. 0.81 ± 0.17 ml·min−1·mmHg−1, exercise vs. exercise with MMR activation, respectively; P < 0.05). A greater increase in CO also occurred (+2.01 ± 0.1 vs. +3.27 ± 1.1 l/min, control vs. prazosin, respectively; P < 0.05). We conclude that the MMR-induced increases in sympathetic activity to the heart functionally restrain coronary vasodilation, which may limit increases in ventricular function.
Doping dose of salbutamol and exercise training: impact on the skeleton of ovariectomized rats
Authors: Bonnet N. , Laroche N. , Beaupied H. , Vico L. , Dolleans E. , Benhamou C. L. , Courteix D.
Published: May 2007

Previous studies in healthy rats have demonstrated a deleterious bone impact of β-agonist treatment. The purpose of this study was to examine the trabecular and cortical effects of β2-agonists at doping dose on treadmill exercising rats with estrogen deficiency. Adult female rats were ovariectomized (OVX; n = 44) or sham operated ( n = 12). Then, OVX rats received a subcutaneous injection of salbutamol (SAB) or vehicle with (EXE) or without treadmill exercise for 10 wk. Bone mineral density (BMD) was analyzed by densitometry. Microcomputed tomography and histomorphometric analysis were performed to study trabecular bone structure and bone cell activities. After 10 wk, SAB rats presented a much more marked decrease of BMD and trabecular parameters. Exercise did not change the high level of bone resorption in OVX EXE SAB compared with OVX SAB group (both on COOH-terminal collagen cross-links and osteoclast number). These results confirm the deleterious effect of β2-agonists on bone quantity (femoral BMD gain: OVX EXE, +6.8%, vs. OVX EXE SAB, −1.8%; P < 0.01) and quality (−8.0% of femoral trabecular thickness in OVX EXE SAB vs. OVX EXE), indicating that SAB suppresses the effect of EXE in OVX rats. Furthermore, we notice that the slight beneficial effect of exercise was mainly localized in the tibia. These findings indicate the presence of a bone alteration threshold below which there is no more alteration in structural bone quantity and quality. The negative effects of SAB on bone observed in this study in trained rats may indicate potential complications in doping female athletes with exercise-induced amenorrhea.
The High-Mobility Group A1 Gene Up-Regulates Cyclooxygenase 2 Expression in Uterine Tumorigenesis
Authors: Tesfaye Abeba , Di Cello Francescopaolo , Hillion Joelle , Ronnett Brigitte M. , Elbahloul Ossama , Ashfaq Raheela , Dhara Surajit , Prochownik Edward , Tworkoski Kathryn , Reeves Raymond , Roden Richard , Ellenson Lora Hedrick , Huso David L. , Resar Linda M. S.
Published: May 2007

Uterine cancer is the most common cancer of the female genital tract and is the fourth most frequent cause of cancer death in women in the U.S. Despite the high prevalence of uterine cancers, the molecular events that lead to neoplastic transformation in the uterus are poorly understood. Moreover, there are limited mouse models to study these malignancies. We generated transgenic mice with high-mobility group A1 gene (HMGA1a) expression targeted to uterine tissue and all female mice developed tumors by 9 months of age. Histopathologically, the tumors resemble human uterine adenosarcoma and are transplantable. To determine whether these findings are relevant to human disease, we evaluated primary human uterine neoplasms and found that HMGA1a mRNA and protein levels are increased in most high-grade neoplasms but not in normal uterine tissue, benign tumors, or most low-grade neoplasms. We also found that HMGA1a up-regulates cyclooxygenase 2 (COX-2) expression in transgenic tumors. Moreover, both HMGA1a and COX-2 expression are up-regulated in high-grade human leiomyosarcomas. Using chromatin immunoprecipitation, HMGA1a binds directly to the COX-2 promoter in human uterine cancer cells in vivo and activates its expression in transfection experiments. We also show that blocking either HMGA1a or COX-2 in high-grade human uterine cancer cells blocks anchorage-independent cell growth in methylcellulose. These findings show that HMGA1a functions as an oncogene when overexpressed in the uterus and contributes to the pathogenesis of human uterine cancer by activating COX-2 expression. Although a larger study is needed to confirm these results, HMGA1a may be a useful marker for aggressive human uterine cancers. [Cancer Res 2007;67(9):3998–4004]
p38 Mitogen-Activated Protein Kinase Pathway Is Involved in Protein Kinase Cα–Regulated Invasion in Human Hepatocellular Carcinoma Cells
Authors: Hsieh Yi-Hsien , Wu Trang-Tiau , Huang Chih-Yang , Hsieh Yih-Shou , Hwang Jin-Ming , Liu Jer-Yuh
Published: May 2007

Protein kinase Cα (PKCα) has been suggested to play an important role in tumorigenesis, invasion, and metastasis. In this study, we investigated the signal pathways selectively activated by PKCα in human hepatocellular carcinoma (HCC) cells to determine the role of mitogen-activated protein kinases (MAPK) in PKCα-mediated HCC migration and invasion. A stable SK-Hep-1 cell clone (siPKCα-SK) expressing DNA-based small interfering RNA (siRNA) PKCα was established and was then characterized by cell growth, migration, and invasion. The expression of PKCα was decreased in siPKCα-SK, and cell growth, migration, and invasion were reduced. These changes were associated with the decrease in p38 MAPK phosphorylation level, but not in c-jun-NH2-kinase-1/2 (JNK-1/2) and extracellular signal-regulated kinase-1/2 (ERK-1/2). This phenomenon was confirmed in the SK-Hep-1 cells treated with antisense PKCα olignucleotide. The p38 MAPK inhibitor SB203580 or dominant negative p38 mutant plasmid (DN-p38) was used to evaluate the dependency of p38 MAPK in PKCα-regulated migration and invasion. Attenuation of cell migration and invasion was revealed in the SK-Hep-1 cells treated with the SB203580 or DN-p38, but not with ERK-1/2 inhibitor PD98059 or JNK-1/2 inhibitor SP600125. Overexpression of constitutively active MKK6 or PKCα may restore the inactivation of p38 and the attenuation of cell migration and invasion in siPKCα-SK. Similar findings were observed in the stable HA22T/VGH cell clone expressing siRNA PKCα. This study provides new insight into the role of p38 MAPK in PKCα-mediated malignant phenotypes, especially in PKCα-mediated cancer cell invasion, which may have valuable implications for developing new therapies for some PKCα-overexpressing cancers. [Cancer Res 2007;67(9):4320–7]
Transgenic E2F1 Expression in the Mouse Brain Induces a Human-Like Bimodal Pattern of Tumors
Authors: Olson Melissa V. , Johnson David G. , Jiang Hong , Xu Jing , Alonso Marta M. , Aldape Kenneth D. , Fuller Gregory N. , Bekele B. Nebiyou , Yung W.K. Alfred , Gomez-Manzano Candelaria , Fueyo Juan
Published: May 2007

The Rb/E2F pathway is deregulated in most human brain tumors, and the finding that loss of E2F1 reduced pituitary tumorigenesis in Rb+/− mice suggests that loss of pRb induces brain tumors by activating E2F1. We therefore investigated the role of E2F1 in the development and maintenance of brain cancer using a transgenic mouse model engineered to express E2F1 specifically within glial cells (GFAP-tgE2F1). GFAP-tgE2F1 mice developed a highly penetrant phenotype characterized by neurologic defects, and examination of the brains revealed the presence of brain tumors in 20% of these animals. Importantly, the distribution of tumors according to mouse age suggests the existence of a bimodal pattern of tumor development, forcing a comparison with the human disease. Mice, at an early age, with deregulated E2F1 show the formation of embryonal brain tumors such as medulloblastoma, choroid plexus carcinoma, and primary neuroectodermal tumor. Conversely, at an older age, mice escaping embryonal tumor formation present with malignant gliomas, which are typically identified in the human adult population. Thus, this study offers the first evidence for a global role of E2F1 in the formation and maintenance of multilineage brain tumors, irrefutably establishing E2F1 as an oncogene in the brain. [Cancer Res 2007;67(9):4005–9]
A Coregulatory Role for the Mediator Complex in Prostate Cancer Cell Proliferation and Gene Expression
Authors: Vijayvargia Ravi , May Michael S. , Fondell Joseph D.
Published: May 2007

Androgen receptor (AR) signaling pathways are important for the survival and proliferation of prostate cancer cells. Because AR activity is facilitated by distinct coregulatory factors and complexes, it is conceivable that some of these proteins might also play a role in promoting prostate oncogenesis. The multisubunit Mediator complex is an important coactivator for a broad range of regulatory transcriptional factors including AR, yet its role in prostate cancer is unclear. Here, we used RNA interference to knock down the expression of two integral Mediator components, MED1/TRAP220 and MED17, in prostate cancer cells. MED1/TRAP220 plays a particularly important role in androgen signaling in that it serves as a direct binding target for AR. We found that the knockdown of either subunit markedly decreases transcription from transiently transfected androgen-responsive reporter genes, as well as inhibits androgen-dependent expression of endogenous AR target genes. We show for the first time that loss of either MED1/TRAP220 or MED17 in prostate cancer cells significantly decreases both androgen-dependent and -independent cellular proliferation, inhibits cell cycle progression, and increases apoptosis. Furthermore, we show that MED1/TRAP220 is overexpressed in both AR-positive and -negative prostate cancer cells lines, as well as in 50% (10 of 20) of the clinically localized human prostate cancers we examined, thus suggesting that MED1/TRAP220 hyperactivity may have implications in prostate oncogenesis. In sum, our data suggest that Mediator plays an important coregulatory role in prostate cancer cell proliferation and survival, and therefore, may represent a new target for therapeutic intervention. [Cancer Res 2007;67(9):4034–41]
Oligomerization Domain of the Multidrug Resistance–Associated Transporter ABCG2 and Its Dominant Inhibitory Activity
Authors: Xu Junkang , Peng Hui , Chen Qun , Liu Yang , Dong Zizheng , Zhang Jian-Ting
Published: May 2007

Overexpression of human ATP-binding cassette transporter ABCG2 in cancer cells causes multidrug resistance by effluxing anticancer drugs. ABCG2 is considered as a half transporter and is thought to function as a homodimer. However, recent evidence suggests that it may exist as a higher form of oligomer consisting of 12 subunits. In this study, we mapped the oligomerization domain of human ABCG2 to its transmembrane domain consisting of TM5-loop-TM6. This oligomerization domain, when expressed alone in HEK293 cells, also forms a homododecamer. Furthermore, this domain has activity that inhibits drug efflux and resistance function of the full-length ABCG2 likely by disrupting the formation of the homo-oligomeric full-length ABCG2. These findings suggest that human ABCG2 may exist and work as a homo-oligomer by interactions located in TM5-loop-TM6, and that ABCG2 oligomerization may be used as a target for therapeutic development to circumvent ABCG2-mediated drug resistance in cancer treatment. [Cancer Res 2007;67(9)4373:–81]
Her-2 Overexpression Increases the Metastatic Outgrowth of Breast Cancer Cells in the Brain
Authors: Palmieri Diane , Bronder Julie L. , Herring Jeanne M. , Yoneda Toshiyuki , Weil Robert J. , Stark Andreas M. , Kurek Raffael , Vega-Valle Eleazar , Feigenbaum Lionel , Halverson Douglas , Vortmeyer Alexander O. , Steinberg Seth M. , Aldape Kenneth , Steeg Patricia S.
Published: May 2007

Retrospective studies of breast cancer patients suggest that primary tumor Her-2 overexpression or trastuzumab therapy is associated with a devastating complication: the development of central nervous system (brain) metastases. Herein, we present Her-2 expression trends from resected human brain metastases and data from an experimental brain metastasis assay, both indicative of a functional contribution of Her-2 to brain metastatic colonization. Of 124 archival resected brain metastases from breast cancer patients, 36.2% overexpressed Her-2, indicating an enrichment in the frequency of tumor Her-2 overexpression at this metastatic site. Using quantitative real-time PCR of laser capture microdissected epithelial cells, Her-2 and epidermal growth factor receptor (EGFR) mRNA levels in a cohort of 12 frozen brain metastases were increased up to 5- and 9-fold, respectively, over those of Her-2–amplified primary tumors. Co-overexpression of Her-2 and EGFR was also observed in a subset of brain metastases. We then tested the hypothesis that overexpression of Her-2 increases the colonization of breast cancer cells in the brain in vivo. A subclone of MDA-MB-231 human breast carcinoma cells that selectively metastasizes to brain (231-BR) overexpressed EGFR; 231-BR cells were transfected with low (4- to 8-fold) or high (22- to 28-fold) levels of Her-2. In vivo, in a model of brain metastasis, low or high Her-2–overexpressing 231-BR clones produced comparable numbers of micrometastases in the brain as control transfectants; however, the Her-2 transfectants yielded 3-fold greater large metastases (>50 μm2; P < 0.001). Our data indicate that Her-2 overexpression increases the outgrowth of metastatic tumor cells in the brain in this model system. [Cancer Res 2007;67(9):4190–8]
Phosphatase and Tensin Homologue Deficiency in Glioblastoma Confers Resistance to Radiation and Temozolomide that Is Reversed by the Protease Inhibitor Nelfinavir
Authors: Jiang Zibin , Pore Nabendu , Cerniglia George J. , Mick Rosemarie , Georgescu Maria-Magdelena , Bernhard Eric J. , Hahn Stephen M. , Gupta Anjali K. , Maity Amit
Published: May 2007

Glioblastomas are malignant brain tumors that are very difficult to cure, even with aggressive therapy consisting of surgery, chemotherapy, and radiation. Glioblastomas frequently have loss of the phosphatase and tensin homologue (PTEN), leading to the activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway. We examined whether PTEN deficiency leads to radioresistance and whether this can be reversed by nelfinavir, a protease inhibitor that decreases Akt signaling. Nelfinavir decreased Akt phosphorylation and enhanced radiosensitization in U251MG and U87MG glioblastoma cells, both of which are PTEN deficient. In the derivative line U251MG-PTEN, induction of wild-type PTEN with doxycycline decreased P-Akt expression and increased radiosensitivity to a similar extent as nelfinavir. Combining these two approaches had no greater effect on radiosensitivity than either alone. This epistasis-type analysis suggests that the nelfinavir acts along the Akt pathway to radiosensitize cells. However, nelfinavir neither decreased Akt phosphorylation in immortalized human astrocytes nor radiosensitized them. Radiosensitization was also assessed in vivo using a tumor regrowth delay assay in nude mice implanted with U87MG xenografts. The mean time to reach 1,000 mm3 in the radiation + nelfinavir group was 71 days, as compared with 41, 34, or 45 days for control, nelfinavir alone, or radiation alone groups, respectively. A significant synergistic effect on tumor regrowth was detected between radiation and nelfinavir. (P = 0.01). Nelfinavir also increased the sensitivity of U251MG cells to temozolomide. These results support the clinical investigation of nelfinavir in combination with radiation and temozolomide in future clinical trials for patients with glioblastomas. [Cancer Res 2007;67(9):4467–72]
MHC Class II–Transduced Tumor Cells Originating in the Immune-Privileged Eye Prime and Boost CD4+ T Lymphocytes that Cross-react with Primary and Metastatic Uveal Melanoma Cells
Authors: Bosch Jacobus J. , Thompson James A. , Srivastava Minu K. , Iheagwara Uzoma K. , Murray Timothy G. , Lotem Michal , Ksander Bruce R. , Ostrand-Rosenberg Suzanne
Published: May 2007

Uveal melanoma, the most common malignancy of the eye, has a 50% rate of liver metastases among patients with large primary tumors. Several therapies prolong survival of metastatic patients; however, none are curative and no patients survive. Therefore, we are exploring immunotherapy as an alternative or adjunctive treatment. Uveal melanoma may be particularly appropriate for immunotherapy because primary tumors arise in an immune-privileged site and may express antigens to which the host is not tolerized. We are developing MHC class II (MHC II)–matched allogeneic, cell-based uveal melanoma vaccines that activate CD4+ T lymphocytes, which are key cells for optimizing CD8+ T-cell immunity, facilitating immune memory, and preventing tolerance. Our previous studies showed that tumor cells genetically modified to express costimulatory and MHC II molecules syngeneic to the recipient are potent inducers of antitumor immunity. Because the MHC II–matched allogeneic vaccines do not express the accessory molecule, Invariant chain, they present MHC II–restricted peptides derived from endogenously encoded tumor antigens. We now report that MHC II–matched allogeneic vaccines, prepared from primary uveal melanomas that arise in the immune-privileged eye, prime and boost IFNγ-secreting CD4+ T cells from the peripheral blood of either healthy donors or uveal melanoma patients that cross-react with primary uveal melanomas from other patients and metastatic tumors. In contrast, vaccines prepared from metastatic cells in the liver are less effective at activating CD4+ T cells, suggesting that tumor cells originating in immune-privileged sites may have enhanced capacity for inducing antitumor immunity and for serving as immunotherapeutic agents. [Cancer Res 2007;67(9):4499–506]
DNA Double-Strand Breaks Form in Bystander Cells after Microbeam Irradiation of Three-dimensional Human Tissue Models
Authors: Sedelnikova Olga A. , Nakamura Asako , Kovalchuk Olga , Koturbash Igor , Mitchell Stephen A. , Marino Stephen A. , Brenner David J. , Bonner William M.
Published: May 2007

The “radiation-induced bystander effect,” in which irradiated cells can induce genomic instability in unirradiated neighboring cells, has important implications for cancer radiotherapy and diagnostic radiology as well as for human health in general. Although the mechanisms of this effect remain to be elucidated, we reported previously that DNA double-strand breaks (DSBs), directly measured by γ-H2AX focus formation assay, are induced in bystander cultured cells. To overcome the deficiencies of cultured cell studies, we examined α-particle microbeam irradiation–induced bystander effects in human tissue models, which preserve the three-dimensional geometric arrangement and communication of cells present in tissues in vivo. In marked contrast to DNA DSB dynamics in irradiated cells, in which maximal DSB formation is seen 30 min after irradiation, the incidence of DSBs in bystander cells reached a maximum by 12 to 48 h after irradiation, gradually decreasing over the 7-day time course. At the maxima, 40% to 60% of bystander cells were affected, a 4- to 6-fold increase over controls. These increases in bystander DSB formation were followed by increased levels of apoptosis and micronucleus formation, by loss of nuclear DNA methylation, and by an increased fraction of senescent cells. These findings show the involvement of DNA DSBs in tissue bystander responses and support the notion that bystander DNA DSBs are precursors to widespread downstream effects in human tissues. Bystander cells exhibiting postirradiation signs of genomic instability may be more prone than unaffected cells to become cancerous. Thus, this study points to the importance of considering the indirect biological effects of radiation in cancer risk assessment. [Cancer Res 2007;67(9):4295–302]
Identification of Novel Amplification Gene Targets in Mouse and Human Breast Cancer at a Syntenic Cluster Mapping to Mouse ch8A1 and Human ch13q34
Authors: Abba Martin C. , Fabris Victoria T. , Hu Yuhui , Kittrell Frances S. , Cai Wei-Wen , Donehower Lawrence A. , Sahin Aysegul , Medina Daniel , Aldaz C. Marcelo
Published: May 2007

Serial analysis of gene expression from aggressive mammary tumors derived from transplantable p53 null mouse mammary outgrowth lines revealed significant up-regulation of Tfdp1 (transcription factor Dp1), Lamp1 (lysosomal membrane glycoprotein 1) and Gas6 (growth arrest specific 6) transcripts. All of these genes belong to the same linkage cluster, mapping to mouse chromosome band 8A1. BAC-array comparative genomic hybridization and fluorescence in situ hybridization analyses revealed genomic amplification at mouse region ch8A1.1. The minimal region of amplification contained genes Cul4a, Lamp1, Tfdp1, and Gas6, highly overexpressed in the p53 null mammary outgrowth lines at preneoplastic stages, and in all its derived tumors. The same amplification was also observed in spontaneous p53 null mammary tumors. Interestingly, this region is homologous to human chromosome 13q34, and some of the same genes were previously observed amplified in human carcinomas. Thus, we further investigated the occurrence and frequency of gene amplification affecting genes mapping to ch13q34 in human breast cancer. TFDP1 showed the highest frequency of amplification affecting 31% of 74 breast carcinomas analyzed. Statistically significant positive correlation was observed for the amplification of CUL4A, LAMP1, TFDP1, and GAS6 genes (P < 0.001). Meta-analysis of publicly available gene expression data sets showed a strong association between the high expression of TFDP1 and decreased overall survival (P = 0.00004), relapse-free survival (P = 0.0119), and metastasis-free interval (P = 0.0064). In conclusion, our findings suggest that CUL4A, LAMP1, TFDP1, and GAS6 are targets for overexpression and amplification in breast cancers. Therefore, overexpression of these genes and, in particular, TFDP1 might be of relevance in the development and/or progression in a significant subset of human breast carcinomas. [Cancer Res 2007;67(9):4104–12]
Innate versus Adaptive Immunity: A Paradigm Past Its Prime?
Authors: Borghesi Lisa , Milcarek Christine
Published: May 2007

Studies in tumor immunology have relied upon the classic paradigm of distinct innate and adaptive parts of the immune system. However, recent advances in immunology suggest that this division may be overly simplistic, with emerging evidence of a breakdown in conventional hallmarks of each system. Here, we provide an overview of this area and discuss how the concept of a continuum of immune cell populations suggests novel areas of investigation in cancer research. [Cancer Res 2007;67(9):3989–93]