bluuebunny/crossref_metadata_2025 huggingface dataset:
Parallelization of Catalytic Packed-Bed Microchannels with Pressure-Drop Microstructures for Gas–Liquid Multiphase Reactions
Authors: Murakami Sunao , Ohtaki Kenichiro , Matsumoto Sohei , Inoue Tomoya
Published: June 2012

High-throughput and stable treatments are required to achieve the practical production of chemicals with microreactors. However, the flow maldistribution to the paralleled microchannels has been a critical problem in achieving the productive use of multichannel microreactors for multiphase flow conditions. In this study, we newly designed and fabricated a glass four-channel catalytic packed-bed microreactor for the scale-up of gas–liquid multiphase chemical reactions. We embedded microstructures generating high pressure losses at the upstream side of each packed bed, and experimentally confirmed the efficacy of the microstructures in decreasing the maldistribution of the gas–liquid flow to the parallel microchannels.
Vibration Analysis of Original Shape Quartz Resonator for High Quality Factor Realization
Authors: Oigawa Hiroshi , Sakano Yuuya , Ji Jing , Yamazaki Daisuke , Ueda Toshitsugu
Published: June 2012

AT-cut quartz resonators are widely used as timing devices in computers, mobile information, and communication tools, etc. Recently, quartz resonators have been applied to highly sensitive devices. To improve frequency stability, AT-cut quartz resonators must have an excellent temperature characteristic and high quality (Q) factor. Energy trapping and spurious mode coupling strongly affect the performance of resonators, and both parameters are determined by the shape of the resonator. As for achieving a higher Q, the most effective technique is to process the quartz cross-sectional shape into a plano-convex or bi-convex shape. However, it is difficult to manufacture a convex shape on the surface of a quartz wafer. For this reason, we propose an equivalent plano-convex shape, which was realized by arranging fine protrusions on the surface of quartz. In addition, the optimization of the original resonator shape has been discussed.
High Quality Factor 80 MHz Microelectromechanical Systems Resonator Utilizing Torsional-to-Transverse Vibration Conversion
Authors: Kiso Masaya , Okada Mitsuhiro , Fujiura Hideaki , Miyauchi Hideo , Niki Kazuya , Tanigawa Hiroshi , Suzuki Kenichiro
Published: June 2012

A silicon microelectromechanical systems (MEMS) resonator utilizing torsional-to-transverse vibration conversion with quarter-wavelength torsional support beams is designed, fabricated, and evaluated. The resonant frequency for torsional modes mostly depends only on beam length, providing a large tolerance in the fabrication process. However, the following have remained critical issues: the increase in the quality factor (Q-factor) and the reduction in the motional resistance. We propose a new beam structure, in which the MEMS resonator utilizing torsional-to-transverse vibration conversion is anchored by four quarter-wavelength torsional support beams. First, the fabricated resonators are measured with a laser-Doppler (LD) vibrometer. The measured resonant frequency of 78.224 MHz has been in good agreement with the simulated one. The Q-factor has also been measured to be as high as 3.0×104 in vacuum. Then, the electrical characteristic is evaluated with an impedance analyzer. The Q-factor has been electrically measured to be as high as 3.1×104 in vacuum, which agrees well with the mechanically measured one of 3.0×104. The Q-factor has also been electrically measured to be as high as 1.3×104 at atmospheric pressure. In the measurement, a spring softening effect has been clearly observed. By increasing the DC bias voltage from 20 to 40 V, the resonant frequency has decreased by 640 Hz. The extracted motional resistance for a 0.1-µm-gap resonator has been greatly reduced to 0.039 MΩ at 5 V DC, owing to the narrow-gap effect, from that of a 0.25-µm-gap resonator. The tolerance in the fabrication process has also been evaluated and successfully verified from the measurement of the fabricated MEMS resonators.
Frequency Stability of a Closed-Loop Oscillator Using Micro-Electro-Mechanical Cantilever Resonator Against Temperature Fluctuation
Authors: Ikehara Tsuyoshi , Konno Mitsuo , Murakami Sunao , Mihara Takashi
Published: June 2012

The frequency stability of a silicon cantilever resonator against temperature was investigated under open-loop and closed-loop conditions. The authors found that the adjustment of the circuit phase in the closed-loop condition induced a significant change in temperature coefficient. The observed temperature coefficient dependence on the circuit phase was analyzed with the temperature dependence of elasticity in silicon and the phase shift originated from the oscillation circuit. The existence of a phase shift of 1.37°/°C was evaluated from the measured results. The phase effect was comparable to the elasticity effect on the temperature coefficient.
Implementation of Complementary Metal–Oxide–Semiconductor Microelectromechanical Systems Lorentz Force Two Axis Angular Actuator
Authors: Sun Chih-Ming , Wu Chung-Lin , Wang Chuanwei , Chang Chun-I , Yip Ming-Chuen , Fang Weileun
Published: June 2012

We present a novel dual-axis complementary metal–oxide–semiconductor (CMOS) microelectromechanical systems (MEMS) angular actuator driven by Lorentz force. The device has been successfully implemented using the Taiwan Semiconductor Manufacturing Company (TSMC) two-poly four-metal (2P4M) process. The current routing achieved with three metal layers enables independent driving for each axis. The measurement results show that the device has resonant frequencies of 1.36 and 2.26 kHz for the two axes.
High-Sensitivity Fiber-Optic Fabry–Perot Interferometer Temperature Sensor
Authors: Li Xuefeng , Lin Shuo , Liang Jinxing , Oigawa Hiroshi , Ueda Toshitsugu
Published: June 2012

A novel structure of a fiber-optic Fabry–Perot interferometric (FFPI) temperature sensor is presented in this paper. The design of the sensor is analyzed and evaluated by the finite-difference time-domain (FDTD) method. Then, the proposed sensor is fabricated using a conventional single-mode fiber (SMF). A gold (Au) layer and a nickel (Ni) layer are sputtered and electroplated on the surface of the SMF, respectively. As a Fabry–Perot (FP) cavity, a micro-punch-hole is machined by focused ion beam (FIB) milling. Here, the structure of the FP cavity can be considered a pair of bimetallic strips. On the basis of the sharp difference in thermal expansion coefficient between the fused silica and the metallic materials, the temperature sensitivity of the proposed sensor was determined to be over 70 pm/°C in the 0 to +60 °C range. The standard deviation of temperature is less than 0.15 °C in 1 h.
Demonstration of Vibrational Braille Code Display Using Large Displacement Micro-Electro-Mechanical Systems Actuators
Authors: Watanabe Junpei , Ishikawa Hiroaki , Arouette Xavier , Matsumoto Yasuaki , Miki Norihisa
Published: June 2012

In this paper, we present a vibrational Braille code display with large-displacement micro-electro-mechanical systems (MEMS) actuator arrays. Tactile receptors are more sensitive to vibrational stimuli than to static ones. Therefore, when each cell of the Braille code vibrates at optimal frequencies, subjects can recognize the codes more efficiently. We fabricated a vibrational Braille code display that used actuators consisting of piezoelectric actuators and a hydraulic displacement amplification mechanism (HDAM) as cells. The HDAM that encapsulated incompressible liquids in microchambers with two flexible polymer membranes could amplify the displacement of the MEMS actuator. We investigated the voltage required for subjects to recognize Braille codes when each cell, i.e., the large-displacement MEMS actuator, vibrated at various frequencies. Lower voltages were required at vibration frequencies higher than 50 Hz than at vibration frequencies lower than 50 Hz, which verified that the proposed vibrational Braille code display is efficient by successfully exploiting the characteristics of human tactile receptors.
Magnetic Micro Actuator Using Interactive Force between Magnetic Elements
Authors: Hatama Kenji , Tsumori Fujio , Xu Yang , Kang Hyungoo , Osada Toshiko , Miura Hideshi
Published: June 2012

In micro electro mechanical system (MEMS) field, there have been used many kinds of actuators. Among them, the magnetic actuator has some advantages. As magnetic micro actuators do not need electric wiring for energy supply, the structure can be simple and be downsized easily. However, the magnetic force would be very small with downsizing, which is the main problem for conventional magnetic actuators. We propose a new type actuator using magnetic interaction force between magnetic elements to solve this matter. This actuator can work even if it gets smaller, because the interaction force is dominant in a microscopic region. We fabricated the actuator by a casting process with photolithography using the SU-8 resist material. Then, the structure was fabricated by casting the mixture of poly(dimethylsiloxane) (PDMS) and a magnetic powder material. The beam type actuator works successfully and also shows interesting behavior. We can control the behavior of this actuator by changing the arrangement of magnetic elements on the structure. We also show theoretical evaluation of the deformation of the present actuator.
Design and Fabrication of Microelectromechanical Systems Probe Card with Vertical Trench Guide for Fine Pitch Probing
Authors: Kim Bonghwan , Cho Chanseob , Lee Byeungleul , Kim Hyeon Cheol , Chun Kukjin
Published: June 2012

In this study, we developed a new microelectromechanical systems (MEMS) probe card with a vertically guided and electroplated cantilever in order to overcome pitch limitation, which has a compliant structure and is capable of a 35 µm pad pitch, with through-wafer interconnections for IC testing. We also investigated the reliability of the MEMS probe card using tribology and scaling of the MEMS probe card for fine pitch probing. The measured contact resistance was less than 0.5 Ω at 1.5 gf applied force and the leakage current was approximately 10 pA between one tip and an adjacent tip. In addition, the planarity of tips and the alignment of x- and y-axes were satisfied with a conventional needle probe card performance. Therefore, this probe card is suitable for wafer-level burn-in testing and function testing of memory and RF devices.
Fabrication of Nickel Microlens Dies Using Hemispherical Resist Patterns as Electroplating Molds
Authors: Ono Hiroshi , Horiuchi Toshiyuki
Published: June 2012

Technology to control the sidewall profiles of resist patterns was newly developed, and its usability for three-dimensional microfabrication was verified. The technology was applied to fabricating nickel dies of microlens arrays using the hemispherical resist patterns as electroplating molds. It was already known that resist sidewall profiles of line-and-space patterns were intentionally controllable, if the exposure wavelength and defocus of projection exposure were appropriately chosen. However, it had not been clarified if the same controllability could be attained for dot patterns. For this reason, it was investigated whether this sidewall control exposure was applicable to dot patterns printed on a 10-µm-thick positive resist. The resist patterns were used as molds of nickel electroplating, and nickel dies were fabricated. A dot-matrix reticle with 1.0 mm pitch and 0.5 mm diameter was used, and hemispherical patterns were formed using a 1/19 reduction projection exposure system. The exposure was executed using light with a central wavelength of 405 nm, and defocus conditions of +150 and +200 µm were selected. Fabricated hemispherical resist patterns were coated with spattered thin gold film before electroplating nickel. The sizes and profiles of the nickel dies were almost equal to those of the resist molds, and it was demonstrated that the resist mold profiles were faithfully transferred to the nickel dies. It was verified that the new method for fabricating dies of microlens arrays was feasible.
Mutual Solid Solubility and Phase Equilibrium in the System BaTiO3–BaCeO3
Authors: Lu Da-Yong , Han Dan-Dan , Sun Xiu-Yun
Published: June 2012

A series of (1-x)BaTiO3–xBaCeO3 (x = 0.1–1.0) ceramics were prepared at 1480 °C by a cold-pressing ceramic technique. The mutual solid solubility and phase equilibrium in the system BaTiO3–BaCeO3 were investigated by X-ray diffraction analysis, scanning electron microscopy, and Raman spectroscopy. The results indicate that no pure BaCeO3 phase can be separated from the Ba(Ti1-x
Ce
x
)O3 phase. The mutual solid solution limits of BaCeO3 and BaTiO3 are given. In the range of 0.4 ≤x ≤0.8, the system is well separated into the Ce- and Ti-rich Ba(Ti,Ce)O3 perovskite phases, corresponding to Ce/Ti ratios of 4.3:1 and 1:2, respectively.
Channel Length and Time Dependent Interface Trap Generation near the Source Due to Hot-Carrier Injection in Metal–Oxide–Semiconductor Field-Effect Transistors
Authors: Hu Ming , Tsuchiya Toshiaki
Published: June 2012

Interface traps generated due to the hot-carrier effect in metal–oxide–semiconductor field-effect transistors (MOSFETs) are usually considered to be concentrated near the drain. However, hot-carrier induced interface trap generation near the source has also been experimentally observed. As channel lengths shrink, the MOS interface near the source begins to be affected by hot-carriers. In this paper, we studied the channel length dependent interface trap generation near the source. With the initial application of hot carrier stress the number of interface traps generated near the source was much smaller than that near the drain. However, with continued stress, the traps generated near the source become comparable to those near the drain. This phenomenon is explained by the saturation behavior of interface trap generation in MOSFETs by hot-carrier injection.
Electrical Field Gradient Pumping of Parametric Oscillation in a High-Frequency Nanoelectromechanical Resonator
Authors: Cho Sungwan , Cho Myung Rae , Shim Seung-Bo , Park Yun Daniel
Published: June 2012

We report on enhancements in the gain of silicon nitride (SiN
x
) nanomechanical resonators by parametric amplification using a dielectric gradient force pumping. With this technique, high mechanical quality factors (Q) of over 20,000 at resonant frequency of 6.79 MHz are achieved even at room temperature. By applying a constant electric bias voltage (V
dc), we show the resonant frequency to be dependent on static tension. To periodically modulate the spring constant of the resonator, a parametric pumping signal twice its resonant frequency (2f
0) is applied simultaneously with the V
dc, and at room temperature, the phase-sensitive parametric gain is 9.62.
Etching Behavior and Mechanism of In- and Ga-Doped ZnO Thin Films in Inductively Coupled BCl3/Cl2/Ar Plasmas
Authors: Kwon Kwang-Ho , Efremov Alexander , Kang Sungchil , Jang Hanbyeol , Yang Hyungjin , Kim Kwangsoo
Published: June 2012

The etching characteristics and mechanism of In- and Ga-doped ZnO (IGZO) thin films in BCl3/Cl2/Ar inductively coupled plasma at a fixed gas pressure (6 mTorr) were investigated. It was found that the substitution of Cl2for BCl3in the BCl3/Cl2/Ar gas mixture results in the maximum IGZO etching rate in 40% BCl3+ 40% Cl2+ 20% Ar. In both Cl2-rich (20% BCl3+ 60% Cl2+ 20% Ar) and BCl3-rich (60% BCl3+ 20% Cl2+ 20% Ar) plasmas, increases in input power (500–800 W) and bias power (100–250 W) cause the monotonic acceleration of the IGZO etching process. Plasma diagnostics using Langmuir probes and zero-dimensional plasma modeling provided the data on plasma parameters and fluxes of active species. It was concluded that the IGZO etching process is not limited by the ion–surface interaction kinetics as well as involves BClxradicals.
Impact of Deposition Temperature of the Silicon Oxide Passivation on the Performance of Indium Zinc Oxide Thin-Film Transistors
Authors: Li Min , Lan Linfeng , Xu Miao , Xu Hua , Luo Dongxiang , Xiong Nana , Peng Junbiao
Published: June 2012

Indium zinc oxide (IZO) thin-film transistors (TFTs) with SiO2 passivation deposited by plasma-enhanced chemical vapor deposition (PECVD) were fabricated. The impact of deposition temperature of the SiO2 passivation on the performance of the IZO-TFTs was investigated. It is found that the hydrogen content in the IZO film increases and the number of oxygen vacancies decreases as the SiO2 deposition temperature increases. The IZO-TFTs with SiO2 deposited at temperature higher than 230 °C show high conductive, and those with SiO2 deposited at temperature lower than 210 °C are less stable under positive bias stress (PBS). X-ray photoelectron spectroscopy (XPS) dept profile experiments show that IZO films covered by SiO2 deposited at lower temperature have larger amount of loosely bound oxygen impurities which act as acceptor-type traps. We propose that the origin of the positive V
on shift under PBS is the electrons trapped by the loosely bound oxygen impurities generated during the deposition of the SiO2 passivation.
An Autonomously Controllable Plasma Etching System Based on Radical Monitoring
Authors: Takahashi Shunji , Kawauchi Ryota , Takashima Seigo , Den Shoji , Katagiri Toshiro , Kano Hiroyuki , Ohta Takayuki , Ito Masafumi , Suzuki Tatsuya , Takeda Keigo , Hori Masaru
Published: June 2012

The optimum conditions for a plasma etching device are generally determined from the results of etching a sample while varying an external parameter (e.g., gas mass flow, gas mixing ratio, process chamber pressure, or plasma source power). However, to realize controlled plasma etching with few fluctuations on a subnanometer scale, it is essential to develop a system that is controlled in real-time based on internal plasma parameters (e.g., densities and energies of radicals and ions), which directly determine process characteristics, rather than external plasma parameters. We have developed an autonomously controlled plasma etching system that performs integrated monitoring of radicals in the gas phase and on the surface of films. The etching rate of organic materials could be autonomously controlled based on hydrogen and nitrogen radical densities obtained in real-time.
Development of Highly Sensitive Ion Imager Corresponding to Real-Time Readout Having Single-Ion Detectability
Authors: Sakamoto Naoya , Aoyama Satoshi , Kawahito Shoji , Yurimoto Hisayoshi
Published: June 2012

We designed a new type of stacked complementary metal–oxide–semiconductor active pixel sensor (SCAPS) for charged particles with real-time readout and single-ion detection capabilities. Here we present the characteristics of a new imager, SCAPS-II, which implements a newly devised pixel structure of 504×504 pixels for high sensitivity and a noise-reduction mechanism with analog accumulation capabilities inside the column readout circuits. The sensitivity for ions was estimated to be 150 µV/ion under 10 keV Si+ ion irradiation, which is 5 times greater than that of conventional SCAPS. The noise floor was at the 3 ion level without the noise-reduction mechanism at a frame rate of 0.16 s/frame. The noise reduction mechanism reduced the noise to the 1.7 ion level at 0.3 s/frame with 13 samplings. A combination of the noise-reduction mechanism and a multiple-frame-averaging technique achieved a noise level of 0.3 ions. Single-ion detectability was demonstrated using a combination of the noise-reduction mechanism and the multiple-frame-averaging technique that reduced the noise to the 0.3 ion level with 13 samplings, employing an integration circuit and 50-frame averaging at 14.4 s/frame.
Densification Dynamics of Gadolinium-Doped Ceria upon Sintering
Authors: Sato Kiminori
Published: June 2012

Densification behavior upon sintering is studied for gadolinium-doped ceria (GDC) by making use of X-ray diffraction, Archimedes method, high-resolution dilatometry (DLT), and element-specific positron annihilation spectroscopy. We found high concentration of vacancy-like nano-defects at GDC-crystallite interfaces participating in densification. Time-resolved length change and positron lifetime measurements enable to discuss the densification dynamics at the particle boundary relevant to a sintering neck and inside the particles. The particle boundary largely contributes to densification at the initial stage of sintering, whereas the crystallite interface gets to be responsible for prolonged densification. The densification inside the particle is developed by the growth of the crystallites followed by the transfer of Gd atoms from the interfaces to the crystallites.
Business models for strategy and innovation
Authors: Sako Mari
Published: June 2012

While often ambiguously defined, business models are central to innovation.
An information strategy for environmental sustainability
Authors: Watson R. T. , Corbett J. , Boudreau M. C. , Webster J.
Published: June 2012

Seeking solutions to a problem of change.
The challenges of privacy by design
Authors: Spiekermann Sarah
Published: June 2012

Heralded by regulators, Privacy by Design holds the promise to solve the digital world's privacy problems. But there are immense challenges, including management commitment and step-by-step methods to integrate privacy into systems.
Getting what you measure
Authors: Bouwers Eric , Visser Joost , van Deursen Arie
Published: June 2012

Four common pitfalls in using software metrics for project management.
Large-scale complex IT systems
Authors: Sommerville Ian , Cliff Dave , Calinescu Radu , Keen Justin , Kelly Tim , Kwiatkowska Marta , Mcdermid John , Paige Richard
Published: June 2012

The reductionism behind today's software-engineering methods breaks down in the face of systems complexity.
Why on-chip cache coherence is here to stay
Authors: Martin Milo M. K. , Hill Mark D. , Sorin Daniel J.
Published: June 2012

On-chip hardware coherence can scale gracefully as the number of cores increases.
Behavioral programming
Authors: Harel David , Marron Assaf , Weiss Gera
Published: June 2012

A novel paradigm for programming reactive systems centered on naturally specified modular behavior.
Looking back and looking forward
Authors: Esmaeilzadeh Hadi , Cao Ting , Yang Xi , Blackburn Stephen M. , McKinley Kathryn S.
Published: June 2012

The past 10 years have delivered two significant revolutions. (1) Microprocessor design has been transformed by the limits of chip power, wire latency, and Dennard scaling---leading to multicore processors and heterogeneity. (2) Managed languages and an entirely new software landscape emerged---revolutionizing how software is deployed, is sold, and interacts with hardware. Researchers most often examine these changes in isolation. Architects mostly grapple with microarchitecture design through the narrow software context of native sequential SPEC CPU benchmarks, while language researchers mostly consider microarchitecture in terms of performance alone. This work explores the clash of these two revolutions over the past decade by measuring power, performance, energy, and scaling, and considers what the results may mean for the future. Our diverse findings include the following: (a) native sequential workloads do not approximate managed workloads or even native parallel workloads; (b) diverse application power profiles suggest that future applications and system software will need to participate in power optimization and management; and (c) software and hardware researchers need access to real measurements to optimize for power and energy.
Accelerometry: A Feasible Method to Quantify Physical Activity in Ambulatory and Nonambulatory Adolescents with Cerebral Palsy
Authors: Gorter Jan Willem , Noorduyn Stephen G. , Obeid Joyce , Timmons Brian W.
Published: June 2012

Objective. To determine the feasibility of physical activity monitoring in adolescents with cerebral palsy (CP).Methods. A convenience sample of ambulatory and non-ambulatory adolescents (N=23; 17 males, 6 females; mean age 13.5 y, SD 2.6 y; Gross Motor Function Classification System (GMFCS) distribution:n=9Level I,n=5Level II,n=5Level III,n=4Level IV) was recruited. Physical activity (PA) was objectively assessed using theActiGraphGT1M activity monitor. Discomfort or adverse effects of wearing the accelerometers were recorded by participants. Levels of physical activity were determined as total PA, light PA (LPA), moderate PA (MPA), moderate-to-vigorous (MVPA), and vigorous PA (VPA) using cut-points recently validated for CP.Results. Most participants showed little reluctance. Mean daily MVPA for all participants was 30.7 minutes (SD 30.3), which corresponded to 2.7 (SD 2.4) minutes of MVPA per hour or 4.5% (SD 3.9) of the total monitoring time. Total PA and MVPA were greatest in ambulatory youth (GMFCS levels I and II) compared with youth who use a walking aid or wheelchair (GMFCS levels III and IV) (P<0.05).Conclusion(s). The results support the use of the accelerometer as a feasible and useful measure of activity in ambulatory and nonambulatory adolescents with CP.
Lenalidomide in Diffuse Large B-Cell Lymphomas
Authors: Chiappella Annalisa , Vitolo Umberto
Published: June 2012

Diffuse Large B-cell Lymphomas (DLBCL) are the most frequent Non-Hodgkin Lymphomas (NHL). The addition of Rituximab to the standard chemotherapy CHOP improved the outcome in this patients, but so far 40% of patients experienced relapse or progressive disease. Lenalidomide, an immunomodulatory agent, had direct tumoricidal and antiangiogenetic actions on tumor cells and was able to modulate tumor-cell microenvironment, with the restoration of impaired T-cell activity and the formation of immuno-synapsis. Based on these actions, lenalidomide represented an active drug on aggressive relapsed NHL. In this review, the most relevant clinical trials for the use of lenalidomide in DLBCL were reported. Monotherapy with lenalidomide showed an activity in term of overall response rate, with acceptable hematological and extrahematological toxicities in relapsed/refractory aggressive NHL. The role of lenalidomide as salvage therapy in both cell of origin patterns in DLBCL (germinal center B-cell/activated B-cell) was reported in preliminary data. Preliminary data regarding the role of lenalidomide in addition to chemoimmunotherapy (R-CHOP) in first line clinical trials were discussed; data of safety, feasibility and efficacy were promising.
Effects of Additional Oxygen Flow on the Optical and Electrical Properties of Ion Beam Sputtering Deposited Molybdenum‐Doped Zinc Oxide Layer
Authors: Kuo Chin-Chiuan , Liu Chi-Chang , He Shao-Chih , Chang Jing-Tang , He Ju-Liang
Published: June 2012

The transparent conductive molybdenum‐doped zinc oxide (MZO) was deposited onto a flexible polyethersulfone (PES) substrate by using an ion beam sputtering system. An argon ion beam was used to sputter an MZO target at constant pressure of 0.67 Pa and substrate temperature of 130∘C with varying the oxygen flow rate from 0 to 12 sccm. The influences of additional oxygen flow on the microstructure, optical, and electrical properties of films were investigated. The obtained MZO films present a crystalline structure. With increasing the oxygen flow rate, their electrical resistivity increases, and the optical band gap decreases from 3.46 to 3.20 eV. The film deposited in the atmosphere without introducing oxygen exhibits the best optical transmittance of 82.9% at 550 nm wavelength, electrical resistivity of 8.32 × 10−3 Ω cm, carrier concentration of 6.82 × 1020 cm−3, and carrier mobility of 2.45 cm2/Vs.
Feminizing Adrenal Carcinoma Presenting with Heart Failure and Ventricular Tachycardia
Authors: Harnoor Anjana , West R. Lee , Cook Fiona J.
Published: June 2012

We present a case of feminizing adrenal carcinoma with severe elevation in serum estradiol and otherwise unexplained congestive heart failure with ventricular arrhythmia and review the literature on feminizing adrenal tumors and the potential relationship between estrogen and cardiac problems. A 54-year-old man presented with congestive heart failure and ventricular arrhythmia. Imaging revealed a large adrenal mass. Hormonal evaluation revealed a very high serum level of estradiol, elevated DHEA-sulfate and androstenedione, and lack of cortisol suppression on a low-dose overnight dexamethasone suppression test. The patient underwent a left adrenalectomy with subsequent normalization of serum estradiol. Surgical pathology examination established adrenocortical carcinoma MacFarlane stage II. Upon 15-month followup, the patient continued to have a normal serum estradiol level, his cardiac function was significantly improved, and he had no further episodes of ventricular arrhythmia. To the best of our knowledge, the serum estradiol level that was detected in our case is the highest that has been reported. Further, we hypothesize that the very high serum concentration of estradiol in our case may have played a role in his cardiac presentation with congestive heart failure and arrhythmia, particularly as these problems resolved with normalization of his serum estradiol level.
Some Fixed Point Theorems for Nonlinear Set‐Valued Contractive Mappings
Authors: Liu Zeqing , Wu Zhihua , Kang Shin Min , Lee Sunhong
Published: June 2012

Four fixed point theorems for nonlinear set‐valued contractive mappings in complete metric spaces are proved. The results presented in this paper are extensions of a few well‐known fixed point theorems. Two examples are also provided to illustrate our results.
Activation of Thermogenesis in Brown Adipose Tissue and Dysregulated Lipid Metabolism Associated with Cancer Cachexia in Mice
Authors: Tsoli Maria , Moore Melissa , Burg Dominic , Painter Arran , Taylor Ryland , Lockie Sarah H. , Turner Nigel , Warren Alessandra , Cooney Greg , Oldfield Brian , Clarke Stephen , Robertson Graham
Published: June 2012

Cancer cachexia/anorexia is a complex syndrome that involves profound metabolic imbalances and is directly implicated as a cause of death in at least 20% to 30% of all cancers. Brown adipose tissue (BAT) plays a key role in thermogenesis and energy balance and potentially contributes to the physiologic perturbations associated with cachexia. In this study, we investigated the impact of cachexia-inducing colorectal tumor on BAT in mice. We found that brown adipocytes were smaller and exhibited profound delipidation in cachectic tumor–bearing mice. Diurnal expression profiling of key regulators of lipid accumulation and fatty acid β-oxidation and their corresponding target genes revealed dramatic molecular changes indicative of active BAT. Increased Ucp1, Pbe, and Cpt1α expression at specific points coincided with higher BAT temperatures during the dark cycle, suggestive of a temporal stimulation of thermogenesis in cachexia. These changes persisted when cachectic mice were acclimatized to 28°C confirming inappropriate stimulation of BAT despite thermoneutrality. Evidence of inflammatory signaling also was observed in the BAT as an energetically wasteful and maladaptive response to anorexia during the development of cachexia. Cancer Res; 72(17); 4372–82. ©2012 AACR.
DEDD Interacts with PI3KC3 to Activate Autophagy and Attenuate Epithelial–Mesenchymal Transition in Human Breast Cancer
Authors: Lv Qi , Wang Wei , Xue Jianfei , Hua Fang , Mu Rong , Lin Heng , Yan Jun , Lv Xiaoxi , Chen Xiaoguang , Hu Zhuo-Wei
Published: June 2012

Epithelial-to-mesenchymal transition (EMT), a crucial developmental program, contributes to cancer invasion and metastasis. In this study, we show that death-effector domain-containing DNA-binding protein (DEDD) attenuates EMT and acts as an endogenous suppressor of tumor growth and metastasis. We found that expression levels of DEDD were conversely correlated with poor prognosis in patients with breast and colon cancer. Both in vitro and in vivo, overexpression of DEDD attenuated the invasive phenotype of highly metastatic cells, whereas silencing of DEDD promoted the invasion of nonmetastatic cells. Via direct interaction with the class III PI-3-kinase (PI3KC3)/Beclin1, DEDD activated autophagy and induced the degradation of Snail and Twist, two master regulators of EMT. The DEDD–PI3KC3 interaction led to stabilization of PI3KC3, which further contributed to autophagy and the degradation of Snail and Twist. Together, our findings highlight a novel mechanism in which the intracellular signaling protein DEDD functions as an endogenous tumor suppressor. DEDD expression therefore may represent a prognostic marker and potential therapeutic target for the prevention and treatment of cancer metastasis. Cancer Res; 72(13); 3238–50. ©2012 AACR.
The Proinflammatory Myeloid Cell Receptor TREM-1 Controls Kupffer Cell Activation and Development of Hepatocellular Carcinoma
Authors: Wu Juan , Li Jiaqi , Salcedo Rosalba , Mivechi Nahid F. , Trinchieri Giorgio , Horuzsko Anatolij
Published: June 2012

Chronic inflammation drives liver cancer pathogenesis, invasion, and metastasis. Liver Kupffer cells have crucial roles in mediating the inflammatory processes that promote liver cancer, but the mechanistic basis for their contributions are not fully understood. Here we show that expression of the proinflammatory myeloid cell surface receptor TREM-1 expressed by Kupffer cells is a crucial factor in the development and progression of liver cancer. Deletion of the murine homolog Trem1 in mice attenuated hepatocellular carcinogenesis triggered by diethylnitrosamine (DEN). Trem1 deficiency attenuated Kupffer cell activation by downregulating transcription and protein expression of interleukin (IL)-6, IL-1β, TNF, CCL2, and CXCL10. In addition, Trem1 ablation diminished activation of the p38, extracellular regulated kinase 1/2, JNK, mitogen-activated protein kinase, and NF-κB signaling pathways in Kupffer cells, resulting in diminished liver injury after DEN exposure. Adoptive transfer of wild-type Kupffer cells to Trem1-deficient mice complemented these defects and reversed unresponsiveness to DEN-induced liver injury and malignant development. Together, our findings offer causal evidence that TREM-1 is a pivotal determinant of Kupffer cell activation in liver carcinogenesis, deepening mechanistic insights into how chronic inflammation underpins the development and progression of liver cancer. Cancer Res; 72(16); 3977–86. ©2012 AACR.
Carbonyl Reductase 1 Offers a Novel Therapeutic Target to Enhance Leukemia Treatment by Arsenic Trioxide
Authors: Jang Miran , Kim Yeonghwan , Won Hyeran , Lim Sangbin , K.R Jyothi , Dashdorj Amarjargal , Min Yoo Hong , Kim Si-Young , Shokat Kevan M. , Ha Joohun , Kim Sung Soo
Published: June 2012

Arsenic trioxide (As2O3) is used, in current practice, as an effective chemotherapeutic agent for acute promyelocytic leukemia (APL). However, the side effects and relatively low efficacy of As2O3 in treating other leukemias have limited its wider use in therapeutic applications. In the present study, we found that the expression of carbonyl reductase 1 (CBR1) affects the resistance to As2O3 in leukemias, including APL; As2O3 upregulated CBR1 expression at the transcriptional level by stimulating the activity of the transcription factor activator protein-1. Moreover, CBR1 overexpression was sufficient to protect cells against As2O3 through modulation of the generation of reactive oxygen species, whereas the attenuation of CBR1 was sufficient to sensitize cells to As2O3. A combination treatment with the specific CBR1 inhibitor hydroxy-PP-Me remarkably increased As2O3-induced apoptotic cell death compared with As2O3 alone, both in vitro and in vivo. These results were confirmed in primary cultured human acute and chronic myeloid leukemia cells, with no significant cell death observed in normal leukocytes. Taken together, our findings indicate that CBR1 contributes to the low efficacy of As2O3 and, therefore, is a rational target for the development of combination chemotherapy with As2O3 in diverse leukemias including APL. Cancer Res; 72(16); 4214–24. ©2012 AACR.
P1-17-01: Figitumumab Plus Exemestane Versus Exemestane as First-Line Treatment of Postmenopausal Hormone Receptor-Positive Advanced Breast Cancer: A Randomized, Open-Label Phase II Trial.
Authors: Ryan PD , Neven P , Blackwell KL , Dirix LY , Barrios CH , Miller WH , Fein LE , Fenton D , Benner RJ , Meech SJ , Paccagnella L , Sleight B , Yee D , Goss PE
Published: June 2012

Background Figitumumab (CP-751,871) is a fully human IgG2 monoclonal antibody that inhibits IGF-1R. Exemestane profoundly reduces estrogen production and has activity as first-line treatment in postmenopausal metastatic hormone receptor-positive (HR+) breast cancer (BC). Preclinical studies suggest cross-talk between the IGF-1R and estrogen receptor pathways. Combining agents that inhibit these pathways could benefit women with advanced BC.

Methods This was an open-label, multicenter, randomized, phase II trial of first-line figitumumab + exemestane (Arm A) vs. exemestane alone (Arm B) in HR+ postmenopausal advanced BC. Eligibility included: age >18 yrs with Stage IIIB or IV disease; baseline ECOG PS ≤2. A high rate of grade [G] 3 and 4 hyperglycemia after figitumumab treatment prompted a protocol amendment in February 2010 requiring patients (pts) to have a baseline HbA1c <5.7%. Patients received exemestane 25 mg po daily ± intravenous figitumumab 20 mg/kg every 21 days. The primary endpoint was progression-free survival (PFS) in pts with baseline HbA1c <5.7%. Secondary endpoints included clinical benefit rate (CBR) and safety.

Results Between 2007 and February 2011, 103 pts were randomized to Arm A and 102 to Arm B. Of these, 37 pts in Arm A and 40 pts in Arm B had baseline HbA1c <5.7%. These data are from an unplanned interim analysis which preceded premature study termination by the Sponsor for clinical development reasons and to expedite availability of data collected to date. Baseline demographics were balanced between arms. PFS, CBR and safety are summarized in Table 1.

The majority of AEs were G1/2. In the Arm A overall population, the most common G3/4 events (in decreasing frequency) were hyperglycemia, diabetes mellitus, weight loss, isolated GGT elevation and fatigue. Hyperglycemia was uncommon in Arm B and in all pts with HbA1c <5.7%.[Table 2].

Conclusions The addition of figitumumab to exemestane was tolerable but overall did not improve PFS compared with exemestane alone in pts eligible for this trial. However, a trend toward benefit with figitumumab combined with exemestane in pts without evidence of baseline metabolic syndrome (HbA1c <5.7%) was observed together with improved tolerability; further study with this combination may be warranted.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-01.
S5-6: Neoadjuvant Pertuzumab and Trastuzumab Concurrent or Sequential with an Anthracycline-Containing or Concurrent with an Anthracycline-Free Standard Regimen: A Randomized Phase II Study (TRYPHAENA).
Authors: Schneeweiss A , Chia S , Hickish T , Harvey V , Eniu A , Hegg R , Tausch C , Seo J-H , Tsai Y-F , Ackrill A , Ross G , Cortés J
Published: June 2012

Background: Pertuzumab (P) is a fully humanized investigational monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2), preventing homo- and heterodimerization of HER2 and other HER family members and inducing antibody-dependent cell-mediated cytotoxicity. The NeoSphere study demonstrated significantly increased antitumor activity in the neoadjuvant setting for the combination of P and trastuzumab (H) plus docetaxel (T) compared with HT alone (Gianni et al. SABCS 2010), consistent with the hypothesis of complementary mechanisms of action of P and H. No increase in cardiac risk was observed with the addition of P to H and HT regimens. Anthracyclines have an important role in the treatment of breast cancer and may be especially efficacious in HER2−positive disease. In the TRYPHAENA study, P and H are being administered either sequentially or concurrently with an anthracycline-containing or concurrently with an anthracycline-free standard regimen in order to establish the tolerability profile of these regimens for testing in the adjuvant setting.

Methods: Patients with centrally confirmed stage II or III (including locally advanced and inflammatory disease) HER2−positive breast cancer (defined as centrally confirmed HER2 IHC 3+ or FISH/CISH+) were randomized to receive:

Study medication: P 840 mg loading dose and 420 mg maintenance; H 8 mg/kg loading dose and 6 mg/kg maintenance; T was given at 75 mg/m2 with dose escalation to 100 mg/m2 if the starting dose was well tolerated (no dose escalation in Arm C); FEC (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 600 mg/m2) and carboplatin AUC 6. All treatments were given intravenously q3w. The study is ongoing. All patients will receive H for 1 year. The primary endpoint is assessment of the safety and tolerability of neoadjuvant treatment. During neoadjuvant treatment, left ventricular ejection fraction is assessed at Cycles 2, 4, and 6 by echocardiogram or multiple-gated acquisition. Safety data are supervised by a data and safety monitoring board. The key secondary endpoint is the rate of pathological complete response (pCR) defined as absence of invasive disease in the breast at surgery. Tissue specimens at baseline and post-surgery were required for all patients.

This study is registered at ClinicalTrials.gov: NCT00976989.

Results: 225 patients have been recruited. No arm has required modification due to safety concerns or to excessive incidence of disease progression. Analysis of the study results is anticipated in Q3 2011. Safety/tolerability and efficacy (pCR) data will be presented.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-6.
Molecular Pathways: The Hedgehog Signaling Pathway in Cancer
Authors: McMillan Ross , Matsui William
Published: June 2012

The Hedgehog (Hh) signaling pathway regulates embryonic development and may be aberrantly activated in a wide variety of human cancers. Efforts to target pathogenic Hh signaling have steadily progressed from the laboratory to the clinic, and the recent approval of the Hh pathway inhibitor vismodegib for patients with advanced basal cell carcinoma represents an important milestone. On the other hand, Hh pathway antagonists have failed to show significant clinical activity in other solid tumors. The reasons for these negative results are not precisely understood, but it is possible that the impact of Hh pathway inhibition has not been adequately measured by the clinical endpoints used thus far or that aberrancies in Hh signal transduction limits the activity of currently available pathway antagonists. Further basic and correlative studies to better understand Hh signaling in human tumors and validate putative antitumor mechanisms in the clinical setting may ultimately improve the success of Hh pathway inhibition to other tumor types. Clin Cancer Res; 18(18); 4883–8. ©2012 AACR.
Molecular Pathways: Tumor-Infiltrating Myeloid Cells and Reactive Oxygen Species in Regulation of Tumor Microenvironment
Authors: Lu Tangying , Gabrilovich Dmitry I.
Published: June 2012

Tumor-associated myeloid cells are the major type of inflammatory cells involved in the regulation of antitumor immune responses. One key characteristic of these cells is the generation of reactive oxygen (ROS) and reactive nitrogen species (RNS) in the tumor microenvironment. Recent studies have shown the important role of ROS and RNS, especially peroxynitrite, in immune suppression in cancer. ROS and RNS are involved in induction of antigen-specific T-cell tolerance, inhibition of T-cell migration to the tumor site, and tumor cell evasion of recognition by cytotoxic T cells. In preclinical settings, a number of potential therapeutic agents showed activity in blocking ROS/RNS in cancer and in improving the efficacy of cancer immune therapy. A better understanding of ROS/RNS-associated pathways in myeloid cells will help to identify more specific and direct targets to facilitate the development of more effective immune therapy for cancer. Clin Cancer Res; 18(18); 4877–82. ©2012 AACR.
The HSP90 Inhibitor, AT13387, Is Effective against Imatinib-Sensitive and -Resistant Gastrointestinal Stromal Tumor Models
Authors: Smyth Tomoko , Van Looy Thomas , Curry Jayne E. , Rodriguez-Lopez Ana M. , Wozniak Agnieszka , Zhu Meijun , Donsky Rachel , Morgan Jennifer G. , Mayeda Mark , Fletcher Jonathan A. , Schöffski Patrick , Lyons John , Thompson Neil T. , Wallis Nicola G.
Published: June 2012

The majority of gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT, an HSP90 client protein. Further secondary resistance mutations within KIT limit clinical responses to tyrosine kinase inhibitors, such as imatinib. The dependence of KIT and its mutated forms on HSP90 suggests that HSP90 inhibition might be a valuable treatment option for GIST, which would be equally effective on imatinib-sensitive and -resistant clones. We investigated the activity of AT13387, a potent HSP90 inhibitor currently being evaluated in clinical trials, in both in vitro and in vivo GIST models. AT13387 inhibited the proliferation of imatinib-sensitive (GIST882, GIST-T1) and -resistant (GIST430, GIST48) cell lines, including those resistant to the geldanamycin analogue HSP90 inhibitor, 17-AAG. Treatment with AT13387 resulted in depletion of HSP90 client proteins, KIT and AKT, along with their phospho-forms in imatinib-sensitive and -resistant cell lines, irrespective of KIT mutation. KIT signaling was ablated, whereas HSP70, a marker of HSP90 inhibition, was induced. In vivo, antitumor activity of AT13387 was showed in both the imatinib-sensitive, GIST-PSW, xenograft model and a newly characterized imatinib-resistant, GIST430, xenograft model. Induction of HSP70, depletion of phospho-KIT and inhibition of KIT signaling were seen in tumors from both models after treatment with AT13387. A combination of imatinib and AT13387 treatment in the imatinib-resistant GIST430 model significantly enhanced tumor growth inhibition over either of the monotherapies. Importantly, the combination of AT13387 and imatinib was well tolerated. These results suggest AT13387 is an excellent candidate for clinical testing in GIST in combination with imatinib. Mol Cancer Ther; 11(8); 1799–808. ©2012 AACR.