bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental and Theoretical Characteristics of Sub-Terahertz and Terahertz Oscillations of Resonant Tunneling Diodes Integrated with Slot Antennas
Authors: Orihashi Naoyuki , Hattori Shinnosuke , Suzuki Safumi , Asada Masahiro
Published: December 2005

Experimental and theoretical characteristics of sub-terahertz and terahertz oscillations in resonant tunneling diodes (RTDs) integrated with slot antennas are reported. In the experiments, oscillations up to 0.6 THz were obtained in GaInAs/AlAs double-barrier RTDs. The oscillation characteristics were theoretically analyzed for the total device structure including RTD and slot antenna. The equivalent circuit with all parasitic elements was taken into account for the RTD, and the actual structure of the antenna was analyzed using a three-dimensional electromagnetic simulator. The theoretical analysis was in good agreement with the measurements of oscillation frequency and output power. It was shown from the theoretical results that the RTD itself has the potential to oscillate up to 3.0 THz, and that the RTD oscillator with slot antenna is able to oscillate up to 2.8 THz if the device structure is optimized. The output power analysis showed that 90 µW at 1 THz is possible by optimizing the device structure.
Laser Chaos Induced by Delayed-Feedback and External Modulation
Authors: Juang Cheng , Chang Shu-Ming , Hu Nien-Kuo , Lee Charleson , Lin Wen-Wei
Published: December 2005

Electronic-controlled routes to chaos in a quantum-well laser diode are produced using a delayed-feedback technique. By introducing an extra delayed-feedback control term c
S

n
(t-τ), chaotic light output can be achieved at a relatively low bias and a small modulation depth. The interaction between external modulation and delay forms quasi-two-period routes to chaos by varying modulation amplitude b and intermittency routes to chaos by varying modulation frequency f
0. Numerical analysis and experimental results agree qualitatively.
Slurry Transport during Chemical Mechanical Polishing
Authors: Fu Ming-Nan , Liao Shan-Hui , Li Ching-Chung , Chang Pai-Yu
Published: December 2005

An optical technique for flow diagnostics is developed to study the slurry transport on the surface of a pad and in an inter-pad-wafer region during chemical mechanical polishing. In this paper, we show that the variations in mean gray scale and nonuniformity with the wafer and pad rotation speeds agree in trend with the existing data of removal rate and nonuniformity for a 150 mm wafer. The simulation results of wafer-scale-averaged slurry shearing stress and nonuniformity also agree in trend with the data of mean gray scale and nonuniformity for a 200 mm wafer. The present flow diagnostics technique can be further used for the optimization of slurry injection rate and injection position to simultaneously obtain a high removal rate as well as a low nonuniformity. In this paper, we also show the optimum slurry injection rate.
Effects of Different n-Electrode Patterns on Optical Characteristics of Large-Area p-Side-Down InGaN Light-Emitting Diodes Fabricated by Laser Lift-Off
Authors: Chu Jung-Tang , Kao Chih-Chiang , Huang Hung-Wen , Liang Wen-Deng , Chu Chen-Fu , Lu Tien-Chang , Kuo Hao-Chung , Wang Shing-Chung
Published: December 2005

Large-area p-side-down InGaN light-emitting diodes (LEDs) 1000×1000 µm2 in size have been fabricated by laser lift-off (LLO). The p-side-down LEDs with different geometric patterns of n-electrodes were fabricated to investigate electrode pattern-dependent optical characteristics. The current crowding effect was observed in the large-area p-side-down InGaN LLO-LEDs. A LED with a well-designed n-electrode pattern shows a uniform distribution of light emission and a higher output power due to uniform current spreading. The output power saturation induced by the current crowding effect was investigated. In the absence of a transparent contact layer for current spreading, the n-electrode pattern has a marked influence on the current distribution and the consequent light output power of the large-area p-side-down LEDs.
Nitride-Based UV Metal–Insulator–Semiconductor Photodetector with Liquid-Phase-Deposition Oxide
Authors: Hwang J. D. , Yang Gwo Huei , Yang Yuan Yi , Yao Pin Cuan
Published: December 2005

A low-temperature (30–40°C), low-cost and reliable method of liquid phase deposition (LPD) has been employed to grow SiO2 layers on GaN. The LPD process uses a supersaturated acid aqueous solution of hydrofluosilicic (H2SiF6) as a source liquid and an aqueous solution of boric acid (H3BO3) as a deposition rate controller. In this study, the LPD SiO2 was prepared at 40°C with concentrations of H2SiF6 and H3BO3 at 0.2 and 0.01 M, respectively. The minimum interface-trap density, Dit, of a metal–insulator–semiconductor (MIS) capacitor with a structure of Al/20 nm LPD-SiO2/n-GaN was estimated to be 8.4×1011 cm-2 V-1. Furthermore, a MIS photodetector with a 10-nm-thick LPD-SiO2 layer has been fabricated successfully. The dark current density was as low as 4.41×10-6 A/cm2 for an applied field of 4 MV/cm. A maximum responsivity of 0.112 A/W was observed for incident ultraviolet light of 366 nm with an intensity of 4.15 mW/cm2. Defect-assisted tunneling was invoked to explain these results.
Determination of Raman Phonon Strain Shift Coefficient of Strained Silicon and Strained SiGe
Authors: Wong L. H. , Wong C. C. , Liu J. P. , Sohn D. K. , Chan L. , Hsia L. C. , Zang H. , Ni Z. H. , Shen Z. X.
Published: December 2005

The use of Raman spectroscopy to characterize strain in strained Si and strained SiGe has been widely accepted. To use Raman spectroscopy for quantitative biaxial strain measurements, the strain shift coefficient for Si–Si vibration from strained Si (b
Si–Si
StSi) and strained SiGe (b
Si–Si
StSiGe) must be known. So far, b
Si–Si
StSiGe is commonly used to calculate strain in strained Si, which may result in inaccurate strain values. In this work, we report the first direct measurement of b
Si–Si
StSi by correlating high-resolution X-ray diffraction and Raman spectroscopy, which yields a measured value of -784±4 cm-1. We also show that the strain shift coefficient of SiGe, b
Si–Si
StSiGe, is a strong function of Ge concentration (x), and follows the empirical relation: b=-773.9-897.7x for x<0.35.
Comparative Study of Effect of Initial Sintering in Rod/Tube Shape on Jc and Fracture Strength of Bi-2223: 10 wt % Ag Bulk Rod Conductors
Authors: Padam Gursharan K. , Ekbote Shrikant N. , Arora Narendra K. , Sharma Mukul , Sood Kedar N. , Das Bijoy K.
Published: December 2005

The effect of two different initial sintering routes, (1) initial sintering in the rod shape (RS) and (2) initial sintering in the tube shape (TS), has been studied especially on the critical current density (J
c) and diametric fracture strength (σ) of Bi-2223 as 10 wt % Ag bulk rod conductors from a cold isostatic pressing (CIP) process. Apart from studying J
c and σ, these rods have been characterized by X-ray diffraction (XRD), energy dispersive analysis for X-rays (EDAX) and scanning electron microscopy (SEM). These studies showed that the final Bi-2223 rods achieved using the tube shape initial sintering route (TSR) in a for shorter duration exhibit higher J
c and σ values compared with final rods prepared from the rod shape using the initial sintering route (RSR).
Thermally Induced Stability Issues of Head-Disk Interface in Heat-Assisted Magnetic Recording Systems
Authors: Li Hui , Liu Bo , Ye Huanyi , Chong Tow-Chong
Published: December 2005

It is widely assumed that heat-assisted magnetic recording (HAMR) technology can further push magnetic recording technology to and beyond 1 Tb/in2 in area density. However, one of the major concerns of HAMR technology is the robustness and long-term stability of its head-disk interface. In this paper, we report our efforts in answering the uncertainties of head-disk interface design and stability of HAMR systems. The investigations focuses on (a) heating-induced pressure change by air and evaporation and its possible effects to a slider's flying stability (b) a laser-induced slider's thermal protrusion and its effects to the slider's flying stability. Results suggest that, among the factors under consideration, the thermal protrusion effects are much more severe. Possible solutions on how to reduce such effects are also discussed.
Fabrication of Hexagonally Arrayed Nanoholes Using Femtosecond Laser Pulse Ablation with Template of Subwavelength Polystyrene Particle Array
Authors: Takada Hiroto , Obara Minoru
Published: December 2005

We present nanohole array fabrication on a silicon substrate using a femtosecond laser pulse at 820 nm and 100 fs, and a subwavelength polystyrene (PS) particle array as a template. Nanohole array fabrication uses a particle field enhancement effect and two-dimensional (2-D) arrayed PS nanoparticles deposited on a (100) silicon (Si) substrate. PS spheres 200, 450, and 820 nm in diameter are used. The fabricated nanohole profiles in terms of the particle diameter and irradiated laser fluence are investigated. The nanohole diameter and depth become larger and deeper, respectively, as the diameter of the particles used or the irradiated laser fluence is increased. Light intensity enhancement by the particles is obtained experimentally by comparing ablation rates of the Si substrate with and without particles. The enhanced light intensity between a PS particle and a Si substrate is also calculated by the finite difference time domain (FDTD) method. The calculated optical enhancement factor is consistent with the experimental value.
Generation of Debris in Water-Assisted Femtosecond Laser Drilling of Silica Glass
Authors: Iga Yasunobu , Watanabe Wataru , Li Yudong , Li Yan , Nishii Junji , Itoh Kazuyoshi
Published: December 2005

We report on the generation of debris in the femtosecond laser drilling of silica glass in water. The morphology of the debris ejected from the amorphous synthesized silica is examined by scanning electron microscopy and the chemical structures are investigated by X-ray diffraction analysis and Fourier transform infrared spectroscopy.
Inorganic Alignment Layers Using Noncontact Method for Liquid Crystal Displays
Authors: Kim Kyung Chan , Ahn Han Jin , Kim Jong Bok , Hwang Byoung Har , Baik Hong Koo , Lee Se Jong
Published: December 2005

Inorganic alignment materials were deposited on indium–tin-oxide (ITO) glass by reactive sputtering deposition. After deposition, inorganic alignment materials such as a-SiO
x
and a-SiO
x
:H were irradiated using an Ar+ ion beam (IB) for liquid crystal (LC) alignment. On the basis of the experimental results, an a-SiO
x
film deposited by sputtering does not align LCs regardless of IB treatment, but an a-SiO
x
:H film treated with varying IB energies, IB incident angles, IB doses, and IB irradiation times has excellent alignment properties and electro optical properties, the same as polyimide (PI). We investigated period of the stability of an inorganic alignment layer treated with IB after a long time. From the experimental results, the inorganic alignment layer irradiated with an IB does not experience degradation of its electro optical properties. These results imply that an inorganic alignment layer irradiated with IB can be adopted as an LC alignment layer instead of rubbed PI and that hydrogen plays an important role in LC alignment due to the difference in alignment properties between a-SiO
x
films and a-SiO
x
:H films.
Numerical Simulation of Electrical Model for Organic Light-Emitting Devices with Fluorescent Dopant in the Emitting Layer
Authors: Lee Chih-Chien , Jong Yeung-Dong , Huang Ping-Tsung , Chen Yen Chun , Hu Peir-Jy , Chang Yih
Published: December 2005

We present a numerical model for the quantitative simulation of electrical characteristics for organic light-emitting devices (OLEDs) with fluorescent dopants in the host. We use drift-diffusion equations in terms of the electron and hole current densities coupled with the Poisson's equation. Compared with other models proposed in previous literature, we include charge carrier trapping and direct carrier recombination phenomena on the fluorescent dopants in the simulation. Furthermore, current density, charge distribution, and recombination data in the device are obtained from this numerical study. Results for several multilayer devices with different fluorescent dopant concentrations are presented in this article. On the basis of the experimental data of a typical doped device, we have found good agreement between the simulation results and the experimental results.
Analysis of Interactions between Green Fluorescent Protein and Silicon Substrates Using Molecular Dynamics Simulations
Authors: Nishiyama Katsuhiko , Watanabe Takanobu , Hoshino Tadatsugu , Ohdomari Iwao
Published: December 2005

We have performed a series of molecular dynamics (MD) simulations on interactions between green fluorescent protein (GFP) and Si substrates. The results show that GFP adsorbs directly on the hydrophobic substrate, and via water molecules on the hydrophilic substrate. The adsorption-induced changes in the conformation of GFP are smaller on the hydrophilic substrate than on the hydrophobic substrate. On the other hand, the dynamic atom motions in GFP are larger on the hydrophobic substrate than on the hydrophilic substrate. In order to prevent the denaturation of proteins caused by immobilization on a substrate, the Si surface should be prepared from the viewpoints of both conformation and dynamic atom motions.
Direct Growth of Single-Walled Carbon Nanotube Networks on Alumina Substrate: A Novel Route to Ultrasensitive Gas Sensor Fabrication
Authors: Wongwiriyapan Winadda , Honda Shin-ichi , Konishi Hirofumi , Mizuta Tomoaki , Ohmori Takafumi , Ito Tatsuya , Maekawa Toru , Suzuki Kengo , Ishikawa Hiroshi , Murakami Toshiya , Kisoda Kenji , Harima Hiroshi , Oura Kenjiro , Katayama Mitsuhiro
Published: December 2005

We explored structural and electrical properties of single-walled carbon nanotube (SWNT) networks directly grown on alumina substrates. The netlike SWNTs were uniformly grown on the substrate at a high quality. From the Raman spectroscopy analysis it was found that the as-grown SWNT networks were a mixture of metallic and semiconducting SWNTs, while the SWNT networks after their electrical breakdown exhibited a predominance of the semiconducting property. The direct growth method and subsequent electrical breakdown facilitated high-throughput production of practical ultrasensitive sensors for pollutant gases with a high sensitivity, which was demonstrated by NO2 detection.
n-Type Doping for Single-Walled Carbon Nanotubes by Oxygen Ion Implantation with 25 eV Ultralow-Energy Ion Beam
Authors: Kamimura Takafumi , Yamamoto Kazuhiro , Kawai Takushi , Matsumoto Kazuhiko
Published: December 2005

Oxygen ions with the ultralow-energy of 25 eV are implanted in single walled carbon nanotube (SWNT) field-effect transistors (FETs), which convert the SWNT from p-type to n-type. The dose amount ranged from 1.8×1011 to 8.2×1012 ions/cm2. In the drain current–gate voltage characteristic, the hole current begins to decrease while the electron current begins to increase as the dose of the oxygen ions implanted in SWNT-FETs increases. Moreover, the threshold voltage of the hole transport shifted to the negative direction of the gate voltage. These changes in the electrical properties of SWNT-FET after the oxygen-ion implantation correspond to the n-type conversion and to the shift in Fermi level from the valence band edge to the conduction band edge. The implanted oxygen ions may substitute the carbon atoms in the SWNT and act as donor impurities.
Nanoscale Capacitance–Voltage Characterization of Two-Dimensional Electron Gas in AlGaN/GaN Heterostructures
Authors: Koley G. , Lakshmanan L. , Tipirneni N. , Gaevski M. , Koudymov A. , Simin G. , Cha Ho-Young , Spencer M. G. , Khan A.
Published: December 2005

A simple technique for quantitative nanoscale capacitance–voltage (C–V) measurements has been developed and used to characterize the two-dimensional electron gas (2DEG) at the interface of AlGaN/GaN heterostructures. The measurements indicate change in confinement of the 2DEG at the AlGaN/GaN interface depending on the direction of the dc voltage sweep during C–V measurements, indicating surface state charging and discharging. Under UV illumination, the 2DEG increased significantly as inferred from the increase in threshold voltage of the nanoscale C–V scans, while no change in 2DEG confinement was observed.
Role of Intermolecular Separation in Nanoscale Patterning C60 Films by Local Injection of Electrons from Scanning Tunneling Microscope Tip
Authors: Nakamura Yoshiaki , Mera Yutaka , Maeda Koji
Published: December 2005

A systematic study on the polymerization and decomposition of C60 molecules induced by electron injection from scanning tunneling microscope (STM) tips has revealed that increasing intermolecular separation in the lateral directions with respect to the surface reduces both polymerization and decomposition reaction efficiencies and suppresses the spreading effect of polymerization from the electron injection point, down to ∼2 nm under a good condition. This is understood by considering that the wider lateral intermolecular separation and hence the smaller intermolecular spacing vertical to the surface lead to a suppression of electron spreading parallel to the surface but its enhancement normal to the surface, resulting in the small localization of molecular reactions on the surface.
Intrinsic Switching Characteristics of Ferroelectric Ultrathin Vinylidene Fluoride/Trifluoroethylene Copolymer Films Revealed Using Au Electrode
Authors: Nakajima Takashi , Abe Ryosuke , Takahashi Yoshiyuki , Furukawa Takeo
Published: December 2005

Time-domain measurements of ferroelectric polarization reversal were conducted for spin-coated ultrathin vinylidene fluoride/trifluoroethylene copolymer films deposited with an Au electrode. It was found that full polarization reversal occurs in 50–330-nm-thick films that have switching time independent of the film thickness. We conclude that the thinning-induced increase in switching time reported previously is not a general feature of this copolymer but is specific to an Al-electrode-deposited sample. The intrinsic switching characteristics revealed here include the broadening of the switching time distribution with thinning, which is attributed to the nonuniform electric field caused by surface roughness.
ZnO Nanowires Grown by Atmospheric Pressure Chemical Vapor Deposition Using ZnCl2 and H2O as Source Materials and Their Growth Mechanisms
Authors: Terasako Tomoaki , Shirakata Sho
Published: December 2005

Single crystalline ZnO nanowires (NWs) with diameters ranging from 80 to 700 nm were successfully grown on Ni-coated SiO2/Si(100) substrates by atmospheric pressure chemical vapor deposition (CVD) using ZnCl2 and H2O as source materials. Scanning electron microscope (SEM) and transmission electron microscope (TEM) observations revealed that the ZnO NWs grown by two types of CVD systems with different source feeding configurations exhibited different morphologies and growth directions, reflecting the difference in growth mechanism, i.e., vapor–liquid–solid (VLS) growth and vapor–solid (VS) growth. Photoluminescence spectra of the ZnO NWs exhibited a dominant near-band-edge (NBE) emission, indicating their high crystalline quality.
Flat Band Voltage Shifts in Pentacene Organic Thin-Film Transistors
Authors: Kim Sung-Jin , So Myeong-Seob , Suh Min Chul , Chung Ho-Kyoon
Published: December 2005

We have identified the mechanism of capacitance–voltage (C–V) hysteresis behavior often observed in pentacene organic thin-film transistors (OTFTs). The C–V characteristics were measured for pentacene OTFTs fabricated on glass substrates with MoW as gate/source/drain electrode and tetraethoxysilane (TEOS) SiO2 as gate insulator. The measurements were made at room temperature and elevated temperatures. From the room temperature measurements, we found that the hysteresis behavior was caused by hole injection into the gate insulator from the pentacene semiconductor for large negative gate voltages, resulting in the negative flat-band voltage shift. However electron injection was observed only at elevated temperatures.
A Study of Electrical Damage to a-Si:H Thin Film Transistor during Plasma Ashing by a Pin-to-Plate Type Atmospheric Pressure Plasma
Authors: Lee Yong-Hyuk , Kyung Se-Jin , Lim Jong-Hyuk , Yeom Geun-Young
Published: December 2005

In this study, the effect of the plasma ashing of the photoresist on a-Si:H thin film transistor (TFT) devices carried out using an atmospheric pressure plasma on the electrical damage to the TFT devices was investigated. By exposing the TFT devices to the plasma with a photoresist ashing rate of about 860 nm/min for up to 120 s, their electrical characteristics were significantly degraded, possibly due to charge trapping in the SiN
x
of the passivation layer and gate insulator and to bond breaking in a-Si:H. The degradation of the field effect mobility, I
off, and I
on/I
off ratio of the devices is believed to be mostly related to the bond breaking in the a-Si:H and charge trapping caused by the UV radiation, while the change in the threshold voltage appears to be mostly related to the surface charging caused by the charged species in the plasma. The damaged TFT devices, however, could be fully repaired by conventional annealing in a furnace at 290°C in N2 for 60 min.
Fabrication of Nanoparticle Composite Porous Films Having Ultralow Dielectric Constant
Authors: Nunomura Shota , Koga Kazunori , Shiratani Masaharu , Watanabe Yukio , Morisada Yoshinori , Matsuki Nobuo , Ikeda Shingo
Published: December 2005

Nanoparticle composite porous films having a dielectric constant of εr=1.7–3.5 have been deposited using plasma chemical vapor deposition. Nanoparticles as nano-building blocks and radicals as adhesives are generated in plasmas, and nanoparticles are deposited together with radicals on substrates to form porous films. Nano-sized pores are dispersed in the films and their dielectric constants are controlled by the concentrations of pores, i.e., their porosities. The method is applicable to depositing nanoparticle composite porous films for other applications.
Efficient High-Average-Power Operation of Q-Switched Cryogenic Yb:YAG Laser Oscillator
Authors: Tokita Shigeki , Kawanaka Junji , Fujita Masayuki , Kawashima Toshiyuki , Izawa Yasukazu
Published: December 2005

We have demonstrated a cryogenically cooled Q-switched Yb:YAG laser oscillator in a diode pump. A high average power of 74 W was obtained with a pulse energy of several mJ. The optical–optical efficiency was as high as 60%. The spatial beam profile was excellent at M
2<1.4 with no additional compensation optics.
Polarization Raman Microscopic Study of Molecular Alignment Behavior in Liquid Crystal/Polymer Composite Films
Authors: Murashige Takeshi , Fujikake Hideo , Sato Hiroto , Kikuchi Hiroshi , Kurita Taiichiro , Sato Fumio
Published: December 2005

We clarified that the molecular alignment of aggregated polymers is partially synchronized with liquid crystal (LC) director reorientation in an LC/polymer composite film. The molecular alignment behavior in composite films with LC- and polymer-rich regions formed by photopolymerization-induced phase separation was investigated using polarization Raman spectral microscopy. Raman scattering intensity induced by aligned side chains of polymers in the LC-rich region changed with LC director reorientation when voltage was applied to the composite film. It was confirmed for the first time that polymers capable of movement are formed in the LC-rich region.
High Sensitivity and Large Dynamic Range Surface Plasmon Resonance Sensing for DNA Hybridization Using Au-Nanoparticle-Attached Probe DNA
Authors: Hayashida Masayuki , Yamaguchi Akira , Misawa Hiroaki
Published: December 2005

In this study, we demonstrate the use of surface plasmon interaction between Au nanoparticles (GPs) and a Au thin film for enhancement of surface plasmon resonance (SPR) spectroscopy sensing for DNA hybridization. In situ DNA hybridization with a Au-nanoparticle-attached probe DNA (DNA-GP) monolayer is monitored by SPR spectroscopy, and the results reveal that the DNA-GP allows detection of unlabeled target DNA with the large dynamic range of 1 pM to 10 µM.
Photoluminescence from Si Nanocrystals Embedded in SiOxNy Thin Films
Authors: Matsumoto Kimihisa , Imakita Kenji , Fujii Minoru , Hayashi Shinji
Published: December 2005

The luminescence properties of Si nanocrystals embedded in SiO
x
N
y
thin films were studied. At relatively low N concentrations (≈1.0 at. %) an increase in the photoluminescence (PL) intensity and a lengthening of the PL lifetime were observed, suggesting that non-radiative recombination centers on the surface of Si nanocrystals are terminated by N atoms. The increase was accompanied by the redshift of the luminescence band. The redshift indicates that the effect is more efficient for larger Si nanocrystals. At N concentration higher than 1.4 at. %, the PL intensity was smaller than that of the sample without N doping. PL quenching in a high-N-concentration range is due probably to the introduction of new nonradiative recombination centers generated by N induced stress.
Cell proliferation and drug resistance in hepatocellular carcinoma are modulated by Rho GTPase signals
Authors: Sterpetti Paola , Marucci Luca , Candelaresi Cinzia , Toksoz Deniz , Alpini Gianfranco , Ugili Laura , Baroni Gianluca Svegliati , Macarri Giampiero , Benedetti Antonio
Published: December 2005

Hepatocellular carcinoma is highly resistant to chemotherapeutic agents, thus the need to discover effective therapeutic molecules to suppress cancer cell growth and to overcome drug resistance is urgent. The Rho GTPase is implicated in cancer and metastasis and is directly activated by the Lymphoid blast crisis (Lbc) protooncogene, a Rho guanine-nucleotide exchange factor. The aim of the study was to analyze the expression of Lbc in hepatocarcinoma and to determine the effect of Lbc-induced Rho signaling on expression, growth rate and resistance to genotoxic stress. We found, by immunohistochemical analysis of biopsy samples and Northern and Western blot analyses of cell lines, that Lbc is absent in normal adult liver but is abundantly expressed in hepatocarcinoma, implying an increased Rho pathway signaling. Lbc stably transfected hepatocarcinoma cells exhibit increased proliferation and levels of ERK and cyclin D1 activation, which are blocked by a Rho inhibitor. In contrast, AKT activation was not altered. Moreover, Lbc expression confers increased resistance to genotoxic stress induced by doxorubicin, which is associated with upregulation of Bcl-2 and BAD phosphorylation, and this is reversed by a Rho inhibitor. In conclusion, these data support a role for Rho in liver cancer progression and resistance to therapy and may provide a basis for developing effective treatment for hepatocarcinoma.
Vibrotactile Frequency Discrimination in Human Hairy Skin
Authors: Mahns D. A. , Perkins N. M. , Sahai V. , Robinson L. , Rowe M. J.
Published: December 2005

The human capacity for vibrotactile frequency discrimination has been compared directly for glabrous and hairy skin regions by means of a two-alternative, forced-choice psychophysical procedure in five subjects. Sinusoidal vibratory stimuli, delivered by means of a 4-mm-diam probe, were first used to obtain detection threshold values for the two skin sites, the finger tip and the dorsal forearm, at four standard frequencies, 20, 50, 100, and 200 Hz. Values confirmed previous results showing detection thresholds were markedly higher on hairy skin than on glabrous skin. For the discrimination task, each standard frequency, at an amplitude four times detection threshold, was paired with a series of comparison frequencies, and discrimination capacity then was quantified by deriving from psychometric function curves, measures of the discriminable frequency increment (Δƒ) and the Weber Fraction (Δƒ/ƒ), which, when plotted as a function of the four standard frequencies, revealed similar capacities for frequency discrimination at the two skin sites at the standard frequencies of 20, 100, and 200 Hz but an equivocal difference at 50 Hz. Cutaneous local anesthesia produced a marked impairment in vibrotactile detection and discrimination at the low standard frequencies of 20 and 50 Hz but little effect at higher frequencies. In summary, the results reveal, first, a striking similarity in vibrotactile discriminative performance in hairy and glabrous skin despite marked differences in detection thresholds for the two sites, and, second, the results confirm that vibrotactile detection and discrimination in hairy skin depend on superficial receptors at low frequencies but depend on deep, probably Pacinian corpuscle, receptors for high frequencies.
Red Pigment Concentrating Hormone Strongly Enhances the Strength of the Feedback to the Pyloric Rhythm Oscillator But Has Little Effect on Pyloric Rhythm Period
Authors: Thirumalai Vatsala , Prinz Astrid A. , Johnson Christian D. , Marder Eve
Published: December 2005

The neuropeptide, red pigment concentrating hormone (RPCH), strengthened the inhibitory synapse from the lateral pyloric (LP) neuron to the pyloric dilator (PD) neurons in the pyloric network of the stomatogastric ganglion (STG) of the lobster, Homarus americanus. RPCH produced several-fold increases in the amplitude of both action potential–mediated and non–impulse-mediated transmission that persisted for as long as the peptide remained present. Because the LP to PD synapse is the only feedback to the pacemaker kernel of the pyloric network, which consists of the electrically coupled two PD neurons and the anterior burster (AB) neuron, it might have been expected that strengthening the LP to PD synapse would increase the period of the pyloric rhythm. However, the period of the pyloric rhythm increased only transiently in RPCH, and a transient increase in cycle period was observed even when the LP neuron was hyperpolarized. Phase response curves were measured using the dynamic clamp to create artificial inhibitory inputs of variable strength and duration to the PD neurons. Synaptic conductance values seen in normal saline were ineffective at changing the pyloric period throughout the pyloric cycle. Conductances similar to those seen in 10−6M RPCH also did not evoke phase resets at phases when the LP neuron is typically active. Thus the dramatic effects of RPCH on synaptic strength have little role in modulation of the period of the pyloric rhythm under normal operating conditions but may help to stabilize the rhythm when the cycle period is too slow or too fast.
Deciphering Protein Molecular Signatures in Cancer Tissues to Aid in Diagnosis, Prognosis, and Therapy
Authors: Caprioli Richard M.
Published: December 2005

Protein signatures in disease, a portion of the protein complement of cells that directly reflects disease related changes, provide a unique data set that may be correlated with or be an aid to more effective diagnosis, prognosis, and response to therapy. A recent article in this Journal from the author's laboratory described the protein analysis of glioma tissue and the discovery of protein signatures for assessing the stage of disease as well as their correlation with patient survival. This investigation used direct proteomic analysis of glioma biopsies, the discovery of molecular signatures for stage and outcome, and identification of specific proteins of this signature group. This minireview discusses the background and present state of the technology used in this work and the role that direct tissue analysis can play in the discovery of high-quality protein signatures.
Insulin-like Growth Factor-I Receptor/Human Epidermal Growth Factor Receptor 2 Heterodimerization Contributes to Trastuzumab Resistance of Breast Cancer Cells
Authors: Nahta Rita , Yuan Linda X.H. , Zhang Bing , Kobayashi Ryuji , Esteva Francisco J.
Published: December 2005

The majority of breast cancer patients who achieve an initial therapeutic response to the human epidermal growth factor receptor 2 (HER-2)–targeted antibody trastuzumab will show disease progression within 1 year. We previously reported the characterization of SKBR3-derived trastuzumab-resistant pools. In the current study, we show that HER-2 interacts with insulin-like growth factor-I receptor (IGF-IR) uniquely in these resistant cells and not in the parental trastuzumab-sensitive cells. The occurrence of cross talk between IGF-IR and HER-2 exclusively in resistant cells is evidenced by the IGF-I stimulation resulting in increased phosphorylation of HER-2 in resistant cells, but not in parental cells, and by the inhibition of IGF-IR tyrosine kinase activity leading to decreased HER-2 phosphorylation only in resistant cells. In addition, inhibition of IGF-IR tyrosine kinase activity by I-OMe-AG538 increased sensitivity of resistant cells to trastuzumab. HER-2/IGF-IR interaction was disrupted on exposure of resistant cells to the anti–IGF-IR antibody α-IR3 and, to a lesser extent, when exposed to the anti-HER-2 antibody pertuzumab. Heterodimer disruption by α-IR3 dramatically restored sensitivity to trastuzumab and resistant cells showed a slightly increased sensitivity to pertuzumab versus parental cells. Neither α-IR3 nor pertuzumab decreased HER-2 phosphorylation, suggesting that additional sources of phosphorylation other than IGF-IR exist when HER-2 and IGF-IR are not physically bound. Our data support a unique interaction between HER-2 and IGF-IR in trastuzumab-resistant cells such that cross talk occurs between IGF-IR and HER-2. These data suggest that the IGF-IR/HER-2 heterodimer contributes to trastuzumab resistance and justify the need for further studies examining this complex as a potential therapeutic target in breast cancers that have progressed while on trastuzumab.
Twist Overexpression Induces In vivo Angiogenesis and Correlates with Chromosomal Instability in Breast Cancer
Authors: Mironchik Yelena , Winnard Paul T. , Vesuna Farhad , Kato Yoshinori , Wildes Flonne , Pathak Arvind P. , Kominsky Scott , Artemov Dmitri , Bhujwalla Zaver , Van Diest Paul , Burger Horst , Glackin Carlotta , Raman Venu
Published: December 2005

Aggressive cancer phenotypes are a manifestation of many different genetic alterations that promote rapid proliferation and metastasis. In this study, we show that stable overexpression of Twist in a breast cancer cell line, MCF-7, altered its morphology to a fibroblastic-like phenotype, which exhibited protein markers representative of a mesenchymal transformation. In addition, it was observed that MCF-7/Twist cells had increased vascular endothelial growth factor (VEGF) synthesis when compared with empty vector control cells. The functional changes induced by VEGF in vivo were analyzed by functional magnetic resonance imaging (MRI) of MCF-7/Twist-xenografted tumors. MRI showed that MCF-7/Twist tumors exhibited higher vascular volume and vascular permeability in vivo than the MCF-7/vector control xenografts. Moreover, elevated expression of Twist in breast tumor samples obtained from patients correlated strongly with high-grade invasive carcinomas and with chromosome instability, particularly gains of chromosomes 1 and 7. Taken together, these results show that Twist overexpression in breast cancer cells can induce angiogenesis, correlates with chromosomal instability, and promotes an epithelial-mesenchymal-like transition that is pivotal for the transformation into an aggressive breast cancer phenotype.
Hepatitis C Virus Core Protein Inhibits Tumor Suppressor Protein Promyelocytic Leukemia Function in Human Hepatoma Cells
Authors: Herzer Kerstin , Weyer Sandra , Krammer Peter H. , Galle Peter R. , Hofmann Thomas G.
Published: December 2005

Tumor suppressor protein promyelocytic leukemia (PML) is implicated in apoptosis regulation and antiviral response. PML localizes predominantly to PML-nuclear bodies (PML-NB), nuclear macromolecular complexes regulating tumor suppressor protein p53 activity. Consistent with the function of PML in the cellular antiviral response, PML-NBs represent preferential targets in viral infections. In the case of hepatitis C virus (HCV) infection, important characteristics are nonresponsiveness to IFN therapy and development of hepatocellular carcinoma. However, the mechanisms which lead to the development of hepatocellular carcinoma are largely unknown. Here, we show that HCV core protein localizes to the cell nucleus in PML-NBs, where it colocalizes with p53. The HCV core interacts with endogenously expressed PML isoform IV (PML-IV), a key regulator of p53 activity. Importantly, we show that HCV core protein inhibits PML-IV–induced apoptosis and interferes with the coactivator function of PML-IV for proapoptotic p53 target genes including CD95 (Fas/APO-1). In particular, we found that the HCV core inhibits p53-mediated target gene expression by predominantly targeting the coactivator function of PML-IV because HCV core–mediated p53 target gene repression was absent in PML-ablated cells. HCV core expression abrogated both p53 serine 15 phosphorylation and lysine 382 acetylation, two p53-activating posttranslational modifications which were previously linked to an increased PML-NB formation. Taken together, our results suggest a potential mechanism for HCV-associated development of hepatocellular carcinoma through HCV core–mediated inactivation of the PML tumor suppressor pathway.
Dihydroartemisinin Is Cytotoxic to Papillomavirus-Expressing Epithelial Cells In vitro and In vivo
Authors: Disbrow Gary L. , Baege Astrid C. , Kierpiec Katie A. , Yuan Hang , Centeno Jose A. , Thibodeaux Clare A. , Hartmann Dan , Schlegel Richard
Published: December 2005

Nearly all cervical cancers are etiologically attributable to human papillomavirus (HPV) infection and pharmaceutical treatments targeting HPV-infected cells would be of great medical benefit. Because many neoplastic cells (including cervical cancer cells) overexpress the transferrin receptor to increase their iron uptake, we hypothesized that iron-dependent, antimalarial drugs such as artemisinin might prove useful in treating HPV-infected or transformed cells. We tested three different artemisinin compounds and found that dihydroartemisinin (DHA) and artesunate displayed strong cytotoxic effects on HPV-immortalized and transformed cervical cells in vitro with little effect on normal cervical epithelial cells. DHA-induced cell death involved activation of the mitochondrial caspase pathway with resultant apoptosis. Apoptosis was p53 independent and was not the consequence of drug-induced reductions in viral oncogene expression. Due to its selective cytotoxicity, hydrophobicity, and known ability to penetrate epithelial surfaces, we postulated that DHA might be useful for the topical treatment of mucosal papillomavirus lesions. To test this hypothesis, we applied DHA to the oral mucosa of dogs that had been challenged with the canine oral papillomavirus. Although applied only intermittently, DHA strongly inhibited viral-induced tumor formation. Interestingly, the DHA-treated, tumor-negative dogs developed antibodies against the viral L1 capsid protein, suggesting that DHA had inhibited tumor growth but not early rounds of papillomavirus replication. These findings indicate that DHA and other artemisinin derivatives may be useful for the topical treatment of epithelial papillomavirus lesions, including those that have progressed to the neoplastic state.
Platelet-Derived Growth Factor–Induced p42/44 Mitogen-Activated Protein Kinase Activation and Cellular Growth Is Mediated by Reactive Oxygen Species in the Absence of TSC2/Tuberin
Authors: Finlay Geraldine A. , Thannickal Victor J. , Fanburg Barry L. , Kwiatkowski David J.
Published: December 2005

Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in the TSC1 or TSC2 genes, which encode hamartin and tuberin, respectively. TSC is characterized by multiple tumors of the brain, kidney, heart, and skin. Tuberin and hamartin inhibit signaling by the mammalian target of rapamycin (mTOR) but there are limited studies of their involvement in other pathways controlling cell growth. Using ELT-3 cells, which are Eker rat–derived smooth muscle cells, we show that ELT-3 cells expressing tuberin (TSC2+/+) respond to platelet-derived growth factor (PDGF) stimulation by activating the classic mitogen-activated protein (MAP)/extracellular signal-regulated kinase kinase (MEK)-1–dependent phosphorylation of p42/44 MAP kinase (MAPK) with nuclear translocation of phosphorylated p42/44 MAPK. In contrast, in tuberin-deficient ELT-3 cells (TSC2−/−), PDGF stimulation results in MEK-1–independent p42/44 MAPK phosphorylation with reduced nuclear localization of phosphorylated p42/44 MAPK. Moreover, in TSC2−/− cells but not in TSC2+/+ cells, cellular growth and activation of p42/44 MAPK by PDGF requires the reactive oxygen species intermediate, superoxide anion (O2·−). Both baseline and PDGF-induced O2·− levels were significantly higher in TSC2−/− cells and were reduced by treatment with rapamycin and inhibitors of mitochondrial electron transport. Furthermore, the exogenous production of O2·− by the redox cycling compound menadione induced MEK-1–independent cellular growth and p42/44 MAPK phosphorylation in TSC2−/− cells but not in TSC2+/+ cells. Together, our data suggest that loss of tuberin, which causes mTOR activation, leads to a novel cellular growth-promoting pathway involving mitochondrial oxidant–dependent p42/44 MAPK activation and mitogenic growth responses to PDGF.
Identification and Characterization ofSurvival-Related Gene, a Novel Cell Survival Gene Controlling Apoptosis and Tumorigenesis
Authors: Yuan Zeng-Rong , Wang Ruoxiang , Solomon Jennifer , Luo Xunyi , Sun Hong , Zhang Liying , Shi Yufang
Published: December 2005

Apoptosis plays a critical role in cellular homeostasis during development, immune responses, and tumorigenesis. Recent studies have identified a number of genes that control this process. We report here our identification of a novel cell survival-related gene (SRG) from a human expression cDNA library by functional cloning. SRG shows no significant nucleotide sequence homology to any known genes in the Genbank. Our fluorescence in situ hybridization analysis has estimated that SRG is located at 1p36, agreeing with the location at 1p36.22 in the human genome sequence. SRG encodes a putative protein of 172 amino acids, which is mainly located in the perinuclear region. Northern blotting analysis indicates that SRG is highly expressed in many human cancer cell lines although it is low in most tissues except liver and placenta. To investigate the function of SRG in apoptosis, we transfected SRG cDNA into BAF/BO3 and B16/F0 cells and induced apoptosis by cytokine/serum deprivation. We found that SRG-transfected cells are resistant to apoptosis induced by cytokine/serum deprivation. In addition, mice bearing SRG-transfected melanoma had more tumor formation and larger tumor growth. Melanoma transfected with antisense SRG showed significantly less tumor formation and smaller tumor growth. Interestingly, mouse SRG gene was also identified on chromosome 4 and blocking SRG expression with small interfering RNA promoted serum deprivation–induced apoptosis of NIH3T3 cells. Our results show that SRG is a novel cell survival gene that critically controls apoptosis and tumor formation.
Lack of Poly(ADP-Ribose) Polymerase-1 Gene Product Enhances Cellular Sensitivity to Arsenite
Authors: Poonepalli Anuradha , Balakrishnan Lakshmidevi , Khaw Aik Kia , Low Grace Kah Mun , Jayapal Manikandan , Bhattacharjee Rabindra N. , Akira Shizuo , Balajee Adayabalam S. , Hande M. Prakash
Published: December 2005

Arsenite (As3+) has long been known to induce cancer and other degenerative diseases. Arsenite exerts its toxicity in part by generating reactive oxygen species. Identification of genetic factors that contribute to arsenic mutagenicity and carcinogenicity is critical for the treatment and prevention of arsenic exposure in human population. As poly(ADP-ribose) polymerase (PARP) is critical for genomic DNA stability, role of PARP-1 was evaluated in arsenic-induced cytotoxic and genotoxic effects. Our study revealed that telomere attrition, probably owing to arsenite-induced oxidative stress, was much more pronounced in PARP-1−/− mouse embryonic fibroblasts (MEF; 40%) compared with PARP-1+/+ MEFs (10-20%). Correlation observed between telomere reduction and apoptotic death in PARP-1 null cells strongly indicates that the telomere attrition might be a trigger for enhanced apoptotic death after arsenite treatment. Elevated DNA damage detected by alkaline comet assay points to an impaired repair ability of arsenite-induced DNA lesions in PARP-1−/− MEFs. Consistent with elevated DNA damage, increased micronuclei induction reflecting gross genomic instability was also observed in arsenite-treated PARP-1−/− MEFs. Microarray analysis has revealed that arsenite treatment altered the expression of about 311 genes majority of which have known functions in cellular responses to stress/external stimulus and cell growth and/or maintenance. Our results suggest an important role for PARP-1 gene product in the maintenance of chromosome-genome stability in response to arsenite-induced DNA damage.
Triple Gene-Deleted Oncolytic Herpes Simplex Virus Vector Double-Armed with Interleukin 18 and Soluble B7-1 Constructed by Bacterial Artificial Chromosome–Mediated System
Authors: Fukuhara Hiroshi , Ino Yasushi , Kuroda Toshihiko , Martuza Robert L. , Todo Tomoki
Published: December 2005

Conditionally replicating herpes simplex virus type 1 (HSV-1) vectors are promising therapeutic agents for cancer. Certain antitumor functions may be added to oncolytic activities of recombinant HSV-1 vectors by inserting transgenes into the viral genome. Because conventional homologous recombination techniques had required time-consuming processes to create “armed” oncolytic HSV-1 vectors, we established an innovative construction system using bacterial artificial chromosome and two recombinase systems (Cre/loxP and FLPe/FRT). Using G47Δ, a safe and efficacious oncolytic HSV-1 with triple gene mutations, as the backbone, this system allowed a rapid generation of multiple vectors with desired transgenes inserted in the deleted ICP6 locus. Four oncolytic HSV-1 vectors, expressing murine interleukin 18 (mIL-18), soluble murine B7-1 [B7-1-immunoglobulin (B7-1-Ig)], both, or none, were created simultaneously within 3 months. In vitro, all newly created recombinant vectors exhibited virus yields and cytopathic effects similar to the parental G47Δ. In two immunocompetent mouse tumor models, TRAMP-C2 prostate cancer and Neuro2a neuroblastoma, the vector expressing both mIL-18 and B7-1-Ig showed a significant enhancement of antitumor efficacy via T-cell–mediated immune responses. The results show that “arming” with multiple transgenes can improve the efficacy of oncolytic HSV-1 vectors. The use of our system may facilitate the development and testing of various armed oncolytic HSV-1 vectors.
Activated B-RAF Is an Hsp90 Client Protein That Is Targeted by the Anticancer Drug 17-Allylamino-17-Demethoxygeldanamycin
Authors: da Rocha Dias Silvy , Friedlos Frank , Light Yvonne , Springer Caroline , Workman Paul , Marais Richard
Published: December 2005

Hsp90 is a ubiquitously expressed molecular chaperone that folds, stabilizes, and functionally regulates many cellular proteins. The benzoquinone ansamysin 17-allylamino-17-demethoxygeldanamycin (17-AAG) is an anticancer drug that disrupts Hsp90 binding to its clients, causing their degradation through the ubiquitin-dependent proteasomal pathway. The protein kinase B-RAF is mutated in ∼7% of human cancers. The most common mutation (∼90%) is V600EB-RAF, which has constitutively elevated kinase activity, stimulates cancer cell proliferation, and promotes survival. Here, we show that V600EB-RAF is an Hsp90 client protein that requires Hsp90 for its folding and stability. V600EBRAF is more sensitive to degradation by 17-AAG treatment than WTB-RAF and we show that the majority of the other mutant forms of B-RAF are also sensitive to 17-AAG–mediated proteasomal degradation. Our data show that B-RAF is an important target for 17-AAG in human cancer.