bluuebunny/crossref_metadata_2025 huggingface dataset:
High Quality Epitaxial Growth of GaAsyP1-y Alloys on Si1-xGex Virtual Substrates
Authors: Sharma Prithu , Bulsara Mayank T. , Fitzgerald Eugene A.
Published: October 2010

High quality epitaxial growth of GaP on Si would enable the potential for novel, high performance devices. However, the direct deposition of GaP on Si has proved to be challenging despite the low lattice mismatch. In this paper, we explore the initiation of lattice-matched GaAsyP1-y layers on various Si1-xGex alloy compositions to better understand the properties of the GaAsyP1-y/ Si1-xGex interface system.
Interface Reaction and Rate Enhancement of SiGe Thermal Oxidation
Authors: Shimura Takayoshi , Okamoto Yuki , Shimokawa Daisuke , Inoue Tomoyuki , Hosoi Takuji , Watanabe Heiji
Published: October 2010

We investigated the dependences of oxidation reaction on the initial Ge concentration of SiGe substrates under dry oxidation condition and on the oxidation time under wet oxidation condition. Based on these results, we discuss the validity of the rate-limiting model proposed for the difference in the rate enhancement of SiGe substrates between dry and wet oxidation.
(Invited) Graphene FETs: Promises and Challenges
Authors: Miao Congqin , Park Young Ju , Liu Wei , Wang Yanjie , Zhu Jing , Huang BoChao , Woo Jason S.C. , Xie Ya-Hong
Published: October 2010

We present a critical review of graphene for field-effect transistor (FET) application. By using graphene sheet as the channel material, the new FET is expected offer significant advantages in certain aspects over and above that of the present Si-based counterpart. There are many challenges as well since the overall operating principle of the FET channel is different. We present our perspective with regard to these challenges. And we also demonstrate the ability of synthesizing monolayer graphene on Cu foils and placing it on insulator surfaces.
(Invited) Aspect Ratio Trapping: A Unique Technology for Integrating Ge and III-Vs with Silicon CMOS
Authors: Fiorenza James G. , Park Ji-Soo , Hydrick Jennifer , Li Jason , Li Jizhong , Curtin Mike , Carroll Mark , Lochtefeld Anthony
Published: October 2010

This paper describes the recent development of the Aspect Ratio Trapping (ART) heterointegration technique. This technique uses high aspect ratio sub-micron trenches to trap threading dislocations, greatly reducing the dislocation density of lattice mismatched materials grown on silicon. ART is shown to be very effective for a wide variety of materials including Ge, GaAs and InP. It has been combined with epitaxial lateral overgrowth to create long, 18 micron wide strips of low dislocation density material. ART has been used to integrate many types of Ge and III-V devices on silicon including GaAs MOSFETs, GaAs lasers, GaAs tunnel diodes and a silicon infrared imager chip with monolithically integrated Ge photodiodes.
Phosphorus Atomic Layer Doping in Si Using PH3
Authors: Yamamoto Yuji , Murota Junichi , Tillack Bernd
Published: October 2010

Atomic layer doping of P (P-ALD) in Si is investigated using reduced pressure chemical vapor deposition (RPCVD). For P-ALD, PH3 exposure on Si (100) surface followed by Si cap layer deposition using SiH4 or Si2H6 is performed. P adsorption is suppressed by hydrogen-termination of the Si surface. On the hydrogen-free Si surface, the P adsorption is increasing with increasing PH3 exposure temperature saturating at temperatures above 600oC. P adsorption is also increasing with increasing PH3 exposure time. It tends to saturate at long exposure time indicating a self-limitation of the process. By Si deposition using Si2H6, higher P peak concentration and higher P doping level in the Si cap layer is observed compared to those with SiH4 based Si deposition. For both SiH4 and Si2H6 based capping process lower P segregation is observed by lowering the growth temperature.
Self-Aligned NiGeSi Contacts on Gallium Arsenide for III-V MOSFETs
Authors: Zhang Xingui , Guo Huaxin , Chin Hock-Chun , Gong Xiao , Lim Phyllis Shi Ya , Yeo Yee-Chia
Published: October 2010

We developed a Nickel Germanide (NiGe) based self-aligned contact technology for GaAs n-MOSFETs. The self-aligned contact metallization process is salicide-like and is compatible with III-V materials and processes. It comprises selective epitaxy of Germanium-Silicon (GeSi) on n+ doped GaAs region and a two-step metallization process for forming Nickel-Germanosilicide (NiGeSi) contacts on GaAs. With precise control of the metallization process, NiGeSi contacts on GaAs were fabricated with good ohmic behavior. Contact with smaller contact resistance RC was achieved by optimizing the metallization process. The self-aligned NiGeSi contacts were integrated in GaAs n-MOSFETs which show good output characteristics.
Using CMP Model for 45nm/32nm BEOL Process and Design Evaluations
Authors: Economikos Laertis , Bao Jerry , Low Kia , Wei-Tsu Tseng , Matusiewicz Gerald
Published: October 2010

Chemical Mechanical Polishing (CMP) is an essential process in semiconductor manufacturing. It is known to suffer from pattern dependencies such as dishing and erosion, which can lead to potential yield and performance problems, including copper pooling and excessive copper loss. These problems become very significant as lateral and vertical dimensions continue to shrink. They can therefore no longer be neglected in advanced node designs for optimal yield and performance. In this paper, we demonstrate a physics based CMP model in predicting metal line heights in macros with pattern factors from 10% to 90%. Model based checking as opposed to rule based checking can identify more accurately the weak points in a design and enable designers to provide improved layout for areas that will cause under polish or excessive erosion for a given CMP process. Thus CMP modeling can provide information on interlevel effects such as copper puddling from underlying topography.
The L28 STI CMP Dummy Pattern Study on Topography for Advanced Fixed Abrasive and High Selective Slurry
Authors: Hsu Chun-Wei , Huang Po-Cheng , Lin Jen-Chieh , Chen Chia-Hsi , Chen Y. M. , Lin Chih-Hsun , Hsu Chia-Lin , Tsai Teng-Chun , Wu J. Y.
Published: October 2010

The STI CMP performance was major determined by the uniformity of STI step height which was characterized by the ranges of within-die (WID) and within-wafer (WIW) thickness for both silicon nitride and trench oxide surface of isolation area. Currently, for 28nm generation, two advanced approaches for STI CMP were high selective slurry (HSS) and fixed abrasive (FA) CMP. For these two approaches, the design and layout of dummy were important to overcome the effect of various pattern densities and feature sizes. Therefore this research focused on the effect of dummy type for HSS and FA CMP. The result shows HSS CMP is the most robust process in STI CMP. The nitride thickness after HSS CMP shows good uniformity, 2~3 %, and is slightly affected by dummy type and PD of test key comparing with FA CMP.
Effects of CMP Slurry Additives on the Rate of Agglomeration of Alumina Particles
Authors: Brahma Neil A. , Talbot Jan
Published: October 2010

The rate of agglomeration of alumina particles in 1 mM KNO3 solutions with various additives with a range of pH values was measured. The suspensions tested contained only glycine and glycine, H2O2, benzotriazole, and sodium dodecyl sulfate. A fractal dimensional analysis was used to analyze the rate data to indicate the agglomeration mechanism. At pH 4 no aggregation was observed in the glycine only suspension, however significant aggregation occurred in the other suspension, reaching sizes greater than 3 μm within 2 min. Slow agglomeration was observed at pH 7.5 for both suspensions. Both suspensions at pH 10 showed immediate aggregation to mean sizes greater than 3 μm. However, adjustment of the suspension pH was sufficient to increase or reduce the aggregate size.
High K Metal Gate Aluminum CMP Challenges and Solutions
Authors: Xu Kun , Chen Yufei , Iravani Hassan , Wang Yuchun , Swedek Bogdan , Yu May , Wang You , Tu Wen-chiang , Xia Sherry , Karuppiah Lakshmanan
Published: October 2010

Because the gate height is critical to transistor performance, controlling gate height precisely and uniformly is the primary challenge for the replacement metal gate aluminum CMP process. A real-time profile control (RTPC) method was combined with a laser-based endpoint system to achieve within-wafer and wafer-to-wafer gate height uniformity requirements. To meet another challenge in Al CMP, defect performance was improved by 20X via consumables selection and process optimization.
CMP Solutions for the Integration of High-K Metal Gate Technologies
Authors: Dysard Jeffrey M. , Brusic Vlasta , Feeney Paul , Grumbine Steven , Moeggenborg Kevin , Whitener Glenn , Ward William , Burns Gregory , Choi Kyose
Published: October 2010

In order to enable high-k metal gate technology, new CMP steps and slurries are needed to meet the stringent planarity and defect requirements for device performance. This paper will describe several of these slurry technologies in detail, including poly-open-polish, Aluminum CMP, and improvements required in Tungsten polishing. The keys to these technologies are outlined and polishing performance given in detail. The critical mechanisms involved in the material polishing for each of these steps are also introduced. All of these new technologies are needed in order to build a successful high-k metal gate device for advanced node integration via a replacement gate build strategy.
Development of a Production Worthy Non-Selective Slurry W-CMP for Logic Applications at 28nm Technology Node and Beyond
Authors: Hsu Hsin-Kuo , Hsieh Y. H. , Chen Y. M. , Lin Welch , Tsai Teng-Chun , Wu J. Y.
Published: October 2010

In this paper, the electrical failure is analyzed in failure map of 28nm logic pattern wafer. As CD shrinks to 28nm and beyond, the contact metallization face poor gap fill of tungsten and low process win tolerance, is like erosion and within-wafer uniformity. The poor interconnection between metal copper via and contact tungsten via of failure include metal1 (M1) Cu bridge and metal1 open. The M1 bridge is induced by large erosion at high contact via density. Another M1 open is induced by W recess at iso via. A novel non-selective slurry buff process provide non-selective removal speciality and splendid uniformity to reduce erosion and recess, are less than 50A to meet 28nm technology node and beyond.
The TDDB Study of Post-CMP Cleaning Effect for L40 Direct Polished Porous Low K Dielectrics Cu Interconnect
Authors: Hsu Chia-Lin , Lin Welch , Hsu Chun-Wei , Lin Jen-Chieh , Tsai Teng-Chun , Huang Chien-Chung , Wu J. Y. , Perng Dung-Ching
Published: October 2010

In order to realize the high performance of RC delay, direct polished porous type ultra low-K film (ULK) is integrated into Cu dual-damascene interconnects for 45 nm and beyond. In the past, metal line seems not an important role in the world of TDDB. However, because of the minimized feature size and the relative fragile ULK film properties, it was found that the Cu roughness of polished surface also plays an important role to effect on the reliability such as TDDB from this generation. Post-cleaning of Cu CMP is a major process to manage the Cu surface roughness. In this paper, the correlation for post-cleaning time to the TDDB was discussed. The mechanism with two models was built up to explain this behavior as well.
Effect of Inhibiter Concentration on Cu CMP Slurry Analyzed by a Cu-ECMP System
Authors: Chen Chao-Chang A. , Hsieh Chi-Hsiang
Published: October 2010

This paper is to apply an electrochemical mechanical planarization (ECMP) system to analyze the dynamic effects of inhibiter concentration on general Cu-CMP slurry. Experimental results show that the MRR increases when the BTA concentration decreases. Different BTA concentration after slurry analysis process will also affect copper surface condition. The passivation layer has been observed by scanning electron microscopy, potentiodynamic polarization curve and potentialstatic polarization curve during slurry analysis process. Results can be further applied for Cu-CMP slurry analysis with its dynamic effects of inhibiter concentration to achieve higher efficiency of removal rate as well as the non-uniformity, especially for the TSV Cu-CMP required in the 3D IC fabrication process.
Surface Interaction of Barrier Slurry Formulation Additives during Post Chemical Mechanical Polishing (CMP)
Authors: Schlueter James , Pearlstein Ron , Shi Tom , Henry James , Haney Robert J.
Published: October 2010

As today's leading edge manufacturers are developing and preparing to implement 22 nm technology node integrated circuits and beyond into manufacturing, new issues emerge. Certain components used in current generation CMP barrier slurries or new components used to achieve improved performance at the advanced nodes either no longer are sufficient or cause new integration issues. Many of these issues involve the surface state of the polished films after the Cu-barrier CMP step. Surface states during polishing can lead to undesirable topography effects, such as "fangs". Unprotected high density Cu lines can lead to high electrical leakage issues due to corrosion. Thin residual layers left behind on the polished surfaces can create defectivity or downstream deposition and/or contamination issues. This study looks closely at various formulation components used in barrier CMP slurries, how they electrochemically interact with the materials they contact and how they may change the post CMP polished surfaces.
Nanoelectronic Devices from Nanowire Heterostructures
Authors: Lin Yung-Chen , Chen Yu , Huang Yu
Published: October 2010

In this manuscript we report the formation of single crystal PtSi and MnSi nanowires, silicide/silicon/silicide nanowire (NW) heterostructures and studies of the electron and spin transport in silicon nanostructure. Single crystal silicide contact is grown by converting the silicon nanowire into single crystal silicide nanowire through controlled solid state reaction, wherein a coherently and automatically flat silicide/Si interface is maintained. Electrical transport studies of PtSi and MnSi nanowires show a metallic behavior for both, and show that MnSi displays ferromagnetic properties at low temperature. More importantly, a high performance intrinsic-Si NW transistor has been demonstrated with PtSi/Si/PtSi heterostructures, and spin injection and detection are demonstrated in MnSi/Si/MnSi nanowire heterostructure with an ultra-short Si channel ~20 nm. These studies demonstrate for the first time the realization of normally-off intrinsic Si p-type transistor, as well the spin injection and detection in a Si nanostructure.
Growth of Nanowhiskers of Al, Ti, Cr, Mn, Fe, Co, Ni, Zn, Cu, Ag and Au by High-Temperature Glancing Angle Deposition
Authors: Suzuki Motofumi , Hamachi Kenji , Nagai Koji , Kita Ryo , Nakajima Kaoru , Kimura Kenji
Published: October 2010

In this experiment, we demonstrate the high-temperature glancing angle deposition (HT-GLAD) of metals. Whiskers of Cu, Ag, Au, Mn, Fe, Co, Ni, Zn, and Al, grow on substrates of SiO2. Deposition at the glancing angle and at temperatures higher than one-third of the melting point is crucial for the growth of nanowhiskers. Deposition on surfaces with systematically controlled roughness indicates that the surface diffusion of adatoms on the substrate surface is not important for the growth of nanowhiskers and that the atoms are mainly supplied from the vapor directly or from reflection on the surface in front of the growing nanowhiskers. The kinetic growth model that takes into account the GLAD and the reflection agrees with the experimental results.
Nanoimprinted SU-8 Nanopillars and Hierarchically Branched Nanowires by Anodic Aluminum Oxide Templates and Their Optical Properties
Authors: Fang Jun , Song Youngsik , Chen Zhi D.
Published: October 2010

We fabricated well-dispersed SU-8 nanopillars and hierarchically branched nanowires using nanoimprinted method. Anodic aluminum oxide (AAO) templates with branched pore structures were used as templates. We successfully fabricated high density, large aspect ratio, and large area SU-8 patterns. It provides a convenient and powerful approach to produce complicated nanostructures on SU-8 photoresist. The optical reflectivity was measured to characterize the SU-8 surface. Unique optical properties could be observed from these SU-8 nanopillar structures.
Leakage Current Analysis of Lateral p+/n Ge Based Diode Activated at Low Temperature for Three-Dimensional Integrated Circuit (3D-ICs)
Authors: Jung Woo Shik , Park Jin Hong , Kuzum Duygu , Kim Wanki , Wong Simon , Saraswat Krishna C.
Published: October 2010

In this work, we have analyzed the area, perimeter, and corner leakage current components of lateral p+/n Ge based diodes, which were fabricated at a low temperature (sub-400ºC) for three- dimensional integrated circuit (3D-IC) application. In addition, effects of forming gas annealing are included in the analysis, which was done to further reduce the leakage current. The leakage components were extracted by measuring three diodes having different dimensions and constructing a 3x3 matrix. This extraction was performed at different fabrication temperatures in order to identify each component's temperature dependency. Guidelines for minimizing leakage current are presented based on the results.
Use of Polymer Liners for 3D-WLP TSVs: Process, Reliability and Cost
Authors: Sabuncuoglu Tezcan Deniz , Pham Nga P. , Majeed Bivragh , Civale Yann , Beyne Eric
Published: October 2010

Imec has developed 3D-WLP TSVs for the last 3 years using either CVD deposited or spin-on applied dielectric polymers as liner isolation. Three types of TSVs in either 100 or 50µm thick Si wafers are fabricated based on thinning first, via last approach where 3D interconnects are implemented on the backside of thinned IC fabricated device wafers. A 3-mask process sequence is implemented for fabrication of all TSV types, however, the process flow and the Si thickness are different for each one of them. All processes employed in the fabrication of the TSVs are performed at low temperature (<200°C) for post CMOS compatibility. The test vehicle used to develop the TSV technologies includes via daisy chains of various lengths connecting different number of vias to determine the TSV resistance and yield. We summarize in this paper, the key aspects of the three types of TSVs in terms of the fabrication, electrical characterization, and reliability; and we present the cost comparison of these TSVs.
3D Hybrid Integration Technology for Opto-Electronic Hetero-Integrated Systems
Authors: Lee Kangwook , Fukushima Takafumi , Tanaka Tetsu , Koyanagi Mitsuma
Published: October 2010

We developed a 3D hybrid integration technology of complementary metal oxide semiconductor (CMOS), micro electro mechanical systems (MEMS) and photonic circuits for opto-electronic hetero-integrated systems. The 3D opto-electronic multi-chip module comprising CMOS, MEMS, and photonic devices was fabricated by using 3D hybrid integration technology. The electrical chips of amplitude shift keying (ASK) LSI, LC filter and pressure-sensing MEMS were mounted on the electrical Si interposer with Cu through silicon vias (TSVs). The photonic chips of vertical-cavity surface-emitting laser (VCSEL) and photodiode (PD) were embedded into the optical Si interposer with an optical waveguide. The electrical and the optical interposers were precisely bonded together to form 3D opto-electronic multi-chip module. The photonics and electrical devices are communicated via Cu TSVs. The photonic devices were connected via an optical waveguide. Basic functions of CMOS, MEMS and photonic devices in the 3D opto-electronic multi-chip module were successfully evaluated.
CMOS Compatible Anodization Process for Low Cost High Density Capacitors
Authors: Detalle Mikael , Rakowski Michal , Potoms Goedele , Mercha Abdelkarim , De Potter de ten Broeck Muriel , Phommahaxay Alain , Sabuncuoglu Tezcan Deniz , Soussan Philippe
Published: October 2010

Anodization is a low cost, low temperature, technology compatible with post foundry integration, suitable for 3D high aspect ratio deposition. Anodic tantalum pentoxide is used at IMEC as dielectric for integrated high density 3D Metal-Insulator-Metal capacitors. To verify its compatibility with CMOS devices, a 0.13 µm technology has been electrically qualified before and after a post-processing/deprocessing phase including the anodization of a tantalum pentoxide layer at 40 V. Low evolutions, below 6 %, has been monitored on nFET/pFET threshold voltage and subthreshold current. Slight decrease and increase in the leakage current is observed on nFET and pFET devices, respectively. However the monitored values were still in tolerance range. Contact and interconnection integrity have also been verified by measuring contact and sheet resistance of each layer. The study show that all devices were still functional with no or very limited impact of anodization on the performance.
Ultra Low-k Materials: Challenges of Scaling
Authors: Zhao Larry , Baklanov Mikhail , Pantouvaki Marianna , Tőkei Zsolt , Beyer Gerald
Published: October 2010

High porosity and carbon doing are required to achieve low dielectric constant, k values for ultra low-k (ULK) materials based on silicon dioxide. Those characteristics create new challenges in the integration of ULK materials that are being developed for future interconnect scaling. Four of those challenges based on electrical characterizations of ULK films will be presented in this paper. First, a high concentration of porogen residue is typically present in ULK materials fabricated by Plasma Enhanced Chemical Vapor Deposition (PECVD). The high porogen residue concentration leads to a high leakage current density. Second, ULK materials based on Spin-on Glass (SOG) process demonstrate a low leakage current density. But early dielectric breakdown has been observed in SOG k=2.2 material. Third, PVD TaNTa barrier process can introduce significant damage to ULK materials. The damage level increases as the k value decreases or porosity increases. Four, direct deposition of ALD Ru barrier on ULK films results in a high leakage current density.
Ultra-Low Temperature Deposition of Copper Seed Layers by PEALD
Authors: Mao Jiajun , Eisenbraun Eric , Omarjee Vincent , Korolev Andrey , Lansalot Clement , Dussarrat Christian
Published: October 2010

Two novel fluorine-free precursors have been developed and evaluated for use in ultra-low temperature copper deposition by PEALD. Manufacturable PEALD processes have been demonstrated, and processing conditions correlated to film composition, growth rate, resistivity and step coverage. Preliminary integration results indicate that both of these precursors have potential for use in advanced interconnect systems.
CMP for Cu Interconnect with Advanced Barrier Materials
Authors: Wang You , Gage Max , Xu Kun , Wang Yuchun , Chen Yufei , Xia Sherry , Tu Wen-chiang , Karuppiah Lakshmanan
Published: October 2010

In this paper, we discuss CMP technology for Cu interconnects with a Co seed enhancement liner (SEL) and Cu with a Ru barrier. Typical forms of galvanic corrosion for each type of barrier are also reviewed. To meet CMP performance requirements, specific polishing and cleaning processes for each CMP step were developed. The overall performance of CMP was evaluated using a variety of patterned wafers, and results are presented.
Subtractive Etching of Cu with Hydrogen-Based Plasmas
Authors: Wu Fangyu , Levitin Galit , Hess Dennis
Published: October 2010

Due to the inability to form volatile etch products at temperatures less than 180 oC, the damascene process has been the prevailing patterning technology for copper. A simple, hydrogen (H2) plasma-based, low temperature etch process was developed to allow an alternative method to damascene technology. Cu thin films were etched by a H2 plasma in an inductively coupled plasma (ICP) reactor at temperatures below room temperature (10 oC). This process achieved anisotropic Cu features and an etch rate of ~13 nm/min. Ion bombardment was a contributor to Cu removal, since the etch rates were essentially proportional to the platen power with a constant coil power. However, lower etch rates of Cu were observed in an Ar plasma than in the H2 plasma, despite the fact that Ar is a more efficient sputter gas. Based on Cu etch rates and patterning results, the etch process involve both chemical and physical characteristics.
Rescue treatment with a Rho-kinase inhibitor normalizes right ventricular function and reverses remodeling in juvenile rats with chronic pulmonary hypertension
Authors: Xu Emily Z. , Kantores Crystal , Ivanovska Julijana , Engelberts Doreen , Kavanagh Brian P. , McNamara Patrick J. , Jankov Robert P.
Published: October 2010

Chronic pulmonary hypertension in infancy and childhood is characterized by a fixed and progressive increase in pulmonary arterial pressure and resistance, pulmonary arterial remodeling, and right ventricular hypertrophy and systolic dysfunction. These abnormalities are replicated in neonatal rats chronically exposed to hypoxia from birth in which increased activity of Rho-kinase (ROCK) is critical to injury, as evidenced by preventive effects of ROCK inhibitors. Our objective in the present study was to examine the reversing effects of a late or rescue approach to treatment with a ROCK inhibitor on the pulmonary and cardiac manifestations of established chronic hypoxic pulmonary hypertension. Rat pups were exposed to air or hypoxia (13% O2) from postnatal day 1 and were treated with Y-27632 (15 mg/kg) or saline vehicle by twice daily subcutaneous injection commencing on day 14, for up to 7 days. Treatment with Y-27632 significantly attenuated right ventricular hypertrophy, reversed arterial wall remodeling, and completely normalized right ventricular systolic function in hypoxia-exposed animals. Reversal of arterial wall remodeling was accompanied by increased apoptosis and attenuated content of endothelin (ET)-1 and ETAreceptors. Treatment of primary cultured juvenile rat pulmonary artery smooth muscle cells with Y-27632 attenuated serum-stimulated ROCK activity and proliferation and increased apoptosis. Smooth muscle apoptosis was also induced by short interfering RNA-mediated knockdown of ROCK-II, but not of ROCK-I. We conclude that sustained rescue treatment with a ROCK inhibitor reversed both the hemodynamic and structural abnormalities of chronic hypoxic pulmonary hypertension in juvenile rats and normalized right ventricular systolic function. Attenuated expression and activity of ET-1 and its A-type receptor on pulmonary arterial smooth muscle was a likely contributor to the stimulatory effects of ROCK inhibition on apoptosis. In addition, our data suggest that ROCK-II may be dominant in enhancing survival of pulmonary arterial smooth muscle.
Interactions between adenosine and K+channel-related pathways in the coupling of somatosensory activation and pial arteriolar dilation
Authors: Paisansathan Chanannait , Xu Haoliang , Vetri Francesco , Hernandez Moises , Pelligrino Dale A.
Published: October 2010

Multiple, perhaps interactive, mechanisms participate in the linkage between increased neural activity and cerebral vasodilation. In the present study, we assessed whether neural activation-related pial arteriolar dilation (PAD) involved interactions among adenosine (Ado) A2receptors (A2Rs), large-conductance Ca2+-operated K+(BKCa) channels, and inward rectifier K+(Kir) channels. In rats with closed cranial windows, we monitored sciatic nerve stimulation (SNS)-induced PAD in the absence or presence of pharmacological blockade of A2Rs (ZM-241385), ecto-5′-nucleotidase (α,β-methylene-adenosine diphosphate), BKCachannels (paxilline), and Kirchannels (BaCl2). Individually, these interventions led to 53–66% reductions in SNS-induced PADs. Combined applications of these blockers led to little or no further repression of SNS-induced PADs, suggesting interactions among A2Rs and K+channels. In the absence of SNS, BaCl2blockade of Kirchannels produced 52–80% reductions in Ado and NS-1619 (BKCachannel activator)-induced PADs. In contrast, paxilline blockade of BKCachannels was without effect on dilations elicited by KCl (Kirchannel activator) and Ado suffusions, indicating that Ado- and NS-1619-associated PADs involved Kirchannels. In addition, targeted ablation of the superficial glia limitans was associated with a selective 60–80% loss of NS-1619 responses, suggesting that the BKCachannel participation (and paxilline sensitivity) derived largely from channels within the glia limitans. Additionally, blockade of either PKA or adenylyl cyclase caused markedly attenuated pial arteriolar responses to SNS and, in the absence of SNS, responses to Ado, KCl, and NS-1619. These findings suggested a key, possibly permissive, role for A2R-linked cAMP generation and PKA-induced K+channel phosphorylation in somatosensory activation-evoked PAD.
O2uptake and blood pressure regulation at the onset of exercise: interaction of circadian rhythm and priming exercise
Authors: Faisal Azmy , Beavers Keith R. , Hughson Richard L.
Published: October 2010

Circadian rhythm has an influence on several physiological functions that contribute to athletic performance. We tested the hypothesis that circadian rhythm would affect blood pressure (BP) responses but not O2uptake (V̇o2) kinetics during the transitions to moderate and heavy cycling exercises. Nine male athletes (peak V̇o2: 60.5 ± 3.2 ml·kg−1·min−1) performed multiple rides of two different cycling protocols involving sequences of 6-min bouts at moderate or heavy intensities interspersed by a 20-W baseline in the morning (7 AM) and evening (5 PM). Breath-by-breath V̇o2and beat-by-beat BP estimated by finger cuff plethysmography were measured simultaneously throughout the protocols. Circadian rhythm did not affect V̇o2onset kinetics determined from the phase II time constant (τ2) during either moderate or heavy exercise bouts with no prior priming exercise (τ2moderate exercise: morning 22.5 ± 4.6 s vs. evening 22.2 ± 4.6 s and τ2heavy exercise: morning 26.0 ± 2.7 s vs. evening 26.2 ± 2.6 s, P > 0.05). Priming exercise induced the same robust acceleration in V̇o2kinetics during subsequent moderate and heavy exercise in the morning and evening. A novel finding was an overshoot in BP (estimated from finger cuff plethysmography) in the first minutes of each moderate and heavy exercise bout. After the initial overshoot, BP declined in association with increased skin blood flow between the third and sixth minute of the exercise bout. Priming exercise showed a greater effect in modulating the BP responses in the evening. These findings suggest that circadian rhythm interacts with priming exercise to lower BP during exercise after an initial overshoot with a greater influence in the evening associated with increased skin blood flow.
Asymmetric dimethylarginine potentiates lung inflammation in a mouse model of allergic asthma
Authors: Klein Elizabeth , Weigel Jason , Buford Mary C. , Holian Andrij , Wells Sandra M.
Published: October 2010

Nitric oxide (NO), formed by nitric oxide synthase (NOS), is an important mediator of lung inflammation in allergic asthma. Asymmetric dimethylarginine (ADMA), a competitive endogenous inhibitor of NOS, is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Elevated ADMA has been shown to affect lung function in mice, and by inhibiting NOS it alters NO and reactive oxygen species production in mouse lung epithelial cells. However, the effects of altered ADMA levels during lung inflammation have not been explored. A model of allergen-induced airway inflammation was utilized in combination with the modulation of endogenous circulating ADMA levels in mice. Airway inflammation was assessed by quantifying inflammatory cell infiltrates in lung lavage and by histology. Lung DDAH expression was assessed by quantitative PCR and immunohistochemistry. Nitrite levels were determined in lung lavage fluid as a measure of NO production. iNOS expression was determined by immunohistochemistry, immunofluorescence, Western blot, and quantitative PCR. NF-κB binding activity was assessed by a transcription factor binding assay. Allergen-induced lung inflammation was potentiated in mice with elevated circulating ADMA and was reduced in mice overexpressing DDAH. Elevated ADMA reduced nitrite levels in lung lavage fluid in both allergen-challenged and control animals. ADMA increased iNOS expression in airway epithelial cells in vivo following allergen challenge and in vitro in stimulated mouse lung epithelial cells. ADMA also increased NF-κB binding activity in airway epithelial cells in vitro. These data support that ADMA may play a role in inflammatory airway diseases such as asthma through modulation of iNOS expression in lung epithelial cells.
Metabolic consequences of sepsis-induced acute lung injury revealed by plasma1H-nuclear magnetic resonance quantitative metabolomics and computational analysis
Authors: Stringer Kathleen A. , Serkova Natalie J. , Karnovsky Alla , Guire Kenneth , Paine Robert , Standiford Theodore J.
Published: October 2010

Metabolomics is an emerging component of systems biology that may be a viable strategy for the identification and validation of physiologically relevant biomarkers. Nuclear magnetic resonance (NMR) spectroscopy allows for establishing quantitative data sets for multiple endogenous metabolites without preconception. Sepsis-induced acute lung injury (ALI) is a complex and serious illness associated with high morbidity and mortality for which there is presently no effective pharmacotherapy. The goal of this study was to apply1H-NMR based quantitative metabolomics with subsequent computational analysis to begin working towards elucidating the plasma metabolic changes associated with sepsis-induced ALI. To this end, this pilot study generated quantitative data sets that revealed differences between patients with ALI and healthy subjects in the level of the following metabolites: total glutathione, adenosine, phosphatidylserine, and sphingomyelin. Moreover, myoinositol levels were associated with acute physiology scores (APS) (ρ = −0.53, P = 0.05, q = 0.25) and ventilator-free days (ρ = −0.73, P = 0.005, q = 0.01). There was also an association between total glutathione and APS (ρ = 0.56, P = 0.04, q = 0.25). Computational network analysis revealed a distinct metabolic pathway for each metabolite. In summary, this pilot study demonstrated the feasibility of plasma1H-NMR quantitative metabolomics because it yielded a physiologically relevant metabolite data set that distinguished sepsis-induced ALI from health. In addition, it justifies the continued study of this approach to determine whether sepsis-induced ALI has a distinct metabolic phenotype and whether there are predictive biomarkers of severity and outcome in these patients.
LTD4induces HB-EGF-dependent CXCL8 release through EGFR activation in human bronchial epithelial cells
Authors: McGovern Toby , Risse Paul-André , Tsuchiya Kimitake , Hassan Muhannad , Frigola Gerard , Martin James G.
Published: October 2010

Airway epithelial cells release proinflammatory mediators that may contribute to airway remodeling and leukocyte recruitment. We explored the hypothesis that leukotriene D4(LTD4) may trigger the release of proremodeling factors through activation of the EGF receptor (EGFR). We particularly focused on the effects of LTD4on release of heparin-binding EGF-like factor (HB-EGF) and IL-8 (CXCL8), a potent neutrophil chemoattractant that may be released downstream of EGFR activation. To address this hypothesis, both primary (NHBE) and transformed bronchial human epithelial cells (BEAS-2B) were grown on an air-liquid interface and stimulated with LTD4. HB-EGF and CXCL8 were evaluated by ELISA in cell culture supernatants. To explore the EGFR signaling pathway, we used a broad-spectrum matrix metalloproteinase (MMP) inhibitor, GM-6001, two selective EGFR tyrosine kinase inhibitors, AG-1478 and PD-153035, an HB-EGF neutralizing antibody, and a specific small interfering RNA (siRNA) against the EGFR. Expression of the CysLT1cysteinyl leukotriene receptor was demonstrated by RT-PCR and immunocytochemistry in both BEAS-2B and NHBE cells. Four hours after stimulation with LTD4, HB-EGF and CXCL8 were significantly increased in cell culture supernatant. GM-6001 and montelukast, a specific CysLT1receptor antagonist, blocked the LTD4-induced increase in HB-EGF. All inhibitors/antagonists decreased LTD4-induced CXCL8 release. siRNA against EGFR abrogated CXCL8 release following stimulation with LTD4and exogenous HB-EGF. These findings suggest LTD4induced EGFR transactivation through the release of HB-EGF in human bronchial epithelial cells with downstream release of CXCL8. These effects may contribute to epithelial-mediated airway remodeling in asthma and other conditions associated with cysteinyl leukotriene release.
Bioassay-Guided Evaluation of Antinociceptive Effect ofN-Salicyloyltryptamine: A Behavioral and Electrophysiological Approach
Authors: Quintans-Júnior Lucindo J. , Silva Davi A. , Siqueira Jullyana S. , Araújo Adriano A. S. , Barreto Rosana S. S. , Bonjardim Leonardo R. , DeSantana Josimari M. , De Lucca Júnior Waldeci , Souza Maria F. V. , Gutierrez Stanley J. C. , Barbosa-Filho José Maria , Santana-Filho Valter J. , Araújo Demétrius A. M. , Almeida Reinaldo N.
Published: October 2010

We investigated the antinociceptive and nerve excitability effects of theN-salicyloyltryptamine (NST) NST-treated mice exhibited a significant decrease in the number of writhes when 100 and 200 mg/kg (i.p.) were administered (i.p.). This effect was not antagonized by naloxone (1.5 mg/kg, i.p.). NST inhibited the licking response of the injected paw when 100 and 200 mg/kg were administered (i.p.) to mice in the first and second phases of the formalin test. Because the antinociceptive effects could be associated with neuronal excitability inhibition, we performed the single sucrose gap technique and showed that NST (3.57 mM) significantly reduced (29.2%) amplitude of the compound action potential (CAP) suggesting a sodium channel effect induced by NST. Our results demonstrated an antinociceptive activity of the NST that could be, at least in part, associated to the reduction of the action potential amplitude. NST might represent an important tool for pain management.
Aberrant Activation of Fatty Acid Synthesis Suppresses Primary Cilium Formation and Distorts Tissue Development
Authors: Willemarck Nicolas , Rysman Evelien , Brusselmans Koen , Van Imschoot Griet , Vanderhoydonc Frank , Moerloose Katrien , Lerut Evelyne , Verhoeven Guido , van Roy Frans , Vleminckx Kris , Swinnen Johannes V.
Published: October 2010

Aberrant activation of fatty acid synthesis is a key feature of many advanced human cancers. Unlike in classical lipogenic tissues, this process has been implicated in membrane production required for rapid cell proliferation. Here, to gain further insight into the consequences of tumor-associated fatty acid synthesis, we have mimicked the lipogenic phenotype of cancer cells in Xenopus embryos by microinjection of RNA encoding the lipogenic transcription factor sterol regulatory element binding protein 1c (SREBP1c). Dramatic morphologic changes were observed that could be linked to alterations in Wnt and Hedgehog signaling, and ultimately to a distortion of the primary cilium. This is a sophisticated microtubular sensory organelle that is expressed on the surface of nearly every cell type and that is lost in many cancers. SREBP1c-induced loss of the primary cilium could be confirmed in mammalian Madin-Darby canine kidney (MDCK) cells and was mediated by changes in the supply of fatty acids. Conversely, inhibition of fatty acid synthesis in highly lipogenic human prostate cancer cells restored the formation of the primary cilium. Lipid-induced ciliary loss was associated with mislocalization of apical proteins, distortion of cell polarization, and aberrant epithelial tissue development as revealed in three-dimensional cultures of MDCK cells and in the developing mouse prostate. These data imply that tumor-associated lipogenesis, in addition to rendering cells more autonomous in terms of lipid supply, disturbs cilium formation and contributes to impaired environmental sensing, aberrant signaling, and distortion of polarized tissue architecture, which are all hallmarks of cancer. Cancer Res; 70(22); 9453–62. ©2010 AACR.
Expression, Cellular Distribution, and Prognostic Relevance of TRAIL Receptors in Hepatocellular Carcinoma
Authors: Kriegl Lydia , Jung Andreas , Engel Jutta , Jackstadt Rene , Gerbes Alexander L. , Gallmeier Eike , Reiche Jana A. , Hermeking Heiko , Rizzani Antonia , Bruns Christiane J. , Kolligs Frank T. , Kirchner Thomas , Göke Burkhard , De Toni Enrico N.
Published: October 2010

Purpose: After the advent of targeted therapies for hepatocellular carcinoma (HCC), much work is being done to provide a comprehensive description of the different signaling pathways contributing to cell survival and proliferation in this tumor. Apoptotic signaling mediated by tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) represents an important mechanism of tumor surveillance, but its importance in the development of HCC is not known. We thus investigated the cellular distribution and the prognostic importance of TRAIL receptors in HCC.

Experimental Design: Immunohistochemical staining for TRAIL receptors was evaluated in HCC tissues and in matched surrounding nontumor tissues of 157 HCC patients treated with liver transplantation or partial hepatectomy. Survival was analyzed in 93 patients who underwent partial hepatectomy.

Results: The fraction of HCC samples with positive membrane staining for TRAIL receptor 1 (TRAIL-R1) and 2 (TRAIL-R2) was 1.4- and 2.7-fold lower compared with that of hepatocytes from surrounding tissues (P = 0.01). Loss of either TRAIL-R1 or TRAIL-R2, as confirmed by a multivariate analysis, significantly worsened 5-year survival of HCC patients {survival, 27% versus 52% and 15% versus 43%; hazard ratio (HR), 2.3 [95% confidence interval (CI), 1.1-4.4] and 2.4 (95% CI, 1.1-5.2), respectively}. Loss of both TRAIL receptors further decreased survival of patients [HR, 5.72 (95% CI, 2.1-15.5) versus double-negative staining; P = 0.001], indicating an additive effect on survival of TRAIL-R1 and TRAIL-R2.

Conclusions: This pilot study suggests that loss of TRAIL receptors is a frequent feature of HCCs and an independent predictor of survival in patients undergoing partial hepatectomy. Future therapeutic protocols are likely to profit from the characterization of their expression and cellular distribution. Clin Cancer Res; 16(22); 5529–38. ©2010 AACR.
Glycogen Synthase Kinase-3β: A Prognostic Marker and a Potential Therapeutic Target in Human Bladder Cancer
Authors: Naito Sei , Bilim Vladimir , Yuuki Kaori , Ugolkov Andrey , Motoyama Teiichi , Nagaoka Akira , Kato Tomoyuki , Tomita Yoshihiko
Published: October 2010

Purpose: Although recent studies have shown glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase, as a positive regulator of pancreatic, colon, and kidney cancer cell survival and proliferation, the role of GSK-3 in bladder cancer remains unknown. Our objectives were to determine the subcellular localization of GSK-3β and to evaluate the effect of GSK-3 inhibition in bladder cancer.

Experimental Design: We used immunohistochemical staining and nuclear/cytosolic fractionation to determine the expression pattern of GSK-3β in human urothelial carcinomas. To study the effect of GSK-3 inhibition on bladder cancer cell proliferation and survival, we used pharmacologic inhibitors of GSK-3, RNA interference, MTS assay, bromodeoxyuridine incorporation assay, quantitative reverse transcriptase-PCR, and Western blotting.

Results: We found aberrant nuclear accumulation of GSK-3β in 62% (43 of 69) and 91% (21 of 23) of noninvasive and invasive human urothelial carcinomas, respectively. GSK-3β nuclear staining was significantly associated with high-grade tumors (P < 0.001), advanced stage of bladder cancer (P < 0.05), metastasis (P < 0.05), and worse cause-specific survival (P < 0.05) in bladder cancer patients. Moreover, we found that pharmacologic inhibition or genetic depletion of GSK-3β resulted in decreased viability of bladder cancer cells.

Conclusions: Our results suggest nuclear accumulation of GSK-3β as a novel prognostic marker in bladder cancer, show that GSK-3 contributes to urothelial cancer cell proliferation and survival, and identify GSK-3 as a potential therapeutic target in human bladder cancer. Clin Cancer Res; 16(21); 5124–32. ©2010 AACR.
Mechanisms of Synergistic Antileukemic Interactions between Valproic Acid and Cytarabine in Pediatric Acute Myeloid Leukemia
Authors: Xie Chengzhi , Edwards Holly , Xu Xuelian , Zhou Hui , Buck Steven A. , Stout Mark L. , Yu Qun , Rubnitz Jeffrey E. , Matherly Larry H. , Taub Jeffrey W. , Ge Yubin
Published: October 2010

Purpose: To determine the possibility of synergistic antileukemic activity and the underlying molecular mechanisms associated with cytarabine combined with valproic acid (VPA; a histone deacetylase inhibitor and a Food and Drug Administration–licensed drug for treating both children and adults with epilepsy) in pediatric acute myeloid leukemia (AML).

Experimental Design: The type and extent of antileukemic interactions between cytarabine and VPA in clinically relevant pediatric AML cell lines and diagnostic blasts from children with AML were determined by MTT assays and standard isobologram analyses. The effects of cytarabine and VPA on apoptosis and cell cycle distributions were determined by flow cytometry analysis and caspase enzymatic assays. The effects of the two agents on DNA damage and Bcl-2 family proteins were determined by Western blotting.

Results: We showed synergistic antileukemic activities between cytarabine and VPA in four pediatric AML cell lines and nine diagnostic AML blast samples. t(8;21) AML blasts were significantly more sensitive to VPA and showed far greater sensitivities to combined cytarabine and VPA than non-t(8;21) AML cases. Cytarabine and VPA cooperatively induced DNA double-strand breaks, reflected in induction of γH2AX and apoptosis, accompanied by activation of caspase-9 and caspase-3. Further, VPA induced Bim expression and short hairpin RNA knockdown of Bim resulted in significantly decreased apoptosis induced by cytarabine and by cytarabine plus VPA.

Conclusions: Our results establish global synergistic antileukemic activity of combined VPA and cytarabine in pediatric AML and provide compelling evidence to support the use of VPA in the treatment of children with this deadly disease. Clin Cancer Res; 16(22); 5499–510. ©2010 AACR.