bluuebunny/crossref_metadata_2025 huggingface dataset:
Yield Enhanced Reticle Design Considering Both Wafer Dicing and Statistical Model of Defects
Authors: Ye Yi , Zhu Jiaojiao , Shi Zheng , Yan Xiaolang
Published: March 2012

High mask cost increasingly motivates the use of Multiple Project Wafers (MPW). Prior to fabrication, dies chosen for an MPW program should be packed under certain constraints in a reticle, this is called reticle design. The goal of reticle design is using fewer wafers to get the required production volumes of all dies. In this paper, we proposed a yield enhanced reticle design algorithm which considers both wafer dicing and statistical model of defects. On the premise of ensuring required production volumes, the proposed algorithm gives improved average yield. During the reticle floorplan procedure, the die that needs larger production volume and has higher yield loss caused by random defect has higher penalty; therefore it will be placed at a proper position of the reticle automatically to avoid wafer dicing conflicts with the other dies. This approach results in better average yield which is in equivalence with fewer wafers.
Strip Testing - Low Cost Testing
Authors: Beng Loke Chee
Published: March 2012

The cost of manufacturing semiconductors continues to increase and has become a major concern in the industry. A number of cost saving technologies have been developed to reduce cost of test and to keep ahead of the competitors. In final testing operation, a low cost test method is proposed by using strip testing. The proposed method enables testing to be performed in strip form instead of in singulated form. Generally, there are two common strip testing methods in the industry: Punch Isolation Strip Testing and Sawn Isolation Strip Testing. This paper mainly covers the Sawn-through Isolation Strip Testing. Overview of sawn strip test process is introduced. The cost benefits of the implementation are discussed in details, followed by the actual case study based on MLP package.
LED Production Yield Improvement Using Advanced In Situ Metrology Systems
Authors: Thieme Tom , Haberland Kolja
Published: March 2012

Optoelectronic compound semiconductor (CS) structures such as LEDs are typically grown in a complex multi-step hetero epitaxial process. Hence close supervision of the tight growth conditions is a must in order to manufacture high quality devices. Differently to the silicon semiconductor industry, CS devices are still manufactured on relatively small substrates. In 2009 nearly 70% of the compound semiconductor devices were still produced on 2" sapphire wafers. In-situ metrology provides real time access to pocket and wafer temperature, growth rate of individual layers and morphology information to eventually control the complex multi-layer growth. By 2015 market researchers predict a lager penetration of 4" and 6" sapphire wafer, which increases the device count per wafer and is expected to reduce manufacturing cost. However, on such larger substrates several wafer bow effects become much more critical for the device performance. Hence, advanced in-situ control of wafer curvature optimization will become mandatory to improve and maintain high production quality and yield.
The Impact of Isolation Methods on Device Characteristics in Bulk FinFET Using TCAD Simulation
Authors: Ren Zhe , Yin Huaxiang
Published: March 2012

Due to its intrinsic structure, effective electrical isolation in bulk FinFET turns to be a critical concern for 22nm and beyond device performance. In this paper, an air-isolated fin structure for bulk FinFET was proposed and estimated. In addition, one state-of-the-art isolation approach, which contains a punch-through stopper (PTS) obtained from the lateral scattering of implanted ions in shallow trench isolation (STI) regions, is comparatively analyzed. As the fin width has been down to the sub-20 nm regime, the pros and cons of each approach are further evaluated. Our suggested air-isolation structure shows superior electrical performance and this simulated result provides a reliable alternative to support the isolation technique development of 22nm and beyond bulk FinFET.
A New Methodology to Investigate the Effect of Stress and Bias on 2DEG and Drain Current of AlGaN/GaN Based Heterostructure
Authors: Kumar Manoj , Sheu Gene , Tsai Jung-Ruey , Yang Shao-Ming , Guo Yu-Feng
Published: March 2012

The effect of negative, neutral and positive stress by Si3N4 film on AlGaN layer of AlGaN/GaN based high electron mobility transistor (HEMT) heterostructure has been investigated by varying different stress values using Synopsys Sentaurus device simulation. This paper shows a relation between the stresses of passivation layer, two dimensional electron gas (2DEG) formed at the interface of AlGaN/GaN region and respective drain current. The increase in negative stress will result in the increase of 2DEG density, which will result in the increase of drain current. Additionally, the 2DEG density was found to be depended on the applied bias voltage, showing the higher drain sweep voltage will increase the 2DEG density. This study also provides the effect of stress on direct-current (DC) capacitance-voltage characteristics of device electrical performance. It suggests that the capacitance will be increased with the increasing positive stress, indicating the change in interface states due to stress effect.
High Reflectance Contacts to P-type GaN Using Ag-La Alloys
Authors: Cheng Bo-Yuan , Chen I-Chen , Kuo Cheng-Huang , Chang Li-Chuan
Published: March 2012

In this study, we have investigated a new Ag-La alloy contact to p-type GaN for producing high reflectance and low contact resistivity ohmic contacts. A low specific contact resistivity of 5.87×10-5 Ω cm2 and high light reflectance of 85% at 460 nm could be obtained from Ag-La alloy contacts after annealed at 350 oC in air ambient. The formation of lanthanum oxide suppresses the Ag oxidation during annealing process and leads to a good ohmic contact with high reflectance. Additionally, compared with pure Ag contacts, the Ag-La alloy contacts show better thermal stability after a long thermal annealing at 300°C in air ambient.
Electrical and Optical Properties of In-Doped SnS Thin Films Prepared by Thermal Evaporation
Authors: Huang Weihui , Cheng Shuying , Zhou Haifang
Published: March 2012

Tin monosulfide (SnS) and indium thin films were successively deposited onto glass substrates by thermal evaporation (with indium proportion of 0 at.% to 12.49 at.%). Then the films were annealed in vacuum at 300° for 2h in order to obtain different In-doped concentration SnS (SnS:In) films. The structural, electrical and optical properties of the SnS:In thin films were characterized using X-ray diffraction (XRD), scanning electron microscope (SEM), Hall Effect Measurement System and UV/VIS/NIR Spectrometer. The result shows that the films are polycrystalline SnS with orthogonal structure, and the crystallites in the films are exclusively oriented along (111) direction. All the films are of p-type conductivity. With the indium proportion increased from 0 at% to 12.49 at%, the optical bandgaps of the films are decreased from 1.37eV to 1.12eV, and the carrier concentration of the films is increased observably, whereas their resistivity and carrier mobility are decreased straightly. In-doping with a certain quantity can improve the semiconducting properties of the films and it is possible to produce suitable SnS:In thin films as absorbers in thin film solar cells.
Demonstration of a Novel Multilevel Storage Scheme for Phase Change Memory Using a Parameterized HSPICE Model
Authors: Chao Der-Sheng , Lien Chenhsin , Liao Yi-Bo , Chiang Meng-Hsueh , Yen Philip H. , Chen Ming-Jung , Chiang Pei-Chia , Tsai Ming-Jinn
Published: March 2012

A novel scheme for PCM multilevel storage, namely the stacked PCM, was proposed in this study. Multiple PCM cells having various programmed volumes are vertically stacked and connected in series to constitute the architecture of the stacked PCM. To simulate the coupling programming characteristics of the stacked PCM, a parameterized PCM HSPICE model was established on the basis of the specific device parameters extracted from the fabricated double confined cells. The results indicate that 2 bits/cell storage can be accomplished by the stacked PCM with three interconnected cells. The simulated step-like R-I curves demonstrate the desirable attributes of direct overwrite capability and larger programming margin. The phenomena of multiple snapbacks can also be observed from the simulated I-V characteristics. Relying on the simulated results by the PCM HSPICE model, the stacked PCM could be one feasible approach for accomplishing multilevel storage in PCM.
Packaging for MEMS and Sensors - Challenges and Opportunities
Authors: Theuss Horst
Published: March 2012

The wide field of MEMS and Sensor technologies adds numerous aspects to the classical world of semiconductor industry. MEMS-specific requirements impact wafer technologies, assembly and electrical interconnection both on package and system level. Reliability engineers have to cope with materials, which are new to semiconductor environments. Furthermore, degree and level of integration, as well supply chains might have to be reviewed. This paper elaborates on novel flavors which the MEMS- and Sensor features add to the semiconductor industry. A focus is put onto the field of packaging. Striving for low stress packages is the traditional field of sensor packaging development, because package-induced mechanical stress typically deteriorates the performance of a sensor. On the other hand, specific case studies demonstrate, how packaging can as well substantially contribute to the performance of a sensor device.
Effects of the Substrate on Piezoresistive Properties of Silicon Carbide Thin Films
Authors: Fraga Mariana A. , Furlan Humber , Rasia Luiz A. , Koberstein Leandro L.
Published: March 2012

Silicon carbide (SiC), in bulk or film form, has been shown as a promising material to replace the silicon as sensing element in devices for harsh environments. This has motivated several studies on growth and characterization of SiC thin films on different substrates such as silicon, silicon dioxide (SiO2), aluminum nitride (AlN) and silicon nitride (Si3N4), among others. However, less attention has been given to the investigation on how substrates affect the piezoresistive properties of SiC thin films. In this work, we have investigated the effect of substrates on the piezoresistive properties of SiC thin films produced by magnetron sputtering. Three types of substrates were utilized: (100) monocrystalline silicon, AlN on silicon and thermally oxidized silicon. Test structures were fabricated using photolithography, metallization lift-off and RIE (reactive ion etching) processes in order to perform piezoresistive characterization of the SiC samples produced.
Study on a Low Power and High Efficiency Micro Heater Used in μPCR Chip
Authors: Wang Junqiang , Deng Tao , Zhang Pu , Wu Cinan , Liu Zewen
Published: March 2012

Thermal properties and power consumption of a micro heater used in micro polymerase chain reaction (μPCR) chip was analyzed utilizing Finite Element Analysis (FEA), and a low power and high efficiency micro heater was designed. By using borosilicate-glass as the substrate instead of silicon, the power consumption of the μPCR chip reduced 80%. To overcome the high thermal insulation of the borosilicate-glass substrate, water forced cooling system based on micro flow channels was designed to speed up the μPCR cycling. 3D thermal and fluidic models of the μPCR chip with both micro heaters fabricated on silicon and borosilicate-glass were built to analyze their properties. The depth of the micro flow channel was optimized. Experimental results revealed that the cooling rate reached 13.8°/s with the 100μm-deep micro flow channel.
Study on Al-Ge Bonding and Quality Improvement in CMEMS Process
Authors: Gu Athics , Lin Paul-Chang , Chang Vincent , Li Terry , Zhang Ji-Wei , Jiang Jian-Yong , Xing Charles
Published: March 2012

CMEMS(CMOS and Micro Electro Mechanical Systems) process is integration of CMEMS and cap wafer, which is realized through bonding process and has been more and more important in IC industry currently. The bonding process is kernel in CMEMS manufacture and is impacted by material, pressure, temperature and so on. In standard bonding process, Al-Ge bonding which is selected for the good adhesion comparing with other bonding material. In this paper, the bonding process conditions are designed according to the structure of CMEMS and characteristics of Al-Ge material, and experiments including leakage rate and bonding strength are implemented to discuss the bonding quality. In the end, suitable bonding process and its summary of side effect for Al-Ge are put forward.
A Low Power Density Hebbian Eigenfilter VLSI for Neuro-Physiological Sensor Spike Train Analysis
Authors: Liang Peng , Li Xiangyu , Yu Bo , Mak Terrence , Sun Yihe
Published: March 2012

Real-time neuro-physiological signal processing with dramatic increasing data bandwidth and data volume comes up against large computation load and power dissipation. For spike train analysis circuit, the trade-off between power density and throughput rate is a significant problem. In this paper, a principle component analysis approach utilizing hebbian eigenﬁlter for spike train analysis is proposed. An array architecture associated with vector parallel computing function is built to achieve low power density. Experimental result shows that the power density of the hebbian eigenfilter is reduced to 46.1 μW/mm2 at the required sample rate and gate count reaches to about 72000.
Fabrication of Thin Silicon PIN Detector Based on Wafer Bonding Technology
Authors: Dong Xianshan , Yu Min , Tian Dayu , Wang Jinyan , Xiang Hongwen , Jin Yufeng
Published: March 2012

A novel process for fabricating thin silicon PIN detectors based on wafer bonding technology is proposed. Two silicon wafers, device wafer and supporting wafer, with different orientation and resistivity are bonded at high temperature. The bonded device wafer is grinded and polished. Processing this wafer, we successfully produced 100um thick PIN detectors with detecting area ranging from 1 to 113 mm2. The full depletion voltage of all the detectors is about 9V and electrical testing shows a low leakage current of around 100nA/cm3 at 11V. The energy resolution of the fabricated detectors for 5.486Mev alpha particles from 241Am is 0.34%-0.46%.
Analysis and Optimization of GMR Based Current Sensors with Identical Pinning Orientation
Authors: Ma Weichao , Jia Ze , Yin Cong , Ren Tianling
Published: March 2012

A scheming methodology of Giant Magnetoresistance (GMR) based current sensors is proposed in this paper, in order to minimize the nonlinearity and offset voltage caused by layout design without affecting the sensitivity. Based on the theoretical analysis of the current sensors with identical pinning orientation, several proper schemes of design are presented and discussed. Then, the finite-element method (FEM) is applied to model the 2D and 3D magnetic distribution of the sensors. The distance between two current paths, the location of the y-direction current path are well arranged to eliminate the interferences of the undesired magnetic resources. The relationships among width and thickness of the sensing element, electrical current and distance between the current path and the sensing element are also quantified to guide the dimensional design of the current sensor.
Study on Infrared Absorption Characteristics of Ti and TiNx Nanofilms
Authors: Yuan Mingquan , Zhou Xiaoxiong , Yu Xiaomei
Published: March 2012

Infrared detector has a wide range of applications. To fabricate an IR detector with good sensitivity, an efficient IR absorber is needed. In this paper, we theoretically and experimentally investigated the absorption characteristics of Ti, multi-layer structured Ti-SiO2 and TiNx-SiNx nano films. The multi-layer structured TiNx-SiNx films with different nitrogen contents and Ti nano films with different thicknesses were deposited by e-beam sputtering. For single nano Ti film, 35% absorptivity was obtained at a wavelength of 1.67μm when the film thickness was 15.3nm. A better IR absorption characteristic was achieved for multi-layer structured Ti-SiO2 nano film. In this structure, an absorption peak of appears at a wavelength of 9.5μm. Compared with the absorption behavior of single SiNx film, an additional nano TiNx film obviously improved IR absorption at a wider band. And a maximum IR absorptivity of 27% was obtained at the wavelength of 14μm.
Modulation of SRCa2+release by the triadin-to-calsequestrin ratio in ventricular myocytes
Authors: Kučerová Dana , Baba Hideo A. , Bokník Peter , Fabritz Larissa , Heinick Alexander , Mát'uš Marek , Müller Frank U. , Neumann Joachim , Schmitz Wilhelm , Kirchhefer Uwe
Published: March 2012

Calsequestrin (CSQ) is a Ca2+storage protein that interacts with triadin (TRN), the ryanodine receptor (RyR), and junctin (JUN) to form a macromolecular tetrameric Ca2+signaling complex in the cardiac junctional sarcoplasmic reticulum (SR). Heart-specific overexpression of CSQ in transgenic mice (TGCSQ) was associated with heart failure, attenuation of SR Ca2+release, and downregulation of associated junctional SR proteins, e.g., TRN. Hence, we tested whether co-overexpression of CSQ and TRN in mouse hearts (TGCxT) could be beneficial for impaired intracellular Ca2+signaling and contractile function. Indeed, the depressed intracellular Ca2+concentration ([Ca]i) peak amplitude in TGCSQwas normalized by co-overexpression in TGCxTmyocytes. This effect was associated with changes in the expression of cardiac Ca2+regulatory proteins. For example, the protein level of the L-type Ca2+channel Cav1.2 was higher in TGCxTcompared with TGCSQ. Sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) expression was reduced in TGCxTcompared with TGCSQ, whereas JUN expression and [3H]ryanodine binding were lower in both TGCxTand TGCSQcompared with wild-type hearts. As a result of these expressional changes, the SR Ca2+load was higher in both TGCxTand TGCSQmyocytes. In contrast to the improved cellular Ca2+, transient co-overexpression of CSQ and TRN resulted in a reduced survival rate, an increased cardiac fibrosis, and a decreased basal contractility in catheterized mice, working heart preparations, and isolated myocytes. Echocardiographic and hemodynamic measurements revealed a depressed cardiac performance after isoproterenol application in TGCxTcompared with TGCSQ. Our results suggest that co-overexpression of CSQ and TRN led to a normalization of the SR Ca2+release compared with TGCSQmice but a depressed contractile function and survival rate probably due to cardiac fibrosis, a lower SERCA2a expression, and a blunted response to β-adrenergic stimulation. Thus the TRN-to-CSQ ratio is a critical modulator of the SR Ca2+signaling.
Suppression of trophoblast uterine spiral artery remodeling by estrogen during baboon pregnancy: impact on uterine and fetal blood flow dynamics
Authors: Aberdeen Graham W. , Bonagura Thomas W. , Harman Chris R. , Pepe Gerald J. , Albrecht Eugene D.
Published: March 2012

The present study was conducted to determine the impact of suppressing trophoblast remodeling of the uterine spiral arteries by prematurely elevating estrogen levels in the first trimester of baboon pregnancy on uterine and umbilical blood flow dynamics. Uteroplacental blood flow was assessed by Doppler ultrasonography after acute administration of saline (basal state) and serotonin on days 60, 100, and 160 of gestation (term: 184 days) to baboons in which uterine spiral artery remodeling had been suppressed by the administration of estradiol on days 25–59 of gestation. Maternal blood pressure in the basal state was increased ( P < 0.01), and uterine artery diastolic notching and the umbilical artery pulsatility index and systolic-to-diastolic ratio, reflecting downstream flow impedance, were increased ( P < 0.01) after serotonin administration on day 160, but not earlier, in baboons treated with estradiol in early gestation. These changes in uteroplacental flow dynamics in serotonin-infused, estradiol-treated animals were accompanied by a decrease ( P < 0.05) in uterine and umbilical artery volume flow and fetal bradycardia. The results of this study show that suppression of uterine artery remodeling by advancing the rise in estrogen from the second trimester to the first trimester disrupted uteroplacental blood flow dynamics and fetal homeostasis after vasochallenge late in primate pregnancy.
Mechanotransduction through fibronectin-integrin focal adhesion in microvascular smooth muscle cells: is calcium essential?
Authors: Sun Zhe , Li Zhaohui , Meininger Gerald A.
Published: March 2012

It is believed that increased transmural pressure exerts force on vascular smooth muscle cells (VSMCs) and triggers Ca2+signaling as an initiating event responsible for the arteriolar myogenic response. However, the mechanisms linking the pressure increase to Ca2+signaling are unclear. We have shown previously using atomic force microscopy (AFM) that mechanical force induces a VSMC contractile response when applied to single fibronectin (FN; Sun Z, Martinez-Lemus LA, Hill MA, Meininger GA. Am J Physiol Cell Physiol 295; C268–C278, 2008) focal adhesion sites. This current study seeks to determine whether application of force to single focal adhesions can cause a change in VSMC Ca2+. Experiments were performed in low passage (p3∼10) as well as in freshly isolated skeletal muscle arteriole VSMCs. AFM-attached microbeads (5 μm) were coated with FN or collagen type I (CN-I) or type IV (CN-IV) and placed on a VSMC for 20 min, resulting in formation of a focal adhesion between the cell and the microbead. In low passage VSMCs, mechanically pulling on the FN-coated beads (800∼3000 pN) did not induce a Ca2+increase but did cause a contractile response. In freshly isolated VSMCs, application of an FN or CN-I-coated bead onto the cell surface induced global Ca2+increases. However, these Ca2+increases were not correlated with the application of AFM pulling force to the bead or with the VSMC contractile responses to FN-coupled pulling. Chelating cytosolic Ca2+using BAPTA loading had no negative effect on the focal adhesion-related contractile response in both freshly isolated and low passage VSMCs, while the Rho-kinase inhibitor Y27632 abolished the micromyogenic response in both cases. These observations suggest that, in freshly isolated and cultured VSMCs, application of mechanical force to a focal adhesion does not invoke an acute global Ca2+increase. On the other hand, our data support a role for Rho-linked signaling mechanism involved in mechanotransduction leading to focal contraction that is independent of the need for a global increase in VSMC Ca2+.
Attenuation by sphingosine-1-phosphate of rat microvessel acute permeability response to bradykinin is rapidly reversible
Authors: Adamson R. H. , Sarai R. K. , Clark J. F. , Altangerel A. , Thirkill T. L. , Curry F. E.
Published: March 2012

To evaluate the hypothesis that sphingosine-1-phosphate (S1P) and cAMP attenuate increased permeability of individually perfused mesenteric microvessels through a common Rac1-dependent pathway, we measured the attenuation of the peak hydraulic conductivity ( Lp) in response to the inflammatory agent bradykinin (BK) by either S1P or cAMP. We varied the extent of exposure to each agent (test) and measured the ratio Lptest/ LpBK alone for each vessel (anesthetized rats). S1P (1 μM) added at the same time as BK (concurrent, no pretreatment) was as effective to attenuate the response to BK ( Lp ratio: 0.14 ± 0.05; n = 5) as concurrent plus pretreatment with S1P for 30 min ( Lp ratio: 0.26 ± 0.06; n = 11). The same pretreatment with S1P, but with no concurrent S1P, caused no inhibition of the BK response ( Lp ratio 1.07 ± 0.11; n = 8). The rapid on and off action of S1P demonstrated by these results was in contrast to cAMP-dependent changes induced by rolipram and forskolin (RF), which developed more slowly, lasted longer, and resulted in partial inhibition when given either as pretreatment or concurrent with BK. In cultured endothelium, there was no Rac activation or peripheral cortactin localization at 1 min with RF, but cortactin localization and Rac activation were maximal at 1 min with S1P. When S1P was removed, Rac activation returned to control within 2 min. Because of such differing time courses, S1P and cAMP are unlikely to act through fully common effector mechanisms.
Functional scaffold-free 3-D cardiac microtissues: a novel model for the investigation of heart cells
Authors: Desroches B. R. , Zhang P. , Choi B.-R. , King M. E. , Maldonado A. E. , Li W. , Rago A. , Liu G. , Nath N. , Hartmann K. M. , Yang B. , Koren G. , Morgan J. R. , Mende U.
Published: March 2012

To bridge the gap between two-dimensional cell culture and tissue, various three-dimensional (3-D) cell culture approaches have been developed for the investigation of cardiac myocytes (CMs) and cardiac fibroblasts (CFs). However, several limitations still exist. This study was designed to develop a cardiac 3-D culture model with a scaffold-free technology that can easily and inexpensively generate large numbers of microtissues with cellular distribution and functional behavior similar to cardiac tissue. Using micromolded nonadhesive agarose hydrogels containing 822 concave recesses (800 μm deep × 400 μm wide), we demonstrated that neonatal rat ventricular CMs and CFs alone or in combination self-assembled into viable (Live/Dead stain) spherical-shaped microtissues. Importantly, when seeded simultaneously or sequentially, CMs and CFs self-sorted to be interspersed, reminiscent of their myocardial distribution, as shown by cell type-specific CellTracker or antibody labeling. Microelectrode recordings and optical mapping revealed characteristic triangular action potentials (APs) with a resting membrane potential of −66 ± 7 mV ( n = 4) in spontaneously contracting CM microtissues. Under pacing, optically mapped AP duration at 90% repolarization and conduction velocity were 100 ± 30 ms and 18.0 ± 1.9 cm/s, respectively ( n = 5 each). The presence of CFs led to a twofold AP prolongation in heterogenous microtissues (CM-to-CF ratio of 1:1). Importantly, Ba2+-sensitive inward rectifier K+ currents and Ca2+-handling proteins, including sarco(endo)plasmic reticulum Ca2+-ATPase 2a, were detected in CM-containing microtissues. Furthermore, cell type-specific adenoviral gene transfer was achieved, with no impact on microtissue formation or cell viability. In conclusion, we developed a novel scaffold-free cardiac 3-D culture model with several advancements for the investigation of CM and CF function and cross-regulation.
Biaxial vasoactivity of porcine coronary artery
Authors: Huo Yunlong , Cheng Yana , Zhao Xuefeng , Lu Xiao , Kassab Ghassan S.
Published: March 2012

The passive mechanical properties of blood vessel mainly stem from the interaction of collagen and elastin fibers, but vessel constriction is attributed to smooth muscle cell (SMC) contraction. Although the passive properties of coronary arteries have been well characterized, the active biaxial stress-strain relationship is not known. Here, we carry out biaxial (inflation and axial extension) mechanical tests in right coronary arteries that provide the active coronary stress-strain relationship in circumferential and axial directions. Based on the measurements, a biaxial active strain energy function is proposed to quantify the constitutive stress-strain relationship in the physiological range of loading. The strain energy is expressed as a Gauss error function in the physiological pressure range. In K+-induced vasoconstriction, the mean ± SE values of outer diameters at transmural pressure of 80 mmHg were 3.41 ± 0.17 and 3.28 ± 0.24 mm at axial stretch ratios of 1.3 and 1.5, respectively, which were significantly smaller than those in Ca2+-free-induced vasodilated state (i.e., 4.01 ± 0.16 and 3.75 ± 0.20 mm, respectively). The mean ± SE values of the inner and outer diameters in no-load state and the opening angles in zero-stress state were 1.69 ± 0.04 mm and 2.25 ± 0.08 mm and 126 ± 22°, respectively. The active stresses have a maximal value at the passive pressure of 80–100 mmHg and at the active pressure of 140–160 mmHg. Moreover, a mechanical analysis shows a significant reduction of mean stress and strain (averaged through the vessel wall). These findings have important implications for understanding SMC mechanics.
Expression and functional significance of NADPH oxidase 5 (Nox5) and its splice variants in human blood vessels
Authors: Pandey Deepesh , Patel Anand , Patel Vijay , Chen Feng , Qian Jin , Wang Yusi , Barman Scott A. , Venema Richard C. , Stepp David W. , Daniel Rudic R. , Fulton David J. R.
Published: March 2012

The expression and functional significance of NADPH oxidase 5 (Nox5) and its five isoforms in vascular cells is poorly understood. The goal of this study was to determine whether Nox5-α, -β, -δ, -γ, and -ε (short) are expressed in human blood vessels and evaluate their respective functions. Nox5 mRNA and protein were detected in human blood vessels, cultured human vascular smooth muscle (HVSMC) and endothelium, but not fibroblasts. The most abundant isoforms were α and β, whereas δ and γ were not detected. Nox5-α and -β produced reactive oxygen species (ROS), but -δ, -γ, and -ε were not catalytically active. Coexpression of the active Nox5 isoforms with inactive Nox5 variants suppressed ROS production, and coimmunoprecipitation revealed that Nox5-β binds the inactive ε variant, which may account for reduced ROS production. In HVSMC, angiotensin II, endothelin-1 and TNF-α increased endogenous Nox5 mRNA levels, while adenovirus-mediated overexpression of Nox5 promoted p38 MAPK, JAK2, JNK, and ERK1/2 phosphorylation in endothelial cells (EC), but only increased ERK1/2 phosphorylation in HVSMC. At higher levels of Nox5, there was evidence of increased apoptosis in EC, but not in HVSMC, as detected by the presence of cleaved caspase-3 and cleaved poly(ADP-ribose)polymerase. Although catalytically inactive, Nox5-ε potently activated ERK in HVSMC, and increased expression of Nox5-ε promoted HVSMC proliferation. Nox5 is expressed in human blood vessels. The Nox5-α and -β splice variants are the major isoforms that are expressed and the only variants capable of ROS production. Nox5-ε can inhibit Nox5 activity and activate ERK and HVSMC proliferation.
Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes
Authors: Krasnodembskaya Anna , Samarani Gianluca , Song Yuanlin , Zhuo Hanjing , Su Xiao , Lee Jae-Woo , Gupta Naveen , Petrini Mario , Matthay Michael A.
Published: March 2012

The potential therapeutic value of cell-based therapy with mesenchymal stem cells (MSC) has been reported in mouse models of polymicrobial peritoneal sepsis. However, the mechanisms responsible for the beneficial effects of MSC have not been well defined. Therefore, we tested the therapeutic effect of intravenous bone marrow-derived human MSC in peritoneal sepsis induced by gram-negative bacteria. At 48 h, survival was significantly increased in mice treated with intravenous MSC compared with control mice treated with intravenous fibroblasts (3T3) or intravenous PBS. There were no significant differences in the levels of TNF-α, macrophage inflammatory protein 2, or IL-10 in the plasma. However, there was a marked reduction in the number of bacterial colony-forming units of Pseudomonas aeruginosa in the blood of MSC-treated mice compared with the 3T3 and PBS control groups. In addition, phagocytic activity was increased in blood monocytes isolated from mice treated with MSC compared with the 3T3 and PBS groups. Furthermore, levels of C5a anaphylotoxin were elevated in the blood of mice treated with MSC, a finding that was associated with upregulation of the phagocytosis receptor CD11b on monocytes. The phagocytic activity of neutrophils was not different among the groups. There was also an increase in alternately activated monocytes/macrophages (CD163- and CD206-positive) in the spleen of the MSC-treated mice compared with the two controls. Thus intravenous MSC increased survival from gram-negative peritoneal sepsis, in part by a monocyte-dependent increase in bacterial phagocytosis.
Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
Authors: Terme Magali , Ullrich Evelyn , Aymeric Laetitia , Meinhardt Kathrin , Coudert Jérôme D. , Desbois Mélanie , Ghiringhelli François , Viaud Sophie , Ryffel Bernard , Yagita Hideo , Chen Lieping , Mécheri Salaheddine , Kaplanski Gilles , Prévost-Blondel Armelle , Kato Masashi , Schultze Joachim L. , Tartour Eric , Kroemer Guido , Degli-Esposti Mariapia , Chaput Nathalie , Zitvogel Laurence
Published: March 2012

During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1–dependent tumor progression in NK cell–controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit− (CD11b−) into Kit+ natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit+ NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit+ NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1–dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18–binding protein dramatically reduced the accumulation of Kit+CD11b− NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit+CD11b− NK cells endowed with B7-H1–dependent immunoablative functions in mice. Cancer Res; 72(11); 2757–67. ©2012 AACR.
New Strategies in Refractory and Recurrent Neuroblastoma: Translational Opportunities to Impact Patient Outcome
Authors: Cole Kristina A. , Maris John M.
Published: March 2012

Neuroblastoma remains responsible for a disproportionate amount of childhood cancer morbidity and mortality despite recent significant advances in understanding the genetic basis of tumor initiation and progression. About half of newly diagnosed patients can be reliably identified as having tumors of low malignant potential, and these children have cure rates of greater than 95% with little or no cytotoxic therapy. On the other hand, the other half of neuroblastomas typically present in an explosive fashion with widely metastatic disease, and reliable tumor-specific biomarkers have been defined for this phenotype as well. Empiric approaches to high-risk neuroblastoma therapy have relied on dramatic escalation of chemotherapy dose intensity and, recently, the incorporation of targeted immunotherapy, but nearly 50% of children with high-risk disease will be refractory to therapy or suffer a relapse, both of which are invariably fatal. Future improvements in high-risk neuroblastoma outcomes will require the identification of disease and patient-specific oncogenic vulnerabilities that can be leveraged therapeutically. Rational development of novel approaches to neuroblastoma therapy requires forward-thinking strategies to unequivocally prove activity in the relapse setting and, ultimately, efficacy in curing patients when integrated into frontline treatment plans. Clin Cancer Res; 18(9); 2423–8. ©2012 AACR.
Upregulated JAG1 Enhances Cell Proliferation in Adrenocortical Carcinoma
Authors: Simon Derek P. , Giordano Thomas J. , Hammer Gary D.
Published: March 2012

Purpose: The purpose of this study was to examine the expression and molecular significance of JAG1, a ligand for the Notch developmental signaling pathway, in adrenocortical carcinoma (ACC).

Experimental Design: Human microarray data were analyzed for genes expressing ligands for the Notch pathway and validated with quantitative real-time PCR (QPCR) and immunoblots of RNA and protein, respectively. ACC cells lines were assessed for Notch pathway member expression by immunoblot, QPCR, and immunofluorescence. Notch pathway activity was also determined using a reporter gene (luciferase) activation. Proliferation experiments using a Jag1 knockdown strategy (Jag1KD) and an inhibitor of Notch-dependent transcription (DNMaml) used a coculture system with fluorescence-activated cell-sorting (FACS) analysis. Tumor stage and mitotic rate of human ACC samples were correlated to JAG1 expression.

Results: The Notch ligand JAG1 mRNA and protein are upregulated in ACCs. JAG1 upregulation can be modeled in the Y1 mouse ACC cell line that expresses Jag1, Notch receptors, downstream signaling molecules, and exhibits density-dependent Notch activation. Jag1 enhances cell proliferation through activation of canonical Notch signaling as shown through Jag1KD and coculture experiments. Inhibition of Notch signaling at the level of postreceptor signaling (DNMaml), results in similar inhibition of cell proliferation. Analysis of clinical data indicates that Jag1 expression correlates with both grade and stage of ACCs, supporting a role of JAG1-dependent Notch activation in late-stage ACCs.

Conclusions: JAG1 is the primary upregulated Notch ligand in ACCs and enhances ACC cell proliferation and tumor aggressiveness in a non–cell-autonomous manner through activation of Notch signaling in adjacent cells. Clin Cancer Res; 18(9); 2452–64. ©2012 AACR.
Competing Risk Analyses: How Are They Different and Why Should You Care?
Authors: Chappell Rick
Published: March 2012

Competing risks are events in which at least one precludes the observation of the other, such as toxicity and death. This commentary discusses and distinguishes between the two common types of competing risk analyses, the Kaplan–Meier and cumulative incidence curves. Clin Cancer Res; 18(8); 2127–9. ©2012 AACR.
Regulation of mTOR Complex 2 Signaling in Neurofibromatosis 2–Deficient Target Cell Types
Authors: James Marianne F. , Stivison Elizabeth , Beauchamp Roberta , Han Sangyeul , Li Hua , Wallace Margaret R. , Gusella James F. , Stemmer-Rachamimov Anat O. , Ramesh Vijaya
Published: March 2012

Inactivating mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene results in the development of schwannomas and meningiomas. Using NF2-deficient meningioma cells and tumors, together with the normal cellular counterparts that meningiomas derive, arachnoid cells, we identified merlin as a novel negative regulator of mTOR complex 1 (mTORC1). We now show that merlin positively regulates the kinase activity of mTORC2, a second functionally distinct mTOR complex, and that downstream phosphorylation of mTORC2 substrates, including Akt, is reduced upon acute merlin deficiency in cells. In response to general growth factor stimulation, Akt signaling is attenuated in merlin RNA interference-suppressed human arachnoid and Schwann cells by mechanisms mediated by hyperactive mTORC1 and impaired mTORC2. Moreover, Akt signaling is impaired differentially in a cell type–dependent manner in response to distinct growth factor stimuli. However, contrary to activation of mTORC1, the attenuated mTORC2 signaling profiles exhibited by normal arachnoid and Schwann cells in response to acute merlin loss were not consistently reflected in NF2-deficient meningiomas and schwannomas, suggesting additional genetic events may have been acquired in tumors after initial merlin loss. This finding contrasts with another benign tumor disorder, tuberous sclerosis complex, which exhibits attenuated mTORC2 signaling profiles in both cells and tumors. Finally, we examined rapamycin, as well as the mTOR kinase inhibitor, Torin1, targeting both mTOR complexes to identify the most efficacious class of compounds for blocking mTOR-mediated signaling and proliferation in merlin-deficient meningioma cells. These studies may ultimately aid in the development of suitable therapeutics for NF2-associated tumors. Mol Cancer Res; 10(5); 649–59. ©2012 AACR.
Degradation of Human RAP80 is Cell Cycle Regulated by Cdc20 and Cdh1 Ubiquitin Ligases
Authors: Cho Hyun Jung , Lee Eun Hee , Han Seung Hun , Chung Hee Jin , Jeong Ji Hoon , Kwon Junhye , Kim Hongtae
Published: March 2012

Receptor-associated protein 80 (RAP80) is a component of the BRCA1-A complex that recruits BRCA1 to DNA damage sites in the DNA damage–induced ubiquitin signaling pathway. RAP80-depleted cells showed defective G2–M phase checkpoint control. In this study, we show that RAP80 protein levels fluctuate during the cell cycle. Its expression level peaked in the G2 phase and declined during mitosis and progression into the G1 phase. Also, RAP80 is polyubiquitinated and degraded by the anaphase-promoting complex (APC/C)Cdc20 or (APC/C)Cdh1. Consistent with this, knockdown of Cdc20 or Cdh1 expression by transfecting with small interfering RNAs blocked RAP80 degradation during mitosis or the G1 phase, respectively. A conserved destruction box (D box) in RAP80 affected its stability and ubiquitination, which was dependent on APC/cyclosomeCdc20 (CCdc20) or APC/cyclosomeCdh1 (CCdh1). In addition, overexpression of RAP80 destruction box1 deletion mutant attenuated mitotic progression. Thus, APC/CCdc20 or APC/CCdh1 complexes regulate RAP80 stability during mitosis to the G1 phase, and these events are critical for a novel function of RAP80 in mitotic progression. Mol Cancer Res; 10(5); 615–25. ©2012 AACR.
Prevalence of Cervical Human Papillomavirus (HPV) Infection in Vanuatu
Authors: Aruhuri Bernadette , Tarivonda Len , Tenet Vanessa , Sinha Rohit , Snijders Peter J.F. , Clifford Gary , Pang James , McAdam Margaret , Meijer Chris J.L.M. , Frazer Ian H. , Franceschi Silvia
Published: March 2012

To provide information on human papillomavirus (HPV) prevalence and the distribution of individual HPV types in Pacific Islands, we conducted a population-based survey in Vanuatu, South Pacific. Nine hundred and eighty-seven women between 18 and 64 years of age were included. GP5+/6+-mediated PCR assay was used for HPV testing. The prevalence of 44 HPV types was 28.4% corresponding to an age (world)-standardized prevalence of 25.0% [95% confidence interval (CI), 21.9%–28.0%]. The prevalence of high-risk (HR) HPV types was 21.7% (age-standardized prevalence of 19.2%; 95% CI, 16.4%–22.0%). Among 840 women with adequate cytologic results, 13.6% showed cervical abnormalities, including 3.6% with high-grade squamous intraepithelial lesions (HSIL) and 0.8% with invasive cervical carcinoma. HPV prevalence declined from 46.1% in women aged ≤21 to 15.3% in those ≥45 years. Being single was significantly associated with HPV positivity. HR HPV findings by PCR assay and hybrid capture 2 (HC2; conducted in Vanuatu) were moderately correlated (κ test = 0.59). The positive predictive values of HR HPV positivity for HSIL or worse were 27.6% for PCR and 35.2% for HC2 among women aged ≥30. Nearly half of screening-positive women could not be reevaluated mainly on account of the difficulty to trace back women. The availability of a rapid HPV testing method that allows see-and-treat approaches at the same visit would be, therefore, essential. On account of their high cumulative burden of cervical lesions, also women older than 40 years should be included in at least the first screening round in unscreened populations. Cancer Prev Res; 5(5); 746–53. ©2012 AACR.
The Chemopreventive Effect of Mifepristone on Mammary Tumorigenesis Is Associated with an Anti-invasive and Anti-inflammatory Gene Signature
Authors: Yuan Hongyan , Upadhyay Geeta , Lu Jin , Kopelovich Levy , Glazer Robert I.
Published: March 2012

Progesterone receptor (PR) antagonists are potent antitumor agents in carcinogen and progestin-dependent mammary tumorigenesis models through both PR- and non-PR–mediated mechanisms. The PR antagonist mifepristone/RU486 has been used primarily as an abortifacient possessing high affinity for both the PR and glucocorticoid receptors (GR). To determine whether mifepristone would be effective as a chemopreventive agent, we assessed its effect on progestin/7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in wild-type (WT) and estrogen receptor-α–positive (ER+) transgenic mice expressing the dominant-negative Pax8PPARγ (Pax8) fusion protein. Mifepristone administered at a dose of 2.5 mg significantly delayed mammary tumorigenesis in WT, but not in Pax8 mice, whereas, a three-fold higher dose almost completely blocked tumorigenesis in both WT and Pax8 mice. The sensitivity of WT mice to 2.5 mg mifepristone correlated with an expression profile of 79 genes in tumors, 52 of which exhibited the opposite response in Pax8 mice, and corresponded primarily to the downregulation of genes associated with metabolism, inflammation, and invasion. These results suggest that the chemopreventive activity of mifepristone in WT mice correlates with a specific gene expression signature that is associated with multiple nuclear receptor signaling pathways. Cancer Prev Res; 5(5); 754–64. ©2012 AACR.
Proportion of Patients Treated With Thrombolysis in a Centralized Versus a Decentralized Acute Stroke Care Setting
Authors: Lahr Maarten M.H. , Luijckx Gert-Jan , Vroomen Patrick C.A.J. , van der Zee Durk-Jouke , Buskens Erik
Published: March 2012

Background and Purpose—

Today, treatment of acute stroke consists of tissue-type plasminogen activator (tPA), admission to a stroke unit, and aspirin. Although tPA treatment is the most effective, there is substantial undertreatment. Centralized care may affect rate, timing, and outcome of thrombolysis compared to decentralized treatment in community hospitals. The present study aimed to assess the impact of organizational models on the proportion of patients undergoing tPA treatment.

Methods—

A prospective, multicenter, observational study among 13 hospitals in the North of the Netherlands was conducted. In the centralized model, tPA treatment for 4 hospitals was administered in 1 stroke center. The decentralized model comprised 9 community hospitals. Primary outcome was the proportion of patients treated with tPA. Secondary outcome measures were proportion of patients arriving within 4.5 hours, safety, 90-day functional outcome, and onset-to-door, door-to-needle, and onset-to-needle times. Potential confounders were adjusted using logistic regression analysis.

Results—

Two hundred eighty-three and 801 ischemic stroke patients were enrolled in the centralized and decentralized settings. Numbers of patients treated with tPA were 62 (21.9%) and 113 (14.1%) (OR, 1.72; 95% CI, 1.22–2.43). Adjusting for potential confounders did not alter results (OR, 2.03; 95% CI, 1.39–2.96). In the centralized setting, significantly more patients arrived at the hospital within the 4.5-hour time window (
P
<0.01), and shorter door-to-needle times were reached (35 versus 47 minutes). Other secondary outcome measures did not differ across setting.

Conclusions—

In a centralized setting, the results demonstrate a 50% increased likelihood of treatment. Prehospital factors seem to contribute to this result.