bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermal Radiative Cooling Enabled Freeze Tweezer for Manipulating Micro Scale Objects
Authors: Yang Yang , Liu Jing
Published: August 2012

A freeze tweezer is a new kind of manipulation tool which employs the freezing force of a small volume of nucleotide ice for operating the micro-objects in an aqueous state. Previously, such typical device prototypes were respectively realized based on conductive and convective cooling effect. Aiming to present an alternative feasible way for realizing the freeze tweezer in micro or even much smaller size by thermal radiative cooling, a complete 3-D numerical simulation on the operation behaviors of such kind freeze tweezer have been implemented. As a result, the droplet freezing behavior is directly caused by the freeze tweezer rather than the thermal radiative cooling from the sidewall. It indicates that this new freeze tweezer would also complete all the functions as its previous type would achieve.
Reliable Design of TSV in Free-Standing Wafers and 3D Integrated Packages
Authors: Liu Xi , Simmons-Matthews Margaret , Wachtler Kurt P. , Sitaraman Suresh K.
Published: August 2012

Through-silicon via (TSV), being one of the key enabling technologies for three dimensional (3D) Integrated Circuit (IC) stacking, silicon interposer technology, and advanced wafer level packaging (WLP), has attracted tremendous interest throughout the semiconductor industry. However, limited work addresses TSV reliability issue, and most of the existing reliability studies focus on the thermo-mechanical performance of TSVs in a free-standing wafer, rather than in an integrated package. In this paper, three-dimensional thermomechanical Finite-Element (FE) models with TSVs in both free-standing wafers and 3D integrated packages have been built and analyzed. In addition, Design of Experiments (DOE) based approach has been used to understand the effect of various parameters. Results show that the selection of underfill materials between stacked dies is the most dominating design factor for TSV/microbump reliability.
Optimization of Polymer Tube-Bundle Heat Exchangers Using a Genetic Algorithm
Authors: Meng Lingjun , Jacobi Anthony M.
Published: August 2012

Tube-bundle heat exchangers are widely utilized in gas-to-gas and gas-to-liquid applications, and interest remains high in improving the efficiency of these heat exchangers. Due to excellent resistance to fouling and corrosion, polymer heat exchangers have been mainly applied under extreme working conditions, where such concerns are important. Recently, however, there has been interest in using polymer heat exchangers as a substitute for conventional metallic heat exchangers in more general applications. The present study explores the optimization of bare polymer tube-bundle (PTB) heat exchangers and determines the cost effectiveness of PTB heat exchangers through comparisons to conventional metallic heat exchangers using a Genetic Algorithm (GA). Most of heat exchanger optimization studies have focused mainly on the physics of the fluid flow or heat transfer enhancement, and a detailed analysis including geometry and cost is rare. The present study is distinguished from others by focusing on objective functions involving cost under volume constraints and undertaking geometry optimization with sensitivity analysis.
Two-Dimensional Discontinous Galerkin Simulations of Crypto-Steady Supersonic Pressure Exchange
Authors: Wang Junfeng , Liang Chunlei , Garris Charles A.
Published: August 2012

This paper reports the development of a third-order discontinuous Galerkin (DG) method for supersonic inviscid flow on a moving grid, as well as simulations of a simple model of crypto-steady supersonic pressure exchange (CSSPE) by solving 2D inviscid Euler equations. A total variation bounded (TVB) limiter is implemented for shock capturing. The third-order DG method is firstly validated using a case of supersonic vortex flow. Subsequently, the method is successfully employed to predict the crypto-steady supersonic flat-plate flow under various pressure ratios. In particular, at high pressure ratios between primary gas and secondary gas, a detached shock away from the trailing edge of the flat plate is accurately predicted. This study is our first step in approaching to developing a 3D numerical tool and modeling a novel pressure-exchange ejector.
PHM of Leadfree Electronic Assemblies Using Resistance Spectroscopy With Sequential Importance Resampling
Authors: Lall Pradeep , Lowe Ryan , Goebel Kai
Published: August 2012

Electronic assemblies have been monitored using state-space vectors from resistance spectroscopy, phase-sensitive detection and particle filtering (PF) to quantify damage initiation, progression and remaining useful life of the electronic assembly. A prognostication health management (PHM) methodology has been presented for electronic components subjected to mechanical shock and vibration. The presented methodology is an advancement of the state-of-art, which presently focuses on reactive failure detection and provides limited or no insight into the system reliability and residual life. Previously damage initiation, damage progression, and residual life in the pre-failure space has been correlated with micro-structural damage based proxies, feature vectors based on time, spectral and joint time-frequency characteristics of electronics [Lall2004a–d, 2005a–b, 2006a–f, 2007a–e, 2008a–f]. Precise resistance measurements based on the resistance spectroscopy method have been used to monitor interconnects for damage and prognosticate failure [Lall 2009a,b, 2010a,b, Constable 1992, 2001]. In this paper, the effectiveness of the proposed particle filter and resistance spectroscopy based approach in a prognostic health management (PHM) framework has been demonstrated for electronics. The measured state variable has been related to the underlying damage state using non-linear finite element analysis. The particle filter has been used to estimate the state variable, rate of change of the state variable, acceleration of the state variable and construct a feature vector. The estimated state-space parameters have been used to extrapolate the feature vector into the future and predict the time-to-failure at which the feature vector will cross the failure threshold. Remaining useful life has been calculated based on the evolution of the state space feature vector. Standard prognostic health management metrics were used to quantify the performance of the algorithm against the actual remaining useful life. Application to part replacement decisions for ultra-high reliability system has been demonstrated. Using the technique described in the paper the appropriate time to reorder a replacement part could be monitored, and defended statistically. Robustness of the prognostication algorithm has been quantified using standard performance evaluation metrics.
Transition Engineering of Urban Transportation for Resilience to Peak Oil Risks
Authors: Krumdieck Susan
Published: August 2012

Oil resources are finite and production decline is a fact for this century. The question is, why there has been so little policy action? This paper proposes that dealing with the complex changes involved in the transition to oil supply contraction requires new kinds of engineering modeling and analysis. There are no miracle technologies that will mitigate the need for major policy, economic, infrastructure and land use changes. Researchers have the responsibility to develop new methods and tools necessary for policy makers and planners to manage this change in direction. Without the right tools, the policy choice is between denying the problem and hoping for miracles. With the right Transition Engineering tools, the policy choices involve changes in land use, incentives, taxes and investments that efficiently reduce vulnerability and risk, increase adaptive capacity and build resilience. For more than a decade, the research and development program at the Advanced Energy and Material Systems Lab (AEMSLab) has focused on Transition Engineering. The first Transition Engineering project assesses vulnerability and risk to essential activities from oil supply contraction in the near and long term. The risk assessment method employs a probabilistic model of future fuel availability and an impact model of travel behavior adaptation to meet the probable fuel constraint. The second project is to assess travel adaptive capacity of current travel behavior and of the current urban forms using a new kind of travel survey, and to develop adaptation models for different urban development scenarios. Another important analysis is the active mode accessibility of the current urban form. The model uses GIS data and an activity model based on the demographic profile. Future urban form development, technology and infrastructure investments and behavior change are modeled using the strategic analysis method.
Implementation and Nonlinear Stabilization of a MIMO Magnetic Levitation System
Authors: Zhang Jiaji , Mei Xuesong , Zhang Dongsheng , Zhang Yun , Sun Jian
Published: August 2012

This paper presents the implementation of a three degree-of-freedom magnetic levitation system. First the dynamic model of the magnetic levitation is developed. Then based on the nonlinear model, a robust nonlinear double-loop control algorithm is applied to stabilize the system. The double-loop control architecture consists of two components: 1) terminal sliding mode control (TSMC) is employed in the outer loop to stabilize the rigid dynamic model while maintains robustness.2) Auto disturbance rejection control (ADRC) is applied in the inner loop as a current loop controller to track current command. Finally, experimental results are presented to illustrate the performance of the system dynamic response and current response in each coil. The experiment results show that the terminal sliding mode algorithm combined with auto disturbance rejection control algorithm is effective in the nonlinear MIMO magnetic levitation system.
Modeling the Vibroacoustics Response of Structures With Attached Noise Control Materials
Authors: Atalla Noureddine , Rhazi Dilal
Published: August 2012

This paper discusses the modeling of the vibration and acoustic response of panels with attached sound packages, using both analytical and numerical methods. Special attention is devoted to the modeling of various types of porous materials (rigid, limp, porous elastic,…) in various mounting conditions (single wall and double wall) together with the calculation of various vibroacoustic indicators (vibration response, radiated power, transmission loss, added damping, air-borne insertion loss, Structure-borne insertion loss…) under various excitations (acoustical, mechanical and Turbulent Boundary Layer). In particular, examples illustrating the practicality and usefulness of these methods are presented.
3-D Inverse Heat Transfer in a Composite Target Subject to High-Energy Laser Irradiation
Authors: Zhou Jianhua , Zhang Yuwen , Chen J. K. , Feng Z. C.
Published: August 2012

A new numerical model is developed to simulate the 3-D inverse heat transfer in a composite target with pyrolysis and outgassing effects. The gas flow channel size and gas addition velocity are determined by the rate equation of decomposition chemical reaction. The thermophysical properties of the composite considered are temperature-dependent. A nonlinear conjugate gradient method (CGM) is applied to solve the inverse heat conduction problem for high-energy laser-irradiated composite targets. It is shown that the front-surface temperature can be recovered with satisfactory accuracy based on the temperature/heat flux measurements on the back surface and the temperature measurement at an interior plane.
Nominal and Partial Load Operation of a Small-Scale Microturbine With a Liquid Desiccant Cooling System: An Experimental Assessment
Authors: Badami Marco , Ferrero Mauro , Portoraro Armando
Published: August 2012

In a trigeneration plant, the thermal energy recovered from the prime mover is exploited to produce a cooling effect. Although this possibility allows the working hours of the plant to be extended over the heating period, providing summer air conditioning through thermally activated technologies, it is rather difficult to find experimental data on trigeneration plant operation in the literature, and information on the performance characteristics at off-design conditions is rather limited. The paper has the aim of illustrating the experimental data of a real trigeneration system installed at the Politecnico di Torino (Turin, Italy). The system is composed of a natural gas 100 kWel microturbine coupled to a liquid desiccant system. The data are presented for both cogeneration and trigeneration configurations, and for full and partial load operations. An energetic and economic performance assessment, at rated power operation, is presented and compared with the partial load operation strategy. The primary energy savings are calculated through a widely accepted methodology, proposed by the European Union, and through another methodology, reported in literature, which, according to the Authors, seems more suitable to describe the energetic performances of trigeneration plants.
Structural Reliability Analysis With Cross Entropy and Low Discrepancy Sampling Methods
Authors: Pugazhendhi K. , Dhingra A. K.
Published: August 2012

In recent years quasi Monte-Carlo (QMC) techniques are gaining more popularity for reliability evaluation because of their increased accuracy over traditional Monte-Carlo simulation. A QMC technique like Low Discrepancy Sequence (LDS) combined with importance sampling is shown to be more accurate and robust in the past for the evaluation of structural reliability. However, one of the challenges in using importance sampling techniques to evaluate the structural reliability is to identify the optimum sampling density. In this article, a novel technique based on a combination of cross entropy and low discrepancy sampling methods is used for the evaluation of structural reliability. The proposed technique does not require an apriori knowledge of Most Probable Point of failure (MPP), and succeeds in adaptively identifying the optimum sampling density for the structural reliability evaluation. Several benchmark examples verify that the proposed method is as accurate as the quasi Monte-Carlo technique using low discrepancy sequence with the added advantage of being able to accomplish this without a knowledge of the MPP.
Dielectric Elastomer Energy Harvesting and its Application to Human Walking
Authors: Lai Heather , Tan Chin An , Xu Yong
Published: August 2012

Human walking requires sophisticated coordination of muscles, tendons, and ligaments working together to provide a constantly changing combination of force, stiffness and damping. In particular, the human knee joint acts as a variable damper, dissipating greater amounts of energy when the knee undergoes large rotational displacements during walking, running or hopping. Typically, this damping results from the dissipation, or loss, of metabolic energy. It has been proven to be possible however; to collect this otherwise wasted energy through the use of electromechanical transducers of several different types which convert mechanical energy to electrical energy. When properly controlled, this type of device not only provides desirable structural damping effects, but the energy generated can be stored for use in a wide range of applications. A novel approach to an energy harvesting knee joint damper is presented using a dielectric elastomer (DE) smart material based electromechanical transducer. Dielectric elastomers are extremely elastic materials with high electrical permittivity which operate based on electrostatic effects. By placing compliant electrodes on either side of a dielectric elastomer film, a specialized capacitor is created, which couples mechanical and electrical energy using induced electrostatic stresses. Dielectric elastomer energy harvesting devices not only have a high energy density, but the material properties are similar to that of human tissue, making it highly suitable for wearable applications. A theoretical framework for dielectric elastomer energy harvesting is presented along with a mapping of the active phases of the energy harvesting to the appropriate phases of the walking stride. Experimental results demonstrating the energy harvesting capability of a DE generator undergoing strains similar to those experienced during walking are provided for the purpose of verifying the theoretical results. The work presented here can be applied to devices for use in rehabilitation of patients with muscular dysfunction and transfemoral prosthesis as well as energy generation for able-bodied wearers.
Studies on InAs/GaSb superlattice structural properties by high resolution x-ray diffraction
Authors: Zhou Yi , Chen Jianxin , Xu Qingqing , He Li
Published: August 2012

This paper presents work on InAs/GaSb superlattice structural property studies. The superlattice materials were grown by molecular beam epitaxy and measured by high resolution x-ray diffraction, and measured x-ray rocking curves were fitted to the simulated ones in order to fully analyze the superlattice structures. A four-layer model including an InAs layer, a GaSb layer and two interface layers was used for simulation. The results show that the two interface layers are ternary compounds of InSbAs, which have, respectively, an Sb composition of 0.99 at the InAs-on-GaSb interfaces and an Sb composition of 0.01 at the GaSb-on-InAs interfaces. This is the first article, to our knowledge, on the detailed analysis of the InAs/GaSb superlattice interface structures. The experiments also demonstrate that the As flux during the epitaxy growth affects the interface layer InSbAs compositions and hence the lattice mismatch between the superlattices and the substrates. With an As beam equivalent pressure change from 1 × 10−5 to 3 × 10−6 Torr, the lattice mismatch decreases from 3.2 × 10−3 to 5 × 10−4. Measurements on and analysis of Bragg peak broadening under different diffraction geometries show that the broadening depends on both the superlattice period and the lattice mismatch.
Pt(II) and Pd(II) Pyrrolidine-Dithiocarbamates Investigated by XPS
Authors: Wenisch Robert , Montagner Diego , Helm Manfred , Forrer Daniel , Tondello Eugenio , Gross Silvia
Published: August 2012

In the present contribution, a series of four metal dithiocarbamates, namely 1-pyrrolidinecarbodithioate methyl ester (PyDTM) of Pd(II) and Pt(II), PtCl2(PyDTM), PtBr2(PyDTM), PdBr2(PyDTM), PdCl2(PyDTM), were analysed by x-ray Photoelectron Spectroscopy (XPS). Besides the wide scan spectra, detailed spectra for the C 1s, O 1s, N 1s, S 2s, S 2p, Pt 4f (for Pt-based compounds), Pd 3d (for Pd-based compounds), Cl 2p (for Cl containing compounds), Br 3p (for Br containing compounds) regions were acquired and the related data are presented and discussed.
Conduction of Ultracold Fermions Through a Mesoscopic Channel
Authors: Brantut Jean-Philippe , Meineke Jakob , Stadler David , Krinner Sebastian , Esslinger Tilman
Published: August 2012

Pretend Wires

Cold atomic gases have been successfully used to simulate solid-state phenomena such as quantum criticality. However, simulating mesoscopic electronic transport like that realized in quantum wires is challenging.

Brantut
et al.

(p.
1069
, published online 2 August) connected two reservoirs of fermionic
6
Li atoms (simulating electrons) with a narrow channel (simulating a wire), created a nonequilibrium situation by applying a magnetic field gradient, and observed the flow through the channel. When the mean-free path of the atoms exceeded the length of the channel, the atomic density in the channel was constant in the central region and only changed at the ends, indicating the presence of contact resistance. The opposite diffusive regime created by imposing a disordered laser potential produced a uniformly varying density inside the channel.
Angiosarcoma of the liver as a cause of fulminant liver failure
Authors: Montell García Marco , Romero Cabello Raúl , Romero Feregrino Raul , Atri Moises Mercado , Trejo Estrada Rafael , Alvaro Padilla-Rodríguez , Moreno Manlio Gerardo Gama , Feregrino Rodrigo Romero
Published: August 2012

Primary liver sarcomas make up 2% of all malignant neoplasms of the liver; of these, angiosarcoma is the most common type. Primary liver tumours rarely cause fulminant hepatic failure (FHF), which is most frequently caused by non-neoplasmic pathologies. In the case of neoplasms, the most frequent are lymphoma and metastatic carcinomas. We describe the case of a 76-year-old man who suffered from FHF as a result of a liver angiosarcoma and we present a review of the medical literature in which we found only two cases of liver angiosarcomas linked to FHF.
A neurological presentation of intravascular B-cell lymphoma
Authors: Kendall Kimberley Marie , Thomas Rhys H , Corkill Robin G , Robertson Neil P
Published: August 2012

Intravascular B-cell lymphoma is a rare, aggressive subtype of diffuse large B-cell lymphoma that presents insidiously with symptoms relating to organ involvement. We present the case of a male in his late 40s who presented with fluctuating neurological symptoms including episodes of altered upper-limb sensation, seizures and psychotic phenomena. These symptoms and signs were associated with fleeting brain lesions on neuroimaging. A brain biopsy confirmed the diagnosis of intravascular B-cell lymphoma and he was treated with CHOP chemotherapy (cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone). Two years later, he remains well. Timely diagnosis and aggressive treatment provides an optimal chance of long-term survival so it is essential to recognise early disease characteristics.
Prognostic impact of β-2-microglobulin expression in colorectal cancers stratified by mismatch repair status
Authors: Koelzer Viktor Hendrik , Baker Kristi , Kassahn Daniela , Baumhoer Daniel , Zlobec Inti
Published: August 2012

Background

β-2-microglobulin (B2M) is essential for antigen presentation, yet may also possess proto-oncogenic properties.

Aim

To determine the prognostic impact of B2M in patients with mismatch repair (MMR) proficient and deficient colorectal cancer (CRC) and to investigate whether this effect on outcome is dependent on the local immune response.

Methods

B2M protein expression and tumour-infiltrating immune cells (CD3, CD16, CD163, CD20, CD4, CD45RO, CD56, CD68, CD8, FoxP3, GranzymeB, iNOS, mast cell tryptase, MUM1, PD1, TIA-1) were evaluated in a well characterised tissue microarray of 408 CRCs. The predictive value for clinicopathological features and the prognostic significance of B2M expression were analysed, stratified by MMR status and the immunohistological characteristics of immune cell infiltrates.

Results

Interobserver agreement for B2M staining was high (intra-class correlation coefficient=0.91). Complete B2M loss was more frequent in MMR-deficient (19.4%) compared to MMR-proficient (7.1%) tumours (p<0.001). In MMR-deficient cases, B2M loss predicted rare local recurrence (p=0.034), infrequent nodal-positivity (p=0.035), absence of distant metastasis (p=0.048; sensitivity=100%) and a trend towards favourable survival (p=0.124) independent of immune infiltrates. No associations between B2M and clinicopathological features were observed in MMR-proficient cases.

Conclusions

Our data show for the first time that absence of B2M protein expression identifies MMR-deficient cancers with a favourable clinical course and absence of metastatic disease. Validation of B2M protein expression for sub-classification of MMR-deficient CRC is recommended for future clinical trials.
Diagnostic accuracy of icteric index to detect abnormal total bilirubin values
Authors: Salinas Maria , López-Garrigós Maite , Lugo Javier , Gutiérrez Mercedes , Flors Lucia , Leiva-Salinas Carlos
Published: August 2012

Aims

Total bilirubin tests are individually inexpensive but can result in huge costs to healthcare systems worldwide, because they are very commonly requested. The main objective of this study was to evaluate the diagnostic accuracy of the icteric index, a test with zero reagent cost, as a preliminary biomarker to decide when total bilirubin measurement is necessary.

Methods

We retrospectively reviewed all the requested total bilirubin values and their corresponding icteric index results in a 2-year period (2010–11). Receiver operating characteristic (ROC) curve analysis was used to determine the optimal icteric index cut-off value to discriminate between normal and abnormal bilirubin values (>20.5 μmol/l; >1.2 mg/dl).

Results

The study included total bilirubin and icteric index results of 100 207 patients. The ROC curve analysis suggested 34.2 μmol/l (2 mg/dl) as the optimal icteric index threshold to identify abnormal bilirubin values. The area under the curve was 0.981. Regardless of the patient population studied (primary care, hospital and different individual hospital departments), sensitivity was greater than 94% and specificity was over 98%. Likelihood ratio values provided strong evidence that total bilirubin is less than 20.5 μmol/l (<1.2 mg/dl) when the icteric index is less than 34.2 μmol/l (<2 mg/dl).

Conclusions

This study supports the use of the icteric index to identify patients with abnormal total bilirubin values. Considerable economic savings can be achieved if this strategy is applied on a clinical daily basis. Its implementation and report should be discussed and planned by laboratory professionals together with requesting physicians.
MAKING IT REAL: WHAT RISK MANAGERS SHOULD KNOW ABOUT COMMUNITY ENGAGEMENT
Authors: MURO MELANIE , HRUDEY STEVE E. , JUDE SIMON , HEATH LINDA , POLLARD SIMON
Published: August 2012

The "decide-announce-defend" approach to decision-making offers few meaningful opportunities for engagement in decision processes and communities and individuals frequently feel isolated from decisions. Correspondingly, many practitioners believe science is misunderstood by communities and that messages on risk are susceptible to distortion or misrepresentation. Many voices have called for more inclusive approaches to the analysis and management of risk. Here, we draw on theoretical and practical insights from the fields of risk communication, community engagement and contaminated land management, to explore some of the unique issues involved in communicating risk issues to lay audiences, and to identify principles for engaging communities in contaminated land risk management.
Improvement of an Optically Pumped Magnetometer Using a Combination of D1 and D2 Transitions
Authors: Kawabata Ryuzo , Fukuda Kyoya , Kandori Akihiko
Published: August 2012

The magnetic resonance spectra of 133Cs vapor were obtained using a D1 transition, a D2 transition, and a combination of D1 and D2 transitions. Maximum intensity (I
max) and line width (Δf) in the spectra were measured, and an “α value” (i.e., I
max/Δf) was defined as an appropriate figure of merit for an optically pumped magnetometer (OPM). The α value obtained using the combination of D1 and D2 transitions was tenfold larger than that obtained using the D1 transition and 160 times larger than that obtained using the D2 transition. This result indicates that using the combination of D1 and D2 transitions improves the sensitivity of an OPM.
Disturbance Characteristics of Vertical Channel Phase Change Random Access Memory Array
Authors: Kim Kyung Soo , Cho Il Hwan
Published: August 2012

A novel vertical channel phase change random access memory (VPCRAM) was proposed for reducing leakage current and increasing chip density of phase change random access memory (PCRAM). Since VPCRAM cells are integrated into the vertical channel structure, disturbance characteristics between each cell should be important issues for array design. In this work, the dependence of device parameter on electrical disturbance characteristics and thermal disturbance characteristics has been investigated by three-dimensional device simulation and finite element method simulation respectively. Electrical disturbance characteristics are determined by both channel potential coupling and junction leakage current between adjacent cells. The effects of substrate doping concentration and Si wall have been investigated. Thermal distribution has also been investigated with finite element method simulation. The oxide layer on the gate has large effect on thermal transfer within phase change materials due to the small thermal conductivity.
Electronic Structure Modulation of Graphene by Metal Electrodes
Authors: Takagi Yoshiteru , Okada Susumu
Published: August 2012

We investigated electronic structure modulation of graphene partially covered by Pd, Ag, Pt, and Au pillars by using first-principles total-energy calculations to simulate the effects of metal electrodes on the electronic structure of graphene. Our calculations show that the electrostatic potential in graphene strongly depends not only on the metal species but also on its displacement from the electrodes. This potential modulation leads to an energy shift of the Dirac point of graphene, resulting in carrier transfer between graphene and the metal pillars depending on the metal species and spatial position.
Relationship between Stochastic Effect and Line Edge Roughness in Chemically Amplified Resists for Extreme Ultraviolet Lithography Studied by Monte Carlo Simulation
Authors: Kozawa Takahiro
Published: August 2012

The fluctuation of the line edge of resist patterns, called line edge roughness (LER), has been the most serious problem in the development of next-generation lithography. The major root cause of LER is the chemical inhomogeneity at the boundary between the insoluble and soluble regions of the resist. In this study, the stochastic effect induced in the processes of formation of resist patterns was investigated using a Monte Carlo method. The relative standard deviation of acid concentration was smaller than that of absorbed photons. The relative standard deviation of protected units was smaller than that of acid concentration. By comparing the simulation results with the reported values of LER, it was found that the stochastic effect is further reduced in the development and rinse processes.
Altered colorectal afferent function associated with TNBS-induced visceral hypersensitivity in mice
Authors: Feng Bin , La Jun-Ho , Tanaka Takahiro , Schwartz Erica S. , McMurray Timothy P. , Gebhart G. F.
Published: August 2012

Inflammation of the distal bowel is often associated with abdominal pain and hypersensitivity, but whether and which colorectal afferents contribute to the hypersensitivity is unknown. Using a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, we investigated colorectal hypersensitivity following intracolonic TNBS and associated changes in colorectum and afferent functions. C57BL/6 mice were treated intracolonically with TNBS or saline. Visceromotor responses to colorectal distension (15–60 mmHg) were recorded over 8 wk in TNBS- and saline-treated (control) mice. In other mice treated with TNBS or saline, colorectal inflammation was assessed by myeloperoxidase assay and immunohistological staining. In vitro single-fiber recordings were conducted on both TNBS and saline-treated mice to assess colorectal afferent function. Mice exhibited significant colorectal hypersensitivity through day 14 after TNBS treatment that resolved by day 28 with no resensitization through day 56. TNBS induced a neutrophil- and macrophage-based colorectal inflammation as well as loss of nerve fibers, all of which resolved by days 14–28. Single-fiber recordings revealed a net increase in afferent drive from stretch-sensitive colorectal afferents at day 14 post-TNBS and reduced proportions of mechanically insensitive afferents (MIAs) at days 14–28. Intracolonic TNBS-induced colorectal inflammation was associated with the development and recovery of hypersensitivity in mice, which correlated with a transient increase and recovery of sensitization of stretch-sensitive colorectal afferents and MIAs. These results indicate that the development and maintenance of colorectal hypersensitivity following inflammation are mediated by peripheral drive from stretch-sensitive colorectal afferents and a potential contribution from MIAs.
Identification of Galanin and Its Receptor GalR1 as Novel Determinants of Resistance to Chemotherapy and Potential Biomarkers in Colorectal Cancer
Authors: Stevenson Leanne , Allen Wendy L. , Turkington Richard , Jithesh Puthen V. , Proutski Irina , Stewart Gail , Lenz Heinz-Josef , Van Schaeybroeck Sandra , Longley Daniel B. , Johnston Patrick G.
Published: August 2012

Purpose: A major factor limiting the effective clinical management of colorectal cancer (CRC) is resistance to chemotherapy. Therefore, the identification of novel, therapeutically targetable mediators of resistance is vital.

Experimental design: We used a CRC disease-focused microarray platform to transcriptionally profile chemotherapy-responsive and nonresponsive pretreatment metastatic CRC liver biopsies and in vitro samples, both sensitive and resistant to clinically relevant chemotherapeutic drugs (5-FU and oxaliplatin). Pathway and gene set enrichment analyses identified candidate genes within key pathways mediating drug resistance. Functional RNAi screening identified regulators of drug resistance.

Results: Mitogen-activated protein kinase signaling, focal adhesion, cell cycle, insulin signaling, and apoptosis were identified as key pathways involved in mediating drug resistance. The G-protein–coupled receptor galanin receptor 1 (GalR1) was identified as a novel regulator of drug resistance. Notably, silencing either GalR1 or its ligand galanin induced apoptosis in drug-sensitive and resistant cell lines and synergistically enhanced the effects of chemotherapy. Mechanistically, GalR1/galanin silencing resulted in downregulation of the endogenous caspase-8 inhibitor FLIPL, resulting in induction of caspase-8–dependent apoptosis. Galanin mRNA was found to be overexpressed in colorectal tumors, and importantly, high galanin expression correlated with poor disease-free survival of patients with early-stage CRC.

Conclusion: This study shows the power of systems biology approaches to identify key pathways and genes that are functionally involved in mediating chemotherapy resistance. Moreover, we have identified a novel role for the GalR1/galanin receptor–ligand axis in chemoresistance, providing evidence to support its further evaluation as a potential therapeutic target and biomarker in CRC. Clin Cancer Res; 18(19); 5412–26. ©2012 AACR.
Inhibition of the Hedgehog Pathway Targets the Tumor-Associated Stroma in Pancreatic Cancer
Authors: Hwang Rosa F. , Moore Todd T. , Hattersley Maureen Mertens , Scarpitti Meghan , Yang Bin , Devereaux Erik , Ramachandran Vijaya , Arumugam Thiruvengadam , Ji Baoan , Logsdon Craig D. , Brown Jeffrey L. , Godin Robert
Published: August 2012

Purpose: The Hedgehog (Hh) pathway has emerged as an important pathway in multiple tumor types and is thought to be dependent on a paracrine signaling mechanism. The purpose of this study was to determine the role of pancreatic cancer-associated fibroblasts (human pancreatic stellate cells, HPSCs) in Hh signaling. In addition, we evaluated the efficacy of a novel Hh antagonist, AZD8542, on tumor progression with an emphasis on the role of the stroma compartment.

Experimental Design: Expression of Hh pathway members and activation of the Hh pathway were analyzed in both HPSCs and pancreatic cancer cells. We tested the effects of Smoothened (SMO) inhibition with AZD8542 on tumor growth in vivo using an orthotopic model of pancreatic cancer containing varying amounts of stroma.

Results: HPSCs expressed high levels of SMO receptor and low levels of Hh ligands, whereas cancer cells showed the converse expression pattern. HPSC proliferation was stimulated by Sonic Hedgehog with upregulation of downstream GLI1 mRNA. These effects were abrogated by AZD8542 treatment. In an orthotopic model of pancreatic cancer, AZD8542 inhibited tumor growth only when HPSCs were present, implicating a paracrine signaling mechanism dependent on stroma. Further evidence of paracrine signaling of the Hh pathway in prostate and colon cancer models is provided, demonstrating the broader applicability of our findings.

Conclusion: Based on the use of our novel human-derived pancreatic cancer stellate cells, our results suggest that Hh-targeted therapies primarily affect the tumor-associated stroma, rather than the epithelial compartment. Mol Cancer Res; 10(9); 1147–57. ©2012 AACR.
A Novel Approach for Subretinal Implantation of Ultrathin Substrates Containing Stem Cell-Derived Retinal Pigment Epithelium Monolayer
Authors: Hu Yuntao , Liu Laura , Lu Bo , Zhu Danhong , Ribeiro Ramiro , Diniz Bruno , Thomas Padmaja B. , Ahuja Ashish K. , Hinton David R. , Tai Yu-Chong , Hikita Sherry T. , Johnson Lincoln V. , Clegg Dennis O. , Thomas Biju B. , Humayun Mark S.
Published: August 2012

Objective: To evaluate the feasibility of a new technique for the implantation of ultrathin substrates containing stem cell-derived retinal pigment epithelium (RPE) cells into the subretinal space of retina-degenerate Royal College of Surgeon (RCS) rats. Methods: A platform device was used for the implantation of 4-µm-thick parylene substrates containing a monolayer of human embryonic stem cell-derived RPE (hESC-RPE). Normal Copenhagen rats (n = 6) and RCS rats (n = 5) were used for the study. Spectral-domain optical coherence tomography (SD-OCT) scanning and histological examinations were performed to confirm placement location of the implant. hESC-RPE cells attached to the substrate before and after implantation were evaluated using standard cell counting techniques. Results: SD-OCT scanning and histological examination revealed that the substrates were precisely placed in the rat’s subretinal space. The hESC-RPE cell monolayer that covered the surface of the substrate was found to be intact after implantation. Cell counting data showed that less than 2% of cells were lost from the substrate due to the implantation procedure (preimplantation count 2,792 ± 74.09 cells versus postimplantation count 2,741 ± 62.08 cells). Detailed microscopic examination suggested that the cell loss occurred mostly along the edges of the implant. Conclusion: With the help of this platform device, it is possible to implant ultrathin substrates containing an RPE monolayer into the rat’s subretinal space. This technique can be a useful approach for stem cell-based tissue bioengineering techniques in retinal transplantation research.
Molecular Response of the Human Diaphragm on Different Modes of Mechanical Ventilation
Authors: Dermitzaki Despina , Tzortzaki Eleni , Soulitzis Nikolaos , Neofytou Eirini , Prinianakis Georgios , Matalliotakis Ioannis , Askitopoulou Helen , Siafakas Nikolaos M.
Published: August 2012

Background: The mechanical stress that the human diaphragm is exposed to during mechanical ventilation affects a variety of processes, including signal transduction, gene expression, and angiogenesis. Objectives: The study aim was to assess the change in the production of major angiogenic regulators [vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF2), and transforming growth factor beta 1 (TGFB1)] on the human diaphragm before and after contraction/relaxation cycles during mechanical ventilation. Methods: This observational study investigates the diaphragmatic mRNA expression of VEGF, FGF2, and TGFB1 in surgical patients receiving general anesthesia with controlled mechanical ventilation (CMV) with muscle relaxation (group A, n = 13), CMV without muscle relaxation (group B, n = 10), and pressure support of spontaneous breathing (group C, n = 9). Diaphragmatic samples were obtained from each patient at two time points: 30 min after the induction of anesthesia (t1) and 90 min after the first specimen collection (t2). Results: No significant changes in the mRNA expression of VEGF, FGF2, and TGFB1 were documented in groups A and C between time points t1 and t2. In contrast, in group B, the mRNA levels of the above angiogenic factors were increased in time point t2 compared to t1, a finding which was statistically significant (pVEGF = 0.003, pFGF2 = 0.028, pTGFB1 = 0.001). Conclusions: These findings suggest that the molecular response of the human diaphragm before and after application of diverse modes of mechanical ventilation is different. Angiogenesis via the expression of VEGF, FGF2, and TGFB1 was only promoted in CMV without muscle relaxation, and this may have important clinical implications.
Plasma Endothelin-1 and Vascular Endothelial Growth Factor Levels and Their Relationship to Hemodynamics in Idiopathic Pulmonary Fibrosis
Authors: Ventetuolo Corey E. , Kawut Steven M. , Lederer David J.
Published: August 2012

Background: Pulmonary hypertension (PH) is associated with a poor prognosis in idiopathic pulmonary fibrosis (IPF). Endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) are important in both fibrosis and vascular remodeling. Objectives: We sought to determine the relationship between ET-1 and VEGF levels and hemodynamics in patients with IPF. We hypothesized that higher levels of ET-1 and VEGF would be associated with higher pulmonary artery pressures (PAP) and pulmonary vascular resistance (PVR) in patients with IPF. Methods: We performed a cross-sectional analysis of 52 adults with IPF enrolled in a prospective cohort with available clinical data, platelet-free plasma, and hemodynamics. ET-1 and VEGF levels were measured via immunoassay. The associations of ET-1 and VEGF with PAP and PVR were examined using generalized additive models adjusted for age, gender, race/ethnicity, and forced vital capacity (% predicted). Results: Sixteen of 52 (30.8%) had PH (mean PAP ≥25 mm Hg). After multivariable adjustment, higher ET-1 levels were significantly associated with higher systolic (p = 0.01), diastolic (p = 0.02), and mean (p = 0.01) PAP and possibly higher PVR (p = 0.09). There were no significant associations between VEGF levels and hemodynamics. Conclusions: Higher levels of ET-1 were associated with higher PAP and possibly higher PVR in participants with IPF. In a subgroup of patients, ET-1 may be a contributor to pulmonary vascular disease burden in IPF.
Spleen Size in Idiopathic and Heritable Pulmonary Arterial Hypertension
Authors: Tonelli Adriano R. , Yadav Ruchi , Gupta Amit , Arrossi Andrea V. , Heresi Gustavo A. , Dweik Raed A.
Published: August 2012

Background: It is unknown whether the spleen size correlates with disease severity and outcome in patients with idiopathic and heritable pulmonary arterial hypertension (PAH). Objectives: To determine the prevalence of splenomegaly in PAH and assess whether it correlates with severity of disease and outcome. Methods: We identified subjects with either heritable or idiopathic PAH who had Doppler echocardiography, right-heart catheterization and computed tomography (CT) of the chest and/or abdomen that included the spleen. Results: We included 62 subjects with a mean age (±SD) of 49 (±15) years; 82% were women. Spleen dimensions were 10 (±3), 6 (±2) and 9 (±2) cm for the craniocaudal length, thickness and width measurements, respectively. The median [interquartile range (IQR)] spleen volume was 344 (225-533) cm3. Splenomegaly was observed in 52-63% of the patients, depending on the formula used. The spleen volume was not associated with clinical, echocardiographic or hemodynamic variables. Spleen volume was not associated with adjusted mortality. We studied the characteristics of the spleen during autopsy in 9 patients with idiopathic PAH who died of right-heart failure. The mean (IQR) spleen weight was 220 (151-325) g. We observed early congestion in all but 2 patients who had chronic congestion. Conclusions: Splenomegaly of predominantly mild degree is common in idiopathic and heritable PAH. However, spleen size was not associated with clinical, echocardiographic, hemodynamic and survival data in these patients.
Neuroprotective Effects of Granulocyte Colony-Stimulating Factor on Ischemia-Reperfusion Injury of the Retina
Authors: Shima Chieko , Adachi Yasushi , Minamino Keizo , Okigaki Mitsuhiko , Shi Ming , Imai Yuichiro , Yanai Seiji , Takahashi Kanji , Ikehara Susumu
Published: August 2012

Purpose: It has been reported that granulocyte colony-stimulating factor (G-CSF) provides neuroprotection in models in which neuronal cell death is induced. This research was designed to investigate the effects of G-CSF on neurodegeneration of the inner retinal layer in a rat model of ischemic reperfusion (I/R) injury. Materials and Methods: Retinal ischemia was induced by increasing the intraocular pressure to 110 mm Hg for 45 min in the left eyes of the rats. A sham operation was carried out on the right eyes. G-CSF (100 µg/kg/day in 0.3 ml saline) or the same volume of saline was intraperitoneally injected just before the operation and continued for 4 consecutive days (a total of 5 consecutive days). Morphological examinations, including the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, were performed 7 days after I/R induction. The expression of phosphorylated AKT in the retina was examined by Western blot analysis and immunohistochemistry. Results: Cell loss in the ganglion cell layer was more significantly reduced in the I/R-induced eyes of the G-CSF-injected rats than in the I/R-induced eyes of the saline-injected rats (20.3 vs. 6.6%). The inner retinal thickness ratios, such as the inner plexiform layer to the inner limiting membrane/outer nuclear layer and the inner nuclear layer/outer nuclear layer, were significantly better preserved in the I/R-induced eyes of the G-CSF-injected rats than in the I/R-induced eyes of the saline-injected rats. TUNEL assays showed fewer apoptotic cells in the retinal sections of the I/R-induced eyes of the G-CSF-injected rats. The phosphorylation of AKT (p-AKT/AKT) was upregulated in the retinas of the I/R-induced eyes of the G-CSF-injected rats. Conclusion: Our results demonstrated that systemic injection of G-CSF can protect retinal ganglion cells and inner retinal layers from I/R injury. The effects could be associated with the activation of AKT.
Low-Cost High-Speed Imaging System for Observing Vocal Fold Vibration in Voice Disorders
Authors: Kaneko Kenichi , Sakaguchi Koichi , Inoue Masato , Takahashi Haruo
Published: August 2012

Purpose: The aim of this study was to establish a method to observe vocal fold vibration using a low-cost high-speed laryngeal imaging system. Procedures: We assembled a high-speed imaging system with a consumer digital camera and a rigid laryngeal endoscope. The camera can shoot digital images at a rate of 1,200 frames per second and be purchased for about USD 1,000 in Japan. Results: We examined the normal and pathological vocal folds of 215 subjects with our new system and analyzed the vocal fold vibration in these subjects by playback of a video and kymograph images. Conclusions: Our high-speed laryngeal imaging system is highly cost-effective and can be a useful tool for examining the vocal folds of patients with voice disorders.