bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantum energy flow and the kinetics of water shuttling between hydrogen bonding sites on trans-formanilide
Authors: Agbo Johnson K. , Leitner David M. , Myshakin Evgeniy M. , Jordan Kenneth D.
Published: August 2007

A potential energy surface for trans-formanilide (TFA)-H2O is calculated and applied to study energy flow in the complex as well as the kinetics of water shuttling between hydrogen bonding sites on TFA. In addition to the previously identified H2O-TFA(CO) and H2O-TFA(NH) minima, with the water monomer bound to the CO and NH groups, respectively, the new surface reveals a second local minimum with the water bound to the CO group, and which lies energetically 310cm−1 above the previously identified H2O-TFA(CO) global minimum. On this surface, the energy barrier for water shuttling from H2O-TFA(CO) global minimum to H2O-TFA(N–H) is 984cm−1, consistent with the experimental bounds of 796 and 988cm−1 [J. R. Clarkson et al. Science 307, 1443 (2005)]. The ergodicity threshold of TFA is calculated to be 1450cm−1; for the TFA-H2O complex, the coupling to the water molecule is found to lower the ergodicity threshold to below the isomerization barrier. Energy transfer between the activated complex and the vibrational modes of TFA is calculated to be sufficiently rapid that the Rice-Ramsperger-Kassel-Marcus (RRKM) theory does not overestimate the rate of water shuttling. The possibility that the rate constant for water shuttling is higher than the RRKM theory estimate is discussed in light of the relatively high energy of the ergodicity threshold calculated for TFA.
The interface between Gd2O3 films and Ge(001): A comparative study between molecular and atomic oxygen mediated growths
Authors: Molle Alessandro , Perego Michele , Bhuiyan Md. Nurul Kabir , Wiemer Claudia , Tallarida Grazia , Fanciulli Marco
Published: August 2007

The interface properties of thin Gd2O3 films grown on Ge(001) are studied as a function of the oxidizing species used during the deposition. The mediation of molecular oxygen during growth produces a crystalline oxide with an atomically sharp and contamination-free interface on the Ge substrate. Conversely, an interface layer of substoichiometric germanium oxide occurs whenever atomic oxygen radicals are used. The two different Gd2O3∕Ge interfacial configurations are discussed basing on thermodynamic arguments.
Optical modeling of the ultimate efficiency of pentacene: N, N′-ditridecylperylene-3, 4, 9, 10-tetracarboxylic diimide–blend solar cells
Authors: Monestier Florent , Pandey Ajay K. , Simon Jean-Jacques , Torchio Philippe , Escoubas Ludovic , Nunzi Jean-Michel
Published: August 2007

Molecular blends of pentacene: N, N′-ditridecylperylene-3, 4, 9, 10-tetracarboxylic diimide (PTCDI-C13H27) permit to cover the visible part of the solar spectrum with an absorption onset at 730nm. Although charge mobilities of pentacene and PTCDI are rather large, the efficiency of pentacene:PTCDI-C13H27 blended devices is still lower than that of poly(3-hexylthiophene):[6,6]-phenyl C61-butyric acid methyl ester devices. Comparisons between experimental results and optical modeling indicate that more than 30% of the photocurrent is lost in the blend while the short circuit current should reach 13mAcm−2 in the absence of recombination processes.
Hard x-ray source for flash radiography based on a 2.5kJ plasma focus
Authors: Di Lorenzo F. , Raspa V. , Knoblauch P. , Lazarte A. , Moreno C. , Clausse A.
Published: August 2007

A compact tabletop plasma focus suitable for hard x-ray imaging applications is presented. The hard x-ray emission was characterized by means of an effective energy analysis, based on images obtained with a single shot. The effective energy of the radiation was estimated to be around 83keV from radiographic images of metallic pieces. Numerical calculations, based on validated codes, are presented to give a quantitative interpretation of the experimental results. Experimental demonstration of the suitability of this device for introspective imaging of metallic pieces is also given.
Possible model of degradation mechanism that increments the gate current (nonbiased interval) after constant-current stress
Authors: Omura Yasuhisa
Published: August 2007

This article evaluates the time evolution of stress-induced leakage current (SILC) in metal-oxide-semiconductor capacitors during unstressed interval after electrical stressing sub-5-nm-thick SiO2 films. It is demonstrated that the normalized increment in gate leakage current increases and then saturates as unstressed interval is increased; this characteristic is basically independent of electrical stress conditions. The experiment is carried out at various temperatures during the unstressed interval in order to identify the diffusive species in the oxide film that impact SILC evolution during the unstressed interval. Important chemical reactions are identified and several diffusion-reaction equations to be solved are elucidated. Numerical simulations of SILC evolution are performed assuming the diffusion-reaction equation of likely species. Simulation results reproduce the experimental results. The results suggest that the increment in SILC component is identical to the increment in Si–OH bond density, and that the Si–OH bonds (neutral E′ center) raise the conduction of tunneling electrons after the unstressed interval rather than the neutral electron traps that are generated by the electrical stress.
High-frequency torsional modal testing of a long cylinder by magnetostriction
Authors: Cho Seung Hyun , Han Soon Woo , Park Chan Il , Kim Yoon Young
Published: August 2007

The torsional modal testing of cylindrical bodies still remains formidable. This is because pure torsional eigenfrequencies typically lying in the kilohertz frequency range are nearly impossible to excite by popular excitation methods. In this study, a torsional modal testing method using a set of magnetostrictive patches, specially arranged permanent magnets, and solenoids is investigated to cover a frequency range of a few kilohertz. The use of magnetostrictive patches for the testing was motivated by torsional wave experiments using the patches, but the use of special magnet configurations was a key to successful modal testing. The developed method was validated with experiments.
Buried heterostructure quantum cascade lasers with high continuous-wave wall plug efficiency
Authors: Evans A. , Darvish S. R. , Slivken S. , Nguyen J. , Bai Y. , Razeghi M.
Published: August 2007

The authors report on the development of λ∼4.7μm strain-balanced InP-based quantum cascade lasers with high wall plug efficiency and room temperature continuous-wave operation. The use of narrow-ridge buried heterostructure waveguides and thermally optimized packaging is presented. Over 9.3% wall plug efficiency is reported at room temperature from a single device producing over 0.675W of continuous-wave output power. Wall plug efficiencies greater than 18% are also reported for devices at a temperature of 150K, with continuous-wave output powers of more than 1W.
Modified effective medium formulation for the thermal conductivity of nanocomposites
Authors: Minnich Austin , Chen Gang
Published: August 2007

This letter introduces a modified effective medium formulation for composites where the characteristic length of the inclusion is on the order of or smaller than the phonon mean free path. The formulation takes into account the increased interface scattering in the different phases of the nanocomposite and the thermal boundary resistance between the phases. The interface density of inclusions is introduced and is found to be a primary factor in determining the thermal conductivity. The predictions are in good agreement with results from Monte Carlo simulations and solutions to the Boltzmann equation.
Pump-power-controlled luminescence switching in Yb3+∕Tm3+ codoped water-free low silica calcium aluminosilicate glasses
Authors: Jacinto C. , Vermelho M. V. D. , Gouveia E. A. , de Araujo M. T. , Udo P. T. , Astrath N. G. C. , Baesso M. L.
Published: August 2007

Intense infrared-to-visible upconversion emissions in Tm3+∕Yb3+ codoped water-free low silica calcium aluminosilicate glasses have been obtained under excitation at 976nm. The results showed that as the pump power/intensity is increased, a reduction of up to one order of magnitude at the 800∕480nm emitted intensity ratio is observed; characterizing what can be denominated as luminescent switching. The physical origin of this switching is discussed and explained in terms of the tailoring of luminescent switchers to operate in a large range of pump powers, what could be used in the development of sensors and networks for optical processing and optical communications.
Nuclear magnetic resonance in the earth’s magnetic field using a nitrogen-cooled superconducting quantum interference device
Authors: Qiu Longqing , Zhang Yi , Krause Hans-Joachim , Braginski Alex I. , Burghoff Martin , Trahms Lutz
Published: August 2007

The authors recorded nuclear magnetic resonance (NMR) spectra of water, benzene, fluorobenzene, and 2,2,2-trifluoroethanol in the earth’s magnetic field (EMF) using a nitrogen-cooled superconducting quantum interference device (SQUID). In trifluoroethanol, the broadband detection characteristics of the SQUID with a noise floor of about 70fT∕√Hz enabled authors to simultaneously observe fluorine and proton spectra at 1940 and 2060Hz Larmor frequency, reflecting their heteronuclear J coupling in the high-field limit without showing a measurable chemical shift. To reduce the noise in EMF-NMR, the authors suggest the use of frequency-adjusted averaging, which compensates line broadening due to EMF fluctuations.
Yeast aconitase binds and provides metabolically coupled protection to mitochondrial DNA
Authors: Chen Xin Jie , Wang Xiaowen , Butow Ronald A.
Published: August 2007

Aconitase (Aco1p) is a multifunctional protein: It is an enzyme of the tricarboxylic acid cycle. In animal cells, Aco1p also is a cytosolic protein binding to mRNAs to regulate iron metabolism. In yeast, Aco1p was identified as a component of mtDNA nucleoids. Here we show that yeast Aco1p protects mtDNA from excessive accumulation of point mutations and ssDNA breaks and suppresses reductive recombination of mtDNA. Aconitase binds to both ds- and ssDNA, with a preference for GC-containing sequences. Therefore, mitochondria are opportunistic organelles that seize proteins, such as metabolic enzymes, for construction of the nucleoid, an mtDNA maintenance/segregation apparatus.
Range maps and species richness patterns: errors of commission and estimates of uncertainty
Authors: La Sorte Frank A. , Hawkins Bradford A.
Published: August 2007

Range maps are often combined into “range overlap maps” to estimate spatial variation in species richness. Range maps are, in most cases, designed to represent a species’ maximum geographical extent and not patterns of occupancy within the range. As a consequence, range maps overestimate occupancy by presenting false occupancy (errors of commission) within the interior of the range. To assess the implications of errors of commission when developing and applying range overlap maps, we used neutral landscapes to simulate range maps and patterns of occupancy within ranges. We explored several scenarios based on combinations of six parameters defining biogeographical and cartographic factors typically encountered by investigators. Our results suggest that, in general, uncertainty is lowest when map resolutions are moderately fine, the majority of species have geographically restricted ranges, species occur throughout their range, patterns of occupancy within the range are not correlated among species, and geographically local and widespread species tend to occupy different regions. Several of these outcomes are associated with broad geographical extents, the scale at which range overlap maps are typically applied. Thus, under most circumstances, reasonably accurate and precise representation of species richness patterns can be achieved. However, these representations can be improved by enhancing occupancy data for widespread species – a primary source of uncertainty – and selecting a map resolution that captures relevant biological and environmental heterogeneity. Hence, by determining where a study is situated within the scenarios examined in our simulations, uncertainty and its sources and implications can be ascertained. With this knowledge, research goals, methods, and data sources can be reassessed and refined and, in the end, conclusions and recommendations can be qualified. Alternatively, unique regional, taxonomic, or cartographic factors could be included in future simulations to provide direct assessments of uncertainty.
Simplified Model to Predict Incipient Flooding/Dehydration in Proton Exchange Membrane Fuel Cells
Authors: Maharudrayya S. , Jayanti S. , Deshpande A. P.
Published: August 2007

Proper water management is critical for near-ambient temperature operation of a fuel cell. A simplified water balance model has been developed to predict when incipient flooding/dehydration may take place. The present model is based on multicomponent diffusion in the electrodes and molar balance in the flow channels. The overall model is in the form of a closed-form expression for the critical or threshold or balance current density at which the water production rate and the water vapor evacuation rate are exactly balanced. The model incorporates the influence of the operating conditions, properties of electrodes, and flow and geometric parameters in the gas channels on the balance current density. Predictions from the model of the state—incipient flooding or dehydration—of operation of the fuel cell agree well with the available experimental data. Using the model, a parametric study has been conducted over a range of parameters.
Improvement of Power Generation Efficiency of an Independent Microgrid Composed of Distributed Engine Generators
Authors: Obara Shin’ya
Published: August 2007

The power generation efficiency and power cost of an independent microgrid that distributes the power from a small diesel engine power generator was investigated using numerical analysis. The fuel consumption of a small diesel engine and the relation between power generation and heat power were obtained in experiments using a prototype. The independent microgrid built using one to six sets of 20 average houses in Sapporo and the distributed engine generators were examined using these test results. However, the operation of a diesel engine power generator controls the number of operations according to the magnitude of the power load of the microgrid. When a diesel engine power generator is distributed, since the power generation capacity per set decreases compared with the central system, the load factor of each engine generator rises. As a result, the operation of an engine at partial load with low efficiency can be reduced. When the number of distributions of the engine generator increases as a result of numerical analysis, the cost of the fuel decreases. However, when the rise in facility cost is taken into consideration, the number of engine generators for distribution is in fact 3 or 4.
Thermal System Interactions in Optimizing Advanced Thermoelectric Energy Recovery Systems
Authors: Hendricks Terry J.
Published: August 2007

Energy recovery is gaining importance in various transportation and industrial process applications because of rising energy costs and geopolitical uncertainties impacting basic energy supplies. Various advanced thermoelectric (TE) materials have properties that are inherently advantageous for particular TE energy recovery applications. Skutterudites, zero- and one-dimensional quantum-well materials, and thin-film superlattice materials are providing enhanced opportunities for advanced TE energy recovery in transportation and industrial processes. This work demonstrates (1) the potential for advanced thermoelectric systems in vehicle energy recovery and (2) the inherently complex interaction between thermal system performance and thermoelectric device optimization in energy recovery. Potential power generation at specific exhaust temperature levels and for various heat exchanger performance levels is presented showing the current design sensitivities using different TE material sets. Mathematical relationships inherently linking optimum TE design variables and the thermal systems design (i.e., heat exchangers and required mass flow rates) are also investigated and characterized.
Flow and Heat Transfer in Heat Recovery Steam Generators
Authors: Hegde N. , Han I. , Lee T. W. , Roy R. P.
Published: August 2007

Computational simulations of flow and heat transfer in heat recovery steam generators (HRSGs) of vertical- and horizontal-tube designs are reported. The main objective of the work was to obtain simple modifications of their internal configuration that render the flow of combustion gas more spatially uniform. The computational method was validated by comparing some of the simulation results for a scaled-down laboratory model with experimental measurements in the same. Simulations were then carried out for two plant HRSGs—without and with the proposed modifications. The results show significantly more uniform combustion gas flow in the modified configurations. Heat transfer calculations were performed for one superheater section of the vertical-tube HRSG to determine the effect of the configuration modification on heat transfer from the combustion gas to the steam flowing in the superheater tubes.
Application of Exergoeconomic Techniques to the Optimization of a Refrigeration Evaporator Coil With Continuous Fins
Authors: Khir Tahar , Jassim Rahim K. , Zaki Galal M.
Published: August 2007

An optimization for the geometrical parameters of continuous fins on an array of tubes of a refrigeration evaporator is developed in this paper using the exergy method. The method is based on exergy, economic analysis, and optimization theory. As there are humid air and refrigerant single- and two-phase streams involved in the heat transfer process, then there are irreversibilities or exergy destruction, due to pressure losses İΔP, due to temperature difference İΔT and due to specific humidity gradient İΔω. These principal components of total irreversibility are not independent, and their relative contribution to total irreversibility of a cross-flow refrigeration evaporator is investigated. A change in geometry was obtained by varying the evaporator tube diameter for a selected evaporator capacity, and hence the evaporator tube length and total heat transfer area are calculated for a fixed evaporator face length. In this way, the effect of changes in the geometry on the total number of exergy destruction units of the heat exchange process is investigated. The optimum balance between the three components of irreversibility (İΔP,İΔT, and İΔω) is also determined, thereby giving the optimum solution for the heat exchanger area. The total cost function, which provides a measure of the contribution of the evaporator to the total cost of the refrigeration system, is expressed on the basis of annual capital and electrical energy costs. The total cost function is minimized with respect to the total heat transfer area and the total number of exergy destruction units (NI). The relationship between the operational variables, heat transfer area, refrigerant and air irreversibilities, and the total annual cost for this type of evaporator are developed, presented, and discussed. The pressure, temperature, and specific humidity irreversibilities are found to be 30.34%, 33.78%, and 35.88%, respectively, of the total irreversibility, which is 8.5% of the evaporator capacity.
Live cell adhesion assay with attenuated total reflection infrared spectroscopy
Authors: Schmidt Martin , Wolfram Tobias , Rumpler Monika , Tripp Carl P. , Grunze Michael
Published: August 2007

Living confluent fish fibroblast cells RTG-P1 from rainbow trout adherent on diamond were examined by attenuated total reflection ATR infrared IR spectroscopy. In particular, IR spectra were recorded dynamically during the adsorption of the cells onto the diamond and during their biochemically induced structural responses to the subsequent addition of trypsin and cytochalasin D. It is shown that changes in the IR spectra result from changes in cell morphology and surface coverage. The results demonstrate the potential and the applicability ofATR IR spectroscopy for live cell adhesion assays.
Generic surface modification strategy for sensing applications based on Au/SiO2 nanostructures
Authors: Marie Rodolphe , Dahlin Andreas B. , Tegenfeldt Jonas O. , Höök Fredrik
Published: August 2007

A generic protocol for the creation of material-mediated self-assembled patterns of streptavidin, defined solely by patterns of gold and SiO2, is presented. Protein-adsorption resistance of selected regions was obtained by material-specific adsorption of thiol-modified poly(ethylene)glycol (thiol-PEG) on gold followed by adsorption of poly-l-lysine (PLL) modified PEG (PLL-g-PEG) on SiO2. Selective streptavidin binding to either gold or SiO2 (or both) was ensured by introducing biotin-modified thiolated (thiol-biotin) and/or biotin-modified PLL-g-PEG (PLL-g-PEGbiotin) compounds. The introduction of biotin did not influence the protein-adsorption resistance. On the macroscopic scale, the protein-adsorption-resistant properties and the streptavidin-binding capacity were optimized using quartz crystal microbalance with dissipation monitoring. The reproduction of micrometer-scale gold patterns on SiO2 into patterns of streptavidin was verified using fluorescence microscopy, while the compatibility of the material-specific surface-modification strategy with nanoscale features was accomplished by modifying a localized surface plasmon resonance (LSPR) active template, defined by randomly distributed nanoapertures in a thin gold film on SiO2. The demonstrated compatibility of the latter substrate with LSPR-based label-free sensing of biorecognition reactions, combined with the fact that all compounds utilized are commercially available, makes the surface-modification protocol attractive as a generic surface modification solution for a broad range of biorecognition-based assays.
Pulling a Door Open by Pushing on It
Authors: van den Berg Willem H.
Published: August 2007

Ordinarily, opening a door by pulling on the knob or handle causes a net torque on the door, and hence an angular acceleration, about a vertical axis. However, it may be that the top or bottom of the door sticks to the door frame; this horizontal force perpendicular to the plane of the door causes a torque on the door about a horizontal axis. This latter torque is countered by an opposite torque caused by horizontal forces exerted by the hinges; the result is that the door is deformed but does not readily open. The horizontal forces between the door and the hinges can potentially tear loose the hinges. When the sticking is released, the elastic potential energy stored in the deformation of the door becomes the alternating kinetic and potential energy of an annoying oscillation.
Why Do Calculators Have Rubber Feet?
Authors: Heavers Richard M.
Published: August 2007

Our students like using the covers of their TI graphing calculators in an inquiry-based extension of a traditional exercise1 that challenges their preconceived ideas about friction. Biology major Fiona McGraw (Fig. 1) is obviously excited about the large coefficient of static friction (μs = 1.3) for the four little rubber feet on her TI calculator cover. The angle of repose of 53° is three times the value she just obtained for a wood block on the same plane. That block fits nicely inside her calculator cover. By using the string already attached to the block, the cover with the block inside can be pulled along the board at a constant speed to obtain the coefficient of kinetic friction μk for rubber on wood (Fig. 2). Results vary with the age and condition of the rubber feet. Observations with only three rubber feet on some covers help to reinforce the idea that the friction force is independent of the area of the surface in contact. (Students first study the effect of area by working with the wood block on its wide side and then on its narrow side.)
Strategies for Adopting Interactive Engagement Methods
Authors: Belloni Mario , Cox Anne J.
Published: August 2007

Editor's note: It's very likely that interactive teaching methods may not be something you have seen modeled in your educational experiences thus far. Perhaps as you have read about effective teaching strategies, you found evidence that thoughtful interactions are essential and effective in moving students from being passive learners to actively engaged constructors of their own knowledge. To provide you with some ideas on establishing interactive engagement opportunities in your classroom, Mario Belloni and Anne Cox share suggestions from their years of experience designing quality instructional settings to foster these interactions.
GAUGE INVARIANT EXACT RENORMALIZATION GROUP AND PERFECT ACTIONS IN THE OPEN BOSONIC STRING THEORY
Authors: SATHIAPALAN B.
Published: August 2007

The exact renormalization group is applied to the worldsheet theory describing bosonic open string backgrounds to obtain the equations of motion for the fields of the open string. Using loop variable techniques the equations can be constructed to be gauge invariant. Furthermore they are valid off the (free) mass shell. This requires keeping a finite cutoff. Thus we have the interesting situation of a scale invariant worldsheet theory with a finite worldsheet cutoff. This is possible because there is infinite number of operators whose coefficients can be tuned. This is in the same sense that "perfect actions" or "improved actions" have been proposed in lattice gauge theory to reproduce the continuum results even while keeping a finite lattice spacing.
ON THE STUDY OF ONE FLOW FOR ASD CONNECTION
Authors: YU ZHENG
Published: August 2007

In this paper one flow for anti-self-dual (ASD) connection in Ω2+(AdP) on the principal bundle P over 4 dimensional compact Riemannian manifold (M, g) was studied. The local existence and the analysis of the blowing up phenomenon, including the local small energy regularity for this flow, are given.
ALGORITHM COMPARING BINARY STRING PROBABILITIES IN COMPLEX STOCHASTIC BOOLEAN SYSTEMS USING INTRINSIC ORDER GRAPH
Authors: GONZÁLEZ LUIS
Published: August 2007

This paper deals with a special kind of complex systems which depend on an arbitrary (and usually large) number n of random Boolean variables. The so-called complex stochastic Boolean systems often appear in many different scientific, technical or social areas. Clearly, there are 2n binary states associated to such a complex system. Each one of them is given by a binary string u = (u1,…,un) ∈ {0, 1}n of n bits, which has a certain occurrence probability Pr {u}. The behavior of a complex stochastic Boolean system is determined by the current values of its 2n binary n-tuple probabilities Pr {u} and by the ordering between pairs of them. Hence, the intrinsic order graph provides a useful representation of these systems by displaying (scaling) the 2n binary n-tuples which are ordered in decreasing probability of occurrence. The intrinsic order reduces the complexity of the problem from exponential (2n binary n-tuples) to linear (n Boolean variables). For any fixed binary n-tuple u, this paper presents a new, simple algorithm enabling rapid, elegant determination of all the binary n-tuples v with occurrence probabilities less than or equal to (greater than or equal to) Pr {u}. This algorithm is closely related to the lexicographic (truth-table) order in {0, 1}n, and this is illustrated through the connections (paths) in the intrinsic order graph.
Frequency-Modulation Encoding in the Primary Auditory Cortex of the Awake Owl Monkey
Authors: Atencio Craig A. , Blake David T. , Strata Fabrizio , Cheung Steven W. , Merzenich Michael M. , Schreiner Christoph E.
Published: August 2007

Many communication sounds, such as New World monkey twitter calls, contain frequency-modulated (FM) sweeps. To determine how this prominent vocalization element is represented in the auditory cortex we examined neural responses to logarithmic FM sweep stimuli in the primary auditory cortex (AI) of two awake owl monkeys. Using an implanted array of microelectrodes we quantitatively characterized neuronal responses to FM sweeps and to random tone-pip stimuli. Tone-pip responses were used to construct spectrotemporal receptive fields (STRFs). Classification of FM sweep responses revealed few neurons with high direction and speed selectivity. Most neurons responded to sweeps in both directions and over a broad range of sweep speeds. Characteristic frequency estimates from FM responses were highly correlated with estimates from STRFs, although spectral receptive field bandwidth was consistently underestimated by FM stimuli. Predictions of FM direction selectivity and best speed from STRFs were significantly correlated with observed FM responses, although some systematic discrepancies existed. Last, the population distributions of FM responses in the awake owl monkey were similar to, although of longer temporal duration than, those in the anesthetized squirrel monkeys.
Hypoxia Enhances Metastatic Efficiency in HT1080 Fibrosarcoma Cells by Increasing Cell Survival in Lungs, Not Cell Adhesion and Invasion
Authors: Zhang Li , Hill Richard P.
Published: August 2007

This study examined possible mechanisms for hypoxia-increased metastasis in a green fluorescent protein–labeled human fibrosarcoma cell line (HT1080). The efficiency of the lung arrest of tumor cells, which can be dependent on the adhesive potential of the tumor cells, was assessed by measuring the level of integrin α3β1 protein and by adhesion assays, whereas the extravasation potential was examined by an invasion assay. These properties were not changed by exposure to hypoxia, indicating that lung arrest and extravasation are unlikely to play a major role in the effect of hypoxia on metastasis in this model. The main effect of hypoxic exposure was found to be increased survival after lung arrest as determined by clonogenic assay of tumor cells recovered from mouse lungs after i.v. injection. Concomitantly, apoptosis was identified as responsible for the death of lung-arrested cells, suggesting the involvement of an altered apoptotic response following hypoxic exposure of these cells. Consistent with this finding, we found that the effect of hypoxia on both increased metastasis and survival of arrested cells was inhibited by treatment with farnesylthiosalicylic acid. However, this effect was not due to down-regulation of hypoxia-inducible factor-1α, a mechanism of action of this drug reported by previous studies. Further detailed studies of the mechanisms of action of the drug are needed. [Cancer Res 2007;67(16):7789–97]
Retinoblastoma: From the Two-Hit Hypothesis to Targeted Chemotherapy
Authors: MacPherson David , Dyer Michael A.
Published: August 2007

Studies on retinoblastoma have been at the heart of many of the landmark discoveries in cancer genetics over the past 35 years. However, these advances in the laboratory have had little effect on the treatment of children with retinoblastoma. One of the reasons for this has been the lack of preclinical models that recapitulated the genetic and histopathologic features of human retinoblastoma. In the past three years, a series of new animal models of retinoblastoma has been developed and characterized from several different laboratories using a variety of experimental approaches. It is encouraging that there is broad agreement about the consequences of inactivation of the Rb family in retinal development from these studies. More importantly, these new mouse models of retinoblastoma have contributed to clinical trials and novel therapeutic approaches for treating this debilitating childhood cancer. [Cancer Res 2007;67(16):7547–50]
Circulating Insulin-Like Growth Factor Binding Protein-1 and the Risk of Pancreatic Cancer
Authors: Wolpin Brian M. , Michaud Dominique S. , Giovannucci Edward L. , Schernhammer Eva S. , Stampfer Meir J. , Manson JoAnn E. , Cochrane Barbara B. , Rohan Thomas E. , Ma Jing , Pollak Michael N. , Fuchs Charles S.
Published: August 2007

Insulin-like growth factor (IGF)-I has growth-promoting effects on pancreatic cancer cells, and elevated fasting serum insulin has been linked to pancreatic cancer risk. IGF binding protein-1 (IGFBP-1) is a downstream target of insulin and inhibits IGF-I activity. To investigate whether prediagnostic plasma levels of IGFBP-1 are associated with pancreatic cancer risk, we did a prospective, case-control study nested within the Health Professionals Follow-up Study, the Nurses' Health Study, the Physicians' Health Study, and the Women's Health Initiative. We assayed circulating IGFBP-1 among 144 pancreatic cancer cases that occurred ≥4 years after plasma collection and in 429 controls, matched for date of birth, prospective cohort, smoking status, and fasting status. When compared with participants in the three highest quartiles of plasma IGFBP-1, those in the lowest quartile experienced a relative risk (RR) for pancreatic cancer of 2.07 [95% confidence intervals (95% CI), 1.26–3.39], after adjusting for other risk factors, including circulating IGF-I, IGF binding protein-3, and C-peptide. Only participants in the lowest quartile of plasma IGFBP-1 showed an elevated risk of pancreatic cancer. The influence of low plasma IGFBP-1 became progressively stronger with time; among cases diagnosed ≥8 years after blood collection, the adjusted RR was 3.47 (95% CI, 1.48–8.14), comparing the bottom versus the top three quartiles. The influence of plasma IGFBP-1 was most marked among participants who never smoked cigarettes (RR, 3.30; 95% CI, 1.48–7.35). Among participants in four U.S. prospective cohort studies, low plasma IGFBP-1 levels significantly predicted an increased risk of pancreatic cancer. [Cancer Res 2007;67(16):7923–8]
Farnesol-Induced Apoptosis in Human Lung Carcinoma Cells Is Coupled to the Endoplasmic Reticulum Stress Response
Authors: Joo Joung Hyuck , Liao Grace , Collins Jennifer B. , Grissom Sherry F. , Jetten Anton M.
Published: August 2007

Farnesol (FOH) and other isoprenoid alcohols induce apoptosis in various carcinoma cells and inhibit tumorigenesis in several in vivo models. However, the mechanisms by which they mediate their effects are not yet fully understood. In this study, we show that FOH is an effective inducer of apoptosis in several lung carcinoma cells, including H460. This induction is associated with activation of several caspases and cleavage of poly(ADP-ribose) polymerase (PARP). To obtain insight into the mechanism involved in FOH-induced apoptosis, we compared the gene expression profiles of FOH-treated and control H460 cells by microarray analysis. This analysis revealed that many genes implicated in endoplasmic reticulum (ER) stress signaling, including ATF3, DDIT3, HERPUD1, HSPA5, XBP1, PDIA4, and PHLDA1, were highly up-regulated within 4 h of FOH treatment, suggesting that FOH-induced apoptosis involves an ER stress response. This was supported by observations showing that treatment with FOH induces splicing of XBP1 mRNA and phosphorylation of eIF2α. FOH induces activation of several mitogen-activated protein kinase (MAPK) pathways, including p38, MAPK/extracellular signal–regulated kinase (ERK) kinase (MEK)-ERK, and c-jun NH2-terminal kinase (JNK). Inhibition of MEK1/2 by U0126 inhibited the induction of ER stress response genes. In addition, knockdown of the MEK1/2 and JNK1/2 expression by short interfering RNA (siRNA) effectively inhibited the cleavage of caspase-3 and PARP and apoptosis induced by FOH. However, only MEK1/2 siRNAs inhibited the induction of ER stress–related genes, XBP1 mRNA splicing, and eIF2α phosphorylation. Our results show that FOH-induced apoptosis is coupled to ER stress and that activation of MEK1/2 is an early upstream event in the FOH-induced ER stress signaling cascade. [Cancer Res 2007;67(16):7929–36]
p73 Loss Triggers Conversion to Squamous Cell Carcinoma Reversible upon Reconstitution with TAp73α
Authors: Johnson Jodi , Lagowski James , Sundberg Alexandra , Lawson Sarah , Liu Yuangang , Kulesz-Martin Molly
Published: August 2007

The expression level of the p53 family member, p73, is frequently deregulated in human epithelial cancers, correlating with tumor invasiveness, therapeutic resistance, and poor patient prognosis. However, the question remains whether p73 contributes directly to the process of malignant conversion or whether aberrant p73 expression represents a later selective event to maintain tumor viability. We explored the role of p73 in malignant conversion in a clonal model of epidermal carcinogenesis. Whether sporadic or small interfering RNA (siRNA) induced, loss of p73 in initiated p53+/+ keratinocytes leads to loss of cellular responsiveness to DNA damage by ionizing radiation (IR) and conversion to squamous cell carcinoma (SCC). Reconstitution of TAp73α but not ΔNp73α reduced tumorigenicity in vivo, but did not restore cellular sensitivity to IR, uncoupling p73-mediated DNA damage response from its tumor-suppressive role. These studies provide direct evidence that loss of p73 can contribute to malignant conversion and support a role for TAp73α in tumor suppression of SCC. The results support the activation of TAp73α as a rational mechanism for cancer therapy in solid tumors of the epithelium. [Cancer Res 2007;67(16):7723–30]
Myeloproliferative Defects following Targeting of the Drf1 Gene Encoding the Mammalian Diaphanous–Related Formin mDia1
Authors: Peng Jun , Kitchen Susan M. , West Richard A. , Sigler Robert , Eisenmann Kathryn M. , Alberts Arthur S.
Published: August 2007

Rho GTPase-effector mammalian diaphanous (mDia)–related formins assemble nonbranched actin filaments as part of cellular processes, including cell division, filopodia assembly, and intracellular trafficking. Whereas recent efforts have led to thorough characterization of formins in cytoskeletal remodeling and actin assembly in vitro, little is known about the role of mDia proteins in vivo. To fill this knowledge gap, the Drf1 gene, which encodes the canonical formin mDia1, was targeted by homologous recombination. Upon birth, Drf1+/− and Drf1−/− mice were developmentally and morphologically indistinguishable from their wild-type littermates. However, both Drf1+/− and Drf1−/− developed age-dependent myeloproliferative defects. The phenotype included splenomegaly, fibrotic and hypercellular bone marrow, extramedullary hematopoiesis in both spleen and liver, and the presence of immature myeloid progenitor cells with high nucleus-to-cytoplasm ratios. Analysis of cell surface markers showed an age-dependent increase in the percentage of CD11b+-activated and CD14+-activated monocytes/macrophages in both spleen and bone marrow in Drf1+/− and Drf1−/− animals. Analysis of the erythroid compartment showed a significant increase in the proportion of splenic cells in S phase and an expansion of erythroid precursors (TER-119+ and CD71+) in Drf1-targeted mice. Overall, knocking out mDia1 expression in mice leads to a phenotype similar to human myeloproliferative syndrome (MPS) and myelodysplastic syndromes (MDS). These observations suggest that defective DRF1 expression or mDia1 function may contribute to myeloid malignancies and point to mDia1 as an attractive therapeutic target in MDS and MPS. [Cancer Res 2007;67(16):7565–71]
Comparison of Ductal Lavage and Random Periareolar Fine Needle Aspiration as Tissue Acquisition Methods in Early Breast Cancer Prevention Trials
Authors: Arun Banu , Valero Vicente , Logan Catherine , Broglio Kristine , Rivera Edgardo , Brewster Abenaa , Yin Guosheng , Green Marjorie , Kuerer Henry , Gong Yun , Browne Doris , Hortobagyi Gabriel N. , Sneige Nour
Published: August 2007

Purpose: Short-term phase I and phase II breast cancer prevention trials require tissue acquisition at baseline and after intervention to evaluate modulation of potential biomarkers. Currently used tissue acquisition methods include ductal lavage (DL), random periareolar fine needle aspiration (RPFNA), and core needle biopsy. The optimum method to retrieve adequate samples and the most accepted method by study participants is not known.

Experimental Design: We compared RPFNA and DL as breast tissue acquisition methods for short-term breast cancer prevention trials by evaluating sample adequacy and tolerability in subjects who participated in two prospective phase II breast cancer prevention trials. Eighty-six women at increased risk for breast cancer were included in this study and underwent baseline DL and RPFNA. High risk was defined as having a 5-year Gail score of >1.67% or a history of atypical hyperplasia (AH), lobular carcinoma, or breast cancer.

Results: Median age was 54.5 years (range, 39-75 years); 75% of the women were postmenopausal. About 51% of the women yielded nipple aspiration fluid, and breast fluid samples via DL were retrieved in 73% of these subjects. Of these samples, 71% were adequate samples (greater than 10 epithelial cells). However, when the entire cohort was considered, only 31% of the subjects had adequate samples. RPFNA was also attempted in all subjects, and sample retrieval rate was 100%. Out of these, 96% of the subjects had adequate samples. In DL samples, AH rate was 3.7% was and hyperplasia (H) rate was 11.1%. In RPFNA samples, AH rate was 12.9%, and H rate was 24.7%. Cytology findings in RPFNA samples correlated with age, menopausal status, and breast cancer risk category (previous history of lobular carcinoma in situ). Both procedures were well tolerated, and no complications occurred among participants.

Conclusions: Considering that the main end point for short-term prevention trials is the modulation of biomarkers, it is important to optimize adequate sample acquisition; therefore, RPFNA is a more practical option for future phase I and II breast cancer prevention trials compared with DL.
Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells
Authors: Meyers John A. , Taverna Josephine , Chaves Jorge , Makkinje Anthony , Lerner Adam
Published: August 2007

Type 4 cyclic AMP (cAMP) phosphodiesterase (PDE4) inhibitors, a class of compounds in clinical development that activate cAMP-mediated signaling by inhibiting cAMP catabolism, offer a feasible means by which to potentiate glucocorticoid-mediated apoptosis in lymphoid malignancies such as B-cell chronic lymphocytic leukemia (B-CLL). In this study, we show that PDE4 inhibitors up-regulate glucocorticoid receptor (GRα) transcript levels in B-CLL cells but not T-CLL cells or Sezary cells or normal circulating T cells, B cells, monocytes, or neutrophils. Because GRα transcript half-life does not vary in CLL cells treated with the prototypic PDE4 inhibitor rolipram, the 4-fold increase in GRα mRNA levels observed within 4 h of rolipram treatment seems to result from an increase in GRα transcription. Rolipram treatment increases levels of transcripts derived from the 1A3 promoter to a greater extent than the 1B promoter. Treatment of B-CLL cells with two other PDE4 inhibitors currently in clinical development also augments GR transcript levels and glucocorticoid-mediated apoptosis. Washout studies show that simultaneous treatment with both drug classes irreversibly augments apoptosis over the same time frame that GR up-regulation occurs. Although treatment of B-CLL cells with glucocorticoids reduces basal GRα transcript levels in a dose-related manner, cotreatment with rolipram maintained GRα transcript levels above baseline. Our results suggest that as a result of their unusual sensitivity to PDE4 inhibitor–mediated up-regulation of GRα expression, treatment of B-CLL patients with combined PDE4 inhibitor/glucocorticoid therapy may be of therapeutic benefit in this disease.
Phase I Targeted Combination Trial of Sorafenib and Erlotinib in Patients with Advanced Solid Tumors
Authors: Duran Ignacio , Hotté Sebastien J. , Hirte Holger , Chen Eric X. , MacLean Martha , Turner Sandra , Duan Lixia , Pond Gregory R. , Lathia Chetan , Walsh Scott , Wright John J. , Dancey Janet , Siu Lillian L.
Published: August 2007

Purpose: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities.

Experimental Design: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed.

Results: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response.

Conclusions: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.
Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species–mediated damage
Authors: Oh Se-Yeong , Sohn Young-Woo , Park Jong-Whi , Park Hyo-Jung , Jeon Hye-Min , Kim Tae-Kyung , Lee Joong-Seob , Jung Ji-Eun , Jin Xun , Chung Yong Gu , Choi Young-Ki , You Seungkwon , Lee Jang-Bo , Kim Hyunggee
Published: August 2007

We have established several glioma-relevant oncogene-engineered cancer cells to reevaluate the oncogene-selective cytotoxicity of previously well-characterized anticancer drugs, such as etoposide, doxorubicin, staurosporine, and carmustine. Among several glioma-relevant oncogenes (activated epidermal growth factor receptor, Ras, and Akt, as well as Bcl-2 and p53DD used in the present study), the activated epidermal growth factor receptor, Ras, and Akt exerted oncogenic transformation of Ink4a/Arf−/− murine astrocyte cells. We identified that etoposide, a topoisomerase II inhibitor, caused selective killing of myristylated Akt (Akt-myr)–transduced Ink4a/Arf−/− astrocytes and U87MG cells in a dose- and time-dependent manner. Etoposide-selective cytotoxicity in the Akt-myr–transduced cells was shown to be caused by nonapoptotic cell death and occurred in a p53-independent manner. Etoposide caused severe reactive oxygen species (ROS) accumulation preferentially in the Akt-myr–transduced cells, and elevated ROS rendered these cells highly sensitive to cell death. The etoposide-selective cell death of Akt-myr–transduced cells was attenuated by pepstatin A, a lysosomal protease inhibitor. In the present study, we show that etoposide might possess a novel therapeutic activity for oncogenic Akt-transduced cancer cells to kill preferentially through ROS-mediated damage. [Mol Cancer Ther 2007;6(8):2178–87]