bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced Multi-Functional Coatings for Land-Based Industrial Gas Turbines
Authors: Subramanian Ramesh , Burns Andrew , Stamm Werner
Published: August 2009

The utilization of fossil fuels for powering industrial gas turbines is expected to continue growing resulting in continued emphasis on increasing performance and reliability while simultaneously providing a cost effective, efficient, and environmentally sound power generation solution. The push to higher firing temperatures, increased efficiencies, reduced emissions and multiple fuel capability continues to demand more out of the gas turbine design and materials systems capabilities. Coatings are an integral part of many IGT materials systems, contributing several key functions such as thermal and oxidation protection, clearance control, wear resistance and sensing capabilities. Each of these coating functionalities presents unique challenges and requirements as they are super-imposed upon each other, especially with engine operating conditions becoming harsher and increasing service interval expectations. A full life cycle systematic approach in understanding the materials systems performance limits is essential for a successful engine implementation. As an example, thermal barrier coating (TBC) systems degradation mechanisms will be presented and examples of innovative systematic approaches towards engineering of production feasible, advanced high temperature capable coating systems will be provided.
Development and F-Class Industrial Gas Turbine Engine Testing of Smart Components With Direct-Write Embedded Sensors and High Temperature Wireless Telemetry
Authors: Mitchell David , Kulkarni Anand , Roesch Edward , Subramanian Ramesh , Burns Andrew , Brogan Jeffrey , Greenlaw Robert , Lostetter Alex , Schupbach Marcelo , Fraley John , Waits Rod
Published: August 2009

The potential for savings provided to worldwide operators of industrial gas turbines, by transitioning from the current standard of interval-based maintenance to condition-based maintenance may be in the tens of millions of dollars per year. Knowledge of the historical and current condition of life-limiting components will enable more efficient use of industrial gas turbine resources via increased operational flexibility, with less risk of unplanned outages as a result of off-parameter operations. To date, it has been impossible to apply true condition-based maintenance to industrial gas turbines because the extremely harsh operating conditions in the heart of a gas turbine preclude using the necessary advanced sensor systems to monitor the machine’s condition continuously. The U.S. Department of Commerce’s National Institute of Standards and Technology – Advanced Technology Program (NIST-ATP) awarded the Joint Venture team of Siemens Power Generation, Inc. and MesoScribe Technologies, Inc. a four-year, $5.4 million program in November, 2004, titled Conformal, Direct-Write-Technology-Enabled, Wireless, Smart Turbine Components. The target was to develop a potentially industry-changing technology to build smart, self-aware engine components that incorporate embedded, harsh-environment-capable sensors and high temperature capable wireless telemetry systems for continuously monitoring component condition in both the compressor and turbine sections. The approach involves several difficult engineering challenges, including the need to embed sensors on complex shapes, such as turbine blades, embedding wireless telemetry systems in regions with temperatures that preclude the use of conventional silicon-based electronics, protecting both sensors and wireless devices from the extreme temperatures and environments of an operating gas turbine, and successfully transmitting the sensor information from an environment very hostile to wireless signals. The program included full-scale, F-class industrial gas turbine engine test demonstrations with smart components in both the compressor and turbine sections. The results of the development program and engine testing to date will be discussed.
Optimal Harvest Rate Policies for Rebuilding the Adams River Sockeye Salmon (Oncorhynchus nerka)
Authors: Welch David W. , Noakes Donald J.
Published: August 2009

This paper examines how a currently depressed population, the Adams River sockeye salmon (Oncorhynchus nerka), should be rebuilt over time in order to maximize the economic benefit. We use dynamic optimization techniques to answer two questions which previous static optimization work on the Adams River sockeye controversy did not address: (1) what changes from current management policies are required over time to maximize the net economic yield from the population and (2) just how much economic benefit can accrue from following such a policy? We find that following the optimal policy identified by this methodology could contribute more than $600 million to the net value of the Adams River stock. Examination of various confounding factors (co-migrating stocks, parameter uncertainty, and the discount rate applied) indicates that the optimal harvest policy is remarkably robust to these sources of uncertainty. The study also lays the basis for repeating such numerical analysis on other populations of interest.
Analysis of Length Frequency Samples with Relative Abundance Data for the Gulf of Maine Northern Shrimp (Pandalus borealis) by the MULTIFAN Method
Authors: Fournier David A. , Sibert John R. , Terceiro Mark
Published: August 2009

We present an extension of the MULTIFAN method for simultaneously analyzing several length frequency data sets from length frequency data collected by research trawl surveys. The assumption that the research trawl samples the animals in a regular fashion allows the proportions at age in the samples to be parameterized in terms of relative year class strengths and the age-dependent selectivity of the sampling procedure. When available, relative abundance data can be incorporated into the analysis and permit the estimation of mortality. The method is applied to Gulf of Maine northern shrimp (Pandalus borealis) data. The parameter estimates obtained agree substantially with those previously obtained using a more detailed knowledge of the species' biology.
Assessing the Potential Extent of Damage to Inland Lakes in Eastern Canada due to Acidic Deposition. IV. Uncertainty Analysis of a Regional Model
Authors: Jones Michael L. , Minns Charles K. , Marmorek David R. , Heltcher Kim J.
Published: August 2009

In this paper, we consider the significance of uncertainty in inputs to the regional surface water acidification model of Marmorek et al. (1990. Can. J. Fish. Aquat. Sci. 47: 55–66). Monte Carlo methods are used to propagate input uncertainty through to measures of uncertainty in the model's overall predictions. We consider four key inputs which represent primary areas of input uncertainty: acidic sulphate deposition (Da), original lake sulphate concentrations ([SO4]0), a watershed neutralization parameter (FW), and an in-lake neutralization parameter (SS). The analysis is repeated for secondary watersheds from north-central Ontario, the Quebec Laurentians, and insular Newfoundland. Uncertainty in Daand [SO4]0consistently overwhelms the effect of uncertainty in FWand SSon overall model uncertainty. The relative importance of Dadecreases as one moves east from the high-deposition regions of central Ontario. We discuss the implications of our results for priority setting for future acidification research and monitoring.
Models of the Fish Yield from Lakes: Does the Random Component Matter?
Authors: Bajdik Chris D. , Schneider David C.
Published: August 2009

Generalized linear models were used to investigate the sensitivity of paramater estimates to choice of the random error assumption in models of fisheries data. We examined models of fish yield from lakes as a function of (i) Ryder's morphoedaphic index, (ii) lake area, lake depth, and concentration of dissolved solids, and (iii) fishing effort. Models were fit using a normal, log-normal, gamma, or Poisson distribution to generate the random error. Plots of standardized Pearson residuals and standardized deviance residuals were used to evaluate the distributional assumptions. For each data set, observations were found to be consistent with several distributions; however, some distributions were shown to be clearly inappropriate. Inappropriate distributional assumptions produced substantially different parameter estimates. Generalized linear models allow a variety of distributional assumptions to be incorporated in a model, and thereby let us study their effects.
Taking Stock of Genetic Concepts in Fisheries Management
Authors: Gauldie R. W.
Published: August 2009

The historical development of the idea of isolated stocks of fish that can be managed as separate management units has been as strongly tied to the intuitive idea of separate races as it has been to the practical necessities of jurisprudence and the estimation of both biomass and sustainable yield by fisheries managers. Demonstrating the existence of isolated fish stocks and delineating their boundaries has generally proved unsuccessful. Various techniques ranging from meristic count differences to polymorphic allelism have usually failed. However, in the pursuit of isolated stocks, biochemists have uncovered a great deal of information about the variation of polymorphic allele frequencies over time and space. Following the shift in opinion away from stochastic to natural selection mechanisms in allele frequency variation, it is evident that the observed variation in allele frequencies allows more insight into the biology of fishes than into the breeding structure of populations. These insights argue against the idea of isolated stocks of fish with homogeneous growth rates that are the basis of the sustainable yield models in favour of migration-linked stocks with heterogeneous growth rates.
Application of the otolith weight – age relationship for the pilchard, Sardinops sagax neopilchardus
Authors: Fletcher W. J.
Published: August 2009

Adult pilchard (Sardinops sagax neopilchardus) from southwestern Australia held in fish cages for 1 year showed minimal increase in mean length but a steady increase in mean otolith weight (1.61–1.83 mg); this increase (0.22 mg) closely parallels the previously calculated mean difference between adjacent age classes (0.24 mg). Modes in otolith weight frequency distributions of fishery-caught pilchards, previously suggested as corresponding with separate year classes, generally persisted and progressed through subsequent samples. By contrast, fish length frequency distributions of these samples showed no consistent modal progression. The average weight of otoliths for year classes 2–8 were used to calculate growth rates: following sexual maturity, at age 2, males grew to a significantly smaller maximum size than females (L∞ = 162 and 172 mm respectively). The otolith weight – age relationship, validated by following a cohort of unusually low abundance as it moved through the fishery, indicated that recruitment to the fishery generally began at age 2 but was not complete until age 4. These data have been successfully used in forecasting the catch rate of the fishery up to 2 years in advance and providing an estimate of the rate for natural mortality of 0.43.
Field transplantation of a freshwater bivalve, Pyganodon grandis, across a metal contamination gradient. II. Metallothionein response to Cd and Zn exposure, evidence for cytotoxicity, and links to effects at higher levels of biological organization
Authors: Couillard Y. , Campbell P. G. C. , Auclair J. G. , Pellerin-Massicotte J.
Published: August 2009

To examine links between the metallothionein (MT) status of an organism and its general health, we transplanted adult specimens of the freshwater bivalve Pyganodon grandis (formerly Anodonta grandis) from a less to a more contaminated lake in the mining area of Rouyn-Noranda, in northwestern Québec. The transplanted bivalves were maintained in open enclosures placed in the bottom sediments of the contaminated lake; in addition, indigenous specimens were maintained in control enclosures in their lake of origin. Up to 16 individuals were removed from pairs of enclosures at times t = 0 (June 1990), 5, 14, 30, 60, 90, and 400 d. Excised gill tissue was analyzed for metallothionein, Cd, Cu, Zn, Ca, and malondialdehyde (MDA), a product of lipid peroxidation. Metal partitioning in the gill cytosol, as determined on a subset of gill samples from transplanted molluscs, changed markedly during the experiment. After 400 d, Cd was present in the low molecular weight fraction of the gill cytosol, and symptoms of cellular toxicity were detected in the transplanted molluscs (elevated [MDA] and [Ca]). At the whole organism level, the marked transplanted bivalves grew more slowly over the 400-d experiment than did marked control bivalves in Lake Opasatica, and their condition index deteriorated over time.
Groundwater contribution to the water and chemical budgets of Williams Lake, Minnesota, 1980–1991
Authors: LaBaugh James W. , Rosenberry Donald O. , Winter Thomas C.
Published: August 2009

Groundwater seepage was the largest annual flux of water into (58–76%) and out of (73–83%) Williams Lake during a 12-year study, during which the entire volume of the lake was replaced four times. The only other water fluxes to and from the lake, which has no surface-water inlet or outlet, were atmospheric precipitation and evaporation. Nearly all of the annual input of calcium, magnesium, sodium, potassium, chloride, sulfate, and silica was provided by groundwater. Although much of the calcium and most of the silica input was retained in the lake, this retention did not result in increased chemical mass in the lake water mass because biologically mediated removal of calcium and silica to the sediments equaled or exceeded loss by lake seepage to groundwater. Groundwater represented as much as one-half the annual hydrological input of phosphorus and nitrogen; the remainder was supplied by atmospheric precipitation. From about 70 to 90% of the annual input of phosphorus and nitrogen was retained in the lake. Although water and chemical fluxes varied from year to year, interaction of the lake with groundwater determined the hydrological and chemical characteristics of Williams Lake.
EDTA toxicity and background concentrations of copper and zinc in Hyalella azteca
Authors: Borgmann U. , Norwood W. P.
Published: August 2009

The effect of the strong metal-complexing agent EDTA on survival, growth, and copper and zinc concentrations in Hyalella azteca was studied to determine if metal concentrations in control amphipods represent minimum physiological levels. Exposure to EDTA concentrations of up to 560 μM for 1 week did not reduce metal levels (mean background = 1.2 μmol Cu/g and 1.0 μmol Zn/g dry weight), indicating that background metals are firmly bound to Hyalella. Chronic (4 week) exposure to EDTA resulted in increased mortality and reduced growth rates, both of which could be partially ameliorated by adding zinc to culture media. This implies that EDTA toxicity results, in part, from zinc deficiency. In spite of this, however, zinc concentrations in Hyalella were not reduced in amphipods raised in the presence of high EDTA, implying that the observed background zinc levels represent minimum physiological levels. Copper additions to media were ineffective at reducing EDTA toxicity. Nevertheless, control concentrations are probably close to minimum physiological levels for copper as well, because high EDTA did not appreciably reduce copper in Hyalella in chronic tests, in spite of its ability to impair copper uptake from water at moderate water concentrations.
Aquatic acetylene-reduction techniques: solutions to several problems
Authors: Flett R. J. , Hamilton R. D. , Campbell N. E. R.
Published: August 2009

Previous methods of performing aquatic acetylene-reduction assays are described and several problems associated with them are discussed. A refinement of these older techniques is introduced and problems that it overcomes are also discussed. A depth profile of nitrogen fixation (C2H4 production), obtained by the refined technique, is shown for a fertilized Canadian Shield lake in the Experimental Lakes Area of northwestern Ontario.
Association of a ribonuclease with the purified influenza virus
Authors: Arora D. J. S. , Pavilanis V. , Soula A. , Robert P. , Croteau G.
Published: August 2009

Purified influenza virus contains ribonuclease activity. The enzyme does not hydrolyze viral RNA but both 28 S and 18 S host cell RNA are degraded forming large (about 16 S) and small (about 5 S) fragments with the release of the acid-soluble material.It has an optimum temperature of 37 °C, requires no divalent ions, and is inhibited by 0.1 M EDTA and 1% SDS. Treatment with 4 M urea increases enzymatic activity considerably (42%) but is not a prerequisite for eliciting ribonuclease activity suggesting that the enzyme is probably located near the surface of the virus particle. Results show that the observed enzyme activity is virus-associated as no host cell protein is detectable in the purified virus.
Penicillin tolerance in Neisseria gonorrhoeae: evidence disallowing a penicillinase-mediated mechanism from a refined microbiological assay method
Authors: Scudamore R. A. , Goldner M.
Published: August 2009

A microbiological assay method has been developed and applied to Neisseria gonorrhoeae, for the purpose of detecting enzymatic deactivation of benzyl penicillin. Calibration of the method, using strains of Escherichia coli K-12 with previously reported penicillinase (EC 3.5.2.6.) activities, has shown that it is extremely sensitive and may be used in a quantitative manner. At the limit of sensitivity the test is able to detect penicillin breakdown in the order of 3 × 10−3 μg in 48 h, which is equivalent to about 7 × 10−8 μmol/min per milligram dry weight of cells. Over 100 strains of N. gonorrhoeae, most of them resistant to penicillin, were screened for their ability to deactivate penicillin during 48 h of growth in the presence of subinhibitory levels. No deactivation was detected. It is concluded, from quantitative evidence, that reduced penicillin sensitivity in N. gonorrhoeae is not due to the enzymatic deactivation of the antibiotic.
The in vitro hydroxylation of 4′-chloro-4-biphenylol by a mushroom tyrosinase preparation
Authors: Safe S. , Ellis B. E. , Hutzinger O.
Published: August 2009

Incubation of 4′-chloro-4-biphenylol with a mushroom tyrosinase preparation gave the catechol, 4′-chIoro-3,4-biphenyldiol as the sole in vitro metabolite. This compound was identical with the major rat urinary metabolite of 4′-chloro-4-biphenylol and thus confirms the structure assigned to the metabolite. This result also demonstrates a possible degradation pathway of hydroxylated chlorobiphenyls which are themselves the major metabolic degradation products of polychlorinated biphenyls.
IDENTIFICATION OF COHERENT STRUCTURES IN THREE-DIMENSIONAL SIMULATIONS OF A FLUID-MIX PROBLEM
Authors: KAMATH CHANDRIKA , GEZAHEGNE ABEL , MILLER PAUL
Published: August 2009

The use of high-performance computers in computer simulations of physical phenomena has resulted in the generation of massive amounts of data. The analysis of these data can be challenging given their size and the complexity of the structures observed. In this paper, we describe how we can use image processing techniques to identify and count coherent structures in three-dimensional simulations of the Rayleigh-Taylor instability, which occurs when one fluid is being accelerated by a second fluid. As the two fluids mix, coherent structures are formed which grow, shrink, change shape, split, and merge with time. We describe the challenges faced in the analysis and show how we can combine image processing techniques with problem-specific characteristics to successfully analyze terabyte-sized data sets.
DEATH OF DISTANCE? — BIOTECHNOLOGY AGGLOMERATION PATTERNS, ALLIANCE PROXIMITY, AND FIRM PERFORMANCE
Authors: AHN MARK J. , MEEKS MICHAEL D. , DAVENPORT SALLY , BEDNAREK REBECCA
Published: August 2009

Leading biopharmaceutical firms need to dynamically optimize pipeline portfolios of internally and externally generated product candidates to ensure sustainable growth. This paper provides an empirical analysis of leading global biotechnology firms with respect to technology agglomeration patterns, proximity to alliance partners, and firm performance for the period 1996–2006. Findings suggest that the absolute number of technology and product alliances were approximately twice as important as proximity to partners in terms of firm performance. These results indicate that a strategy of relentless pipeline building, without regard to geographic proximity of alliance partners, may enhance relative and absolute performance of biopharmaceutical industry leaders.
VISUAL ENVIRONMENT AND JOYSTICK BASED CONTROL FOR HUMANOID TELEOPERATION
Authors: KEERIO MUHAMMAD USMAN , LU YUEPIN
Published: August 2009

In the case of dark/bad light environments cameras cannot shoot images clearly for the operator to complete the task. Also, video information from camera or robot vision is not enough for some typical applications like telesurgery to pick up an object. In this paper a novel controlling approach for humanoid teleoperation using virtual reality is presented, such that the robot can work safely and accurately in such circumstances. In this regard the work has been enhanced by developing the virtual/visual environment using joystick control interface for controlling Humanoid BHR-2 motion to complete a task safely and accurately. Software Maya is chosen for this work, which can perform all the vision-related calculations. Experiments are conducted using joystick control commands where the operator controls BHR-2 walking motion while looking at virtual scene on his computer to confirm the effectiveness of novel control technique.
NEW MECHANICS OF GENERIC MUSCULO-SKELETAL INJURY
Authors: IVANCEVIC VLADIMIR G.
Published: August 2009

Prediction and prevention of musculo-skeletal injuries is an important aspect of preventive health science. Using as an example a human knee joint, this paper proposes a new coupled-loading-rate hypothesis, which states that a generic cause of any musculo-skeletal injury is a Euclidean jolt, or SE(3)-jolt, an impulsive loading that hits a joint in several coupled degrees-of-freedom simultaneously. Informally, it is a rate-of-change of joint acceleration in all six-degrees-of-freedom simultaneously, times the corresponding portion of the body mass. In the case of a human knee, this happens when most of the body mass is on one leg with a semi-flexed knee — and then, caused by some external shock, the knee suddenly "jerks"; this can happen in running, skiing, sports games (e.g., soccer, rugby) and various crashes/impacts. To show this formally, based on the previously defined covariant force law and its application to traumatic brain injury (Ref. 52), we formulate the coupled Newton–Euler dynamics of human joint motions and derive from it the corresponding coupled SE(3)-jolt dynamics of the joint in case. The SE(3)-jolt is the main cause of two forms of discontinuous joint injury: (i) mild rotational disclinations and (ii) severe translational dislocations. Both the joint disclinations and dislocations, as caused by the SE(3)-jolt, are described using the Cosserat multipolar viscoelastic continuum joint model.
SINGLE-MOLECULE DNA CONDUCTANCE IN WATER SOLUTIONS: ROLE OF EXPLICIT WATER–COUNTERION SHEATH AND CHEMICAL MODIFICATION OF NUCLEOBASES
Authors: STARIKOV E. B. , NGANOU C. , LEE K. H. , CUNIBERTI G. , WENZEL W.
Published: August 2009

Dependence of charge transmission through several conventional and extended DNA duplexes on the explicit presence of their water–counterion surrounding has been theoretically studied. We show here that: (a) the latter does not form specific charge transmission channels in addition to those available in DNA duplexes themselves; (b) chemically modifying DNA bases to extend their π-electronic systems does not significantly alter time-averaged charge transmission probability through DNA duplexes.
Mechanisms to conserve glucose in lactating women during a 42-h fast
Authors: Mohammad Mahmoud A. , Sunehag Agneta L. , Chacko Shaji K. , Pontius Amy S. , Maningat Patricia D. , Haymond Morey W.
Published: August 2009

Little is known about how lactating women accommodate for their increased glucose demands during fasting to avoid maternal hypoglycemia. The objective of this study was to determine whether lactating women conserve plasma glucose by reducing maternal glucose utilization by increasing utilization of FFA and ketone bodies and/or increasing gluconeogenesis and mammary gland hexoneogenesis. Six healthy exclusively breastfeeding women and six nonlactating controls were studied during 42 h of fasting and 6 h of refeeding. Glucose and protein kinetic parameters were measured using stable isotopes and GCMS and energy expenditure and substrate oxidation using indirect calorimetry. After 42 h of fasting, milk production decreased by 16% but remained within normal range. Glucose, insulin, and C-peptide concentrations decreased with the duration of fasting in both groups but were lower ( P < 0.05) in lactating women. Glucagon, FFA, and β-hydroxybutyrate concentrations increased with fasting time ( P < 0.001) and were higher ( P < 0.0001) in lactating women during both fasting and refeeding. During 42 h of fasting, gluconeogenesis was higher in lactating women compared with nonlactating controls (7.7 ± 0.4 vs. 6.5 ± 0.2 μmol·kg−1·min−1, P < 0.05), whereas glycogenolysis was suppressed to similar values (0.4 ± 0.1 vs. 0.9 ± 0.2 μmol·kg−1·min−1, respectively). Mammary hexoneogenesis did not increase with the duration of fasting. Carbohydrate oxidation was lower and fat and protein oxidations higher ( P < 0.05) in lactating women. In summary, lactating women are at risk for hypoglycemia if fasting is extended beyond 30 h. The extra glucose demands of extended fasting during lactation appear to be compensated by increasing gluconeogenesis associated with ketosis, decreasing carbohydrate oxidation, and increasing protein and FFA oxidations.
Postischemic inflammatory syndrome: a critical mechanism of progression in diabetic nephropathy
Authors: Kelly K. J. , Burford James L. , Dominguez Jesus H.
Published: August 2009

Diabetes is a major epidemic, and diabetic nephropathy is the most common cause of end-stage renal disease. Two critical components of diabetic nephropathy are persistent inflammation and chronic renal ischemia from widespread vasculopathy. Moreover, acute ischemic renal injury is common in diabetes, potentially causing chronic kidney disease or end-stage renal disease. Accordingly, we tested the hypothesis that acute renal ischemia accelerates nephropathy in diabetes by activating proinflammatory pathways. Lean and obese-diabetic ZS rats (F1 hybrids of spontaneously hypertensive heart failure and Zucker fatty diabetic rats) were subjected to bilateral renal ischemia or sham surgery before the onset of proteinuria. The postischemic state in rats with obesity-diabetes was characterized by progressive chronic renal failure, increased proteinuria, and renal expression of proinflammatory mediators. Leukocyte number in obese-diabetic rat kidney was markedly increased for months after ischemia. Intrarenal blood flow velocity was decreased after ischemia in lean control and obese-diabetic rats, although it recovered in lean rats. At 2 mo after ischemia, blood flow velocity decreased further in sham-surgery and postischemia obese-diabetic rats, so that RBC flow velocity was only 39% of control in the obese-diabetic rats after ischemia. In addition, microvascular density remained depressed at 2 mo in kidneys of obese-diabetic rats after ischemia. Abnormal microvascular permeability and increases in interstitial fibrosis and apoptotic renal cell death were also more pronounced after ischemia in obese-diabetic rats. These data support the hypothesis that acute renal ischemia in obesity-diabetes severely aggravates chronic inflammation and vasculopathy, creating a self-perpetuating postischemia inflammatory syndrome, which accelerates renal failure.
Inhibition ofCandida albicansby Fluvastatin Is Dependent on pH
Authors: Schmidt Martin , Dzogbeta Seli , Boyer Michael P.
Published: August 2009

The cholesterol-lowering drug fluvastatin (FS) has an inhibitory effect on the growth of the pathogenic yeastCandida albicansthat is dependent on the pH of the medium. At the low pH value of the vagina, FS is growth inhibitory at low and at high concentrations, while at intermediate concentrations (1–10 mM), it has no inhibitory effect. Examination of the effect of the common antifungal drug fluconazole in combination with FS demonstrates drug interactions in the low concentration range. Determination of intracellular stress and the activity of the FS target enzyme HMG-CoA reductase confirm our hypothesis that in the intermediate dose range adjustments to the sterol biosynthesis pathway can compensate for the action of FS. We conclude that the pH dependent uptake of FS across yeast membranes might make FS combination therapy an attractive possibility for treatment of vaginalC. albicansinfections.
50Hz Extremely Low Frequency Electromagnetic Fields Enhance Protein Carbonyl Groups Content in Cancer Cells: Effects on Proteasomal Systems
Authors: Eleuteri A. M. , Amici M. , Bonfili L. , Cecarini V. , Cuccioloni M. , Grimaldi S. , Giuliani L. , Angeletti M. , Fioretti E.
Published: August 2009

Electromagnetic fields are an assessed cause of prolonging free radicals lifespan. This study was carried out to investigate the influence of extremely low frequency electromagnetic fields on protein oxidation and on the 20S proteasome functionality, the complex responsible for the degradation of oxidized proteins. Caco 2 cells were exposed, for 24–72 hours, to 1 mT, 50 Hz electromagnetic fields. The treatment induced a time‐dependent increase both in cell growth and in protein oxidation, more evident in the presence of TPA, while no changes in cell viability were detected. Exposing the cells to 50 Hz electromagnetic fields caused a global activation of the 20S proteasome catalytic components, particularly evident at 72 hours exposure and in the presence of TPA. The finding that EGCG, a natural antioxidant compound, counteracted the field‐related pro‐oxidant effects demonstrates that the increased proteasome activity was due to an enhancement in intracellular free radicals.
A Nanoparticle System Specifically Designed to Deliver Short Interfering RNA Inhibits Tumor Growth In vivo
Authors: Yagi Nobuhiro , Manabe Ichiro , Tottori Tsuneaki , Ishihara Atsushi , Ogata Fusa , Kim Jong Heon , Nishimura Satoshi , Fujiu Katsuhito , Oishi Yumiko , Itaka Keiji , Kato Yasuki , Yamauchi Masahiro , Nagai Ryozo
Published: August 2009

Use of short interfering RNA (siRNA) is a promising new approach thought to have a strong potential to lead to rapid development of gene-oriented therapies. Here, we describe a newly developed, systemically injectable siRNA vehicle, the “wrapsome” (WS), which contains siRNA and a cationic lipofection complex in a core that is fully enveloped by a neutral lipid bilayer and hydrophilic polymers. WS protected siRNA from enzymatic digestion, providing a long half-life in the systemic circulation. Moreover, siRNA/WS leaked from blood vessels within tumors into the tumor tissue, where it accumulated and was subsequently transfected into the tumor cells. Because the transcription factor KLF5 is known to play a role in tumor angiogenesis, we designed KLF5-siRNA to test the antitumor activity of siRNA/WS. KLF5-siRNA/WS exhibited significant antitumor activity, although neither WS containing control scrambled-siRNA nor saline containing KLF5-siRNA affected tumor growth. KLF5-siRNA/WS inhibited Klf5 expression within tumors at both mRNA and protein levels, significantly reducing angiogenesis, and we detected no significant acute or long-term toxicity. Our findings support the idea that siRNA/WS can be used to knock down specific genes within tumors and thereby exert therapeutic effects against cancers. [Cancer Res 2009;69(16):6531–8]
Atopic Disease and Risk of Non–Hodgkin Lymphoma: An InterLymph Pooled Analysis
Authors: Vajdic Claire M. , Falster Michael O. , de Sanjose Silvia , Martínez-Maza Otoniel , Becker Nikolaus , Bracci Paige M. , Melbye Mads , Smedby Karin Ekström , Engels Eric A. , Turner Jennifer , Vineis Paolo , Costantini Adele Seniori , Holly Elizabeth A. , Kane Eleanor , Spinelli John J. , La Vecchia Carlo , Zheng Tongzhang , Chiu Brian C-H. , Maso Luigino Dal , Cocco Pierluigi , Maynadié Marc , Foretova Lenka , Staines Anthony , Brennan Paul , Davis Scott , Severson Richard , Cerhan James R. , Breen Elizabeth C. , Birmann Brenda , Cozen Wendy , Grulich Andrew E.
Published: August 2009

We performed a pooled analysis of data on atopic disease and risk of non–Hodgkin lymphoma (NHL) from 13 case-control studies, including 13,535 NHL cases and 16,388 controls. Self-reported atopic diseases diagnosed 2 years or more before NHL diagnosis (cases) or interview (controls) were analyzed. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were computed in two-stage random-effects or joint fixed-effects models, and adjusted for age, sex, and study center. When modeled individually, lifetime history of asthma, hay fever, specific allergy (excluding hay fever, asthma, and eczema), and food allergy were associated with a significant reduction in NHL risk, and there was no association for eczema. When each atopic condition was included in the same model, reduced NHL risk was only associated with a history of allergy (OR, 0.80; 95% CI, 0.68–0.94) and reduced B-cell NHL risk was associated with history of hay fever (OR, 0.85; 95% CI, 0.77–0.95) and allergy (OR, 0.84; 95% CI, 0.76–0.93). Significant reductions in B-cell NHL risk were also observed in individuals who were likely to be truly or highly atopic—those with hay fever, allergy, or asthma and at least one other atopic condition over their lifetime. The inverse associations were consistent for the diffuse large B-cell and follicular subtypes. Eczema was positively associated with lymphomas of the skin; misdiagnosis of lymphoma as eczema is likely, but progression of eczema to cutaneous lymphoma cannot be excluded. This pooled study shows evidence of a modest but consistent reduction in the risk of B-cell NHL associated with atopy. [Cancer Res 2009;69(16):6482–9]
A Loss-of-Function Polymorphism in the Propeptide Domain of the LOX Gene and Breast Cancer
Authors: Min Chengyin , Yu Ziyang , Kirsch Kathrin H. , Zhao Yingshe , Vora Siddharth R. , Trackman Philip C. , Spicer Douglas B. , Rosenberg Lynn , Palmer Julie R. , Sonenshein Gail E.
Published: August 2009

The lysyl oxidase (LOX) gene reverted Ras transformation of NIH 3T3 fibroblasts and tumor formation by gastric cancer cells, which frequently carry mutant RAS genes. The secreted lysyl oxidase proenzyme is processed to a propeptide (LOX-PP) and a functional enzyme (LOX). Unexpectedly, the tumor suppressor activity mapped to the LOX-PP domain, which inhibited tumor formation and the invasive phenotype of NF639 breast cancer cells driven by human epidermal growth factor receptor-2/neu, which signals via Ras. A single-nucleotide polymorphism, G473A (rs1800449), resulting in an Arg158Gln substitution in a highly conserved region within LOX-PP, occurs with an average 473A allele carrier frequency of 24.6% in the HapMap database, but was present in many breast cancer cell lines examined. Here, we show that the Arg-to-Gln substitution profoundly impairs the ability of LOX-PP to inhibit the invasive phenotype and tumor formation of NF639 cells in a xenograft model. LOX-PP Gln displayed attenuated ability to oppose the effects of LOX, which promoted a more invasive phenotype. In a case-control study of African American women, a potential association of the Gln-encoding A allele was seen with increased risk of estrogen receptor (ER)-α–negative invasive breast cancer in African American women. Consistently, LOX gene expression was higher in ER-negative versus ER-positive primary breast cancers, and LOX-PP Gln was unable to inhibit invasion by ER-negative cell lines. Thus, these findings identify for the first time genetic polymorphism as a mechanism of impaired tumor suppressor function of LOX-PP and suggest that it may play an etiologic role in ER-negative breast cancer. [Cancer Res 2009;69(16):6685–93]
Migratory and Antigen Presentation Functions of IFN-Producing Killer Dendritic Cells
Authors: Himoudi Nourredine , Yan Mengyong , Bouma Gerben , Morgenstern Daniel , Wallace Rebecca , Seddon Ben , Buddle Jo , Eddaoudi Ayad , Howe Steven J. , Cooper Nichola , Anderson John
Published: August 2009

The CD11cint B220+ NK1.1+ CD49+ subset of cells has recently been described as IFN-producing killer dendritic cells (IKDC), which share phenotypic and functional properties with both dendritic cells and natural killer cells. We have previously shown that IKDCs within murine bone marrow–derived DC preparations are essential for the antitumor activity of unpulsed DCs. Here we show that bone marrow–derived IKDCs (BM-IKDC) migrate in vivo into tumors and thence to tumor draining lymph nodes, where they highly express MHC class II and costimulatory molecules. In vitro, freshly isolated BM-IKDCs, fluorescence-activated cell sorted to homogeneity, have no intrinsic antigen presentation function unless cocultured with tumor target cells. On killing of target cells, they can cross-present antigens to stimulate antigen-primed CD8 T cells and can also present antigens to antigen-primed CD4 cells. In vivo, in mice lacking class I–restricted antigen-presenting cell function, robust proliferation of antigen-specific T cells is achieved after adoptive transfer of BM-IKDCs at an injection site distant to the tumor site. Therefore, BM-IKDCs are capable of cytotoxic killing of tumor targets and also of potent antigen presentation after encountering antigen in the context of a viable target cell. [Cancer Res 2009;69(16):6598–606]
Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL–Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
Authors: Jagani Zainab , Song Keli , Kutok Jeffery L. , Dewar M. Rajan , Melet Armelle , Santos Tanya , Grassian Alexandra , Ghaffari Saghi , Wu Catherine , Ren Ruibao , Rodin Heather Yeckes , Miller Kenneth , Khosravi-Far Roya
Published: August 2009

BCR-ABL plays an essential role in the pathogenesis of chronic myeloid leukemia (CML) and some cases of acute lymphocytic leukemia (ALL). Although ABL kinase inhibitors have shown great promise in the treatment of CML, the persistence of residual disease and the occurrence of resistance have prompted investigations into the molecular effectors of BCR-ABL. Here, we show that BCR-ABL stimulates the proteasome-dependent degradation of members of the forkhead family of tumor suppressors in vitro, in an in vivo animal model, and in samples from patients with BCR-ABL–positive CML or ALL. As several downstream mediators of BCR-ABL are regulated by the proteasome degradation pathway, we also show that inhibition of this pathway, using bortezomib, causes regression of CML-like disease. Bortezomib treatment led to inhibition of BCR-ABL–induced suppression of FoxO proteins and their proapoptotic targets, tumor necrosis factor–related apoptosis-inducing ligand and BIM, thereby providing novel insights into the molecular effects of proteasome inhibitor therapy. We additionally show sensitivity of imatinib-resistant BCR-ABL T315I cells to bortezomib. Our data delineate the involvement of FoxO proteins in BCR-ABL–induced evasion of apoptosis and provide evidence that bortezomib is a candidate therapeutic in the treatment of BCR-ABL–induced leukemia. [Cancer Res 2009;69(16):6546–55]
Tissue Selectivity in Multiple Endocrine Neoplasia Type 1-Associated Tumorigenesis
Authors: Gracanin Ana , Dreijerink Koen M. A. , van der Luijt Rob B. , Lips Cornelis J. M. , Höppener Jo W. M.
Published: August 2009

The phenotype of the multiple endocrine neoplasia type 1 (MEN1) syndrome cannot be explained solely by the expression pattern of the predisposing gene MEN1 and its encoded protein, menin. This review addresses putative factors determining MEN1-associated tissue-selective tumorigenesis. Menin's interaction with mixed-lineage leukemia protein-containing histone methyl transferase (MLL-HMT) complex mediates tissue-selective tumor-suppressing and tumor-promoting effects of menin, and as such could be decisive for the predisposition of individual tissues to MEN1-associated tumorigenesis. In tissues in which menin acts as a tumor suppressor, tumorigenesis could depend on the inability of such tissues to adequately compensate for MEN1 gene loss, whereas the variable clinical presentation of MEN1 in individual patients could be a reflection of additional epigenetic factors and/or modifier genes. Further research on this topic may facilitate development of novel therapeutic strategies that could prevent or delay the onset of MEN1-associated tumorigenesis. [Cancer Res 2009;69(16):6371–4]
Functional Restoration of BRCA2 Protein by SecondaryBRCA2Mutations inBRCA2-Mutated Ovarian Carcinoma
Authors: Sakai Wataru , Swisher Elizabeth M. , Jacquemont Céline , Chandramohan Kurapaty Venkatapoorna , Couch Fergus J. , Langdon Simon P. , Wurz Kaitlyn , Higgins Jake , Villegas Emily , Taniguchi Toshiyasu
Published: August 2009

Acquired platinum resistance is a serious problem in the treatment of ovarian carcinomas. However, the mechanism of the drug resistance has not been elucidated. Here, we show functional significance of restoration of BRCA2 protein by secondary BRCA2 mutations in acquired drug resistance of BRCA2-mutated ovarian carcinoma. Three ovarian cancer cell lines (PEO1, PEO4, and PEO6) were derived from a BRCA2 mutation [5193C>G (Y1655X)] carrier with ovarian carcinoma with acquired cisplatin resistance and a secondary BRCA2 mutation [5193C>T (Y1655Y)] that canceled the inherited mutation. PEO1 was BRCA2 deficient and sensitive to cisplatin and a poly(ADP-ribose) polymerase inhibitor, AG14361, whereas PEO4 was resistant. PEO4 and PEO6, derived from ascites at the time of relapse with cisplatin resistance, had the secondary mutation and were BRCA2 proficient. In vitro cisplatin/AG14361 selection of PEO1 led to restoration of BRCA2 due to another secondary BRCA2 mutation. BRCA2 depletion sensitized BRCA2-restored PEO1 clones and PEO4 to cisplatin/AG14361. Thus, restoration of BRCA2 due to secondary BRCA2 mutation is involved in acquired drug resistance of BRCA2-mutated ovarian carcinoma. [Cancer Res 2009;69(16):6381–6]
Up-regulation of miR-200 and let-7 by Natural Agents Leads to the Reversal of Epithelial-to-Mesenchymal Transition in Gemcitabine-Resistant Pancreatic Cancer Cells
Authors: Li Yiwei , VandenBoom Timothy G. , Kong Dejuan , Wang Zhiwei , Ali Shadan , Philip Philip A. , Sarkar Fazlul H.
Published: August 2009

Pancreatic cancer is the fourth most common cause of cancer death in the United States, and the aggressiveness of pancreatic cancer is in part due to its intrinsic and extrinsic drug resistance characteristics, which are also associated with the acquisition of epithelial-to-mesenchymal transition (EMT). Emerging evidence also suggests that the processes of EMT are regulated by the expression status of many microRNAs (miRNA), which are believed to function as key regulators of various biological and pathologic processes during tumor development and progression. In the present study, we compared the expression of miRNAs between gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells and investigated whether the treatment of cells with “natural agents” [3,3′-diindolylmethane (DIM) or isoflavone] could affect the expression of miRNAs. We found that the expression of miR-200b, miR-200c, let-7b, let-7c, let-7d, and let-7e was significantly down-regulated in gemcitabine-resistant cells, which showed EMT characteristics such as elongated fibroblastoid morphology, lower expression of epithelial marker E-cadherin, and higher expression of mesenchymal markers such as vimentin and ZEB1. Moreover, we found that reexpression of miR-200 by transfection studies or treatment of gemcitabine-resistant cells with either DIM or isoflavone resulted in the down-regulation of ZEB1, slug, and vimentin, which was consistent with morphologic reversal of EMT phenotype leading to epithelial morphology. These results provide experimental evidence, for the first time, that DIM and isoflavone could function as miRNA regulators leading to the reversal of EMT phenotype, which is likely to be important for designing novel therapies for pancreatic cancer. [Cancer Res 2009;69(16):6704–12]
Serum Insulin-like Growth Factor-I and Mammary Tumor Development inAd libitum–Fed, Chronic Calorie–Restricted, and Intermittent Calorie–Restricted MMTV-TGF-α Mice
Authors: Rogozina Olga P. , Bonorden Melissa J.L. , Grande Joseph P. , Cleary Margot P.
Published: August 2009

The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum insulin-like growth factor (IGF)-I levels and mammary tumor (MT) development was investigated. Ten-week-old MMTV-TGF-α female mice were assigned to ad libitum–fed (AL; AIN-93M diet), ICR [3-week 50% caloric restriction using AIN-93M-mod diet, 2× protein, fat, vitamins, and minerals followed by 3 weeks of daily 100% AL consumption of AIN-93M (∼75% of AL for each 6-week cycle)], and CCR (calorie and nutrient intake matched for each 6-week ICR cycle) groups. Half of the mice from each group were sacrificed at 79 (end of restriction) or 82 (end of refeeding) weeks of age. Serum was obtained at euthanasia and in cycles 1, 3, 5, 8, and 11. MT incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice. ICR-Restricted mice had significantly lower terminal serum IGF-I and IGF-I/IGF binding protein-3 (IGFBP-3) ratio than CCR, ICR-Refed, and AL mice. There were no differences in terminal IGFBP-3. Final body, internal, and mammary fat pad weights correlated positively with IGF-I and negatively with IGFBP-3. Few changes were found for protein expression of IGF-IRα and IGFBP-3 in mammary tissue and MTs. During the study, IGF-I levels of ICR-Restricted mice were reduced, whereas refeeding allowed partial recovery. For all groups, elevated IGF-I levels preceded MT detection, although not all values were significant versus mice without MTs. However, the specific role of IGF-I in the protective effect of calorie restriction remains to be determined. These results confirm that ICR prevents MT development to a greater extent than CCR.
Macronutrient Intake and Cancer: How Does Dietary Restriction Influence Tumor Growth and Why Should We Care?
Authors: Pollak Michael
Published: August 2009

This perspective on the report by Rogozina and colleagues (beginning on page 712 in this issue of the journal) reviews mechanisms that may underlie inhibitory effects of dietary restriction on tumor growth in the mouse mammary tumor virus transforming growth factor alpha (MMTV-TGF-alpha) breast cancer model and comments on the potential clinical relevance of these mechanisms. The inhibitory effect of caloric restriction on carcinogenesis and tumor growth in rodent models is a classic finding that is receiving increasing attention. In some experimental models, the magnitude of the effect is significant, rivaling what can be achieved by pharmacologic approaches to cancer prevention or treatment. Major challenges include defining the underlying mechanisms and determining the clinical relevance of laboratory models of caloric restriction.