bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Protective Agents on the Viability of Geotrichum candidum during Freeze‐Drying and Storage
Authors: Hamoudi Latifa , Goulet Jacques , Ratti Cristina
Published: February 2007

ABSTRACT:  The effect of 3 cryoprotective agents (trehalose, sucrose, and maltose) on the survival of concentrated cultures of Geotrichum candidum was studied. Initially, the effect of the carbohydrates at 9% and 23% concentrations or combined with skim milk (16%) was compared to the control (skim milk alone) immediately after freeze‐drying. Two freeze‐drying shelf temperatures, 25 °C and 35 °C, were investigated. Afterwards, the survival of G. candidum freeze‐dried with carbohydrates at 23% concentration (alone or combined with skim milk 16%) was studied during 12 wk of storage at 4 °C, in the darkness, under vacuum, and at 0% relative humidity. The glass transition temperature (Tg) of the dehydrated protective agents was measured by differential scanning calorimetry. The results showed that the survival after freeze‐drying was proportional to the concentration of the protective agents, with skim milk alone giving poor survival of G. candidum. However, when skim milk was combined with disaccharides, a clear improvement was noted. No general tendency of shelf temperature on the survival of G. candidum was noted immediately after freeze‐drying. However, changes in the viability were observed during storage. Glass transition temperature (Tg) of protective agents linked to their moisture may contribute to predict the stability of lyophilized G. candidum during freeze‐drying and storage.
Effect of Washing on Pesticide Residues in Olives
Authors: Guardia‐Rubio M. , Ayora‐Cañada M.J. , Ruiz‐Medina A.
Published: February 2007

ABSTRACT:  The present work aims at contributing to the knowledge of the fate of 5 pesticides in olives in order to evaluate how washing may affect the presence of these residues in this fruit (and consequently in olive oil). For this purpose, olives were sprayed with commercial formulations containing the active ingredients and a series of analyses were performed for 64 d by using gas chromatography with mass spectrometric detection. Selected pesticides, ranked by their importance, were diuron, terbuthylazine, simazine, α‐endosulfan, and β‐endosulfan. The pesticide fraction, which was not removable from olives by washing, increased with time after treatment until their degradation started at week 6. Washing performed 1 d after treatment was the most effective in reducing residues, especially for simazine. Consequently, the washing step performed in olive mills could be effective in removing those herbicide residues present in olives as a consequence of contact with contaminated soil for a short time. This happens when olives are dropped and harvested off the ground by means of brushes or suction equipment.
The Rheology of Colloidal and Noncolloidal Food Dispersions
Authors: Genovese D. B. , Lozano J. E. , Rao M. A.
Published: February 2007

ABSTRACT:  Rheological data on a food together with data on its composition and structure or microstructure should lead to understanding the interrelationships between them. A number of foods are dispersions of solids in liquids, liquids in liquids, or gas in liquids. The dispersed particles may be colloidal in nature with dimensions < 10 μm, or larger noncolloidal particles (> 10 μm). For both colloidal and noncolloidal dispersions (either in dilute or concentrated regimes), several theoretical equations exist that provide insights into the role of key rheological parameters, such as particle volume fraction and size, interparticle forces, and fractal dimension on their viscosity, yield stress, and modulus. When theoretical models cannot be easily applied to foods with complex structures, structural analysis and structure‐based models provide insight into the role of solids loading and interparticle bonding on rheological behavior. In this review, recent studies on colloidal and noncolloidal food dispersions in which theoretical models as well as structural analysis were employed are discussed.
Dietary fat stimulates endogenous enkephalin and dynorphin in the paraventricular nucleus: role of circulating triglycerides
Authors: Chang G.-Q. , Karatayev O. , Ahsan R. , Gaysinskaya V. , Marwil Z. , Leibowitz S. F.
Published: February 2007

The opioid peptides enkephalin (ENK) and dynorphin (DYN), when injected into the hypothalamus, are known to stimulate feeding behavior and preferentially increase the ingestion of a high-fat diet. Studies of another peptide, galanin (GAL), with similar effects on feeding demonstrate that a high-fat diet, in turn, can stimulate the expression of this peptide in the hypothalamus. The present study tested different diets and variable periods of high- vs. low-fat diet consumption to determine whether the opioid peptides respond in a similar manner as GAL. In six experiments, the effects of dietary fat on ENK and DYN were examined in three hypothalamic areas: the paraventricular nucleus (PVN), perifornical hypothalamus (PFH), and arcuate nucleus (ARC). The results demonstrated that the ingestion of a high-fat diet increases gene expression and peptide levels of both ENK and DYN in the hypothalamus. The strongest and most consistent effect is seen in the PVN. In this nucleus, ENK and DYN are increased by 50–100% after 1 wk, 1 day, 60 min, and even 15 min of high-fat diet consumption. While showing some effect in the PFH, these peptides in the ARC are considerably less responsive, exhibiting no change in response to the briefer periods of diet intake. This effect of dietary fat on PVN opioids can be observed with diets equal in caloric density and palatability and without a change in caloric intake, body weight, fat pad weight, or levels of insulin or leptin. The data reveal a strong and consistent association between these peptides and a rise in circulating levels of triglycerides, supporting a role for these lipids in the fat-induced stimulation of opioid peptides in the PVN, similar to GAL.
Photochemical Characterization and Photocatalytic Properties of a Nanostructure CompositeTiO2Film
Authors: Habibi Mohammad Hossein , Esfahani Mojtaba Nasr , Egerton Terry A.
Published: February 2007

An efficient and new composite titania film photocatalyst was fabricated by sol-gel technique, using precalcined nanopowder titanium dioxide filler mixed with a sol, spin coating, and heat treatment. The structural and photocatalytic properties of these films were characterized using SEM, XRD, and UV/Vis spectroscopies. Problems of film inhomogenity and defects which caused peeling and cracking during calcination because of film shrinkage were overcome by using methylcellulose (MC) as a dispersant. Composite films heat-treated at approximately500∘C have the greatest hardness values. Surface morphology of composite deposits by scanning electron microscopy (SEM) showed that the composite films have much rougher surface than films made without MC. Photocatalytic activities of the composites film were evaluated through the degradation of three commercial diazo textile dyes, Light Yellow X6G (C.I. Reactive Yellow 2), Solophenyl red 3BL (C.I. Direct 80), and Tertrodirect light blue R (C.I. Direct blue 71) as a model pollutant.
A 3D Smale Horseshoe in a Hyperchaotic Discrete-Time System
Authors: Li Qingdu , Yang Xiao-Song
Published: February 2007

This paper presents a three-dimensional topological horseshoe in the hyperchaotic generalized Hénon map. It looks like a planar Smale horseshoe with an additional vertical expansion, so we call it 3D Smale horseshoe. In this way, a computer assisted verification of existence of hyperchaos is provided by means of interval analysis.
On Global Periodicity of a Class of Difference Equations
Authors: Stevic Stevo
Published: February 2007

We show that the difference equationxn=f3(xn−1)f2(xn−2)f1(xn−3),n∈ℕ0, wherefi∈C[(0,∞),(0,∞)],i∈{1,2,3}, is periodic with period 4 if and only iffi(x)=ci/xfor some positive constantsci, i∈{1,2,3}or iffi(x)=ci/xwheni=2andfi(x)=cixifi∈{1,3}, withc1c2c3=1. Also, we prove that the difference equationxn=f4(xn−1)f3(xn−2)f2(xn−3)f1(xn−4),n∈ℕ0, wherefi∈C[(0,∞),(0,∞)], i∈{1,2,3,4}, is periodic with period 5 if and only iffi(x)=ci/x, for some positive constantsci, i∈{1,2,3,4}.
Buffer Overflow Period in a MAP Queue
Authors: Chydzinski Andrzej
Published: February 2007

The buffer overflow period in a queue with Markovian arrival process (MAP) and general service time distribution is investigated. The results include distribution of the overflow period in transient and stationary regimes and the distribution of the number of cells lost during the overflow interval. All theorems are illustrated via numerical calculations.
Frequency of Cancer Genes on the Chicken Z Chromosome and Its Human Homologues: Implications for Sex Chromosome Evolution
Authors: Stiglec Rami , Kohn Matthias , Fong James , Ezaz Tariq , Hameister Horst , Marshall Graves Jennifer A.
Published: February 2007

It has been suggested that there are special evolutionary forces that act on sex chromosomes. Hemizygosity of the X chromosome in male mammals has led to selection for male-advantage genes, and against genes posing extreme risks of tumor development. A similar bias against cancer genes should also apply to the Z chromosome that is present as a single copy in female birds. Using comparative database analysis, we found that there was no significant underrepresentation of cancer genes on the chicken Z, nor on the Z-orthologous regions of human chromosomes 5 and 9. This result does not support the hypothesis that genes involved in cancer are selected against on the sex chromosomes.
Laws of Large Numbers for Asymmetrical Cauchy Random Variables
Authors: Adler André
Published: February 2007

We generalize the Cauchy distribution so that we can have asymmetrical
tails. This allows us to obtain unusual laws of large numbers involving weighted sums of these random variables. Unusual in the sense that even though in every case E|X|=∞, we can still obtain a nonzero limit for these weighted sums.
Antioxidant Mechanism is Involved in the Gastroprotective Effects of Ozonized Sunflower Oil in Ethanol-Induced Ulcers in Rats
Authors: Zamora Rodríguez Zullyt B. , González Álvarez Ricardo , Guanche Dailén , Merino Nelson , Hernández Rosales Frank , Menéndez Cepero Silvia , Alonso González Yaima , Schulz Siegfried
Published: February 2007

This research was performed in order to determine the potential protective effects of ozonized sunflower oil (OSO) in the injury of rat gastric mucosa induced by absolute ethanol and as well as to elucidate the role of reactive oxygen species (ROS), lipid peroxidation, and some important constituents of antioxidant defense such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in these effects. OSO was administered to rats intragastrically by a cannula and it was applied during four days to animals. The doses of OSO administered daily to each group of rats were 4, 12, and 24 mg/kg, respectively, and one hour after the last treatment, absolute ethanol (1 mL/200 mg body weight) was administered. Our results showed that gastric ulcer index was significantly reduced in rats pretreated with OSO as compared with ethanol-treated controls. However, in rats pretreated with OSO, no significant reduction of TBARS content in gastric mucosa was found as compared to those rats treated with ethanol alone. In contrast, SOD and GSH-Px activities were significantly increased in gastric mucosa of OSO-pretreated rats with respect to those treated with ethanol alone. In summary, our results demonstrate that OSO pretreatment exerts protective effects in ethanol-induced gastric ulcers in rats. Furthermore, these results provide evidence that these protective effects of OSO are mediated at least partially by stimulation of some important antioxidant enzymes such as SOD and GSH-Px, which are scavengers of ROS and therefore prevent gastric injury induced by them.
Hereditary Portfolio Optimization with Taxes and Fixed Plus
Proportional Transaction Costs—Part I
Authors: Chang Mou-Hsiung
Published: February 2007

This is the first of the two companion papers which treat an
infinite time horizon hereditary portfolio optimization problem in a market
that consists of one savings account and one stock account. Within the solvency region, the investor is allowed to consume from the savings account and can make transactions between the two assets subject to paying capital gain taxes as well as a fixed plus proportional transaction cost. The investor is to seek an optimal consumption-trading strategy in order to maximize the expected utility from the total discounted consumption.
The portfolio optimization problem is formulated as an infinite dimensional
stochastic classical-impulse control problem. The quasi-variational HJB inequality
(QVHJBI) for the value function is derived in this paper. The second paper contains the verification theorem for the optimal strategy. It is also shown there that the value function is a viscosity solution of the QVHJBI.
The Level of hs-CRP in Coronary Artery Ectasia and Its Response to Statin and Angiotensin-Converting Enzyme Inhibitor Treatment
Authors: Ozbay Yilmaz , Akbulut Mehmet , Balin Mehmet , Kayancicek Hidayet , Baydas Adil , Korkmaz Hasan
Published: February 2007

Background/Aim. Coronary artery ectasia (CAE) was thought of as a variant of atherosclerosis. C-reactive protein (CRP) which is among the most sensitive markers of systemic inflammation, and elevation of systemic and local levels of this inflammatory marker which has been associated with an increased risk for cardiovascular disease in the obstructive coronary artery disease (O-CAD) are well known, but little was known in CAE. The anti-inflammatory effects of statins and the effect of angiotensin-converting enzyme (ACE) inhibitors on endothelial dysfunction are well established in atherosclerosis. The aim of the present study was to investigate CRP level and its response to statin and ACE inhibitor treatment in CAE.Materials and method. We measured serum hs-CRP level in 40 CAE (26 males, mean age:56.32±9years) and 41 O-CAD (34 males, mean age:57.19±10years) patients referred for elective coronary angiography at baseline and after 3-month statin and ACE inhibitor treatment.Results. Plasma hs-CRP levels were significantly higher in CAE group than O-CAD group at baseline (2.68±66mg/L versus1,64±64, resp.,P<.0001). Plasma hs-CRP levels significantly decreased from baseline 3 months later in the CE (from2.68±0.66mg/L to1.2±0.53mg/L,P<.0001) as well as in the O-CAD group (from1.64±0.64mg/L to1.01±0.56mg/L, P<.001).Conclusion. We think that hs-CRP measurement may be a good prognostic value in CAE patients as in stenotic ones. Further placebo-controlled studies are needed to evaluate the clinical significance of this decrease in hs-CRP.
Erratum to: Mann Iteration Converges Faster than Ishikawa Iteration for the Class of Zamfirescu Operators
Authors: Babu GVR , Vara Prasad KNVV
Published: February 2007

The aim of this erratum is to make necessary corrections in the proof of Theorem 2.1 of Babu and Prasad (2006).
Reactions Between Chalcogen Donors and Dihalogens/Interalogens: Typology of Products and Their Characterization by FT‐Raman Spectroscopy
Authors: Arca Massimiliano , Aragoni M. Carla , Devillanova Francesco A. , Garau Alessandra , Isaia Francesco , Lippolis Vito , Mancini Annalisa , Verani Gaetano
Published: February 2007

The chemical bond and structural features for the most important classes of solid products obtained by reacting chalcogen donors with dihalogens and interhalogens are reviewed. Particular attention is paid to the information the FT‐Raman spectroscopy can confidently give about each structural motif considered in the absence of X‐ray structural analyses.
Protective Effect of Meso‐Tetrakis‐(3,5‐di‐tert‐ butyl‐4‐hydroxyphenyl)porphyrin on the In Vivo Impact of Trimethyltin Chloride on the Antioxidative Defense System
Authors: Milaeva Elena R. , Tyurin Vladimir Yu. , Gracheva Yulia A. , Dodochova Margarita A. , Pustovalova Lydia M. , Chernyshev Victor N.
Published: February 2007

The in vivo effect of trimethyltin chloride (Me3SnCl), free base meso‐tetrakis(3,5‐di‐tert‐butyl‐4‐hydroxyphenyl)porphyrin
() and their equimolar mixture, on the enzymatic activity of catalase (CAT), superoxide dismutase (SOD), and on the total content of free sulfhydryl groups has been studied in rat liver and kidney. It was demonstrated that the simultaneous treatment of tested animals with the combination of
Me3SnCl and
reduced the toxic impact of
Me3SnCl.
Subordination by convex functions
Authors: Ali Rosihan M. , Ravichandran V. , Seenivasagan N.
Published: February 2007

For a fixed analytic function defined on the open unit disk and γ < 1, let Tg(γ) denote the class of all analytic functions satisfying . For functions in Tg(γ), a subordination result is derived involving the convolution with a normalized convex function. Our result includes as special cases several earlier works.
On Eulerian equilibria in K‐order approximation of the gyrostat in the three‐body problem
Authors: Vera J. A. , Vigueras A.
Published: February 2007

We consider the noncanonical Hamiltonian dynamics of a gyrostat in the three‐body problem. By means of geometric‐mechanics methods we study the approximate Poisson dynamics that arises when we develop the potential in series of Legendre and truncate this in an arbitrary order k. Working in the reduced problem, the existence and number of equilibria, that we denominate of Euler type in analogy with classic results on the topic, are considered. Necessary and sufficient conditions for their existence in an approximate dynamics of order k are obtained and we give explicit expressions of these equilibria, useful for the later study of the stability of the same ones. A complete study of the number of Eulerian equilibria is made in approximate dynamics of orders zero and one. We obtain
the main result of this work, the number of Eulerian equilibria in an approximate dynamics of order k for k ≥ 1 is independent of the order of truncation of the potential if the gyrostat S0 is close to the sphere. The instability of Eulerian equilibria is proven for any approximate dynamics if the gyrostat is close to the sphere. In this way, we generalize the classical results on equilibria of the three‐body problem and many of those obtained by other authors using more classic techniques for the case of rigid bodies.
J‐aggregates of amphiphilic cyanine dyes: Self‐organization of artificial light harvesting complexes
Authors: Kirstein Stefan , Daehne Siegfried
Published: February 2007

The simultaneous chemical linkage of cyanine dye chromophores with both hydrophobic and hydrophilic substituents leads to a new type of amphiphilic molecules with the ability of spontaneous self‐organization into highly ordered aggregates of various structures and morphologies. These aggregates carry the outstanding optical properties of J‐aggregates, namely, efficient exciton coupling and fast exciton energy migration, which are essential for the build up of artificial light harvesting systems. The morphology of the aggregates depends sensitively on the molecular structure of the chemical substituents of the dye chromophore. Accordingly, lamellar ribbon‐like structures, vesicles , tubes, and bundles of tubes are found depending on the dyes and the structure can further be altered by addition of surfactants, alcohols, or other additives. Altogether the tubular structure is the most noticeable structural motif of these types of J‐aggregates. The optical spectra are characterized in general by a complex exciton spectrum which is composed of several electronic transitions. The spectrum is red‐shifted as a total with respect to the monomer absorption and exhibits resonance fluorescence from the lowest energy transition. For the tubular structures, the optical spectra can be related to a structural model. Although the molecules itself are strictly achiral, a pronounced circular dichroism (CD) is observed for the tubular aggregates and explained by unequal distribution of left‐ and right‐handed helicity of the tubes. Photo‐induced electron transfer (PET) reactions from the dye aggregates to electron acceptor molecules lead to superquenching which proves the delocalization of the excitation. This property is used to synthesize metal nanoparticles on the aggregate surface by photo‐induced reduction of metal ions.
Preparation and Properties of Polyester‐Based Nanocomposite Gel Coat System
Authors: Jawahar P. , Balasubramanian M.
Published: February 2007

Nanocomposite gel coat system is prepared using unsaturated polyester resin with aerosil powder, CaCO3, and organoclay. The influence of organoclay addition on mechanical and water barrier properties of gel coat system is studied for different amount (1, 2, and 3 wt %) of organoclay. The nanolevel incorporation of organoclay improves the mechanical and water barrier properties of nanocomposite gel coat system. The nanocomposite gel coat system exhibits 55% improvement in tensile modulus and 25% improvement in flexural modulus. There is a 30% improvement in impact property of nanocomposite gel coat system. The dynamic mechanical analysis shows a slight increase in glass transition temperature for nanocomposite gel coat system.
Study on the Effect of Nano‐SiO2 in ULSI Silicon Substrate Chemical Mechanical Polishing Process
Authors: Yuling Liu , Juan Wang , Ming Sun , Chenglin Liu
Published: February 2007

Both process and mechanical of silicon substrate chemical mechanical polishing (CMP) are studied in detail, and the effects of experiments designed indicate that nano‐SiO2 grinding particles seem to be acted as catalyzer besides the grinding action during the CMP process. This is different from the traditional function. As a result, in the condition of low pH, the nano‐SiO2 slurry can be recycled. In the meanwhile, the removal rate can gain stability and pH value does not change obviously.
Control Effect of Nanometer SiO2 Hydrosol on Alloy Impurity in CMP Process of ULSI
Authors: Yuling Liu , Weiwei Li , Xihui Zhang , Changyu Liu
Published: February 2007

This article analyzed and studied the concentration mechanism of metal impurities of ULSI multilayered wiring CMP in the special‐purpose nanometer SiO2grinding compound in the substrate chip surface and the process of purification with chelating agent; we also obtained the remarkable effect and the effective application in the microelectron component preparation.
Photocatalytic Oxidation of a Volatile Organic Component of Acetaldehyde Using Titanium Oxide Nanotubes
Authors: Xu Huifang , Vanamu Ganesh , Nie Ziming , Konishi Hiromi , Yeredla Rakesh , Phillips Jonathan , Wang Yifeng
Published: February 2007

Titanium oxide nanotubes are prepared and treated with Au (Au/nanotube sample) and Pt (Pt/nanotube sample), and the photoactivity of these catalysts compared to a standard Degussa P25 photocatalyst is investigated. The samples were analyzed using X‐ray diffraction, field emission gun scanning transmission electron microscopy (STEM). Both high‐resolution TEM images and high‐angle annular dark‐field (HAAD) images were recorded for the specimens. Oxidation of acetaldehyde was used to test the efficiency of the catalysts. Nanotube samples showed better photoactivity than the standard P25, because the P25 titania deactivates quickly. Enhanced reactivity of the nanotube is related to surface charge polarity developed on outer and inner surfaces due to the difference in overlap of oxygen anions that resulted from curving of octahedral sheets. A tentative and qualitative surface polarity model is proposed for enhancing electron‐hole pair separation. The inner surface benefits reduction; whereas, the outer surface benefits oxidation reactions. Both the metal identity and the size of the metal particles in the nanotubes affected the photocatalytic activity. Specifically, the addition of platinum increased the activity significantly, and increased the total yield. The addition of gold had lesser impact compared to the platinum. Formation of Pt large nanoparticles on the nanotube surfaces reduces the oxidation reactivity.
Starting solutions for some simple oscillating motions ofsecond‐grade fluids
Authors: Fetecau C. , Fetecau Corina
Published: February 2007

The exact starting solutions corresponding to the motions of a second‐grade fluid, due to the cosine and sine oscillations of an infinite edge and of an infinite duct of rectangular cross‐section as well as those induced by an oscillating pressure gradient in such a duct, are determined by means of the double Fourier sine transforms. These solutions, presented as sum of the steady‐state and transient solutions, satisfy both the governing equations and all associate initial and boundary conditions. In the special case when α1 → 0, they reduce to those for a Navier‐Stokes fluid.
Transforming Growth Factor-β, Estrogen, and Progesterone Converge on the Regulation of p27Kip1 in the Normal and Malignant Endometrium
Authors: Lecanda Jon , Parekh Trilok V. , Gama Patricia , Lin Ke , Liarski Vladimir , Uretsky Seth , Mittal Khush , Gold Leslie I.
Published: February 2007

Hormones and growth factors regulate endometrial cell growth. Disrupted transforming growth factor-β (TGF-β) signaling in primary endometrial carcinoma (ECA) cells leads to loss of TGF-β–mediated growth inhibition, which we show herein results in lack of up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 (p27) to arrest cells in G1 phase of the cell cycle. Conversely, in normal primary endometrial epithelial cells (EECs), TGF-β induces a dose-dependent increase in p27 protein, with a total 3.6-fold maximal increase at 100 pmol/L TGF-β, which was 2-fold higher in the nuclear fraction; mRNA levels were unaffected. In addition, ECA tissue lysates show a high rate of ubiquitin-mediated degradation of p27 compared with normal secretory-phase endometrial tissue (SE) such that 4% and 89% of recombinant p27 added to the lysates remains after 3 and 20 h, respectively. These results are reflected in vivo as ECA tissue lacks p27 compared with high expression of p27 in SE (P ≤ 0.001). Furthermore, we show that estrogen treatment of EECs causes mitogen-activated protein kinase–driven proteasomal degradation of p27 whereas progesterone induces a marked increase in p27 in both normal EECs and ECA cells. Therefore, these data suggest that TGF-β induces accumulation of p27 for normal growth regulation of EECs. However, in ECA, in addition to enhanced proteasomal degradation of p27, TGF-β cannot induce p27 levels due to dysregulated TGF-β signaling, thereby causing 17β-estradiol–driven p27 degradation to proceed unchecked for cell cycle progression. Thus, p27 may be a central target for growth regulation of normal endometrium and in the pathogenesis of ECA. [Cancer Res 2007;67(3):1007–18]
Long-term Treatment with Tamoxifen Facilitates Translocation of Estrogen Receptor α out of the Nucleus and Enhances its Interaction with EGFR in MCF-7 Breast Cancer Cells
Authors: Fan Ping , Wang Jiping , Santen Richard J. , Yue Wei
Published: February 2007

The therapeutic benefit of tamoxifen in patients with hormone-dependent breast cancer is limited by acquired resistance to this drug. To investigate the biological alterations responsible for tamoxifen resistance, an in vitro model was established. After 6-month continuous exposure to tamoxifen (10−7 mol/L), growth of MCF-7 breast cancer cells was no longer inhibited by this antiestrogen. Although there was no significant increase in the basal levels of activated mitogen-activated protein kinase (MAPK), tamoxifen-resistant (TAM-R) cells exhibited enhanced sensitivity to epidermal growth factor (EGF) and estradiol stimulated activation of MAPK. Tamoxifen elicited rapid phosphorylation of MAPK, in contrast to its antagonistic activity in control cells. Blockade of the EGF receptor (EGFR)/MAPK pathway caused more dramatic inhibition of growth of TAM-R cells than the control cells. An increased amount of estrogen receptor α (ERα) was coimmunoprecipitated with EGFR from TAM-R cells although the total levels of these receptors were not increased. Notably, ERα seemed to redistribute to extranuclear sites in TAM-R cells. Increased ERα immunoreactivity in the cytoplasm and plasma membrane of TAM-R cells was shown by fluorescent microscopy and by Western analysis of isolated cellular fractions. In TAM-R cells, an increased amount of c-Src was coprecipitated with EGFR or ERα. Blockade of c-Src activity resulted in redistribution of ERα back to the nucleus and in reduction of its interaction with EGFR. Prolonged blockade of c-Src activity restored sensitivity of TAM-R cells to tamoxifen. Our results suggest that enhanced nongenomic function of ERα via cooperation with the EGFR pathway is one of the mechanisms responsible for acquired tamoxifen resistance. [Cancer Res 2007;67(3):1352–60]
Genetic Variation in Base Excision Repair Genes and the Prevalence of Advanced Colorectal Adenoma
Authors: Berndt Sonja I. , Huang Wen-Yi , Fallin M. Daniele , Helzlsouer Kathy J. , Platz Elizabeth A. , Weissfeld Joel L. , Church Timothy R. , Welch Robert , Chanock Stephen J. , Hayes Richard B.
Published: February 2007

Base excision repair (BER) corrects DNA damage caused by oxidative stress and low folate intake, which are putative risk factors for colorectal neoplasia. To examine the relationship between genetic variation in BER genes and colorectal adenoma risk, we conducted a case-control study of 767 cases of advanced colorectal adenoma and 773 controls from the baseline screening exam of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases included participants diagnosed with advanced left-sided adenoma, and controls were subjects without evidence of a left-sided polyp by sigmoidoscopy, frequency-matched to cases on race and gender. Twenty single nucleotide polymorphisms were genotyped in four BER genes (APEX1, PARP1, POLB, and XRCC1), and conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association with colorectal adenoma. Two variants with possible functional significance were associated with risk. The APEX1 51H variant was associated with a borderline significant decreased risk of colorectal adenoma (OR, 0.66; 95% CI, 0.44–1.00), and the XRCC1 399Q variant was inversely associated with risk among Caucasians (OR, 0.80; 95% CI, 0.64–0.99). Homozygotes at two PARP1 loci (A284A and IVS13+118G>A) were also associated with a decreased risk of colorectal adenoma compared with wild-type carriers (OR, 0.70; 95% CI, 0.49–0.98 for both), which was restricted to advanced adenomas displaying histologically aggressive characteristics (OR, 0.51; 95% CI, 0.33–0.78, P = 0.002 for PARP1 A284A). This study suggests that polymorphisms in APEX1, XRCC1, and PARP1 may be associated with advanced colorectal adenoma. [Cancer Res 2007;67(3):1395–404]
p53 Short Peptide (p53pep164) Regulates Lipopolysaccharide-Induced Tumor Necrosis Factor-α Factor/Cytokine Expression
Authors: Tang Xiaoren , Molina Manuel , Amar Salomon
Published: February 2007

The p53 protein is a sequence-specific DNA-binding factor that can induce apoptosis or activate genes whose dysregulation is involved in cancer. By using serial analysis of gene expression technique, p53-induced genes (PIGs) have been identified, one of which was lipopolysaccharide (LPS)–induced tumor necrosis factor-α (TNF-α) factor (LITAF/PIG7). LITAF regulates the transcription of cytokines such as TNF-α. To further elucidate the role of p53 in LITAF expression, LITAF promoter activity was carefully dissected. In this study, we found that the element required for transcriptional activity is mainly located in the region from −990 to −500 of the LITAF promoter; the specific site required for p53 protein-DNA binding is located between −550 and −500. We also found that transient transfection of either a p53 short DNA sequence, called p53LFB12, or its corresponding 7-amino-acid synthetic peptide from amino acids 164 to 170 (K164Q165S166Q167H168M169T170), named p53pep164, significantly reduced LITAF promoter activity to 15% in p53-null H1299 cells. Transfection of p53pep164 into H1299 cells significantly down-regulated LPS-induced LITAF expression as well. Furthermore, transfection of p53pep164 into human monocytes resulted in down-regulation of nine proinflammatory cytokines, including TNF-α. We also found that the LPS-activated p53 is a short-lived protein, and that p53-orchestrated apoptosis occurs shortly after the initiation stage following LPS stimulation and lasts a short time. Once p53 levels return to baseline, the p53-mediated inhibition of LITAF is released, and LITAF-mediated cytokine production can proceed. The present finding proposes a novel link between p53 and the inflammatory processes and highlights potential interventional approaches to control p53-associated inflammatory processes. [Cancer Res 2007;67(3):1308–16]
Prevention of Mantle Lymphoma Tumor Establishment by Routing Transferrin Receptor toward Lysosomal Compartments
Authors: Lepelletier Yves , Camara-Clayette Valérie , Jin Hulin , Hermant Aurélie , Coulon Séverine , Dussiot Michaël , Arcos-Fajardo Michelle , Baude Cédric , Canionni Danielle , Delarue Richard , Brousse Nicole , Benaroch Philippe , Benhamou Marc , Ribrag Vincent , Monteiro Renato C. , Moura Ivan C. , Hermine Olivier
Published: February 2007

Mantle cell lymphoma (MCL) is one of the most frequent of the newly recognized non-Hodgkin's lymphomas. The major problem of MCL therapy is the occurrence of relapse and subsequent resistance to chemotherapy and immunotherapy in virtually all cases. Here, we show that one injection of anti-human transferrin receptor (TfR) monoclonal antibody A24 totally prevented xenografted MCL tumor establishment in nude mice. It also delayed and inhibited tumor progression of established tumors, prolonging mice survival. In vitro, A24 induced up to 85% reduction of MCL cell proliferation (IC50 = 3.75 nmol/L) independently of antibody aggregation, complement-dependent or antibody-dependent cell-mediated cytotoxicity. A24 induced MCL cell apoptosis through caspase-3 and caspase-9 activation, either alone or synergistically with chemotherapeutic agents. A24 induced TfR endocytosis via the clathrin adaptor protein-2 complex pathway followed by transport to lysosomal compartments. Therefore, A24-based therapies alone or in association with classic chemotherapies could provide a new alternative strategy against MCL, particularly in relapsing cases. [Cancer Res 2007;67(3):1145–54]
p53 Enhances Gefitinib-Induced Growth Inhibition and Apoptosis by Regulation of Fas in Non–Small Cell Lung Cancer
Authors: Rho Jin Kyung , Choi Yun Jung , Ryoo Baek-Yeol , Na Im II , Yang Sung Hyun , Kim Cheol Hyeon , Lee Jae Cheol
Published: February 2007

Treatment with gefitinib, a specific inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK), has resulted in dramatic responses in some patients with non–small cell lung cancer (NSCLC). Most patients who respond to gefitinib have EGFR-TK mutations; however, >10% of patients with EGFR-TK mutations do not respond. Similarly, some patients without EGFR-TK mutations respond to this drug, suggesting that other factors determine sensitivity to gefitinib. Aberrations of the tumor suppressor gene p53 are frequently associated with drug resistance. In this study, we investigated the role of p53 in growth-inhibitory and apoptotic effects of gefitinib in the human NSCLC cell lines NCI-H1299 and A549, which have no EGFR-TK mutations. NCI-H1299 cells, which had a p53-null genotype, were more resistant to gefitinib compared with A549 cells, which were wild-type p53 (IC50, 40 μmol/L in NCI-H1299 and 5 μmol/L in A549). Treatment of A549 with gefitinib resulted in the translocation of p53 from cytosol to nucleus and the up-regulation of Fas, which was localized to the plasma membrane. In the stable H1299 cell line with tetracycline-inducible p53 expression, induced p53 enhanced growth inhibition and apoptosis by gefitinib through the up-regulation of Fas and restoration of caspase activation. A caspase inhibitor, Z-VAD-fmk, reduced these effects. Conversely, inhibition of p53 using antisense oligonucleotide in A549 caused a significant decrease in apoptosis by gefitinib and down-regulation of Fas under the same conditions. In conclusion, p53 may play a role in determining gefitinib sensitivity by regulating Fas expression in NSCLC. [Cancer Res 2007;67(3):1163–9]
Lapatinib Antitumor Activity Is Not Dependent upon Phosphatase and Tensin Homologue Deleted on Chromosome 10 in ErbB2-Overexpressing Breast Cancers
Authors: Xia Wenle , Husain Intisar , Liu Leihua , Bacus Sarah , Saini Shermini , Spohn Janice , Pry Karen , Westlund Ron , Stein Steven H. , Spector Neil L.
Published: February 2007

Trastuzumab antitumor activity in ErbB2-overexpressing breast cancers seems to be dependent upon the presence of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphatase that dampens phosphatidylinositol 3-kinase-Akt signaling. Consequently, PTEN deficiency, which occurs in 50% of breast cancers, predicts for resistance to trastuzumab monotherapy. Here, we show that lapatinib, a small-molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, exerts its antitumor activity in a PTEN-independent manner. Steady-state phosphorylated ErbB2 (p-ErbB2) and p-Akt (S473) protein levels were inhibited within 30 min following lapatinib but not in response to trastuzumab in BT474 and Au565 cells (two ErbB2-overexpressing breast cancer cell lines that are sensitive to the proapoptotic effects of lapatinib). Whereas trastuzumab reportedly inhibits SRC phosphorylation (Y416), which in turn reduced SRC-ErbB2 protein interactions, lapatinib had no effect on either variable. To assess the potential functional role that PTEN might play in lapatinib antitumor activity, we selectively knocked down PTEN in BT474 and Au565 cells using small interfering RNA transfection. Loss of PTEN did not affect induction of tumor cell apoptosis by lapatinib in either cell line. In addition, lapatinib inhibited Akt phosphorylation in MDA-MB-468 cells, an ErbB1-expressing/ErbB2 non-overexpressing breast cancer line, despite their PTEN-null status. Moreover, patients with ErbB2-overexpressing inflammatory breast cancers responded to lapatinib monotherapy regardless of PTEN status. Thus, lapatinib seems to exert its antitumor activity in ErbB2-overexpressing breast cancers in a PTEN-independent manner. These data emphasize the importance of assessing PTEN status in tumors when selecting ErbB2-targeted therapies in patients with breast cancer. [Cancer Res 2007;67(3):1170–5]
Influence of Bcl-2 Family Members on the Cellular Response of Small-Cell Lung Cancer Cell Lines to ABT-737
Authors: Tahir Stephen K. , Yang Xiufen , Anderson Mark G. , Morgan-Lappe Susan E. , Sarthy Aparna V. , Chen Jun , Warner Robert B. , Ng Shi-Chung , Fesik Stephen W. , Elmore Steve W. , Rosenberg Saul H. , Tse Christin
Published: February 2007

ABT-737 is a novel and potent Bcl-2 antagonist with single-agent activity against small-cell lung cancer (SCLC) cell lines. Here, we evaluated the contribution of Bcl-2 family members to the in vitro cellular response of several SCLC cell lines to ABT-737. Relatively higher levels of Bcl-2, Bcl-XL, Bim and Noxa, and lower levels of Mcl-1 characterized naïve SCLC cell lines that were sensitive to ABT-737. Conversely, a progressive decrease in the relative levels of Bcl-2 and Noxa and a progressive increase in Mcl-1 levels characterized the increased resistance of H146 cells following chronic exposure to ABT-737. Knockdown of Mcl-1 with small interfering RNA sensitized two resistant SCLC cell lines H196 and DMS114 to ABT-737 by enhancing the induction of apoptosis. Likewise, up-regulation of Noxa sensitized H196 cells to ABT-737. Combination treatment with DNA-damaging agents was extremely synergistic with ABT-737 and was associated with the down-regulation of Mcl-1 and the up-regulation of Noxa, Puma, and Bim in H196 cells. Thus, SCLC cells sensitive to ABT-737 expressed the target proteins Bcl-2 and Bcl-XL, whereas Mcl-1 and factors regulating Mcl-1 function seem to contribute to the overall resistance of SCLC cells to ABT-737. Overall, these observations provide further insight as to the mechanistic bases for ABT-737 efficacy in SCLC and will be helpful for profiling patients and aiding in the rational design of combination therapies. [Cancer Res 2007;67(3):1176–83]
Colon Cancer Cell–Derived Tumor Necrosis Factor-α Mediates the Tumor Growth–Promoting Response in Macrophages by Up-regulating the Colony-Stimulating Factor-1 Pathway
Authors: Zins Karin , Abraham Dietmar , Sioud Mouldy , Aharinejad Seyedhossein
Published: February 2007

The interplay between malignant and stromal cells is essential in tumorigenesis. We have previously shown that colony-stimulating factor (CSF)-1, matrix metalloprotease (MMP)-2, and vascular endothelial growth factor (VEGF)-A production by stromal cells is enhanced by CSF-1–negative SW620 colon cancer cells. In the present study, the mechanisms by which colon cancer cells up-regulate host factors to promote tumorigenesis were investigated. Profiling of tumor cell cytokine expression in SW620 tumor xenografts in nude mice showed increased human tumor necrosis factor (TNF)-α mRNA expression with tumor growth. Incubation of macrophages with small interfering (si) RNAs directed against TNF-α or TNF-α–depleted SW620 cell conditioned medium versus SW620 cell conditioned medium failed to support mouse macrophage proliferation, migration, and expression of CSF-1, VEGF-A, and MMP-2 mRNAs. Consistent with these results, human TNF-α gene silencing decreased mouse macrophage TNF-α, CSF-1, MMP-2, and VEGF-A mRNA expression in macrophages cocultured with human cancer cells. In addition, inhibition of human TNF-α or mouse CSF-1 expression by siRNA reduced tumor growth in SW620 tumor xenografts in mice. These results suggest that colon cancer cell–derived TNF-α stimulates TNF-α and CSF-1 production by macrophages, and that CSF-1, in turn, induces macrophage VEGF-A and MMP-2 in an autocrine manner. Thus, interrupting tumor cell–macrophage communication by targeting TNF-α may provide an alternative therapeutic approach for the treatment of colon cancer. [Cancer Res 2007;67(3):1038–45]
Ku70 and Poly(ADP-Ribose) Polymerase-1 Competitively Regulate β-Catenin and T-Cell Factor-4–Mediated Gene Transactivation: Possible Linkage of DNA Damage Recognition and Wnt Signaling
Authors: Idogawa Masashi , Masutani Mitsuko , Shitashige Miki , Honda Kazufumi , Tokino Takashi , Shinomura Yasuhisa , Imai Kohzoh , Hirohashi Setsuo , Yamada Tesshi
Published: February 2007

Formation of the T-cell factor-4 (TCF-4) and β-catenin nuclear complex is considered crucial to embryonic development and colorectal carcinogenesis. We previously reported that poly(ADP-ribose) polymerase-1 (PARP-1) interacts with the TCF-4 and β-catenin complex and enhances its transcriptional activity. However, its biological significance remains unexplained. Using immunoprecipitation and mass spectrometry, we found that two Ku proteins, Ku70 and Ku80, were also associated with the complex. Knockdown of Ku70 by RNA interference increased the amount of β-catenin associated with TCF-4 and enhanced the transcriptional activity. PARP-1 competed with Ku70 for binding to TCF-4. Treatment with bleomycin, a DNA-damaging alkylating agent, induced polyADP-ribosylation of PARP-1 protein and inhibited its interaction with TCF-4. Bleomycin conversely increased the amounts of Ku70 coimmunoprecipitated with TCF-4 and removed β-catenin from TCF-4. We propose a working model in which the transcriptional activity of TCF-4 is regulated by the relative amount of Ku70, PARP-1, and β-catenin proteins binding to TCF-4. Identification of the functional interaction of Ku70 as well as PARP-1 with the TCF-4 and β-catenin transcriptional complex may provide insights into a novel linkage between DNA damage recognition/repair and Wnt signaling. [Cancer Res 2007;67(3):911–8]
Extracellular Signal-Related Kinase Positively Regulates Ataxia Telangiectasia Mutated, Homologous Recombination Repair, and the DNA Damage Response
Authors: Golding Sarah E. , Rosenberg Elizabeth , Neill Steven , Dent Paul , Povirk Lawrence F. , Valerie Kristoffer
Published: February 2007

The accurate joining of DNA double-strand breaks by homologous recombination repair (HRR) is critical to the long-term survival of the cell. The three major mitogen-activated protein (MAP) kinase (MAPK) signaling pathways, extracellular signal-regulated kinase (ERK), p38, and c-Jun-NH2-kinase (JNK), regulate cell growth, survival, and apoptosis. To determine the role of MAPK signaling in HRR, we used a human in vivo I-SceI–based repair system. First, we verified that this repair platform is amenable to pharmacologic manipulation and show that the ataxia telangiectasia mutated (ATM) kinase is critical for HRR. The ATM-specific inhibitor KU-55933 compromised HRR up to 90% in growth-arrested cells, whereas this effect was less pronounced in cycling cells. Then, using well-characterized MAPK small-molecule inhibitors, we show that ERK1/2 and JNK signaling are important positive regulators of HRR in growth-arrested cells. On the other hand, inhibition of the p38 MAPK pathway generated an almost 2-fold stimulation of HRR. When ERK1/2 signaling was stimulated by oncogenic RAF-1, an ∼2-fold increase in HRR was observed. KU-55933 partly blocked radiation-induced ERK1/2 phosphorylation, suggesting that ATM regulates ERK1/2 signaling. Furthermore, inhibition of MAP/ERK kinase (MEK)/ERK signaling resulted in severely reduced levels of phosphorylated (S1981) ATM foci but not γ-H2AX foci, and suppressed ATM phosphorylation levels >85% throughout the cell cycle. Collectively, these results show that MAPK signaling positively and negatively regulates HRR in human cells. More specifically, ATM-dependent signaling through the RAF/MEK/ERK pathway is critical for efficient HRR and for radiation-induced ATM activation, suggestive of a regulatory feedback loop between ERK and ATM. [Cancer Res 2007;67(3):1046–53]
Microscopic Intratumoral Dosimetry of Radiolabeled Antibodies Is a Critical Determinant of Successful Radioimmunotherapy in B-Cell Lymphoma
Authors: Du Yong , Honeychurch Jamie , Glennie Martin , Johnson Peter , Illidge Tim
Published: February 2007

Radioimmunotherapy is a highly effective treatment for some hematologic malignancies; however, the underlying mechanisms of tumor clearance remain poorly understood. We have previously shown that both targeted radiation using 131I-labeled anti–MHC class II (MHCII) monoclonal antibody (mAb) plus mAb signaling with unlabeled anti-idiotype are required for the long-term clearance of tumor in syngeneic murine lymphoma models. In this study, we have investigated how the microdistribution of the targeted radiation component of this combination affects the long-term clearance of lymphoma. 131I-labeled mAb targeting CD45 and MHCII antigens was found to deliver similar doses of radiation to tumor-bearing organ using conventional dosimetry (∼1.0 Gy per MBq when 131I was labeled to 500 μg mAb and given i.v. per mouse), but when used as radiation vectors in combination therapy only, 131I-anti-MHCII plus anti-idiotype produced long-term survival. The profound differences in therapy did not seem to be dependent on levels of 131I-mAb tumor-binding or antibody-dependent cytotoxicity. Instead, the microscopic intratumoral dosimetry seemed to be critical with the 131I-anti-MHCII, delivering more concentrated and therefore substantially higher radiation dose to tumor cells. When the administered activity of 131I-anti-CD45 was increased, a radiation dose response was shown in the presence of anti-idiotype and long-term survival was seen. We believe that these new insights should influence the selection of new antigen targets and the design of dosimetric methods in radioimmunotherapy of lymphoma. [Cancer Res 2007;67(3):1335–43]