bluuebunny/crossref_metadata_2025 huggingface dataset:
Economic effects of environmental quality change on recreational hunting in northwestern Saskatchewan: a contingent behaviour analysis
Authors: Morton K.M. , Adamowicz W.L. , Boxall P.C.
Published: January 2008

This study estimates changes in the value of a recreational hunting experience as road access, game populations, congestion, and travel distance change in the forest environment because of harvesting operations. Values were estimated using a model that considers changes in one or more environmental quality factors simultaneously. The model is a variant of the contingent valuation method that evaluates multiple environmental quality changes. The model is applied to big-game hunters in a particular forest management licence area in northern Saskatchewan. The results suggest that the welfare of these hunters increases with reductions in congestion and improvements in game populations and access levels. The annual value of those improvements that generate the highest welfare for moose and deer hunters ranges from about $12 000 to $19 000, depending on the welfare measure used. The highest values of welfare losses ranged from about −$2750 to −$19 500 depending on the welfare measure, and were associated with increases in congestion and decreases in access and game population levels. The methods and results presented in this paper suggest an approach for the values of nontimber products, such as recreational hunting, to be incorporated more explicitly in integrated forest management plans.
Model computations on the impact of changing climate on natural regeneration of Scots pine in Finland
Authors: Kellomäki Seppo , Väisänen Hannu
Published: January 2008

Based on model computations, the regeneration of Scots pine (Pinussylvestris L.) in southern (60°N) and northern (66°N) Finland was studied in relation to an elevating temperature. The temperature elevation increased flowering and the subsequent seed crop, particularly in northern Finland, with a decrease in the frequency of zero crops. In southern Finland, the number of seedlings produced by each seed crop increased when applying wide spacing, but decreased when applying narrow spacing of parent trees. This was due to a decrease in soil moisture induced by the increasing evaporative demand and transpiration of the parent trees. In northern Finland, temperature elevation substantially increased the success of regeneration in terms of seedlings produced by each seed crop regardless of the spacing of parent trees. In terms of the density of seedling stands and the height and diameter growth of seedlings, the establishment of a seedling stand within a given period of time was substantially improved under the improved temperature conditions in both southern and northern Finland.
Aboveground biomass and nitrogen nutrition in a chronosequence of pristine Dahurian Larix stands in eastern Siberia
Authors: Schulze E.-D. , Schulze W. , Koch H. , Arneth A. , Bauer G. , Kelliher F.M. , Hollinger D.Y. , Vygodskaya N.N. , Kusnetsova W.A. , Sogatchev A. , Ziegler W. , Kobak K.I. , Issajev A.
Published: January 2008

Measurements of aboveground biomass and nitrogen (N) nutrition were made during July 1993 in 50-, 130-, and 380-year-old stands of Larixgmelinii (Rupr.) Rupr. in eastern Siberia. Constituting six forest types based on understorey plants, the stands were representative of vegetation throughout the Yakutsk region. Average tree height, diameter, and density ranged from 2 m, 23 mm, and 50 800 stems/ha in the 50-year-old stand to 11 m, 160 mm, and 600 stems/ha in the oldest stand. Aboveground biomass in the 50-year-old stand was 4.4 kg•m−2, and the aboveground N pool was 1.1 mol•m−2. This was slightly higher than the N pool in a 125-year-old stand with a Ledum understorey (1.0 mol•m−2), despite its higher biomass (7.2 kg•m−2). The highest observed aboveground biomass in a 125-year-old stand (characterized by the N2-fixing understorey plant Alnasterfruticosa) reached 12.0 kg•m−2, but the corresponding N pool was only 1.6 mol•m−2. In the oldest stand, aboveground biomass was 8.9 kg•m−2 and the N pool was 1.1 mol•m−2. There was thus a relatively constant quantity of N in the aboveground biomass of stands differing in age by almost 400 years. We postulate that N sets a limit on carbon accumulation in this boreal forest type. Trees were extremely slow growing, and there was essentially no aboveground biomass accumulation between the ages of 130 and 380 years because of a lack of available N. This conclusion was supported by graphical analysis indicating that the self-thinning process in our stands was not governed by the availability of radiation according to allometric theory. Much of the available N was used in the production of tree stems where 86% of the aboveground N (and 96% of aboveground biomass) was immobilized in the oldest stand. N in wood of the old stand exceeded the N pool in the litter layer and was 20% of the N pool in the Ah horizon. The processes of carbon and N partitioning were further explored by the estimation of carbon and N fluxes during three periods of forest development. We calculated a loss of ecosystem N during the period of self-thinning, while in the mature stands the N cycle appeared to be very tight. The immobilized N is returned from the wood into a plant-available form only by a recurrent fire cycle, which regenerates the N cycle. Thus fire is an essential component for the persistence of the L. gmelinii forest.
The economic effect of forest policy changes in British Columbia: an event study of stock-market returns
Authors: Zhang Daowei , Binkley Clark S.
Published: January 2008

In 1987 the government of British Columbia (B.C.) made substantial changes in its forest policy, including "clawing back" 5% of the volume committed on all of its replaceable licenses and shifting of reforestation costs to the licensees. Analysis of the reaction of stock prices to the announcement of these policy changes reveals that the policy had a negative, but not statistically significant impact on B.C. forest products companies taken as a whole. Those medium-sized B.C. forest products firms that own little private land and operate mainly in B.C. suffered small but statistically insignificant losses. The policy changes apparently did not affect large B.C. forest products firms and non BC-based forest products firms. The results may arise because (i) as a result of restrictions on log exports the volume reductions were simply reallocated within extant timber markets, (ii) timber from the replaceable licences is fully priced, (iii) the adjustments were small when compared with the overall market capitalization of the firms involved, and (iv) there was general financial euphoria in the late 1980 s. These findings should not be extended to larger policy adjustments or to the problem of evaluating the impact of province-wide reductions in allowable harvest levels.
Understory alder in three boreal forests of Alaska: local distribution and effects on soil fertility
Authors: Wurtz Tricia L.
Published: January 2008

The distribution and effects on soil chemistry of shrub alders (Alnus spp.) occurring in the understory of the boreal forest of Alaska were examined. Understory alder ramet distribution was mapped on three sites; ramet density ranged from 150 to 5280 ramets/ha. Allometric biomass models were developed for alder ramets; maps of the spatial distribution of ramets and of estimated aboveground alder biomass are presented. Biomass of alders in the understory ranged from 20 to 690 g•m−2. The total nitrogen of soils collected beneath alder and from areas without alder differed among the three sites and between two sampling episodes. In undisturbed forest, alder soils tended to have more nitrogen than nonalder soils. On the two sites where background soil fertility was low, a greenhouse bioassay matched these results: alder soils had greater nutrient-supplying capacity than nonalder soils. In soil collected after the sites were harvested, however, results varied. Areas that had supported dense alder before harvesting had more soil nitrogen than areas with no alder at only one site, and at another site, alder soils had significantly less total nitrogen. This study suggests that the effect of understory alders on the boreal forest soil mosaic is a function of site characteristics such as canopy openness and soil background fertility.
Effects of water stress on chestnut blight
Authors: Gao S. , Shain L.
Published: January 2008

A range of moisture stress was induced in American chestnut (Castaneadentata (Marsh.) Borkh.) stem segments by incubating them in chambers maintained at humidities of 100%, 90%, or 70% or by soaking their unsealed lower ends in water. Stems then were inoculated with mycelial discs or conidial suspensions of a virulent strain of the chestnut blight fungus (Cryphonectriaparasitica (Murr.) Barr, Ep 155 (American Type Culture Collection No. 38755)). Bark osmotic potential and relative turgidity were monitored on these stems during the development of chestnut blight cankers. Canker expansion was greatest on the stem segments that were lowest in bark osmotic potential (−1.8 MPa) and relative turgidity (56.3%), whereas expansion was least on those stems that were highest in bark osmotic potential (−1.1 MPa) and relative turgidity (68.4%). Water stress, however, had little effect on conidial infection of wounds on stems collected during the growing season, but fewer conidial inoculations of wounds were successful on water-stressed stems collected during the dormant season. Bark osmotic potential of living trees ranged from −0.8 to −2.0 MPa in monthly samplings during the year. Mycelial growth and conidial germination of C. parasitica generally was not affected at osmotic potentials above −2.0 MPa (see companion paper). These results indicate that canker expansion, but not necessarily canker initiation, is favored by water stress and that the effects of water stress are greater on the host than on the pathogen.
NONEXISTENCE OF IRREVERSIBLE PROCESSES IN COMPACT SPACE–TIME
Authors: NIELSEN HOLGER B. , NINOMIYA MASAO
Published: January 2008

It is shown that if physical space–time were truly compact there would only be of the order-of-one solutions to the classical field equations with a weighting to be explained. But that would not allow any peculiar choice of initial conditions that could support a nontrivial second law of thermodynamics. We present a no-go theorem: irreversible processes would be extremely unlikely to occur for the almost unique solution for the intrinsically compact space–time world, although irreversible processes are well known to occur in general. What we assume here — the compact space–time — is that universe could not exist eternally. In other word if universe stays on forever (i.e. noncompact in time direction) our no-go theorem is not applicable.
OBSERVABLE ELECTRON EDM AND LEPTOGENESIS
Authors: JOAQUIM F. R. , MASINA I. , RIOTTO A.
Published: January 2008

In the context of the minimal supersymmetric seesaw model, the CP-violating neutrino Yukawa couplings might induce an electron electric dipole moment (EDM). The same interactions may also be responsible for the generation of the observed baryon asymmetry of the universe via leptogenesis. In the framework of mSUGRA, we identify in a model-independent way those patterns within the seesaw models which predict, barring unnatural cancelations, an electron EDM at a level probed by planned laboratory experiments and show that negative searches on τ→eγ decay may provide the strongest upper bound on the electron EDM. We also conclude that a possible future detection of the electron EDM is incompatible with thermal leptogenesis, even when flavor effects are accounted for.
HARMONIC OSCILLATOR IN NONCOMMUTING TWO-DIMENSIONAL SPACE
Authors: STREKLAS ANTONY
Published: January 2008

In the present paper, we study a two-dimensional harmonic oscillator in a constant magnetic field in noncommuting space. We use the following Hamiltonian [Formula: see text] with commutation relations [Formula: see text] and [Formula: see text].

The parameter λ expresses the presence of the magnetic field. We find the exact propagator of the system and the time evolution of the basic operators. We prove that the system is equivalent to a two-dimensional system where the operators of momentum and coordinates of the second dimension satisfy a deformed commutation relation [Formula: see text]. The deformation parameter, μ, depends on λ and θ, and is independent of the Hamiltonian. Finally, we investigate the thermodynamic properties of the system in Boltzmann statistics. We find the statistical density matrix and the partition function, which is equivalent to that of a two-dimensional harmonic oscillator with two deformed frequencies Ω1and Ω2.
Reduced adiposity and improved insulin sensitivity in obese mice with antisense suppression of 4E-BP2 expression
Authors: Yu Xing Xian , Pandey Sanjay K. , Booten Sheri L. , Murray Susan F. , Monia Brett P. , Bhanot Sanjay
Published: January 2008

To investigate the possible role of eukaryotic initiation factor 4E-binding protein-2 (4E-BP2) in metabolism and energy homeostasis, high-fat diet-induced obese mice were treated with a 4E-BP2-specific antisense oligonucleotide (ASO) or a control 4E-BP2 ASO at a dose of 25 mg/kg body wt or with saline twice a week for 6 wk. 4E-BP2 ASO treatment reduced 4E-BP2 levels by >75% in liver and white (WAT) and brown adipose (BAT) tissues. Treatment did not change food intake but lowered body weight by ∼7% and body fat content by ∼18%. Treatment decreased liver triglyceride (TG) content by >50%, normalized plasma glucose and insulin levels, and reduced glucose excursion during glucose tolerance test. 4E-BP2 ASO-treated mice showed >8.5% increase in metabolic rate, >40% increase in UCP1 levels in BAT, >45% increase in β3-adrenoceptor mRNA, and 40–55% decrease in mitochondrial dicarboxylate carrier, fatty acid synthase, and diacylglycerol acyltransferase 2 mRNA levels in WAT. 4E-BP2 ASO-transfected mouse hepatocytes showed an increased fatty acid oxidation rate and a decreased TG synthesis rate. In addition, 4E-BP2 ASO-treated mice demonstrated ∼60 and 29% decreases in hepatic glucose-6-phosphatase and phospho enolpyruvate carboxykinase mRNA, respectively, implying decreased hepatic glucose output. Furthermore, increased phosphorylation of AktSer473in both liver and fat of 4E-BP2 ASO-treated mice and increased GLUT4 levels in plasma membrane in WAT of the ASO-treated mice were observed, indicating enhanced insulin signaling and increased glucose uptake as a consequence of reduced 4E-BP2 expression. These data demonstrate for the first time that peripheral 4E-BP2 plays an important role in metabolism and energy homeostasis.
Stanniocalcin-1 secretion and receptor regulation in kidney cells
Authors: Sazonova Olga , James Kathi A. , McCudden Christopher R. , Segal Daniel , Talebian Asghar , Wagner Graham F.
Published: January 2008

Kidney collecting duct principal cells are the main source of stanniocalcin-1 (STC-1) production and secretion. From there, the hormone targets thick ascending limb and distal convoluted tubule cells, as well as collecting duct cells. More specifically, STC-1 targets their mitochondria to exert putative antiapoptotic effects. Two distal tubule cell lines serve as models of STC-1 production and/or mechanism of action. Madin-Darby canine kidney-1 (MDCK-1) cells mimic collecting duct cells in their synthesis of STC-1 ligand and receptor, whereas inner medullary collecting duct-3 (IMCD-3) cells respond to additions of STC-1 by increasing their respiration rate. In the present study, MDCK cell STC-1 secretion was examined under normal and hypertonic conditions, vectorally, and in response to hormones and signal transduction pathway activators/inhibitors. STC-1 receptor regulation was monitored in both cell lines in response to changing ligand concentration. The results showed that NaCl-induced hypertonicity had concentration-dependent stimulatory effects on STC-1 secretion, as did the PKC activator TPA. Calcium and ionomycin were inhibitory, whereas calcium receptor agonists had no effect. Angiotensin II, aldosterone, atrial natriuretic factor, antidiuretic hormone, and forskolin also had no effects. Moreover, STC-1 secretion exhibited no vectoral preference. STC-1 receptors were insensitive to homologous downregulation in both cell lines. In contrast, they were upregulated when STC-1 secretion was inhibited by calcium. The findings suggest that hypertonicity-induced STC-1 secretion is regulated through PKC activation and that high intracellular calcium levels are a potent inhibitor of release. More intriguingly, the results suggest that the receptor may not accompany STC-1 in its passage to the mitochondria.
Tactile Speed Scaling: Contributions of Time and Space
Authors: Dépeault Alexandra , Meftah El-Mehdi , Chapman C. Elaine
Published: January 2008

A major challenge for the brain is to extract precise information about the attributes of tactile stimuli from signals that co-vary with multiple parameters, e.g., speed and texture in the case of scanning movements. We determined the ability of humans to estimate the tangential speed of surfaces moved under the stationary fingertip and the extent to which the physical characteristics of the surfaces modify speed perception. Scanning speed ranged from 33 to 110 mm/s (duration of motion constant). Subjects could scale tactile scanning speed, but surface structure was essential because the subjects were poor at scaling the speed of a moving smooth surface. For textured surfaces, subjective magnitude estimates increased linearly across the range of speeds tested. The spatial characteristics of the surfaces influenced speed perception, with the roughest surface (8 mm spatial period, SP) being perceived as moving 15% slower than the smoother, textured surfaces (2–3 mm SP). Neither dot disposition (periodic, non periodic) nor dot density contributed to the results, suggesting that the critical factor was dot spacing in the direction of the scan. A single monotonic relation between subjective speed and temporal frequency (speed/SP) was obtained when the ratings were normalized for SP. This provides clear predictions for identifying those cortical neurons that play a critical role in tactile motion perception and the underlying neuronal code. Finally, the results were consistent with observations in the visual system (decreased subjective speed with a decrease in spatial frequency, 1/SP), suggesting that stimulus motion is processed similarly in both sensory systems.
Sound Localization Deficits During Reversible Deactivation of Primary Auditory Cortex and/or the Dorsal Zone
Authors: Malhotra Shveta , Stecker G. Christopher , Middlebrooks John C. , Lomber Stephen G.
Published: January 2008

We examined the contributions of primary auditory cortex (A1) and the dorsal zone of auditory cortex (DZ) to sound localization behavior during separate and combined unilateral and bilateral deactivation. From a central visual fixation point, cats learned to make an orienting response (head movement and approach) to a 100-ms broadband noise burst emitted from a central speaker or one of 12 peripheral sites (located in front of the animal, from left 90° to right 90°, at 15° intervals) along the horizontal plane. Following training, each cat was implanted with separate cryoloops over A1 and DZ bilaterally. Unilateral deactivation of A1 or DZ or simultaneous unilateral deactivation of A1 and DZ (A1/DZ) resulted in spatial localization deficits confined to the contralateral hemifield, whereas sound localization to positions in the ipsilateral hemifield remained unaffected. Simultaneous bilateral deactivation of both A1 and DZ resulted in sound localization performance dropping from near-perfect to chance (7.7% correct) across the entire field. Errors made during bilateral deactivation of A1/DZ tended to be confined to the same hemifield as the target. However, unlike the profound sound localization deficit that occurs when A1 and DZ are deactivated together, deactivation of either A1 or DZ alone produced partial and field-specific deficits. For A1, bilateral deactivation resulted in higher error rates (performance dropping to ∼45%) but relatively small errors (mostly within 30° of the target). In contrast, bilateral deactivation of DZ produced somewhat fewer errors (performance dropping to only ∼60% correct), but the errors tended to be larger, often into the incorrect hemifield. Therefore individual deactivation of either A1 or DZ produced specific and unique sound localization deficits. The results of the present study reveal that DZ plays a role in sound localization. Along with previous anatomical and physiological data, these behavioral data support the view that A1 and DZ are distinct cortical areas. Finally, the findings that deactivation of either A1 or DZ alone produces partial sound localization deficits, whereas deactivation of either posterior auditory field (PAF) or anterior ectosylvian sulcus (AES) produces profound sound localization deficits, suggests that PAF and AES make more significant contributions to sound localization than either A1 or DZ.
Regulation of Angiogenic Factors by HDM2 in Renal Cell Carcinoma
Authors: Carroll Veronica A. , Ashcroft Margaret
Published: January 2008

The oncogene HDM2 has been implicated in the regulation of the transcription factor, hypoxia inducible factor (HIF). We show in von Hippel-Lindau (VHL)-defective renal carcinoma cells that express constitutively high levels of HIF-1α and HIF-2α that down-regulation of HDM2 by siRNA leads to decreased levels of both HIF-1α and HIF-2α protein levels. However, we show a differential regulation of HDM2 on the HIF angiogenic targets, vascular endothelial growth factor (VEGF), plasminogen activator inhibitor-1 (PAI-1), and endothelin-1 (ET-1): siRNA to HDM2 leads to increased expression of VEGF and PAI-1 proteins but decreased levels of ET-1. We show that HDM2-mediated regulation of these proteins is independent of VHL and p53 but dependent on a novel action of HDM2. Ablation of HDM2 leads to phosphorylation of extracellular-regulated kinase (ERK)1/2 in renal carcinoma cells. We show that regulation of these angiogenic factors is dependent on ERK1/2 phosphorylation, which can be reversed by addition of the MAP/ERK1/2 kinase inhibitors PD98059 and PD184352. This study identifies a novel role for the HDM2 oncoprotein in the regulation of angiogenic factors in renal cell carcinoma. [Cancer Res 2008;68(2):545–52]
Regulation of Gastric Carcinogenesis by Helicobacter pylori Virulence Factors
Authors: Franco Aime T. , Johnston Elizabeth , Krishna Uma , Yamaoka Yoshio , Israel Dawn A. , Nagy Toni A. , Wroblewski Lydia E. , Piazuelo Maria Blanca , Correa Pelayo , Peek Richard M.
Published: January 2008

Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, and strains that possess the cag secretion system, which translocates the bacterial effector CagA into host cells, augment cancer risk. H. pylori strains that express the vacuolating cytotoxin or the outer membrane protein OipA are similarly associated with severe pathologic outcomes. We previously reported that an in vivo adapted H. pylori strain, 7.13, induces gastric adenocarcinoma in rodent models of gastritis. In the current study, we used carcinogenic strain 7.13 as a prototype to define the role of virulence constituents in H. pylori–mediated carcinogenesis. Mongolian gerbils were infected with wild-type strain 7.13 or cagA−, vacA−, or oipA− mutants for 12 to 52 weeks. All infected gerbils developed gastritis; however, inflammation was significantly attenuated in animals infected with the cagA− but not the vacA− or oipA− strains. Gastric dysplasia and cancer developed in >50% of gerbils infected with either the wild-type or vacA− strain but in none of the animals infected with the cagA− strain. Inactivation of oipA decreased β-catenin nuclear localization in vitro and reduced the incidence of cancer in gerbils. OipA expression was detected significantly more frequently among H. pylori strains isolated from human subjects with gastric cancer precursor lesions versus persons with gastritis alone. These results indicate that loss of CagA prevents the development of cancer in this model. Inactivation of oipA attenuates β-catenin nuclear translocation and also decreases the incidence of carcinoma. In addition to defining factors that mediate H. pylori–induced cancer, these results provide insight into mechanisms that may regulate the development of other malignancies arising within the context of inflammatory states. [Cancer Res 2008;68(2):379–87]
α2-6–Linked Sialic Acids on N-Glycans Modulate Carcinoma Differentiation In vivo
Authors: Hedlund Maria , Ng Elisa , Varki Ajit , Varki Nissi M.
Published: January 2008

Sialic acids on vertebrate cell surfaces mediate many biological roles. Altered expression of certain sialic acid types or their linkages can have prognostic significance in human cancer. A classic but unexplained example is enhanced α2-6-sialylation on N-glycans resulting from overexpression of the Golgi enzyme β-galactoside:α2-6-sialyltransferase (ST6Gal-I). Previous data supporting a role for the resulting Siaα2-3Galβ1-4GlcNAc (Sia6LacNAc) structure in tumor biology were based on in vitro studies in transfected carcinoma cells, in which increased Sia6LacNAc on β1-integrins enhanced their binding to ligands, and stimulated cell motility. Here, we examine for the first time the in vivo role of the ST6Gal-I enzyme in the growth and differentiation of spontaneous mammary cancers in mice transgenic for a mouse mammary tumor virus promoter–driven polyomavirus middle T antigen, a tumor in which β1-integrin function is important for tumorigenesis and in maintaining the proliferative state of tumor cells. Tumors induced in St6gal1-null animals were more differentiated compared with those in the wild-type background, both by histologic analysis and by protein expression profiles. Furthermore, we show the St6gal1-null tumors have selectively altered expression of genes associated with focal adhesion signaling and have decreased phosphorylation of focal adhesion kinase, a downstream target of β1-integrins. This first in vivo evidence for a role of ST6Gal-I in tumor progression was confirmed using a novel approach, which conditionally restored St6gal1 in cell lines derived from the null tumors. These findings indicate a role for ST6Gal-I as a mediator of tumor progression, with its expression causing a less differentiated phenotype, via enhanced β1-integrin function. [Cancer Res 2008;68(2):388–94]
Inhibition of Hsp90 Down-regulates Mutant Epidermal Growth Factor Receptor (EGFR) Expression and Sensitizes EGFR Mutant Tumors to Paclitaxel
Authors: Sawai Ayana , Chandarlapaty Sarat , Greulich Heidi , Gonen Mithat , Ye Qing , Arteaga Carlos L. , Sellers William , Rosen Neal , Solit David B.
Published: January 2008

Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are found in a subset of patients with lung cancer and correlate with response to EGFR tyrosine kinase inhibitors (TKI). Resistance to these agents invariably develops, and current treatment strategies have limited efficacy in this setting. Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), induce the degradation of EGFR and other Hsp90 interacting proteins and may thus have utility in tumors dependent upon sensitive Hsp90 clients. We find that the EGFR mutations found most commonly in patients with lung adenocarcinoma who respond to EGFR TKIs are potently degraded by 17-AAG. Although the expression of wild-type EGFR was also down-regulated by 17-AAG, its degradation required higher concentrations of drug and a longer duration of drug exposure. In animal models, a single dose of 17-AAG was sufficient to induce degradation of mutant EGFR and inhibit downstream signaling. 17-AAG treatment, at its maximal tolerated dose, caused a significant delay in H3255 (L858R EGFR) xenograft growth but was less effective than the EGFR TKI gefitinib. 17-AAG alone delayed, but did not completely inhibit, the growth of H1650 and H1975 xenografts, two EGFR mutant models which show intermediate and high levels of gefitinib resistance. 17-AAG could be safely coadministered with paclitaxel, and the combination was significantly more effective than either drug alone. These data suggest that Hsp90 inhibition in combination with chemotherapy may represent an effective treatment strategy for patients whose tumors express EGFR kinase domain mutations, including those with de novo and acquired resistance to EGFR TKIs. [Cancer Res 2008;68(2):589–96]
t-Darpp Promotes Cancer Cell Survival by Up-regulation of Bcl2 through Akt-Dependent Mechanism
Authors: Belkhiri Abbes , Dar Altaf A. , Zaika Alexander , Kelley Mark , El-Rifai Wael
Published: January 2008

t-Darpp is a cancer-related truncated isoform of Darpp-32 (dopamine and cyclic-AMP–regulated phosphoprotein of Mr 32,000). We detected overexpression of t-Darpp mRNA in two thirds of gastric cancers compared with normal samples (P = 0.004). Using 20 μmol/L ceramide treatment as a model for induction of apoptosis in AGS cancer cells, we found that expression of t-Darpp led to an increase in Bcl2 protein levels and blocked the activation of caspase-3 and caspase-9. The MitoCapture mitochondrial apoptosis and cytochrome c release assays indicated that t-Darpp expression enforces the mitochondrial transmembrane potential and protects against ceramide-induced apoptosis. Interestingly, the expression of t-Darpp in AGS cells led to ≥2-fold increase in Akt kinase activity with an increase in protein levels of p-Ser473 Akt and p-Ser9 GSK3β. These findings were further confirmed using tetracycline-inducible AGS cells stably expressing t-Darpp. We also showed transcriptional up-regulation of Bcl2 using the luciferase assay with Bcl2 reporter containing P1 full promoter, quantitative reverse transcription-PCR, and t-Darpp small interfering RNA. The Bcl2 promoter contains binding sites for cyclic AMP–responsive element binding protein CREB/ATF1 transcription factors and using the electrophoretic mobility shift assay with a CREB response element, we detected a stronger binding in t-Darpp–expressing cells. The t-Darpp expression led to an increase in expression and phosphorylation of CREB and ATF-1 transcription factors that were required for up-regulating Bcl2 levels. Indeed, knockdown of Akt, CREB, or ATF1 in t-Darpp–expressing cells reduced Bcl2 protein levels. In conclusion, the t-Darpp/Akt axis underscores a novel oncogenic potential of t-Darpp in gastric carcinogenesis and resistance to drug-induced apoptosis. [Cancer Res 2008;68(2):395–403]
Integrating Global Gene Expression and Radiation Survival Parameters across the 60 Cell Lines of the National Cancer Institute Anticancer Drug Screen
Authors: Amundson Sally A. , Do Khanh T. , Vinikoor Lisa C. , Lee R. Anthony , Koch-Paiz Christine A. , Ahn Jaeyong , Reimers Mark , Chen Yidong , Scudiero Dominic A. , Weinstein John N. , Trent Jeffrey M. , Bittner Michael L. , Meltzer Paul S. , Fornace Albert J.
Published: January 2008

The 60 cell lines of the National Cancer Institute Anticancer Drug Screen (NCI-60) constitute the most extensively characterized in vitro cancer cell model. They have been tested for sensitivity to more than 100,000 potential chemotherapy agents and have been profiled extensively at the DNA, RNA, protein, functional, and pharmacologic levels. We have used the NCI-60 cell lines and three additional lines to develop a database of responses of cancer cells to ionizing radiation. We compared clonogenic survival, apoptosis, and gene expression response by microarray. Although several studies have profiled relative basal gene expression in the NCI-60, this is the first comparison of large-scale gene expression changes in response to genotoxic stress. Twenty-two genes were differentially regulated in cells with low survival after 2-Gy γ-rays; 14 genes identified lines more sensitive to 8 Gy. Unlike reported basal gene expression patterns, changes in expression in response to radiation showed little tissue-of-origin effect, except for differentiating the lymphoblastoid cell lines from other cell types. Basal expression patterns, however, discriminated well between radiosensitive and more resistant lines, possibly being more informative than radiation response signatures. The most striking patterns in the radiation data were a set of genes up-regulated preferentially in the p53 wild-type lines and a set of cell cycle regulatory genes down-regulated across the entire NCI-60 panel. The response of those genes to γ-rays seems to be unaffected by the myriad of genetic differences across this diverse cell set; it represents the most penetrant gene expression response to ionizing radiation yet observed. [Cancer Res 2008;68(2):415–24]
Antibody-Mediated Blockade of Integrin αvβ6 Inhibits Tumor Progression In vivo by a Transforming Growth Factor-β–Regulated Mechanism
Authors: Koopman Van Aarsen Louise A. , Leone Diane R. , Ho Steffan , Dolinski Brian M. , McCoon Patricia E. , LePage Doreen J. , Kelly Rebecca , Heaney Glenna , Rayhorn Paul , Reid Carl , Simon Kenneth J. , Horan Gerald S. , Tao Nianjun , Gardner Humphrey A. , Skelly Marilyn M. , Gown Allen M. , Thomas Gareth J. , Weinreb Paul H. , Fawell Stephen E. , Violette Shelia M.
Published: January 2008

The αvβ6 integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of αvβ6 expression in 10 human tumor types showed increased expression relative to normal tissues. Squamous carcinomas of the cervix, skin, esophagus, and head and neck exhibited the highest frequency of expression, with positive immunostaining in 92% (n = 46), 84% (n = 49), 68% (n = 56), and 64% (n = 100) of cases, respectively. We studied the role of αvβ6 in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent αvβ6 expression was detected on tumor xenografts at the tumor-stroma interface resembling the expression on human head and neck carcinomas. Nonetheless, coculturing cells in vitro with matrix proteins did not up-regulate αvβ6 expression. Detroit 562 cells showed αvβ6-dependent adhesion and activation of transforming growth factor-β (TGF-β) that was inhibited >90% with an αvβ6 blocking antibody, 6.3G9. Although both recombinant soluble TGF-β receptor type-II (rsTGF-βRII-Fc) and 6.3G9 inhibited TGF-β–mediated Smad2/3 phosphorylation in vitro, there was no effect on proliferation. Conversely, in vivo, 6.3G9 and rsTGF-βRII-Fc inhibited xenograft tumor growth by 50% (n = 10, P < 0.05) and >90% (n = 10, P < 0.001), respectively, suggesting a role for the microenvironment in this response. However, stromal collagen and smooth muscle actin content in xenograft sections were unchanged with treatments. Although further studies are required to consolidate in vitro and in vivo results and define the mechanisms of tumor inhibition by αvβ6 antibodies, our findings support a role for αvβ6 in human cancer and underscore the therapeutic potential of function blocking αvβ6 antibodies. [Cancer Res 2008;68(2):561–70]
MicroRNA Expression Profiling in Human Ovarian Cancer: miR-214 Induces Cell Survival and Cisplatin Resistance by Targeting PTEN
Authors: Yang Hua , Kong William , He Lili , Zhao Jian-Jun , O'Donnell Joshua D. , Wang Jiawang , Wenham Robert M. , Coppola Domenico , Kruk Patricia A. , Nicosia Santo V. , Cheng Jin Q.
Published: January 2008

MicroRNAs (miRNA) represent a novel class of genes that function as negative regulators of gene expression. Recently, miRNAs have been implicated in several cancers. However, aberrant miRNA expression and its clinicopathologic significance in human ovarian cancer have not been well documented. Here, we show that several miRNAs are altered in human ovarian cancer, with the most significantly deregulated miRNAs being miR-214, miR-199a*, miR-200a, miR-100, miR-125b, and let-7 cluster. Further, we show the frequent deregulation of miR-214, miR-199a*, miR-200a, and miR-100 in ovarian cancers. Significantly, miR-214 induces cell survival and cisplatin resistance through targeting the 3′-untranslated region (UTR) of the PTEN, which leads to down-regulation of PTEN protein and activation of Akt pathway. Inhibition of Akt using Akt inhibitor, API-2/triciribine, or introduction of PTEN cDNA lacking 3′-UTR largely abrogates miR-214–induced cell survival. These findings indicate that deregulation of miRNAs is a recurrent event in human ovarian cancer and that miR-214 induces cell survival and cisplatin resistance primarily through targeting the PTEN/Akt pathway. [Cancer Res 2008;68(2):425–33]
CSN5 Isopeptidase Activity Links COP9 Signalosome Activation to Breast Cancer Progression
Authors: Adler Adam S. , Littlepage Laurie E. , Lin Meihong , Kawahara Tiara L.A. , Wong David J. , Werb Zena , Chang Howard Y.
Published: January 2008

CSN5 has been implicated as a candidate oncogene in human breast cancers by genetic linkage with activation of the poor-prognosis, wound response gene expression signature. CSN5 is a subunit of the eight-protein COP9 signalosome, a signaling complex with multiple biochemical activities; the mechanism of CSN5 action in cancer development remains poorly understood. Here, we show that CSN5 isopeptidase activity is essential for breast epithelial transformation and progression. Amplification of CSN5 is required for transformation of primary human breast epithelial cells by defined oncogenes. The transforming effects of CSN5 require CSN subunits for assembly of the full COP9 signalosome and the isopeptidase activity of CSN5, which potentiates the transcriptional activity of MYC. Transgenic inhibition of CSN5 isopeptidase activity blocks breast cancer progression evoked by MYC and RAS in vivo. These results highlight CSN5 isopeptidase activity in breast cancer progression, suggesting it as a therapeutic target in aggressive human breast cancers. [Cancer Res 2008;68(2):506–15]
The Transcriptional Repressor ZEB1 Promotes Metastasis and Loss of Cell Polarity in Cancer
Authors: Spaderna Simone , Schmalhofer Otto , Wahlbuhl Mandy , Dimmler Arno , Bauer Katja , Sultan Aneesa , Hlubek Falk , Jung Andreas , Strand Dennis , Eger Andreas , Kirchner Thomas , Behrens Jürgen , Brabletz Thomas
Published: January 2008

Invasion and metastasis are the hallmarks of malignant tumor progression and the main cause of death in cancer. The embryonic program “epithelial-mesenchymal transition” (EMT) is thought to trigger invasion by allowing tumor cell dissemination. Here, we describe that the EMT-inducing transcriptional repressor ZEB1 promotes colorectal cancer cell metastasis and loss of cell polarity. Thereby, ZEB1 suppresses the expression of cell polarity factors, in particular of Lgl2, which we found reduced in colorectal and breast cancers. We further show that retention of Lgl2 expression is critical for the epithelial phenotype and that its loss might be involved in metastasis. Thus, by linking EMT, loss of polarity, and metastasis, ZEB1 is a crucial promoter of malignant tumor progression. [Cancer Res 2008;68(2):537–44]
Equol Status Modifies the Association of Soy Intake and Mammographic Density in a Sample of Postmenopausal Women
Authors: Fuhrman Barbara J. , Teter Barbara E. , Barba Maddalena , Byrne Celia , Cavalleri Adalberto , Grant Brydon J. , Horvath Peter J. , Morelli Daniele , Venturelli Elisabetta , Muti Paola C.
Published: January 2008

Only 30% to 50% of people produce the daidzein-metabolite equol after eating soy. We conducted a cross-sectional study of the associations between equol status, intake of soy foods, and mammographic density in a sample of postmenopausal women recruited at a radiology clinic near Buffalo, New York. Participants were 48 to 82 years old, had no history of cancer or breast reduction/augmentation, and no recent use of antibiotics or hormones. Percent density was measured by computer-assisted analysis of digitized images of craniocaudal films. Equol status was assessed using a soy-challenge protocol and usual soy intake by questionnaire. General linear models were used to assess independent and joint effects of equol status and intake of soy on multivariate adjusted percent density (covariates included age, body mass index, parity, age at first birth, and ever use of combined hormone therapy). Of 325 enrolled, 232 (71%) participants completed study assessments and are included in the present analysis. Mean percent density was 34% (±18%). Seventy-five (30%) participants were producers of equol. Forty-three (19%) participants reported regularly eating >1 soy food or supplement/wk. There were no significant independent associations of equol status or soy intake with percent density, but the interaction between these factors was significant (P < 0.01). Among equol producers, those with weekly soy intake had lower percent density (30.7% in weekly consumers of soy versus 38.9% in others; P = 0.08); among nonproducers, weekly soy intake was associated with higher percent density (37.5% in weekly soy consumers versus 30.7% in others; P = 0.03). Results suggest that equol producers and nonproducers may experience different effects of dietary soy on breast tissue. (Cancer Epidemiol Biomarkers Prev 2008;17(1):33–42)
Cigarette Smoking, N-Acetyltransferase 2 Genotypes, and Breast Cancer Risk: Pooled Analysis and Meta-analysis
Authors: Ambrosone Christine B. , Kropp Silke , Yang Jun , Yao Song , Shields Peter G. , Chang-Claude Jenny
Published: January 2008

Approximately 10 years ago, it was noted that smoking increased risk of breast cancer among women with N-acetyltransferase 2 (NAT2) slow acetylation genotypes. This report was followed by a number of studies to address this question. We pooled data from 10 existing studies and also conducted a meta-analysis of 13 studies published from 1996 to October 2006 that were conducted among women, were published in English, and had adequate information on smoking and NAT2 genotyping. Raw data were requested from authors. Unconditional logistic regression was done for pooled analysis, and random effect models was done for meta-analysis. Study heterogeneity was assessed, and sensitivity tests were done when subgroups were excluded from the analysis. In the pooled analysis, there was a significant interaction between smoking, NAT2 genotype, and risk of breast cancer [pack-years (continuous variable, Pinteraction = 0.03)], with higher pack-years significantly associated with an increased risk of breast cancer among women with NAT2 slow genotypes (pooled analysis relative risk, 1.49; 95% confidence interval, 1.08-2.04). These findings were supported by the meta-analysis including all studies; pack-years were significantly associated with risk among slow acetylators in a dose-dependent fashion (meta-analysis relative risk, 1.44; 95% confidence interval, 1.23-1.68 for ≥20 pack-years versus never smokers), but not among rapid acetylators. Similar relationships were noted for smoking status (ever, never) and duration of smoking. Our results show that cigarette smoking is associated with an increase in breast cancer risk among women with NAT2 slow acetylation genotypes. Because slow NAT2 genotypes are present in 50% to 60% of Caucasian populations, smoking is likely to play an important role in breast cancer etiology. (Cancer Epidemiol Biomarkers Prev 2008;17(1):15–26)
Body Mass and Physical Activity and Risk of Gastric Cancer in a Population-Based Cohort Study in Norway
Authors: Sjödahl Krister , Jia Chongqi , Vatten Lars , Nilsen Tom , Hveem Kristian , Lagergren Jesper
Published: January 2008

There is a relation between excess body mass index and overall cancer incidence and mortality, but the relation to noncardia gastric cancer is inconsistent. A high physical activity level decreases the risk of several cancers, but few studies have focused on gastric cancer. We conducted a population-based, prospective cohort study in Nord-Trondelag county in Norway. During 1984 to 1986, all adult residents were invited to participate in a health survey, where body height and weight were measured, and frequency, duration, and intensity of recreational physical activity, together with potential confounding factors, were assessed by questionnaires. New gastric cancers occurring during follow-up in 1984 to 2002 were identified by linkage to the Cancer Registry of Norway. Cox proportional hazards regression models were used to calculate hazard ratios with 95% confidence intervals, adjusted for age, sex, occupation, salt intake, smoking, and alcohol drinking. Follow-up of 73,133 cohort members (88% of all inhabitants) revealed 313 gastric cancers, including 264 noncardia cancers. No statistically significant associations were revealed between different levels of body mass index and risk of noncardia gastric cancer. A statistically significant 50% risk reduction among persons reporting at least a moderate level of recreational physical activity, based on a summary score of physical activity (hazard ratio, 0.5; 95% confidence interval, 0.3-0.9), and a dose-response relation was indicated (P for trend = 0.01). It is concluded that recreational physical activity might have a protective effect against gastric cancer. The sedentary lifestyle gaining ground in western societies might counteract the ongoing decrease in incidence of gastric cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(1):135–40)
Recreational Physical Activity and Cancer Risk in Subsites of the Colon (the Nord-Trøndelag Health Study)
Authors: Nilsen Tom I.L. , Romundstad Pål R. , Petersen Hermod , Gunnell David , Vatten Lars J.
Published: January 2008

Physical activity may reduce colon cancer risk, but the underlying mechanisms remain unclear. Relating physical activity to cancer risk in anatomic segments of the colon may advance our understanding of possible mechanisms. We conducted a prospective study of 59,369 Norwegian men and women who were followed up for cancer incidence and mortality. Cox proportional hazards models were used to estimate multivariably adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). All statistical tests were two sided. During 17 years of follow-up, 736 colon cancers and 294 rectal cancers were diagnosed. Overall, we found an inverse association between recreational physical activity and colon cancer risk, but subsite analyses showed that the association was confined to cancer in the transverse and sigmoid colon. The adjusted HR, comparing people who reported high versus no physical activity, was 0.44 (95% CI, 0.25-0.78) for cancer in the transverse colon and 0.48 (95% CI, 0.31-0.75) for cancer in the sigmoid colon. The corresponding HR for cancer mortality was 0.33 (95% CI, 0.14-0.76) for the transverse colon and 0.29 (95% CI, 0.15-0.56) for the sigmoid colon. For rectal cancer, there was no association with physical activity in these data. In conclusion, the inverse association of recreational physical activity with cancer risk and mortality in the transverse and sigmoid segments of the colon may point at increased colon motility and reduced fecal transit time as possible underlying mechanisms. (Cancer Epidemiol Biomarkers Prev 2008;17(1):183–8)