bluuebunny/crossref_metadata_2025 huggingface dataset:
Does increased information about reproductive potential result in better prediction of recruitment?
Authors: Morgan M. Joanne , Perez-Rodriguez Alfonso , Saborido-Rey Fran
Published: August 2011

The relationship between stock size and recruitment is an essential element in the understanding of the productivity of a population. However, predicting the number of recruits produced by a population has proven to be a difficult challenge. This may in part be a result of poor estimation of reproductive potential (RP). We determined if including increased information on reproductive biology in indices of RP results in better predictions of recruitment. We investigated some of the conditions that lead to better (or worse) recruitment prediction when more biologically complex indices of RP are used. Data from four populations in the Northwest Atlantic were examined: southern Grand Bank (NAFO Division 3NO) cod ( Gadus morhua ), Flemish Cap (NAFO Division 3M) cod, Newfoundland (NAFO Division 3LNO) American plaice ( Hippoglossoides platessoides ), and Greenland halibut ( Reinhardtius hippoglossoides ) (NAFO Subarea 2 + Division 3KLMNO). Stock–recruit models paired with complex indices of RP gave a better estimate of recruitment in slightly more than half of the tests conducted. When there were larger trends in the reproductive biology (maturity at age, sex ratio and egg production), more complex indices of RP were more likely to provide a better estimate of recruitment.
Biogeochemical responses of two alpine lakes to climate change and atmospheric deposition, Jasper and Banff National parks, Canadian Rocky Mountains
Authors: Hobbs William O. , Vinebrooke Rolf D. , Wolfe Alexander P.
Published: August 2011

The sensitivity of remote alpine ecosystems to global change has been documented by 20th century changes in climate, glacial recession, and terrestrial and aquatic ecosystems. Here we present sedimentary records of biogeochemical responses in two alpine lake ecosystems to multiple environmental drivers over the last ∼500 years in Banff and Jasper National Parks (Alberta, Canada). We combine paleoecological measures of primary production and diatom community structure with geochemical proxies of reactive N (Nr) deposition to describe the nature and rate of recent ecosystem changes. Curator Lake in Jasper shows a strong diatom response to the limnological effects of climate warming (e.g., thermal stratification), but little evidence of changes in Nr cycling over the last ∼500 years. The response of McConnell Lake in Banff to climate change is strongly mediated by glacial activity within the catchment and changing inputs of Nr. Our findings highlight the range of limnological responses that may be expressed by similar ecosystems subjected to comparable abiotic stressors, while further documenting the magnitude of the ecological footprint associated with recent environmental change in mountain park environments.
Elemental fingerprints of southern calamary (Sepioteuthis australis) reveal local recruitment sources and allow assessment of the importance of closed areas
Authors: Pecl Gretta T. , Tracey Sean R. , Danyushevsky Leonid , Wotherspoon Simon , Moltschaniwskyj Natalie A.
Published: August 2011

Movement of individuals over a range of temporal and spatial scales is a critical process in determining the structure and size of populations. For most marine species, a substantial amount of movement that is responsible for connecting subpopulations occurs when individuals are too small and numerous to be tagged using conventional methods. Using the elemental fingerprints of the statoliths of the squid Sepioteuthis australis and a robust machine learning classification technique, this study determined that newly hatched squid had elemental signatures that exhibited sufficient spatial variation to act as natural tags for natal origin and that elemental signatures can be used to allocate adult squid back to their natal site. Between 55% and 84% of the adult squid caught throughout the east and southeast of Tasmania, Australia, were classified back to an area that is closed to commercial fishing over much of the peak spawning period, and this was the only location with substantive evidence of natal recruitment. Although many studies have demonstrated the potential of this approach to discern connectivity between population units, few studies have successfully done so by then examining the trace element profiles of adults in addition to those of hatchlings as we have demonstrated with S. australis.
Does timber harvest influence the dynamics of marine-derived nutrients in Southeast Alaska streams?
Authors: Levi Peter S. , Tank Jennifer L. , Tiegs Scott D. , Rüegg Janine , Chaloner Dominic T. , Lamberti Gary A.
Published: August 2011

Streams often rely on nutrient subsidies, and variation in nutrient delivery may alter the ecosystem response. Pacific salmon (Oncorhynchus spp.) provide marine-derived nutrients to their natal streams but also cause benthic disturbance, with the net effect determined by watershed and stream characteristics. To understand the factors contributing to variation in salmon-derived nutrients (SDN), we studied nutrient concentration and export in seven streams with varying physical characteristics due to timber harvest (e.g., channel complexity) over three years in Southeast Alaska, USA. Salmon increased concentrations and export of dissolved and particulate nitrogen, phosphorus, and carbon, but the magnitude of increase varied up to 41-fold among streams. The density of live salmon best predicted the increase in nutrient concentration and export, whereas the density of carcasses had a negligible effect. Nutrient export was predicted by transient storage before and after the salmon run. Streams in harvested watersheds with simplified channels had greater nutrient export than those in pristine watersheds with complex channels. However, enrichment from salmon overrode the effect of timber harvest on export during the run. Our study demonstrates that enrichment via SDN is short-lived and related to run size, whereas timber harvest and carcasses exert little influence on SDN dynamics.
Why does egg size of salmonids increase with the mean size of population spawning gravels?
Authors: Rollinson Njal , Hutchings Jeffrey A.
Published: August 2011

Population mean egg size of salmonids increases with the mean size of gravels in which a population spawns. A long-standing hypothesis is that large larvae cannot navigate small-gravel interstices, so mothers must decrease per-offspring investment when spawning gravels are small. We manipulated the size of incubation gravels and egg size of Atlantic salmon (Salmo salar) to test whether size-related entombment of larvae occurs. We find little evidence of size-related entombment, but we find evidence that gravel size does not affect all larval sizes equally. Larger larvae emerge from small gravels before development is complete and with a visible yolk sac, possibly due to oxygen limitation in small gravels. Smaller larvae always complete development in the gravel and emerge without a yolk sac. Although growth and survival may increase with juvenile size following yolk-sac absorption, juveniles with yolk sacs may fare worse when depredation rates are high. The egg size – gravel size correlation may therefore reflect increased postemergence mortality among larger offspring in small-gravel environments. Alternatively, compaction stress in fine gravels coupled with size asymmetries in larval strength may have caused the patterns that we observed, in which case our data may not help explain the egg size – gravel size correlation.
Prediction of biomass in Norwegian fish farms
Authors: Løland Anders , Aldrin Magne , Steinbakk Gunnhildur Högnadóttir , Huseby Ragnar Bang , Grøttum Jon Arne
Published: August 2011

We have constructed a statistical model to forecast, with uncertainty, the stock of Norwegian farmed Atlantic salmon ( Salmo salar ). The model provided good predictions of future biomass of Norwegian farmed salmon and can also be used to perform “what-if” analysis exploring the impact of varying scenarios for stocking and slaughtering. The model is based on the number of fish in each mass class (0–1, 1–2, …, 10+ kg) and their average mass. The model, which is related to standard size-structured models, computes the number of fish growing into the next mass class the next month and the number of fish remaining in the same mass class. In addition, the number of new fish stocked, fish lost, slaughtered, and wasted, as well as the sea temperature related to the growth, were modelled. All the model parameters were estimated based on monthly data from 2002 to 2007, and the model was validated statistically. Any animal production involving cycles may benefit from this forecasting tool.
Environment trumps predation and spatial factors in structuring cladoceran communities from Boreal Shield lakes
Authors: Kurek Joshua , Weeber Russ C. , Smol John P.
Published: August 2011

Understanding local and regional controls on communities is a major theme in ecology. Are communities mainly determined by local environmental gradients, local biotic interactions, and (or) dispersal processes? To address this, subfossil Cladocera were enumerated from the surface sediments of 50 remote Boreal Shield lakes in northwestern Ontario, Canada, to examine three ecologically relevant explanatory categories. Variation partitioning analyses were used to test and quantify the unique and shared effects of local abiotic measures, local predation factors, and spatial variables as predictors of community composition. Thirty-nine taxa were identified and communities were typically composed of pelagic taxa, such as Bosmina , daphniids, and Holopedium gibberum . Environmental variables (i.e., pH, lake surface area, specific conductivity, and lake water total aluminum concentration) explained uniquely 8.8% of the variation, which was 2.5 times greater than the unique contributions of predation or dispersal-related spatial variables. Predation and dispersal processes assumed lesser roles in structuring communities. Considering the extensive geographic scale of this study, our paleolimnological approach indicates that broad-scale dispersal limitation of cladocerans seems negligible for the many taxa examined here. Our findings further support the utility of cladocerans as key biological indicators to track environmental changes within Boreal Shield lakes.
Salmon carcasses alter leaf litter species diversity effects on in-stream decomposition
Authors: Bretherton Welles D. , Kominoski John S. , Fischer Dylan G. , LeRoy Carri J.
Published: August 2011

Marine-derived nutrients from salmon carcasses and leaf litter inputs from riparian vegetation may interactively support stream biodiversity and ecosystem functioning through enhanced resource heterogeneity. Using a full-factorial design of single- and mixed-species litters, we tested for influences of salmon carcasses on in-stream litter decomposition. Overall, nonadditive (synergistic and antagonistic) effects on decomposition were detected for litter species mixtures, and these effects were explained by litter species composition, but not species richness. In middle to late stages of decay, mixtures of labile (high-quality) litters showed faster than expected mass loss, and recalcitrant (low-quality) litter mixtures showed slower than expected mass loss. The presence or absence of each litter species differentially affected decomposition, but these patterns were stronger when salmon carcasses were available. Across all treatments, the influence of salmon carcasses on decomposition was most pronounced in mid-stages of litter decay, where deceleration of decomposition was likely caused by macroinvertebrates feeding on salmon carcasses and less on litter. Combined, these data demonstrate that salmon carcass inputs to streams can enhance detrital heterogeneity, alter interactions among species in litter mixtures, and influence ecosystem functioning (i.e., decomposition).
DIELECTRIC PROPERTIES AND ELECTRODYNAMIC PROCESS OF NATURAL ESTER-BASED INSULATING NANOFLUID
Authors: ZOU PING , LI JIAN , SUN CAI-XIN , ZHANG ZHAO-TAO , LIAO RUI-JIN
Published: August 2011

Natural ester is currently used as an insulating oil and coolant for medium-power transformers. The biodegradability of insulating natural ester makes it a preferable insulation liquid to mineral oils. In this work, Fe 3 O 4 nanoparticles were used along with oleic acid to improve the performance of insulating natural ester. The micro-morphology of Fe 3 O 4 nanoparticles before and after surface modification was observed through transmission electron microscopy. Attenuated total reflection-Fourier transform infrared spectroscopy, thermal gravimetric analysis, and differential thermal analysis were employed to investigate functional groups and their thermal stability on the surface-modified Fe 3 O 4 nanoparticles. Basic dielectric properties of natural ester-based insulating nanofluid were measured. The electrodynamic process in the natural ester-based insulating nanofluid is also presented.
SUPER-QUANTUM NONLOCAL CORRELATIONS IN QUATERNIONIC QUANTUM THEORY
Authors: MCKAGUE MATTHEW
Published: August 2011

We consider the nonlocal properties of naive quaternionic quantum theory, in which the complex numbers are replaced by the quaternions as the underlying algebra. Specifically, we show that it is possible to construct a nonlocal box. This allows one to rule out quaternionic quantum theory using assumptions about communication complexity or information causality while also providing a model for a nonlocal box using familiar structures.
MULTIPARTY REMOTELY PREPARING MULTIPARTITE EQUATORIAL ENTANGLED STATES IN HIGH DIMENSIONS
Authors: LI YI-BAO , HOU KUI , SHI SHOU-HUA
Published: August 2011

We propose two kinds of schemes for multiparty remote state preparation (MRSP) of the multiparticle d-dimensional equatorial quantum states by using partial entangled state as the quantum channel. Unlike more remote state preparation scheme which only one sender knows the original state to be remotely prepared, the quantum state is shared by two-party or multiparty in this scheme. We show that if and only if all the senders agree to collaborate with each other, the receiver can recover the original state with certain probability. It is found that the total success probability of MRSP is only by means of the smaller coefficients of the quantum channel and the dimension d.
QUANTUM ORACLES IN TERMS OF UNIVERSAL GATE SET
Authors: TANAKA YUJI , ICHIKAWA TSUBASA , TADA-UMEZAKI MASAHITO , OTA YUKIHIRO , NAKAHARA MIKIO
Published: August 2011

We present a systematic construction of quantum circuits implementing Grover's database search algorithm for arbitrary number of targets. We introduce a new operator which flips the sign of the targets and evaluate its circuit complexity. We find the condition under which the circuit complexity of the database search algorithm based on this operator is less than that of the conventional one.
The laxative effect of bisacodyl is attributable to decreased aquaporin-3 expression in the colon induced by increased PGE2secretion from macrophages
Authors: Ikarashi Nobutomo , Baba Kohta , Ushiki Takashi , Kon Risako , Mimura Ayako , Toda Takahiro , Ishii Makoto , Ochiai Wataru , Sugiyama Kiyoshi
Published: August 2011

The purpose of this study was to investigate the role of aquaporin3 (AQP3) in the colon in the laxative effect of bisacodyl. After oral administration of bisacodyl to rats, AQP3, macrophages, cyclooxygenase 2 (COX2), and prostaglandin E2(PGE2) were examined in the colon. The mechanism by which bisacodyl decreases the expression of AQP3 was examined using HT-29 and Raw264.7 cells. When diarrhea occurred, a significant increase in the expression of PGE2and a decrease in AQP3 expression were observed. Immunostaining showed COX2 expression only in macrophages. The PGE2concentration increased significantly 30 min after the addition of bisacodyl to Raw264.7 cells. Thirty minutes after PGE2addition to HT-29 cells, the AQP3 expression level decreased to 40% of the control. When pretreated with indomethacin, bisacodyl did not induce an increase in the colon PGE2level, a decrease in the AQP3 expression level, or diarrhea. The results suggest that bisacodyl may decrease the expression of AQP3 in the colon, which inhibits water transfer from the luminal to the vascular side and leads to a laxative effect. This study also showed that direct activation of colon macrophages by bisacodyl increases the secretion of PGE2, which acts as a paracrine factor and decreases AQP3 expression in colon mucosal epithelial cells.
Induction of Sca-1 via activation of STAT3 system in the duct cells of the mouse submandibular gland by ligation of the main excretory duct
Authors: Purwanti Nunuk , Karabasil Mileva Ratko , Matsuo Shinsuke , Chen Gang , Javkhlan Purevjav , Azlina Ahmad , Hasegawa Takahiro , Yao Chenjuan , Akamatsu Tetsuya , Hosoi Kazuo
Published: August 2011

To examine the very initial step that takes place immediately after tissue injury and is linked to tissue regeneration, we employed the submandibular gland (SMG), which was injured by ligation of its main excretory duct (MED). Ligation of the MED of the SMG in mice induced the expression of Sca-1, a protein marker of hematopoietic stem cells. In the normal gland, a low level of Sca-1 was expressed, which was localized predominantly in the excretory duct cells. At 1 day after ligation, Sca-1 expression increased prominently in almost all of cells in the duct system, but not in the acinar cells. The level of Sca-1 mRNA had begun to increase at 6 h after ligation and continuously rose thereafter until it reached a plateau, which occurred ∼12 h after ligation. STAT3 phosphorylated at its tyrosine-705 (p-STAT3) in the ligated gland increased immediately after ligation, and it was localized in the nuclei of all duct cells. The results of an EMSA revealed the specific binding of a nuclear extract to the sequence of the γ-interferon activation site (GAS) present in the Sca-1 promoter and confirmed that such binding increased after ligation. Thus the present study suggests that STAT3, having been phosphorylated following MED ligation, was transferred to the nucleus, where it bound to the GAS element in the promoter of Sca-1 gene, resulting in promotion of Sca-1 gene expression. Actual prevention of STAT3 phosphorylation reduced the ligation-induced Sca-1 elevation.
Mesenteric lymph flow in adult and aged rats
Authors: Akl Tony J. , Nagai Takashi , Coté Gerard L. , Gashev Anatoliy A.
Published: August 2011

The objective of study was to evaluate the aging-associated changes, contractile characteristics of mesenteric lymphatic vessels (MLV), and lymph flow in vivo in male 9- and 24-mo-old Fischer-344 rats. Lymphatic diameter, contraction amplitude, contraction frequency, and fractional pump flow, lymph flow velocity, wall shear stress, and minute active wall shear stress load were determined in MLV in vivo before and after Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME) application at 100 μM. The active pumping of the aged rat MLV in vivo was found to be severely depleted, predominantly through the aging-associated decrease in lymphatic contractile frequency. Such changes correlate with enlargement of aged MLV, which experienced much lower minute active shear stress load than adult vessels. At the same time, pumping in aged MLV in vivo may be rapidly increased back to levels of adult vessels predominantly through the increase in contraction frequency induced by nitric oxide (NO) elimination. Findings support the idea that in aged tissues surrounding the aged MLV, the additional source of some yet unlinked lymphatic contraction-stimulatory metabolites is counterbalanced or blocked by NO release. The comparative analysis of the control data obtained from experiments with both adult and aged MLV in vivo and from isolated vessel-based studies clearly demonstrated that ex vivo isolated lymphatic vessels exhibit identical contractile characteristics to lymphatic vessels in vivo.
Acute response of plasma markers of bone turnover to a single bout of resistance training or plyometrics
Authors: Rogers Robert S. , Dawson Andrew W. , Wang Ze , Thyfault John P. , Hinton Pamela S.
Published: August 2011

The time course of changes in plasma bone turnover markers following an acute bout of resistance training (RT) or plyometrics (PLY) has not been well characterized. This study is the first to compare the acute response of bone formation and resorption markers to a single bout of RT or PLY. Using a partially randomized, cross-over study design, 12 recreationally active men, aged 43 ± 5 yr, each completed four exercise trials: RT (Fed/Fasted) and PLY (Fed/Fasted). In addition to the RT and PLY trials, 5 of the original 12 participants also completed a fasted, no-exercise control trial to examine time-of-day variation. For each trial, blood was drawn immediately before exercise (PRE), immediately following exercise, and 15 min, 30 min, 1 h, 2 h, and 24 h following PRE for determination of plasma bone-specific alkaline phosphatase (BAP), osteocalcin (OC), tartrate-resistant acid phosphatase 5b (TRAP5b), COOH-terminal telopeptide of type I collagen (CTX), testosterone, parathyroid hormone, and cortisol. A one-factor repeated-measures ANOVA was performed for each trial to detect changes in bone markers during the 2 h following RT or PLY. TRAP5b transiently decreased during the 2 h following all exercise trials (main effect for time, P < 0.05), but returned to PRE concentrations 2 h postexercise. BAP, CTX, and OC remained unchanged, except for reductions in BAP and CTX following PLY-Fasted and PLY-Fed, respectively. During the control trial, BAP decreased, while TRAP5b, CTX, and OC remained unchanged. In general, plasma hormone concentrations decreased during the 2 h following PLY or RT, and cumulative decreases in TRAP5b during the 2 h following exercise were positively correlated with cumulative decreases in parathyroid hormone. The results of the present study suggest that the timing of the measurement of bone turnover markers relative to the last exercise bout is important for detection of exercise-associated changes in bone turnover markers, as the markers returned to preexercise values within 2 h of RT or PLY.
Effect of old age on human skeletal muscle force-velocity and fatigue properties
Authors: Callahan Damien M. , Kent-Braun Jane A.
Published: August 2011

It is generally accepted that the muscles of aged individuals contract with less force, have slower relaxation rates, and demonstrate a downward shift in their force-velocity relationship. The factors mediating age-related differences in skeletal muscle fatigue are less clear. The present study was designed to test the hypothesis that age-related shifts in the force-velocity relationship impact the fatigue response in a velocity-dependent manner. Three fatigue protocols, consisting of intermittent, maximum voluntary knee extension contractions performed for 4 min, were performed by 11 young (23.5 ± 0.9 yr, mean ± SE) and 10 older (68.9 ± 4.3) women. The older group fatigued less during isometric contractions than the young group (to 71.1 ± 3.7% initial torque and 59.8 ± 2.5%, respectively; P = 0.02), while the opposite was true during contractions performed at a relatively high angular velocity of 270°·s−1(old: 28.0 ± 3.9% initial power, young: 52.1 ± 6.9%; P < 0.01). Fatigue was not different ( P = 0.74) between groups during contractions at an intermediate velocity, which was selected for each participant based on their force-velocity relationship. There was a significant association between force-velocity properties and fatigue induced by the intermediate-velocity fatigue protocol in the older ( r = 0.72; P = 0.02) and young ( r = 0.63; P = 0.04) groups. These results indicate that contractile velocity has a profound impact on age-related skeletal muscle fatigue resistance and suggest that changes in the force-velocity relationship partially mediate this effect.
Extracting phase-dependent human vestibular reflexes during locomotion using both time and frequency correlation approaches
Authors: Blouin Jean-Sébastien , Dakin Christopher J. , van den Doel Kees , Chua Romeo , McFadyen Bradford J. , Inglis John Timothy
Published: August 2011

Daily activities, such as walking, may require dynamic modulation of vestibular input onto motoneurons. This dynamic modulation is difficult to identify in humans due to limitations in the delivery and analysis of current vestibular probes, such as galvanic vestibular stimulation. Stochastic vestibular stimulation, however, provides an alternative method to extract human vestibular reflexes. Here, we used time-dependent coherence and time-dependent cross-correlation, coupled with stochastic vestibular stimulation, to investigate the phase dependency of human vestibular reflexes during locomotion. We found that phase-dependent activity from the medial gastrocnemius muscles is correlated with the vestibular signals over the 2- to 20-Hz bandwidth during the stance phase of locomotion. Vestibular-gastrocnemius coherence and time-dependent cross-correlations reached maximums at 21 ± 4 and 23 ± 8% of the step cycle following heel contact and before the period of maximal electromyographic activity (38 ± 5%). These results demonstrate 1) the effectiveness of these techniques in extracting the phase-dependent modulation of vestibulomuscular coupling during a cyclic task; 2) that vestibulomuscular coupling is phasically modulated during locomotion; and 3) that the period of strongest vestibulomuscular coupling does not correspond to the period of maximal electromyographic activity in the gastrocnemius. Therefore, we have shown that stochastic vestibular stimulation, coupled with time-frequency decomposition, provides an effective tool to assess the contribution of vestibular ex-afference to the muscular control during locomotion.
Band 3 Missense Mutations and Stomatocytosis: Insight into the Molecular Mechanism Responsible for Monovalent Cation Leak
Authors: Barneaud-Rocca Damien , Pellissier Bernard , Borgese Franck , Guizouarn Hélène
Published: August 2011

Missense mutations in the erythroid band 3 protein (Anion Exchanger 1) have been associated with hereditary stomatocytosis. Features of cation leaky red cells combined with functional expression of the mutated protein led to the conclusion that the AE1 point mutations were responsible for and leak through a conductive mechanism. A molecular mechanism explaining mutated AE1-linked stomatocytosis involves changes in AE1 transport properties that become leaky to and . However, another explanation suggests that point-mutated AE1 could regulate a cation leak through other transporters. This short paper intends to discuss these two alternatives.
Existence and Uniqueness Theorem of Fractional Mixed Volterra‐Fredholm Integrodifferential Equation with Integral Boundary Conditions
Authors: Murad Shayma Adil , Zekri Hussein Jebrail , Hadid Samir
Published: August 2011

We study the existence and uniqueness of the solutions of mixed Volterra‐Fredholm type integral equations with integral boundary condition in Banach space. Our analysis is based on an application of the Krasnosel′skii fixed‐point theorem.
Automated Online Solid-Phase Extraction Coupled with Sequential Injection-HPLC-EC System for the Determination of Sulfonamides in Shrimp
Authors: Chantarateepra Pimkwan , Siangproh Weena , Motomizu Shoji , Chailapakul Orawon
Published: August 2011

The use of fully automated online solid-phase extraction (SPE) coupled with sequential injection analysis, high-performance liquid chromatography (HPLC), and electrochemical detection (EC) for the separation and determination of sulfonamides has been developed. A homemade microcolumn SPE system coupled with sequential injection analysis (SIA) was used to automate the sample cleanup and extraction of sulfonamides. The optimal flow rate of sample loading and elution was found to be 10 μL/s, and optimal elution time of zone was 20–24 s. Under the optimal conditions, a linear relationship between peak area and sulfonamide concentrations was obtained in the range of 0.01–8.0 μg mL−1. Detection limits for seven sulfonamides were between 1.2 ng mL−1and 11.2 ng mL−1. The proposed method has been applied for the determination of sulfonamides in shrimp. Recoveries in the range of 84–107% and relative standard deviations (RSDs) below 6.5% for intraday and 13% for inter-day were received for three concentration levels of spiking. The results showed that the present method was simple, rapid, accurate and highly sensitive for the determination of sulfonamides.
Activation of the Glucocorticoid Receptor Is Associated with Poor Prognosis in Estrogen Receptor-Negative Breast Cancer
Authors: Pan Deng , Kocherginsky Masha , Conzen Suzanne D.
Published: August 2011

Estrogen receptor–negative (ER−) breast cancers have limited treatment options and are associated with earlier relapses. Because glucocorticoid receptor (GR) signaling initiates antiapoptotic pathways in ER− breast cancer cells, we hypothesized that activation of these pathways might be associated with poor prognosis in ER− disease. Here we report findings from a genome-wide study of GR transcriptional targets in a premalignant ER− cell line model of early breast cancer (MCF10A-Myc) and in primary early-stage ER− human tumors. Chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) coupled to time-course expression profiling led us to identify epithelial-to-mesenchymal transition (EMT) pathways as an important aspect associated with GR activation. We validated these findings by carrying out a meta-analysis of primary breast tumor gene expression from 1,378 early-stage breast cancer patients with long-term clinical follow-up, confirming that high levels of GR expression significantly correlated with shorter relapse-free survival in ER− patients who were treated or untreated with adjuvant chemotherapy. Notably, in ER+ breast cancer patients, high levels of GR expression in tumors were significantly associated with better outcome relative to low levels of GR expression. Gene expression analysis revealed that ER− tumors expressing high GR levels exhibited differential activation of EMT, cell adhesion, and inflammation pathways. Our findings suggest a direct transcriptional role for GR in determining the outcome of poor-prognosis ER− breast cancers. Cancer Res; 71(20); 6360–70. ©2011 AACR.
miR-152 Is a Tumor Suppressor microRNA That Is Silenced by DNA Hypermethylation in Endometrial Cancer
Authors: Tsuruta Tomohiko , Kozaki Ken-ichi , Uesugi Atsushi , Furuta Mayuko , Hirasawa Akira , Imoto Issei , Susumu Nobuyuki , Aoki Daisuke , Inazawa Johji
Published: August 2011

The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer. Cancer Res; 71(20); 6450–62. ©2011 AACR.
Intratumoral De Novo Steroid Synthesis Activates Androgen Receptor in Castration-Resistant Prostate Cancer and Is Upregulated by Treatment with CYP17A1 Inhibitors
Authors: Cai Changmeng , Chen Sen , Ng Patrick , Bubley Glenn J. , Nelson Peter S. , Mostaghel Elahe A. , Marck Brett , Matsumoto Alvin M. , Simon Nicholas I. , Wang Hongyun , Chen Shaoyong , Balk Steven P.
Published: August 2011

Relapse of castration-resistant prostate cancer (CRPC) that occurs after androgen deprivation therapy of primary prostate cancer can be mediated by reactivation of the androgen receptor (AR). One important mechanism mediating this AR reactivation is intratumoral conversion of the weak adrenal androgens DHEA and androstenedione into the AR ligands testosterone and dihydrotestosterone. DHEA and androstenedione are synthesized by the adrenals through the sequential actions of the cytochrome P450 enzymes CYP11A1 and CYP17A1, so that CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, the significance of intratumoral CYP17A1 and de novo androgen synthesis from cholesterol in CRPC, and the mechanisms contributing to CYP17A1 inhibitor resistance/relapse, remain to be determined. We report that AR activity in castration-resistant VCaP tumor xenografts can be restored through CYP17A1-dependent de novo androgen synthesis, and that abiraterone treatment of these xenografts imposes selective pressure for increased intratumoral expression of CYP17A1, thereby generating a mechanism for development of resistance to CYP17A1 inhibitors. Supporting the clinical relevance of this mechanism, we found that intratumoral expression of CYP17A1 was markedly increased in tumor biopsies from CRPC patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a progesterone responsive T877A mutant AR are not CYP17A1 dependent, but that AR activity in these cells is still steroid dependent and mediated by upstream CYP11A1-dependent intraturmoral pregnenolone/progesterone synthesis. Together, our results indicate that CRPCs resistant to CYP17A1 inhibition may remain steroid dependent and therefore responsive to therapies that can further suppress de novo intratumoral steroid synthesis. Cancer Res; 71(20); 6503–13. ©2011 AACR.
Pivotal Role of Reducedlet-7gExpression in Breast Cancer Invasion and Metastasis
Authors: Qian Pengxu , Zuo Zehua , Wu Zhengsheng , Meng Xianyi , Li Gaopeng , Wu Zhengzhou , Zhang Weijie , Tan Sheng , Pandey Vijay , Yao Yandan , Wang Puyue , Zhao Liqing , Wang Jun , Wu Qiang , Song Erwei , Lobie Peter E. , Yin Zhinan , Zhu Tao
Published: August 2011

Screening of the entire let-7 family of microRNAs (miRNA) by in situ hybridization identified let-7g as the only member, the diminished expression of which was significantly associated with lymph node metastasis and poor survival in breast cancer patients. Abrogation of let-7g expression in otherwise nonmetastatic mammary carcinoma cells elicited rapid metastasis from the orthotopic location, through preferential targets, Grb2-associated binding protein 2 (GAB2) and fibronectin 1 (FN1), and consequent activation of p44/42 mitogen-activated protein kinase (MAPK) and specific matrix metalloproteinases. Treatment with estrogen or epidermal growth factor specifically reduced the expression of mature let-7g through activation of p44/42 MAPK and subsequently stimulated expression of GAB2 and FN1, which, in turn, promoted tumor invasion. We thus identify let-7g as a unique member of the let-7 miRNA family that can serve as a prognostic biomarker in breast cancer and also propose a paradigm used by specific signaling molecules via let-7g to cooperatively promote breast cancer invasion and metastasis. Thus, let-7 family members neither possess equivalent clinicopathologic correlation nor function in breast cancer. Cancer Res; 71(20); 6463–74. ©2011 AACR.
Asialoglycoprotein Receptor Promotes Cancer Metastasis by Activating the EGFR–ERK Pathway
Authors: Ueno Suguru , Mojic Marija , Ohashi Yoshimi , Higashi Nobuaki , Hayakawa Yoshihiro , Irimura Tatsuro
Published: August 2011

Although the importance of glycans in malignant cell behavior is well documented, the potential involvement of endogenous lectins as modifiers of progression and metastasis in the tumor microenvironment has not been explored. In this study, we show that loss of the hepatic asialoglycoprotein receptor (ASGPR) in mice severely reduces the frequency of spontaneous lung metastasis after intrahepatic implantation of murine Lewis lung carcinoma (3LL) cells. Conversely, in vitro treatment with recombinant ASGPR increased the invasive and metastatic capacity of 3LL cells before intrahepatic implantation. ASGPR treatment in vitro increased the expression and production of matrix metalloproteinase-9 through activation of the epidermal growth factor receptor–extracellular signal-regulated kinase (EGFR–ERK) pathway. Our findings identify ASGPR as a novel important factor that responds to endogenous lectins in the tumor microenvironment to promote cancer metastasis by activating the EGFR–ERK pathway through interactions with counter-receptors on cancer cells. Cancer Res; 71(20); 6419–27. ©2011 AACR.
Discriminant Analysis of 18F-Fluorothymidine Kinetic Parameters to Predict Survival in Patients with Recurrent High-Grade Glioma
Authors: Wardak Mirwais , Schiepers Christiaan , Dahlbom Magnus , Cloughesy Timothy , Chen Wei , Satyamurthy Nagichettiar , Czernin Johannes , Phelps Michael E. , Huang Sung-Cheng
Published: August 2011

Purpose: The primary objective of this study was to investigate whether changes in 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) kinetic parameters, taken early after the start of therapy, could predict overall survival (OS) and progression-free survival (PFS) in patients with recurrent malignant glioma undergoing treatment with bevacizumab and irinotecan.

Experimental Design: High-grade recurrent brain tumors were investigated in 18 patients (8 male and 10 female), ages 26 to 76 years. Each had 3 dynamic positron emission tomography (PET) studies as follows: at baseline and after 2 and 6 weeks from the start of treatment, 18F-FLT (2.0 MBq/kg) was injected intravenously, and dynamic PET images were acquired for 1 hour. Factor analysis generated factor images from which blood and tumor uptake curves were derived. A three-compartment, two-tissue model was applied to estimate tumor 18F-FLT kinetic rate constants using a metabolite- and partial volume–corrected input function. Different combinations of predictor variables were exhaustively searched in a discriminant function to accurately classify patients into their known OS and PFS groups. A leave-one-out cross-validation technique was used to assess the generalizability of the model predictions.

Results: In this study population, changes in single parameters such as standardized uptake value or influx rate constant did not accurately classify patients into their respective OS groups (<1 and ≥1 year; hit ratios ≤78%). However, changes in a set of 18F-FLT kinetic parameters could perfectly separate these two groups of patients (hit ratio = 100%) and were also able to correctly classify patients into their respective PFS groups (<100 and ≥100 days; hit ratio = 88%).

Conclusions: Discriminant analysis using changes in 18F-FLT kinetic parameters early during treatment seems to be a powerful method for evaluating the efficacy of therapeutic regimens. Clin Cancer Res; 17(20); 6553–62. ©2011 AACR.
Gain and Loss of Function for Glutathione Synthesis
Authors: Callegari Andrea , Liu Yuhua , White Collin C. , Chait Alan , Gough Peter , Raines Elaine W. , Cox David , Kavanagh Terrance J. , Rosenfeld Michael E.
Published: August 2011

Objective—

Glutamate-cysteine ligase (GCL) is the rate-limiting step in glutathione synthesis. The enzyme is a heterodimer composed of a catalytic subunit, GCLC, and a modifier subunit, GCLM. We generated apolipoprotein E (apoE)−/− mice deficient in GCLM (
apoE
−/−/
Gclm
−/−) and transgenic mice that overexpress GCLC specifically in macrophages (
apoE
−/−/
Gclc-Tg
) to test the hypothesis that significantly altering the availability of glutathione has a measurable impact on both the initiation and progression of atherosclerosis.

Methods and Results—

Atherosclerotic plaque size and composition were measured in the innominate artery in chow-fed male and female mice at 20, 30, 40, and 50 weeks of age and in the aortic sinus at 40 and 50 weeks of age. The
apoE
−/−/
Gclm
−/− mice more rapidly developed complex lesions, whereas the
apoE
−/−/
Gclc-Tg
mice had reduced lesion development compared with the littermate
apoE
−/− control mice. Transplantation of bone marrow from the
apoE
−/−/
Gclm
−/− and
apoE
−/−/
Gclc-Tg
mice into
apoE
−/− mice with established lesions also stimulated or inhibited further lesion development at 30 weeks posttransplant.

Conclusion—

Gain and loss of function in the capacity to synthesize glutathione especially in macrophages has reciprocal effects on the initiation and progression of atherosclerosis at multiple sites in apoE−/− mice.
Angiogenesis in Skeletal Muscle Precede Improvements in Peak Oxygen Uptake in Peripheral Artery Disease Patients
Authors: Duscha Brian D. , Robbins Jennifer L. , Jones William S. , Kraus William E. , Lye R. John , Sanders John M. , Allen Jason D. , Regensteiner Judith G. , Hiatt William R. , Annex Brian H.
Published: August 2011

Objective—

Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, causing claudication and exercise intolerance. The mechanism(s) by which exercise training improves functional capacity is not understood. This study tested the hypothesis that in PAD patients who undergo supervised exercise training, increases in capillary density (CD) in calf muscle take place before improvements in peak oxygen uptake (VO
2
).

Methods and Results—

Thirty-five PAD patients were randomly assigned to 12 weeks of directly supervised or home-based exercise training. Peak VO
2
testing and gastrocnemius muscle biopsies were performed at baseline and after training. CD (endothelial cells/mm
2
) was measured using immunofluorescence staining. After 3 weeks of directly supervised training, patients had an increase in CD (216±66 versus 284±77,
P
<0.01) but no increase in peak VO
2
. However, after 12 weeks, peak VO
2
increased (15.3±2.8 versus 16.8±3.8,
P
<0.01), whereas in muscle, CD remained increased over baseline, but there were no changes in markers of oxidative capacity. Within subjects, CD was related to peak VO
2
before and after directly supervised training.

Conclusion—

Changes in CD in ischemic muscle with training may modulate the response to training, and those changes precede the increase in VO
2
.
Myofibroblast-Mediated Adventitial Remodeling
Authors: Coen Matteo , Gabbiani Giulio , Bochaton-Piallat Marie-Luce
Published: August 2011

The arterial adventitia has been long considered an essentially supportive tissue; however, more and more data suggest that it plays a major role in the modulation of the vascular tone by complex interactions with structures located within intima and media. The purpose of this review is to summarize these data and to describe the mechanisms involved in adventitia/media and adventitia/intima cross-talk. In response to a plethora of stimuli, the adventitia undergoes remodeling processes, resulting in positive (adaptive) remodeling, negative (constrictive) remodeling, or both. The differentiation of the adventitial fibroblast into myofibroblast (MF), a key player of wound healing and fibrosis development, is a hallmark of negative remodeling; this can lead to vessel stenosis and thus contribute to major cardiovascular diseases. The mechanisms of fibroblast-to-MF differentiation and the role of the MF in adventitial remodeling are highlighted herein.
Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression
Authors: Arderiu Gemma , Peña Esther , Aledo Rosa , Juan-Babot Oriol , Badimon Lina
Published: August 2011

Objective—

Tissue factor (TF) triggers arterial thrombosis. TF is also able to initiate cellular signaling mechanisms leading to angiogenesis. Because high cardiovascular risk atherosclerotic plaques show significant angiogenesis, our objective was to investigate whether TF is able to trigger and stabilize atherosclerotic plaque neovessel formation.

Methods and Results—

In this study, we showed, by real-time confocal microscopy in 3-dimensional basement membrane cocultures, that TF in human microvascular endothelial cells (HMEC-1) and in human vascular smooth muscle cells (HVSMCs) plays an important role in the formation of capillary-like networks. TF silencing in endothelial cells and smooth muscle cells inhibits the formation of tube-like structures with stable phenotype. Using an in vivo model, we observed that TF inhibition in either HMEC-1 or HVSMCs reduced their shared ability to form new capillaries. The phenotypic changes induced by TF silencing were linked to reduced chemokine (C-C motif) ligand 2 (CCL2) expression in endothelial cells. Wound healing and chemotactic assays demonstrated that TF-induced release of CCL2 stimulated HVSMC migration to HMEC-1.

Conclusion—

Endogenous TF regulates CCL2 production in endothelial cells. Secreted CCL2 mediates the angiogenic effect of TF by recruiting smooth muscle cells toward endothelial cells and facilitates the maturation of newly formed microvessels.
Smooth Muscle Cholesterol Enables BK β1 Subunit-Mediated Channel Inhibition and Subsequent Vasoconstriction Evoked by Alcohol
Authors: Bukiya Anna N. , Vaithianathan Thirumalini , Kuntamallappanavar Guruprasad , Asuncion-Chin Maria , Dopico Alex M.
Published: August 2011

Objective—

Hypercholesterolemia and alcohol drinking constitute independent risk factors for cerebrovascular disease. Alcohol constricts cerebral arteries in several species, including humans. This action results from inhibition of voltage- and calcium-gated potassium channels (BK) in vascular smooth muscle cells (VSMC). BK activity is also modulated by membrane cholesterol. We investigated whether VSMC cholesterol regulates ethanol actions on BK and cerebral arteries.

Methods and Results—

After myogenic tone development, cholesterol depletion of rat, resistance-size cerebral arteries ablated ethanol-induced constriction, a result that was identical in intact and endothelium-free vessels. Cholesterol depletion reduced ethanol inhibition of BK whether the channel was studied in VSMC or after rat cerebral artery myocyte subunit (cbv1+β1) reconstitution into phospholipid bilayers. Homomeric cbv1 channels reconstituted into bilayers and VSMC BK from β1 knockout mice were both resistant to ethanol-induced inhibition. Moreover, arteries from β1 knockout mice failed to respond to ethanol even when VSMC cholesterol was kept unmodified. Remarkably, ethanol inhibition of cbv1+β1 in bilayers and wt mouse VSMC BK were drastically blunted by cholesterol depletion. Consistently, cholesterol depletion suppressed ethanol constriction of wt mouse arteries.

Conclusion—

VSMC cholesterol and BK β1 are both required for ethanol inhibition of BK and the resulting cerebral artery constriction, with health-related implications for manipulating cholesterol levels in alcohol-induced cerebrovascular disease.