bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.
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

Abstract
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

Abstract
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

Abstract
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

AbstractScreening 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

Abstract
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

Abstract
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 (&lt;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 (&lt;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.
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.
Urokinase-Type Plasminogen Activator Deficiency in Bone Marrow–Derived Cells Augments Rupture of Angiotensin II–Induced Abdominal Aortic Aneurysms
Authors: Uchida Haruhito A. , Poduri Aruna , Subramanian Venkateswaran , Cassis Lisa A. , Daugherty Alan 
Published: August 2011

Objective—
Abdominal aortic aneurysms (AAAs) are associated with fragmentation of extracellular matrix during development of aortic dilation and rupture. Therefore, it is important to identify specific protease systems involved in extracellular matrix degradation during AAA formation. The present study determined the contribution of the urokinase system to AAA formation and rupture.

Methods and Results—
Angiotensin II (Ang II)–induced AAAs were associated with increased aortic abundance of both urokinase-type plasminogen activator receptor (uPAR) and urokinase-type plasminogen activator (uPA) proteins. However, this increased presence was unrelated to AAA formation because deficiencies of either uPAR or uPA had no effect on either the incidence or size of Ang II–induced AAAs in both normolipidemic mice and low-density lipoprotein receptor−/− mice fed a saturated fat–enriched diet. Although uPA deficiency did not affect development of AAAs, there was an effect of increasing mortality rate from AAA rupture in hypercholesterolemic mice. Bone marrow transplantation demonstrated that enhanced aneurysmal rupture was attributable to deficiency of uPA in leukocytes. uPA deficiency led to an increased propensity for impaired resolution of the thrombotic material within the aneurysmal tissue. Neither uPAR nor uPA deficiency had any effect on Ang II–induced atherosclerosis in low-density lipoprotein receptor−/− mice.

Conclusion—
The uPA-uPAR axis has no effect on the formation of Ang II–induced AAAs, but uPA deficiency promotes aneurysmal rupture.