bluuebunny/crossref_metadata_2025_split huggingface dataset:
Downregulation of microRNA-515-5p by the Estrogen Receptor Modulates Sphingosine Kinase 1 and Breast Cancer Cell Proliferation
Authors: Pinho Filipa G. , Frampton Adam E. , Nunes Joao , Krell Jonathan , Alshaker Heba , Jacob Jimmy , Pellegrino Loredana , Roca-Alonso Laura , de Giorgio Alexander , Harding Victoria , Waxman Jonathan , Stebbing Justin , Pchejetski Dmitry , Castellano Leandro 
Published: August 2013

Abstract
Sphingosine kinase 1 (SK1) plays an important role in estrogen-dependent breast tumorigenesis, but its regulation is poorly understood. A subset of microRNAs (miRNA, miR) is regulated by estrogen and contributes to cellular proliferation and cancer progression. Here, we describe that miR-515-5p is transcriptionally repressed by estrogen receptor α (ERα) and functions as a tumor suppressor in breast cancer. Its downregulation enhances cell proliferation and estrogen-dependent SK1 activity, mediated by a reduction of miR-515-5p posttranscriptional repression. Enforced expression of miR-515-5p in breast cancer cells causes a reduction in SK1 activity, reduced cell proliferation, and the induction of caspase-dependent apoptosis. Conversely, opposing effects occur with miR-515-5p inhibition and by SK1 silencing. Notably, we show that estradiol (E2) treatment downregulates miR-515-5p levels, whereas the antiestrogen tamoxifen causes a decrease in SK1, which is rescued by silencing miR-515-5p. Analysis of chromatin immunoprecipitation sequencing (ChIP-Seq) data reveals that miR-515-5p suppression is mediated by a direct interaction of ERα within its promoter. RNA-sequencing (RNA-Seq) analysis of breast cancer cells after overexpressing miR-515-5p indicates that it partly modulates cell proliferation by regulating the Wnt pathway. The clinical implications of this novel regulatory system are shown as miR-515-5p is significantly downregulated in ER-positive (n = 146) compared with ER-negative (n = 98) breast cancers. Overall, we identify a new link between ERα, miR-515-5p, proliferation, and apoptosis in breast cancer tumorigenesis. Cancer Res; 73(19); 5936–48. ©2013 AACR.
Breast Tumor Kinase (Brk/PTK6) Is a Mediator of Hypoxia-Associated Breast Cancer Progression
Authors: Regan Anderson Tarah M. , Peacock Danielle L. , Daniel Andrea R. , Hubbard Gregory K. , Lofgren Kristopher A. , Girard Brian J. , Schörg Alexandra , Hoogewijs David , Wenger Roland H. , Seagroves Tiffany N. , Lange Carol A. 
Published: August 2013

Abstract
Basal-type triple-negative breast cancers (TNBC) are aggressive and difficult to treat relative to luminal-type breast cancers. TNBC often express abundant Met receptors and are enriched for transcriptional targets regulated by hypoxia-inducible factor-1α (HIF-1α), which independently predict cancer relapse and increased risk of metastasis. Brk/PTK6 is a critical downstream effector of Met signaling and is required for hepatocyte growth factor (HGF)–induced cell migration. Herein, we examined the regulation of Brk by HIFs in TNBC in vitro and in vivo. Brk mRNA and protein levels are upregulated strongly in vitro by hypoxia, low glucose, and reactive oxygen species. In HIF-silenced cells, Brk expression relied upon both HIF-1α and HIF-2α, which we found to regulate BRK transcription directly. HIF-1α/2α silencing in MDA-MB-231 cells diminished xenograft growth and Brk reexpression reversed this effect. These findings were pursued in vivo by crossing WAP-Brk (FVB) transgenic mice into the METMut knockin (FVB) model. In this setting, Brk expression augmented METMut-induced mammary tumor formation and metastasis. Unexpectedly, tumors arising in either METMut or WAP-Brk × METMut mice expressed abundant levels of Sik, the mouse homolog of Brk, which conferred increased tumor formation and decreased survival. Taken together, our results identify HIF-1α/2α as novel regulators of Brk expression and suggest that Brk is a key mediator of hypoxia-induced breast cancer progression. Targeting Brk expression or activity may provide an effective means to block the progression of aggressive breast cancers. Cancer Res; 73(18); 5810–20. ©2013 AACR.
Telomere Length in Peripheral Blood Lymphocytes Contributes to the Development of HPV-Associated Oropharyngeal Carcinoma
Authors: Zhang Yang , Sturgis Erich M. , Dahlstrom Kristina R. , Wen Juyi , Liu Hongliang , Wei Qingyi , Li Guojun , Liu Zhensheng 
Published: August 2013

Abstract
Sexual transmission of human papillomavirus (HPV), particularly HPV16, has been associated with an increasing incidence of oropharyngeal squamous cell carcinoma (OPC). Telomere shortening results in chromosomal instability, subsequently leading to cancer development. Given that HPV16 can affect telomerase activity and telomere length, we conjectured that telomere length in peripheral blood lymphocytes (PBL) might affect the risk of HPV16-associated OPC and tumor HPV16 status in patients. Telomere length in PBLs and HPV16 serologic status were measured in peripheral blood samples in 188 patients with OPC, 137 patients with oral cavity cancer (OCC) and 335 controls of non-Hispanic Whites. Tumor HPV status was determined in 349 OPC cases. ORs and 95% confidence intervals were calculated in univariate and multivariable logistic regression models. Overall, as compared with the long telomere length, short telomere length was significantly associated with a moderately increased risk of OPC but not with increased risk of OCC. When we stratified the data by HPV16 serologic status, using long telomere length and HPV16 seronegativity as the reference group, we found that the risk associated with HPV16 seropositivity was higher among patients with OPC with short telomere length. Notably, such risk was particularly pronounced in never smokers, never drinkers, and those more than 50 years of age. Furthermore, short telomere length was also associated significantly with tumor HPV-positive OPC. Together, our findings suggest that telomere length in PBLs may be associated with higher risk of HPV16-associated OPC and tumor HPV16 status, particularly in certain patient subgroups. Larger studies are needed to validate these findings. Cancer Res; 73(19); 5996–6003. ©2013 AACR.
Dynamic and Nuclear Expression of PDGFRα and IGF-1R in Alveolar Rhabdomyosarcoma
Authors: Aslam M. Imran , Hettmer Simone , Abraham Jinu , LaTocha Dorian , Soundararajan Anuradha , Huang Elaine T. , Goros Martin W. , Michalek Joel E. , Wang Shuyu , Mansoor Atiya , Druker Brian J. , Wagers Amy J. , Tyner Jeffrey W. , Keller Charles 
Published: August 2013

Abstract
Since the advent of tyrosine kinase inhibitors as targeted therapies in cancer, several receptor tyrosine kinases (RTK) have been identified as operationally important for disease progression. Rhabdomyosarcoma (RMS) is a malignancy in need of new treatment options; therefore, better understanding of the heterogeneity of RTKs would advance this goal. Here, alveolar RMS (aRMS) tumor cells derived from a transgenic mouse model expressing two such RTKs, platelet-derived growth factor (PDGFR)α and insulin-like growth factor (IGF)-1R, were investigated by fluorescence-activated cell sorting (FACS). Sorted subpopulations that were positive or negative for PDGFRα and IGF-1R dynamically altered their cell surface RTK expression profiles as early as the first cell division. Interestingly, a difference in total PDGFRα expression and nuclear IGF-1R expression was conserved in populations. Nuclear IGF-1R expression was greater than cytoplasmic IGF-1R in cells with initially high cell surface IGF-1R, and cells with high nuclear IGF-1R established tumors more efficiently in vivo. RNA interference–mediated silencing of IGF-1R in the subpopulation of cells initially harboring higher cell surface and total IGF-1R resulted in significantly reduced anchorage-independent colony formation as compared with cells with initially lower cell surface and total IGF-1R expression. Finally, in accordance with the findings observed in murine aRMS, human aRMS also had robust expression of nuclear IGF-1R.
Implications: RTK expression status and subcellular localization dynamics are important considerations for personalized medicine. Mol Cancer Res; 11(11); 1303–13. ©2013 AACR.
Sirolimus Stimulates Vascular Stem/Progenitor Cell Migration and Differentiation Into Smooth Muscle Cells via Epidermal Growth Factor Receptor/Extracellular Signal–Regulated Kinase/β-Catenin Signaling Pathway
Authors: Wong Mei Mei , Winkler Bernhard , Karamariti Eirini , Wang Xiaocong , Yu Baoqi , Simpson Russell , Chen Ting , Margariti Andriani , Xu Qingbo 
Published: August 2013

Objective—
Sirolimus-eluting stent therapy has achieved considerable success in overcoming coronary artery restenosis. However, there remain a large number of patients presenting with restenosis after the treatment, and the source of its persistence remains unclarified. Although recent evidence supports the contribution of vascular stem/progenitor cells in restenosis formation, their functional and molecular responses to sirolimus are largely unknown.

Approach and Results—
Using an established technique, vascular progenitor cells were isolated from adventitial tissues of mouse vessel grafts and purified with microbeads specific for stem cell antigen-1. We provide evidence that vascular progenitor cells treated with sirolimus resulted in an induction of their migration in both transwell and wound healing models, clearly mediated by CXCR4 activation. We confirmed the sirolimus-mediated increase of migration from the adventitial into the intima side using an ex vivo decellularized vessel scaffold, where they form neointima-like lesions that expressed high levels of smooth muscle cell (SMC) markers (SM-22α and calponin). Subsequent in vitro studies confirmed that sirolimus can induce SMC but not endothelial cell differentiation of progenitor cells. Mechanistically, we showed that sirolimus-induced progenitor-SMC differentiation was mediated via epidermal growth factor receptor and extracellular signal–regulated kinase 1/2 activation that lead to β-catenin nuclear translocation. The ablation of epidermal growth factor receptor, extracellular signal–regulated kinase 1/2, or β-catenin attenuated sirolimus-induced SM-22α promoter activation and SMC differentiation.

Conclusions—
These findings provide direct evidence of sirolimus-induced progenitor cell migration and differentiation into SMC via CXCR4 and epidermal growth factor receptor/extracellular signal–regulated kinase/β-catenin signal pathways, thus implicating a novel mechanism of restenosis formation after sirolimus-eluting stent treatment.
Relation of Regional Fat Distribution to Left Ventricular Structure and Function
Authors: Neeland Ian J. , Gupta Sachin , Ayers Colby R. , Turer Aslan T. , Rame J. Eduardo , Das Sandeep R. , Berry Jarett D. , Khera Amit , McGuire Darren K. , Vega Gloria L. , Grundy Scott M. , de Lemos James A. , Drazner Mark H. 
Published: August 2013

Background—
The relation of body fat distribution to left ventricular (LV) structure and function is poorly defined.

Methods and Results—

A total of 2710 participants without heart failure or LV dysfunction in the Dallas Heart Study underwent dual energy x-ray absorptiometry and MRI assessment of fat distribution, LV morphology, and hemodynamics. Cross-sectional associations of fat distribution with LV structure and function were examined after adjustment for age, sex, race, comorbidities, and lean mass. Mean age was 44 years with 55% women; 48% blacks; and 44% obese. After multivariable adjustment, visceral adipose tissue was associated with concentric remodeling characterized by lower LV end-diastolic volume (β=−0.21), higher concentricity (β=0.20), and wall thickness (β=0.09;
P
<0.0001 for all). In contrast, lower body subcutaneous fat was associated with higher LV end-diastolic volume (β=0.48), reduced concentricity (β=−0.50), and wall thickness (β=−0.28,
P
<0.0001 for all). Visceral adipose tissue was also associated with lower cardiac output (β=−0.10,
P
<0.05) and higher systemic vascular resistance (β=0.08,
P
<0.05), whereas lower body subcutaneous fat associated with higher cardiac output (β=0.20,
P
<0.0001) and lower systemic vascular resistance (β=−0.18,
P
<0.0001). Abdominal subcutaneous fat showed weaker associations with concentric remodeling and was not associated with hemodynamics. Among the subset of obese participants, visceral adipose tissue, but not abdominal subcutaneous fat, was significantly associated with concentric remodeling.

Conclusions—
Visceral adipose tissue, a marker of central adiposity, was independently associated with concentric LV remodeling and adverse hemodynamics. In contrast, lower body subcutaneous fat was associated with eccentric remodeling. The impact of body fat distribution on heart failure risk requires prospective study.
Serum Brain–Derived Neurotrophic Factor and Vascular Endothelial Growth Factor Levels Are Associated With Risk of Stroke and Vascular Brain Injury
Authors: Pikula Aleksandra , Beiser Alexa S. , Chen Tai C. , Preis Sarah R. , Vorgias Demetrios , DeCarli Charles , Au Rhoda , Kelly-Hayes Margaret , Kase Carlos S. , Wolf Philip A. , Vasan Ramachandran S. , Seshadri Sudha 
Published: August 2013

Background and Purpose—
Brain-derived neurotrophic factor (BDNF), a major neurotrophin and vascular endothelial growth factor (VEGF) have a documented role in neurogenesis, angiogenesis, and neuronal survival. In animal experiments, they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample.

Methods—
In 3440 Framingham Study participants (mean age, 65±11 years; 56% women) who were free of stroke/transient ischemic attack (TIA), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological tests available (n=1863 and 2104, respectively; mean age, 61±9 years, 55% women, in each), we related baseline BDNF and logVEGF to log-white matter hyperintensity volume on brain MRI, and to visuospatial memory and executive function tests.

Results—

During a median follow-up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age, sex, and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (hazard ratio comparing BDNF Q1 versus Q2–Q4, 1.47; 95% confidence interval, 1.09–2.00;
P
=0.012 and hazard ratio/SD increase in logVEGF, 1.21; 95% confidence interval, 1.04–1.40;
P
=0.012). Persons with higher BDNF levels had less log-white matter hyperintensity volume (β±SE=−0.05±0.02;
P
=0.025), and better visual memory (β±SE=0.18±0.07;
P
=0.005).

Conclusions—
Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury.
Genome-Wide Analysis of Blood Pressure Variability and Ischemic Stroke
Authors: Yadav Sunaina , Cotlarciuc Ioana , Munroe Patricia B. , Khan Muhammad S. , Nalls Michael A. , Bevan Steve , Cheng Yu-Ching , Chen Wei-Min , Malik Rainer , McCarthy Nina S. , Holliday Elizabeth G. , Speed Douglas , Hasan Nazeeha , Pucek Mateusz , Rinne Paul E. , Sever Peter , Stanton Alice , Shields Denis C. , Maguire Jane M. , McEvoy Mark , Scott Rodney J. , Ferrucci Luigi , Macleod Mary J. , Attia John , Markus Hugh S. , Sale Michele M. , Worrall Bradford B. , Mitchell Braxton D. , Dichgans Martin , Sudlow Cathy , Meschia James F. , Rothwell Peter M. , Caulfield Mark , Sharma Pankaj 
Published: August 2013

Background and Purpose—
Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke.

Methods—
A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings.

Results—

The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the
NLGN1
gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (
P
=1.4×10
−8
). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02; 95% CI, 0.97–1.07;
P
=0.52) or its subtypes: cardioembolic (odds ratio, 1.07; 95% CI, 0.97–1.16;
P
=0.17), large vessel disease (odds ratio, 0.98; 95% CI, 0.89–1.07;
P
=0.60), and small vessel disease (odds ratio, 1.07; 95% CI, 0.97–1.17;
P
=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (
P
=0.18).

Conclusions—

We identified a cluster of single nucleotide polymorphisms at the
NLGN1
locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes.
Geometric, Hemodynamic, and Pathological Study of a Distal Internal Carotid Artery Aneurysm Model in Dogs
Authors: Yan Lei , Zhu Yue-Qi , Li Ming-Hua , Tan Hua-Qiao , Cheng Ying-Sheng 
Published: August 2013

Background and Purpose—
We created a distal internal carotid artery side-wall aneurysm model in dogs and compared its geometric, hemodynamic, and histological similarities with human models.

Methods—
Eight distal internal carotid artery–shaped devices were constructed using rapid prototyping, and 8 aneurysms were created via surgical reconstruction and elastase incubation. The geometric and hemodynamic parameters of the aneurysm and the parent artery of the dog and human models were compared, and histological response was evaluated at 12 weeks.

Results—
Eight aneurysms were successfully created with good geometric simulation of the arteries between the dog and human models. Hemodynamic analysis revealed similar changes in the hemodynamic parameters both in the aneurysm sac and in the parent artery of the dog and human models. Histological analysis revealed internal elastic lamina discontinuity, elastic fiber disruption, a thinner muscular layer, increased smooth muscle cell proliferation rate, increased inflammation cell infiltration, and higher matrix metalloproteinase-2 and matrix metalloproteinase-9 expression indices in the medial aneurysm wall.

Conclusions—
The distal internal carotid artery aneurysm model in dogs is feasible and exhibited considerable geometric, hemodynamic, and histological similarities with the original human models.
Effects of Acute Dopamine Precusor Depletion on Immediate Reward Selection Bias and Working Memory Depend on Catechol-O-methyltransferase Genotype
Authors: Kelm Mary Katherine , Boettiger Charlotte A. 
Published: August 2013

Abstract
Little agreement exists as to acute dopamine (DA) manipulation effects on intertemporal choice in humans. We previously found that catechol-O-methyltransferase (COMT) Val158Met genotype predicts individual differences in immediate reward selection bias among adults. Moreover, we and others have shown that the relationship between COMT genotype and immediate reward bias is inverted in adolescents. No previous pharmacology studies testing DA manipulation effects on intertemporal choice have accounted for COMT genotype, and many have included participants in the adolescent age range (18–21 years) as adults. Moreover, many studies have included female participants without strict cycle phase control, although recent evidence demonstrates that cyclic estradiol elevations interact with COMT genotype to affect DA-dependent cognition. These factors may have interacted with DA manipulations in past studies, potentially occluding detection of effects. Therefore, we predicted that, among healthy male adults (ages 22–40 years), frontal DA tone, as indexed by COMT genotype, would interact with acute changes in DA signaling to affect intertemporal choice. In a double-blind, placebo-controlled design, we decreased central DA via administration of an amino acid beverage deficient in the DA precursors, phenylalanine and tyrosine, and tested effects on immediate reward bias in a delay-discounting (DD) task and working memory (WM) in an n-back task. We found no main effect of beverage on DD or WM performance but did find significant beverage*genotype effects. These results suggest that the effect of DA manipulations on DD depends on individual differences in frontal DA tone, which may have impeded some past efforts to characterize DA's role in immediate reward bias in humans.
The Use of Scripture in 4Q175
Authors: Katzin David 
Published: August 2013

Abstract
It has been previously suggested that 4Q175 21–30 utilizes rare words and phrases obtained through its use of a lexicon derived from the Hebrew scriptures. It has not been noticed, however, that this entire section is made up of a string of rare or otherwise conspicuous words and phrases that function as allusions to “biblical” verses. As a result of identifying the context and primary meaning of these allusions, it will be shown that 4Q175 as a whole can be understood as being a stylized blessing-cursing text as is seen elsewhere in the Qumran Library (QL). Further, the synonymous root words for arising, ק-ו-ם and ע-מ-ד serve as unifiers of the four sections of 4Q175. Most importantly, it will be shown through this exercise that the ultimate unifying aspect of 4Q175 is that it serves as a contemporizing exegesis on Deut 11:26–13. It will also become clear that Josh 6, which is the basis for 4Q175 21–30, is itself an intra-biblical midrash on Deuteronomy 13. This suggests that Jericho is being used as a cipher for the wayward city which is being discussed in 4Q175 21–30. All of this points to 4Q175 21–30 being an intrinsic part of 4Q175 rather than having been borrowed from 4Q379.
Faith in a Fashionable Age: Abraham Kuyper and Charles Taylor on the Secular Nexus Between Mode and Modernité
Authors: Covolo Robert Stephen 
Published: August 2013

AbstractThis article examines two Christian thinkers who detect a close relationship between fashion and secularity. First, the article discusses Reformed theologian Abraham Kuyper’s suspicion that the French fashion of his day carried political, cultural and social capacities that reinforced secularization in nineteenth century Holland. Having considered Kuyper’s perspective, the article turns to contemporary Roman Catholic philosopher Charles Taylor’s understanding of fashion. Drawing on Taylor’s magnum opus, A Secular Age, the article traces fashion’s complicit relationship with secularity as a ‘fourth axis of simultaneity’. In spite of their very different historical, intellectual and confessional contexts, Kuyper and Taylor share a similar analysis of the secularizing power of fashion, thereby pointing a way forward for those seeking to understand the relationship between mode and modernité.