bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Insulin Receptor in Breast Cancer Using Small Engineered Protein Scaffolds
Authors: Chan Jie Ying , Hackel Benjamin J. , Yee Douglas 
Published: May 2017

Abstract
Insulin receptor (InsR) and the type I insulin-like growth factor (IGF1R) are homologous receptors necessary for signal transduction by their cognate ligands insulin, IGF-I and IGF-II. IGF1R mAbs, intended to inhibit malignant phenotypic signaling, failed to show benefit in patients with endocrine-resistant tumors in phase III clinical trials. Our previous work showed that in tamoxifen-resistant cells, IGF1R expression was lacking, but InsR inhibition effectively blocked growth. In endocrine-sensitive breast cancer cells, insulin was not growth stimulatory, likely due to the presence of hybrid InsR/IGF1R, which has high affinity for IGF-I, but not insulin. Combination inhibition of InsR and IGF1R showed complete suppression of the system in endocrine-sensitive breast cancer cells. To develop InsR-binding agents, we employed a small protein scaffold, T7 phage gene 2 protein (Gp2) with the long-term goal of creating effective InsR inhibitors and diagnostics. Using yeast display and directed evolution, we identified three Gp2 variants (Gp2 #1, #5, and #10) with low nanomolar affinity and specific binding to cell surface InsR. These Gp2 variants inhibited insulin-mediated monolayer proliferation in both endocrine-sensitive and resistant breast cancer, but did not downregulate InsR expression. Gp2 #5 and Gp2 #10 disrupted InsR function by inhibiting ligand-induced receptor activation. In contrast, Gp2 #1 did not block InsR phosphorylation. Notably, Gp2 #1 binding was enhanced by pretreatment of cells with insulin, suggesting a unique receptor-ligand–binding mode. These Gp2 variants are the first nonimmunoglobulin protein scaffolds to target insulin receptor and present compelling opportunity for modulation of InsR signaling. Mol Cancer Ther; 16(7); 1324–34. ©2017 AACR.
Endothelial Myocyte Enhancer Factor 2c Inhibits Migration of Smooth Muscle Cells Through Fenestrations in the Internal Elastic Lamina
Authors: Lu Yao Wei , Lowery Anthony M. , Sun Li-Yan , Singer Harold A. , Dai Guohao , Adam Alejandro P. , Vincent Peter A. , Schwarz John J. 
Published: May 2017

Objective—
Laminar flow activates myocyte enhancer factor 2 (MEF2) transcription factors in vitro to induce expression of atheroprotective genes in the endothelium. Here we sought to establish the role of Mef2c in the vascular endothelium in vivo.

Approach and Results—

To study endothelial Mef2c, we generated endothelial-specific deletion of Mef2c using Tie2-Cre or Cdh5-Cre-ER
T2
and examined aortas and carotid arteries by en face immunofluorescence. We observed enhanced actin stress fiber formation in the Mef2c-deleted thoracic aortic endothelium (laminar flow region), similar to those observed in normal aortic inner curvature (disturbed flow region). Furthermore, Mef2c deletion resulted in the de novo formation of subendothelial intimal cells expressing markers of differentiated smooth muscle in the thoracic aortas and carotids. Lineage tracing showed that these cells were not of endothelial origin. To define early events in intimal development, we induced endothelial deletion of Mef2c and examined aortas at 4 and 12 weeks postinduction. The number of intimal cell clusters increased from 4 to 12 weeks, but the number of cells within a cluster peaked at 2 cells in both cases, suggesting ongoing migration but minimal proliferation. Moreover, we identified cells extending from the media through fenestrations in the internal elastic lamina into the intima, indicating transfenestral smooth muscle migration. Similar transfenestral migration was observed in wild-type carotid arteries ligated to induce neointimal formation.

Conclusions—
These results indicate that endothelial Mef2c regulates the endothelial actin cytoskeleton and inhibits smooth muscle cell migration into the intima.
Aortic Stiffness, Increased White Matter Free Water, and Altered Microstructural Integrity
Authors: Maillard Pauline , Mitchell Gary F. , Himali Jayandra J. , Beiser Alexa , Fletcher Evan , Tsao Connie W. , Pase Matthew P. , Satizabal Claudia L. , Vasan Ramachandran S. , Seshadri Sudha , DeCarli Charles 
Published: May 2017

Background and Purpose—
Previous reports from the Framingham Heart Study have identified cross-sectional associations of arterial stiffness, as reflected by carotid–femoral pulse wave velocity (CFPWV) and systolic blood pressure with vascular brain injury. The purpose of this study is to examine free water (FW), fractional anisotropy (FA), and white matter hyperintensities (WMH) in relation to arterial stiffness among subjects of the Framingham Offspring and Third-Generation cohorts.

Methods—
In 2422 participants aged 51.3±11.6 years, FA, FW, and WMH were related to CFPWV using voxel-based linear and generalized linear regressions, adjusting for relevant covariables. Mean FW, mean FA, and WMH burden (log transformed) were computed within white matter (WM) region and related to systolic blood pressure and CFPWV using multiple mediation analyses.

Results—

CFPWV was found to be associated with higher FW, lower FA, and higher WMH incidence in WM areas covering, respectively, 356.1, 211.8, and 10.9 mL of the WM mask. Mediation analyses revealed that the effect of systolic blood pressure on FW was mediated by CFPWV (direct and indirect effects: a=0.040;
P
<0.001, and a′=0.020;
P
>0.05). Moreover, the effect of CFPWV on FA was mediated by FW (direct and indirect effects: b=−0.092;
P
<0.001, and b′=0.012;
P
>0.05), whose effect on WMH was, in turn, mediated by FA (direct and indirect effects: c=0.246;
P
<0.001, and c′=0.116;
P
>0.05).

Conclusions—
From these data, we propose a biomechanical hypothesis designed for future research experiments to explain how hemodynamic alteration may lead to WM injury by impacting cerebral water content and more subtly WM integrity, to finally lead to WMH development.
Meanderings Around the Notion of ‘Contact’ in Reference to Languages, their Dynamics, and to ‘we’
Authors: Nicolaï Robert 
Published: May 2017

This paper is a linguistic, anthropological and philosophical exploration of language, with particular focus on language contact. The goal is not to address linguistic phenomena from a descriptive perspective, in the classical sense of the term, nor as if they were a “given”, and nothing further. Nor is the goal to craft a model. Instead it is an attempt to account for all relevant elements which (empirically) come into play in ordinary language use, considering them both in terms of language dynamics and in terms of language usage; this necessarily entails taking into consideration our own practices, as actors of communication and as builders of knowledge. We are ever stakeholders in this play (and its plays) because we are the ones who identify and/or attribute relevance.
In other words, this text is a reflection on the (our) frameworks established through communication practices (frameworks which naturally have an impact on the form of our tools, including languages!) It highlights that the objectivization of phenomena which underlies our practices (whether academic or not) is closely dependent on the means by which we grasp the phenomena—this is nothing new but is worth noting afresh.
Methodologically speaking, observing this point is an essential element in the elaboration of a theory to account for how phenomena are empirically grasped, and more particularly what it entails in the field of ‘language contact’.
Planning for Winter Road Maintenance in the Context of Climate Change
Authors: Matthews Lindsay , Andrey Jean , Picketts Ian 
Published: May 2017

Abstract
Winter weather creates mobility challenges for most northern jurisdictions, leading to significant expenditures on winter road maintenance (WRM) activities. While the science and practice of snow and ice control is continually evolving, climate change presents particular challenges for the strategic planning of WRM. The purpose of this study is 1) to develop a winter severity index (WSI) to better understand how winter weather translates into interannual variations in WRM activities and 2) to apply the WSI to future climate change projections to assist a northern community in preparing for climate change. A new method for creating a WSI model is explored, using readily available data from maintenance records and meteorological stations. The WSI is created by optimizing values for three levels of snowfall as well as potential icing events and is shown to have high predictive accuracy for WRM (coefficient of determination R2 of 0.93). The WSI is then applied to historic and future climate data in a municipality located in central British Columbia, Canada. Findings reveal that much of the variability in WRM can be attributed to weather. The results of the climate change analysis show that winter precipitation in the region is expected to increase by 5.2%–12.3%, and winter average temperatures are projected to increase by 1.5°–2.8°C in the 2050s, compared to the 1976–2000 baseline based on 65 GCMs. Based on the midrange (25th to 75th percentiles) of the 65 GCM projections, annual demand for WRM activities is estimated to decrease by 13.0%–22.0%.
Hybrid ECG-gated versus non-gated 512-slice CT angiography of the aorta and coronary artery: image quality and effect of a motion correction algorithm
Authors: Lee Ji Won , Kim Chang Won , Lee Geewon , Lee Han Cheol , Kim Sang-Pil , Choi Bum Sung , Jeong Yeon Joo 
Published: May 2017

Background Using the hybrid electrocardiogram (ECG)-gated computed tomography (CT) technique, assessment of entire aorta, coronary arteries, and aortic valve can be possible using single-bolus contrast administration within a single acquisition. Purpose To compare the image quality of hybrid ECG-gated and non-gated CT angiography of the aorta and evaluate the effect of a motion correction algorithm (MCA) on coronary artery image quality in a hybrid ECG-gated aorta CT group. Material and Methods In total, 104 patients (76 men; mean age = 65.8 years) prospectively randomized into two groups (Group 1 = hybrid ECG-gated CT; Group 2 = non-gated CT) underwent wide-detector array aorta CT. Image quality, assessed using a four-point scale, was compared between the groups. Coronary artery image quality was compared between the conventional reconstruction and motion correction reconstruction subgroups in Group 1. Results Group 1 showed significant advantages over Group 2 in aortic wall, cardiac chamber, aortic valve, coronary ostia, and main coronary arteries image quality (all P < 0.001). All Group 1 patients had diagnostic image quality of the aortic wall and left ostium. The MCA significantly improved the image quality of the three main coronary arteries ( P < 0.05). Moreover, per-vessel interpretability improved from 92.3% to 97.1% with the MCA ( P = 0.013). Conclusion Hybrid ECG-gated CT significantly improved the heart and aortic wall image quality and the MCA can further improve the image quality and interpretability of coronary arteries.
The Effect of Subcritical Bone Loss and Exposure on Recurrent Instability After Arthroscopic Bankart Repair in Intercollegiate American Football
Authors: Dickens Jonathan F. , Owens Brett D. , Cameron Kenneth L. , DeBerardino Thomas M. , Masini Brendan D. , Peck Karen Y. , Svoboda Steven J. 
Published: May 2017

Background:There is no consensus on the optimal method of stabilization (arthroscopic or open) in collision athletes with anterior shoulder instability.Purpose:To examine the effect of “subcritical” bone loss and football-specific exposure on the rate of recurrent shoulder instability after arthroscopic stabilization in an intercollegiate American football population.Study Design:Case-control study; Level of evidence, 3.Methods:Fifty intercollegiate football players underwent primary arthroscopic stabilization for anterior shoulder instability and returned to football for at least a single season. Preoperatively, 32 patients experienced recurrent subluxations, and 18 patients experienced a single or recurrent dislocation. Shoulders with glenoid bone loss >20%, an engaging Hill-Sachs lesion, an off-track lesion, and concomitant rotator cuff repair were excluded from the study. The primary outcome of interest was the ability to return to football without subsequent instability. Patients were followed for time to a subsequent instability event after return to play using days of exposure to football and total follow-up time after arthroscopic stabilization.Results:Fifty consecutive patients returned to American football for a mean 1.5 seasons (range, 1-3) after arthroscopic stabilization. Three of 50 (6%; 95% CI, 1.3%-16.5%) patients experienced recurrent instability. There were no subsequent instability events after a mean 3.2 years of military service. All shoulders with glenoid bone loss >13.5% (n = 3) that underwent arthroscopic stabilization experienced recurrent instability upon returning to sport, while none of the shoulders with <13.5% glenoid bone loss (n = 47) sustained a recurrent instability event during football ( X2= 15.80, P < .001). Shoulders with >13.5% glenoid bone loss had an incidence rate of 5.31 cases of recurrent instability per 1000 athlete-exposures of football. In 72,000 athlete-exposures to football with <13.5% glenoid bone loss, there was no recurrent instability. Significantly more anchors were used during the primary arthroscopic stabilization procedure in patients who experienced multiple preoperative instability events ( P = .005), and lesions spanned significantly more extensive portions along the circumference of the glenoid ( P = .001) compared with shoulders having a single preoperative instability event before surgical stabilization.Conclusion:Arthroscopic stabilization of anterior shoulder instability in American football players with <13.5% glenoid bone loss provides reliable outcomes and low recurrence rates.
ABC gene expression profiles have clinical importance and possibly form a new hallmark of cancer
Authors: Dvorak Pavel , Pesta Martin , Soucek Pavel 
Published: May 2017

Adenosine triphosphate–binding cassette proteins constitute a large family of active transporters through extracellular and intracellular membranes. Increased drug efflux based on adenosine triphosphate–binding cassette protein activity is related to the development of cancer cell chemoresistance. Several articles have focused on adenosine triphosphate–binding cassette gene expression profiles (signatures), based on the expression of all 49 human adenosine triphosphate–binding cassette genes, in individual tumor types and reported connections to established clinicopathological features. The aim of this study was to test our theory about the existence of adenosine triphosphate–binding cassette gene expression profiles common to multiple types of tumors, which may modify tumor progression and provide clinically relevant information. Such general adenosine triphosphate–binding cassette profiles could constitute a new attribute of carcinogenesis. Our combined cohort consisted of tissues from 151 cancer patients—breast, colorectal, and pancreatic carcinomas. Standard protocols for RNA isolation and quantitative real-time polymerase chain reaction were followed. Gene expression data from individual tumor types as well as a merged tumor dataset were analyzed by bioinformatics tools. Several general adenosine triphosphate–binding cassette profiles, with differences in gene functions, were established and shown to have significant relations to clinicopathological features such as tumor size, histological grade, or clinical stage. Genes ABCC7, A3, A8, A12, and C8 prevailed among the most upregulated or downregulated ones. In conclusion, the results supported our theory about general adenosine triphosphate–binding cassette gene expression profiles and their importance for cancer on clinical as well as research levels. The presence of ABCC7 (official symbol CFTR) among the genes with key roles in the profiles supports the emerging evidence about its crucial role in various cancers. Graphical abstract
A Novel Intervention for System-Involved Intimate Partner Violence Survivors: Changes in Parenting
Authors: Wretman Christopher J. , Rizo Cynthia Fraga , Macy Rebecca J. , Guo Shenyang , Ermentrout Dania 
Published: May 2017

Purpose: A growing subpopulation of intimate partner violence (IPV) victims comprises mothers who have been mandated to services by either the court system or child protective services (CPS). Two human service agencies in the United States developed a 13-week novel intervention to address these women. All participants were assigned to the intervention, which featured group psychoeducation sessions, social events, and childcare. Method: This quasi-experimental study gathered preliminary evidence regarding whether the intervention promoted participants’ ( N = 70) parenting practices. Specifically, growth curve analyses using hierarchical linear modeling examined outcomes at completion (3 months) and follow-up (6 months). Results: Participants reported statistically significant improvements on key parenting practices at both postintervention time points. Conclusions: This study provides preliminary support for engaging court- and CPS-involved female IPV survivors in specialized, group-based interventions such as that investigated herein. Future research should investigate similar programs using larger samples and more robust designs.
Dietary constituent, decanoic acid suppresses the excitability of nociceptive trigeminal neuronal activity associated with hypoalgesia via muscarinic M2 receptor signaling
Authors: Noguchi Yuna , Matsuzawa Nichiwa , Akama Youichi , Sekiguchi Kenta , Takehana Shiori , Shimazu Yoshihito , Takeda Mamoru 
Published: May 2017

Background Although decanoic acid (DA) is thought to act as a muscarinic cholinergic agonist, effect of DA on nociceptive behavioral responses and the excitability of nociceptive neuronal activity under in vivo conditions remain to be determined. The aim of the present study, therefore, was to investigate whether in vivo acute administration of ointment containing DA affects the excitability of nociceptive trigeminal spinal nucleus caudalis (SpVc) neurons associated with hypoalgesia in naïve rats. Results After local application of DA, the threshold of escape from mechanical stimulation applied to the shaved orofacial skin was significantly higher than before DA application. Vehicle treatment (without DA) had no significant effect on the escape threshold from mechanical stimulation. Extracellular single unit recordings were made from SpVc wide-dynamic range (WDR) neurons in response to orofacial non-noxious and noxious mechanical stimuli of pentobarbital-anesthetized rats. The mean firing frequency of SpVc WDR neurons in response to noxious, but not non-noxious, mechanical stimuli was inhibited by local application of DA, and the maximum inhibition of discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 1–5 min. The DA-induced short-term inhibitory effects were reversed after approximately 10 min. Pretreatment intravenously with the muscarinic-specific M2 receptor antagonist, methoctramine, abolished the DA-induced suppression of firing frequency of SpVc WDR neurons in response to noxious stimulation. Fluorogold (FG) labeling was identified as the trigeminal ganglion (TG) neurons innervating orofacial skin. FG-labeled small-diameter TG neurons expressed M2 receptor immunoreactivity. Conclusion These results suggest that acute DA application induces short-term mechanical hypoalgesia and this effect was mainly due to suppression of the excitability of SpVc WDR neurons via the peripheral M2 receptor signaling pathway in the trigeminal primary afferents. These findings support the idea that DA is a potential therapeutic agent and complementary alternative medicine for the attenuation of trigeminal nociception in the absence of inflammatory/neuropathic conditions.
A mathematical framework to quantify the masking effect associated with the confidence intervals of measures of disproportionality
Authors: Maignen François , Hauben Manfred , Dogné Jean-Michel 
Published: May 2017

Background: The lower bound of the 95% confidence interval of measures of disproportionality (Lower95CI) is widely used in signal detection. Masking is a statistical issue by which true signals of disproportionate reporting are hidden by the presence of other medicines. The primary objective of our study is to develop and validate a mathematical framework for assessing the masking effect of Lower95CI. Methods: We have developed our new algorithm based on the masking ratio (MR) developed for the measures of disproportionality. A MR for the Lower95CI (MRCI) is proposed. A simulation study to validate this algorithm was also conducted. Results: We have established the existence of a very close mathematical relation between MR and MRCI. For a given drug–event pair, the same product will be responsible for the highest masking effect with the measure of disproportionality and its Lower95CI. The extent of masking is likely to be very similar across the two methods. An important proportion of identical drug–event associations affected by the presence of an important masking effect is revealed by the unmasking exercise, whether the proportional reporting ratio (PRR) or its confidence interval are used. Conclusion: The detection of the masking effect of Lower95CI can be automated. The real benefits of this unmasking in terms of new true-positive signals (rate of true-positive/false-positive) or time gained by the revealing of signals using this method have not been fully assessed. These benefits should be demonstrated in the context of prospective studies.
Zolpidem prescribing practices before and after Food and Drug Administration required product labeling changes
Authors: Norman Jessica L , Fixen Danielle R , Saseen Joseph J , Saba Laura M , Linnebur Sunny A 
Published: May 2017

Background: Women have higher morning serum zolpidem concentrations than men after taking an evening dose, potentially leading to increased risk of harm. On 19 April 2013, the United States Food and Drug Administration required labeling changes for zolpidem, recommending an initial dose of no greater than 5 mg (immediate release) or 6.25 mg (controlled release) per night in women. Objectives: The primary objective of this study was to compare prescribing practices before and after the 2013 zolpidem labeling change. A secondary objective was to evaluate serious adverse events potentially related to zolpidem. Methods: Electronic medical records of adults receiving care through the University of Colorado Health system were accessed for study inclusion if patients were provided a first-time prescription for zolpidem either prior to or after the Food and Drug Administration labeling change. Patients were randomly chosen from eight strata based on age, gender, and date of zolpidem initiation (before/after the labeling change). Demographic and zolpidem prescribing data were collected. Low-dose zolpidem was considered 5 mg (immediate release) or 6.25 mg (controlled release) daily or less. Documentation of potentially related serious adverse events within the patients’ records was also evaluated. Results: A total of 400 patients were included in the study. The overall percentage of patients prescribed low-dose zolpidem increased from 44% to 58% after the labeling change (p = 0.0020). In a pre-specified subgroup analysis, the percentage of patients prescribed low-dose zolpidem increased in all groups, including young men (38%–50%, p = 0.23), elderly men (34%–40%, p = 0.53), and elderly women (60%–74%, p = 0.14), but the change was only significant in young women (42%–70%, p = 0.0045). Conclusion: After Food and Drug Administration–mandated labeling changes for zolpidem in 2013, the percentage of overall patients in our health system, and specifically young women, with initial prescriptions for low-dose zolpidem significantly increased as compared to before the labeling change.