bluuebunny/crossref_metadata_2025_split huggingface dataset:
Failure to Induce Apoptosis via BCL-2 Family Proteins Underlies Lack of Efficacy of Combined MEK and PI3K Inhibitors for KRAS-Mutant Lung Cancers
Authors: Hata Aaron N. , Yeo Alan , Faber Anthony C. , Lifshits Eugene , Chen Zhao , Cheng Katherine A. , Walton Zandra , Sarosiek Kristopher A. , Letai Anthony , Heist Rebecca S. , Mino-Kenudson Mari , Wong Kwok-Kin , Engelman Jeffrey A. 
Published: March 2014

Abstract
Although several groups have demonstrated that concomitant use of MEK and phosphoinositide 3-kinase (PI3K) inhibitors (MEKi/PI3Ki) can induce dramatic tumor regressions in mouse models of KRAS-mutant non–small cell lung cancer (NSCLC), ongoing clinical trials investigating this strategy have been underwhelming to date. While efficacy may be hampered by a narrow therapeutic index, the contribution of biologic heterogeneity in the response of KRAS-mutant NSCLCs to MEKi/PI3Ki has been largely unexplored. In this study, we find that most human KRAS-mutant NSCLC cell lines fail to undergo marked apoptosis in response to MEKi/PI3Ki, which is key for tumor responsiveness in vivo. This heterogeneity of apoptotic response occurs despite relatively uniform induction of growth arrest. Using a targeted short hairpin RNA screen of BCL-2 family members, we identify BIM, PUMA, and BCL-XL as key regulators of the apoptotic response induced by MEKi/PI3Ki, with decreased expression of BIM and PUMA relative to BCL-XL in cell lines with intrinsic resistance. In addition, by modeling adaptive resistance to MEKi/PI3Ki both in vitro and in vivo, we find that, upon the development of resistance, tumors have a diminished apoptotic response due to downregulation of BIM and PUMA. These results suggest that the inability to induce apoptosis may limit the effectiveness of MEKi/PI3Ki for KRAS-mutant NSCLCs by contributing to intrinsic and adaptive resistance to this therapy. Cancer Res; 74(11); 3146–56. ©2014 AACR.
Coenzyme Q10 Promotes Macrophage Cholesterol Efflux by Regulation of the Activator Protein-1/miR-378/ATP-Binding Cassette Transporter G1–Signaling Pathway
Authors: Wang Dongliang , Yan Xiao , Xia Min , Yang Yan , Li Dan , Li Xinrui , Song Fenglin , Ling Wenhua 
Published: March 2014

Objective—
Recent studies have shown the role of miRNAs in macrophage reverse cholesterol transport and atherogenesis. We hypothesized that coenzyme Q10 (CoQ10) may increase macrophage reverse cholesterol transport by regulating miRNA expression that contributes to the prevention of atherosclerosis.

Approach and Results—
CoQ10 treatment suppressed oxidized low-density lipoprotein–induced macrophage foam cell formation by ameliorating the binding of activator protein-1 to the putative promoter region of miR-378 primary transcript, thus decreasing the miR-378 level and enhancing the ATP-binding cassette transporter G1–mediated macrophage cholesterol efflux to high-density lipoprotein. Subsequently, the axis of activator protein-1/miR-378/ATP-binding cassette transporter G1 cholesterol efflux was confirmed in peritoneal macrophages isolated from CoQ10-treated apolipoprotein E–deficient mice. Finally, CoQ10 consumption promoted macrophage reverse cholesterol transport and inhibited the progression of atherosclerosis in apolipoprotein E–deficient mice.

Conclusions—
This study identified activator protein-1/miR-378/ATP-binding cassette transporter G1 as a novel cascade for CoQ10 in facilitating macrophage cholesterol efflux in vitro and in vivo. Our data thus imply that both CoQ10 and miR-378 are promising candidates for atherosclerosis prevention and treatment.
Mechanistic Insights and Characterization of Sickle Cell Disease–Associated Cardiomyopathy
Authors: Desai Ankit A. , Patel Amit R. , Ahmad Homaa , Groth John V. , Thiruvoipati Thejasvi , Turner Kristen , Yodwut Chattanong , Czobor Peter , Artz Nicole , Machado Roberto F. , Garcia Joe G.N. , Lang Roberto M. 
Published: March 2014

Background—
Cardiovascular disease is an important cause of morbidity and mortality in sickle cell disease (SCD). We sought to characterize sickle cell cardiomyopathy using multimodality noninvasive cardiovascular testing and identify potential causative mechanisms.

Methods and Results—

Stable adults with SCD (n=38) and healthy controls (n=13) prospectively underwent same day multiparametric cardiovascular magnetic resonance (cine, T2* iron, vasodilator first pass myocardial perfusion, and late gadolinium enhancement imaging), transthoracic echocardiography, and applanation tonometry. Compared with controls, patients with SCD had severe dilation of the left ventricle (124±27 vs 79±12 mL/m
2
), right ventricle (127±28 vs 83±14 mL/m
2
), left atrium (65±16 vs 41±9 mL/m
2
), and right atrium (78±17 vs 56±17 mL/m
2
;
P
<0.01 for all). Patients with SCD also had a 21% lower myocardial perfusion reserve index than control subjects (1.47±0.34 vs 1.87±0.37;
P
=0.034). A significant subset of patients with SCD (25%) had evidence of late gadolinium enhancement, whereas only 1 patient had evidence of myocardial iron overload. Diastolic dysfunction was present in 26% of patients with SCD compared with 8% in controls. Estimated filling pressures (E/e′, 9.3±2.7 vs 7.3±2.0;
P
=0.0288) were higher in patients with SCD. Left ventricular dilation and the presence of late gadolinium enhancement were inversely correlated to hepatic T2* times (ie, hepatic iron overload because of frequent blood transfusions;
P
<0.05 for both), whereas diastolic dysfunction and increased filling pressures were correlated to aortic stiffness (augmentation pressure and index,
P
<0.05 for all).

Conclusions—
Sickle cell cardiomyopathy is characterized by 4-chamber dilation and in some patients myocardial fibrosis, abnormal perfusion reserve, diastolic dysfunction, and only rarely myocardial iron overload. Left ventricular dilation and myocardial fibrosis are associated with increased blood transfusion requirements, whereas left ventricular diastolic dysfunction is predominantly correlated with increased aortic stiffness.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01044901.
Gift, Sale, and Theft: Juan de Ribera and the Sacred Economy of Relics in the Early Modern Mediterranean
Authors: Harris A. Katie 
Published: March 2014

Abstract
In 1599 Valencia celebrated the arrival of an ancient Christian martyr whose remains were the latest addition to the collection of the city’s archbishop, Juan de Ribera (1532-1611). Through an examination of some of Archbishop Ribera’s relic acquisitions, I explore the inner workings of the early modern sacred economy of relics. Ribera’s collection strategies blended distinct modes of exchange and linked him to a clandestine economy of relic theft. These transactions reflected the relic’s own uncertain ontological status as both person and object. This ambivalence became a factor that fostered an atmosphere of anxiety around the early modern relic economy, as did Protestant reformers’ critiques and their upending of the traditional Christian symbolic order. The reaffirmations of the cult of relics by the Tridentine Church stabilized the value of the sacred commodities. The economy of relics illustrates how the sacred constitutes a heretofore underexamined area of inquiry for commodity studies.
Essentially Contested Concepts and Semantic Externalism
Authors: Evnine Simon J. 
Published: March 2014

Abstract
In 1956, W.B. Gallie introduced his idea of essentially contested concepts. In my paper, I offer a novel interpretation of his theory and argue that his theory, thus interpreted, is correct. The key to my interpretation lies in a condition Gallie places on essentially contested concepts that other interpreters downplay or dismiss: that the use of an essentially contested concept must be derived “from an original exemplar whose authority is acknowledged by all the contestant users of the concept.” This reveals a similarity between Gallie’s views and the semantic externalist views of Hilary Putnam, and others, about natural kind terms like “water” and “tiger.” I argue that natural kind terms and terms for essentially contested concepts are two species of a single semantic genus. In the case of natural kind terms, a term refers to a natural kind, the exemplars are instances of that kind, and the relation between the exemplars and anything to which the term applies is co-membership of the kind. In the case of terms for essentially contested concepts, a term refers to an historical tradition, the exemplar is a stage or temporal part of that tradition, and the relation between the exemplar and anything to which the term refers is being the heir of. This allows me to understand the contests that alerted Gallie to the phenomenon of essentially contested concepts as contests over the ownership of historical traditions.
Consistency of metagenomic assignment programs in simulated and real data
Authors: Garcia-Etxebarria Koldo , Garcia-Garcerà Marc , Calafell Francesc 
Published: March 2014

Abstract

Background
Metagenomics is the genomic study of uncultured environmental samples, which has been greatly facilitated by the advent of shotgun-sequencing technologies. One of the main focuses of metagenomics is the discovery of previously uncultured microorganisms, which makes the assignment of sequences to a particular taxon a challenge and a crucial step. Recently, several methods have been developed to perform this task, based on different methodologies such as sequence composition or sequence similarity. The sequence composition methods have the ability to completely assign the whole dataset. However, their use in metagenomics and the study of their performance with real data is limited. In this work, we assess the consistency of three different methods (BLAST + Lowest Common Ancestor, Phymm, and Naïve Bayesian Classifier) in assigning real and simulated sequence reads.

Results
Both in real and in simulated data, BLAST + Lowest Common Ancestor (BLAST + LCA), Phymm, and Naïve Bayesian Classifier consistently assign a larger number of reads in higher taxonomic levels than in lower levels. However, discrepancies increase at lower taxonomic levels. In simulated data, consistent assignments between all three methods showed greater precision than assignments based on Phymm or Bayesian Classifier alone, since the BLAST + LCA algorithm performed best. In addition, assignment consistency in real data increased with sequence read length, in agreement with previously published simulation results.

Conclusions
The use and combination of different approaches is advisable to assign metagenomic reads. Although the sensitivity could be reduced, the reliability can be increased by using the reads consistently assigned to the same taxa by, at least, two methods, and by training the programs using all available information.
DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: a comprehensive profiling approach
Authors: Loh Marie , Liem Natalia , Vaithilingam Aparna , Lim Pei Li , Sapari Nur Sabrina , Elahi Eiram , Mok Zuan Yu , Cheng Chee Leong , Yan Benedict , Pang Brendan , Salto-Tellez Manuel , Yong Wei Peng , Iacopetta Barry , Soong Richie 
Published: March 2014

AbstractBackgroundMethylation-induced silencing of promoter CpG islands in tumor suppressor genes plays an important role in human carcinogenesis. In colorectal cancer, the CpG island methylator phenotype (CIMP) is defined as widespread and elevated levels of DNA methylation and CIMP+ tumors have distinctive clinicopathological and molecular features. In contrast, the existence of a comparable CIMP subtype in gastric cancer (GC) has not been clearly established. To further investigate this issue, in the present study we performed comprehensive DNA methylation profiling of a well-characterised series of primary GC.MethodsThe methylation status of 1,421 autosomal CpG sites located within 768 cancer-related genes was investigated using the Illumina GoldenGate Methylation Panel I assay on DNA extracted from 60 gastric tumors and matched tumor-adjacent gastric tissue pairs. Methylation data was analysed using a recursively partitioned mixture model and investigated for associations with clinicopathological and molecular features including age,Helicobacter pyloristatus, tumor site, patient survival, microsatellite instability andBRAFandKRASmutations.ResultsA total of 147 genes were differentially methylated between tumor and matched tumor-adjacent gastric tissue, withHOXA5and hedgehog signalling being the top-ranked gene and signalling pathway, respectively. Unsupervised clustering of methylation data revealed the existence of 6 subgroups under two main clusters, referred to as L (low methylation; 28% of cases) and H (high methylation; 72%). Female patients were over-represented in the H tumor group compared to L group (36% vs 6%; P = 0.024), however no other significant differences in clinicopathological or molecular features were apparent. CpG sites that were hypermethylated in group H were more frequently located in CpG islands and marked for polycomb occupancy.ConclusionsHigh-throughput methylation analysis implicates genes involved in embryonic development and hedgehog signaling in gastric tumorigenesis. GC is comprised of two major methylation subtypes, with the highly methylated group showing some features consistent with a CpG island methylator phenotype.
Solitary myofibroma of the mandible in an adult with magnetic resonance imaging and positron emission tomography findings: a case report
Authors: Tanaka Yoko , Yamada Hiroyuki , Saito Tomoyuki , Nakaoka Kazutoshi , Kumagai Kenichi , Fujihara Hisako , Mishima Kenji , Hamada Yoshiki 
Published: March 2014

Abstract
Myofibroma is a benign tumor composed of myoid spindle cells. The prevalence of myofibroma in the oral cavity is very low, with the mandible being the most common site. This report describes an adult case of myofibroma that arose on the mandible and includes magnetic resonance imaging (MRI) and positron emission tomography (PET) findings. On the MRI T1-weighted images, the tumor appeared with signal iso-intensity and was highly and heterogeneously enhanced with contrast material. On the T2-weighted images, it appeared with increased signal intensity. 18 F-fluorodeoxyglucose (FDG)-PET imaging showed abnormal strong accumulation of FDG in the left mandibular region. The tumor was removed by marginal resection of the left mandible under general anesthesia. Histopathological findings revealed that the tumor stroma contained abundant thin-walled vessels. The postoperative course was uneventful, and we found no evidence of recurrence at the postoperative 34-month follow-up.
Iterative algorithms for quasi-variational inclusions and fixed point problems of pseudocontractions
Authors: Yao Yonghong , Agarwal Ravi P , Liou Yeong-Cheng 
Published: March 2014

Abstract
In this paper, quasi-variational inclusions and fixed point problems of pseudocontractions are considered. An iterative algorithm is presented. A strong convergence theorem is demonstrated.

MSC:49J40, 47J20, 47H09, 65J15.
Food allergen sensitization pattern in adults in relation to severity of atopic dermatitis
Authors: Röckmann Heike , van Geel Maartje J , Knulst Andre C , Huiskes Jorike , Bruijnzeel‐Koomen Carla AFM , de Bruin‐Weller Marjolein S 
Published: March 2014

AbstractBackgroundLimited data are available on the frequency of IgE mediated food sensitization and food allergy (FA) in adults with atopic dermatitis (AD).ObjectiveWe investigated the pattern of food sensitization in adults with AD in relation to AD severity using multiplexed allergen microarray.Methods211 adult patients referred between January 2010‐July 2011 for evaluation of AD were unselectively included. Severity of AD was determined by therapy intensity, SASSAD‐skin‐score and sTARC levels. Allergen specific sIgE levels were measured by ImmunoCAP ISAC® microarray. FA was defined as convincing history taken by physician and sensitization to the corresponding allergen.ResultsSensitization to food was found in 74.4% of the AD patients, 54% had a positive history of FA and 20.4% asymptomatic sensitization. There was no association between severity of AD and frequency of food sensitization or history of FA.Sensitization to PR‐10 related food allergens occurred most frequently (63.5%) and was independent from AD severity. Correspondingly, pollen‐food syndrome accounted for most of the FA, being also independent from AD severity. Of all plant food allergens only sensitization to nAra h 1 was significantly more frequent in patients with severe AD. In the total group 75 (35.5%) patients with AD showed sensitization to any animal food allergen. The percentage was significantly higher in patients with severe AD (51.4%) compared to patients with mild/moderate AD (27.7%). Sensitization to cow's milk allergens, in particular to nBos d lactoferrin, was more frequent in severe AD patients.ConclusionAD was frequently associated with food sensitization. The percentage of sensitization to animal food allergens was significantly higher in severe AD patients.
Maintenance cognitive stimulation therapy for dementia: single-blind, multicentre, pragmatic randomised controlled trial
Authors: Orrell Martin , Aguirre Elisa , Spector Aimee , Hoare Zoe , Woods Robert T. , Streater Amy , Donovan Helen , Hoe Juanita , Knapp Martin , Whitaker Christopher , Russell Ian 
Published: March 2014

BackgroundThere is good evidence for the benefits of short-term cognitive stimulation therapy for dementia but little is known about possible long-term effects.AimsTo evaluate the effectiveness of maintenance cognitive stimulation therapy (CST) for people with dementia in a single-blind, pragmatic randomised controlled trial including a substudy with participants taking acetylcholinesterase inhibitors (AChEIs).MethodThe participants were 236 people with dementia from 9 care homes and 9 community services. Prior to randomisation all participants received the 7-week, 14-session CST programme. The intervention group received the weekly maintenance CST group programme for 24 weeks. The control group received usual care. Primary outcomes were cognition and quality of life (clinical trial registration: ISRCTN26286067).ResultsFor the intervention group at the 6-month primary end-point there were significant benefits for self-rated quality of life (Quality of Life in Alzheimer's Disease (QoL-AD) P = 0.03). At 3 months there were improvements for proxy-rated quality of life (QoL-AD P = 0.01, Dementia Quality of Life scale (DEMQOL) P = 0.03) and activities of daily living (P = 0.04). The intervention subgroup taking AChEIs showed cognitive benefits (on the Mini-Mental State Examination) at 3 (P = 0.03) and 6 months (P = 0.03).ConclusionsContinuing CST improves quality of life; and improves cognition for those taking AChEIs.
Upper body contributions to power generation during rapid, overhand throwing in humans
Authors: Roach Neil T. , Lieberman Daniel E. 
Published: March 2014

AbstractHigh-speed and accurate throwing is a distinctive human behavior. Achieving fast projectile speeds during throwing requires a combination of elastic energy storage at the shoulder, as well as the transfer of kinetic energy from proximal body segments to distal segments. However, the biomechanical bases of these mechanisms are not completely understood. We used inverse dynamics analyses of kinematic data from 20 baseball players fitted with 4 different braces that inhibit specific motions to test a model of power generation at key joints during the throwing motion. We found that most of the work produced during throwing is generated at the hips, and much of this work (combined with smaller contributions from the pectoralis major) is used to load elastic elements in the shoulder and power the rapid acceleration of the projectile. Despite rapid angular velocities at the elbow and wrist, the restrictions confirm that much of the power generated to produce these distal movements comes from larger proximal segments, such as the shoulder and torso. Wrist hyperextension enhances performance only modestly. Together, our data also suggest heavy reliance on elastic energy storage may help explain some common throwing injuries and can provide further insight into the evolution of the upper body and when our ancestors first developed the ability to produce high speed throws.
Active gated imaging in driver assistance system
Authors: Grauer Yoav 
Published: March 2014

Abstract
In this paper, we shall present the active gated imaging system (AGIS) in relation to the automotive field. AGIS is based on a fast-gated camera and pulsed illuminator, synchronized in the time domain to record images of a certain range of interest. A dedicated gated CMOS imager sensor and near infra-red (NIR) pulsed laser illuminator, is presented in this paper to provide active gated technology. In recent years, we have developed these key components and learned the system parameters, which are most beneficial to nighttime (in all weather conditions) driving in terms of field of view, illumination profile, resolution, and processing power. We shall present our approach of a camera-based advanced driver assistance systems (ADAS) named BrightEye™, which makes use of the AGIS technology in the automotive field.
Cicero’s Theology and the Concept of Fate
Authors: Begemann Elisabeth 
Published: March 2014

Abstract This article examines Cicero’s discussion of theology in the context of providing Rome with philosophical writings. I argue that in his treatises de natura deorum, de divinatione and de fato, Cicero conceptualized a traditional, idealized version of Roman theology under the premise that religio and cultus deorum are indispensable for a moral society as it is outlined in de re publica and de legibus. In continually stressing active divine participation in the lives of men, Cicero underlines the importance of goodwill between the divine and human spheres which finds expression in cultus deorum. As concepts such as Stoic fate run counter to the belief that the gods can be ritually influenced by prayer or ritual, the gods can neither be identified with fate itself nor be subject to it. Cicero rather stresses free will in all contexts to uphold the moral society, both human and divine.
Management of neonates born to women with Graves' disease: a cohort study
Authors: Besançon Alix , Beltrand Jacques , Le Gac Isabelle , Luton Dominique , Polak Michel 
Published: March 2014

ObjectiveHyperthyroidism in neonates born to mothers with Graves' disease (GD) can be associated with significant morbidity and mortality, but is still overlooked by clinicians. Management of neonatal hyperthyroidism would be improved by a better understanding of the predictive factors involved. The aim of this study was to evaluate the course of thyroid function and clinical outcomes during the first postnatal month in babies born to mothers with GD.DesignProspective observational study.MethodsSixty-eight neonates born to mothers with GD were managed from birth and divided into three groups based on thyrotropin receptor antibody (TRAb) and anti-thyroid drug (ATD) status in the mother: TRAb−ve/ATD−ve,n=27; TRAb−ve/ATD+ve,n=8; and TRAb+ve/ATD+ve,n=33. The main outcome measures were clinical examination, thyroid function tests (TSH, free thyroxine (FT4), free triiodothyronine, and TRAb), echocardiography, thyroid ultrasonography, and bone maturation assessment.ResultsNone of the infants born to TRAb−vemothers with GD developed neonatal hyperthyroidism. Of the 33 TRAb+ve/ATD+veneonates, 24 (72.7%) had positive TRAb on cord blood assays, and seven of these developed neonatal hyperthyroidism. FT4elevation between days 3 and 7 but not at birth was predictive of the development of hyperthyroidism.ConclusionsTRAb status should be checked in the third trimester in mothers with GD and on cord blood in their neonates; if positive, it indicates a high risk of neonatal hyperthyroidism. FT4measurement at birth should be repeated between days 3 and 5 (and by day 7 at the latest); rapid FT4elevation during the first postnatal week is predictive of hyperthyroidism and warrants ATD therapy.