bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer
Authors: Barr Martin P , Gray Steven G , Gately Kathy , Hams Emily , Fallon Padraic G , Davies Anthony Mitchell , Richard Derek J , Pidgeon Graham P , O’Byrne Kenneth J 
Published: February 2015

Abstract
Background
The VEGF pathway has become an important therapeutic target in lung cancer, where VEGF has long been established as a potent pro-angiogenic growth factor expressed by many types of tumors. While Bevacizumab (Avastin) has proven successful in increasing the objective tumor response rate and in prolonging progression and overall survival in patients with NSCLC, the survival benefit is however relatively short and the majority of patients eventually relapse. The current use of tyrosine kinase inhibitors alone and in combination with chemotherapy has been underwhelming, highlighting an urgent need for new targeted therapies. In this study, we examined the mechanisms of VEGF-mediated survival in NSCLC cells and the role of the Neuropilin receptors in this process.

Methods
NSCLC cells were screened for expression of VEGF and its receptors. The effects of recombinant VEGF and its blockade on lung tumor cell proliferation and cell cycle were examined. Phosphorylation of Akt and Erk1/2 proteins was examined by high content analysis and confocal microscopy. The effects of silencing VEGF on cell proliferation and survival signaling were also assessed. A Neuropilin-1 stable-transfected cell line was generated. Cell growth characteristics in addition to pAkt and pErk1/2 signaling were studied in response to VEGF and its blockade. Tumor growth studies were carried out in nude mice following subcutaneous injection of NP1 over-expressing cells.

Results
Inhibition of the VEGF pathway with anti-VEGF and anti-VEGFR-2 antibodies or siRNA to VEGF, NP1 and NP2 resulted in growth inhibition of NP1 positive tumor cell lines associated with down-regulation of PI3K and MAPK kinase signaling. Stable transfection of NP1 negative cells with NP1 induced proliferation in vitro, which was further enhanced by exogenous VEGF. In vivo, NP1 over-expressing cells significantly increased tumor growth in xenografts compared to controls.

Conclusions
Our data demonstrate that VEGF is an autocrine growth factor in NSCLC signaling, at least in part, through NP1. Targeting this VEGF receptor may offer potential as a novel therapeutic approach and also support the evaluation of the role of NP1 as a biomarker predicting sensitivity or resistance to VEGF and VEGFR-targeted therapies in the clinical arena.
Dexmedetomidine versus standard care sedation with propofol or midazolam in intensive care: an economic evaluation
Authors: Turunen Heidi , Jakob Stephan M , Ruokonen Esko , Kaukonen Kirsi-Maija , Sarapohja Toni , Apajasalo Marjo , Takala Jukka 
Published: February 2015

Abstract
Introduction
Dexmedetomidine was shown in two European randomized double-blind double-dummy trials (PRODEX and MIDEX) to be non-inferior to propofol and midazolam in maintaining target sedation levels in mechanically ventilated intensive care unit (ICU) patients. Additionally, dexmedetomidine shortened the time to extubation versus both standard sedatives, suggesting that it may reduce ICU resource needs and thus lower ICU costs. Considering resource utilization data from these two trials, we performed a secondary, cost-minimization analysis assessing the economics of dexmedetomidine versus standard care sedation.

Methods
The total ICU costs associated with each study sedative were calculated on the basis of total study sedative consumption and the number of days patients remained intubated, required non-invasive ventilation, or required ICU care without mechanical ventilation. The daily unit costs for these three consecutive ICU periods were set to decline toward discharge, reflecting the observed reduction in mean daily Therapeutic Intervention Scoring System (TISS) points between the periods. A number of additional sensitivity analyses were performed, including one in which the total ICU costs were based on the cumulative sum of daily TISS points over the ICU period, and two further scenarios, with declining direct variable daily costs only.

Results
Based on pooled data from both trials, sedation with dexmedetomidine resulted in lower total ICU costs than using the standard sedatives, with a difference of €2,656 in the median (interquartile range) total ICU costs—€11,864 (€7,070 to €23,457) versus €14,520 (€7,871 to €26,254)—and €1,649 in the mean total ICU costs. The median (mean) total ICU costs with dexmedetomidine compared with those of propofol or midazolam were €1,292 (€747) and €3,573 (€2,536) lower, respectively. The result was robust, indicating lower costs with dexmedetomidine in all sensitivity analyses, including those in which only direct variable ICU costs were considered. The likelihood of dexmedetomidine resulting in lower total ICU costs compared with pooled standard care was 91.0% (72.4% versus propofol and 98.0% versus midazolam).

Conclusions
From an economic point of view, dexmedetomidine appears to be a preferable option compared with standard sedatives for providing light to moderate ICU sedation exceeding 24 hours. The savings potential results primarily from shorter time to extubation.

Trial registration
ClinicalTrials.gov NCT00479661 (PRODEX), NCT00481312 (MIDEX).
Dynamic changes of microbial flora and therapeutic consequences in persistent peritonitis
Authors: Montravers Philippe , Dufour Guillaume , Guglielminotti Jean , Desmard Mathieu , Muller Claudette , Houissa Hamda , Allou Nicolas , Marmuse Jean-Pierre , Augustin Pascal 
Published: February 2015

Abstract
Introduction
Persistent peritonitis is a frequent complication of secondary peritonitis requiring additional reoperations and antibiotic therapy. This situation raises specific concerns due to microbiological changes in peritoneal samples, especially the emergence of multidrug-resistant (MDR) strains. Although this complication has been extensively studied, the rate and dynamics of MDR strains have rarely been analysed.

Methods
We compared the clinical, microbiological and therapeutic data of consecutive ICU patients admitted for postoperative peritonitis either without subsequent reoperation (n = 122) or who underwent repeated surgery for persistent peritonitis with positive peritoneal fluid cultures (n = 98). Data collected on index surgery for the treatment of postoperative peritonitis were compared between these two groups. In the patients with persistent peritonitis, the data obtained at the first, second and third reoperations were compared with those of index surgery. Risk factors for emergence of MDR strains were assessed.

Results
At the time of index surgery, no parameters were able to differentiate patients with or without persistent peritonitis except for increased severity and high proportions of fungal isolates in the persistent peritonitis group. The mean time to reoperation was similar from the first to the third reoperation (range: 5 to 6 days). Septic shock was the main clinical expression of persistent peritonitis. A progressive shift of peritoneal flora was observed with the number of reoperations, comprising extinction of susceptible strains and emergence of 85 MDR strains. The proportion of patients harbouring MDR strains increased from 41% at index surgery, to 49% at the first, 54% at the second (P = 0.037) and 76% at the third reoperation (P = 0.003 versus index surgery). In multivariate analysis, the only risk factor for emergence of MDR strains was time to reoperation (OR 1.19 per day, 95%CI (1.08 to 1.33), P = 0.0006).

Conclusions
Initial severity, presence of Candida in surgical samples and inadequate source control are the major risk factors for persistent peritonitis. Emergence of MDR bacteria is frequent and increases progressively with the number of reoperations. No link was demonstrated between emergence of MDR strains and antibiotic regimens, while source control and its timing appeared to be major determinants of emergence of MDR strains.
Superior vena cava drainage improves upper body oxygenation during veno-arterial extracorporeal membrane oxygenation in sheep
Authors: Hou Xiaotong , Yang Xiaofang , Du Zhongtao , Xing Jialin , Li Hui , Jiang Chunjing , Wang Jinhong , Xing Zhichen , Li Shuanglei , Li Xiaokui , Yang Feng , Wang Hong , Zeng Hui 
Published: February 2015

Abstract
Introduction
Differential hypoxia is a pivotal problem in patients with femoral veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) support. Despite recognition of differential hypoxia and attempts to deliver more oxygenated blood to the upper body, the mechanism of differential hypoxia as well as prevention strategies have not been well investigated.

Methods
We used a sheep model of acute respiratory failure that was supported with femoral VA ECMO from the inferior vena cava to the femoral artery (IVC-FA), ECMO from the superior vena cava to the FA (SVC-FA), ECMO from the IVC to the carotid artery (IVC-CA) and ECMO with an additional return cannula to the internal jugular vein based on the femoral VA ECMO (FA-IJV). Angiography and blood gas analyses were performed.

Results
With IVC-FA, blood oxygen saturation (SO2) of the IVC (83.6 ± 0.8%) was higher than that of the SVC (40.3 ± 1.0%). Oxygen-rich blood was drained back to the ECMO circuit and poorly oxygenated blood in the SVC entered the right atrium (RA). SVC-FA achieved oxygen-rich blood return from the IVC to the RA without shifting the arterial cannulation. Subsequently, SO2 of the SVC and the pulmonary artery increased (70.4 ± 1.0% and 73.4 ± 1.1%, respectively). Compared with IVC-FA, a lesser difference in venous oxygen return and attenuated differential hypoxia were observed with IVC-CA and FA-IJV.

Conclusions
Differential venous oxygen return is a key factor in the etiology of differential hypoxia in VA ECMO. With knowledge of this mechanism, we can apply better cannula configurations in clinical practice.
Rare variant association studies: considerations, challenges and opportunities
Authors: Auer Paul L , Lettre Guillaume 
Published: February 2015

AbstractGenome-wide association studies (GWASs) have successfully uncovered thousands of robust associations between common variants and complex traits and diseases. Despite these successes, much of the heritability of these traits remains unexplained. Because low-frequency and rare variants are not tagged by conventional genome-wide genotyping arrays, they may represent an important and understudied component of complex trait genetics. In contrast to common variant GWASs, there are many different types of study designs, assays and analytic techniques that can be utilized for rare variant association studies (RVASs). In this review, we briefly present the different technologies available to identify rare genetic variants, including novel exome arrays. We also compare the different study designs for RVASs and argue that the best design will likely be phenotype-dependent. We discuss the main analytical issues relevant to RVASs, including the different statistical methods that can be used to test genetic associations with rare variants and the various bioinformatic approaches to predicting in silico biological functions for variants. Finally, we describe recent rare variant association findings, highlighting the unexpected conclusion that most rare variants have modest-to-small effect sizes on phenotypic variation. This observation has major implications for our understanding of the genetic architecture of complex traits in the context of the unexplained heritability challenge.
Follow-up plasma apolipoprotein E levels in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) cohort
Authors: Gupta Veer B , Wilson Andrea C , Burnham Samantha , Hone Eugene , Pedrini Steve , Laws Simon M , Lim Wei Ling Florence , Rembach Alan , Rainey-Smith Stephanie , Ames David , Cobiac Lynne , Macaulay S Lance , Masters Colin L , Rowe Christopher C , Bush Ashley I , Martins Ralph N ,   for the AIBL Research Group
Published: February 2015

Abstract
Introduction
Alzheimer’s disease (AD) is a growing socioeconomic problem worldwide. Early diagnosis and prevention of this devastating disease have become a research priority. Consequently, the identification of clinically significant and sensitive blood biomarkers for its early detection is very important. Apolipoprotein E (APOE) is a well-known and established genetic risk factor for late-onset AD; however, the impact of the protein level on AD risk is unclear. We assessed the utility of plasma ApoE protein as a potential biomarker of AD in the large, well-characterised Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) cohort.

Methods
Total plasma ApoE levels were measured at 18-month follow-up using a commercial bead-based enzyme-linked immunosorbent assay: the Luminex xMAP human apolipoprotein kit. ApoE levels were then analysed between clinical classifications (healthy controls, mild cognitive impairment (MCI) and AD) and correlated with the data available from the AIBL cohort, including but not limited to APOE genotype and cerebral amyloid burden.

Results
A significant decrease in ApoE levels was found in the AD group compared with the healthy controls. These results validate previously published ApoE protein levels at baseline obtained using different methodology. ApoE protein levels were also significantly affected, depending on APOE genotypes, with ε2/ε2 having the highest protein levels and ε4/ε4 having the lowest. Plasma ApoE levels were significantly negatively correlated with cerebral amyloid burden as measured by neuroimaging.

Conclusions
ApoE is decreased in individuals with AD compared with healthy controls at 18-month follow-up, and this trend is consistent with our results published at baseline. The influence of APOE genotype and sex on the protein levels are also explored. It is clear that ApoE is a strong player in the aetiology of this disease at both the protein and genetic levels.
Metastatic neuroblastoma cancer stem cells exhibit flexible plasticity and adaptive stemness signaling
Authors: Pandian Vijayabaskar , Ramraj Satishkumar , Khan Faizan H , Azim Tasfia , Aravindan Natarajan 
Published: February 2015

Abstract
Introduction
High-risk neuroblastoma (HR-NB) presenting with hematogenous metastasis is one of the most difficult cancers to cure. Patient survival is poor. Aggressive tumors contain populations of rapidly proliferating clonogens that exhibit stem cell properties, cancer stem cells (CSCs). Conceptually, CSCs that evade intensive multimodal therapy dictate tumor progression, relapse/recurrence, and poor clinical outcomes. Herein, we investigated the plasticity and stem-cell related molecular response of aggressive metastatic neuroblastoma cells that fit the CSC model.

Methods
Well-characterized clones of metastatic site-derived aggressive cells (MSDACs) from a manifold of metastatic tumors of clinically translatable HR-NB were characterized for their CSC fit by examining epithelial-to-mesenchymal transition (EMT) (E-cadherin, N-Cadherin), survival (NFκB P65, p50, IκB and pIκB) and drug resistance (ABCG2) by immunoblotting; pluripotency maintenance (Nanog, SOX2) by immunofluorescence; and EMT and stemness related transcription of 93 genes by QPCR profiling. Plasticity of MSDACs under sequential alternation of culture conditions with serum and serum-free stem-cell conditions was assessed by clonal expansion (BrdU incorporation), tumorosphere formation (anchorage independent growth), EMT and stemness related transcriptome (QPCR profiling) and validated with MYC, SOX2, EGFR, NOTCH1 and CXCL2 immunoblotting.

Results
HR-NB MSDACs maintained in alternated culture conditions, serum-free stem cell medium to growth medium with serum and vice versa identified its flexible revocable plasticity characteristics. We observed signatures of stem cell-related molecular responses consistent with phenotypic conversions. Successive reintroduction to the favorable niche not only regained identical EMT, self-renewal capacity, pluripotency maintenance, and other stem cell-related signaling events, but also instigated additional events depicting aggressive adaptive plasticity.

Conclusions
Together, these results demonstrated the flexible plasticity of HR-NB MSDACs that typically fit the CSC model, and further identified the intrinsic adaptiveness of the successive phenotype switching that clarifies the heterogeneity of HR-NB. Moreover, the continuous ongoing acquisition of stem cell-related molecular rearrangements may hold the key to the switch from favorable disease to HR-NB.
Microbial production of Propionic and Succinic acid from Sorbitol using Propionibacterium acidipropionici
Authors: Duarte Juliana C , Valença Gustavo P , Moran Paulo J S , Rodrigues J Augusto R 
Published: February 2015

Abstract
Three sequential fermentative batches were carried out with cell recycle in four simultaneously operating bioreactors maintained at pH 6.5, 30°C, and 100 rpm. P. acidipropionici ATCC 4875 was able to produce propionic and succinic acid from sorbitol. The concentration of propionic acid decreased slightly from 39.5 ± 5.2 g L−1 to 34.4 ± 1.9 g L−1, and that of succinic acid increased significantly from 6.1 ± 2.1 g L−1 to 14.8 ± 0.9 g L−1 through the sequential batches. In addition, a small amount of acetic acid was produced that decreased from 3.3 ± 0.4 g L−1 to 2.0 ± 0.3 g L−1 through the batches. The major yield for propionic acid was 0.613 g g−1 in the first batch and succinic acid it was 0.212 g g−1 in the third batch. The minor yield of acetic acid was 0.029 g g−1, in the second and third batches.
Entrapment and Release of Guest Molecules by Reduction-Responsive Cyclophane Dimers Based on Disulfide Linkage
Authors: Hayashida Osamu , Kojima Keiko 
Published: February 2015

Abstract
Reduction-responsive cyclophane dimer 2 having a disulfide linkage derived from an l-cystine residue was synthesized. Complex formation of 2 with anionic guests such as 6-p-toluidinonaphthalene-2-sulfonate (TNS) and 6-anilinonaphthalene-2-sulfonate (2,6-ANS) were proven by fluorescence titration experiments. The evaluated 1:1 binding constants (K) of 2 with TNS and 2,6-ANS were calculated to be 7.6 × 104 and 5.5 × 104 M−1, respectively. These binding affinities were increased 11- and 13-fold in comparison with those of a corresponding monocyclic cyclophane 3, respectively. Reduction of disulfide bond of 2 by dithiothreitol (DTT) gave the corresponding monocyclic cyclophanes having less guest-binding affinity. Consequently, such a DTT treatment promotes release of guest molecules entrapped by 2 to the bulk aqueous media.
Solid-State Optical Properties and Crystal Structures of 1,4-Dipropoxy-9,10-anthraquinone Polymorphs
Authors: Kitamura Chitoshi , Li Sining , Takehara Munenori , Inoue Yoshinori , Ono Katsuhiko , Kawase Takeshi , Fujimoto Kazuhiro J 
Published: February 2015

Abstract
Recrystallization of 1,4-dipropoxy-9,10-anthraquinone from hexane solution afforded two polymorphs: red prisms and yellow needles. X-ray crystallographic analyses revealed that the molecular arrangement was an anti-parallel orientation for red solids and a slipped-parallel orientation for yellow solids. The difference in solid-state color was analyzed by TD-DFT calculations of their multimers.
Modeling of the Excise Taxation Influence on Components of Human Potential
Authors: Londar Serhii , Kozarezenko Liudmila 
Published: February 2015

The purpose of the research is analysis of a model of influence of excise tax rate increase for tobacco products in Ukraine on financial indices of state funds, prevalence of tobacco smoking, and indices of society health. Due to the results of research, the author determined the opportunities of the excise tax for tobacco smoking prevalence regulation in Ukraine. The dynamics of changes of specific and ad valorem rates of the excise tax and the dynamics of its contribution to the revenues of the State Budget of Ukraine were analyzed. The author estimated the changes of tobacco smoking prevalence in Ukraine on the basis of an adapted imitation model under conditions of increase of excise tax rates to the level of rates of the European Union countries. The research shows the excise tax is an effective financial regulator of tobacco smoking prevalence in Ukraine and it influences a population health condition. Increase of the excise tax rates causes reduction of amounts of tobacco product consumption and decrease of the share of smoking adults. Gradual increase of the Ukrainian rates to the level of the EU before 2018 may allow pulling from 1.0 to 1.9 million of people through premature death. Aside from a positive social effect of health enhancement, increase of the share of excise tax within a structure of a retail price of tobacco products will positively influence the growth of tax incomings to the State Budget. Consequently, under the Ukrainian contemporary economic environment the excise tax is an effective financial regulator of tobacco smoking prevalence.
An Interproduct Competition Model Incorporating Branding Hierarchy and Product Similarities Using Store-Level Data
Authors: Voleti Sudhir , Kopalle Praveen K. , Ghosh Pulak 
Published: February 2015

We develop and implement a Bayesian semiparametric model of demand under interproduct competition that enables us to assess the respective contributions of brand-SKU (stock keeping unit) hierarchy and interproduct similarity to explaining and predicting demand. To incorporate brand-SKU hierarchy effects, we use Bayesian hierarchical clustering inherent in a nested Dirichlet process to simultaneously partition brands, and SKUs conditional on brands, into groups of “similarity clusters.” We examine cluster memberships and postprocess the Markov chain Monte Carlo output to infer cluster properties by accounting for parameter uncertainty. Our proposed approach lends to a spatial competition interpretation in latent attribute space and helps uncover the extent to which competition across SKUs in the latent attribute space is local or global. In a related vein, we discuss the implications of well-defined groups of similar SKUs as subcategory or submarket boundaries in latent attribute space. We empirically test our model using aggregate beer category sales data from a midsize U.S. retail chain. We find that branding hierarchy effects dominate those from product similarity. We find that the model partitions the 15 brands in the data into 4 brand clusters and the 96 SKUs into 25 SKU clusters conditional on brand cluster membership. In estimating a set of models of spatial interproduct competition, we find that SKU competition is more local than global in that only subsets of products compete within groups of comparable products. Finally, we discuss the substantive implications of our results.This paper was accepted by Pradeep Chintagunta, marketing.