bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microstructure Modeling and Ultrasonic Wave Propagation Simulation of A206–Al2O3 Metal Matrix Nanocomposites for Quality Inspection
Authors: Liu Yuhang , Wu Jianguo , Zhou Shiyu , Li Xiaochun 
Published: July 2015

AbstractUltrasonic testing is a promising alternative quality inspection technique to the expensive microscopic imaging to characterize metal matrix nanocomposites. However, due to the complexity of the wave–microstructure interaction, and the difficulty in fabricating nanocomposites of different microstructural features, it is very challenging to build reliable relationships between ultrasonic testing results and nanocomposites quality. In this research, we propose a microstructure modeling and wave propagation simulation method to simulate ultrasonic attenuation characteristic for A206–Al2O3 metal matrix nanocomposites (MMNCs). In particular, a modified Voronoi diagram is used to reproduce the microstructures and the numeric method elastodynamic finite integration technique (EFIT) is used to simulate the wave propagation through the generated microstructures. Linear mixed effects model (LME) is used to quantify the between-curve variation of ultrasonic attenuation from both experiment and simulation. Permutation test is employed to quantify the similarity of the quantified variation between experiment and simulation. This research supports the experimental results through the simulation approach and provides a better understanding of the relationship between attenuation curves and the microstructures.
Efficacy and Safety of Pergoveris in Assisted Reproductive Technology—ESPART: rationale and design of a randomised controlled trial in poor ovarian responders undergoing IVF/ICSI treatment
Authors: Humaidan P , Schertz J , Fischer R 
Published: July 2015

IntroductionThe results of a recent meta-analysis showed that adding recombinant human luteinising hormone (r-hLH) to recombinant human follicle-stimulating hormone (r-hFSH) for ovarian stimulation was beneficial in poor responders, resulting in a 30% relative increase in the clinical pregnancy rate compared with r-hFSH monotherapy. However, a limitation of the meta-analysis was that the included studies used heterogeneous definitions of poor ovarian response (POR). Furthermore, the use of r-hLH supplementation during ovarian stimulation is a topic of ongoing debate, and well-designed, adequately powered, multicentre, randomised controlled trials in this setting are warranted. Therefore, the objective of the ESPART trial is to explore the possible superiority of a fixed-dose combination of r-hFSH plus r-hLH over r-hFSH monotherapy in patients with POR, as per a definition aligned with the European Society of Human Reproduction and Embryology (ESHRE) Bologna criteria.Methods and analysisPhase III, randomised, single-blind, parallel-group trial in women undergoingin vitrofertilisation and/or intracytoplasmic sperm injection. Approximately 946 women aged 18–<41 years from 18 countries will be randomised (1:1) to receive a fixed-dose combination of r-hFSH plus r-hLH in a 2:1 ratio (Pergoveris) or r-hFSH monotherapy (GONAL-f). The primary end point is the total number of retrieved oocytes per participant. Secondary end points include: ongoing pregnancy rate, live birth rate, implantation rate, biochemical pregnancy rate and clinical pregnancy rate. Safety end points include: incidence and severity of ovarian hyperstimulation syndrome, and of adverse events and serious adverse events.Ethics and disseminationThe study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki, with the International Conference on Harmonisation–Good Clinical Practice guidelines and all applicable regulatory requirements. All participants will provide written informed consent prior to entry. The results of this study will be publically disseminated.Trial registration numbersClinicalTrials.gov identifier:NCT02047227; EudraCT Number: 2013-003817-16; Clinical Trial Protocol Number: EMR200061-005 V.3.0, 15 April 2014.
Developing a primary care patient measure of safety (PC PMOS): a modified Delphi process and face validity testing
Authors: Hernan Andrea L , Giles Sally J , O'Hara Jane K , Fuller Jeffrey , Johnson Julie K , Dunbar James A 
Published: July 2015

BackgroundPatients are a valuable source of information about ways to prevent harm in primary care and are in a unique position to provide feedback about the factors that contribute to safety incidents. Unlike in the hospital setting, there are currently no tools that allow the systematic capture of this information from patients. The aim of this study was to develop a quantitative primary care patient measure of safety (PC PMOS).MethodsA two-stage approach was undertaken to develop questionnaire domains and items. Stage 1 involved a modified Delphi process. An expert panel reached consensus on domains and items based on three sources of information (validated hospital PMOS, previous research conducted by our study team and literature on threats to patient safety). Stage 2 involved testing the face validity of the questionnaire developed during stage 1 with patients and primary care staff using the ‘think aloud’ method. Following this process, the questionnaire was revised accordingly.ResultsThe PC PMOS was received positively by both patients and staff during face validity testing. Barriers to completion included the length, relevance and clarity of questions. The final PC PMOS consisted of 50 items across 15 domains. The contributory factors to safety incidents centred on communication, access to care, patient-related factors, organisation and care planning, task performance and information flow.DiscussionThis is the first tool specifically designed for primary care settings, which allows patients to provide feedback about factors contributing to potential safety incidents. The PC PMOS provides a way for primary care organisations to learn about safety from the patient perspective and make service improvements with the aim of reducing harm in this setting. Future research will explore the reliability and construct validity of the PC PMOS.
Concise Care Bundles In Acute Medicine
Authors: Kivlin Jude , Altemimi Harith 
Published: July 2015

AbstractThe Queen Elizabeth Hospital in King's Lynn, Norfolk is a 488 bed hospital providing services to approximately 331,000 people across 750 square miles. In 2012 a need was recognised for documentation (pathways) in a practical format to increase usage of national guidelines and facilitate adherence to best practice (gold standards of care) that could be easily version controlled, auditable and provide support in clinical decision-making by junior doctors.BMJ Action Sets[1] fulfilled the brief with expert knowledge, version control and support, though they were deemed too lengthy and unworkable in fast paced settings like the medical assessment unit; they formed the base creation of concise care bundles (CCB). CCB were introduced for 21 clinical presentations and one procedure. Outcomes were fully audited and showed significant improvement in a range of measures, including an increase in completions of CHADVASC score in atrial fibrillation, antibiotics prescribed per protocol in chronic obstructive pulmonary disease (COPD), and Blatchford score recorded for patients presenting with upper gastrointestinal bleed.
Ambient air pollution and racial/ethnic differences in carotid intima-media thickness in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Jones Miranda R , Diez-Roux Ana V , O'Neill Marie S , Guallar Eliseo , Sharrett A Richey , Post Wendy , Kaufman Joel D , Navas-Acien Ana 
Published: July 2015

BackgroundIn the USA, ethnic disparities in atherosclerosis persist after accounting for known risk factors. Ambient air pollution is associated with increased levels of atherosclerosis and differs in the USA by race/ethnicity. We estimated the influence of ambient air pollution exposure to ethnic differences in common carotid intima-media thickness (IMT).MethodsWe cross-sectionally studied 6347 Caucasian-American, African-American, Hispanic and Chinese adults across 6 US cities in 2000–2002. Annual ambient air pollution concentrations (fine particulate matter [PM2.5] and oxides of nitrogen [NOX]) were estimated at each participant's residence. IMT was assessed by ultrasound.ResultsThe mean IMT was 19.4 and 37.6 μm smaller for Hispanic women and men, 53.6 and 7.1 μm smaller for Chinese women and men, and 23.4 and 38.7 μm higher for African-American women and men compared with Caucasian-American women and men. After adjustment for PM2.5, the differences in IMT remained similar for Hispanic and African-American participants but was even more negative for Chinese participants (mean IMT difference of −58.4 μm for women and −15.7 μm for men) compared with Caucasian-American participants. The IMT difference in Chinese participants compared with Caucasian-American participants related to their higher PM2.5exposures was 4.8 μm (95% CI 0.2 to 10.8) for women and 8.6 μm (95% CI 3.4 to 15.3) for men. NOXwas not related to ethnic differences in IMT.ConclusionsThe smaller carotid IMT levels in Chinese participants were even smaller after accounting for higher PM2.5concentrations in Chinese participants compared with Caucasian-American participants. Air pollution was not related to IMT differences in African-American and Hispanic participants compared with Caucasian-American participants.
Soil geochemical survey of abandoned mining sites in the Eastern-Central Peloritani Mountains, Sicily, Italy
Authors: Cosenza A. , Lima A. , Ayuso R. A. , Foley N. K. , Albanese S. , Messina A. , De Vivo B. 
Published: July 2015

This investigation focused on topsoils (
n
= 122) and vertical profiles (
n
= 6) distributed over an area of 250 km
2
in the eastern-central Peloritani Mountains, northeastern Sicily. Georeferenced concentration of 53 elements (including potentially harmful ones), determined by ICP-MS after an aqua regia leach, were used to produce geochemical maps by means of a GIS-aided spatial interpolation process. Results show that there are two distinct areas: the larger, located between the Fiumendinisi, Budali and Ali villages, and the other between C. Postlioni and Femmina Morta, which contain anomalous As (up to 727 mg/kg), Sb (up to 60 mg/kg), Ag (up to 1 mg/kg) and Au (up to 0.1 mg/kg) concentrations. Most of the investigated areas have high contamination levels for As, Zn, Sb, and Pb that exceed the threshold values (As = 20 mg/kg, Zn = 150 mg/kg, Sb = 10 mg/kg and Pb = 100 mg/kg) established for soils by the Italian Environmental Law (
Decreto Legislativo 2006
, number 152).

The isotopic ratios of
206
Pb/
207
Pb and
208
Pb/
207
Pb have been measured in selected soils on both leaches [using 1M HNO
3
–1.75M HCl (50:50)] and residues thereof. Soil leach reflects possible anthropogenic contamination, whereas soil residues indicate geogenic contributions. Results suggest that most of contamination in the soils is related to the presence of sulphide and sulphosalt rock-forming minerals in the surveyed area. The soil fraction contains a Pb value >1600 mg/kg and has ratios of 1.1695 for
206
Pb/
207
Pb and 2.4606 for
208
Pb/
207
Pb. Only one soil leach isotopic composition could reflect possible anthropogenic contamination. The correlation among As, Zn, Pb contents v. Pb isotopic signatures of
206
Pb/
207
Pb indicates that surface and deep soils collected from profiles are dominated by geogenic compositions.
CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus
Authors: Koh Siang-Boon , Courtin Aurélie , Boyce Richard J. , Boyle Robert G. , Richards Frances M. , Jodrell Duncan I. 
Published: July 2015

Abstract
Combining cell-cycle checkpoint kinase inhibitors with the DNA-damaging chemotherapeutic agent gemcitabine offers clinical appeal, with a mechanistic rationale based chiefly on abrogation of gemcitabine-induced G2–M checkpoint activation. However, evidence supporting this mechanistic rationale from chemosensitization studies has not been consistent. Here we report a systematic definition of how pancreatic cancer cells harboring mutant p53 respond to this combination therapy, by combining mathematical models with large-scale quantitative biologic analyses of single cells and cell populations. Notably, we uncovered a dynamic range of mechanistic effects at different ratios of gemcitabine and CHK1 inhibitors. Remarkably, effective synergy was attained even where cells exhibited an apparently functional G2–M surveillance mechanism, as exemplified by a lack of both overt premature CDK1 activation and S-phase mitotic entry. Consistent with these findings, S–G2 duration was extended in treated cells, leading to a definable set of lineage-dependent catastrophic fates. At synergistic drug concentrations, global replication stress was a distinct indicator of chemosensitization as characterized molecularly by an accumulation of S-phase cells with high levels of hyperphosphorylated RPA-loaded single-stranded DNA. In a fraction of these cells, persistent genomic damage was observed, including chromosomal fragmentation with a loss of centromeric regions that prevented proper kinetochore-microtubule attachment. Together, our results suggested a “foot-in-the-door” mechanism for drug synergy where cells were destroyed not by frank G2–M phase abrogation but rather by initiating a cumulative genotoxicity that deregulated DNA synthesis. Cancer Res; 75(17); 3583–95. ©2015 AACR.
Depleting MET-Expressing Tumor Cells by ADCC Provides a Therapeutic Advantage over Inhibiting HGF/MET Signaling
Authors: Hultberg Anna , Morello Virginia , Huyghe Leander , De Jonge Natalie , Blanchetot Christophe , Hanssens Valérie , De Boeck Gitte , Silence Karen , Festjens Els , Heukers Raimond , Roux Benjamin , Lamballe Fabienne , Ginestier Christophe , Charafe-Jauffret Emmanuelle , Maina Flavio , Brouckaert Peter , Saunders Michael , Thibault Alain , Dreier Torsten , de Haard Hans , Michieli Paolo 
Published: July 2015

Abstract
Hepatocyte growth factor (HGF) and its receptor MET represent validated targets for cancer therapy. However, HGF/MET inhibitors being explored as cancer therapeutics exhibit cytostatic activity rather than cytotoxic activity, which would be more desired. In this study, we engineered an antagonistic anti-MET antibody that, in addition to blocking HGF/MET signaling, also kills MET-overexpressing cancer cells by antibody-dependent cellular cytotoxicity (ADCC). As a control reagent, we engineered the same antibody in an ADCC-inactive form that is similarly capable of blocking HGF/MET activity, but in the absence of any effector function. In comparing these two antibodies in multiple mouse models of cancer, including HGF-dependent and -independent tumor xenografts, we determined that the ADCC-enhanced antibody was more efficacious than the ADCC-inactive antibody. In orthotopic mammary carcinoma models, ADCC enhancement was crucial to deplete circulating tumor cells and to suppress metastases. Prompted by these results, we optimized the ADCC-enhanced molecule for clinical development, generating an antibody (ARGX-111) with improved pharmacologic properties. ARGX-111 competed with HGF for MET binding, inhibiting ligand-dependent MET activity, downregulated cell surface expression of MET, curbing HGF-independent MET activity, and engaged natural killer cells to kill MET-expressing cancer cells, displaying MET-specific cytotoxic activity. ADCC assays confirmed the cytotoxic effects of ARGX-111 in multiple human cancer cell lines and patient-derived primary tumor specimens, including MET-expressing cancer stem-like cells. Together, our results show how ADCC provides a therapeutic advantage over conventional HGF/MET signaling blockade and generates proof-of-concept for ARGX-111 clinical testing in MET-positive oncologic malignancies. Cancer Res; 75(16); 3373–83. ©2015 AACR.
LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms
Authors: King Constance , Diaz H. Bruce , McNeely Samuel , Barnard Darlene , Dempsey Jack , Blosser Wayne , Beckmann Richard , Barda David , Marshall Mark S. 
Published: July 2015

Abstract
CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe. Mol Cancer Ther; 14(9); 2004–13. ©2015 AACR.
Heat Shock Protein 90 Is a Potential Therapeutic Target in Cholangiocarcinoma
Authors: Shirota Tomoki , Ojima Hidenori , Hiraoka Nobuyoshi , Shimada Kazuaki , Rokutan Hirofumi , Arai Yasuhito , Kanai Yae , Miyagawa Shinichi , Shibata Tatsuhiro 
Published: July 2015

Abstract
Cholangiocarcinoma is an aggressive malignancy with a poor prognosis, with no effective therapy other than surgical resection. Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the posttranslational folding of a number of client proteins, many of which play essential roles in tumorigenesis. Here, we attempted to clarify its prognostic significance and potential utility as a therapeutic target in cholangiocarcinoma. Immunohistochemical expression of HSP90 was assessed retrospectively in 399 cholangiocarcinoma cases and 17 human cholangiocarcinoma cell lines, along with the effect of a small-molecule HSP90 inhibitor (NVP-AUY922) on cholangiocarcinoma tumor growth and angiogenesis in human cholangiocarcinoma cell lines and xenografts. The positivity of HSP90 was 44.6% in intrahepatic cholangiocarcinoma (IHCC) and 32.8% in extrahepatic cholangiocarcinoma (EHCC), respectively. HSP90 expression was significantly associated with the 5-year survival rate for IHCC (P &lt; 0.001) and EHCC (P &lt; 0.001). HSP90 inhibition showed potent antiproliferative activity and reduced growth-associated signaling in human cholangiocarcinoma cells in vitro. Furthermore, treatment of cholangiocarcinoma xenograft-bearing mice with NVP-AUY922 significantly inhibited growth at doses far below the maximum-tolerated dose. HSP90 overexpression is a prognostic marker for cholangiocarcinoma. HSP90-targeted therapy may be an option for a subset of cholangiocarcinoma. Mol Cancer Ther; 14(9); 1985–93. ©2015 AACR.
Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling
Authors: Dulong Sandrine , Ballesta Annabelle , Okyar Alper , Lévi Francis 
Published: July 2015

Abstract
Cancer chronotherapy aims at enhancing tolerability and efficacy of anticancer drugs through their delivery according to circadian clocks. However, mouse and patient data show that lifestyle, sex, genetics, drugs, and cancer can modify both host circadian clocks and metabolism pathways dynamics, and thus the optimal timing of drug administration. The mathematical modeling of chronopharmacology could indeed help moderate optimal timing according to patient-specific determinants. Here, we combine in vitro and in silico methods, in order to characterize the critical molecular pathways that drive the chronopharmacology of irinotecan, a topoisomerase I inhibitor with complex metabolism and known activity against colorectal cancer. Large transcription rhythms moderated drug bioactivation, detoxification, transport, and target in synchronized colorectal cancer cell cultures. These molecular rhythms translated into statistically significant changes in pharmacokinetics and pharmacodynamics according to in vitro circadian drug timing. The top-up of the multiple coordinated chronopharmacology pathways resulted in a four-fold difference in irinotecan-induced apoptosis according to drug timing. Irinotecan cytotoxicity was directly linked to clock gene BMAL1 expression: The least apoptosis resulted from drug exposure near BMAL1 mRNA nadir (P &lt; 0.001), whereas clock silencing through siBMAL1 exposure ablated all the chronopharmacology mechanisms. Mathematical modeling highlighted circadian bioactivation and detoxification as the most critical determinants of irinotecan chronopharmacology. In vitro–in silico systems chronopharmacology is a new powerful methodology for identifying the main mechanisms at work in order to optimize circadian drug delivery. Mol Cancer Ther; 14(9); 2154–64. ©2015 AACR.
A new Zoropsis species from China, with notes on Zoropsis pekingensis Schenkel, 1953 (Araneae, Zoropsidae)
Authors: LI ZHIYUE , HU LANLAN , ZHANG FENG 
Published: July 2015

The family Zoropsidae is currently represented by 15 genera and 87 species (World Spider Catalog 2015). Zoropsids are medium to large size spiders, with a narrow, bipartite cribellum and calamistrum; eight eyes in two rows, anterior eye row nearly straight, posterior row strongly recurved; median furrow longitudinal; toothed chelicerae; tibiae and metatarsi I, II equipped with several pairs of ventral spines; metatarsi and tarsi bearing scopulae; two tarsal claws (Bosselaers 2002). They are often collected from houses, under stones or in leaf litter in forest.
In vitro, in carta. Progettazione e genesi dei testi di Crêuza de mä
Authors: Ivaldi Federica 
Published: July 2015

Il saggio ripercorre l’immaginario viaggio nel Mediterraneo rappresentato dal disco Crêuza de mä (Ricordi, 1984). Si propone di analizzare le tappe della ricostruzione in vitro di un’idea di “sound mediterraneo” – inteso come somma di sonorità che rispecchi la varietà di culture e paesaggi del Mediterraneo – e di indagare le ragioni della scelta linguistica del genovese, che acquista il valore ideologico forte di un ritorno alle origini e all’autenticità del “popolo”. Il saggio, inoltre, prende in considerazione alcuni dei materiali preparatori per i testi dell’album conservati nell’Archivio Fabrizio De André (nelle citazioni afda) presso la biblioteca della Facoltà di Lettere e Filosofia dell’Università degli Studi di Siena, osservando: il ricorrere di alcuni temi particolarmente importanti per lo chansonnier; il continuo rifluire di immagini e temi da una canzone all’altra; l’oscillazione dei titoli; l’analisi di alcune varianti prima della redazione definitiva di un testo; il rapporto fra le letture di Fabrizio De André e la scrittura delle sue canzoni; il lavoro per la scelta del punto di vista, momento sempre delicato per la resa del testo e la trasmissione del messaggio che gli è affidato.