bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Multicenter Phase I Study of Pazopanib in Combination with Paclitaxel in First-Line Treatment of Patients with Advanced Solid Tumors
Authors: Kendra Kari L. , Plummer Ruth , Salgia Ravi , O'Brien Mary E. R. , Paul Elaine M. , Suttle A. Benjamin , Compton Natalie , Xu Chun-Fang , Ottesen Lone H. , Villalona-Calero Miguel A. 
Published: December 2014

Abstract
This study was designed to evaluate the safety, pharmacokinetics, and clinical activity of pazopanib combined with paclitaxel to determine the recommended phase II dose in the first-line setting in patients with advanced solid tumors. Patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated regimen (MTR) of once daily pazopanib plus paclitaxel administered every 3 weeks at four dose levels (DL1-4). Safety, pharmacokinetics, pharmacogenetics, and disease assessments were performed. Twenty-eight patients received treatment. One patient at DL1 had dose-limiting toxicity (DLT) of elevated hepatic enzymes. After pazopanib discontinuation, liver enzyme concentrations remained high until a concurrent medication, simvastatin, was discontinued. This patient had the defective CYP2C8*3*3 genotype. At DL2, 1 patient had DLT of elevated hepatic enzymes with rash and 1 patient had DLT of rash. The MTR was paclitaxel 150 mg/m2 plus pazopanib 800 mg. The most common toxicities were alopecia, fatigue, hypertension, nausea, diarrhea, dysgeusia, neutropenia, myalgia, hair color changes, and peripheral neuropathy. Coadministration of pazopanib and paclitaxel resulted in a 38% increase in systemic exposure to paclitaxel, relative to administration of paclitaxel alone, at the MTR. Of the 28 patients treated with the combination, 10 achieved a partial response and 10 achieved stable disease of ≥12 weeks. Pazopanib 800 mg daily plus paclitaxel 150 mg/m2 every 3 weeks was the recommended phase II dose, with a manageable safety profile, and with clinical activity in both melanoma and non–small cell lung cancer that suggest further evaluation of this combination is warranted. Mol Cancer Ther; 14(2); 461–9. ©2014 AACR.
Glycogen Synthase Kinase 3β Sustains Invasion of Glioblastoma via the Focal Adhesion Kinase, Rac1, and c-Jun N-Terminal Kinase-Mediated Pathway
Authors: Chikano Yuri , Domoto Takahiro , Furuta Takuya , Sabit Hemragul , Kitano-Tamura Ayako , Pyko Ilya V. , Takino Takahisa , Sai Yoshimichi , Hayashi Yutaka , Sato Hiroshi , Miyamoto Ken-ichi , Nakada Mitsutoshi , Minamoto Toshinari 
Published: December 2014

Abstract
The failure of current treatment options for glioblastoma stems from their inability to control tumor cell proliferation and invasion. Biologically targeted therapies offer great hope and one promising target is glycogen synthase kinase-3β (GSK3β), implicated in various diseases, including cancer. We previously reported that inhibition of GSK3β compromises the survival and proliferation of glioblastoma cells, induces their apoptosis, and sensitizes them to temozolomide and radiation. Here, we explore whether GSK3β also contributes to the highly invasive nature of glioblastoma. The effects of GSK3β inhibition on migration and invasion of glioblastoma cells were examined by wound-healing and Transwell assays, as well as in a mouse model of glioblastoma. We also investigated changes in cellular microarchitectures, cytoskeletal components, and proteins responsible for cell motility and invasion. Inhibition of GSK3β attenuated the migration and invasion of glioblastoma cells in vitro and that of tumor cells in a mouse model of glioblastoma. These effects were associated with suppression of the molecular axis involving focal adhesion kinase, guanine nucleotide exchange factors/Rac1 and c-Jun N-terminal kinase. Changes in cellular phenotypes responsible for cell motility and invasion were also observed, including decreased formation of lamellipodia and invadopodium-like microstructures and alterations in the subcellular localization, and activity of Rac1 and F-actin. These changes coincided with decreased expression of matrix metalloproteinases. Our results confirm the potential of GSK3β as an attractive therapeutic target against glioblastoma invasion, thus highlighting a second role in this tumor type in addition to its involvement in chemo- and radioresistance. Mol Cancer Ther; 14(2); 564–74. ©2014 AACR.
Wee-1 Kinase Inhibition Overcomes Cisplatin Resistance Associated with High-RiskTP53Mutations in Head and Neck Cancer through Mitotic Arrest Followed by Senescence
Authors: Osman Abdullah A. , Monroe Marcus M. , Ortega Alves Marcus V. , Patel Ameeta A. , Katsonis Panagiotis , Fitzgerald Alison L. , Neskey David M. , Frederick Mitchell J. , Woo Sang Hyeok , Caulin Carlos , Hsu Teng-Kuei , McDonald Thomas O. , Kimmel Marek , Meyn Raymond E. , Lichtarge Olivier , Myers Jeffrey N. 
Published: December 2014

AbstractAlthough cisplatin has played a role in “standard-of-care” multimodality therapy for patients with advanced squamous cell carcinoma of the head and neck (HNSCC), the rate of treatment failure remains particularly high for patients receiving cisplatin whose tumors have mutations in the TP53 gene. We found that cisplatin treatment of HNSCC cells with mutant TP53 leads to arrest of cells in the G2 phase of the cell cycle, leading us to hypothesize that the wee-1 kinase inhibitor MK-1775 would abrogate the cisplatin-induced G2 block and thereby sensitize isogenic HNSCC cells with mutant TP53 or lacking p53 expression to cisplatin. We tested this hypothesis using clonogenic survival assays, flow cytometry, and in vivo tumor growth delay experiments with an orthotopic nude mouse model of oral tongue cancer. We also used a novel TP53 mutation classification scheme to identify which TP53 mutations are associated with limited tumor responses to cisplatin treatment. Clonogenic survival analyses indicate that nanomolar concentration of MK-1775 sensitizes HNSCC cells with high-risk mutant p53 to cisplatin. Consistent with its ability to chemosensitize, MK-1775 abrogated the cisplatin-induced G2 block in p53-defective cells leading to mitotic arrest associated with a senescence-like phenotype. Furthermore, MK-1775 enhanced the efficacy of cisplatin in vivo in tumors harboring TP53 mutations. These results indicate that HNSCC cells expressing high-risk p53 mutations are significantly sensitized to cisplatin therapy by the selective wee-1 kinase inhibitor, supporting the clinical evaluation of MK-1775 in combination with cisplatin for the treatment of patients with TP53 mutant HNSCC. Mol Cancer Ther; 14(2); 608–19. ©2014 AACR.
Safety of fibrinogen concentrate: analysis of more than 27 years of pharmacovigilance data
Authors: Gröner Albrecht , Jian Ye , Inna Pendrak , Solomon Cristina 
Published: December 2014

SummaryFibrinogen concentrate use as a haemostatic agent has been increasingly explored. This study evaluates spontaneous reports of potential adverse drug reactions (ADRs) that occurred during postmarketing pharmacovigilance of Haemocomplettan P/RiaSTAP, and reviews published safety data. This descriptive study analysed postmarketing safety reports recorded in the CSL Behring pharmacovigilance database from January 1986 to December 2013. A literature review of clinical studies published during the same period was performed. Commercial data indicated that 2,611,294 g of fibrinogen concentrate were distributed over the pharmacovigilance period, main-contribonding to 652,824 standard doses of 4 g each, across a range of clinical settings and indications. A total of 383 ADRs in 106 cases were reported (approximately 1 per 24,600 g or 6,200 standard doses). Events of special interest included possible hypersensitivity reactions in 20 cases (1 per 130,600 g or 32,600 doses), possible thromboembolic events in 28 cases (1 per 93,300 g or 23,300 doses), and suspected virus transmission in 21 cases (1 per 124,300 g or 31,000 doses). One virus transmission case could not be analysed due to insufficient data; for all other cases, a causal relationship was assessed as unlikely due to negative polymerase chain reaction tests and/or alternative explanations. The published literature revealed a similar safety profile. In conclusion, underreporting of ADRs is a known limitation of pharmacovigilance. However, the present assessment indicates that fibrinogen concentrate is administered across a range of indications, with few ADRs and a low thromboembolic event rate. Overall, fibrinogen concentrate showed a promising safety profile.Institution to which work should be attributed: CSL Behring, Marburg, Germany.
Venous thromboembolism diagnosis: unresolved issues
Authors: Le Gal Grégoire , Bounameaux Henri , Righini Marc 
Published: December 2014

SummaryRecent advances in the management of patients with suspected VTE have both improved diagnostic accuracy and made management algorithms safer, easier to use and well standardised. These diagnostic algorithms are mainly based on the assessment of clinical pretest probability, D-dimer measurement and imaging tests, mainly represented by compression ultrasound (CUS) for suspected DVT and computed tomography pulmonary angiography (CTPA) or lung ventilationperfusion scan for pulmonary embolism. These diagnostic algorithms allow a safe and cost-effective diagnosis for most patients with suspected VTE. In this review, we focus on the challenge of diagnosing VTE in special patient populations, such as elderly patients, pregnant women, or patients with a prior VTE. Some additional challenges are arising that might require adjustments to current diagnostic strategies, such as the reduced clinical suspicion threshold, resulting in a lower proportion of VTE among suspected patients; the overdiagnosis and overtreatment of VTE, especially regarding calf deep-vein thrombosis (DVT) and subsegmental pulmonary embolism (SSPE).
The Birmingham Urban Climate Laboratory: An Open Meteorological Test Bed and Challenges of the Smart City
Authors: Chapman Lee , Muller Catherine L. , Young Duick T. , Warren Elliott L. , Grimmond C. S. B. , Cai Xiao-Ming , Ferranti Emma J. S. 
Published: December 2014

Abstract
The Birmingham Urban Climate Laboratory (BUCL) is a near-real-time, high-resolution urban meteorological network (UMN) of automatic weather stations and inexpensive, nonstandard air temperature sensors. The network has recently been implemented with an initial focus on monitoring urban heat, infrastructure, and health applications. A number of UMNs exist worldwide; however, BUCL is novel in its density, the low-cost nature of the sensors, and the use of proprietary Wi-Fi networks. This paper provides an overview of the logistical aspects of implementing a UMN test bed at such a density, including selecting appropriate urban sites; testing and calibrating low-cost, nonstandard equipment; implementing strict quality-assurance/quality-control mechanisms (including metadata); and utilizing preexisting Wi-Fi networks to transmit data. Also included are visualizations of data collected by the network, including data from the July 2013 U.K. heatwave as well as highlighting potential applications. The paper is an open invitation to use the facility as a test bed for evaluating models and/or other nonstandard observation techniques such as those generated via crowdsourcing techniques.
The Deep Convective Clouds and Chemistry (DC3) Field Campaign
Authors: Barth Mary C. , Cantrell Christopher A. , Brune William H. , Rutledge Steven A. , Crawford James H. , Huntrieser Heidi , Carey Lawrence D. , MacGorman Donald , Weisman Morris , Pickering Kenneth E. , Bruning Eric , Anderson Bruce , Apel Eric , Biggerstaff Michael , Campos Teresa , Campuzano-Jost Pedro , Cohen Ronald , Crounse John , Day Douglas A. , Diskin Glenn , Flocke Frank , Fried Alan , Garland Charity , Heikes Brian , Honomichl Shawn , Hornbrook Rebecca , Huey L. Gregory , Jimenez Jose L. , Lang Timothy , Lichtenstern Michael , Mikoviny Tomas , Nault Benjamin , O’Sullivan Daniel , Pan Laura L. , Peischl Jeff , Pollack Ilana , Richter Dirk , Riemer Daniel , Ryerson Thomas , Schlager Hans , St. Clair Jason , Walega James , Weibring Petter , Weinheimer Andrew , Wennberg Paul , Wisthaler Armin , Wooldridge Paul J. , Ziegler Conrad 
Published: December 2014

Abstract
The Deep Convective Clouds and Chemistry (DC3) field experiment produced an exceptional dataset on thunderstorms, including their dynamical, physical, and electrical structures and their impact on the chemical composition of the troposphere. The field experiment gathered detailed information on the chemical composition of the inflow and outflow regions of midlatitude thunderstorms in northeast Colorado, west Texas to central Oklahoma, and northern Alabama. A unique aspect of the DC3 strategy was to locate and sample the convective outflow a day after active convection in order to measure the chemical transformations within the upper-tropospheric convective plume. These data are being analyzed to investigate transport and dynamics of the storms, scavenging of soluble trace gases and aerosols, production of nitrogen oxides by lightning, relationships between lightning flash rates and storm parameters, chemistry in the upper troposphere that is affected by the convection, and related source characterization of the three sampling regions. DC3 also documented biomass-burning plumes and the interactions of these plumes with deep convection.
The LatMix Summer Campaign: Submesoscale Stirring in the Upper Ocean
Authors: Shcherbina Andrey Y. , Sundermeyer Miles A. , Kunze Eric , D’Asaro Eric , Badin Gualtiero , Birch Daniel , Brunner-Suzuki Anne-Marie E. G. , Callies Jörn , Kuebel Cervantes Brandy T. , Claret Mariona , Concannon Brian , Early Jeffrey , Ferrari Raffaele , Goodman Louis , Harcourt Ramsey R. , Klymak Jody M. , Lee Craig M. , Lelong M.-Pascale , Levine Murray D. , Lien Ren-Chieh , Mahadevan Amala , McWilliams James C. , Molemaker M. Jeroen , Mukherjee Sonaljit , Nash Jonathan D. , Özgökmen Tamay , Pierce Stephen D. , Ramachandran Sanjiv , Samelson Roger M. , Sanford Thomas B. , Shearman R. Kipp , Skyllingstad Eric D. , Smith K. Shafer , Tandon Amit , Taylor John R. , Terray Eugene A. , Thomas Leif N. , Ledwell James R. 
Published: December 2014

Abstract
Lateral stirring is a basic oceanographic phenomenon affecting the distribution of physical, chemical, and biological fields. Eddy stirring at scales on the order of 100 km (the mesoscale) is fairly well understood and explicitly represented in modern eddy-resolving numerical models of global ocean circulation. The same cannot be said for smaller-scale stirring processes. Here, the authors describe a major oceanographic field experiment aimed at observing and understanding the processes responsible for stirring at scales of 0.1–10 km. Stirring processes of varying intensity were studied in the Sargasso Sea eddy field approximately 250 km southeast of Cape Hatteras. Lateral variability of water-mass properties, the distribution of microscale turbulence, and the evolution of several patches of inert dye were studied with an array of shipboard, autonomous, and airborne instruments. Observations were made at two sites, characterized by weak and moderate background mesoscale straining, to contrast different regimes of lateral stirring. Analyses to date suggest that, in both cases, the lateral dispersion of natural and deliberately released tracers was O(1) m2 s–1 as found elsewhere, which is faster than might be expected from traditional shear dispersion by persistent mesoscale flow and linear internal waves. These findings point to the possible importance of kilometer-scale stirring by submesoscale eddies and nonlinear internal-wave processes or the need to modify the traditional shear-dispersion paradigm to include higher-order effects. A unique aspect of the Scalable Lateral Mixing and Coherent Turbulence (LatMix) field experiment is the combination of direct measurements of dye dispersion with the concurrent multiscale hydrographic and turbulence observations, enabling evaluation of the underlying mechanisms responsible for the observed dispersion at a new level.
The Wind Forecast Improvement Project (WFIP): A Public–Private Partnership Addressing Wind Energy Forecast Needs
Authors: Wilczak James , Finley Cathy , Freedman Jeff , Cline Joel , Bianco Laura , Olson Joseph , Djalalova Irina , Sheridan Lindsay , Ahlstrom Mark , Manobianco John , Zack John , Carley Jacob R. , Benjamin Stan , Coulter Richard , Berg Larry K. , Mirocha Jeffrey , Clawson Kirk , Natenberg Edward , Marquis Melinda 
Published: December 2014

Abstract
The Wind Forecast Improvement Project (WFIP) is a public–private research program, the goal of which is to improve the accuracy of short-term (0–6 h) wind power forecasts for the wind energy industry. WFIP was sponsored by the U.S. Department of Energy (DOE), with partners that included the National Oceanic and Atmospheric Administration (NOAA), private forecasting companies (WindLogics and AWS Truepower), DOE national laboratories, grid operators, and universities. WFIP employed two avenues for improving wind power forecasts: first, through the collection of special observations to be assimilated into forecast models and, second, by upgrading NWP forecast models and ensembles. The new observations were collected during concurrent year-long field campaigns in two high wind energy resource areas of the United States (the upper Great Plains and Texas) and included 12 wind profiling radars, 12 sodars, several lidars and surface flux stations, 184 instrumented tall towers, and over 400 nacelle anemometers. Results demonstrate that a substantial reduction (12%–5% for forecast hours 1–12) in power RMSE was achieved from the combination of improved numerical weather prediction models and assimilation of new observations, equivalent to the previous decade’s worth of improvements found for low-level winds in NOAA/National Weather Service (NWS) operational weather forecast models. Data-denial experiments run over select periods of time demonstrate that up to a 6% improvement came from the new observations. Ensemble forecasts developed by the private sector partners also produced significant improvements in power production and ramp prediction. Based on the success of WFIP, DOE is planning follow-on field programs.
Arctic Tropospheric Warming: Causes and Linkages to Lower Latitudes
Authors: Perlwitz Judith , Hoerling Martin , Dole Randall 
Published: December 2014

Abstract
Arctic temperatures have risen dramatically relative to those of lower latitudes in recent decades, with a common supposition being that sea ice declines are primarily responsible for amplified Arctic tropospheric warming. This conjecture is central to a hypothesis in which Arctic sea ice loss forms the beginning link of a causal chain that includes weaker westerlies in midlatitudes, more persistent and amplified midlatitude waves, and more extreme weather. Through model experimentation, the first step in this chain is examined by quantifying contributions of various physical factors to October–December (OND) mean Arctic tropospheric warming since 1979. The results indicate that the main factors responsible for Arctic tropospheric warming are recent decadal fluctuations and long-term changes in sea surface temperatures (SSTs), both located outside the Arctic. Arctic sea ice decline is the largest contributor to near-surface Arctic temperature increases, but it accounts for only about 20% of the magnitude of 1000–500-hPa warming. These findings thus disconfirm the hypothesis that deep tropospheric warming in the Arctic during OND has resulted substantially from sea ice loss. Contributions of the same factors to recent midlatitude climate trends are then examined. It is found that pronounced circulation changes over the North Atlantic and North Pacific result mainly from recent decadal ocean fluctuations and internal atmospheric variability, while the effects of sea ice declines are very small. Therefore, a hypothesized causal chain of hemisphere-wide connections originating from Arctic sea ice loss is not supported.
Comparing stigmatising attitudes towards people with substance use disorders between the general public, GPs, mental health and addiction specialists and clients
Authors: van Boekel Leonieke C , Brouwers Evelien PM , van Weeghel Jaap , Garretsen Henk FL 
Published: December 2014

Background: Substance use disorders (SUDs) are among the most severely stigmatised conditions; however, little is known about the nature of these stigmatising attitudes. Aims: To assess and compare stigmatising attitudes towards persons with SUDs among different stakeholders: general public, general practitioners (GPs), mental health and addiction specialists, and clients in treatment for substance abuse. Methods: Cross-sectional study ( N  = 3,326) in which stereotypical beliefs, attribution beliefs (e.g. perceptions about controllability and responsibility for having an addiction), social distance and expectations about rehabilitation opportunities for individuals with substance use disorders were assessed and compared between stakeholders. Results: Individuals with substance use disorders elicited great social distance across all stakeholders. Stereotypical beliefs were not different between stakeholders, whereas attribution beliefs were more diverse. Considering social distance and expectations about rehabilitation opportunities, the general public was most pessimistic, followed by GPs, mental health and addiction specialists, and clients. Stereotypical and attribution beliefs, as well as age, gender and socially desirable answering, were not associated with social distance across all stakeholders. Conclusion: The general public and GPs expressed more social distance and were more negative in their expectations about rehabilitation opportunities, compared to mental health and addiction specialists and clients. Although stigmatising attitudes were prevalent across all groups, no striking differences were found between stakeholders.
Bank credit and trade credit: Evidence from SMEs over the financial crisis
Authors: McGuinness Gerard , Hogan Teresa 
Published: December 2014

This article uses panel data to test the extent to which trade credit acted as a substitute for bank finance in Small and Medium-sized Enterprises (SMEs), in the aftermath of the financial crisis of 2008. It demonstrates that the reduction in the supply of funds to SMEs was compounded by the contraction of net trade credit within the sector. Nevertheless, trade credit played a vital role in the adjustment of the sector by easing the burden of the financial crisis for some SMEs. Thus, the relative importance of trade credit increased for financially “vulnerable” SMEs that were less liquid, highly dependent on short-term bank finance, and with greater levels of intangible assets, when entering the crisis. In terms of a redistribution effect, financially stronger firms extended relatively more trade credit, to financially vulnerable SMEs in the aftermath of the financial crisis. In addition, the analysis demonstrates that the financial position of SMEs entering the crisis was more important in determining the impact of the financial crisis on trade credit use than company characteristics of age and size. JEL Classification: L26, L14, G20, B41, C33