bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemotherapy-Regulated microRNA-125–HER2 Pathway as a Novel Therapeutic Target for Trastuzumab-Mediated Cellular Cytotoxicity in Small Cell Lung Cancer
Authors: Yagishita Shigehiro , Fujita Yu , Kitazono Satoru , Ko Ryo , Nakadate Yusuke , Sawada Takeshi , Kitamura Yuka , Shimoyama Tatsu , Maeda Yoshiharu , Takahashi Fumiyuki , Takahashi Kazuhisa , Tamura Tomohide , Koizumi Fumiaki 
Published: April 2015

AbstractSmall cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and is a highly lethal disease. For the last several decades, the standard treatment for SCLC has been deadlocked, and new therapeutic strategies are urgently needed. HER2 is a member of the HER family and has been reported to be overexpressed in 30% of SCLC cases with poor prognosis. However, the clinical relevance of HER2-targeted therapy for SCLC remains unclear. Here, we first identify that cytotoxic drugs induce significant HER2 overexpression through microRNA-125a (miR-125a) and miR-125b downregulation, which in turn act as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in SCLC. In this study, we showed that treatment of the HER2-positive SCLC cells, SBC-3 and SBC-5, with cytotoxic drugs induced a significant upregulation of HER2. Cisplatin (CDDP) treatment of SCLC cells resulted in a significant downregulation of miR-125a and miR-125b. We confirmed that miR-125a and miR-125b bound to the 3′-untranslated regions of HER2 mRNA, and that downregulation of miR-125a and miR-125b resulted in upregulation of HER2 in SCLC cells, suggesting a relationship between cytotoxic drug exposure and miR-125/HER2 dysregulation. Furthermore, using a calcein assay, we demonstrated a significantly enhanced cytotoxic effect of CDDP and trastuzumab that was mediated via antibody-dependent cellular cytotoxicity. Finally, we clearly demonstrated the enhanced antitumor effect of these agents in an orthotopic lung cancer model in vivo. Our results offer a novel therapeutic strategy for HER2-positive SCLCs by using trastuzumab combined with cytotoxic drugs. Mol Cancer Ther; 14(6); 1414–23. ©2015 AACR.
Vascular wall hypoxia promotes arterial thrombus formation via augmentation of vascular thrombogenicity
Authors: Matsuura Yunosuke , Yamashita Atsushi , Iwakiri Takashi , Sugita Chihiro , Okuyama Nozomi , Kitamura Kazuo , Asada Yujiro 
Published: April 2015

SummaryAtherosclerotic lesions represent a hypoxic milieu. However, the significance of this milieu in atherothrombosis has not been established. We aimed to assess the hypothesis that vascular wall hypoxia promotes arterial thrombus formation. We examined the relation between vascular wall hypoxia and arterial thrombus formation using a rabbit model in which arterial thrombosis was induced by 0.5 %- cholesterol diet and repeated balloon injury of femoral arteries. Vascular wall hypoxia was immunohistochemically detected by pimonidazole hydrochloride, a hypoxia marker. Rabbit neointima and THP-1 macrophages were cultured to analyse prothrombotic factor expression under hypoxic conditions (1 % O2). Prothrombotic factor expression and nuclear localisation of hypoxia-inducible factor (HIF)-1α and nuclear factor-kappa B (NF-κB) p65 were immunohisto-chemically assessed using human coronary atherectomy plaques. Hypoxic areas were localised in the macrophage-rich deep portion of rabbit neointima and positively correlated with the number of nuclei immunopositive for HIF-1α and NF-κB p65, and tissue factor (TF) expression. Immunopositive areas for glycoprotein IIb/IIIa and fibrin in thrombi were significantly correlated with hypoxic areas in arteries. TF and plasminogen activator inhibitor-1 (PAI-1) expression was increased in neointimal tissues and/or macrophages cultured under hypoxia, and both were suppressed by inhibitors of either HIF-1 or NF-κB. In human coronary plaques, the number of HIF-1α-immuno-positive nuclei was positively correlated with that of NF-κB-immuno-positive nuclei and TF-immunopositive and PAI-1-immunopositive area, and it was significantly higher in thrombotic plaques. Vascular wall hypoxia augments the thrombogenic potential of atherosclerotic plaque and thrombus formation on plaques via prothrombotic factor upregulation.
Pro-oxidant HDL predicts poor outcome in patients with ST-elevation acute coronary syndrome
Authors: Distelmaier Klaus , Schrutka Lore , Seidl Veronika , Winter Max P. , Wurm Raphael , Mangold Andreas , Perkmann Thomas , Maurer Gerald , Adlbrecht Christopher , Lang Irene M. 
Published: April 2015

SummaryOxidative stress affects clinical outcome in patients with ST-elevation acute coronary syndrome (STE-ACS). Although high-density lipoprotein (HDL) particles are generally considered protective, deleterious properties of HDL have been observed in patients with acute myocardial infarction. Here, we analysed the association between pro oxidant HDL and all-cause mortality in STE-ACS patients. We determined the antioxidant function of HDL in 247 prospectively enrolled patients undergoing primary percutaneous coronary intervention for STE-ACS. Patients were stratified as by a pro-oxidant serum HDL oxidant index (HOI 1) or with an antioxidant serum HOI (HOL< 1) capacity. Multivariate regression analysis was used to relate HOI to survival. The median follow-up time was 23 months (IQR 14.4–40.0 months). Pro-oxidant HDL was observed in 44.1 % of STE-ACS patients and was independently associated with all-cause mortality with a hazard ratio of 3.30(95 %CI 1.50–7.27, p = 0.003). Mortality rates were higher in patients with baseline pro-oxidant HDL compared to patients with preserved HDL function at 30 days (11.9 % vs 2.2 %, p=0.002), and at 4 years (22.9 % vs 8.7 %, p=0.002). Elevated neutrophil counts were a strong and independent predictor for pro-oxidant HDL with an odds ratio per standard deviation of 1.50 (95 %CI 1.11–2.03, p=0.008), as was history of prior acute myocardial infarction, elevated triglycerides levels and reduced glomerular filtration rate. In conclusion, pro-oxidant HDL represents a strong and independent predictor of long-term as well as short-term all-cause mortality in STE-ACS patients. Elevated neutrophil counts predicted the presence of serum pro-oxidant HDL. The maintenance of HDL functions might be a promising therapeutic target in STE-ACS patients.
Endogenous tissue factor pathway inhibitor has a limited effect on host defence in murine pneumococcal pneumonia
Authors: van ’t Veer Cornelis , Roelofs Joris J. T. H. , Meijers Joost C. M. , Schultz Marcus J. , Broze Jr George , van der Poll Tom , van den Boogaard Florry E. 
Published: April 2015

SummaryStreptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. Coagulation and inflammation interact in the host response to infection. Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant protein that inhibits tissue factor (TF), the main activator of inflammation-induced coagulation. It was the objective of this study to investigate the effect of endogenous TFPI levels on coagulation, inflammation and bacterial growth during S. pneumoniae pneumonia in mice. The effect of low endogenous TFPI levels was studied by administration of a neutralising anti-TFPI antibody to wild-type mice, and by using genetically modified mice expressing low levels of TFPI, due to a genetic deletion of the first Kunitz domain of TFPI (TFPIK1(-/-)) rescued with a human TFPI transgene. Pneumonia was induced by intranasal inoculation with S. pneumoniae and samples were obtained at 6, 24 and 48 hours after infection. Anti-TFPI reduced TFPI activity by ~50 %. Homozygous lowTFPI mice and heterozygous controls had ~10 % and ~50 % of normal TFPI activity, respectively. TFPI levels did not influence bacterial growth or dissemination. Whereas lung pathology was unaffected in all groups, mice with ~10 % (but not with ~50 %) of TFPI levels displayed elevated lung cytokine and chemokine concentrations 24 hours after infection. None of the groups with low TFPI levels showed an altered procoagulant response in lungs or plasma during pneumonia. These data argue against an important role for endogenous TFPI in the antibacterial, inflammatory and procoagulant response during pneumococcal pneumonia.
Forward Problem of Electrocardiography
Authors: Bear Laura R. , Cheng Leo K. , LeGrice Ian J. , Sands Gregory B. , Lever Nigel A. , Paterson David J. , Smaill Bruce H. 
Published: April 2015

Background—
The relationship between epicardial and body surface potentials defines the forward problem of electrocardiography. A robust formulation of the forward problem is instrumental to solving the inverse problem, in which epicardial potentials are computed from known body surface potentials. Here, the accuracy of different forward models has been evaluated experimentally.

Methods and Results—

Body surface and epicardial potentials were recorded simultaneously in anesthetized closed-chest pigs (n=5) during sinus rhythm, and epicardial and endocardial ventricular pacing (65 records in total). Body surface potentials were simulated from epicardial recordings using experiment-specific volume conductor models constructed from magnetic resonance imaging. Results for homogeneous (isotropic electric properties) and inhomogeneous (incorporating lungs, anisotropic skeletal muscle, and subcutaneous fat) forward models were compared with measured body surface potentials. Correlation coefficients were 0.85±0.08 across all animals and activation sequences with no significant difference between homogeneous and inhomogeneous solutions (
P
=0.85). Despite this, there was considerable variance between simulated and measured body surface potential distributions. Differences between the body surface potential extrema predicted with homogeneous forward models were 55% to 78% greater than observed (
P
<0.05) and attenuation of potentials adjacent to extrema were 10% to 171% greater (
P
<0.03). The length and orientation of the vector between potential extrema were also significantly different. Inclusion of inhomogeneous electric properties in the forward model reduced, but did not eliminate these differences.

Conclusions—
These results demonstrate that homogeneous volume conductor models introduce substantial spatial inaccuracies in forward problem solutions. This probably affects the precision of inverse reconstructions of cardiac potentials, in which this assumption is made.
Propensity-Matched Comparisons of Clinical Outcomes After Transapical or Transfemoral Transcatheter Aortic Valve Replacement
Authors: Blackstone Eugene H. , Suri Rakesh M. , Rajeswaran Jeevanantham , Babaliaros Vasilis , Douglas Pamela S. , Fearon William F. , Miller D. Craig , Hahn Rebecca T. , Kapadia Samir , Kirtane Ajay J. , Kodali Susheel K. , Mack Michael , Szeto Wilson Y. , Thourani Vinod H. , Tuzcu E. Murat , Williams Mathew R. , Akin Jodi J. , Leon Martin B. , Svensson Lars G. 
Published: April 2015

Background—
The higher risk of adverse outcomes after transapical (TA) versus transfemoral (TF) transcatheter aortic valve replacement (TAVR) could be attributable to TA-TAVR being an open surgical procedure or to clinical differences between TA- and TF-TAVR patients. We compared outcomes after neutralizing patient differences using propensity score matching.

Methods and Results—

From April 2007 to February 2012, 1100 Placement of Aortic Transcatheter Valves (PARTNER)-I patients underwent TA-TAVR and 1521 underwent TF-TAVR with Edwards SAPIEN balloon-expandable bioprostheses. Propensity matching based on 111 preprocedural variables, exclusive of femoral access morphology, identified 501 well-matched patient pairs (46% of possible matches), 95% of whom had peripheral arterial disease. Matched TA-TAVR patients experienced more adverse procedural events, longer length of stay (5 versus 8 days;
P
<0.0001), and slower recovery (New York Heart Association class I, 31% versus 38% at 30 days, equalizing by 6 months at 51% versus 47%); stroke risk was similar (3.4% versus 3.3% at 30 days and 6.0% versus 6.7% at 3 years); mortality was elevated for the first 6 postprocedural months (19% versus 12%;
P
=0.01); but aortic regurgitation was less (34% versus 52% mild and 8.9% versus 12% moderate to severe at discharge,
P
=0.001; 36% versus 50% mild and 10% versus 15% moderate to severe at 6 months,
P
<0.0001).

Conclusions—
The likelihood of adverse periprocedural events and prolonged recovery is greater after TA-TAVR than TF-TAVR in vasculopathic patients after accounting for differences in cardiovascular risk factors, although stroke risk is equivalent and aortic regurgitation is less. As smaller delivery systems permit TF-TAVR in many of these patients, we recommend a TF-first access strategy for TAVR when anatomically feasible.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00530894.
A Qualitative Synthesis of Children’s Experiences of Shared Care Post Divorce
Authors: Birnbaum Rachel , Saini Michael 
Published: April 2015

Objectives: Children’s views and experiences of shared care arrangements post separation were explored to provide their voices to the ongoing discussions of shared parenting.Methods: Qualitative synthesis included a systematic and transparent method for retrieval, screening, and analysing qualitative studies. The inclusion criteria accepted studies that were: qualitative in design; included children as participants in shared care parenting time post-separation.Results: Ten qualitative studies in six different countries with 466 children and young adults were included in the final analysis. Children’s experiences of shared care parenting post separation were mixed and varied depending on contextual factors related to their relationship with both parents, as well the quality of these relationships and the flexibility/rigidity of the parenting arrangement.Implications: Hearing from children and young adults directly helps to move the shared care debate away from binary arguments about sole versus shared care based on parents’ rights and advocacy views.
Restraint and Seclusion of Students with Disabilities
Authors: Lyons Darcie 
Published: April 2015

Students with disabilities are being subjected to restraint and seclusion in some schools in Victoria, Australia. The practices are being used for purposes such as punishment, behaviour change and harm prevention. This article analyses the legality of the practices under the Victorian Charter of Human Rights and Responsibilities and the United Nations Convention on the Rights of the Child, which Australia has ratified.
It concludes that the use of restraint and seclusion on students with disabilities in some Victorian schools has violated children’s rights, under both domestic and international human rights law. The Australian and Victorian governments have failed to recognise the presumption against the use of restraint and seclusion on children with disabilities in school and have failed to justify the associated rights limitations. A cultural shift is required to ensure that children with disabilities no longer experience unlawful rights violations, injuries and mental anguish as a result of restraint and seclusion in the very institutions that have a duty of care to protect them.
Dictionary of the British English Spelling System
Authors: Brooks Greg 
Published: April 2015

This book will tell all you need to know about British English spelling. It’s a reference work intended for anyone interested in the English language, especially those who teach it, whatever the age or mother tongue of their students. It will be particularly useful to those wishing to produce well-designed materials for teaching initial literacy via phonics, for teaching English as a foreign or second language, and for teacher training.
English spelling is notoriously complicated and difficult to learn; it is correctly described as much less regular and predictable than any other alphabetic orthography. However, there is more regularity in the English spelling system than is generally appreciated. This book provides, for the first time, a thorough account of the whole complex system. It does so by describing how phonemes relate to graphemes and vice versa. It enables searches for particular words, so that one can easily find, not the meanings or pronunciations of words, but the other words with which those with unusual phoneme-grapheme/grapheme-phoneme correspondences keep company.
Other unique features of this book include teacher-friendly lists of correspondences and various regularities not described by previous authorities, for example the strong tendency for the letter-name vowel phonemes (the names of the letters <a, e, i, o, u>) to be spelt with those single letters in non-final syllables.
Diagnostic Comparison of Tropospheric Blocking Events with and without Sudden Stratospheric Warming
Authors: Colucci Stephen J. , Kelleher Michael E. 
Published: April 2015

Abstract
Tropospheric blocking events over the Northern Hemisphere during 1980–2012 were composited and contrasted according to whether they coincided in time with a sudden stratospheric warming (SSW). Those that coincided with an SSW were associated with significantly greater poleward eddy heat fluxes in the upper troposphere near the block onset time than were those blocking events not coinciding with an SSW. Furthermore, the heat fluxes in the SSW–blocking composites were concentrated inside the stratospheric polar vortex (i.e., within an area enclosed by the outer edge of an objectively defined polar vortex). Thermally forced stratospheric geopotential height rises were also significantly larger near block onset time inside the stratospheric polar vortex in the SSW–blocking composites than in the non-SSW–blocking cases. Although all the SSW events during the investigated period coincided with tropospheric blocking, the reverse was not true since there were many more blocking events than SSWs. Therefore, blocking itself was not a sufficient condition for an SSW. It is conjectured that blocking may not be a necessary condition for an SSW if persistently anomalous tropospheric heat fluxes and thermally forced, stratospheric geopotential height rises, concentrated inside the stratospheric vortex, occur in the absence of blocking.
Multiple Regimes of Wind, Stratification, and Turbulence in the Stable Boundary Layer
Authors: Monahan Adam H. , Rees Tim , He Yanping , McFarlane Norman 
Published: April 2015

Abstract
A long time series of temporally high-resolution wind and potential temperature data from the 213-m tower at Cabauw in the Netherlands demonstrates the existence of two distinct regimes of the stably stratified nocturnal boundary layer at this location. Hidden Markov model (HMM) analysis is used to objectively characterize these regimes and classify individual observed states. The first regime is characterized by strongly stable stratification, large wind speed differences between 10 and 200 m, and relatively weak turbulence. The second is associated with near-neutral stratification, weaker wind speed differences between 10 and 200 m, and relatively strong turbulence. In this second regime, the state of the boundary layer is similar to that during the day. The occupation statistics of these regimes are shown to covary with the large-scale pressure gradient force and cloud cover such that the first regime predominates under clear skies with weak geostrophic wind speed and the second regime predominates under conditions of extensive cloud cover or large geostrophic wind speed. These regimes are not distinguished by standard measures of stability, such as the Obukhov length or the bulk Richardson number. Evidence is presented that the mechanism generating these distinct regimes is associated with a previously documented feedback resulting from the existence of an upper limit on the maximum downward heat flux that can be sustained for a given near-surface wind speed.
Toward Clarity on Understanding Tropical Cyclone Intensification
Authors: Smith Roger K. , Montgomery Michael T. 
Published: April 2015

Abstract
The authors review an emerging paradigm of tropical cyclone intensification in the context of the prototype intensification problem, which relates to the spinup of a preexisting vortex near tropical storm strength in a quiescent environment. In addition, the authors review briefly what is known about tropical cyclone intensification in the presence of vertical wind shear. The authors go on to examine two recent lines of research that seem to offer very different views to understanding the intensification problem. The first of these proposes a mechanism to explain rapid intensification in terms of surface pressure falls in association with upper-level warming accompanying outbreaks of deep convection. The second line of research explores the relationship between the contraction of the radius of maximum tangential wind and intensification in the classical axisymmetric convective ring model, albeit in an unbalanced framework. The authors challenge a finding of the second line of research that appears to cast doubt on a recently suggested mechanism for the spinup of maximum tangential wind speed in the boundary layer—a feature seen in observations. In doing so, the authors recommend some minimum requirements for a satisfactory explanation of tropical cyclone intensification.
Revisiting ENSO Coupled Instability Theory and SST Error Growth in a Fully Coupled Model
Authors: Larson Sarah M. , Kirtman Ben P. 
Published: April 2015

Abstract
A coupled model framework is presented to isolate coupled instability induced SST error growth in the ENSO region. The modeling framework using CCSM4 allows for seasonal ensembles of initialized simulations that are utilized to quantify the spatial and temporal behavior of coupled instabilities and the associated implications for ENSO predictability. The experimental design allows for unstable growth of initial perturbations that are not prescribed, and several cases exhibit sufficiently rapid growth to produce ENSO events that do not require a previous ENSO event, large-scale wind trigger, or subsurface heat content precursor. Without these precursors, however, ENSO amplitude is reduced.
The initial error growth exhibits strong seasonality with fastest growth during spring and summer and also dependence on the initialization month with the fastest growth occurring in the July ensemble. Peak growth precedes the peak error, and evidence suggests that the final state error may be sensitive to a slight temperature bias in the initialized SST. The error growth displays a well-defined seasonal limit, with ensembles initialized prior to fall exhibiting a clear seasonal halt in error growth around September, consistent with increased background stability typical during fall. Overall, coupled instability error growth in CCSM4 is deemed best characterized by strong seasonality, dependence on the initialization month, and nonlinearity. The results pose real implications for predictability because the final error structure is ENSO-like and occurs without a subsurface precursor, which studies have shown to be essential to ENSO predictability. Despite the large error growth induced by coupled instabilities, analysis reveals that ENSO predictability is retained for most seasonal ensembles.