bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitivity of Selected Human Tumor Models to PF-04217903, a Novel Selective c-Met Kinase Inhibitor
Authors: Zou Helen Y. , Li Qiuhua , Lee Joseph H. , Arango Maria E. , Burgess Kristina , Qiu Ming , Engstrom Lars D. , Yamazaki Shinji , Parker Max , Timofeevski Sergei , Cui Jingrong Jean , McTigue Michele , Los Gerrit , Bender Steven L. , Smeal Tod , Christensen James G. 
Published: March 2012

Abstract
The c-Met pathway has been implicated in a variety of human cancers for its critical role in tumor growth, invasion, and metastasis. PF-04217903 is a novel ATP-competitive small-molecule inhibitor of c-Met kinase. PF-04217903 showed more than 1,000-fold selectivity for c-Met compared with more than 150 kinases, making it one of the most selective c-Met inhibitors described to date. PF-04217903 inhibited tumor cell proliferation, survival, migration/invasion in MET-amplified cell lines in vitro, and showed marked antitumor activity in tumor models harboring either MET gene amplification or a hepatocyte growth factor (HGF)/c-Met autocrine loop at well-tolerated dose levels in vivo. Antitumor efficacy of PF-04217903 was dose-dependent and showed a strong correlation with inhibition of c-Met phosphorylation, downstream signaling, and tumor cell proliferation/survival. In human xenograft models that express relatively high levels of c-Met, complete inhibition of c-Met activity by PF-04217903 only led to partial tumor growth inhibition (38%–46%) in vivo. The combination of PF-04217903 with Recepteur d'origine nantais (RON) short hairpin RNA (shRNA) knockdown in the HT29 model that also expresses activated RON kinase–induced tumor cell apoptosis and resulted in enhanced antitumor efficacy (77%) compared with either PF-04217903 (38%) or RON shRNA alone (56%). PF-04217903 also showed potent antiangiogenic properties in vitro and in vivo. Furthermore, PF-04217903 strongly induced phospho-PDGFRβ (platelet-derived growth factor receptor) levels in U87MG xenograft tumors, indicating a possible oncogene switching mechanism in tumor cell signaling as a potential resistance mechanism that might compromise tumor responses to c-Met inhibitors. Collectively, these results show the use of highly selective inhibition of c-Met and provide insight toward targeting tumors exhibiting different mechanisms of c-Met dysregulation. Mol Cancer Ther; 11(4); 1036–47. ©2012 AACR.
Mitral Valve Prolapse With Mid-Late Systolic Mitral Regurgitation
Authors: Topilsky Yan , Michelena Hector , Bichara Valentina , Maalouf Joseph , Mahoney Douglas W. , Enriquez-Sarano Maurice 
Published: March 2012

Background—
Mitral regurgitation (MR) of mitral valve prolapse predominates in late systole but may be holosystolic or purely mid-late systolic, but the impact of MR timing on MR left ventricular and left atrial consequences and outcome is unknown. Whether effective regurgitant orifice (ERO) by the flow convergence method is similarly linked to outcome in mid-late systolic MR and holosystolic MR is uncertain.

Methods and Results—

We comprehensively and prospectively quantified MR in 111 patients with mitral valve prolapse and mid-late systolic MR and matched them to 90 patients with mitral valve prolapse and holosystolic MR for age, gender, atrial fibrillation, ejection fraction, and ERO (flow convergence). Mid-late systolic MR versus holosystolic MR groups were well matched, including for comorbidity, blood pressure, and heart rate (all
P
>0.10). Mid-late systolic MR versus holosystolic MR caused similar color jet area, midsystolic regurgitant flow, and peak velocity (
P
>0.40). Despite identical ERO (0.25±0.15 versus 0.25±0.15 cm
2
;
P
=0.53), the shorter duration of mid-late systolic MR (233±56 versus 426±50 ms;
P
<0.0001) yielded lower regurgitant volume (24.8±13.4 versus 48.6±25.6 mL;
P
<0.0001). MR consequences, systolic pulmonary pressure, and left ventricular and left atrial volume index (all
P
<0.001) were more benign in mid-late systolic MR versus holosystolic MR. Under medical management, fewer cardiac events (5 years: 15.8±4.6% versus 40.4±6.1%;
P
<0.0001) occurred in mid-late systolic MR versus holosystolic MR, requiring less mitral surgery. Multivariable analysis confirmed the independent association of mid-late systolic MR with benign consequences and outcomes (all
P
<0.01). Absolute ERO was not linked to outcome, in contrast to regurgitant volume.

Conclusions—
MR of mitral valve prolapse that is purely mid-late systolic causes more benign consequences and outcomes than holosystolic MR. Assessment may be misleading because jet area and ERO by flow convergence appear similar to those of holosystolic MR. However, shorter MR yields lower regurgitant volume, consequences, and benign outcomes. Instantaneous ERO by flow convergence should be interpreted in context, and in mid-late systolic MR, regurgitant volume provides information more reflective of MR severity. Therefore, for clinical management and surgical referral, clinicians should carefully take into account the timing and consequences of MR.
A Method for Estimating Potential Seasonal Predictability: Analysis of Covariance
Authors: Feng Xia , DelSole Timothy , Houser Paul 
Published: March 2012

AbstractThis paper proposes a new method for assessing potential predictability of seasonal means using a single realization of daily time series. Potential predictability is defined as variability in seasonal means that exceeds the variability due to weather stochastic processes. The proposed method is based on analysis of covariance and accounts for autocorrelation in daily time series and uncertainties in statistical parameters. The method is applied to reanalyzed daily surface air temperature and detects significant potential predictability over the oceans and equatorial land areas. Potential predictability is weaker and varies significantly with season over extratropical land areas, with the fraction of potentially predictable variance rarely exceeding 60%. The proposed method also produces an estimate of the potentially predictable component of seasonal means, which can be used to investigate the relation between potential predictability and possible boundary forcings. The results are generally consistent with previous studies, although a more detailed study will be made in a future paper.
Using a Multiphysics Ensemble for Exploring Diversity in Cloud–Shortwave Feedback in GCMs
Authors: Watanabe Masahiro , Shiogama Hideo , Yokohata Tokuta , Kamae Youichi , Yoshimori Masakazu , Ogura Tomoo , Annan James D. , Hargreaves Julia C. , Emori Seita , Kimoto Masahide 
Published: March 2012

Abstract
This study proposes a systematic approach to investigate cloud-radiative feedbacks to climate change induced by an increase of CO2 concentrations in global climate models (GCMs). Based on two versions of the Model for Interdisciplinary Research on Climate (MIROC), which have opposite signs for cloud–shortwave feedback (ΔSWcld) and hence different equilibrium climate sensitivities (ECSs), hybrid models are constructed by replacing one or more parameterization schemes for cumulus convection, cloud, and turbulence between them. An ensemble of climate change simulations using a suite of eight models, called a multiphysics ensemble (MPE), is generated. The MPE provides a range of ECS as wide as the Coupled Model Intercomparison Project phase 3 (CMIP3) multimodel ensemble and reveals a different magnitude and sign of ΔSWcld over the tropics, which is crucial for determining ECS.
It is found that no single process controls ΔSWcld, but that the coupling of two processes does. Namely, changing the cloud and turbulence schemes greatly alters the mean and the response of low clouds, whereas replacing the convection and cloud schemes affects low and middle clouds over the convective region. For each of the circulation regimes, ΔSWcld and cloud changes in the MPE have a nonlinear, but systematic, relationship with the mean cloud amount, which can be constrained from satellite estimates. The analysis suggests a positive feedback over the subsidence regime and a near-neutral or weak negative ΔSWcld over the convective regime in these model configurations, which, however, may not be carried into other models.
Assessment of Regional Global Climate Model Water Vapor Bias and Trends Using Precipitable Water Vapor (PWV) Observations from a Network of Global Positioning Satellite (GPS) Receivers in the U.S. Great Plains and Midwest
Authors: Roman Jacola A. , Knuteson Robert O. , Ackerman Steven A. , Tobin David C. , Revercomb Henry E. 
Published: March 2012

Abstract
Precipitable water vapor (PWV) observations from the National Center of Atmospheric Research (NCAR) SuomiNet networks of ground-based global positioning system (GPS) receivers and the National Oceanic and Atmospheric Administration (NOAA) Profiler Network (NPN) are used in the regional assessment of global climate models. Study regions in the U.S. Great Plains and Midwest highlight the differences among global climate model output from the Fourth Assessment Report (AR4) Special Report on Emissions Scenarios (SRES) A2 scenario in their seasonal representation of column water vapor and the vertical distribution of moisture. In particular, the Community Climate System model, version 3 (CCSM3) is shown to exhibit a dry bias of over 30% in the summertime water vapor column, while the Goddard Institute for Space Studies Model E20 (GISS E20) agrees well with PWV observations. A detailed assessment of vertical profiles of temperature, relative humidity, and specific humidity confirm that only GISS E20 was able to represent the summertime specific humidity profile in the atmospheric boundary layer (&lt;3%) and thus the correct total column water vapor. All models show good agreement in the winter season for the region. Regional trends using station-elevation-corrected GPS PWV data from two complimentary networks are found to be consistent with null trends predicted in the AR4 A2 scenario model output for the period 2000–09. The time to detect (TTD) a 0.05 mm yr−1 PWV trend, as predicted in the A2 scenario for the period 2000–2100, is shown to be 25–30 yr with 95% confidence in the Oklahoma–Kansas region.
PF4/Heparin Antibody Testing and Treatment of Heparin-Induced Thrombocytopenia in the Intensive Care Unit
Authors: Wanat Matthew , Fitousis Kalliopi , Hall Jeff , Rice Lawrence 
Published: March 2012

Background: The diagnosis of heparin-induced thrombocytopenia (HIT) may be challenging in critically ill patients, as heparin exposures are ubiquitous, and thrombocytopenia is common. Unwarranted ordering and incorrect interpretation of heparin antibody tests can expose a patient to adverse drug events and imposes a significant economic burden on our health care system. Methods: A prospective, observational study was performed over 4 months on all adult patients located in 5 intensive care units, with a heparin antibody test ordered. Results: A platelet factor 4/heparin enzyme-linked immunosorbent assay (ELISA) test was ordered in 131 patients. In total, 110 patients had a low 4Ts score (0-3), and of these 103 had a negative ELISA result. In patients with a low 4Ts score, 0 (0%) of 110 had an optical density value >1.0. One hundred twenty-nine patients (98%) had another possible cause of thrombocytopenia identified. Conclusion: In critically ill patients, low 4Ts scores indicate a low probability of HIT, and heparin antibody testing in these patients is not useful.
Cognitive reserve in secondary progressive multiple sclerosis
Authors: Sumowski James F , Chiaravalloti Nancy , Leavitt Victoria M , DeLuca John 
Published: March 2012

Background: Consistent with the cognitive reserve hypothesis, lifetime intellectual enrichment protects MS patients from cognitive impairment. As studies have focused predominately on patients with relapsing–remitting courses, it is unknown whether lifetime enrichment is protective against cognitive impairment in patients with secondary-progressive MS (SPMS), a more advanced disease course. Objective: Examine whether greater lifetime intellectual enrichment moderates/reduces the deleterious effect of SPMS on memory and cognitive efficiency. Methods: Twenty-five SPMS patients and 25 healthy controls (HC) completed neuropsychological tasks, yielding two composite scores: memory and cognitive efficiency. An estimate of lifetime enrichment was created from educational attainment and vocabulary knowledge. Regression analyses predicted memory and cognitive efficiency, with age, sex, intellectual enrichment and group (SPMS, HC) controlled in step one, and the interaction between intellectual enrichment and group evaluated within step two. Results: Interactions emerged between intellectual enrichment and group when predicting memory ( R2Δ=0.081, p = 0.041) and cognitive efficiency ( R2Δ=0.064, p = 0.024), such that SPMS patients exhibited deficits relative to HCs at lower levels of enrichment, but these SPMS-related cognitive deficits were absent at higher levels of enrichment. Conclusion: Intellectual enrichment protects SPMS patients from cognitive impairment, thereby extending the cognitive reserve hypothesis to this more advanced MS disease course.
Motivations of patients with pulmonary arterial hypertension to participate in randomized clinical trials
Authors: Carroll Ricki , Antigua Jules , Taichman Darren , Palevsky Harold , Forfia Paul , Kawut Steven , Halpern Scott D 
Published: March 2012

Background There is substantial need to rigorously evaluate existing and new therapies for pulmonary arterial hypertension (PAH) and other severe and relatively rare conditions affecting younger patients. However, the ability to conduct meaningful randomized clinical trials (RCTs) in such contexts often is limited by difficulties obtaining adequate patient enrollment. Purpose  To understand the motivations of patients with PAH for participating in RCTs so as to facilitate enrollment in future trials among patients with similar diseases. Methods  We conducted semistructured interviews of a diverse sample of patients with World Health Organization (WHO) Group I PAH. We purposefully recruited a diverse sample of participants until theoretical saturation was reached. We randomly assigned patients to review hypothetical RCTs that did or did not allow continuation of background PAH therapies and elicited their reasons for or against enrolling. Interviews were transcribed and analyzed using constant comparison techniques to code and sort data into discrete themes. Results The 26 PAH patients enrolled before theoretical saturation was reached identified 24 factors that would influence their RCT enrollment decisions. These factors grouped naturally into four themes: (1) personal medical benefits, (2) personal medical risks/harms, (3) nonmedical benefits, and (4) nonmedical burdens. Personal benefits were cited as commonly as altruistic motives. One third of the patients (9/26) suggested that they would defer enrollment decisions to their treating clinicians. Seventy-nine percent of patients (11/14) assigned to consider trials without background therapies expressed concerns about clinical deterioration (vs. 17% (2/12) among patients assigned to consider trials allowing background therapies). Limitations The sample was recruited from a single academic center. Furthermore, the use of hypothetical trials may not elicit identical decision-making processes as may be used among patients contemplating actual trial participation. Conclusion For PAH patients considering RCT enrollment, the potentials for personal benefit and risk are at least as important as altruistic motives. Minimizing the time demands of participating, financial remuneration, and allowing participants to continue current therapies are factors, which might enhance enrollment to trials in similar disease areas.
Allelic expression analysis of the osteoarthritis susceptibility locus that maps to MICAL3
Authors: Ratnayake Madhushika , Reynard Louise N , Raine Emma VA , Santibanez-Koref Mauro , Loughlin John 
Published: March 2012

AbstractBackgroundA genome-wide association scan with subsequent replication study that involved over 67,000 individuals of European ancestry has produced evidence of association of single nucleotide polymorphism rs2277831 to primary osteoarthritis (OA) with a P-value of 2.9 × 10-5. rs2277831, an A/G transition, is located in an intron ofMICAL3. This gene is located on chromosome 22q11.21 and the association signal encompasses two additional genes,BCL2L13andBID. It is becoming increasingly apparent that many common complex traits are mediated bycis-acting regulatory polymorphisms that influence, in a tissue-specific manner, gene expression or transcript stability.MethodsWe used total and allelic expression analysis to assess whether the OA association to rs2277831 is mediated by an influence on MICAL3, BCL2L13 or BID expression. Using RNA extracted from joint tissues of 60 patients who had undergone elective joint replacement surgery, we assessed whether rs2277831 correlated with allelic expression of either of the three genes by: 1) measuring the expression of each gene by quantitative PCR and then stratifying the data by genotype at rs2277831 and 2) accurately discriminating and quantifying the mRNA synthesised from the alleles of OA patients using allelic-quantitative PCR.ResultsWe found no evidence for a correlation between gene expression and genotype at rs2277831, with P-values of 0.09 forBCL2L13, 0.07 forBIDand 0.33 forMICAL3. In the allelic expression analysis we observed several examples of significant (p < 0.05) allelic imbalances, with an allelic expression ratio of 2.82 observed inBCL2L13(P = 0.004), 2.09 atBID(P = 0.001) and the most extreme case being atMICAL3, with an allelic expression ratio of 5.47 (P = 0.001). However, there was no correlation observed between the pattern of allelic expression and the genotype at rs2277831.ConclusionsIn the tissues that we have studied, our data do not support our hypothesis that the association between rs2277831 and OA is due to the effect this SNP has onMICAL3, BCL2L13orBIDgene expression. Instead, our data point towards other functional effects accounting for the OA associated signal.
A role of multi-modal rhythms in physical interaction and cooperation
Authors: Yonekura Kenta , Kim Chyon Hae , Nakadai Kazuhiro , Tsujino Hiroshi , Sugano Shigeki 
Published: March 2012

Abstract
As fundamental research for human-robot interaction, this paper addresses the rhythmic reference of a human while turning a rope with another human. We hypothyzed that when interpreting rhythm cues to make a rhythm reference, humans will use auditory and force rhythms more than visual ones. We examined 21-23 years old test subjects. We masked perception of each test subject using 3 kinds of masks, an eye-mask, headphones, and a force mask. The force mask is composed of a robot arm and a remote controller. These instruments allow a test subject to turn a rope without feeling force from the rope. In the first experiment, each test subject interacted with an operator that turned a rope with a constant rhythm. 8 experiments were conducted for each test subject that wore combinations of masks. We measured the angular velocity of force between a test subject/the operator and a rope. We calculated error between the angular velocities of the force directions, and validated the error. In the second experiment, two test subjects interacted with each other. 1.6 - 2.4 Hz auditory rhythm was presented from headphones so as to inform target turning frequency. Addition to the auditory rhythm, the test subjects wore eye-masks. The first experiment showed that visual rhythm has little influence on rope-turning cooperation between humans. The second experiment provided firmer evidence for the same hypothesis because humans neglected their visual rhythms.
Visual mismatch negativity elicited by facial expressions: new evidence from the equiprobable paradigm
Authors: Li Xiying , Lu Yongli , Sun Gang , Gao Lei , Zhao Lun 
Published: March 2012

Abstract

Background
Converging evidence revealed that facial expressions are processed automatically. Recently, there is evidence that facial expressions might elicit the visual mismatch negativity (MMN), expression MMN (EMMN), reflecting that facial expression could be processed under non-attentional condition. In the present study, using a cross modality task we attempted to investigate whether there is a memory-comparison-based EMMN.

Methods
12 normal adults were instructed to simultaneously listen to a story and pay attention to a non-patterned white circle as a visual target interspersed among face stimuli. In the oddball block, the sad face was the deviant with a probability of 20% and the neutral face was the standard with a probability of 80%; in the control block, the identical sad face was presented with other four kinds of face stimuli with equal probability (20% for each). Electroencephalogram (EEG) was continuously recorded and ERPs (event-related potentials) in response to each kind of face stimuli were obtained. Oddball-EMMN in the oddball block was obtained by subtracting the ERPs elicited by the neutral faces (standard) from those by the sad faces (deviant), while controlled-EMMN was obtained by subtracting the ERPs elicited by the sad faces in the control block from those by the sad faces in the oddball block. Both EMMNs were measured and analyzed by ANOVAs (Analysis of Variance) with repeated measurements. sLORETA (standardized low-resolution brain electromagnetic tomography) was used to investigate the cortical generators of controlled-EMMN.

Results
Both the oddball-EMMN in deviant-standard comparison and the controlled-EMMN in deviant-control comparison were observed at occipital-temporal regions with right hemisphere predominance. The oddball-EMMN was bigger and earlier than the controlled-EMMN because, besides the memory-based comparison, the former included a difference of refractoriness due to the distinction of presented probability between the deviant and standard face stimuli. The source analysis of controlled-EMMN indicated a current source primarily involved in posterior areas including superior temporal gyrus, postcentral gyrus, inferior parietal lobule as well as the insula.

Conclusions
The valid EMMN properly reflecting the memory-based comparison of facial expressions could be obtained, i.e., the controlled-EMMN.