bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Trial of Atopaxar in the Treatment of Patients With Coronary Artery Disease
Authors: Wiviott Stephen D. , Flather Marcus D. , O'Donoghue Michelle L. , Goto Shinya , Fitzgerald Desmond J. , Cura Fernando , Aylward Philip , Guetta Victor , Dudek Dariusz , Contant Charles F. , Angiolillo Dominick J. , Bhatt Deepak L. 
Published: April 2011

Background—
Thrombin is a key mediator of platelet activation. Atopaxar is a reversible protease-activated receptor-1 antagonist that interferes with thrombin-mediated platelet effects. The phase II Lessons From Antagonizing the Cellular Effect of Thrombin–Coronary Artery Disease (LANCELOT–CAD) trial examined the safety and tolerability of prolonged therapy with atopaxar in subjects with CAD.

Methods and Results—

Subjects with a qualifying history were randomized in a double-blind fashion to 3 dosing regimens of atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. The key safety end points were bleeding according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Thrombolysis in Myocardial Infarction (TIMI) classifications. Secondary objectives included platelet aggregation and major adverse cardiac events. Seven hundred and twenty subjects were randomized. Overall bleeding rates tended to be higher with atopaxar compared with placebo by CURE criteria (placebo, 0.6%; atopaxar, 3.9%; relative risk, 6.82,
P
=0.03; 50 mg, 3.9%; 100 mg, 1.7%; 200 mg, 5.9%;
P
for trend=0.01) and TIMI criteria (placebo, 6.8%; atopaxar, 10.3%; relative risk, 1.52,
P
=0.17; 50 mg, 9.9%; 100 mg, 8.1%; 200 mg, 12.9%;
P
for trend=0.07). There was no difference in major bleeding. Major adverse cardiac events were numerically lower in the atopaxar subjects. All atopaxar regimens achieved high levels of platelet inhibition. A transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose atopaxar treatment groups.

Conclusions—
In this dose-ranging study of patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events. Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects.

Clinical Trial Registration—

URL:
http://www.ClinicalTrials.gov
. Unique identifier: NCT00312052.
Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults
Authors: Smith Nicholas L. , Huffman Jennifer E. , Strachan David P. , Huang Jie , Dehghan Abbas , Trompet Stella , Lopez Lorna M. , Shin So-Youn , Baumert Jens , Vitart Veronique , Bis Joshua C. , Wild Sarah H. , Rumley Ann , Yang Qiong , Uitterlinden Andre G. , Stott David. J. , Davies Gail , Carter Angela M. , Thorand Barbara , Polašek Ozren , McKnight Barbara , Campbell Harry , Rudnicka Alicja R. , Chen Ming-Huei , Buckley Brendan M. , Harris Sarah E. , Peters Annette , Pulanic Drazen , Lumley Thomas , de Craen Anton J.M. , Liewald David C. , Gieger Christian , Campbell Susan , Ford Ian , Gow Alan J. , Luciano Michelle , Porteous David J. , Guo Xiuqing , Sattar Naveed , Tenesa Albert , Cushman Mary , Slagboom P. Eline , Visscher Peter M. , Spector Tim D. , Illig Thomas , Rudan Igor , Bovill Edwin G. , Wright Alan F. , McArdle Wendy L. , Tofler Geoffrey , Hofman Albert , Westendorp Rudi G.J. , Starr John M. , Grant Peter J. , Karakas Mahir , Hastie Nicholas D. , Psaty Bruce M. , Wilson James F. , Lowe Gordon D.O. , O'Donnell Christopher J. , Witteman Jacqueline C.M. , Jukema J. Wouter , Deary Ian J. , Soranzo Nicole , Koenig Wolfgang , Hayward Caroline 
Published: April 2011

Background—
Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

Methods and Results—

A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (
P
=6.4×10
−52
) was 46.0 kb upstream from
F3
, coagulation factor III (tissue factor). At 1q24, rs6687813 (
P
=2.4×10
−14
) was 79.7 kb downstream of
F5
, coagulation factor V. At 4q32, rs13109457 (
P
=2.9×10
−18
) was located between 2 fibrinogen genes: 10.4 kb downstream from
FGG
and 3.0 kb upstream from
FGA
. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in
F5
and
FGA
loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

Conclusions—

Three genes were associated with fibrin D-dimer levels. Of these 3, the
F3
association was the strongest, and has not been previously reported.
The One in Syrianus’ Teachings on the Parmenides: Syrianus on Parm., 137d and 139a1
Authors: Wear S. Klitenic 
Published: April 2011

AbstractThis article describes Syrianus’ teachings on the One, as found in his testimonia on the Parmenides. In order to preserve the transcendence of the One, while still providing a fluid universe connected to the One, Syrianus shows how the nature of the One is seen in the structure of the Parmenides itself: the first hypothesis of the Parmenides outlines the primal God, while the intelligible universe is the subject of the second hypothesis, in so far as the intelligible universe is a product of the One. Thus, whatever is negated of the One in the first hypothesis contains a positive analogue in the second hypothesis. With this description of the One in the Parmenides, Syrianus is able to create a complete, fluid universe. Readings of two lemmata, in particular, illuminate Syrianus’ manner of interpreting the Parmenides to show how the One is both transcendent and connected to the universe. In his interpretations of Parmenides 137d and 138a, Syrianus shows how the One is partless with respect to itself, but contains parts with respect to the rest of the universe; and that the One is in itself and in another, again, with respect to itself and with respect to the rest of the universe. With his interpretation of the Parmenides, moreover, one can see how Syrianus differs from the interpretations of Porphyry and Iamblichus, and how he paves the way for Proclus’ reading of the dialogue.
SPLIDHOM: A Method for Homogenization of Daily Temperature Observations
Authors: Mestre Olivier , Gruber Christine , Prieur Clémentine , Caussinus Henri , Jourdain Sylvie 
Published: April 2011

AbstractOne major concern of climate change is the possible rise of temperature extreme events, in terms of occurrence and intensity. To study this phenomenon, reliable daily series are required, for instance to compute daily-based indices: high-order quantiles, annual extrema, number of days exceeding thresholds, and so on. Because observed series are likely to be affected by changes in the measurement conditions, adapted homogenization procedures are required. Although a very large number of procedures have been proposed for adjustment of observed series at a monthly time scale, few have been proposed for adjustment of daily temperature series. This article proposes a new adjustment method for temperature series at a daily time scale. This method, called spline daily homogenization (SPLIDHOM), relies on an indirect nonlinear regression method. Estimation of the regression functions is performed by cubic smoothing splines. This method is able to adjust the mean of the series as well as high-order quantiles and moments of the series. When using well-correlated series, SPLIDHOM improves the results of two widely used methods, as a result of an optimal selection of the smoothing parameter. Applications to the Toulouse, France, temperature series are shown as a real example.
Vegetation Feedbacks to Climate in the Global Monsoon Regions*
Authors: Notaro Michael , Chen Guangshan , Liu Zhengyu 
Published: April 2011

Abstract
Vegetation feedbacks on climate, on the subannual time scale, are examined across six monsoon regions with a fully coupled atmosphere–ocean–ice–land model with dynamic vegetation. Initial value ensemble experiments are run in which the total vegetation cover fraction across the six monsoon regions is reduced and the climatic response assessed. Consistent responses among the regions include reductions in leaf area index, turbulent fluxes, and atmospheric moisture; enhanced subsidence; and increases in ground and surface air temperature. The most distinct changes in vertical motion, precipitable water, and precipitation occur along the flanks of the monsoon season, with small changes in midmonsoon rainfall. Unique responses to reduced vegetation cover are noted among the monsoon regions. While the monsoon is delayed and weaker over north Australia owing to diminished leaf area, it occurs earlier over China and the southwest United States. The subtropical monsoon regions are characterized by a larger decrease in sensible heat than latent heat flux, while the opposite is true for tropical monsoon regions. North Australia experiences the most substantial decline in both moisture flux convergence and precipitation.
Comparing NWS PoP Forecasts to Third-Party Providers
Authors: Bickel J. Eric , Floehr Eric , Kim Seong Dae 
Published: April 2011

Abstract
In this paper, the authors verify probability of precipitation (PoP) forecasts provided by the National Weather Service (NWS), The Weather Channel (TWC), and CustomWeather (CW). The n-day-ahead forecasts, where n ranges from 1 to 3 for the NWS, from 1 to 9 for TWC, and from 1 to 14 for CW, are analyzed. The dataset includes almost 13 million PoP forecasts, or about 500 000 PoPs per provider per day of lead time. Data were collected over a 2-yr period (1 November 2008–31 October 2010) at 734 observation stations across the contiguous United States. In addition to verifying these PoP forecasts in an absolute sense, relative comparisons are made between the providers. It is found that, in most cases, TWC does not add skill to NWS forecasts. Perhaps most interestingly, it is also found that CW does have the ability to forecast PoPs at a resolution of 0.01.
The SKP2 E3 ligase regulates basal homeostasis and stress-induced regeneration of HSCs
Authors: Rodriguez Sonia , Wang Lin , Mumaw Christen , Srour Edward F. , Lo Celso Cristina , Nakayama Kei-ichi , Carlesso Nadia 
Published: April 2011

Abstract
Exit from quiescence and reentry into cell cycle is essential for HSC self-renewal and regeneration. Skp2 is the F-box unit of the SCF E3-ligase that targets the CDK inhibitors (CKIs) p21Cip1, p27Kip1, p57Kip2, and p130 for degradation. These CKIs inhibit the G1 to S-phase transition of the cell cycle, and their deletion results in increased cell proliferation and decreased stem cell self-renewal. Skp2 deletion leads to CKIs stabilization inducing cell-cycle delay or arrest, and conversely, increased Skp2 expression is often found in cancers. Here, we show that SKP2 expression is increased in HSC and progenitors in response to hematopoietic stress from myelosuppression or after transplantation. At steady state, SKP2 deletion decreased the mitotic activity of HSC and progenitors resulting in enhanced HSC quiescence, increased HSC pool size, and maintenance. However, the inability to rapidly enter cell cycle greatly impaired the short-term repopulating potential of SKP2 null HSC and their ability to regenerate after myeloablative stress. Mechanistically, deletion of SKP2 in HSC and progenitors stabilized CKIs in vivo, particularly p27Kip1, p57Kip2, and p130. Our results demonstrate a previously unrecognized role for SKP2 in regulating HSC and progenitor expansion and hematopoietic regeneration after stress.
Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations
Authors: Kuijpers Taco W. , IJspeert Hanna , van Leeuwen Ester M. M. , Jansen Machiel H. , Hazenberg Mette D. , Weijer Kees C. , van Lier Rene A. W. , van der Burg Mirjam 
Published: April 2011

Abstract
A girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4+ T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, or autoimmunity. Immunophenotyping demonstrated strongly reduced naive T and B cells with intact proliferative capacity. Antibody reactivity on in vivo immunizations was normal. T-cell receptor-Vβ repertoire was polyclonal with a very low content of T-cell receptor excision circles (TRECs). Kappa-deleting recombination excision circles (KRECs) were also abnormal in the B cells. Both reflect extensive in vivo proliferation. Patient-derived CD34+ hematopoietic stem cells could not repopulate RAG2−/−IL2Rγc−/− mice, indicating the lymphoid origin of the defect. We identified 2 novel missense mutations in RAG1 (p.Arg474Cys and p.Leu506Phe) resulting in reduced RAG activity. This report gives the first genetic clue for ICL and extends the clinical spectrum of RAG mutations from severe immune defects to an almost normal condition.
Randomized Phase II Study of Bevacizumab in Combination With Chemotherapy in Previously Untreated Extensive-Stage Small-Cell Lung Cancer: Results From the SALUTE Trial
Authors: Spigel David R. , Townley Peter M. , Waterhouse David M. , Fang Liang , Adiguzel Ibrahim , Huang Jane E. , Karlin David A. , Faoro Leonardo , Scappaticci Frank A. , Socinski Mark A. 
Published: April 2011

Purpose Because of promising efficacy signals in single-arm studies, a placebo-controlled, double-blind, randomized phase II trial was designed to assess the efficacy and safety of adding bevacizumab to first-line standard chemotherapy for treatment of extensive-stage small-cell lung cancer (SCLC). Patients and Methods Patients with SCLC were randomly assigned to receive bevacizumab or placebo, with cisplatin or carboplatin plus etoposide, for four cycles followed by single-agent bevacizumab or placebo until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Results Fifty-two patients were randomly assigned to the bevacizumab group and 50 to the placebo group; 69% versus 66%, respectively, completed four cycles of therapy. Median PFS was higher in the bevacizumab group (5.5 months) than in the placebo group (4.4 months; hazard ratio [HR], 0.53; 95% CI, 0.32 to 0.86). Median overall survival (OS) was similar for both groups (9.4 v 10.9 months for bevacizumab and placebo groups, respectively), with an HR of 1.16 (95% CI, 0.66 to 2.04). Overall response rates were 58% (95% CI, 43% to 71%) for the bevacizumab group and 48% (95% CI, 34% to 62%) for the placebo group. Median duration of response was 4.7 months for the bevacizumab group and 3.2 months for the placebo group. In the bevacizumab and placebo groups, 75% versus 60% of patients, respectively, experienced one or more grade 3 or higher adverse events. No new or unexpected safety signals for bevacizumab were observed. Conclusion The addition of bevacizumab to cisplatin or carboplatin plus etoposide for treatment of extensive-stage SCLC improved PFS, with an acceptable toxicity profile. However, no improvement in OS was observed.
International Phase III Trial Assessing Neoadjuvant Cisplatin, Methotrexate, and Vinblastine Chemotherapy for Muscle-Invasive Bladder Cancer: Long-Term Results of the BA06 30894 Trial
Authors:   International Collaboration of Trialists on behalf of the Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group), the European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group, the Australian Bladder Cancer Study Group, the National Cancer Institute of Canada Clinical Trials Group, Finnbladder, Norwegian Bladder Cancer Study Group, and Club Urologico Espanol de Tratamiento Oncologic
Published: April 2011

Purpose This article presents the long-term results of the international multicenter randomized trial that investigated the use of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy in patients with muscle-invasive urothelial cancer of the bladder treated by cystectomy and/or radiotherapy. Nine hundred seventy-six patients were recruited between 1989 and 1995, and median follow-up is now 8.0 years. Patients and Methods This was a randomized phase III trial of either no neoadjuvant chemotherapy or three cycles of CMV. Results The previously reported possible survival advantage of CMV is now statistically significant at the 5% level. Results show a statistically significant 16% reduction in the risk of death (hazard ratio, 0.84; 95% CI, 0.72 to 0.99; P = .037, corresponding to an increase in 10-year survival from 30% to 36%) after CMV. Conclusion We conclude that CMV chemotherapy improves outcome as first-line adjunctive treatment for invasive bladder cancer. Two large randomized trials (by the Medical Research Council/European Organisation for Research and Treatment of Cancer and Southwest Oncology Group) have confirmed a statistically significant and clinically relevant survival benefit, and neoadjuvant chemotherapy followed by definitive local therapy should be viewed as state of the art, as compared with cystectomy or radiotherapy alone, for deeply invasive bladder cancer.
Concordance between thyroglobulin antibody assays
Authors: Taylor Kevin P , Parkington Damon , Bradbury Sonia , Simpson Helen L , Jefferies Sarah J , Halsall David J 
Published: April 2011

Background Antithyroglobulin antibodies are a prevalent cause of interference in serum thyroglobulin immunoassays. Current guidelines recommend that antithyroglobulin antibodies should be measured concurrently with thyroglobulin when monitoring thyroid cancer patients post‐thyroidectomy. However, the concordance between different antithyroglobulin assays has been questioned despite the availability of an international thyroglobulin antibody Reference Preparation. Methods Four antithyroglobulin assays currently in use in UK laboratories (Siemens Immulite®, Brahms GmbH, PerkinElmer AutoDELFIA and Siemens ADVIA Centaur®) were compared in a cohort of 145 thyroid cancer patients. Results Using reference data provided by the kit manufacturer, concordance between the assays was 74%. Adjusting the cut-offs to maximize agreement increased concordance to 90%. Recovery of exogenous thyroglobulin using the Brahms Tg-plus immunoradiometric assay was neither a specific nor a sensitive test for the presence of a positive antibody result by any assay. Conclusions Despite the availability of an international reference preparation, current antithyroglobulin assays show unacceptable variance.
Studies on electrooxidation of lignin and lignin model compounds. Part 1: Direct electrooxidation of non-phenolic lignin model compounds
Authors: Shiraishi Takumi , Takano Toshiyuki , Kamitakahara Hiroshi , Nakatsubo Fumiaki 
Published: April 2011

Abstract
The direct anodic oxidation of non-phenolic lignin model compounds was investigated to understand their basic behaviors. The results of cyclic voltammetry (CV) studies of monomeric model, such as 1-(4-ethoxy-3-methoxyphenyl)ethanol, are interpreted as the oxidation for Cα-carbonylation did not proceed in the reaction without a catalyst, but a base promotes this reaction. Indeed, the bulk electrolyses of the monomeric lignin model compounds with 2,6-lutidine afforded the corresponding Cα-carbonyl compounds in high yields (60–80%). It is suggested that deprotonation at Cα-H in the ECEC mechanism (E=electron transfer and C=chemical step) is important for Cα-carbonylation. In the uncatalyzed bulk electrolysis of a β-O-4 model dimeric compound, 4-ethoxy-3-methoxyphenylglycerol-β-guaiacyl ether, the corresponding Cα-carbonyl compound was not detected but as a result of Cα-Cβcleavage 4-O-ethylvanillin was found in 40% yield. In the electrolysis reaction in the presence of 2,6-lutidine (as a sterically hindered light base), the reaction stopped for a short time unexpectedly. These results indicate the different electrochemical behavior of simple monomeric model compounds and dimeric β-O-4 models. The conclusion is that direct electrooxidation is unsuitable for Cα-carbonylation of lignin.
Modeling of Dispersion and Settling of Micron-Sized Dust Particles in Pressure Regulator Used in Oxygen-Enriched Environment
Authors: Oza Aditi , Ghosh Sudipto , Chowdhury Kanchan 
Published: April 2011

Abstract
It is essential to maintain cleanliness in an oxygen system as many accidents occurring in oxygen-enriched environment indicate contamination as a major source of ignition. Computational fluid dynamics (CFD) analyses show that valve seats, T-joints, elbows and spots with complex geometries are possible locations for accumulation of the dust particles. It is important to understand the mechanisms of contaminant accumulation, the initiation of fire and its propagation in valves and regulators in order to suggest ways for their prevention. As contaminant dust particles flow with oxygen through valves and piping systems, the solid dust particles impact or rub with the pipe wall or with each other. This results in the building up of static electric charges in them. These charged dust particles may eventually accumulate and lead to electrostatic discharge, thus creating a potential cause of initiation of fire. The aim of the present work is to develop a mathematical model based on CFD, of the dispersion and settling of micron-sized charged dust particles in the pressure regulator, commonly used in oxygen application. A two-dimensional numerical model of flow, dust particle dispersion and particle settling, utilizing finite volume approach, has been developed on FLUENT 6.3.26 platform. The results show that there is a possibility of electrical discharge due to the settlement of charged dust particles if a regulator is attempted to be reopened within a short time of it being closed. Since it is practically impossible to make all oxygen systems free of contaminants at all times, it may be worthwhile to analyze ways about how to avoid ignition even in presence of large concentration of dust particles. The present study may give an insight into the possibility of ignition and offer suggestions to avoid it through appropriate system configuration and operation timings.