bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diet–tissue discrimination factors of carbon and nitrogen stable isotopes in blood of Snowy Owl (Bubo scandiacus)
Authors: Therrien J.-F. , Fitzgerald G. , Gauthier G. , Bêty J. 
Published: April 2011

Analysis of carbon (13C/12C) and nitrogen (15N/14N) stable isotope ratios (hereafter δ13C and δ15N, respectively) in animal tissues is a powerful tool in food-web studies. However, isotopic ratios of prey are not transmitted directly to a consumer, as a diet–tissue discrimination factor (denoted Δ) occurs between sources and consumer’s tissues. An accurate assessment of the diet of a consumer with stable isotopes thus requires that the Δ13C and Δ15N of the studied species are known. Our aim was to establish Δ13C and Δ15N values in the Snowy Owl ( Bubo scandiacus (L., 1758)). Moreover, we assessed the potential effect of ethanol preservation of blood samples on δ13C and δ15N values. We kept four captive adult Snowy Owls on a pure diet of mice for ≥6 weeks. We then collected mouse muscle and blood samples from the owls and analyzed their δ13C and δ15N values. Δ13C and Δ15N values (mean ± SE) for owl blood were +0.3‰ ± 0.2‰ and +1.9‰ ± 0.1‰, respectively. These values are the first discrimination factors ever reported in Strigiformes and are lower, for Δ15N, than those obtained in terrestrial carnivores and other bird species, including falcons. Preservation in ethanol did not significantly affect δ13C and δ15N values.
The BATTLE Trial: Personalizing Therapy for Lung Cancer
Authors: Kim Edward S. , Herbst Roy S. , Wistuba Ignacio I. , Lee J. Jack , Blumenschein George R. , Tsao Anne , Stewart David J. , Hicks Marshall E. , Erasmus Jeremy , Gupta Sanjay , Alden Christine M. , Liu Suyu , Tang Ximing , Khuri Fadlo R. , Tran Hai T. , Johnson Bruce E. , Heymach John V. , Mao Li , Fossella Frank , Kies Merrill S. , Papadimitrakopoulou Vassiliki , Davis Suzanne E. , Lippman Scott M. , Hong Waun K. 
Published: April 2011

Abstract
The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial represents the first completed prospective, biopsy-mandated, biomarker-based, adaptively randomized study in 255 pretreated lung cancer patients. Following an initial equal randomization period, chemorefractory non–small cell lung cancer (NSCLC) patients were adaptively randomized to erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib, based on relevant molecular biomarkers analyzed in fresh core needle biopsy specimens. Overall results include a 46% 8-week disease control rate (primary end point), confirm prespecified hypotheses, and show an impressive benefit from sorafenib among mutant-KRAS patients. BATTLE establishes the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials. (ClinicalTrials.gov numbers: NCT00409968, NCT00411671, NCT00411632, NCT00410059, and NCT00410189.)
Significance: The BATTLE study is the first completed prospective, adaptively randomized study in heavily pretreated NSCLC patients that mandated tumor profiling with “real-time” biopsies, taking a substantial step toward realizing personalized lung cancer therapy by integrating real-time molecular laboratory findings in delineating specific patient populations for individualized treatment. Cancer Discovery; 1(1); 44–53. © 2011 AACR.
Read the Commentary on this article by Sequist et al., p. 14
Read the Commentary on this article by Rubin et al., p. 17
This article is highlighted in the In This Issue feature, p. 4
A Novel Two-Stage, Transdisciplinary Study Identifies Digoxin as a Possible Drug for Prostate Cancer Treatment
Authors: Platz Elizabeth A. , Yegnasubramanian Srinivasan , Liu Jun O. , Chong Curtis R. , Shim Joong Sup , Kenfield Stacey A. , Stampfer Meir J. , Willett Walter C. , Giovannucci Edward , Nelson William G. 
Published: April 2011

Abstract
Identification of novel indications for commonly prescribed drugs could accelerate translation of therapies. We investigated whether any clinically used drugs might be useful in treating prostate cancer by coupling an efficient, high-throughput laboratory-based screen and a large prospective cohort study. In stage one, we conducted an in vitro prostate cancer cell cytotoxicity screen of 3,187 compounds. Digoxin emerged as the leading candidate, given its potency in inhibiting proliferation in vitro (the concentration of the drug at which proliferation was inhibited by 50%: mean of 163 nM) and its common use. In stage two, we evaluated the association between the leading candidate drug from stage one and prostate cancer risk in 47,884 men followed up from 1986 through 2006. Regular digoxin users [vs nonusers: relative risk (RR) = 0.76; 95% confidence interval (CI), 0.61–0.95], especially users for ≥10 years (RR = 0.54; 95% CI, 0.37–0.79; P trend &lt; 0.001), had a lower prostate cancer risk. Digoxin was highly potent in inhibiting prostate cancer cell growth in vitro, and its use was associated with a 25% lower prostate cancer risk.
Significance: Our two-stage transdisciplinary approach for drug repositioning provides compelling justification for further mechanistic and possibly clinical testing of the leading nonchemotherapy candidate, digoxin, a cardiac glycoside, as a drug for prostate cancer treatment. Perhaps of equal importance, our study illustrates the power of the transdisciplinary approach in translational cancer research. By coupling laboratory and epidemiologic methods and thinking, we reduced the probability of identifying false-positive candidate drugs for the next steps in testing. Cancer Discovery; 1(1); 68–77. ©2011 AACR.
Read the Commentary on this article by Spitz et al., p. 21
This article is highlighted in the In This Issue feature, p. 4
The BATTLE Trial: A Bold Step toward Improving the Efficiency of Biomarker-Based Drug Development
Authors: Rubin Eric H. , Anderson Keaven M. , Gause Christine K. 
Published: April 2011

Abstract
Successful completion of the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, reported in this issue of Cancer Discovery, is an important advance in the effort to improve clinical trial approaches to the simultaneous development of new therapeutics with matching diagnostic tests so that patients most likely to benefit from these therapies can be identified. Cancer Discovery; 1(1); 17–20. ©2011 AACR.
Commentary on Kim et al., p. 44
Telmisartan Exerts Antiatherosclerotic Effects by Activating Peroxisome Proliferator-Activated Receptor-γ in Macrophages
Authors: Matsumura Takeshi , Kinoshita Hiroyuki , Ishii Norio , Fukuda Kazuki , Motoshima Hiroyuki , Senokuchi Takafumi , Taketa Kayo , Kawasaki Shuji , Nishimaki-Mogami Tomoko , Kawada Teruo , Nishikawa Takeshi , Araki Eiichi 
Published: April 2011

Objective—
Telmisartan, an angiotensin type I receptor blocker (ARB), protects against the progression of atherosclerosis. Here, we investigated the molecular basis of the antiatherosclerotic effects of telmisartan in macrophages and apolipoprotein E–deficient mice.

Methods and Results—

In macrophages, telmisartan increased peroxisome proliferator-activated receptor-γ (PPARγ) activity and PPAR ligand-binding activity. In contrast, 3 other ARBs, losartan, valsartan, and olmesartan, did not affect PPARγ activity. Interestingly, high doses of telmisartan activated PPARα in macrophages. Telmisartan induced the mRNA expression of CD36 and ATP-binding cassette transporters A1 and G1 (ABCA1/G1), and these effects were abrogated by PPARγ small interfering RNA. Telmisartan, but not other ARBs, inhibited lipopolysaccharide-induced mRNA expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α, and these effects were abrogated by PPARγ small interfering RNA. Moreover, telmisartan suppressed oxidized low-density lipoprotein-induced macrophage proliferation through PPARγ activation. In apolipoprotein E
−/−
mice, telmisartan increased the mRNA expression of ABCA1 and ABCG1, decreased atherosclerotic lesion size, decreased the number of proliferative macrophages in the lesion, and suppressed MCP-1 and tumor necrosis factor-α mRNA expression in the aorta.

Conclusion—
Telmisartan induced ABCA1/ABCG1 expression and suppressed MCP-1 expression and macrophage proliferation by activating PPARγ. These effects may induce antiatherogenic effects in hypertensive patients.
Serum Amyloid A Facilitates the Binding of High-Density Lipoprotein From Mice Injected With Lipopolysaccharide to Vascular Proteoglycans
Authors: Chiba Tsuyoshi , Chang Mary Y. , Wang Shari , Wight Thomas N. , McMillen Timothy S. , Oram John F. , Vaisar Tomas , Heinecke Jay W. , De Beer Frederick C. , De Beer Maria C. , Chait Alan 
Published: April 2011

Objective—
Levels of serum amyloid A (SAA), an acute-phase protein carried on high-density lipoprotein (HDL), increase in inflammatory states and are associated with increased risk of cardiovascular disease. HDL colocalizes with vascular proteoglycans in atherosclerotic lesions. However, its major apolipoprotein, apolipoprotein A-I, has no proteoglycan-binding domains. Therefore, we investigated whether SAA, which has proteoglycan-binding domains, plays a role in HDL retention by proteoglycans.

Methods and Results—
HDL from control mice and mice deficient in both SAA1.1 and SAA2.1 (SAA knockout mice) injected with bacterial lipopolysaccharide (LPS) was studied. SAA mRNA expression in the liver and plasma levels of SAA increased dramatically in C57BL/6 mice after LPS administration, although HDL cholesterol did not change. Fast protein liquid chromatography analysis showed most of the SAA to be in HDL. Mass spectrometric analysis indicated that HDL from LPS-injected control mice had high levels of SAA1.1/2.1 and reduced levels of apolipoprotein A-I. HDL from LPS-injected control mice demonstrated high-affinity binding to biglycan relative to normal mouse HDL. In contrast, HDL from LPS-injected SAA knockout mice showed very little binding to biglycan, consistent with SAA facilitating the binding of HDL to vascular proteoglycans.

Conclusion—
SAA enrichment of HDL under inflammatory conditions plays an important role in the binding of HDL to vascular proteoglycans.
Role of Interleukin 17 in Inflammation, Atherosclerosis, and Vascular Function in Apolipoprotein E–Deficient Mice
Authors: Madhur Meena S. , Funt Samuel A. , Li Li , Vinh Antony , Chen Wei , Lob Heinrich E. , Iwakura Yoichiro , Blinder Yelena , Rahman Ayaz , Quyyumi Arshed A. , Harrison David G. 
Published: April 2011

Objective—
Interleukin 17A (IL17A) is involved in many inflammatory processes, but its role in atherosclerosis remains controversial. We examined the role of IL17A in mouse and human atherosclerosis.

Methods and Results—

Atherosclerosis was induced in apolipoprotein E (ApoE)
−/−
and IL17A/ApoE
−/−
mice using high-fat feeding, angiotensin II infusion, or partial carotid ligation. In ApoE
−/−
mice, 3 months of high-fat diet induced interferon-γ production by splenic lymphocytes, and this was abrogated in IL17A/ApoE
−/−
mice. IL17A/ApoE
−/−
mice had reduced aortic superoxide production, increased aortic nitric oxide levels, decreased aortic leukocyte and dendritic cell infiltration, and reduced weight gain after a high-fat diet compared with ApoE
−/−
mice. Despite these favorable effects, IL17A deficiency did not affect aortic plaque burden after a high-fat diet or angiotensin II infusion. In a partial carotid ligation model, IL17A deficiency did not affect percentage of stenosis but reduced outward remodeling. In this model, neutralization of the related isoform, IL17F, in IL17A/ApoE
−/−
mice did not alter atherosclerosis. Finally, there was no correlation between IL17A levels and carotid intima-media thickness in humans.

Conclusion—
IL17 contributes to vascular and systemic inflammation in experimental atherosclerosis but does not alter plaque burden. The changes in plaque composition caused by IL17 might modulate plaque stability.
1
H-NMR-Based Metabolomics Study of Cerebral Infarction
Authors: Jung Jee Youn , Lee Ho-Sub , Kang Dae-Gill , Kim No Soo , Cha Min Ho , Bang Ok-Sun , Ryu Do Hyun , Hwang Geum-Sook 
Published: April 2011

Background and Purpose—

Stroke is one of the leading causes of adult disability and death in developing countries. However, early diagnosis is difficult and no reliable biomarker is currently available. Thus, we applied a
1
H-NMR metabolomics approach to investigate the altered metabolic pattern in plasma and urine from patients with cerebral infarctions and sought to identify metabolic biomarkers associated with stroke.

Methods—

Metabolic profiles of plasma and urine from patients with cerebral infarctions, especially small vessel occlusion, were investigated using
1
H-NMR spectroscopy coupled with multivariate statistical analysis, such as principal components analysis and orthogonal partial least-squares discriminant analysis.

Results—
Multivariate statistical analysis showed a significant separation between patients and healthy individuals. The plasma of stroke patients was characterized by the increased excretion of lactate, pyruvate, glycolate, and formate, and by the decreased excretion of glutamine and methanol; the urine of stroke patients was characterized by decreased levels of citrate, hippurate, and glycine. These metabolites detected from plasma and urine of patients with cerebral infarctions were associated with anaerobic glycolysis, folic acid deficiency, and hyperhomocysteinemia. Furthermore, the presence of cerebral infarction in the external validation model was predicted with high accuracy.

Conclusions—
These data demonstrate that a metabolomics approach may be useful for the effective diagnosis of cerebral infarction and for the further understanding of stroke pathogenesis.
Refining the Definition of the Malignant Profile
Authors: Mlynash Michael , Lansberg Maarten G. , De Silva Deidre A. , Lee Jun , Christensen Soren , Straka Matus , Campbell Bruce C.V. , Bammer Roland , Olivot Jean-Marc , Desmond Patricia , Donnan Geoffrey A. , Davis Stephen M. , Albers Gregory W. 
Published: April 2011

Background and Purpose—
To refine the definition of the malignant magnetic resonance imaging profile in acute stroke patients using baseline diffusion-weighted magnetic resonance imaging (DWI) and perfusion-weighted magnetic resonance imaging (PWI) findings from the pooled DEFUSE/EPITHET database.

Methods—
Patients presenting with acute stroke within 3 to 6 hours from symptom onset were treated with tissue plasminogen activator or placebo. Baseline and follow-up DWI and PWI images from both studies were reprocessed using the same software program. A receiver operating characteristic curve analysis was used to identify Tmax and DWI volumes that optimally predicted poor outcomes (modified Rankin Scale 5–6) at 90 days in patients who achieved reperfusion.

Results—

Sixty-five patients achieved reperfusion and 46 did not reperfuse. Receiver operating characteristic analysis identified a PWI (Tmax>8 s) volume of >85 mL as the optimal definition of the malignant profile. Eighty-nine percent of malignant profile patients had poor outcome with reperfusion versus 39% of patients without reperfusion (
P
=0.02). Parenchymal hematomas occurred more frequently in malignant profile patients who experienced reperfusion versus no reperfusion (67% versus 11%,
P
<0.01). DWI analysis identified a volume of 80 mL as the best DWI threshold, but this definition was less sensitive than were PWI-based definitions.

Conclusions—
Stroke patients likely to suffer parenchymal hemorrhages and poor outcomes following reperfusion can be identified from baseline magnetic resonance imaging findings. The current analysis demonstrates that a PWI threshold (Tmax>8 s) of approximately 100 mL is appropriate for identifying these patients. Exclusion of malignant profile patients from reperfusion therapies may substantially improve the efficacy and safety of reperfusion therapies.

Clinical Trial Registration Information—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00238537.
Early Prediction of Outcome of Activities of Daily Living After Stroke
Authors: Veerbeek Janne M. , Kwakkel Gert , van Wegen Erwin E.H. , Ket Johannes C.F. , Heymans Martijn W. 
Published: April 2011

Background and Purpose—
Knowledge about robust and unbiased factors that predict outcome of activities of daily living (ADL) is paramount in stroke management. This review investigates the methodological quality of prognostic studies in the early poststroke phase for final ADL to identify variables that are predictive or not predictive for outcome of ADL after stroke.

Methods—
PubMed, Ebsco/Cinahl and Embase were systematically searched for prognostic studies in which stroke patients were included ≤2 weeks after onset and final outcome of ADL was determined ≥3 months poststroke. Risk of bias scores were used to distinguish high- and low-quality studies and a qualitative synthesis was performed.

Results—
Forty-eight of 8425 identified citations were included. The median risk of bias score was 17 out of 27 (range, 6–22) points. Most studies failed to report medical treatment applied, management of missing data, rationale for candidate determinants and outcome cut-offs, results of univariable analysis, and validation and performance of the model, making the predictive value of most determinants indistinct. Six high-quality studies showed strong evidence for baseline neurological status, upper limb paresis, and age as predictors for outcome of ADL. Gender and risk factors such as atrial fibrillation were unrelated to this outcome.

Conclusions—
Because of insufficient methodological quality of most prognostic studies, the predictive value of many clinical determinants for outcome of ADL remains unclear. Future cohort studies should focus on early prediction using simple models with good clinical performance to enhance application in stroke management and research.
The Epidemiology of Slips, Trips, and Falls in a Helicopter Manufacturing Plant
Authors: Amandus Harlan , Bell Jennifer , Tiesman Hope , Biddle Elyce 
Published: April 2011

Objective: The purpose of this evaluation was to evaluate the causes and costs of slips, trips, and falls (STFs) in a helicopter manufacturing plant. Background: STFs are a significant portion of the total industry injury burden. Method: For this study, 4,070 helicopter plant workers who were employed from January 1, 2004, through February 28, 2008, were enrolled. Company records on workers’ compensation claims, occupational health first report of injury, and payroll records on hours worked were collected. Cause and source of all injuries, including STFs, were coded for analysis. Results: During the 4-year study period, there were 2,378 injuries and 226 STFs (46 falls [20%] to a lower level, 117 [52%] falls on the same level, 41 [18%] from loss of balance without a fall, and 22 [10%] from other events). Of the 226 STFs, 123 falls to the same level were caused by slippery substances (52), objects on floor (43), and surface hazards (28), and they cost $1,543,946. Falls to lower levels primarily involved access to stands to and from aircraft and falling off large machines. Conclusion: More than half of the STF injury claims likely could have been prevented by housekeeping and maintenance, and this cost saving could reasonably offset a considerable portion of the cost of prevention. Training and stand modifications could be considered to prevent falls from elevation from stands, machines, and aircraft. Application: Recommendations for STF prevention are discussed.
The use of group sequential, information-based sample size re-estimation in the design of the PRIMO study of chronic kidney disease
Authors: Pritchett Yili , Jemiai Yannis , Chang Yuchiao , Bhan Ishir , Agarwal Rajiv , Zoccali Carmine , Wanner Christoph , Lloyd-Jones Donald , Cannata-Andía Jorge B , Thompson Taylor , Appelbaum Evan , Audhya Paul , Andress Dennis , Zhang Wuyan , Solomon Scott , Manning Warren J , Thadhani Ravi 
Published: April 2011

Background Chronic kidney disease is associated with a marked increase in risk for left ventricular hypertrophy and cardiovascular mortality compared with the general population. Therapy with vitamin D receptor activators has been linked with reduced mortality in chronic kidney disease and an improvement in left ventricular hypertrophy in animal studies. Purpose PRIMO ( Paricalcitol capsules benefits in Renal failure Induced cardia MOrbidity) is a multinational, multicenter randomized controlled trial to assess the effects of paricalcitol (a selective vitamin D receptor activator) on mild to moderate left ventricular hypertrophy in patients with chronic kidney disease. Methods Subjects with mild-moderate chronic kidney disease are randomized to paricalcitol or placebo after confirming left ventricular hypertrophy using a cardiac echocardiogram. Cardiac magnetic resonance imaging is then used to assess left ventricular mass index at baseline, 24 and 48 weeks, which is the primary efficacy endpoint of the study. Because of limited prior data to estimate sample size, a maximum information group sequential design with sample size re-estimation is implemented to allow sample size adjustment based on the nuisance parameter estimated using the interim data. An interim efficacy analysis is planned at a pre-specified time point conditioned on the status of enrollment. The decision to increase sample size depends on the observed treatment effect. A repeated measures analysis model, using available data at Week 24 and 48 with a backup model of an ANCOVA analyzing change from baseline to the final nonmissing observation, are pre-specified to evaluate the treatment effect. Gamma-family of spending function is employed to control family-wise Type I error rate as stopping for success is planned in the interim efficacy analysis. Limitations If enrollment is slower than anticipated, the smaller sample size used in the interim efficacy analysis and the greater percent of missing week 48 data might decrease the parameter estimation accuracy, either for the nuisance parameter or for the treatment effect, which might in turn affect the interim decision-making. Conclusions The application of combining a group sequential design with a sample-size re-estimation in clinical trial design has the potential to improve efficiency and to increase the probability of trial success while ensuring integrity of the study.