bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral Blood Immune Cell Methylation Profiles Are Associated with Nonhematopoietic Cancers
Authors: Koestler Devin C. , Marsit Carmen J. , Christensen Brock C. , Accomando William , Langevin Scott M. , Houseman E. Andres , Nelson Heather H. , Karagas Margaret R. , Wiencke John K. , Kelsey Karl T. 
Published: August 2012

Abstract
Background: Blood leukocytes from patients with solid tumors exhibit complex and distinct cancer-associated patterns of DNA methylation. However, the biologic mechanisms underlying these patterns remain poorly understood. Because epigenetic biomarkers offer significant clinical potential for cancer detection, we sought to address a mechanistic gap in recently published works, hypothesizing that blood-based epigenetic variation may be due to shifts in leukocyte populations.
Methods: We identified differentially methylated regions (DMR) among leukocyte subtypes using epigenome-wide DNA methylation profiling of purified peripheral blood leukocyte subtypes from healthy donors. These leukocyte-tagging DMRs were then evaluated using epigenome-wide blood methylation data from three independent case-control studies of different cancers.
Results: A substantial proportion of the top 50 leukocyte DMRs were significantly differentially methylated among head and neck squamous cell carcinoma (HNSCC) cases and ovarian cancer cases compared with cancer-free controls (48 and 47 of 50, respectively). Methylation classes derived from leukocyte DMRs were significantly associated cancer case status (P &lt; 0.001, P &lt; 0.03, and P &lt; 0.001) for all three cancer types: HNSCC, bladder cancer, and ovarian cancer, respectively and predicted cancer status with a high degree of accuracy (area under the curve [AUC] = 0.82, 0.83, and 0.67).
Conclusions: These results suggest that shifts in leukocyte subpopulations may account for a considerable proportion of variability in peripheral blood DNA methylation patterns of solid tumors.
Impact: This illustrates the potential use of DNA methylation profiles for identifying shifts in leukocyte populations representative of disease, and that such profiles may represent powerful new diagnostic tools, applicable to a range of solid tumors. Cancer Epidemiol Biomarkers Prev; 21(8); 1293–302. ©2012 AACR.
Combined PI3K/mTOR and MEK Inhibition Provides Broad Antitumor Activity in Faithful Murine Cancer Models
Authors: Roberts Patrick J. , Usary Jerry E. , Darr David B. , Dillon Patrick M. , Pfefferle Adam D. , Whittle Martin C. , Duncan James S. , Johnson Soren M. , Combest Austin J. , Jin Jian , Zamboni William C. , Johnson Gary L. , Perou Charles M. , Sharpless Norman E. 
Published: August 2012

Abstract
Purpose: Anticancer drug development is inefficient, but genetically engineered murine models (GEMM) and orthotopic, syngeneic transplants (OST) of cancer may offer advantages to in vitro and xenograft systems.
Experimental Design: We assessed the activity of 16 treatment regimens in a RAS-driven, Ink4a/Arf-deficient melanoma GEMM. In addition, we tested a subset of treatment regimens in three breast cancer models representing distinct breast cancer subtypes: claudin-low (T11 OST), basal-like (C3-TAg GEMM), and luminal B (MMTV-Neu GEMM).
Results: Like human RAS-mutant melanoma, the melanoma GEMM was refractory to chemotherapy and single-agent small molecule therapies. Combined treatment with AZD6244 [mitogen-activated protein–extracellular signal-regulated kinase kinase (MEK) inhibitor] and BEZ235 [dual phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor] was the only treatment regimen to exhibit significant antitumor activity, showed by marked tumor regression and improved survival. Given the surprising activity of the “AZD/BEZ” combination in the melanoma GEMM, we next tested this regimen in the “claudin-low” breast cancer model that shares gene expression features with melanoma. The AZD/BEZ regimen also exhibited significant activity in this model, leading us to testing in even more diverse GEMMs of basal-like and luminal breast cancer. The AZD/BEZ combination was highly active in these distinct breast cancer models, showing equal or greater efficacy compared with any other regimen tested in studies of over 700 tumor-bearing mice. This regimen even exhibited activity in lapatinib-resistant HER2+ tumors.
Conclusion: These results show the use of credentialed murine models for large-scale efficacy testing of diverse anticancer regimens and predict that combinations of PI3K/mTOR and MEK inhibitors will show antitumor activity in a wide range of human malignancies. Clin Cancer Res; 18(19); 5290–303. ©2012 AACR.
Long-term risk of vascular events after peripheral bypass surgery
Authors: Tangelder Marco J. D. , Lawson James A. , Moll Frans L. , Algra Ale , Van Hattum Eline S. 
Published: August 2012

SummaryPatients with peripheral arterial disease (PAD) are at high risk of major ischaemic events. Long-term data of all major ischaemic events in PAD patients are scarce and outdated, especially for patients with severe PAD requiring bypass surgery. Our objective was to define their longterm prognosis and develop a prediction model which quantifies this risk up to a decade after surgery. We conducted a retrospective cohort study in patients from the Dutch Bypass Oral anticoagulants or Aspirin (BOA) Study; a multicentre randomised trial comparing oral anticoagulants with aspirin after infrainguinal bypass surgery. The primary outcome was the composite event of nonfatal myocardial infarction, non-fatal ischaemic stroke, major amputation, and vascular death. Cumulative risks were assessed by Kaplan-Meier analysis and independent determinants by multivariable Cox regression models. From 1995 until 2009, 482 patients were followed for a median period of 7.8 years. Follow-up was complete in 94%. Overall 60% of patients experienced a primary outcome event, of which the majority was a vascular death (30%), followed by major amputations (12%). The primary cause of vascular death was a cardiovascular event (29%), whereas the minority was due to complications directly related to PAD (6%). Within five years after bypass surgery vascular death occurred in about a quarter of patients and within 10 years in nearly half of patients. This was double the rate as for non-vascular death. The primary outcome event occurred in over a third and over half of patients in 5 and 10 years after bypass surgery, respectively. From four independent determinants for the primary outcome event: age, diabetes, critical limb ischaemia, and prior vascular interventions, we developed a risk chart, which systematically classifies the 10-year risks of the primary outcome event, ranging from 25% to 85%. This study provided a detailed insight in the course of PAD long after peripheral bypass surgery and enables individual risk assessment of major fatal and non-fatal ischaemic events by means of cumulative incidences and a risk chart.
Thrombogenic changes in young and old mice upon subchronic exposure to air pollution in an urban roadside tunnel
Authors: Emmerechts Jan , De Vooght Vanessa , Haenen Steven , Loyen Serena , Van kerckhoven Soetkin , Hemmeryckx Bianca , Vanoirbeek Jeroen A. J. , Hoet Peter H. , Nemery Ben , Hoylaerts Marc F. 
Published: August 2012

SummaryEpidemiological studies indicate that elderly persons are particularly susceptible to the cardiovascular health complications of air pollution, but pathophysiological mechanisms behind the increased susceptibility remain unclear. Therefore, we investigated how continuous traffic-related air pollution exposure affects haemostasis parameters in young and old mice. Young (10 weeks) and old (20 months) mice were placed in an urban roadside tunnel or in a clean environment for 25 or 26 days and markers of inflammation and endothelial cells or blood platelet activation were measured, respectively. Plasma microvesicles and pro/ anticoagulant factors were analysed, and thrombin generation analysis was performed. Despite elevated macrophage carbon load, tunnel mice showed no overt pulmonary or systemic inflammation, yet manifested reduced pulmonary thrombomudulin expression and elevated endothelial von Willebrand factor (VWF) expression in lung capillaries. In young mice, soluble P-selectin (sP-sel) increased with exposure and correlated with soluble E-selectin and VWF. Baseline plasma factor VIII (FVIII), sP-sel and VWF were higher in old mice, but did not pronouncedly increase further with exposure. Traffic-related air pollution markedly raised red blood cell and blood platelet numbers in young and old mice and procoagulant blood platelet-derived microvesicle numbers in old animals. Changes in coagulation factors and thrombin generation were mild or absent. Hence, continuous traffic-related air pollution did not trigger overt lung inflammation, yet modified pulmonary endothelial cell function and enhanced platelet activity. In old mice, subchronic exposure to polluted air raised platelet numbers, VWF, sP-sel and microvesicles to the highest values presently recorded, collectively substantiating a further elevation of thrombogenicity, already high at old age.
Effects of intracoronary delivery of allogenic bone marrow-derived stem cells expressing heme oxygenase-1 on myocardial reperfusion injury
Authors: Tendera Michal , Cybulski Wieslaw , Zuba-Surma Ewa K. , Szade Krzysztof , Florczyk Urszula , Kozakowska Magdalena , Szymula Agnieszka , Krzych Lukasz , Paslawska Urszula , Paslawski Robert , Milewski Krzysztof , Buszman Piotr P. , Nabialek Edyta , Kuczmik Waclaw , Janiszewski Adrian , Dziegiel Piotr , Buszman Pawel E. , Józkowicz Alicja , Wojakowski Wojciech , Dulak Jozef 
Published: August 2012

SummaryHeme oxygenase-1 (HO-1) decreases apoptosis, inflammation and oxidative stress. The aim of the study was to investigate the effects of intracoronary infusion of allogenic bone marrow cells (BMC) overexpressing HO-1 in the porcine model of myocardial infarction (MI). MI was produced by balloon occlusion of a coronary artery. BMC were transduced with adenoviruses encoding for HO-1 (HO-1 BMC) or GFP (GFP-BMC) genes. Prior to reperfusion animals received HO-1 BMC, control BMC (unmodified or GFP-BMC) or placebo. Left ventricular (LV) ejection fraction (EF), shortening fraction (SF), end-systolic and enddiastolic diameters (EDD, ESD) were assessed by echocardiography before, 30 minutes (min) and 14 days after reperfusion. BMC significantly improved LVEF and SF early (30 min) after reperfusion as well as after 14 days. Early after reperfusion HO-1 BMC were significantly more effective than control BMC, but after 14 days, there were no differences. There were no effect of cells on LV remodelling and diastolic function. Both HO-1 BMC and control BMC significantly reduced the infarct size vs. placebo (17.2 ± 2.7 and 18.8 ± 2.5, respectively, vs. 27.5 ± 5.1, p= 0.02) in histomorphometry. HO-1-positive donor BMC were detected in the infarct border area in pigs receiving HO-1-cells. No significant differences in expression of inflammatory genes (SDF-1, TNF-α, IL-6, miR21, miR29a and miR133a) in the myocardium were found. In conclusion, intracoronary delivery of allogeneic BMC immediately prior to reperfusion improved the LVEF and reduced the infarct size. HO-1 BMC were not superior to control cells after 14 days, however, produced faster recovery of LVEF. Transplanted cells survived in the peri-infarct zone.
Clinical scores to predict recurrence risk of venous thromboembolism
Authors: Eichinger Sabine , Kyrle Paul 
Published: August 2012

SummaryVenous thromboembolism (VTE) is a common and chronic disease with a considerable risk of recurrence. Patients with unprovoked (in the absence of a transient risk factor) VTE have a recurrence risk as high as 30% within five years after cessation of anticoagulation. Depending on patient selection the case-fatality rate of recurrence ranges between 3.6%-10%. Thus, indefinite anticoagulation treatment should be considered in these patients. However, anticoagulation confers a considerable risk of bleeding (fatal bleedings 0.1%–0.5%/year). It is therefore of utmost clinical importance to identify those patients, who will not benefit from indefinite anticoagulation, i.e. patients, in whom the bleeding risk during anticoagulant treatment is higher than the risk of recurrence. Several attempts to discriminate patients with a high from those with a low risk of recurrence including screening for acquired and inherited thrombotic risk factors or measurement of coagulation activation markers have either failed (thrombophilia screening) or were of moderate success (stratification according to D-dimer only). A novel approach for assessing risk of recurrent VTE consists of linking clinical patient characteristics with laboratory testing. Several such scoring models which can be used to assess the risk of recurrent VTE have been developed and await prospective validation before they can be applied in daily routine care. The aim of this report is to describe currently available scoring systems in more detail.
Detection of Paroxysmal Atrial Fibrillation by 30-Day Event Monitoring in Cryptogenic Ischemic Stroke
Authors: Flint Alexander C. , Banki Nader M. , Ren Xiushui , Rao Vivek A. , Go Alan S. 
Published: August 2012

Background and Purpose—
Patients with cryptogenic ischemic stroke may have undetected paroxysmal atrial fibrillation (PAF). We established the Stroke and Monitoring for PAF in Real Time (SMART) Registry to determine the yield of 30-day outpatient PAF monitoring in cryptogenic ischemic stroke.

Methods—
The SMART Registry was a 3-year, prospective multicenter registry of 239 patients with cryptogenic ischemic stroke undergoing 30-day outpatient autotriggered PAF detection in Kaiser Permanente Northern California.

Results—
In intention-to-monitor analysis, PAF was detected in 29 of 239 patients (12.1%; 95% CI, 8.6%–16.9%). After retrospective chart review was performed, a new diagnosis of PAF was confirmed in 26 of 236 patients (11.0%; 95% CI, 7.6%–15.7%). The majority of detected PAF events were asymptomatic; only 6 of 98 recorded PAF events (6.1%) were patient-triggered or associated with symptoms.

Conclusions—
-Approximately 1 in every 9 patients with cryptogenic ischemic stroke was found to have new PAF within 30 days. Routine monitoring in this population should be strongly considered.
Histopathological Assessment in Glossectomy
Authors: Cristalli Giovanni , Mercante Giuseppe , Covello Renato , Sperduti Isabella , Cristalli Maria Paola , Spriano Giuseppe 
Published: August 2012

ObjectivesThe aim of the study was to gather information on outcomes and effect sizes of 2 surgical methods of glossectomy by using a grade system and an objective measure of artifacts in micrometers (µm). The collected data would be used to plan a definitive study.Study DesignPilot study.SettingTertiary referral center.Material and MethodsNineteen patients affected with tongue cancer were consecutively enrolled in a pilot study and treated by partial glossectomy. Eleven patients (57.89%) of group A were treated with monopolar electrocautery, while 8 patients (42.10%) of group B were treated with Harmonic Focus Curved Shears. Specimens were examined by a pathologist blinded to the surgical procedure, using a 4‐grade system for margin artifact assessment (margin fragmentation, cautery/crush artifact, extravascular blood clot, capillary congestion) and for measuring artifact depth.ResultsArtifact depth was more relevant in group A (765,633 µm) than in group B (473,939 µm). The difference between groups was significant at the 95% confidence interval (P <. 0001). Margin fragmentation and capillary congestion compared between the 2 groups were of no significance. There were less cautery/crush artifacts and extravascular blood clots observed in the harmonic shears group.ConclusionWhen used to perform a partial glossectomy, Harmonic Focus Curved Shears produce less cautery/crush artifact and a smaller artifact depth compared with monopolar cautery.
Preparation of poly(vinyl chloride)/copper nanocomposite films with reduced bacterial adhesion
Authors: Becerra Abraham , Rodríguez-Llamazares Saddys , Carrasco Claudia , Díaz-Visurraga Judith , Riffo Carla , Mondaca M. A. 
Published: August 2012

Films of poly(vinyl chloride)/copper (Cu) nanocomposites exhibiting reduced bacterial adhesion were prepared by film-casting method. Cu nanoparticles (NPs) synthesized using polyol method and stabilized with poly( N-vinyl-2-pyrrolidone) (PVP) at different Cu/PVP molar ratio were previously characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD) and ultraviolet–visible spectroscopy. Zero valent Cu NPs with average diameter of 4 nm were obtained. The nanocomposite films with low and high Cu content were prepared with Cu NPs obtained from Cu/PVP molar ratio of 7.2, 45 and 270. XRD patterns of PVC/Cu nanocomposite films did not show peaks associated at copper oxide and other impurities. Scanning electron microscopy (SEM) and X-ray energy dispersive spectroscopy Cu-mapping revealed a homogenous distribution of Cu NPs agglomerates in nanocomposite films prepared with Cu NPs obtained from Cu/PVP ratio of 7.2 and high Cu content, while TEM images of this nanocomposite film with low Cu content showed well-dispersed and distributed Cu NPs in PVC matrix. The films prepared with Cu NPs obtained from Cu/PVP ratio of 270 showed a vertical phase separation, where PVP was segregated to the free surface. SEM images revealed a reduced Escherichia coli adhesion to PVC/Cu nanocomposite films after 4 days of incubation with respect to plasticized PVC.
Ranolazine-Induced Postrepolarization Refractoriness Suppresses Induction of Atrial Flutter and Fibrillation in Anesthetized Rabbits
Authors: Aidonidis Isaac , Doulas Konstantinos , Hatziefthimiou Apostolia , Tagarakis Georgios , Simopoulos Vassilios , Rizos Ioannis , Tsilimingas Nikolaos , Molyvdas Paschalis-Adam 
Published: August 2012

Ranolazine (Ran) is a novel anti-ischemic agent with electrophysiologic properties mainly attributed to the inhibition of late Na+ current and atrial-selective early Na+ current. However, there are only limited data regarding its efficacy and mechanism of action against atrial flutter (Afl) and atrial fibrillation (AF) in intact animals. Therefore, we aimed to investigate the electrophysiologic mechanism of Ran in a rabbit model of inducible atrial tachyarrhythmias elicited by acetylcholine (ACh). Arrhythmias were produced in 19 rabbits by rapid atrial burst pacing during control, after intravenous ACh and after Ran + ACh administration. Recording of right atrial monophasic action potentials (MAPs) and programmed stimulation were utilized to determine the duration of atrial repolarization at various cycle lengths and voltage levels of action potential, including 75% of total MAP duration (MAPD75), effective refractory period (ERP), and postrepolarization refractoriness (PRR = ERP − MAPD75) prior to and after Ran. Control stimulation yielded no arrhythmias or maximal nonsustained runs of Afl/AF. Upon ACh, 17 of 19 rabbits exhibited sustained Afl and AF as well as mixed forms of Afl/AF, while 2 animals revealed none or short runs of nonsustained arrhythmias and were excluded from the study. High-frequency burst pacing during the first 30 minutes after Ran + ACh failed to induce any arrhythmia in 13 of 17 rabbits (76%), while 2 animals displayed sustained Afl/AF and 2 other animals nonsustained Afl/AF. At basic stimulation cycle length of 250 milliseconds, Ran prolonged baseline atrial ERP (80 ± 8 vs 120 ± 9 milliseconds, P < .001) much more than MAPD75 (65 ± 7 vs 85 ± 7 milliseconds, P < .001), leading to atrial PRR which was more pronounced after Ran compared with control measurements (35 ± 11 vs 15 ± 10 milliseconds, P < .001). This in vivo study demonstrates that Ran exerts antiarrhythmic activity by suppressing inducibility of ACh-mediated Afl/AF in intact rabbits. Its action may predominantly be related to a significant increase in atrial PRR, resulting in depressed electrical excitability and impediment of arrhythmia initiation.
Meta-analysis of effect sizes reported at multiple time points: A multivariate approach
Authors: Trikalinos Thomas A , Olkin Ingram 
Published: August 2012

Background Many comparative studies report results at multiple time points. Such data are correlated because they pertain to the same patients, but are typically meta-analyzed as separate quantitative syntheses at each time point, ignoring the correlations between time points. Purpose To develop a meta-analytic approach that estimates treatment effects at successive time points and takes account of the stochastic dependencies of those effects. Methods We present both fixed and random effects methods for multivariate meta-analysis of effect sizes reported at multiple time points. We provide formulas for calculating the covariance (and correlations) of the effect sizes at successive time points for four common metrics (log odds ratio, log risk ratio, risk difference, and arcsine difference) based on data reported in the primary studies. We work through an example of a meta-analysis of 17 randomized trials of radiotherapy and chemotherapy versus radiotherapy alone for the postoperative treatment of patients with malignant gliomas, where in each trial survival is assessed at 6, 12, 18, and 24 months post randomization. We also provide software code for the main analyses described in the article. Results We discuss the estimation of fixed and random effects models and explore five options for the structure of the covariance matrix of the random effects. In the example, we compare separate (univariate) meta-analyses at each of the four time points with joint analyses across all four time points using the proposed methods. Although results of univariate and multivariate analyses are generally similar in the example, there are small differences in the magnitude of the effect sizes and the corresponding standard errors. We also discuss conditional multivariate analyses where one compares treatment effects at later time points given observed data at earlier time points. Limitations Simulation and empirical studies are needed to clarify the gains of multivariate analyses compared with separate meta-analyses under a variety of conditions. Conclusions Data reported at multiple time points are multivariate in nature and are efficiently analyzed using multivariate methods. The latter are an attractive alternative or complement to performing separate meta-analyses.