bluuebunny/crossref_metadata_2025_split huggingface dataset:
Styles, origins and implications of syndepositional deformation structures in Ediacaran microbial carbonates (Nama Basin, Namibia)
Authors: Winterleitner G. , Le Heron D. P. , Mapani B. , Vining B. A. , McCaffrey K. J. W. 
Published: April 2015

Abstract
Outstanding exposures of Ediacaran-aged thrombolite–stromatolite bioherms and biostromes crop out in the Nama Basin, SW Namibia. Fieldwork, dovetailed with remote sensing and a terrestrial laser scanning (LiDAR) survey, allow the fracture network of this succession to be characterized, and the relative age of fracture sets and families to be determined. The results show that the microbial carbonates were affected by intense syndepositional brittle and ductile deformation. Early brittle fracturing was favoured where early lithification of microbialites took place upon deposition. Such deposits were prone to gravitational collapse due to internal weaknesses during early lithification. Timing of syndepositional fracturing of bioherms and biostromes is demonstrated by contemporaneous microbial overgrowth over brecciated material in open-mode fractures. Ductile deformation occurs preferentially around massive thrombolite domes and columns, represented by folding of mud-dominated sediments in inter-column fill. Secondary fractures developed during the long-lived structural history of the Nama Basin, resulting in a complex fracture network of syndepositional fractures overprinted by secondary fractures. These findings have important implications for carbonate reservoir characterization in microbial reservoirs and subsurface fluid-flow estimations. The observed syndepositional fractures form due to body forces that are intrinsic to the microbial system and thus do not require an external tectonic driver.
Tectonic setting and stratigraphic architecture of an Early Cretaceous lacustrine carbonate platform, Sugar Loaf High, Santos Basin, Brazil
Authors: Buckley J. P. , Bosence D. , Elders C. 
Published: April 2015

Abstract
The Sugar Loaf High is an extensive basement structure within the Santos Basin, offshore Brazil, in which all of the elements of the pre-salt hydrocarbon play are present. Following a clastic-dominated early synrift phase, the later synrift and sag phases are characterized by an extensive non-marine carbonate platform over the basement high. The study area within this new 3D seismic dataset contains carbonates stratigraphically equivalent to the reservoirs within the Lula and Sapinhoá fields. Analysis of the 3D seismic data shows that the pre-salt carbonates onlap the basement of the Sugar Loaf High and form aggradational geometries on a platform that has a proximal to distal width of about 100 km and an interpreted relief of some 900 m. The carbonate platform has an aggradational and mounded basinward-facing gullied margin with slope deposits. Progradational units are imaged on the platform top that may be either carbonate or clastic in composition. The platform is preserved beneath evaporites that form the regional seal within the Santos Basin. Platforms of this size are previously unknown from lacustrine settings outside the pre-salt stratigraphy of the Santos and Campos Basins, Brazil.
A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis
Authors: Choi Seo-Hyun , Hong Zhen-Yu , Nam Jae-Kyung , Lee Hae-June , Jang Junho , Yoo Ran Ji , Lee Yong Jin , Lee Chang Young , Kim Kyung Hwan , Park Seungwoo , Ji Young Hoon , Lee Yun-Sil , Cho Jaeho , Lee Yoon-Jin 
Published: April 2015

Abstract
Purpose: Radiation-induced pulmonary fibrosis (RIPF) is a late side effect of thoracic radiotherapy. The purpose of our study was to gain further insight into the development of RIPF.
Experimental Design/Results: Here, we observed that irradiation of mouse lungs induced collagen deposition, particularly around blood vessels, in the early phase of RIPF. Such deposition subsequently became evident throughout the irradiated tissues. Accompanied by the collagen deposition, vascular EndMT (endothelial-to-mesenchymal transition) began to develop in the early phase of RIPF, before the appearance of EMT (epithelial-to-mesenchymal transition) of alveolar epithelial (AE) II cells in the substantive fibrotic phase. Concomitant with the EndMT, we detected vascular endothelial cell (EC)–specific hypoxic damage in the irradiated lung tissues. In human pulmonary artery endothelial cells (HPAEC), the radiation-induced EndMT via activation of TGFβ-R1/Smad signaling was dependent on HIF1α expression. A novel HIF1α inhibitor, 2-methoxyestradiol (2-ME), inhibited the irradiation-induced EndMT via downregulation of HIF1α-dependent Smad signaling. In vivo, 2-ME inhibited the vascular EndMT, and decreased the collagen deposition associated with RIPF. Furthermore, HIF1α-related EndMT was observed also in human RIPF tissues.
Conclusions: We provide the first evidence that an EndMT occurs in RIPF development and that the EndMT may be effectively inhibited by modulating vascular EC-specific hypoxic damage. Clin Cancer Res; 21(16); 3716–26. ©2015 AACR.
Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic
Authors: Kearns Jeffrey D. , Bukhalid Raghida , Sevecka Mark , Tan Gege , Gerami-Moayed Nastaran , Werner Shannon L. , Kohli Neeraj , Burenkova Olga , Sloss Callum M. , King Anne M. , Fitzgerald Jonathan B. , Nielsen Ulrik B. , Wolf Beni B. 
Published: April 2015

Abstract
Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by high-affinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor–antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR:ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics. Mol Cancer Ther; 14(7); 1625–36. ©2015 AACR.
Three-Dimensional Cell Culture-Based Screening Identifies the Anthelmintic Drug Nitazoxanide as a Candidate for Treatment of Colorectal Cancer
Authors: Senkowski Wojciech , Zhang Xiaonan , Olofsson Maria Hägg , Isacson Ruben , Höglund Urban , Gustafsson Mats , Nygren Peter , Linder Stig , Larsson Rolf , Fryknäs Mårten 
Published: April 2015

Abstract
Because dormant cancer cells in hypoxic and nutrient-deprived regions of solid tumors provide a major obstacle to treatment, compounds targeting those cells might have clinical benefits. Here, we describe a high-throughput drug screening approach, using glucose-deprived multicellular tumor spheroids (MCTS) with inner hypoxia, to identify compounds that specifically target this cell population. We used a concept of drug repositioning—using known molecules for new indications. This is a promising strategy to identify molecules for rapid clinical advancement. By screening 1,600 compounds with documented clinical history, we aimed to identify candidates with unforeseen potential for repositioning as anticancer drugs. Our screen identified five molecules with pronounced MCTS-selective activity: nitazoxanide, niclosamide, closantel, pyrvinium pamoate, and salinomycin. Herein, we show that all five compounds inhibit mitochondrial respiration. This suggests that cancer cells in low glucose concentrations depend on oxidative phosphorylation rather than solely glycolysis. Importantly, continuous exposure to the compounds was required to achieve effective treatment. Nitazoxanide, an FDA-approved antiprotozoal drug with excellent pharmacokinetic and safety profile, is the only molecule among the screening hits that reaches high plasma concentrations persisting for up to a few hours after single oral dose. Nitazoxanide activated the AMPK pathway and downregulated c-Myc, mTOR, and Wnt signaling at clinically achievable concentrations. Nitazoxanide combined with the cytotoxic drug irinotecan showed anticancer activity in vivo. We here report that the FDA-approved anthelmintic drug nitazoxanide could be a potential candidate for advancement into cancer clinical trials. Mol Cancer Ther; 14(6); 1504–16. ©2015 AACR.
The Influence of Known Genetic Variants on Subclinical Cardiovascular Outcomes in Childhood
Authors: Punwasi Rani V.G. , Monnereau Claire , Hofman Albert , Jaddoe Vincent W.V. , Felix Janine F. 
Published: April 2015

Background—
Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) for subclinical cardiovascular outcomes in adults. We examined the influence of these variants on the same outcomes in childhood.

Methods and Results—
In a population-based prospective cohort study among 4137 children, we examined the associations of SNPs, individually and incorporated in genetic risk scores, which were identified in adults for cardiac (2 SNPs for left ventricular end-diastolic diameter and 5 SNPs for aortic root diameter) and blood pressure outcomes (29 SNPs for systolic and diastolic blood pressure, 22 SNPs for mean arterial pressure, and 10 SNPs for pulse pressure) with the same outcomes in children (median age of 6.0 years [95% range, 4.5–8.7]). Weighted and unweighted risk scores for aortic root diameter were associated with childhood aortic root diameter (difference per additional average risk allele 0.09 mm [95% CI: 0.05, 0.13]). Weighted and unweighted risk scores for pulse pressure were associated with childhood pulse pressure (difference per additional average risk allele 0.22 mm Hg [95% CI: 0.08, 0.35] and 0.18 mm Hg [95% CI: 0.05, 0.31], respectively), but not with childhood systolic or diastolic blood pressure or mean arterial pressure. The risk scores for blood pressure and mean arterial pressure were not associated with any of the childhood blood pressure outcomes.

Conclusions—
Genetic risk scores based on SNPs for aortic root diameter and pulse pressure in adults are associated with the same outcomes in children. SNPs related to cardiovascular outcomes in adulthood at least partly influence cardiovascular development from early life onwards.
Clinical Impact of Gastrointestinal Bleeding in Patients Undergoing Percutaneous Coronary Interventions
Authors: Koskinas Konstantinos C. , Räber Lorenz , Zanchin Thomas , Wenaweser Peter , Stortecky Stefan , Moschovitis Aris , Khattab Ahmed A. , Pilgrim Thomas , Blöchlinger Stefan , Moro Christina , Jüni Peter , Meier Bernhard , Heg Dik , Windecker Stephan 
Published: April 2015

Background—

The risk factors and clinical sequelae of gastrointestinal bleeding (GIB) in the current era of drug-eluting stents, prolonged dual antiplatelet therapy, and potent P2Y
12
inhibitors are not well established. We determined the frequency, predictors, and clinical impact of GIB after percutaneous coronary interventions (PCIs) in a contemporary cohort of consecutive patients treated with unrestricted use of drug-eluting stents.

Methods and Results—

Between 2009 and 2012, all consecutive patients undergoing PCI were prospectively included in the Bern PCI Registry. Bleeding Academic Research Consortium (BARC) GIB and cardiovascular outcomes were recorded within 1 year of follow-up. Among 6212 patients, 84.1% received new-generation drug-eluting stents and 19.5% received prasugrel. At 1 year, GIB had occurred in 65 patients (1.04%); 70.8% of all events and 84.4% of BARC ≥3B events were recorded >30 days after PCI. The majority of events (64.4%) were related to upper GIB with a more delayed time course compared with lower GIB. Increasing age, previous GIB, history of malignancy, smoking, and triple antithrombotic therapy (ie, oral anticoagulation plus dual antiplatelet therapy) were independent predictors of GIB in multivariable analysis. GIB was associated with increased all-cause mortality (adjusted hazard ratio, 3.40; 95% confidence interval, 1.67–6.92;
P
=0.001) and the composite of death, myocardial infarction, or stroke (adjusted hazard ratio, 3.75; 95% confidence interval, 1.99–7.07;
P
<0.001) and was an independent predictor of all-cause mortality during 1 year.

Conclusions—
Among unselected patients undergoing PCI, GIB has a profound effect on prognosis. Triple antithrombotic therapy emerged as the single drug-related predictor of GIB in addition to patient-related risk factors within 1 year of PCI.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02241291.
Reperfusion Times for Radial Versus Femoral Access in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Cantor Warren J. , Ko Dennis T. , Natarajan Madhu K. , Džavík Vladimír , Wijeysundera Harindra C. , Wang Julie T. , Kingsbury Kori J. , Velianou James L. , Cohen Eric A. , Le May Michel R. , Tu Jack V. 
Published: April 2015

Background—
Radial access is associated with less bleeding and vascular complications. However, it may delay reperfusion during primary percutaneous coronary intervention for ST-segment–elevation myocardial infarction.

Methods and Results—

A provincial database prospectively collected clinical and procedural characteristics for all urgent percutaneous coronary intervention procedures performed between June 2010 and September 2011 in Ontario for ST-segment–elevation myocardial infarction, including time of arrival in the catheterization laboratory and time of first balloon inflation. After excluding patients with cardiogenic shock, with previous bypass surgery, or who received fibrinolysis, 2947 patients were included in the analysis. Propensity score matching was used to minimize difference in clinical characteristics between radial and femoral access procedures. Predictors of radial access included younger age and male sex. After propensity score matching, the median time from arrival in the cardiac catheterization laboratory to first balloon was 27 minutes (25th%–75th%, 21–34) for the femoral group and 30 minutes (25th%–75th %, 24–39) for the radial group (
P
<0.001). When hospitals were stratified based on the proportion of primary percutaneous coronary intervention cases that were performed using radial access, there was no difference in treatment times between radial and femoral access in the tercile of hospitals that used radial access most frequently. There were no significant differences in the rates of death or myocardial infarction at 30 days.

Conclusions—
This contemporary multicenter registry demonstrates that the time to first balloon inflation is slightly longer with radial access than with femoral access, although the 3 minute difference is unlikely to be clinically relevant. There is no difference in treatment times at hospitals that frequently use radial access for primary percutaneous coronary intervention. Short-term mortality and reinfarction rates are similar with radial and femoral access.
Mass Screening for Untreated Atrial Fibrillation
Authors: Svennberg Emma , Engdahl Johan , Al-Khalili Faris , Friberg Leif , Frykman Viveka , Rosenqvist Mårten 
Published: April 2015

Background—
The aims of the present study were to define the prevalence of untreated atrial fibrillation (AF) in a systematic screening program using intermittent ECG recordings among 75- to 76-year-old individuals and to study the feasibility of initiating protective oral anticoagulant (OAC) treatment.

Methods and Results—
Half of the 75- to 76-year-old population in 2 Swedish regions were invited to a screening program for AF. Participants without a previous diagnosis of AF underwent intermittent ECG recordings over 2 weeks. If AF was detected, participants were offered OAC. During the 28-month inclusion period, 13 331 inhabitants were invited. Of these, 7173 (53.8%) participated. Of the participants, 218 (3.0%; 95% confidence interval [CI], 2.7–3.5) were found to have previously unknown AF, and of these, AF was found in 37 (0.5% of the screened population) on their first ECG. The use of intermittent ECGs increased new AF detection 4-fold. A previous diagnosis of AF was known in 9.3% (n=666; 95% CI, 8.6–10.0). Total AF prevalence in the screened population was 12.3%. Of participants with known AF, 149 (2.1%; 95% CI, 1.8–2.4) had no OAC treatment. In total, 5.1% (95% CI, 4.6–5.7) of the screened population had untreated AF; screening resulted in initiation of OAC treatment in 3.7% (95% CI, 3.3–4.2) of the screened population. More than 90% of the participants with previously undiagnosed AF accepted initiation of OAC treatment.

Conclusions—
Mass screening for AF in a 75- to 76-year-old population identifies a significant proportion of participants with untreated AF. Initiation of stroke prophylactic treatment was highly successful in individuals with newly diagnosed AF.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01593553.
Accumulation of Metabolic Cardiovascular Risk Factors in Black and White Young Adults Over 20 Years
Authors: Paynter Nina P. , Kiefe Catarina I. , Lewis Cora E. , Loria Catherine M. , Goff David C. , Lloyd‐Jones Donald M. 
Published: April 2015

Background
Cross‐sectional clustering of metabolic risk factors for cardiovascular disease in middle‐aged adults is well described, but less is known regarding the order in which risk factors develop through young adulthood and their relation to subclinical atherosclerosis.

Method and Results

A total of 3178 black and white women and men in the Coronary Artery Risk Development in Young Adults study were assessed to identify the order in which cardiovascular disease risk factors including diabetes, hypertension, dyslipidemia (low high‐density lipoprotein cholesterol or high triglyceride levels), hypercholesterolemia (high total or low‐density lipoprotein cholesterol), and obesity develop. Observed patterns of risk factor development were compared with those expected if risk factors accumulated randomly, given their overall distribution in the population. Over the 20 years of follow‐up, 80% of participants developed at least 1 risk factor. The first factor to occur was dyslipidemia in 39% of participants, obesity in 20%, hypercholesterolemia in 11%, hypertension in 7%, and diabetes in 1%. Dyslipidemia was the only risk factor both to occur first and to be followed by additional risk factors more often than expected (
P
<0.001 for both). Order of risk factor accrual did not affect subclinical atherosclerosis at year 20. Results were similar by sex, race, and smoking status.

Conclusions
Multiple patterns of cardiovascular risk factor development were observed from young adulthood to middle age. Dyslipidemia, a potentially modifiable condition, often preceded the development of other risk factors and may be a useful target for intervention and monitoring.
Increased Interannual Precipitation Extremes over California under Climate Change
Authors: Berg Neil , Hall Alex 
Published: April 2015

Abstract
Changes to mean and extreme wet season precipitation over California on interannual time scales are analyzed using twenty-first-century precipitation data from 34 global climate models. Models disagree on the sign of projected changes in mean precipitation, although in most models the change is very small compared to historical and simulated levels of interannual variability. For the 2020/21–2059/60 period, there is no projected increase in the frequency of extremely dry wet seasons in the ensemble mean. Wet extremes are found to increase to around 2 times the historical frequency, which is statistically significant at the 95% level. Stronger signals emerge in the 2060/61–2099/2100 period. Across all models, extremely dry wet seasons are roughly 1.5 to 2 times more common, and wet extremes generally triple in their historical frequency (statistically significant). Large increases in precipitation variability in most models account for the modest increases to dry extremes. Increases in the frequency of wet extremes can be ascribed to equal contributions from increased variability and increases to the mean. These increases in the frequency of interannual precipitation extremes will create severe water management problems in a region where coping with large interannual variability in precipitation is already a challenge. Evidence from models and observations is examined to understand the causes of the low precipitation associated with the 2013/14 drought in California. These lines of evidence all strongly indicate that the low 2013/14 wet season precipitation total can be very likely attributed to natural variability, in spite of the projected future changes in extremes.
Idiopathic Subglottic and Tracheal Stenosis
Authors: Gnagi Sharon H. , Howard Brittany E. , Anderson Catherine , Lott David G. 
Published: April 2015

Objectives: To report and compare patients’ experiences with acquired subglottic stenosis (AS) versus idiopathic subglottic and tracheal stenosis (ISTS). Methods: A survey was made available to patients with AS and ISTS. Results were analyzed for inter- and intragroup differences using a 2-tailed t test. Results: The study included 160 survey participants (AS n = 28; ISTS n = 132), with a predominance of female participants (82% AS, 98% ISTS). Acid reflux was the most prevalent comorbidity across groups (42%-43%). A significant difference in time to diagnosis was found between groups, with 32% of AS patients diagnosed within 3 months of symptom onset, compared to 2% with ISTS. A diagnosis delay greater than 18 months occurred for 58% of ISTS patients. There was no difference in treatment approach, with the most common treatment being balloon dilation, followed by laser dilation. Tracheal resection was performed in 36% of patients in both groups. Patient satisfaction with surgical outcomes was significantly higher after tracheal resection (76%) compared to other treatment modalities (39%). Conclusions: ISTS remains a diagnostic challenge as highlighted by the delay in diagnosis compared to AS. There appears to be no historical or symptomatic factors specific to ISTS. Additionally, patients report increased satisfaction and symptom resolution after tracheal resection.