bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic impact of renal dysfunction in patients with acute coronary syndrome—role beyond the CHA2DS2‐VASc score: Data from Taiwan acute coronary syndrome full spectrum registry
Authors: Chua Su‐Kiat , Lo Huey‐Ming , Chiu Chiung‐Zuan , Shyu Kou‐Gi ,   Taiwan ACS Full Spectrum Registry Investigators
Published: October 2015

AbstractAimCHA2DS2‐VASc score has been proven to have great prognostic value in patients with acute coronary syndrome (ACS). We aimed to determine whether the addition of renal dysfunction in the CHA2DS2‐VASc score would improve the prognostic impact of the scoring system to predict prognosis among ACS patients.MethodsA total of 3031 ACS patients were prospectively enrolled at 39 hospitals and followed for 1 year. The patients were divided into three groups based on estimated glomerular filtration rate (eGFR) (group 1, eGFR>90; group 2, eGFR between 60 and 90; and group 3, eGFR<60 mL/min per 1.73 m2). The occurrence of subsequent myocardial infarction (MI), stroke, or death was recorded.ResultsAs renal function progressively decreased from group 1 to 3, the patients were, respectively older and had higher incidence of comorbidity, worse Killip classification, and less evidence‐based medical therapies. The rate of subsequent MI, stroke or death increased from 3.4% in group 1 to 7.4% in group 2 and 17.2% in group 3 (P < 0.001). Renal dysfunction (eGFR<60 mL/min per 1.73 m2) and CHA2DS2‐VASc scores were both significant predictors of adverse events in multivariable regression analyses. Renal dysfunction can further stratify patients with CHA2DS2‐VASc score of 0 or 1 into 3 groups with different adverse event rates (group 1, 3.0%; group 2, 4.1%; and group 3, 9.2%, P < 0.001). A new scoring system (R‐CHA2DS2‐VASc score) derived by assigning one more point for eGFR ≤ 60 mL/min per 1.73 m2 to the CHA2DS2‐VASc score could improve its predictive accuracy (area under the receiver operating curve, 0.70 vs. 0.66, P < 0.001).ConclusionsRenal dysfunction is a significant risk factor of future adverse events in ACS patients and may improve the prognostic impact of the CHA2DS2‐VASc score.
Dioecy does not consistently accelerate or slow lineage diversification across multiple genera of angiosperms
Authors: Sabath Niv , Goldberg Emma E. , Glick Lior , Einhorn Moshe , Ashman Tia‐Lynn , Ming Ray , Otto Sarah P. , Vamosi Jana C. , Mayrose Itay 
Published: October 2015

SummaryDioecy, the sexual system in which male and female organs are found in separate individuals, allows greater specialization for sex‐specific functions and can be advantageous under various ecological and environmental conditions. However, dioecy is rare among flowering plants. Previous studies identified contradictory trends regarding the relative diversification rates of dioecious lineages vs their nondioecious counterparts, depending on the methods and data used.We gathered detailed species‐level data for dozens of genera that contain both dioecious and nondioecious species. We then applied a probabilistic approach that accounts for differential speciation, extinction, and transition rates between states to examine whether there is an association between dioecy and lineage diversification.We found a bimodal distribution, whereby dioecious lineages exhibited higher diversification in certain genera but lower diversification in others. Additional analyses did not uncover an ecological or life history trait that could explain a context‐dependent effect of dioecy on diversification. Furthermore, in‐depth simulations of neutral characters demonstrated that such bimodality is also found when simulating neutral characters across the observed trees.Our analyses suggest that – at least for these genera with the currently available data – dioecy neither consistently places a strong brake on diversification nor is a strong driver.
The Beothukis/Culmofrons problem and its bearing on Ediacaran macrofossil taxonomy: evidence from an exceptional new fossil locality
Authors: Liu Alexander G. , Matthews Jack J. , McIlroy Duncan 
Published: October 2015

AbstractThe late Ediacaran siliciclastic successions of eastern Newfoundland, Canada, are renowned for their fossils of soft‐bodied macro‐organisms, which may include some of the earliest animals. Despite the potential importance of such fossils for evolutionary understanding, the taxonomic framework within which Ediacaran macrofossils are described is not clearly defined. Rangeomorphs from a newly discovered fossil surface on the Bonavista Peninsula, Newfoundland, require us to reconsider contemporary use of morphological characters to distinguish between genera and species within Ediacaran taxa. The new surface exhibits remarkable preservational fidelity, resolving features smaller than 0.1 mm in dimension in both frondose and non‐frondose taxa. Such preservation permits the recognition of rarely observed fourth‐ and fifth‐order rangeomorph branching, offering unparalleled opportunities to investigate the fine‐scale construction of rangeomorph taxa including Culmofrons plumosa Laflamme et al., 2012. Our observations enable resolution of taxonomic issues relating to rangeomorphs, specifically overlap between the diagnoses of the frondose genera Beothukis Brasier and Antcliffe, 2009 and Culmofrons. We propose a taxonomic framework for all Ediacaran macrofossils whereby gross architecture, the presence/absence of discrete morphological characters and consideration of growth programme are used to distinguish genera, whereas morphometric or continuous characters define taxa at the species level. On the basis of its morphological characters, Culmofrons plumosa is herein synonymized to a species (Beothukis plumosa comb. nov.) within the genus Beothukis. This discussion emphasizes the need to standardize the taxonomic approach used to describe Ediacaran macrofossil taxa at both the genus and species levels, and raises important considerations for future formulation of higher‐level taxonomic groups.
Analysis of the sodium chloride‐dependent respiratory kinetics of wheat mitochondria reveals differential effects on phosphorylating and non‐phosphorylating electron transport pathways
Authors: Jacoby R. P. , Che‐Othman M. H. , Millar A. H. , Taylor N. L. 
Published: October 2015

AbstractA number of previous studies have documented the gross response of mitochondrial respiration to salinity treatment, but it is unclear how NaCl directly affects the kinetics of plant phosphorylating and non‐phosphorylating electron transport pathways. This study investigates the direct effects of NaCl upon different respiratory pathways in wheat, by measuring rates of isolated mitochondrial oxygen consumption across different substrate oxidation pathways in saline media. We also profile the abundance of respiratory proteins by using targeted selected reaction monitoring (SRM) mass spectrometry of mitochondria isolated from control and salt‐treated wheat plants. We show that all pathways of electron transport were inhibited by NaCl concentrations above 400 mM; however electron transfer chains showed divergent responses to NaCl concentrations between 0 and 200 mM. Stimulation of oxygen consumption was measured in response to NaCl in scenarios where exogenous NADH was provided as substrate and electron flow was coupled to the generation of a proton gradient across the inner membrane. Protein abundance measurements show that several enzymes with activities less affected by NaCl are induced by salinity, whereas enzymes with activities inhibited by NaCl are depleted. These data deepen our understanding of how plant respiration responds to NaCl, offering new mechanistic explanations for the divergent salinity responses of whole‐plant respiratory rate in the literature.
A novel HLA allele, HLA‐A*29:01:08, identified in a Brazilian individual
Authors: Fabreti‐Oliveira R. A. , Oliveira C. K. F. , Vale E. M. G. , Nascimento E. 
Published: October 2015

AbstractHLA‐A*29:01:08 differs from A*29:01:01:01 by a single synonymous substitution at position 519, codon 149 GCG→GCA in exon 3.
A Novel Staphylococcal Cassette Chromosome
mec
Type XI Primer for Detection of
mecC
-Harboring Methicillin-Resistant Staphylococcus aureus Directly from Screening Specimens
Authors: Petersdorf Sabine , Herma Miriam , Rosenblatt Meike , Layer Franziska , Henrich Birgit 
Published: October 2015

ABSTRACT

Methicillin-resistant
Staphylococcus aureus
(MRSA) screening using real-time PCR has decreased in sensitivity due to the emergence of variant staphylococcal cassette chromosome
mec
element (SCC
mec
) types. We have designed and validated a novel SCC
mec
XI primer, which enables for the first time the rapid detection of
mecC
-harboring MRSA directly from nasopharyngeal swabs without prior cultivation.
Critical Role of K1685 and K1829 in the Large Protein of Rabies Virus in Viral Pathogenicity and Immune Evasion
Authors: Tian Dayong , Luo Zhaochen , Zhou Ming , Li Mingming , Yu Lan , Wang Chong , Yuan Jiaolong , Li Fang , Tian Bin , Sui Baokun , Chen Huanchun , Fu Zhen F. , Zhao Ling 
Published: October 2015

ABSTRACT

Rabies, one of the oldest infectious diseases, still presents a public health threat in most parts of the world today. Its pathogen, rabies virus (RABV), can utilize its viral proteins, such as the nucleoprotein and phosphorylation protein, to subvert the host innate immune system. For a long time, the large (L) protein was believed to be essential for RABV transcription and replication, but its role in viral pathogenicity and immune evasion was not known. Recent studies have found that the conserved K-D-K-E tetrad motif in the L protein is related to the methyltransferase (MTase) activity in the viral mRNA process. In the present study, a series of RABV mutations in this motif was constructed with the recombinant CVS-B2c (rB2c) virus. Two of these mutants, rB2c-K1685A and rB2c-K1829A, were found to be stable and displayed an attenuated phenotype in both
in vitro
growth and
in vivo
pathogenicity in adult and suckling mice. Further studies demonstrated that these two mutants were more sensitive to the expression of the interferon-stimulated gene product IFIT2 than the parent virus. Taken together, our results suggest that K1685 and K1829 in the L protein play important roles in pathogenicity and immune evasion during RABV infection.

IMPORTANCE
Rabies continues to present a public health threat in most areas of the world, especially in the developing countries of Asia and Africa. The pathogenic mechanisms for rabies are not well understood. In the present study, it was found that the recombinant rabies viruses rB2c-K1685A and rB2c-K1829A, carrying mutations at the predicted MTase catalytic sites in the L protein, were highly attenuated both
in vitro
and
in vivo
. Further studies showed that these mutants were more sensitive to the expression of the interferon-stimulated gene product IFIT2 than the parent virus. These findings improve our understanding of rabies pathogenesis, which may help in developing potential therapeutics and an avirulent rabies vaccine.
Development of understanding of the Mesozoic and Cenozoic chondrichthyan fossil record
Authors: Underwood Charlie , Ward David , Guinot Guillaume 
Published: October 2015

Abstract
Fossils of post-Palaeozoic sharks and rays are common and well known, and have been extensively studied. Early studies, especially the monographic works of Agassiz and Smith Woodward, described species based on macroscopic remains of isolated teeth, fin spines and rostral ‘teeth’ as well as rare specimens of articulated skeletons and skulls. This material was obtained from a range of sources but especially from commercial collectors in Britain and mainland Europe. Additional research over subsequent decades also concentrated on large specimens, giving a very biased perception of the chondrichthyan record. The use of large-scale bulk sampling in the latter part of the twentieth century revealed a previously unknown wealth of small fossils, especially teeth, and vastly improved knowledge of ancient sharks and rays. Widening use of these techniques to obtain small specimens has led to a dramatic increase in the fossil taxa known. In addition, reassessment of previously known taxa has allowed generic diversity of some clades to be appreciated. Detailed work on skeletal anatomy, in part aided by new non-destructive methods, continues to improve knowledge of shark and ray diversity, phylogeny and radiation.
Mitochondrial Genetics Regulate Breast Cancer Tumorigenicity and Metastatic Potential
Authors: Feeley Kyle P. , Bray Alexander W. , Westbrook David G. , Johnson Larry W. , Kesterson Robert A. , Ballinger Scott W. , Welch Danny R. 
Published: October 2015

Abstract
Current paradigms of carcinogenic risk suggest that genetic, hormonal, and environmental factors influence an individual's predilection for developing metastatic breast cancer. Investigations of tumor latency and metastasis in mice have illustrated differences between inbred strains, but the possibility that mitochondrial genetic inheritance may contribute to such differences in vivo has not been directly tested. In this study, we tested this hypothesis in mitochondrial–nuclear exchange mice we generated, where cohorts shared identical nuclear backgrounds but different mtDNA genomes on the background of the PyMT transgenic mouse model of spontaneous mammary carcinoma. In this setting, we found that primary tumor latency and metastasis segregated with mtDNA, suggesting that mtDNA influences disease progression to a far greater extent than previously appreciated. Our findings prompt further investigation into metabolic differences controlled by mitochondrial process as a basis for understanding tumor development and metastasis in individual subjects. Importantly, differences in mitochondrial DNA are sufficient to fundamentally alter disease course in the PyMT mouse mammary tumor model, suggesting that functional metabolic differences direct early tumor growth and metastatic efficiency. Cancer Res; 75(20); 4429–36. ©2015 AACR.
Preclinical Validation of the Utility of BLZ-100 in Providing Fluorescence Contrast for Imaging Spontaneous Solid Tumors
Authors: Fidel Janean , Kennedy Katie C. , Dernell William S. , Hansen Stacey , Wiss Valorie , Stroud Mark R. , Molho Joshua I. , Knoblaugh Sue E. , Meganck Jeffrey , Olson James M. , Rice Brad , Parrish-Novak Julia 
Published: October 2015

AbstractThere is a need in surgical oncology for contrast agents that can enable real-time intraoperative visualization of solid tumors that can enable complete resections while sparing normal surrounding tissues. The Tumor Paint agent BLZ-100 is a peptide–fluorophore conjugate that can specifically bind solid tumors and fluoresce in the near-infrared range, minimizing light scatter and signal attenuation. In this study, we provide a preclinical proof of concept for use of this imaging contrast agent as administered before surgery to dogs with a variety of naturally occurring spontaneous tumors. Imaging was performed on excised tissues as well as intraoperatively in a subset of cases. Actionable contrast was achieved between tumor tissue and surrounding normal tissues in adenocarcinomas, squamous cell carcinomas, mast cell tumors, and soft tissue sarcomas. Subcutaneous soft tissue sarcomas were labeled with the highest fluorescence intensity and greatest tumor-to-background signal ratio. Our results establish a foundation that rationalizes clinical studies in humans with soft tissue sarcoma, an indication with a notably high unmet need. Cancer Res; 75(20); 4283–91. ©2015 AACR.
Failures in Phase III: Causes and Consequences
Authors: Seruga Bostjan , Ocana Alberto , Amir Eitan , Tannock Ian F. 
Published: October 2015

Abstract
Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from early-phase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients. Clin Cancer Res; 21(20); 4552–60. ©2015 AACR.
See all articles in this CCR Focus section, “Innovations to Speed Drug Development.”
Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma
Authors: Klanova Magdalena , Andera Ladislav , Brazina Jan , Svadlenka Jan , Benesova Simona , Soukup Jan , Prukova Dana , Vejmelkova Dana , Jaksa Radek , Helman Karel , Vockova Petra , Lateckova Lucie , Molinsky Jan , Maswabi Bokang Calvin Lenyeletse , Alam Mahmudul , Kodet Roman , Pytlik Robert , Trneny Marek , Klener Pavel 
Published: October 2015

Abstract
Purpose: To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL).
Experimental designs: Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, in vitro and in vivo on primary cell-based murine xenograft models of DLBCL.
Results: By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed in vivo using primary cell-based murine xenograft models of DLBCL.
Conclusions: As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL. Clin Cancer Res; 22(5); 1138–49. ©2015 AACR.
Incorporating edoxaban into the choice of anticoagulants for atrial fibrillation
Authors: Eikelboom John , Weitz Jeffrey I. 
Published: October 2015

SummaryThe non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for stroke prevention in many patients with nonvalvular atrial fibrillation. Edoxaban, an oral factor Xa inhibitor, is the newest entrant in this class. Results of the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE AF) study demonstrate that edoxaban is noninferior to warfarin for prevention of stroke and systemic embolic events, and is associated with significantly less major bleeding, including intracranial bleeding, and reduced cardiovascular mortality. With a net clinical benefit over warfarin, edoxaban is well positioned as a choice among the NOACs, which include dabigatran, rivaroxaban, and apixaban. But how will clinicians choose amongst them? The purpose of this paper is to (a) place the ENGAGE AF trial results into context with results of the studies with the other NOACs, and (b) aid clinicians in selection of the right anticoagulant for the right atrial fibrillation patient.
Accuracy of Computed Tomographic Angiography and Single-Photon Emission Computed Tomography–Acquired Myocardial Perfusion Imaging for the Diagnosis of Coronary Artery Disease
Authors: Arbab-Zadeh Armin , Carli Marcelo F. Di , Cerci Rodrigo , George Richard T. , Chen Marcus Y. , Dewey Marc , Niinuma Hiroyuki , Vavere Andrea L. , Betoko Aisha , Plotkin Michail , Cox Christopher , Clouse Melvin E. , Arai Andrew E. , Rochitte Carlos E. , Lima Joao A.C. , Brinker Jeffrey , Miller Julie M. 
Published: October 2015

Background—
Establishing the diagnosis of coronary artery disease (CAD) in symptomatic patients allows appropriately allocating preventative measures. Single-photon emission computed tomography (CT)–acquired myocardial perfusion imaging (SPECT-MPI) is frequently used for the evaluation of CAD, but coronary CT angiography (CTA) has emerged as a valid alternative.

Methods and Results—

We compared the accuracy of SPECT-MPI and CTA for the diagnosis of CAD in 391 symptomatic patients who were prospectively enrolled in a multicenter study after clinical referral for cardiac catheterization. The area under the receiver operating characteristic curve was used to evaluate the diagnostic accuracy of CTA and SPECT-MPI for identifying patients with CAD defined as the presence of ≥1 coronary artery with ≥50% lumen stenosis by quantitative coronary angiography. Sensitivity to identify patients with CAD was greater for CTA than SPECT-MPI (0.92 versus 0.62, respectively;
P
<0.001), resulting in greater overall accuracy (area under the receiver operating characteristic curve, 0.91 [95% confidence interval, 0.88–0.94] versus 0.69 [0.64–0.74];
P
<0.001). Results were similar in patients without previous history of CAD (area under the receiver operating characteristic curve, 0.92 [0.89–0.96] versus 0.67 [0.61–0.73];
P
<0.001) and also for the secondary end points of ≥70% stenosis and multivessel disease, as well as subgroups, except for patients with a calcium score of ≥400 and those with high-risk anatomy in whom the overall accuracy was similar because CTA’s superior sensitivity was offset by lower specificity in these settings. Radiation doses were 3.9 mSv for CTA and 9.8 for SPECT-MPI (
P
<0.001).

Conclusions—
CTA is more accurate than SPECT-MPI for the diagnosis of CAD as defined by conventional angiography and may be underused for this purpose in symptomatic patients.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00934037.