bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical Development of an Anti-NaPi2b (SLC34A2) Antibody–Drug Conjugate as a Therapeutic for Non–Small Cell Lung and Ovarian Cancers
Authors: Lin Kedan , Rubinfeld Bonnee , Zhang Crystal , Firestein Ron , Harstad Eric , Roth Leslie , Tsai Siao Ping , Schutten Melissa , Xu Keyang , Hristopoulos Maria , Polakis Paul 
Published: July 2015

Abstract
Purpose: Antibody–drug conjugates (ADC) selectively deliver a cytotoxic drug to cells expressing an accessible antigenic target. Here, we have appended monomethyl auristatin E (MMAE) to an antibody recognizing the SLC34A2 gene product NaPi2b, the type II sodium–phosphate cotransporter, which is highly expressed on tumor surfaces of the lung, ovary, and thyroid as well as on normal lung pneumocytes. This study evaluated its efficacy and safety in preclinical studies.
Experimental Design: The efficacy of anti-NaPi2b ADC was evaluated in mouse ovarian and non–small cell lung cancer (NSCLC) tumor xenograft models, and its toxicity was assessed in rats and cynomolgus monkeys.
Results: We show here that an anti-NaPi2b ADC is effective in mouse ovarian and NSCLC tumor xenograft models and well-tolerated in rats and cynomolgus monkeys at levels in excess of therapeutic doses. Despite high levels of expression in normal lung of non-human primate, the cross-reactive ADC exhibited an acceptable safety profile with a dose-limiting toxicity unrelated to normal tissue target expression. The nonproliferative nature of normal pneumocytes, together with the antiproliferative mechanism of MMAE, likely mitigates the potential liability of this normal tissue expression.
Conclusions: Overall, our preclinical results suggest that the ADC targeting NaPi2b provides an effective new therapy for the treatment of NSCLC and ovarian cancer and is currently undergoing clinical developments. Clin Cancer Res; 21(22); 5139–50. ©2015 AACR.
NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma
Authors: Huang Junwei , Zhou Yi , Thomas Gregory S. , Gu Zhimin , Yang Ye , Xu Hongwei , Tricot Guido , Zhan Fenghuang 
Published: July 2015

Abstract
Purpose: CKS1B is significantly upregulated in multiple myeloma and associated with poor prognosis. The identification of novel therapies is essential for effective treatment of patients resistant to chemotherapy. The NEDD8 inhibitor MLN4924 selectively targets SCFSkp2 activation and offers a more specific approach to protein degradation inhibition than total proteasomal inhibition. The goal of this study was to evaluate whether MLN4924 is effective in high CKS1B conditions and identify mechanisms regulating drug potency.
Experimental Design: Bortezomib and MLN4924 sensitivity was assessed through proliferation, viability, clonogenic potential, and senescence induction in cells overexpressing CKS1B. The mechanism for MLN4924 sensitivity was elucidated by immunoblot analysis of SCFskp substrates and confirmed by shRNA knockdown. The clinical relevance of the NEDD8 pathway was examined in gene expression profiles (GEP) derived from healthy people, patients with monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma.
Results: Cells overexpressing CKS1B were resistant to bortezomib but sensitive to MLN4924. Treatment of CKS1B-overexpressing cells with MLN4924 decreased proliferation, clonogenicity, and induced senescence. MLN4924, but not bortezomib, induced stabilization of p21 and knockdown of p21 resulted in loss of MLN4924 sensitivity. Patients with MGUS and multiple myeloma exhibited increased expression of NEDD8 pathway genes relative to normal plasma cells. Multiple myeloma patients with high NEDD8 expression were linked to bortezomib resistance in clinical trials, and had inferior outcomes.
Conclusions: Our data demonstrate that cells with elevated CKS1B expression are resistant to bortezomib but sensitive to MLN4924 and offer a mechanism through the stabilization of p21. These findings provide rationale for targeting the NEDD8 pathway in multiple myeloma patients exhibiting elevated expression of CKS1B. Clin Cancer Res; 21(24); 5532–42. ©2015 AACR.
Effect of P2Y12 inhibitors on inflammation and immunity
Authors: Storey Robert , Thomas Mark 
Published: July 2015

SummaryPlatelet P2Y12 inhibitors form a major part of the treatment strategy for patients with acute coronary syndromes (ACS) due to the importance of the platelet P2Y12 receptor in mediating the pathophysiology of arterial thrombosis. It has been increasingly recognised that platelets also have a critical role in inflammation and immune responses. P2Y12 inhibitors reduce platelet release of pro-inflammatory α-granule contents and the formation of pro-inflammatory platelet-leukocyte aggregates. These are important mediators of inflammation in a variety of different contexts. Clinical evidence shows that P2Y12 inhibition by clopidogrel is associated with a reduction in platelet-related mediators of inflammation, such as soluble P-selectin and CD40L, following atherothrombosis. Clopidogrel in addition to aspirin, compared to aspirin alone, also reduces markers of systemic inflammation such as tumour necrosis factor (TNF) α and C-reactive protein (CRP) following ACS. The more potent thienopyridine P2Y12 inhibitor, prasugrel, has been shown to decrease platelet P-selectin expression and platelet-leukocyte aggregate formation compared to clopidogrel. The PLATO study suggested that the novel P2Y12 inhibitor ticagrelor might improve clinical outcomes from pulmonary infections and sepsis compared to clopidogrel in patients with ACS. Ticagrelor is a more potent P2Y12 inhibitor than clopidogrel and also inhibits cellular adenosine uptake via equilibrative nucleoside transporter (ENT) 1, whereas clopidogrel does not. Further examination of the involvement of these mechanisms in inflammation and immunity is therefore warranted.
T- wave axis deviation is associated with biomarkers of low-grade inflammation
Authors: Bonaccio Marialaura , Di Castelnuovo Augusto , Rago Livia , De Curtis Amalia , Assanelli Deodato , Badilini Fabio , Vaglio Martino , Costanzo Simona , Persichillo Mariarosaria , Cerletti Chiara , Donati Maria Benedetta , de Gaetano Giovanni , Iacoviello Licia ,   the MOLI-SANI study Investigators
Published: July 2015

SummaryT-wave axis deviation (TDev) may help identifying subjects at risk for major cardiac events and mortality, but the pathogenesis of TDev is not well established; in particular, the possible association between TDev and inflammation is unexplored and unknown. We aimed at investigating the association between low-grade inflammation and TDev abnormalities by conducting a cross-sectional analysis on 17,507 subjects apparently free from coronary heart and haematological diseases enrolled in the MOLI-SANI study. TDev was measured from a standard 12-lead resting electrocardiogram. High sensitivity (Hs) C-reactive protein (CRP), leukocyte (WBC) and platelet counts, neutrophil or granulocyte to lymphocyte ratios were used as markers of inflammation. In multivariable model subjects reporting high CRP levels had higher odds of having borderline and abnormal TDev (OR=1.70; 95 %CI: 1.53–1.90 and OR=1.72; 95 %CI: 1.23–2.41, respectively); the association was still significant, although reduced, after controlling for body mass index (OR=1.17; 95 %CI: 1.05–1.32, for borderline and OR=1.46; 95 %CI: 1.03–2.08, for abnormal). Similarly, higher neutrophil or granulocyte to lymphocyte ratios were associated with increased odds of having abnormal TDev. Neither platelet nor leukocyte counts were associated with abnormal TDev. The relationship between CRP with TDev abnormalities was significantly stronger in men, in non- obese or normotensive individuals, and in those without metabolic syndrome. In conclusion, C-reactive protein and some cellular biomarkers of inflammation such as granulocyte or neutrophil to lymphocyte ratios were independently associated with abnormal TDev, especially in subjects at low CVD risk. These results suggest that a low-grade inflammation likely contributes to the pathogenesis of T- wave axis deviation.
Practical management of bleeding in patients receiving non-vitamin K antagonist oral anticoagulants
Authors: Pollack Charles V. , Weitz Jeffrey I. 
Published: July 2015

SummaryNon-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used in the prevention and treatment of venous thromboembolism and in the prevention of stroke in patients with non-valvular atrial fibrillation. In phase III clinical trials and meta-analyses, the NOACs were at least as effective as vitamin K antagonists (VKAs) and were associated with a similar or lower incidence of major bleeding, including consistent and significant decreases in intracranial bleeding, although with an increase in gastrointestinal bleeding for some agents compared with VKAs. Subsequent real-world evidence supports these outcomes. Despite this, physicians have concerns about serious bleeding or emergencies because there are no specific reversal agents for the NOACs. However, in clinical trials, patients receiving NOACs generally had similar or better outcomes after these events than those taking VKAs. As with any bleeding, anticoagulant-related bleeding should first be stratified according to severity and location; risk can be minimised by ongoing assessment. Management protocols for NOAC-related bleeding are similar to those for VKAs but should take into account the pharmacological profile of the specific drug. Because of their short half-lives, NOAC-related mild bleeding can often be controlled by temporarily withholding treatment. More severe bleeding requires standard escalating haemodynamic support measures, and non-specific reversal agents can be considered in life-threatening situations, based on limited clinical data. Specific and rapid reversal agents are not currently available for any oral anticoagulant and restoration of coagulation may not necessarily lead to better outcomes. Nevertheless, specific NOAC reversal agents are in development and show promise in healthy volunteers.
Ethnic diversity in the genetics of venous thromboembolism
Authors: Tang Liang , Hu Yu 
Published: July 2015

SummaryGenetic susceptibility is considered as a crucial factor for the development of venous thromboembolism (VTE). Epidemiologic and genetic studies have revealed clear disparities in the incidence of VTE and the distribution of genetic factors for VTE in populations stratified by ethnicity worldwide. While gain-of-function polymorphisms in the procoagulant genes are common inherited factors in European-origin populations, the most prevalent molecular basis for venous thrombosis in Asians is confirmed to be dysfunctional variants in the anticoagulant genes. With the breakthrough of genomic technologies, a set of novel common alleles and rare mutations associated with VTE have also been identified, in different ethnic groups. Several putative pathways contributing to the pathogenesis of thrombophilia in populations of African-ancestry are largely unknown, as current knowledge of hereditary and acquired risk factors do not fully explain the highest risk of VTE in Black groups. In-depth studies across diverse ethnic populations are needed to unravel the whole genetics of VTE, which will help developing individual risk prediction models and strategies to minimise VTE in all populations.
Intramural Ventricular Recording and Pacing in Patients With Refractory Ventricular Tachycardia
Authors: AbdelWahab Amir , Stevenson William , Thompson Kara , Parkash Ratika , Gray Christopher , Gardner Martin , Sapp John 
Published: July 2015

Background—
Ablation of ventricular arrhythmias (VA) can be limited by intramural substrate not amenable to endocardial or epicardial ablation. Feasibility of irrigated needle ablation has been shown, but optimal means of identifying targets is not clear. We analyzed intramural needle electrograms in relation to endocardial electrograms.

Methods and Results—

Eight sequential patients (mean age, 56 years) who had failed 1 to 4 prior ablations underwent irrigated needle ablation were included. At selected sites, the needle was advanced into the myocardium. Bipolar and unipolar electrograms from the needle and catheter tip were analyzed. The needle was deployed at 75 sites with suspected intramural substrate among 2309 mapping sites. Intramural bipolar electrogram amplitude and duration correlated closely with endocardial electrograms, but were greater in amplitude and duration (1.5±1.4 versus 0.6±0.5 mV and 131±66 versus 112±51 ms;
P
=0.001 for both). During sinus rhythm intramural late potentials tended to be more common than endocardial late potentials (53.6% versus 35.7%;
P
=0.12). Intramural electrograms during VA preceded endocardial electrograms (−29±34 versus −15±21 ms;
P
=0.001). Irrigated needle ablation terminated VA at 12 of 28 sites with ablation during VA. Termination site needle electrograms tended to be earlier than nontermination sites (−54±37 versus −36±33 ms pre-QRS;
P
=0.15). Pacemapping from the needle at 19 sites matched the VA at 18 and showed stimulus to QRS of 60±51 ms.

Conclusions—
Recordings from intramural needle may be useful for selecting ablation targets during ventricular tachycardia and for substrate mapping. Further study is needed to develop methods to guide selection of optimal sites for needle deployment and ablation.
Everolimus Eluting Stents Versus Coronary Artery Bypass Graft Surgery for Patients With Diabetes Mellitus and Multivessel Disease
Authors: Bangalore Sripal , Guo Yu , Samadashvili Zaza , Blecker Saul , Xu Jinfeng , Hannan Edward L. 
Published: July 2015

Background—
In patients with diabetes mellitus and multivessel disease, coronary artery bypass graft surgery and percutaneous coronary intervention are treatment options. However, there is paucity of data comparing coronary artery bypass graft surgery against newer generation stents.

Methods and Results—

Patients included in the New York State registries who had diabetes mellitus and underwent isolated coronary artery bypass graft surgery or percutaneous coronary intervention with everolimus eluting stent (EES) for multivessel disease were included. Propensity score matching was used to assemble a cohort with similar baseline characteristics. The primary outcome was all-cause mortality. Secondary outcomes were myocardial infarction (MI), stroke, and repeat revascularization. Short-term (within 30 days) and long-term outcomes were evaluated. Among 16 089 patients with diabetes mellitus and multivessel disease, 8096 patients with similar propensity scores were included. At short-term, EES was associated with a lower risk of death (hazard ratio [HR] =0.58; 95% confidence interval [CI], 0.34–0.98;
P
=0.04) and stroke (HR=0.14; 95% CI, 0.06–0.30;
P
<0.0001) but higher risk of MI (HR=2.44; 95% CI, 1.13–5.31;
P
=0.02). At long-term, EES was associated with a similar risk of death (425 [10.50%] versus 414 [10.23%] events; HR=1.12; 95% CI, 0.96–1.30;
P
=0.16), a lower risk of stroke (118 [2.92%] versus 157 [3.88%] events; HR=0.76; 95% CI, 0.58–0.99;
P
=0.04) but a higher risk of MI (260 [6.42%] versus 166 [4.10%] events; HR=1.64; 95% CI, 1.32–2.04;
P
<0.0001) and repeat revascularization (889 [21.96%] versus 421 [10.40%] events; HR=2.42; 95% CI, 2.12–2.76;
P
<0.0001). The higher risk of MI was not seen in the subgroup of EES patients who underwent complete revascularization (HR=1.37; 95% CI, 0.76–2.47;
P
=0.30).

Conclusions—
In patients with diabetes mellitus and multivessel disease, EES was associated with lower upfront risk of death and stroke when compared with coronary artery bypass graft surgery. However, at long-term, EES was associated with similar risk of death, a higher risk of MI (in those with incomplete revascularization), and repeat revascularization but a lower risk of stroke.
The Paths of Extratropical Cyclones Associated with Wintertime High-Wind Events in the Northeastern United States
Authors: Booth James F. , Rieder Harald E. , Lee Dong Eun , Kushnir Yochanan 
Published: July 2015

AbstractThis study analyzes the association between wintertime high-wind events (HWEs) in the northeastern United States and extratropical cyclones. Sustained wind maxima in the daily summary data from the National Climatic Data Center’s integrated surface database are analyzed for 1979–2012. For each station, a generalized Pareto distribution is fit to the upper tail of the daily maximum wind speed data, and probabilistic return levels at 1, 3, and 5 yr are derived. Wind events meeting the return-level criteria are termed HWEs. The HWEs occurring on the same day are grouped into simultaneous wind exceedance dates, termed multistation events. In a separate analysis, extratropical cyclones are tracked using ERA-Interim. The multistation events are associated with the extratropical cyclone tracks on the basis of cyclone proximity on the day of the event. The multistation wind events are found to be most often associated with cyclones traveling from southwest to northeast, originating west of the Appalachian Mountains. To quantify the relative frequency of the strong-wind-associated cyclones, the full set of northeastern cyclone tracks is separated on the basis of path, using a crosshairs algorithm designed for this region. The tracks separate into an evenly distributed set of four pathways approaching the northeastern United States: from due west, from the southwest, and from the southeast and storms starting off the coast north of the Carolinas. Using the frequency of the tracks in each of the pathways, it is shown that the storms associated with multistation wind events are most likely to approach the northeastern United States from the southwest.
Predicted Changes in the Frequency of Extreme Precipitable Water Vapor Events
Authors: Roman Jacola , Knuteson Robert , Ackerman Steve , Revercomb Hank 
Published: July 2015

Abstract
A high amount of precipitable water vapor (PWV) is a necessary requirement for heavy precipitation and extreme flooding events. This study determined the predicted shift in extreme PWV from a set of CMIP5 global climate models using the highest emission scenario over three different spatial resolutions (global, zonal, and regional) and four different case regions (India, China, Europe, and eastern United States). For the globe, the frequency of the extreme 1% of PWV events between 2006 and 2030 was predicted to increase by a median factor (herein called an X factor) of 9 by 2075–99. Areas of high PWV, like the tropics, tended toward higher factors. The annual median X factor for India, China, central Europe, and the eastern United States was 24, 17, 15, and 16, respectively. For India, the minimum median X factor was 10 during December–February (DJF) and the maximum was 48 during June–August (JJA). In China, the minimum median X factor (8) occurred during DJF, and the maximum was 42 in JJA. For Europe, DJF and September–November (SON) had the smallest median X factor of 15, whereas JJA had the largest median X factor of 30. The smallest median X factor for the eastern United States (11) occurred during March–May (MAM), whereas the largest median X factor (32) occurred in JJA. Regional X factors were significantly larger than global (1.5–2 times larger), illustrating the importance of regional assessments of extreme PWV. The mean trend in the extreme PWV was approximately linear for all regions with a slope of about 3% decade−1. Observations for 10 (20) years are needed for the extreme PWV to change by an amount that exceeds a 3% (5%) measurement error.
Comparing Sudden Stratospheric Warming Definitions in Reanalysis Data*
Authors: Palmeiro Froila M. , Barriopedro David , García-Herrera Ricardo , Calvo Natalia 
Published: July 2015

Abstract
Sudden stratospheric warmings (SSWs) are characterized by a pronounced increase of the stratospheric polar temperature during the winter season. Different definitions have been used in the literature to diagnose the occurrence of SSWs, yielding discrepancies in the detected events. The aim of this paper is to compare the SSW climatologies obtained by different methods using reanalysis data. The occurrences of Northern Hemisphere SSWs during the extended-winter season and the 1958–2014 period have been identified for a suite of eight representative definitions and three different reanalyses. Overall, and despite the differences in the number and exact dates of occurrence of SSWs, the main climatological signatures of SSWs are not sensitive to the considered reanalysis.
The mean frequency of SSWs is 6.7 events decade−1, but it ranges from 4 to 10 events, depending on the method. The seasonal cycle of events is statistically indistinguishable across definitions, with a common peak in January. However, the multidecadal variability is method dependent, with only two definitions displaying minimum frequencies in the 1990s. An analysis of the mean signatures of SSWs in the stratosphere revealed negligible differences among methods compared to the large case-to-case variability within a given definition.
The stronger and more coherent tropospheric signals before and after SSWs are associated with major events, which are detected by most methods. The tropospheric signals of minor SSWs are less robust, representing the largest source of discrepancy across definitions. Therefore, to obtain robust results, future studies on stratosphere–troposphere coupling should aim to minimize the detection of minor warmings.
Geostrophic Closure of the Zonally Averaged Atlantic Meridional Overturning Circulation
Authors: Sévellec Florian , Huck Thierry 
Published: July 2015

AbstractIt is typically assumed that the meridional density gradient in the North Atlantic is well and positively correlated with the Atlantic meridional overturning circulation (AMOC). In numerical “water-hosing” experiments, for example, imposing an anomalous freshwater flux in the Northern Hemisphere leads to a slowdown of the AMOC. However, on planetary scale, the first-order dynamics are linked to the geostrophic balance, relating the north–south pressure gradient to the zonal circulation. In this study, these two approaches are reconciled. At steady state and under geostrophic dynamics, an analytical expression is derived to relate the zonal and meridional pressure gradient. This solution is only valid where the meridional density gradient length scale is shorter than Earth’s curvature length scale, that is, north of 35°N. This theoretical expression links the north–south density gradient to the AMOC and can be used as a closure for zonally averaged ocean models. Assumptions and shortcomings of the approach are presented. Implications of these results for paleoclimate problems such as AMOC collapse and asymmetry in the meridional overturning circulation of the Atlantic and of the Pacific are discussed.