bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity
Authors: Wheeler Heather E. , Gamazon Eric R. , Frisina Robert D. , Perez-Cervantes Carlos , El Charif Omar , Mapes Brandon , Fossa Sophie D. , Feldman Darren R. , Hamilton Robert J. , Vaughn David J. , Beard Clair J. , Fung Chunkit , Kollmannsberger Christian , Kim Jeri , Mushiroda Taisei , Kubo Michiaki , Ardeshir-Rouhani-Fard Shirin , Einhorn Lawrence H. , Cox Nancy J. , Dolan M. Eileen , Travis Lois B. 
Published: December 2016

Abstract
Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).
Experimental Design: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4–12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding.
Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P = 1.4 × 10−8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P = 0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n = 18,620 patients, Bonferroni adjusted P &lt; 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P values in the GWAS (P = 0.048).
Conclusions: We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses. Clin Cancer Res; 23(13); 3325–33. ©2016 AACR.
The Different T-cell Receptor Repertoires in Breast Cancer Tumors, Draining Lymph Nodes, and Adjacent Tissues
Authors: Wang Ting , Wang Changxi , Wu Jinghua , He Chenyang , Zhang Wei , Liu Jiayun , Zhang Ruifang , Lv Yonggang , Li Yongping , Zeng Xiaojing , Cao Hongzhi , Zhang Xiuqing , Xu Xun , Huang Chen , Wang Ling , Liu Xiao 
Published: December 2016

Abstract
T lymphocytes infiltrate the microenvironment of breast cancer tumors and play a pivotal role in tumor immune surveillance. Relationships between the T-cell receptors (TCR) borne by T cells within tumors, in the surrounding tissues, and in draining lymph nodes are largely unexplored in human breast cancer. Consequently, information about the relative extent of possible T-cell exchange between these tissues is also lacking. Here, we have analyzed the TCR repertoire of T cells using multiplex PCR and high-throughput sequencing of the TCRβ chain in the tissues of tumor, adjacent nontumor, and axillary lymph nodes of breast cancer patients. T-cell repertoire diversity in tumors was lower than in lymph nodes, but higher than in nontumor tissue, with a preferential use of variable and joining genes. These data are consistent with the hypothesis that most of the T cells in tumors derive from the lymph node, followed by their expansion in tumor tissue. Positive nodes appeared to enhance T-cell infiltration into tumors and T-cell clonal expansion in lymph nodes. Additionally, the similarity in TCR repertoire between tumor and nontumor tissue was significantly higher in luminal-like, rather than basal-like, breast cancer. Our study elucidated the high heterogeneity of the TCR repertoire and provides potential for future improvements in immune-related diagnosis, therapy, and prognosis for breast cancer patients. Cancer Immunol Res; 5(2); 148–56. ©2016 AACR.
Infiltration of CD8 T Cells and Expression of PD-1 and PD-L1 in Synovial Sarcoma
Authors: Nowicki Theodore S. , Akiyama Ryan , Huang Rong Rong , Shintaku I. Peter , Wang Xiaoyan , Tumeh Paul C. , Singh Arun , Chmielowski Bartosz , Denny Christopher , Federman Noah , Ribas Antoni 
Published: December 2016

Abstract
Tumors expressing programmed death ligand 1 (PD-L1) interact with the corresponding negative-signal generating immune receptor on the surface of CD8 T cells, PD-1, thereby suppressing antitumor activity. Therapeutics blocking this interaction have shown promise in various cancers by restoring functional antitumor T-cell activity. We explored the degree of PD-L1, PD-1, and CD8 expression in a retrospective analysis of 29 clinical synovial sarcoma samples. Quantitative immunohistochemistry and multiplex immunofluorescence were used to determine relative quantification of CD8+ and PD-1+ T cells and PD-L1 expression within the intratumor area and the interface between the tumor and the surrounding nontumor tissue (i.e., invasive margin), and colocalization of these factors, respectively. PD-L1, PD-1, and CD8 cell densities in the tumor-invasive margins were significantly higher in the metastatic tumors than the primary tumors (P &lt; 0.01), and PD-L1, PD-1, and CD8 cell densities were all significantly positively correlated with one other (P &lt; 0.0001). PD-1 cell density in the tumor-invasive margin was significantly associated with worse progression-free survival. Multiplex immunofluorescence demonstrated coexpression of PD-1 and CD8 on lymphocytes within the invasive margin, as well as relative proximity between PD-1+ CD8 cells and PD-L1+ tumor cells. Our results provide a preclinical rationale for screening of patients with synovial sarcoma for the colocalization of CD8, PD-1, and PD-L1, which may be a marker for response to PD-1 blockade therapy. Cancer Immunol Res; 5(2); 118–26. ©2016 AACR.
Backstepping Control of Wind and Photovoltaic Hybrid Renewable Energy System
Authors: El Azzaoui Marouane , Mahmoudi Hassane , Boudaraia Karima 
Published: December 2016

<p>This paper deals with the interconnected grid hybrid renewable energy system (HRES). The wind energy conversion system (WECS), is built around a wind turbine coupled to a doubly fed induction generator (DFIG). The stator of DFIG is directly related to the grid and the rotor is connected to the grid through back-to-back power converters. The proposed algorithm combines the nonlinear Backstepping approach and the eld orientation applied to control the DFIG. In a rst step, this technique is applied to the side converter rotor (RSC), to control the electromagnetic torque and reactive power, and secondly, it is applied to the grid side converter (GSC) to control the power exchanged with the grid and regulate the DC bus voltage. The PV energy system is composed by the PV array and the DC-DC boost converter which controlled by the MPPT method to extract the optimal power. Simulations results present the performances in terms of set point tracking, stability, and robustness with respect to the variation in wind speed and irradiation.</p>
Relationships of Measured and Genetically Determined Height With the Cardiac Conduction System in Healthy Adults
Authors: Kofler Thomas , Thériault Sébastien , Bossard Matthias , Aeschbacher Stefanie , Bernet Selina , Krisai Philipp , Blum Steffen , Risch Martin , Risch Lorenz , Albert Christine M. , Paré Guillaume , Conen David 
Published: December 2016

Background—
Increasing height is an independent risk factor for atrial fibrillation, but the underlying mechanisms are unknown. We hypothesized that height-related differences in electric conduction could be potential mediators of this relationship.

Methods and Results—

We enrolled 2149 adults aged 25 to 41 years from the general population. Height was directly measured, and a resting 12-lead ECG obtained under standardized conditions. Multivariable linear regression models were used to evaluate the association between measured height and ECG parameters. Mendelian randomization analyses were then performed using 655 independent height-associated genetic variants previously identified in the GIANT consortium. Median age was 37 years, and median height was 1.71 m. Median PR interval, QRS duration, and QTc interval were 156, 88, and 402 ms, respectively. After multivariable adjustment, β-coefficients (95% confidence intervals) per 10 cm increase in measured height were 4.17 (2.65–5.69;
P
<0.0001) for PR interval and 2.06 (1.54–2.58;
P
<0.0001) for QRS duration. Height was not associated with QTc interval or the Sokolow–Lyon index. An increase of 10 cm in genetically determined height was associated with increases of 4.33 ms (0.76–7.96;
P
=0.02) in PR interval and 2.57 ms (1.33–3.83;
P
<0.0001) in QRS duration but was not related to QTc interval or Sokolow–Lyon index.

Conclusions—
In this large population-based study, we found significant associations of measured and genetically determined height with PR interval and QRS duration. Our findings suggest that adult height is a marker of altered cardiac conduction and that these relationships may be causal.
Comparison of the Efficacy and Safety of Early Rule-Out Pathways for Acute Myocardial Infarction
Authors: Chapman Andrew R. , Anand Atul , Boeddinghaus Jasper , Ferry Amy V. , Sandeman Dennis , Adamson Philip D. , Andrews Jack , Tan Stephanie , Cheng Sheun F. , D’Souza Michelle , Orme Kate , Strachan Fiona E. , Nestelberger Thomas , Twerenbold Raphael , Badertscher Patrick , Reichlin Tobias , Gray Alasdair , Shah Anoop S.V. , Mueller Christian , Newby David E. , Mills Nicholas L. 
Published: December 2016

Background:
High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the optimal approach is uncertain. We compared the European Society of Cardiology rule-out pathway with a pathway that incorporates lower cardiac troponin concentrations to risk stratify patients.

Methods:

Patients with suspected acute coronary syndrome (n=1218) underwent high-sensitivity cardiac troponin I measurement at presentation and 3 and 6 or 12 hours. We compared the European Society of Cardiology pathway (<99th centile at presentation or at 3 hours if symptoms <6 hours) with a pathway developed in the High-STEACS study (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary
S
yndrome) population (<5 ng/L at presentation or change <3 ng/L and <99th centile at 3 hours). The primary outcome was a comparison of the negative predictive value of both pathways for index type 1 myocardial infarction or type 1 myocardial infarction or cardiac death at 30 days. We evaluated the primary outcome in prespecified subgroups stratified by age, sex, time of symptom onset, and known ischemic heart disease.

Results:

The primary outcome occurred in 15.7% (191 of 1218) patients. In those less than the 99th centile at presentation, the European Society of Cardiology pathway ruled out myocardial infarction in 28.1% (342 of 1218) and 78.9% (961 of 1218) at presentation and 3 hours, respectively, missing 18 index and two 30-day events (negative predictive value, 97.9%; 95% confidence interval, 96.9–98.7). The High-STEACS pathway ruled out 40.7% (496 of 1218) and 74.2% (904 of 1218) at presentation and 3 hours, missing 2 index and two 30-day events (negative predictive value, 99.5%; 95% confidence interval, 99.0–99.9;
P
<0.001 for comparison). The negative predictive value of the High-STEACS pathway was greater than the European Society of Cardiology pathway overall (
P
<0.001) and in all subgroups, including those presenting early or known to have ischemic heart disease.

Conclusions:
Use of the High-STEACS pathway incorporating low high-sensitivity cardiac troponin concentrations rules out myocardial infarction in more patients at presentation and misses 5-fold fewer index myocardial infarctions than guideline-approved pathways based exclusively on the 99th centile.

Clinical Trial Registration:

URL:
http://clinicaltrials.gov
. Unique identifier: NCT01852123.
Is Unexplained Early Neurological Deterioration After Intravenous Thrombolysis Associated With Thrombus Extension?
Authors: Seners Pierre , Hurford Robert , Tisserand Marie , Turc Guillaume , Legrand Laurence , Naggara Olivier , Mas Jean-Louis , Oppenheim Catherine , Baron Jean-Claude 
Published: December 2016

Background and Purpose—
Early neurological deterioration (END) after anterior circulation stroke is strongly associated with poor outcome. Apart from straightforward causes, such as intracerebral hemorrhage and malignant edema, the mechanism of END occurring after intravenous thrombolysis remains unclear in most instances. We tested the hypothesis that unexplained END is associated with thrombus extension.

Methods—
From our database of consecutively thrombolysed patients, we identified anterior circulation stroke patients who had both admission and 24-hour T2* magnetic resonance imaging, visible occlusion on admission magnetic resonance angiography and no recanalization on 24-hour magnetic resonance angiography. END was defined as ≥4 National Institutes of Health Stroke Scale–point deterioration on 24-hour clinical assessment and unexplained END as END without clear cause. The incidence of susceptibility vessel sign extension on T2* imaging, defined as any new occurrence or extension of susceptibility vessel sign from admission to 24-hour follow-up magnetic resonance, was compared between patients with unexplained END and those without END.

Results—

Of 120 eligible patients for the present study, 22 experienced unexplained END. Susceptibility vessel sign extension was present in 41 (34%) patients and was significantly more frequent in the unexplained END than in the no-END group (59% versus 29%, respectively; adjusted odds ratio=3.96; 95% confidence interval, 1.25–12.53;
P
=0.02).

Conclusions—
In this study, unexplained END occurring after thrombolysis was independently associated with susceptibility vessel sign extension, suggesting in situ thrombus extension or re-embolization. These findings strengthen the need to further investigate early post-thrombolysis administration of antithrombotics to reduce the risk of this ominous clinical event.
Public Meaning of the Zasulich Trial 1878: Law, Politics and Gender
Authors: Borisova Tatiana 
Published: December 2016

The article aims to demonstrate that while the jurors’ acquittal of the famous terrorist Vera Zasulich has often been interpreted in terms of sympathy for ‘a desperate girl’, previously underestimated legal and political claims also played an important role in the trial. The key legal experts at the trial – her defense attorney Aleksandrov and the president of the court Koni – interpreted Zasulich’s attempt on Trepov’s life as an act of societal self-defense: Zasulich was presented as a victim of a society which could no longer tolerate arbitrariness by authorities. The flogging of political prisoner Bogolyubov following Trepov’s illegal order made Zasulich desperate to take revenge in order to alert Russian society of the humiliating arbitrariness and the unfairness of the political and legal structures of late Imperial Russia.
Her victimization highlighted her “moral right” to act as a defendant of true law and legality in Russia. This idea of “moral right,” which empowered Zasulich to act in defense of society, was supported by Koni’s conceptualization of law and state power as an embodiment of the people’s will and responsibility. This conceptualization was elaborated in detail in his scholarly legal writings scholarship on the right to self-defense. The article brings together Koni’s theory and his practical role in Zasulich’s acquittal and demonstrates tensions between the Great Reforms and their political and social limitations.
Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events
Authors: Preis Meir , Hirsch Julianna , Kotler Antonio , Zoabi Ahmad , Stein Nili , Rennert Gad , Saliba Walid 
Published: December 2016

Key PointsFactor XI deficiency is associated with reduced risk of cardiovascular events. Factor XI deficiency is associated with reduced risk of VTE.
Nanostructured scaffold as a determinant of stem cell fate
Authors: Krishna Lekshmi , Dhamodaran Kamesh , Jayadev Chaitra , Chatterjee Kaushik , Shetty Rohit , Khora S. S. , Das Debashish 
Published: December 2016

AbstractThe functionality of stem cells is tightly regulated by cues from the niche, comprising both intrinsic and extrinsic cell signals. Besides chemical and growth factors, biophysical signals are important components of extrinsic signals that dictate the stem cell properties. The materials used in the fabrication of scaffolds provide the chemical cues whereas the shape of the scaffolds provides the biophysical cues. The effect of the chemical composition of the scaffolds on stem cell fate is well researched. Biophysical signals such as nanotopography, mechanical forces, stiffness of the matrix, and roughness of the biomaterial influence the fate of stem cells. However, not much is known about their role in signaling crosstalk, stem cell maintenance, and directed differentiation. Among the various techniques for scaffold design, nanotechnology has special significance. The role of nanoscale topography in scaffold design for the regulation of stem cell behavior has gained importance in regenerative medicine. Nanotechnology allows manipulation of highly advanced surfaces/scaffolds for optimal regulation of cellular behavior. Techniques such as electrospinning, soft lithography, microfluidics, carbon nanotubes, and nanostructured hydrogel are described in this review, along with their potential usage in regenerative medicine. We have also provided a brief insight into the potential signaling crosstalk that is triggered by nanomaterials that dictate a specific outcome of stem cells. This concise review compiles recent developments in nanoscale architecture and its importance in directing stem cell differentiation for prospective therapeutic applications.
O3, CH4, CO2, CO, NO2 and NMHC aircraft measurements in the Uinta Basin oil and gas region under low and high ozone conditions in winter 2012 and 2013
Authors: Oltmans S. J. , Karion A. , Schnell R. C. , Pétron G. , Helmig D. , Montzka S. A. , Wolter S. , Neff D. , Miller B. R. , Hueber J. , Conley S. , Johnson B. J. , Sweeney C. 
Published: December 2016

Abstract
Instrumented aircraft measuring air composition in the Uinta Basin, Utah, during February 2012 and January-February 2013 documented dramatically different atmospheric ozone (O3) mole fractions. In 2012 O3 remained near levels of ∼40 ppb in a well-mixed 500–1000 m deep boundary layer while in 2013, O3 mole fractions &gt;140 ppb were measured in a shallow (∼200 m) boundary layer. In contrast to 2012 when mole fractions of emissions from oil and gas production such as methane (CH4), non-methane hydrocarbons (NMHCs) and combustion products such as carbon dioxide (CO2) were moderately elevated, in winter 2013 very high mole fractions were observed. Snow cover in 2013 helped produce and maintain strong temperature inversions that capped a shallow cold pool layer. In 2012, O3 and CH4 and associated NMHCs mole fractions were not closely related. In 2013, O3 mole fractions were correlated with CH4 and a suite of NMHCs identifying the gas field as the primary source of the O3 precursor NMHC emissions. In 2013 there was a strong positive correlation between CH4 and CO2 suggesting combustion from oil and natural gas processing activities. The presence of O3 precursor NMHCs through the depth of the boundary layer in 2013 led to O3 production throughout the layer. In 2013, O3 mole fractions increased over the course of the week-long episodes indicating O3 photochemical production was larger than dilution and deposition rates, while CH4 mole fractions began to level off after 3 days indicative of some air being mixed out of the boundary layer. The plume of a coal-fired power plant located east of the main gas field was not an important contributor to O3 or O3 precursors in the boundary layer in 2013.
The changing face of lower tropospheric sulfur oxides in the United States
Authors: Hidy G. M. , Blanchard C.L. 
Published: December 2016

Abstract
Sulfur oxides, sulfur dioxide and airborne sulfate, SOx, are short-lived species in the troposphere whose concentrations in air and precipitation have changed dramatically in association with fossil fuel combustion. The historic rise in concentration is coincident with the era of the so-called “Anthropocene.” Unlike concentrations of long-lived species such as carbon dioxide, atmospheric SOx in the United States (US) peaked between 1970 and 2005 then declined. The rise and fall of SOx is traced by comparing national data on emission changes, ambient concentrations, and precipitation sulfate from prior to World War II to the present. Surface SOx concentrations and precipitation sulfate have decreased with emissions in most parts of the US after the late 1970s. Continued reduction toward a natural “background” condition has depended on aggressive management of anthropogenic emission sources. Annual average ambient concentrations of SO2 and SO4 have become more uniform across the US at levels of 1–3 ppbv and 0.3–3 µg/m3, respectively. Precipitation SO4 has a nominal concentration generally less than 0.5 mg/L. The effective lifetime of SOx in the troposphere is a few days. This duration limits the spatial extent of emission source influence of SOx to regional scales, wherein spatial gradients in species concentrations lead to variations in human exposure and impacts on vulnerable terrestrial and aquatic ecosystems. The effects of domestic emission reductions on SOx levels are moderated by intra- and intercontinental transport of SOx from Canada, Mexico, Asia and elsewhere. The trends in tropospheric SOx concentrations illustrate the results of more than a century of rising public awareness and action to progressively reduce a US environmental risk, accomplished with advances in energy production technology that have maintained economic well-being.
APPLYING LIFE CYCLE ASSESSMENT TO ANALYSE RESOURCE CONSUMPTIONS AND WASTE GENERATION IN A LABORATORY ANIMALS PRODUCTION
Authors: Viana Ingrid Daré , Peixoto José Antonio Assunção , Xavier Leydervan De Souza , De Souza Cristina Gomes 
Published: December 2016

The objective of this study was to quantify and analyze resource consumptions of a laboratory rabbits production, in a Brazilian animal research facility, in order to produce a harmonized Health-Care Waste (HCW) classification, according to national regulations and international guidelines, as it is a basis to perform health and safety risk analysis, of animals, humans and environment impacts in HCW management. Methodologically, the principles and framework from Life Cycle Assessment were used to produce a door‑to‑door Life Cycle Inventory to produce the HCW classification and a short environmental impact assessment. A high electricity consumption (about 96%), for conditioning facilities maintenance, and a high water consumption transformed into effluents and emissions (about 97.5%) were observed. Specifically, from HCW classification a first analysis of mass pointed: effluents (45.92 %), emissions (52.54 %), biological waste (1.45%) and common waste (0.001 %). These data are primary estimates that lead to deeper analysis of toxic materials and contamination. Finally, the entire study produced a cross fertilization of information giving more transparency about the rationality implied in the modeling of processes and presentation of reports, enabling to relate the local scope of impact assessment through broader reflections on global social responsibility and eco-efficiency.