bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shear-mediated dilation of the internal carotid artery occurs independent of hypercapnia
Authors: Hoiland Ryan L. , Smith Kurt J. , Carter Howard H. , Lewis Nia C.S. , Tymko Michael M. , Wildfong Kevin W. , Bain Anthony R. , Green Daniel J. , Ainslie Philip N. 
Published: April 2017

Evidence for shear stress as a regulator of carotid artery dilation in response to increased arterial CO2was recently demonstrated in humans during sustained elevations in CO2(hypercapnia); however, the relative contributions of CO2and shear stress to this response remains unclear. We examined the hypothesis that, after a 30-s transient increase in arterial CO2tension and consequent increase in internal carotid artery shear stress, internal carotid artery diameter would increase, indicating shear-mediated dilation, in the absence of concurrent hypercapnia. In 27 healthy participants, partial pressures of end-tidal O2and CO2, ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), internal carotid artery flow, diameter, and shear stress (high-resolution duplex ultrasound), and middle cerebral artery blood velocity (transcranial Doppler) were measured during 4-min steady-state and transient 30-s hypercapnic tests (both +9 mmHg CO2). Internal carotid artery dilation was lower in the transient compared with steady-state hypercapnia (3.3 ± 1.9 vs. 5.3 ± 2.9%, respectively, P < 0.03). Increases in internal carotid artery shear stress preceded increases in diameter in both transient (time: 16.8 ± 13.2 vs. 59.4 ± 60.3 s, P < 0.01) and steady-state (time: 18.2 ± 14.2 vs. 110.3 ± 79.6 s, P < 0.01) tests. Internal carotid artery dilation was positively correlated with shear rate area under the curve in the transient ( r2= 0.44, P < 0.01) but not steady-state ( r2= 0.02, P = 0.53) trial. Collectively, these results suggest that hypercapnia induces shear-mediated dilation of the internal carotid artery in humans. This study further promotes the application and development of hypercapnia as a clinical strategy for the assessment of cerebrovascular vasodilatory function and health in humans.NEW & NOTEWORTHY Shear stress dilates the internal carotid artery in humans. This vasodilatory response occurs independent of other physiological factors, as demonstrated by our transient CO2test, and is strongly correlated to shear area under the curve. Assessing carotid shear-mediated dilation may provide a future avenue for assessing cerebrovascular health and the risk of cerebrovascular events.
Impact of RyR2 potentiation on myocardial function
Authors: Lascano E. , Negroni J. , Vila Petroff M. , Mattiazzi A. 
Published: April 2017

This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca2+transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca2+release, shifting the intracellular Ca2+transient versus sarcoplasmic reticulum (SR) Ca2+content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca2+content, to enhance contractility if SR Ca2+content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention.NEW & NOTEWORTHY Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility. However, RyR2 potentiation shifts the intracellular Ca2+transient-sarcoplasmic reticulum (SR) Ca2+content relationship toward an enhanced efficiency state, which may contribute to a positive inotropic effect, preserve contractility despite decreased SR Ca2+content, or successfully counteract the effects of a negative inotropic action.
Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer
Authors: Mostaghel Elahe A. , Cho Eunpi , Zhang Ailin , Alyamani Mohammad , Kaipainen Arja , Green Sean , Marck Brett T. , Sharifi Nima , Wright Jonathan L. , Gulati Roman , True Lawrence D. , Loda Massimo , Matsumoto Alvin M. , Tamae Daniel , Penning Trevor N. , Balk Steven P. , Kantoff Phillip W. , Nelson Peter S. , Taplin Mary-Ellen , Montgomery R. Bruce 
Published: April 2017

Abstract
Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo transport by SLCO-encoded transporters and that SLCO gene variation may influence intracellular abiraterone levels and outcomes.
Experimental Design: Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized prostate cancer in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 SNPs in six SLCO genes.
Results: Abiraterone levels spanned a broad range (serum median 28 ng/mL, 108 nmol/L; tissue median 77 ng/mL, 271 nmol/L) and were correlated (r = 0.355, P = 0.001). Levels correlated positively with steroids upstream of CYP17A (pregnenolone, progesterone), and inversely with steroids downstream of CYP17A (DHEA, AED, testosterone). Serum PSA and tumor volumes were higher in men with undetectable versus detectable tissue abiraterone at prostatectomy (median 0.10 vs. 0.03 ng/dL, P = 0.02; 1.28 vs. 0.44 cc, P = 0.09, respectively). SNPs in SLCO2B1 associated with significant differences in tissue abiraterone (rs1789693, P = 0.0008; rs12422149, P = 0.03) and higher rates of minimal residual disease (tumor volume &lt; 0.5 cc; rs1789693, 67% vs. 27%, P = 0.009; rs1077858, 46% vs. 0%, P = 0.03). LNCaP cells expressing SLCO2B1 showed two- to fourfold higher abiraterone levels compared with vector controls (P &lt; 0.05).
Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized prostate cancer. Variation in SLCO genes may serve as predictors of response to abiraterone treatment. Clin Cancer Res; 23(16); 4592–601. ©2017 AACR.
Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma
Authors: Iida Yuuki , Ciechanover Aaron , Marzese Diego M. , Hata Keisuke , Bustos Matias , Ono Shigeshi , Wang Jinhua , Salomon Matthew P. , Tran Kevin , Lam Stella , Hsu Sandy , Nelson Nellie , Kravtsova-Ivantsiv Yelena , Mills Gordon B. , Davies Michael A. , Hoon Dave S.B. 
Published: April 2017

Abstract
Purpose: Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma.
Experimental Design: The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays; n = 137, JWCI cohort; n = 40) and The Cancer Genome Atlas database (TCGA cohort, n = 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-κB, and the epigenetic regulations of KPC1, including DNA methylation and miRNA expression.
Results: We verified that KPC1 suppresses melanoma proliferation by processing NF-κB1 p105 into p50, thereby modulating NF-κB target gene expression. Concordantly, KPC1 expression was downregulated in American Joint Committee on Cancer stage IV melanoma compared with early stages (stage I/II P = 0.013, stage III P = 0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n = 137; HR 1.810; P = 0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson's r −0.455; P &lt; 0.001), is significantly associated with KPC1 downregulation (JWCI; P = 0.028, TCGA; P = 0.003).
Conclusions: This study revealed novel epigenetic regulation of KPC1 associated with NF-κB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets. Clin Cancer Res; 23(16); 4831–42. ©2017 AACR.
Differential Expression of OATP1B3 Mediates Unconjugated Testosterone Influx
Authors: Sissung Tristan M. , Ley Ariel M. , Strope Jonathan D. , McCrea Edel M. , Beedie Shaunna , Peer Cody J. , Shukla Suneet , van Velkinburgh Jennifer , Reece Kelie , Troutman Sarah , Campbell Tessa , Fernandez Elena , Huang Phoebe , Smith Jordan , Thakkar Nilay , Venzon David J. , Brenner Stefan , Lee Wooin , Merino Maria , Luo Ji , Jager Walter , Price Douglas K. , Chau Cindy H. , Figg William D. 
Published: April 2017

Abstract
Castration-resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. This study was undertaken to ascertain the androgen uptake kinetics, functional, and clinical relevance of de novo expression of the steroid hormone transporter OATP1B3 (SLCO1B3). Experiments testing the cellular uptake of androgens suggest that testosterone is an excellent substrate of OATP1B3 (Km = 23.2 μmol/L; Vmax = 321.6 pmol/mg/minute), and cells expressing a doxycycline-inducible SLCO1B3 construct had greater uptake of a clinically relevant concentration of 3H-testosterone (50 nmol/L; 1.6-fold, P = 0.0027). When compared with Slco1b2 (−/−) mice, Slco1b2 (−/−)/hSLCO1B3 knockins had greater hepatic uptake (15% greater AUC, P = 0.0040) and lower plasma exposure to 3H-testosterone (17% lower AUC, P = 0.0030). Of 82 transporters genes, SLCO1B3 is the second-most differentially expressed transporter in CRPC cell lines (116-fold vs. androgen-sensitive cells), with a differentially spliced cancer-type ct-SLCO1B3 making up the majority of SLCO1B3 expression. Overexpression of SLCO1B3 in androgen-responsive cells results in 1.5- to 2-fold greater testosterone uptake, whereas siRNA knockdown of SLCO1B3 in CRPC cells did not change intracellular testosterone concentration. Primary human prostate tumors express SLCO1B3 to a greater extent than ct-SLCO1B3 (26% of total SLCO1B3 expression vs. 0.08%), suggesting that androgen uptake in these tumor cells also is greater. Non-liver tumors do not differentially express SLCO1B3.
Implications: This study suggests that de novo OATP1B3 expression in prostate cancer drives greater androgen uptake and is consistent with previous observations that greater OATP1B3 activity results in the development of androgen deprivation therapy resistance and shorter overall survival. Mol Cancer Res; 15(8); 1096–105. ©2017 AACR.
Dynamic Computed Tomography Myocardial Perfusion Imaging
Authors: Rossi Alexia , Wragg Andrew , Klotz Ernst , Pirro Federica , Moon James C. , Nieman Koen , Pugliese Francesca 
Published: April 2017

Background—
The clinical analysis of myocardial dynamic computed tomography myocardial perfusion imaging lacks standardization. The objective of this prospective study was to compare different analysis approaches to diagnose ischemia in patients with stable angina referred for invasive coronary angiography.

Methods and Results—

Patients referred for evaluation of stable angina symptoms underwent adenosine-stress dynamic computed tomography myocardial perfusion imaging with a second-generation dual-source scanner. Quantitative perfusion parameters, such as blood flow, were calculated by parametric deconvolution for each myocardial voxel. Initially, perfusion parameters were extracted according to standard 17-segment model of the left ventricle (fully automatic analysis). These were then manually sampled by an operator (semiautomatic analysis). Areas under the receiver-operating characteristic curves of the 2 different approaches were compared. Invasive fractional flow reserve ≤0.80 or diameter stenosis ≥80% on quantitative coronary angiography was used as reference standard to define ischemia. We enrolled 115 patients (88 men; age 57±9 years). There were 72 of 286 (25%) vessels causing ischemia in 52 of 115 (45%) patients. The semiautomatic analysis method was better than the fully automatic method at predicting ischemia (areas under the receiver-operating characteristic curves, 0.87 versus 0.69;
P
<0.001) with readings obtained in the endocardial myocardium performing better than those in the epicardial myocardium (areas under the receiver-operating characteristic curves, 0.87 versus 0.72;
P
<0.001). The difference in performance between blood flow, expressed as relative to remote myocardium, and absolute blood flow was not statistically significant (areas under the receiver-operating characteristic curves, 0.90 versus 0.87;
P
=ns).

Conclusions—
Endocardial perfusion parameters obtained by semiautomatic analysis of dynamic computed tomography myocardial perfusion imaging may permit robust discrimination between coronary vessels causing ischemia versus not causing ischemia.
Coronary Computed Tomography Angiography Predicts Guidewire Crossing and Success of Percutaneous Intervention for Chronic Total Occlusion
Authors: Yu Cheol-Woong , Lee Hyun-Jong , Suh Jon , Lee Nae-Hee , Park Sang-Min , Park Taek Kyu , Yang Jeong Hoon , Song Young Bin , Hahn Joo-Yong , Choi Seung Hyuk , Gwon Hyeon-Cheol , Lee Sang-Hoon , Choe Yeon Hyeon , Kim Sung Mok , Choi Jin-Ho 
Published: April 2017

Background—
We developed a model that predicts difficulty of percutaneous coronary intervention for coronary chronic total occlusion (CTO) using coronary computed tomographic angiography.

Methods and Results—

A total of 684 CTO lesions with preprocedural computed tomographic angiography were enrolled from 4 centers. Data were randomly divided into derivation and validation datasets at 2:1 ratio. The end point was successful guidewire crossing ≤30 minutes, which was met in 50%. The KCCT (Korean Multicenter CTO CT Registry) score was developed based on independent predictors identified by multivariable analysis, which were proximal blunt entry, proximal side branch, bending, occlusion length ≥15 mm, severe calcification, whole luminal calcification, reattempt, and ≥12 months or unknown duration of occlusion. The KCCT score was compared with the other prediction scores, including angiography-based J-CTO, PROGRESS-CTO, CL-score, and CT-based CT-RECTOR. The probability of guidewire crossing ≤30 minutes declined consistently from 100% to 0% according to the KCCT score (
P
<0.01, all). The KCCT score showed higher discriminative performance compared with the other scoring systems (c-statistics=0.78 versus 0.65–0.72,
P
<0.001, all). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of a KCCT score of <4 for guidewire crossing ≤30 minutes was 70%, 68%, 72%, 73%, and 70%, respectively. The KCCT score also showed consistent results with procedural success (
P
<0.05, all). These results could be reproduced in validation data set (
P
<0.05, all).

Conclusions—
KCCT scoring could predict successful guidewire crossing ≤30 minutes and also procedural success. KCCT scoring may enable noninvasive grading difficulty of CTO percutaneous coronary intervention.
Prognostic Value of Noninvasive Cardiovascular Testing in Patients With Stable Chest Pain
Authors: Hoffmann Udo , Ferencik Maros , Udelson James E. , Picard Michael H. , Truong Quynh A. , Patel Manesh R. , Huang Megan , Pencina Michael , Mark Daniel B. , Heitner John F. , Fordyce Christopher B. , Pellikka Patricia A. , Tardif Jean-Claude , Budoff Matthew , Nahhas George , Chow Benjamin , Kosinski Andrzej S. , Lee Kerry L. , Douglas Pamela S. 
Published: April 2017

Background:
Optimal management of patients with stable chest pain relies on the prognostic information provided by noninvasive cardiovascular testing, but there are limited data from randomized trials comparing anatomic with functional testing.

Methods:
In the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), patients with stable chest pain and intermediate pretest probability for obstructive coronary artery disease (CAD) were randomly assigned to functional testing (exercise electrocardiography, nuclear stress, or stress echocardiography) or coronary computed tomography angiography (CTA). Site-based diagnostic test reports were classified as normal or mildly, moderately, or severely abnormal. The primary end point was death, myocardial infarction, or unstable angina hospitalizations over a median follow-up of 26.1 months.

Results:

Both the prevalence of normal test results and incidence rate of events in these patients were significantly lower among 4500 patients randomly assigned to CTA in comparison with 4602 patients randomly assigned to functional testing (33.4% versus 78.0%, and 0.9% versus 2.1%, respectively; both
P
<0.001). In CTA, 54.0% of events (n=74/137) occurred in patients with nonobstructive CAD (1%–69% stenosis). Prevalence of obstructive CAD and myocardial ischemia was low (11.9% versus 12.7%, respectively), with both findings having similar prognostic value (hazard ratio, 3.74; 95% confidence interval [CI], 2.60–5.39; and 3.47; 95% CI, 2.42–4.99). When test findings were stratified as mildly, moderately, or severely abnormal, hazard ratios for events in comparison with normal tests increased proportionally for CTA (2.94, 7.67, 10.13; all
P
<0.001) but not for corresponding functional testing categories (0.94 [
P
=0.87], 2.65 [
P
=0.001], 3.88 [
P
<0.001]). The discriminatory ability of CTA in predicting events was significantly better than functional testing (c-index, 0.72; 95% CI, 0.68–0.76 versus 0.64; 95% CI, 0.59–0.69;
P
=0.04). If 2714 patients with at least an intermediate Framingham Risk Score (>10%) who had a normal functional test were reclassified as being mildly abnormal, the discriminatory capacity improved to 0.69 (95% CI, 0.64–0.74).

Conclusions:
Coronary CTA, by identifying patients at risk because of nonobstructive CAD, provides better prognostic information than functional testing in contemporary patients who have stable chest pain with a low burden of obstructive CAD, myocardial ischemia, and events.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01174550.
Benefits of Emergency Departments’ Contribution to Stroke Prophylaxis in Atrial Fibrillation
Authors: Coll-Vinent Blanca , Martín Alfonso , Sánchez Juan , Tamargo Juan , Suero Coral , Malagón Francisco , Varona Mercedes , Cancio Manuel , Sánchez Susana , Carbajosa José , Ríos José , Casanovas Georgina , Ràfols Carles , del Arco Carmen , Agud María , Aguilar José , Aguirre Alfons , de Simón Almela Amparo , Almirall Mercè , Álvarez Oscar , Amador Luis , Andueza Juan Antonio , Aramburu Francisco José , Ayala Ignacio , Bajo Ángel , Bilbaíno Carlos , Calvo Ricardo , Díaz María Elena , Estévez Maria Jesús , Flaño Cristina , Fuenzalida Carolina , Garcés Cristina , García María Teresa , García Pedro , García-Castrillo Luis , Gargallo Carmen , Garrido José Manuel , González Juan , Herrero Pablo , Jiménez Eduardo , Jiménez Gregorio , Lázaro José , Lopetegui Pedro , López Ignacio , Lubillo José Maria , Marchena María José , Moya Francisco , Mozota Julián , Navarro Francisco José , Palom Xavier , Ochoa Javier , Peiró Ana María , Parra Juan Manuel , Perea Álvaro , Piñera Pascual , Riambau Pere , Richard Fernando , Rodríguez Belén , Rodríguez Roberto , Ruiz Eva , Ruiz Francisco , Segarra Ana Maria , Seijas Carmen , Sesma Javier , Soler Wilfredo , Sousa María del Mar , Torres José Manuel , Trejo Olga Maria , Vicente José 
Published: April 2017

Background and Purpose—
Long-term benefits of initiating stroke prophylaxis in the emergency department (ED) are unknown. We analyzed the long-term safety and benefits of ED prescription of anticoagulation in atrial fibrillation patients.

Methods—
Prospective, multicenter, observational cohort of consecutive atrial fibrillation patients was performed in 62 Spanish EDs. Clinical variables and thromboprophylaxis prescribed at discharge were collected at inclusion. Follow-up at 1 year post-discharge included data about thromboprophylaxis and its complications, major bleeding, and death; risk was assessed with univariate and bivariate logistic regression models.

Results—

We enrolled 1162 patients, 1024 (88.1%) at high risk according to CHA
2
DS
2
-VASc score. At ED discharge, 935 patients (80.5%) were receiving anticoagulant therapy, de novo in 237 patients (55.2% of 429 not previously treated). At 1 year, 48 (4.1%) patients presented major bleeding events, and 151 (12.9%) had died. Anticoagulation first prescribed in the ED was not related to major bleeding (hazard ratio, 0.976; 95% confidence interval, 0.294–3.236) and was associated with a decrease in mortality (hazard ratio, 0.398; 95% confidence interval, 0.231–0.686). Adjusting by the main clinical and sociodemographic characteristics, concomitant antiplatelet treatment, or destination (discharge or admission) did not affect the results.

Conclusions—
Prescription of anticoagulation in the ED does not increase bleeding risk in atrial fibrillation patients at high risk of stroke and contributes to decreased mortality.
Bilirubin and Stroke Risk Using a Mendelian Randomization Design
Authors: Lee Sun Ju , Jee Yon Ho , Jung Keum Ji , Hong Seri , Shin Eun Soon , Jee Sun Ha 
Published: April 2017

Background and Purpose—
Circulating bilirubin, a natural antioxidant, is associated with decreased risk of stroke. However, the nature of the relationship between the two remains unknown. We used a Mendelian randomization analysis to assess the causal effect of serum bilirubin on stroke risk in Koreans.

Methods—

The 14 single-nucleotide polymorphisms (SNP
s
) (<10
–7
) including rs6742078 of uridine diphosphoglucuronyl-transferase were selected from genome-wide association study of bilirubin level in the KCPS-II (Korean Cancer Prevention Study-II) Biobank subcohort consisting of 4793 healthy Korean and 806 stroke cases. Weighted genetic risk score was calculated using 14 SNP
s
selected from the top SNP
s
.

Results—

Both rs6742078 (F statistics=138) and weighted genetic risk score with 14 SNP
s
(F statistics=187) were strongly associated with bilirubin levels. Simultaneously, serum bilirubin level was associated with decreased risk of stroke in an ordinary least-squares analysis. However, in 2-stage least-squares Mendelian randomization analysis, no causal relationship between serum bilirubin and stroke risk was found.

Conclusions—
There is no evidence that bilirubin level is causally associated with risk of stroke in Koreans. Therefore, bilirubin level is not a risk determinant of stroke.