bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential effects of vitamin C or protandim on skeletal muscle adaptation to exercise
Authors: Bruns Danielle R. , Ehrlicher Sarah E. , Khademi Shadi , Biela Laurie M. , Peelor Frederick F. , Miller Benjamin F. , Hamilton Karyn L. 
Published: June 2018

Maintaining proteostasis is a key mechanism for preserving cell function. Exercise-stimulated proteostasis is regulated, in part, by redox-sensitive signaling. Several studies suggest that supplementation with exogenous antioxidants blunts exercise-induced cellular adaptations, although this conclusion lacks consensus. Our group uses a fundamentally different approach to maintain redox balance by treatment with bioactive phytochemicals to activate the transcription factor nuclear factor (erythroid-derived 2)-like 2 and downstream endogenous antioxidant pathways. We hypothesized that vitamin C (VitC) would interfere with redox-sensitive proteostatic mechanisms in skeletal muscle, whereas phytochemical treatment would permit proteostatic maintenance. We measured protein and DNA synthesis in skeletal muscle from high-volume voluntary wheel-running rats. Whereas phytochemical treatment permitted mitochondrial and other proteostatic adaptations to exercise, VitC treatment did not. During an in vitro oxidative challenge, phytochemical treatment helped maintain proteostasis, including the mitochondrial fraction while VitC did not. Our findings support the conclusion that VitC can blunt some of the beneficial adaptations to exercise. We propose that regulation of endogenous antioxidants represents a novel approach to maintain redox balance while still permitting redox-sensitive proteostatic adaptations. NEW & NOTEWORTHY Whether vitamin C blocks aerobic exercise adaptions lacks consensus, perhaps because of approaches that only assess markers of mitochondrial biogenesis. By directly measuring mitochondrial biogenesis, we demonstrate that vitamin C blunts exercise-induced adaptations. Furthermore, we show that treatment with Protandim, a purported nuclear factor (erythroid-derived 2)-like 2 activator that upregulates endogenous antioxidants, permits mitochondrial biogenesis. We confirm that vitamin C blunts aerobic exercise adaptions, whereas Protandim does not, suggesting targeting the endogenous antioxidant network facilitates adaptations to exercise.
Targeting Rac and Cdc42 GTPases in Cancer
Authors: Maldonado María del Mar , Dharmawardhane Suranganie 
Published: June 2018

Abstract
Rac and Cdc42 are small GTPases that have been linked to multiple human cancers and are implicated in epithelial to mesenchymal transition, cell-cycle progression, migration/invasion, tumor growth, angiogenesis, and oncogenic transformation. With the exception of the P29S driver mutation in melanoma, Rac and Cdc42 are not generally mutated in cancer, but are overexpressed (gene amplification and mRNA upregulation) or hyperactivated. Rac and Cdc42 are hyperactivated via signaling through oncogenic cell surface receptors, such as growth factor receptors, which converge on the guanine nucleotide exchange factors that regulate their GDP/GTP exchange. Hence, targeting Rac and Cdc42 represents a promising strategy for precise cancer therapy, as well as for inhibition of bypass signaling that promotes resistance to cell surface receptor-targeted therapies. Therefore, an understanding of the regulatory mechanisms of these pivotal signaling intermediates is key for the development of effective inhibitors. In this review, we focus on the role of Rac and Cdc42 in cancer and summarize the regulatory mechanisms, inhibitory efficacy, and the anticancer potential of Rac- and Cdc42-targeting agents. Cancer Res; 78(12); 3101–11. ©2018 AACR.
Antigen-Specific CD8 Lytic Phenotype Induced by Sipuleucel-T in Hormone-Sensitive or Castration-Resistant Prostate Cancer and Association with Overall Survival
Authors: Antonarakis Emmanuel S. , Small Eric J. , Petrylak Daniel P. , Quinn David I. , Kibel Adam S. , Chang Nancy N. , Dearstyne Erica , Harmon Matt , Campogan Dwayne , Haynes Heather , Vu Tuyen , Sheikh Nadeem A. , Drake Charles G. 
Published: June 2018

Abstract
Purpose: Sipuleucel-T is FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) based on the IMPACT trial showing a 4.1-month benefit in median overall survival (OS) for patients receiving sipuleucel-T versus control. Although efficacy of sipuleucel-T is well established, its mechanism remains incompletely understood.
Patients and Methods: Patient samples from three sipuleucel-T trials were assessed for peripheral cellular immune responses to the immunogen PA2024 and the target antigen prostatic acid phosphatase (PAP). PAP- and PA2024-specific proliferative and cytolytic responses were characterized to delineate sipuleucel-T–induced immune responses. To quantify potential cytotoxic T lymphocyte (CTL) activity, cell-surface CD107a expression on PAP- or PA2024-specific CD8+ T cells was measured in sipuleucel-T–treated patient and healthy volunteer samples.
Results: Increased PA2024-specific CD4+ (P = 0.030) and CD8+ (P = 0.052) T-cell proliferation from baseline to week 6 was observed (N = 14) post–sipuleucel-T, with greater magnitude of PA2024-specific responses compared with PAP. PAP- and PA2024-CTL activity (CD107a positivity) significantly increased at weeks 6 and 26 after sipuleucel-T treatment (P &lt; 0.0001; N = 22). At 26 weeks post–sipuleucel-T, OS correlated with the magnitude of PAP (Pearson R, 0.52; P = 0.013) or PA2024 (Pearson R, 0.67; P = 0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis (P = 0.0005; N = 22), with PA2024 responses correlating with PAP responses at week 26 (R = 0.90; P = 1.53E−08).
Conclusions: This study is the first to report PAP-specific CD8+ T-cell responses elicited by sipuleucel-T treatment. Increased and persistent potential PA2024-specific CTL activity correlated with PAP-specific CTL activity and associated with improved OS following sipuleucel-T treatment. Clin Cancer Res; 24(19); 4662–71. ©2018 AACR.
ERBB Signaling Interrupted: Targeting Ligand-Induced Pathway Activation
Authors: Wilson Frederick H. , Politi Katerina 
Published: June 2018

Abstract
Summary: A patient with advanced lung adenocarcinoma harboring a CD74–NRG1 gene rearrangement, which promotes ERBB2–ERBB3 heterodimerization and activation of downstream signaling, had an exceptional therapeutic response to an experimental anti-ERBB3 antibody. This result illustrates how NRG1 rearrangements, which are observed at a low frequency in a variety of solid tumors, may represent tractable therapeutic targets. Cancer Discov; 8(6); 676–8. ©2018 AACR.
See related article by Drilon et al., p. 686.
Prostate Power Play: Does Pik3ca Accelerate Pten-Deficient Cancer Progression?
Authors: Triscott Joanna , Rubin Mark A. 
Published: June 2018

Abstract
Summary: PI3K pathway alterations are frequently recurrent in metastatic prostate cancer and are associated with the development of currently incurable castration-resistant disease. Candidate inhibitors that target single PI3K pathway members lack efficacy as demonstrated in multiple clinical trials. In this issue, Pearson and colleagues examine the functional importance of co-occurring PIK3CA and PTEN aberrations using a novel mouse model and demonstrate a synergistic acceleration of tumorigenesis that may be responsible for de novo metastatic prostate cancer. Cancer Discov; 8(6); 682–5. ©2018 AACR
See related article by Pearson et al., p. 764.
Cardiomyocyte Functional Etiology in Heart Failure With Preserved Ejection Fraction Is Distinctive—A New Preclinical Model
Authors: Curl Claire L. , Danes Vennetia R. , Bell James R. , Raaijmakers Antonia J. A. , Ip Wendy T. K. , Chandramouli Chanchal , Harding Tristan W. , Porrello Enzo R. , Erickson Jeffrey R. , Charchar Fadi J. , Kompa Andrew R. , Edgley Amanda J. , Crossman David J. , Soeller Christian , Mellor Kimberley M. , Kalman Jonathan M. , Harrap Stephen B. , Delbridge Lea M. D. 
Published: June 2018

Background

Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (
HF
p
EF
). The lack of effective treatments for
HF
p
EF
is a substantial and escalating unmet clinical need—and the lack of
HF
p
EF
‐specific animal models represents a major preclinical barrier in advancing understanding of
HF
p
EF
. As established treatments for heart failure with reduced ejection fraction (
HF
r
EF
) have proven ineffective for
HF
p
EF
, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of
HF
p
EF
, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology.

Methods and Results

The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%–90% control) with marked diastolic dysfunction (increased E/E′). Surprisingly,
HHR
cardiomyocytes were hypercontractile, exhibiting high Ca
2+
operational levels and markedly increased L‐type Ca
2+
channel current. In
HHR
, prominent regions of reparative fibrosis in the left ventricle free wall adjacent to the interventricular septum were observed.

Conclusions

Thus, the cardiomyocyte remodeling process in the etiology of this
HF
p
EF
model contrasts dramatically with the suppressed Ca
2+
cycling state that typifies heart failure with reduced ejection fraction. These findings may explain clinical observations, that treatments considered appropriate for heart failure with reduced ejection fraction are of little benefit for
HF
p
EF
—and suggest a basis for new therapeutic strategies.
Cerebral Microbleeds Are Associated With Mild Cognitive Impairment in Patients With Hypertension
Authors: Zhang Jinbiao , Liu Lifeng , Sun Hairong , Li Menfan , Li Yan , Zhao Junwu , Li Jie , Liu Xinwu , Cong Yannan , Li Fang , Li Zhenguang 
Published: June 2018

Background
Cerebral microbleeds (CMBs) are hypothesized downstream markers of brain damage caused by vascular and amyloid pathologic mechanisms. The aim of this study was to determine whether CMB count and location are associated with an increased risk for mild cognitive impairment (MCI) in patients with essential hypertension without a history of transient ischemic attack or stroke.

Methods and Results

In this cross‐sectional study, patients were prospectively enrolled from consecutive outpatients with essential hypertension 50 years and older at 3 centers in northern China. Generalized linear Poisson models were used to determine the association between the number and location of
CMB
s and
MCI
in patients with hypertension. The association of microbleeds with different cognitive domains was estimated using linear mixed models. The presence, number, and distribution of
CMB
s were greater in patients with hypertension who had
MCI
(
P
<0.001). The presence of any
CMB
s, strictly lobar
CMB
s, and deep or infratentorial
CMB
s were all related to
MCI
after adjusting for age, sex, education, cardiovascular risk factors, body mass index, intima‐media thickness, the presence of silent lacunar infarctions, white matter lesion grade, and brain atrophy. Furthermore, the presence of multiple microbleeds (≥5) was associated with lower Montreal Cognitive Assessment total scores and worse performance on specific domains of cognitive tests, such as global cognitive function, information processing speed, and motor speed.

Conclusions

This study suggests that the presence of and a greater number of cerebral
CMB
s independently correlate with
MCI
in patients with essential hypertension without a history of transient ischemic attack or stroke.
Residual Mitral Regurgitation After Repair for Posterior Leaflet Prolapse—Importance of Preoperative Anterior Leaflet Tethering
Authors: Sakaguchi Taichi , Kagiyama Nobuyuki , Toki Misako , Hiraoka Arudo , Hayashida Akihiro , Totsugawa Toshinori , Tamura Kentaro , Chikazawa Genta , Yoshitaka Hidenori , Yoshida Kiyoshi 
Published: June 2018

Background

Carpentier's techniques for degenerative posterior mitral leaflet prolapse have been established with excellent long‐term results reported. However, residual mitral regurgitation (
MR
) occasionally occurs even after a straightforward repair, though the involved mechanisms are not fully understood. We sought to identify specific preoperative echocardiographic findings associated with residual
MR
after a posterior mitral leaflet repair.

Methods and Results

We retrospectively studied 117 consecutive patients who underwent a primary mitral valve repair for isolated posterior mitral leaflet prolapse including a preoperative 3‐dimensional transesophageal echocardiography examination. Twelve had residual
MR
after the initial repair, of whom 7 required a corrective second pump run, 4 underwent conversion to mitral valve replacement, and 1 developed moderate
MR
within 1 month. Their preoperative parameters were compared with those of 105 patients who had an uneventful mitral valve repair. There were no hospital deaths. Multivariate analysis identified preoperative anterior mitral leaflet tethering angle as a significant predictor for residual
MR
(odds ratio, 6.82; 95% confidence interval, 1.8–33.8;
P
=0.0049). Receiver operator characteristics curve analysis revealed a cut‐off value of 24.3° (area under the curve, 0.77), indicating that anterior mitral leaflet angle predicts residual
MR
. In multivariate regression analysis, smaller anteroposterior mitral annular diameter (
P
<0.001) and lower left ventricular ejection fraction (
P
=0.002) were significantly associated with higher anterior mitral leaflet angle, whereas left ventricular and left atrial dimension had no significant correlation.

Conclusions
Anterior mitral leaflet tethering in cases of posterior mitral leaflet prolapse has an adverse impact on early results following mitral valve repair. The findings of preoperative 3‐dimensional transesophageal echocardiography are important for consideration of a careful surgical strategy.
Trends in Prevalence and Control of Hypertension According to the 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline
Authors: Dorans Kirsten S. , Mills Katherine T. , Liu Yang , He Jiang 
Published: June 2018

Background
Hypertension is a major risk factor for cardiovascular disease and all‐cause mortality. Compared with prior guidelines, the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline recommends lower blood pressure thresholds for defining hypertension, for initiating antihypertensive medication, and for antihypertensive medication treatment goals.

Methods and Results

To better understand potential impacts of the 2017 guideline, we studied trends in mean systolic
blood pressure
and diastolic
blood pressure
, prevalence and burden of hypertension, and proportion of controlled hypertension in the US adult population aged ≥20 from 1999 through 2016. We used data from 38 276 adults from the National Health and Nutrition Examination Survey. Age‐standardized prevalence of hypertension decreased from 48.4% in 1999–2000 to 45.4% in 2015–2016. However, absolute burden of hypertension consistently increased, from 87.0 million in 1999–2000 to 108.2 million in 2015–2016. The age‐standardized proportion of controlled hypertension among adults receiving antihypertensive pharmacologic treatment increased from 1999–2000 (25.6%) to 2015–2016 (43.5%). There was not consistent improvement in control throughout the full period among non‐Hispanic blacks, individuals aged ≥60, or those with diabetes mellitus, chronic kidney disease, or high
cardiovascular disease
risk.

Conclusions
Based on the 2017 guideline, from 1999 to 2016, the age‐standardized prevalence of hypertension decreased and the proportion of control among those treated for hypertension improved. However, the absolute hypertension burden increased. Among those treated, the control rate did not consistently improve in all subgroups. These data emphasize the need for continuous efforts in the prevention and control of hypertension in the US general population.
Clinical Indicators of Admission for Pediatric Cochlear Implant Procedures
Authors: Patel Terral A. , Nguyen Shaun A. , White David R. 
Published: June 2018

Objectives: A minority of children undergoing cochlear implantation (CI) are admitted overnight postoperatively, but there are little data on prognostic indicators. Our goal is to review national data to identify variables associated with admission and identify effects on outcomes. Methods: We analyzed data from the 2012-2015 American College of Surgeons’ National Surgical Quality Improvement Program-Pediatric (ACS NSQIP-P) program use files. The CI patients were identified by CPT code. Demographics, comorbidities, anesthesia time, total operation time, 30-day complications, and 30-day readmission were compared between ambulatory and admitted patients. Results: A total of 2943 CI patients were included, with 17.2% of these admitted post implantation. Single variable analysis revealed multiple factors associated with admission post implantation. Multivariable analysis showed patients with asthma were 2.2 times ( P < .001; odds ratio [OR] = 1.484-3.227) and those with structural central nervous system (CNS) abnormalities 2.1 times ( P < .001; OR = 1.584-2.706) more likely to be admitted. Younger age ( P = .002; OR = 0.995-0.999) and longer operation time ( P < .001; OR = 1.003-1.006) were weak predictors. Two hundred sixteen patients lacked any factors but were still admitted. They had similar outcomes to ambulatory healthy patients. Conclusion: We identified factors associated with admission post-CI and higher readmission rates. Asthma and CNS abnormalities are strong predictors of admission post implantation. Forty-two percent of admitted patients lack any of these factors and have comparable outcomes to corresponding ambulatory patients.
Political Regime Types and Economic Development in Nigeria: Significance of Conflict and Corruption
Authors: Okunlola Olalekan Charles 
Published: June 2018

This article investigates the short- and long-run effects of political regimes (POLREGs) on economic development in Nigeria between 1984 and 2015. It looks at the effects of the conflict (CONFL) and corruption (COR) on economic development indicators and examines the interactive effect of POLREGs and COR as well as CONFL on economic development. COR and CONFL seem to be more prevalent in Nigeria during democracy relative to the periods under dictatorship. Using the Autoregressive Distributed Lag (ARDL) approach to cointegration, it derived a number of robust conclusions. Democracy in the long run yields higher economic development when it is devoid of CONFL and COR, while autocracy hinders economic development. In the short run however, more autocracy fosters economic development in Nigeria while democracy hinders it. COR portends grave threat to the development of Nigeria’s economy as it reduces development in the long run. Effect of CONFL on economic development in Nigeria is unclear. These findings highlight the need to establish effective anti-graft agencies to fight COR to the barest minimum in Nigeria. They also highlight the need to employ CONFL resolution mechanisms in resolving CONFL issues in the democratization process of the country. JEL: D74, K420, P160, O1, Q550
Patient safety in palliative care: A mixed-methods study of reports to a national database of serious incidents
Authors: Yardley Iain , Yardley Sarah , Williams Huw , Carson-Stevens Andrew , Donaldson Liam J 
Published: June 2018

Background: Patients receiving palliative care are vulnerable to patient safety incidents but little is known about the extent of harm caused or the origins of unsafe care in this population. Aim: To quantify and qualitatively analyse serious incident reports in order to understand the causes and impact of unsafe care in a population receiving palliative care. Design: A mixed-methods approach was used. Following quantification of type of incidents and their location, a qualitative analysis using a modified framework method was used to interpret themes in reports to examine the underlying causes and the nature of resultant harms. Setting and participants: Reports to a national database of ‘serious incidents requiring investigation’ involving patients receiving palliative care in the National Health Service (NHS) in England during the 12-year period, April 2002 to March 2014. Results: A total of 475 reports were identified: 266 related to pressure ulcers, 91 to medication errors, 46 to falls, 21 to healthcare-associated infections (HCAIs), 18 were other instances of disturbed dying, 14 were allegations against health professions, 8 transfer incidents, 6 suicides and 5 other concerns. The frequency of report types differed according to the care setting. Underlying causes included lack of palliative care experience, under-resourcing and poor service coordination. Resultant harms included worsened symptoms, disrupted dying, serious injury and hastened death. Conclusion: Unsafe care presents a risk of significant harm to patients receiving palliative care. Improvements in the coordination of care delivery alongside wider availability of specialist palliative care support may reduce this risk.
Leveraging Intelligent Compaction and Thermal Profiling Technologies to Improve Asphalt Pavement Construction Quality: A Case Study
Authors: Chang George K. , Mohanraj Kiran , Stone William A. , Oesch Daniel J. , Gallivan Victor (Lee) 
Published: June 2018

Intelligent compaction (IC) is an emerging technology with rollers equipped with global navigation satellite system (GNSS), an accelerometer-based measurement system, and an onboard color-coded display for real-time monitoring and compaction control. Paver-mounted thermal profiling (PMTP) is used to monitor asphalt surface temperatures behind a paver with a thermal scanner, and to track paver speeds, stops, and stop durations. Leveraging both IC and PMTP technologies allows for paving and compaction controls in real time, and for executing appropriate adjustments as needed. A case study is used to demonstrate the advantage of using both IC and PMTP over conventional operations. Postconstruction asphalt coring and tests, as well as pavement profile surveys were conducted to provide asphalt density data and pavement smoothness acceptance data for comparison and correlation analysis with IC and PMTP data. The data from 2 days of operations, one without the Material Transfer Vehicle (MTV) and another with the MTV, were analyzed and compared to illustrate the benefits of using IC, PMTP, and MTV for producing quality pavement products. Durability and smoothness are two key construction qualities for agencies and users of hot mix asphalt (HMA) pavements. These two factors also affect the long-term structural and functional pavement performance.