bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ventilation inhibits sympathetic action potential recruitment even during severe chemoreflex stress
Authors: Badrov Mark B. , Barak Otto F. , Mijacika Tanja , Shoemaker Leena N. , Borrell Lindsay J. , Lojpur Mihajlo , Drvis Ivan , Dujic Zeljko , Shoemaker J. Kevin 
Published: August 2017

This study investigated the influence of ventilation on sympathetic action potential (AP) discharge patterns during varying levels of high chemoreflex stress. In seven trained breath-hold divers (age 33 ± 12 yr), we measured muscle sympathetic nerve activity (MSNA) at baseline, during preparatory rebreathing (RBR), and during 1) functional residual capacity apnea (FRCApnea) and 2) continued RBR. Data from RBR were analyzed at matched (i.e., to FRCApnea) hemoglobin saturation (HbSat) levels (RBRMatched) or more severe levels (RBREnd). A third protocol compared alternating periods (30 s) of FRC and RBR (FRC-RBRALT). Subjects continued each protocol until 85% volitional tolerance. AP patterns in MSNA (i.e., providing the true neural content of each sympathetic burst) were studied using wavelet-based methodology. First, for similar levels of chemoreflex stress (both HbSat: 71 ± 6%; P = NS), RBRMatched was associated with reduced AP frequency and APs per burst compared with FRCApnea (both P < 0.001). When APs were binned according to peak-to-peak amplitude (i.e., into clusters), total AP clusters increased during FRCApnea (+10 ± 2; P < 0.001) but not during RBRMatched (+1 ± 2; P = NS). Second, despite more severe chemoreflex stress during RBREnd (HbSat: 56 ± 13 vs. 71 ± 6%; P < 0.001), RBREnd was associated with a restrained increase in the APs per burst (FRCApnea: +18 ± 7; RBREnd: +11 ± 5) and total AP clusters (FRCApnea: +10 ± 2; RBREnd: +6 ± 4) (both P < 0.01). During FRC-RBRALT, all periods of FRC elicited sympathetic AP recruitment (all P < 0.001), whereas all periods of RBR were associated with complete withdrawal of AP recruitment (all P = NS). Presently, we demonstrate that ventilation per se restrains and/or inhibits sympathetic axonal recruitment during high, and even extreme, chemoreflex stress. NEW & NOTEWORTHY The current study demonstrates that the sympathetic neural recruitment patterns observed during chemoreflex activation induced by rebreathing or apnea are restrained and/or inhibited by the act of ventilation per se, despite similar, or even greater, levels of severe chemoreflex stress. Therefore, ventilation modulates not only the timing of sympathetic bursts but also the within-burst axonal recruitment normally observed during progressive chemoreflex stress.
Parkinsonism and vigilance: alteration in neural oscillatory activity and phase-amplitude coupling in the basal ganglia and motor cortex
Authors: Escobar Sanabria David , Johnson Luke A. , Nebeck Shane D. , Zhang Jianyu , Johnson Matthew D. , Baker Kenneth B. , Molnar Gregory F. , Vitek Jerrold L. 
Published: August 2017

Oscillatory neural activity in different frequency bands and phase-amplitude coupling (PAC) are hypothesized to be biomarkers of Parkinson’s disease (PD) that could explain dysfunction in the motor circuit and be used for closed-loop deep brain stimulation (DBS). How these putative biomarkers change from the normal to the parkinsonian state across nodes in the motor circuit and within the same subject, however, remains unknown. In this study, we characterized how parkinsonism and vigilance altered oscillatory activity and PAC within the primary motor cortex (M1), subthalamic nucleus (STN), and globus pallidus (GP) in two nonhuman primates. Static and dynamic analyses of local field potential (LFP) recordings indicate that 1) after induction of parkinsonism using the neurotoxin MPTP, low-frequency power (8–30 Hz) increased in the STN and GP in both subjects, but increased in M1 in only one subject; 2) high-frequency power (~330 Hz) was present in the STN in both normal subjects but absent in the parkinsonian condition; 3) elevated PAC measurements emerged in the parkinsonian condition in both animals, but in different sites in each animal (M1 in one subject and GPe in the other); and 4) the state of vigilance significantly impacted how oscillatory activity and PAC were expressed in the motor circuit. These results support the hypothesis that changes in low- and high-frequency oscillatory activity and PAC are features of parkinsonian pathophysiology and provide evidence that closed-loop DBS systems based on these biomarkers may require subject-specific configurations as well as adaptation to changes in vigilance. NEW & NOTEWORTHY Chronically implanted electrodes were used to record neural activity across multiple nodes in the basal ganglia-thalamocortical circuit simultaneously in a nonhuman primate model of Parkinson’s disease, enabling within-subject comparisons of electrophysiological biomarkers between normal and parkinsonian conditions and different vigilance states. This study improves our understanding of the role of oscillatory activity and phase-amplitude coupling in the pathophysiology of Parkinson’s disease and supports the development of more effective DBS therapies based on pathophysiological biomarkers.
Rapid visuomotor feedback gains are tuned to the task dynamics
Authors: Franklin Sae , Wolpert Daniel M. , Franklin David W. 
Published: August 2017

Adaptation to novel dynamics requires learning a motor memory, or a new pattern of predictive feedforward motor commands. Recently, we demonstrated the upregulation of rapid visuomotor feedback gains early in curl force field learning, which decrease once a predictive motor memory is learned. However, even after learning is complete, these feedback gains are higher than those observed in the null field trials. Interestingly, these upregulated feedback gains in the curl field were not observed in a constant force field. Therefore, we suggest that adaptation also involves selectively tuning the feedback sensitivity of the sensorimotor control system to the environment. Here, we test this hypothesis by measuring the rapid visuomotor feedback gains after subjects adapt to a variety of novel dynamics generated by a robotic manipulandum in three experiments. To probe the feedback gains, we measured the magnitude of the motor response to rapid shifts in the visual location of the hand during reaching. While the feedback gain magnitude remained similar over a larger than a fourfold increase in constant background load, the feedback gains scaled with increasing lateral resistance and increasing instability. The third experiment demonstrated that the feedback gains could also be independently tuned to perturbations to the left and right, depending on the lateral resistance, demonstrating the fractionation of feedback gains to environmental dynamics. Our results show that the sensorimotor control system regulates the gain of the feedback system as part of the adaptation process to novel dynamics, appropriately tuning them to the environment. NEW & NOTEWORTHY Here, we test whether rapid visuomotor feedback responses are selectively tuned to the task dynamics. The responses do not exhibit gain scaling, but they do vary with the level and stability of task dynamics. Moreover, these feedback gains are independently tuned to perturbations to the left and right, depending on these dynamics. Our results demonstrate that the sensorimotor control system regulates the feedback gain as part of the adaptation process, tuning them appropriately to the environment.
Vasectomy and Risk of Prostate Cancer in a Screening Trial
Authors: Shoag Jonathan , Savenkov Oleksander , Christos Paul J. , Mittal Sameer , Halpern Joshua A. , Askin Gulce , Shoag Daniel , Golan Ron , Lee Daniel J. , O'Malley Padraic , Najari Bobby , Eisner Brian , Hu Jim C. , Scherr Douglas , Schlegel Peter , Barbieri Christopher E. 
Published: August 2017

Abstract
Background: Vasectomy has been implicated as a risk factor for prostate cancer in multiple epidemiologic studies over the past 25 years. Whether this relationship is causal remains unclear. This study examines the association between vasectomy and prostate cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which randomized men to usual care or annual prostate cancer screening.
Methods: We performed a retrospective analysis of 13-year screening and outcomes data from the PLCO trial. Multivariable Cox proportional hazards regression stratified by study arm and age at vasectomy was performed.
Results: There was an increased risk of prostate cancer in men who had undergone a vasectomy and were randomized to the usual care arm of the study (adjusted HR, 1.11; 95% confidence interval, 1.03–1.20; P = 0.008). There was no association between vasectomy and diagnosis of prostate cancer in men randomized to the prostate cancer screening arm. Only men undergoing vasectomy at an older age in the usual care arm of the study, but not the prostate cancer screening arm, were at increased risk of being diagnosed with prostate cancer.
Conclusions: Vasectomy was not associated with prostate cancer risk among men who were screened for prostate cancer as part of a clinical trial, but was associated with prostate cancer detection in men receiving usual care.
Impact: The positive association between vasectomy and prostate cancer is likely related to increased detection of prostate cancer based on patterns of care rather than a biological effect of vasectomy on prostate cancer development. Cancer Epidemiol Biomarkers Prev; 26(11); 1653–9. ©2017 AACR.
Relationships between Circulating and Intraprostatic Sex Steroid Hormone Concentrations
Authors: Cook Michael B. , Stanczyk Frank Z. , Wood Shannon N. , Pfeiffer Ruth M. , Hafi Muhannad , Veneroso Carmela C. , Lynch Barlow , Falk Roni T. , Zhou Cindy Ke , Niwa Shelley , Emanuel Eric , Gao Yu-Tang , Hemstreet George P. , Zolfghari Ladan , Carroll Peter R. , Manyak Michael J. , Sesterhann Isabell A. , Levine Paul H. , Hsing Ann W. 
Published: August 2017

Abstract
Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases.
Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers.
Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age.
Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu.
Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660–6. ©2017 AACR.
Cell-Free Circulating DNA Integrity Based on Peripheral Blood as a Biomarker for Diagnosis of Cancer: A Systematic Review
Authors: Cheng Jie , Tang Qiuqiong , Cao Xue , Burwinkel Barbara 
Published: August 2017

Abstract
Background: Cell-free DNA integrity (cfDI) has been identified as a potential diagnostic biomarker for different types of cancer, suggesting the importance of liquid biopsy.
Methods: This systematic review aims to assess the diagnostic performance of cfDI in cancer. After an extensive search of literature published through February 28, 2017, 25 articles that included 40 studies were identified. The descriptions of all the studies were analyzed. The sensitivity, specificity, positive and negative likelihood ratios, diagnostic ORs, weighted symmetric summary receiver operating characteristic curve, and the area under the curve (AUC) of cfDI in these studies were calculated.
Results: Aberrant results of cfDI were observed. Some studies observed an increased cfDI in cancer patients, while some studies confirmed a decreased cfDI compared with healthy or benign controls.
Conclusions: This review suggests that cfDI is controversial as a blood-based biomarker of cancers, although the sensitivity and AUC were relatively high.
Impact: cfDI shows heterogeneity between different studies; more perspective studies are needed to further assess its diagnostic performance, especially with other markers in combination. Cancer Epidemiol Biomarkers Prev; 26(11); 1595–602. ©2017 AACR.
Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma Indicate the Potential for CDK4/6 Inhibitors in Targeted Therapy
Authors: Kong Yan , Sheng Xinan , Wu Xiaowen , Yan Junya , Ma Meng , Yu Jiayi , Si Lu , Chi Zhihong , Cui Chuanliang , Dai Jie , Li Yiqian , Yu Huan , Xu Tianxiao , Tang Huan , Tang Bixia , Mao Lili , Lian Bin , Wang Xuan , Yan Xieqiao , Li Siming , Guo Jun 
Published: August 2017

AbstractPurpose: Effective therapies for the majority of metastatic acral melanoma patients have not been established. Thus, we investigated genetic aberrations of CDK4 pathway in acral melanoma and evaluated the efficacy of CDK4/6 inhibitors in targeted therapy of acral melanoma.Experimental Design: A total of 514 primary acral melanoma samples were examined for the copy number variations (CNV) of CDK4 pathway-related genes, including Cdk4, Ccnd1, and P16INK4a, by QuantiGenePlex DNA Assay. The sensitivity of established acral melanoma cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated.Results: Among the 514 samples, 203 cases, 137 cases, and 310 cases, respectively, showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%), and P16INK4a loss (60.3%). The overall frequency of acral melanomas that contain at least one aberration in Cdk4, Ccnd1, and P16INK4a was 82.7%. The median overall survival time for acral melanoma patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations (P = 0.005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of acral melanoma cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss, and Ccnd1 gain plus P16INK4a loss.Conclusions: Genetic aberration of CDK4 pathway is a frequent event in acral melanoma. Acral melanoma cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in acral melanoma patients. Clin Cancer Res; 23(22); 6946–57. ©2017 AACR.
HPMA–Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer
Authors: Zimel Melissa N. , Horowitz Chloe B. , Rajasekhar Vinagolu K. , Christ Alexander B. , Wei Xin , Wu Jianbo , Wojnarowicz Paulina M. , Wang Dong , Goldring Steven R. , Purdue P. Edward , Healey John H. 
Published: August 2017

AbstractPolymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development. Mol Cancer Ther; 16(12); 2701–10. ©2017 AACR.
Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance
Authors: Emdal Kristina B. , Dittmann Antje , Reddy Raven J. , Lescarbeau Rebecca S. , Moores Sheri L. , Laquerre Sylvie , White Forest M. 
Published: August 2017

Abstract
Approximately 10% of non–small cell lung cancer (NSCLC) patients in the United States and 40% of NSCLC patients in Asia have activating epidermal growth factor receptor (EGFR) mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be cotargeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival. Mass spectrometry–based quantitative proteomics was used to profile in vivo signaling changes in 41 therapy-resistant tumors from four xenograft NSCLC models. We identified unique and tumor-specific tyrosine phosphorylation rewiring in tumors resistant to treatment with the irreversible third-generation EGFR-inhibitor, osimertinib, or the novel dual-targeting EGFR/Met antibody, JNJ-61186372. Tumor-specific increases in tyrosine-phosphorylated peptides from EGFR family members, Shc1 and Gab1 or Src family kinase (SFK) substrates were observed, underscoring a differential ability of tumors to uniquely escape EGFR inhibition. Although most resistant tumors within each treatment group displayed a marked inhibition of EGFR as well as SFK signaling, the combination of EGFR inhibition (osimertinib) and SFK inhibition (saracatinib or dasatinib) led to further decrease in cell growth in vitro. This result suggests that residual SFK signaling mediates therapeutic resistance and that elimination of this signal through combination therapy may delay onset of resistance. Overall, analysis of individual resistant tumors captured unique in vivo signaling rewiring that would have been masked by analysis of in vitro cell population averages. Mol Cancer Ther; 16(11); 2572–85. ©2017 AACR.
Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts
Authors: Saber Hamidreza , Yakoob Mohammad Yawar , Shi Peilin , Longstreth W.T. , Lemaitre Rozenn N. , Siscovick David , Rexrode Kathryn M. , Willett Walter C. , Mozaffarian Dariush 
Published: August 2017

Background and Purpose—
The associations of individual long-chain n-3 polyunsaturated fatty acids with incident ischemic stroke and its main subtypes are not well established. We aimed to investigate prospectively the relationship of circulating eicosapentaenoic acid, docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke.

Methods—
We measured circulating phospholipid fatty acids at baseline in 3 separate US cohorts: CHS (Cardiovascular Health Study), NHS (Nurses’ Health Study), and HPFS (Health Professionals Follow-Up Study). Ischemic strokes were prospectively adjudicated and classified into atherothrombotic (large- and small-vessel infarctions) or cardioembolic by imaging studies and medical records. Risk according to fatty acid levels was assessed using Cox proportional hazards (CHS) or conditional logistic regression (NHS, HPFS) according to study design. Cohort findings were pooled using fixed-effects meta-analysis.

Results—
A total of 953 incident ischemic strokes were identified (408 atherothrombotic, 256 cardioembolic, and 289 undetermined subtypes) during median follow-up of 11.2 years (CHS) and 8.3 years (pooled, NHS and HPFS). After multivariable adjustment, lower risk of total ischemic stroke was seen with higher DPA (highest versus lowest quartiles; pooled hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.58–0.92) and DHA (HR, 0.80; 95% CI, 0.64–1.00) but not eicosapentaenoic acid (HR, 0.94; 95% CI, 0.77–1.19). DHA was associated with lower risk of atherothrombotic stroke (HR, 0.53; 95% CI, 0.34–0.83) and DPA with lower risk of cardioembolic stroke (HR, 0.58; 95% CI, 0.37–0.92). Findings in each individual cohort were consistent with pooled results.

Conclusions—
In 3 large US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke and DPA with cardioembolic stroke. These novel findings suggest differential pathways of benefit for DHA, DPA, and eicosapentaenoic acid.
Transport Infrastructure and the Decentralization of Cities in the People's Republic of China
Authors: Baum-Snow Nathaniel , Turner Matthew A. 
Published: August 2017

It is widely believed that transport infrastructure has important impacts on the development of cities. Until recently, however, there has been little systematic evidence with which to evaluate claims about the effects of transport infrastructure on the development of cities and regions. In this paper, we describe the evolution of transport infrastructure in the People's Republic of China and how it relates to the evolution of location patterns of population and production in Chinese cities and their surrounding regions. We summarize empirical evidence from Baum-Snow et al. ( 2017 ) on the causal effects of various types of transport infrastructure on the decentralization of cities in the People's Republic of China. Finally, we put our results in the context of the existing literature on the effects of infrastructure on productivity and the allocation of resources across locations.