bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuromuscular changes of the aged human hamstrings
Authors: Kirk Eric A. , Gilmore Kevin J. , Rice Charles L. 
Published: April 2018

Despite the life-long importance for posture and locomotion, neuromuscular properties of the hamstrings muscle have not been explored with adult aging. The purpose of this study was to assess and compare age-related effects on contractile function, spinal motor neuron output expressed as motor unit (MU) discharge rates in the hamstrings of 11 young (26 ± 4 yr) and 10 old (80 ± 5 yr) men. Maximal voluntary isometric contractions (MVC), stimulated contractile properties, and surface and intramuscular electromyography (EMG) from submaximal to MVC were recorded in the biceps femoris (BF) and semimembranosus-semitendinosus (SS) muscles. MVC torque was ~50% less in the old with both age groups attaining ≥93% mean voluntary activation. Evoked twitches in the old were ~50% lower in amplitude and >150% longer in duration compared with those in the young. At successive voluntary contractions of 25, 50, and 100% MVC, MU discharge rates were up to 45% lower in old, with no differences in relative submaximal surface EMG between age groups. Furthermore, the old had significantly lower MU discharge rates in the SS at all contraction intensities compared with the BF muscle. Men in their 8th to 10th decades of life demonstrate substantially lower strength and MU discharge rates in this functionally important large lower limb muscle group, with greater age-related effect on discharge rates in the medial hamstrings. These findings, compared with those in other muscles studied, highlight that the neuromuscular properties of limb muscles, and indeed within functionally similar portions of a muscle group, are not all affected equally by the aging process. NEW & NOTEWORTHY In the hamstrings, we found that both contractile function and motor unit discharge rates across the range of voluntary intensities were lower in the old. The differences in discharge rates due to age were greater in the medial hamstrings muscle group compared with the lateral hamstrings. Compared with previous studies, these results highlight that not all muscles are affected equally by aging and there may be compartmental differences within functionally similar muscles.
Predictability, force, and (anti)resonance in complex object control
Authors: Maurice Pauline , Hogan Neville , Sternad Dagmar 
Published: April 2018

Manipulation of complex objects as in tool use is ubiquitous and has given humans an evolutionary advantage. This study examined the strategies humans choose when manipulating an object with underactuated internal dynamics, such as a cup of coffee. The dynamics of the object renders the temporal evolution complex, possibly even chaotic, and difficult to predict. A cart-and-pendulum model, loosely mimicking coffee sloshing in a cup, was implemented in a virtual environment with a haptic interface. Participants rhythmically manipulated the virtual cup containing a rolling ball; they could choose the oscillation frequency, whereas the amplitude was prescribed. Three hypotheses were tested: 1) humans decrease interaction forces between hand and object; 2) humans increase the predictability of the object dynamics; and 3) humans exploit the resonances of the coupled object-hand system. Analysis revealed that humans chose either a high-frequency strategy with antiphase cup-and-ball movements or a low-frequency strategy with in-phase cup-and-ball movements. Counter to hypothesis 1, they did not decrease interaction force; instead, they increased the predictability of the interaction dynamics, quantified by mutual information, supporting hypothesis 2. To address hypothesis 3, frequency analysis of the coupled hand-object system revealed two resonance frequencies separated by an antiresonance frequency. The low-frequency strategy exploited one resonance, whereas the high-frequency strategy afforded more choice, consistent with the frequency response of the coupled system; both strategies avoided the antiresonance. Hence, humans did not prioritize small interaction forces but rather strategies that rendered interactions predictable. These findings highlight that physical interactions with complex objects pose control challenges not present in unconstrained movements. NEW & NOTEWORTHY Daily actions involve manipulation of complex nonrigid objects, which present a challenge since humans have no direct control of the whole object. We used a virtual-reality experiment and simulations of a cart-and-pendulum system coupled to hand movements with impedance to analyze the manipulation of this underactuated object. We showed that participants developed strategies that increased the predictability of the object behavior by exploiting the resonance structure of the object but did not minimize the hand-object interaction force.
YAP/TAZ Initiates Gastric Tumorigenesis via Upregulation of MYC
Authors: Choi Wonyoung , Kim Jeongsik , Park Jaeoh , Lee Da-Hye , Hwang Daehee , Kim Jeong-Hwan , Ashktorab Hassan , Smoot Duane , Kim Seon-Young , Choi Chan , Koh Gou Young , Lim Dae-Sik 
Published: April 2018

Abstract
YAP and TAZ play oncogenic roles in various organs, but the role of YAP/TAZ in gastric cancer remains unclear. Here, we show that YAP/TAZ activation initiates gastric tumorigenesis in vivo and verify its significance in human gastric cancer. In mice, YAP/TAZ activation in the pyloric stem cell led to step-wise tumorigenesis. RNA sequencing identified MYC as a decisive target of YAP, which controls MYC at transcriptional and posttranscriptional levels. These mechanisms tightly regulated MYC in homeostatic conditions, but YAP activation altered this balance by impeding miRNA processing, causing a shift towards MYC upregulation. Pharmacologic inhibition of MYC suppressed YAP-dependent phenotypes in vitro and in vivo, verifying its functional role as a key mediator. Human gastric cancer samples also displayed a significant correlation between YAP and MYC. We reanalyzed human transcriptome data to verify enrichment of YAP signatures in a subpopulation of gastric cancers and found that our model closely reflected the molecular pattern of patients with high YAP activity. Overall, these results provide genetic evidence of YAP/TAZ as oncogenic initiators and drivers for gastric tumors with MYC as the key downstream mediator. These findings are also evident in human gastric cancer, emphasizing the significance of YAP/TAZ signaling in gastric carcinogenesis.
Significance: YAP/TAZ activation initiates gastric carcinogenesis with MYC as the key downstream mediator. Cancer Res; 78(12); 3306–20. ©2018 AACR.
Geographic Differences in Baseline Prostate Inflammation and Relationship with Subsequent Prostate Cancer Risk: Results from the Multinational REDUCE Trial
Authors: Allott Emma H. , Markt Sarah C. , Howard Lauren E. , Vidal Adriana C. , Moreira Daniel M. , Castro-Santamaria Ramiro , Andriole Gerald L. , Mucci Lorelei A. , Freedland Stephen J. 
Published: April 2018

Abstract
Background: Prostate cancer incidence rates vary 25-fold worldwide. Differences in PSA screening are largely, but not entirely, responsible. We examined geographic differences in prevalence of histologic prostate inflammation and subsequent prostate cancer risk.
Methods: Seven thousand nonHispanic white men were enrolled in the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial from Europe (n = 4,644), North America (n = 1,746), South America (n = 466), and Australia/New Zealand (n = 144). Histologic inflammation in baseline negative prostate biopsies was classified as chronic (lymphocytes/macrophages) or acute (neutrophils). Multivariable logistic regression was used to examine associations between region and prostate inflammation, and between region and prostate cancer risk at 2-year biopsy.
Results: Prevalence of prostate inflammation varied across region, with broadly similar patterns for acute and chronic inflammation. Relative to Europe, prevalence of acute inflammation was higher in North America [odds ratio (OR), 1.77; 95% confidence interval (CI), 1.51–2.08] and Australia/New Zealand (OR, 2.07; 95% CI, 1.40–3.06). Men from these regions had lower prostate cancer risk than Europeans at biopsy. Among North Americans, prevalence of acute inflammation was higher in Canada versus the United States (OR, 1.40; 95% CI, 1.07–1.83), but prostate cancer risk did not differ between these regions. Among Europeans, prevalence of acute inflammation was lower in Northern and Eastern (OR, 0.79; 95% CI, 0.65–0.97 and OR 0.62; 95% CI, 0.45–0.87, respectively), relative to Western Europe, and these men had higher prostate cancer risk at biopsy.
Conclusions: Prevalence of histologic prostate inflammation varied by region. Geographic differences in prostate inflammation tracked inversely with geographic differences in prostate cancer risk.
Impact: Characterization of premalignant prostate biology and the relationship with subsequent prostate cancer risk could inform prostate cancer prevention efforts. Cancer Epidemiol Biomarkers Prev; 27(7); 783–9. ©2018 AACR.
Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP
Authors: Piggott Luke , Silva Andreia , Robinson Timothy , Santiago-Gómez Angelica , Simões Bruno M. , Becker Michael , Fichtner Iduna , Andera Ladislav , Young Philippa , Morris Christine , Barrett-Lee Peter , Alchami Fouad , Piva Marco , Vivanco Maria dM. , Clarke Robert B. , Gee Julia , Clarkson Richard 
Published: April 2018

AbstractPurpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumors.Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo. In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential. Clin Cancer Res; 24(10); 2452–63. ©2018 AACR.
Alkaline Phosphatase and Outcomes in Patients With Preserved Renal Function
Authors: Zong Lixia , Wang Xianwei , Li Zixiao , Zhao Xingquan , Liu Liping , Li Hao , Meng Xia , Wang Yilong , Wang Yongjun 
Published: April 2018

Background and Purpose—
Alkaline phosphatase (ALP) is associated with risk of adverse cardiovascular events in patients with kidney failure. However, there is little data about effects of ALP on stroke outcomes in patients with preserved kidney function. The study aimed to explore the association between serum ALP level and clinical outcomes after stroke in patients with preserved kidney function.

Methods—
We included 16 367 stroke patients with preserved kidney function from the China National Stroke Registry for current analysis. Serum ALP levels were tested by automated enzymatic method using unfrozen samples in each center. Participants were divided into 5 groups according to ALP quintiles. Composite end point comprised of recurrent stroke, myocardial infarction, other ischemic vascular events, and all-cause mortality. Poor functional outcome is defined as modified Rankin Scale score of 3 to 6. Multivariable logistic regression was used to evaluate the independent association of serum ALP with 1-year all-cause mortality, recurrent stroke, composite end point, and poor functional outcome.

Results—

The mean age of the included 16 367 patients was 63.9 years, and 63.3% of them were men. Among the top ALP quintile (>98.0 U/L), 1-year incidences of all-cause mortality, recurrent stroke, composite end point, and poor functional outcome were 12.6%, 5.7%, 14.4%, and 27.0%, respectively. Compared with the lowest ALP quintile (≤59.0 U/L), the adjusted odds ratios of the top quintile were 1.36 (1.10–1.68) for all-cause mortality, 1.45 (1.11–1.90) for stroke recurrence, 1.35 (1.12–1.63) for composite end point, and 1.36 (1.17–1.60) for poor functional outcome. There was no significant interaction between age, sex, or alcohol consumption and ALP (
P
for interaction ≥0.10) for all outcomes.

Conclusions—
In patients with preserved kidney function, ALP may be an independent predictor of all-cause mortality, stroke recurrence, composite end point, and poor functional outcome after stroke.
CO2 Transport, Variability, and Budget over the Southern California Air Basin Using the High-Resolution WRF-VPRM Model during the CalNex 2010 Campaign
Authors: Park Changhyoun , Gerbig Christoph , Newman Sally , Ahmadov Ravan , Feng Sha , Gurney Kevin R. , Carmichael Gregory R , Park Soon-Young , Lee Hwa-Woon , Goulden Mike , Stutz Jochen , Peischl Jeff , Ryerson Tom 
Published: April 2018

AbstractTo study regional-scale carbon dioxide (CO2) transport, temporal variability, and budget over the Southern California Air Basin (SoCAB) during the California Research at the Nexus of Air Quality and Climate Change (CalNex) 2010 campaign period, a model that couples the Weather Research and Forecasting (WRF) Model with the Vegetation Photosynthesis and Respiration Model (VPRM) has been used. Our numerical simulations use anthropogenic CO2 emissions of the Hestia Project 2010 fossil-fuel CO2 emissions data products along with optimized VPRM parameters at “FLUXNET” sites, for biospheric CO2 fluxes over SoCAB. The simulated meteorological conditions have been validated with ground and aircraft observations, as well as with background CO2 concentrations from the coastal Palos Verdes site. The model captures the temporal pattern of CO2 concentrations at the ground site at the California Institute of Technology in Pasadena, but it overestimates the magnitude in early daytime. Analysis of CO2 by wind directions reveals the overestimate is due to advection from the south and southwest, where downtown Los Angeles is located. The model also captures the vertical profile of CO2 concentrations along with the flight tracks. The optimized VPRM parameters have significantly improved simulated net ecosystem exchange at each vegetation-class site and thus the regional CO2 budget. The total biospheric contribution ranges approximately from −24% to −20% (daytime) of the total anthropogenic CO2 emissions during the study period.
Is use of homeopathy associated with poor prescribing in English primary care? A cross-sectional study
Authors: Walker Alex J , Croker Richard , Bacon Seb , Ernst Edzard , Curtis Helen J , Goldacre Ben 
Published: April 2018

Objectives Prescribing of homeopathy still occurs in a small minority of English general practices. We hypothesised that practices that prescribe any homeopathic preparations might differ in their prescribing of other drugs. Design Cross-sectional analysis. Setting English primary care. Participants English general practices. Main outcome measures We identified practices that made any homeopathy prescriptions over six months of data. We measured associations with four prescribing and two practice quality indicators using multivariable logistic regression. Results Only 8.5% of practices (644) prescribed homeopathy between December 2016 and May 2017. Practices in the worst-scoring quartile for a composite measure of prescribing quality (>51.4 mean percentile) were 2.1 times more likely to prescribe homeopathy than those in the best category (<40.3) (95% confidence interval: 1.6–2.8). Aggregate savings from the subset of these measures where a cost saving could be calculated were also strongly associated (highest vs. lowest quartile multivariable odds ratio: 2.9, confidence interval: 2.1–4.1). Of practices spending the most on medicines identified as ‘low value’ by NHS England, 12.8% prescribed homeopathy, compared to 3.9% for lowest spenders (multivariable odds ratio: 2.6, confidence interval: 1.9–3.6). Of practices in the worst category for aggregated price-per-unit cost savings, 12.7% prescribed homeopathy, compared to 3.5% in the best category (multivariable odds ratio: 2.7, confidence interval: 1.9–3.9). Practice quality outcomes framework scores and patient recommendation rates were not associated with prescribing homeopathy (odds ratio range: 0.9–1.2). Conclusions Even infrequent homeopathy prescribing is strongly associated with poor performance on a range of prescribing quality measures, but not with overall patient recommendation or quality outcomes framework score. The association is unlikely to be a direct causal relationship, but may reflect underlying practice features, such as the extent of respect for evidence-based practice, or poorer stewardship of the prescribing budget.
How family caregivers help older relatives navigate statutory services at the end of life: A descriptive qualitative study
Authors: Williams Lisa Ann , Moeke-Maxwell Tess , Wiles Janine , Black Stella , Trussardi Gabriella , Kerse Ngaire , Gott Merryn 
Published: April 2018

Background: A key challenge in meeting the palliative care needs of people in advanced age is the multiple healthcare and social service agencies typically involved in their care. The ‘patient navigator’ model, originally developed in cancer care, is the professional solution most often recommended to address this challenge. However, little attention has been paid, or is known, about the role that family carers play in enabling their dying relatives to negotiate service gaps. Aim: To explore the role family caregivers play in helping people dying in advanced old age navigate health services at the end of life. Design: Qualitative study using semi-structured interviews and analysed via thematic analysis. Setting/participants: A total of 58 interviews were conducted in New Zealand with the family caregivers of 52 deceased older relatives who had been participants in Life and Living in Advanced Age: a Cohort Study in New Zealand. Results: Fragmentation of services was the key concern, causing distress both for the older person and their family caregivers. Carers identified and engaged with appropriate services in order to facilitate care and treatment. Their involvement was not always met by healthcare professionals with respect or regard to their knowledge of the older person’s needs. Conclusion: Family caregivers are trying to help their older relatives overcome the limitations of fragmented health systems at the end of life. They are doing so at times by stepping in to perform patient navigator tasks usually conceptualised as a role for statutory services to carry out. Programmes and services need to be implemented that will better support family carers who are acting as care navigators.
Blood neutrophil-to-lymphocyte ratio is associated with prognosis in advanced gastrointestinal stromal tumors treated with imatinib
Authors: Rutkowski Piotr , Teterycz Paweł , Klimczak Anna , Bylina Elżbieta , Szamotulska Katarzyna , Lugowska Iwona 
Published: April 2018

Introduction: Neutrophil-to-lymphocyte ratio (NLR) was shown to be prognostic in several solid malignancies. There are limited data about predictive/prognostic value of NLR during targeted therapy of patients with advanced gastrointestinal stromal tumors (GIST). The aim of this study was to asses a clinical value of this ratio in patients with advanced GIST. Methods: Between 2001 and 2016, 385 patients with metastatic/unresectable GIST treated initially with imatinib were included in the analysis. In all patients, the NLR was assessed at the baseline, after 3 months of treatment, and upon disease progression (or last observation). The cutoff values for NLR were set at 2.7 and 5.4. Kaplan-Meier survival probability estimation with log-rank test and Cox proportional hazards model were used for analysis. Results: Median progression-free survival (PFS) on imatinib treatment was 44.8 months, 5-year rate 43%; median overall survival (OS) 87.2 months, 10-year rate 36.3%. NLR >2.7 at baseline was significantly associated with poorer OS and PFS: median OS was 89.3 months (95% confidence interval [CI] 80.2-115) for NLR ratio ≤2.7 vs 59.4 months (95% CI 48.6-82) for NLR >2.7 ( p < .001); median PFS was 59.4 vs 32.7 ( p < .001), respectively. In multivariate model adjusted for mitotic index and driver mutation in the tumor ( KIT exon 11 mutation versus other), NLR ratio was proven to be statistically significant (hazard ratio 1.09; 95% CI 1.01-1.19; p = .030). Among patients with disease progression, NLR >2.7 assessed at the third month of treatment was linked with significantly shorter median time to progression (7.5 vs 19 months). Conclusions: Our results demonstrate the usefulness of NLR as a prognostic and predictive marker as well as a marker for treatment monitoring in patients with advanced GIST treated with imatinib.
223Ra-chloride therapy in men with hormone-refractory prostate cancer and skeletal metastases: Real-world experience
Authors: Boni Giuseppe , Mazzarri Sara , Cianci Claudia , Galli Luca , Farnesi Azzurra , Borsatti Eugenio , Bortolus Roberto , Fratino Lucia , Gobitti Carlo , Lamaj Elda , Ghedini Pietro , Rizzini Elisa Lodi , Massari Francesco , Dionisi Valeria , Fanti Stefano , Volterrani Duccio , Monari Fabio 
Published: April 2018

Background: Radium-223 (223Ra) chloride, an alpha emitter, has been shown to improve overall survival (OS) and pain control, and to delay skeletal-related events, in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Our retrospective observational study presents the first Italian experience on the efficacy and safety of 223Ra therapy in routine clinical practice. Methods: A total of 83 patients with metastatic CRPC were treated with 223Ra at 3 Italian centers between August 2013 and August 2016. 223Ra-chloride (55 kBq/kg) was administered every 4 weeks for a total of 6 cycles. Primary endpoints were OS and progression-free survival (PFS). Secondary endpoints included toxicity, pain evaluation using numeric rating scale (NRS), symptomatic skeletal-related events and biomarkers response. Results: Patients had a median age of 75 (range 53–89) years. The majority of men showed a Gleason score of 7, 8, or 9. Forty-one patients completed 6 treatment cycles; 33 stopped treatment before completing 6 cycles. Nine were still receiving therapy at the time of data collection. At the end of therapy, NRS pain scores significantly improved ( p < .000001). OS was a mean of 10.1 months, while median OS had not been attained. According to Kaplan-Meier estimation, OS and PFS were 17.5 and 7.7 months, respectively. There was a significant correlation between OS and PFS with the number of 223Ra cycles; patients receiving all 6 cycles experienced the major benefit from the therapy. 223Ra was well-tolerated. Conclusions: 223Ra alpha therapy is an important therapeutic option for men with CRPC and symptomatic skeletal metastases.