bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Hepatitis C Virus Genome Replication by Xrn1 and MicroRNA-122 Binding to Individual Sites in the 5′ Untranslated Region
Authors: Thibault Patricia A. , Huys Adam , Amador-Cañizares Yalena , Gailius Julie E. , Pinel Dayna E. , Wilson Joyce A. 
Published: April 2015

ABSTRACT
miR-122 is a liver-specific microRNA (miRNA) that binds to two sites (S1 and S2) on the 5′ untranslated region (UTR) of the hepatitis C virus (HCV) genome and promotes the viral life cycle. It positively affects viral RNA stability, translation, and replication, but the mechanism is not well understood. To unravel the roles of miR-122 binding at each site alone or in combination, we employed miR-122 binding site mutant viral RNAs, Hep3B cells (which lack detectable miR-122), and complementation with wild-type miR-122, an miR-122 with the matching mutation, or both. We found that miR-122 binding at either site alone increased replication equally, while binding at both sites had a cooperative effect. Xrn1 depletion rescued miR-122-unbound full-length RNA replication to detectable levels but not to miR-122-bound levels, confirming that miR-122 protects HCV RNA from Xrn1, a cytoplasmic 5′-to-3′ exoribonuclease, but also has additional functions. In cells depleted of Xrn1, replication levels of S1-bound HCV RNA were slightly higher than S2-bound RNA levels, suggesting that both sites contribute, but their contributions may be unequal when the need for protection from Xrn1 is reduced. miR-122 binding at S1 or S2 also increased translation equally, but the effect was abolished by Xrn1 knockdown, suggesting that the influence of miR-122 on HCV translation reflects protection from Xrn1 degradation. Our results show that occupation of each miR-122 binding site contributes equally and cooperatively to HCV replication but suggest somewhat unequal contributions of each site to Xrn1 protection and additional functions of miR-122.

IMPORTANCE
The functions of miR-122 in the promotion of the HCV life cycle are not fully understood. Here, we show that binding of miR-122 to each of the two binding sites in the HCV 5′ UTR contributes equally to HCV replication and that binding to both sites can function cooperatively. This suggests that active Ago2–miR-122 complexes assemble at each site and can cooperatively promote the association and/or function of adjacent complexes, similar to what has been proposed for translation suppression by adjacent miRNA binding sites. We also confirm a role for miR-122 in protection from Xrn1 and provide evidence that miR-122 has additional functions in the HCV life cycle unrelated to Xrn1. Finally, we show that each binding site may contribute unequally to Xrn1 protection and other miR-122 functions.
Prognostic role of the neutrophil–lymphocyte ratio in renal cell carcinoma: a meta-analysis
Authors: Hu Kaimin , Lou Lixia , Ye Juan , Zhang Suzhan 
Published: April 2015

ObjectiveIncreasing evidence suggests that cancer-associated inflammation is associated with poor prognosis in patients with cancer. The role of the neutrophil–lymphocyte ratio (NLR) as a predictor in renal cell carcinoma (RCC) remains controversial. We conducted the meta-analysis to determine the association between NLR and clinical outcome of patients with RCC.Methods and materialsStudies were identified from PubMed and EMBASE databases in March 2014. Meta-analysis was performed to generate combined HRs with 95% CIs for overall survival (OS) and recurrence-free/progress-free survival (RFS/PFS).Results15 cohorts containing 3357 patients were included. Our analysis results indicated that elevated NLR predicted poorer OS (HR=1.82, 95% CI 1.51 to 2.19) and RFS/PFS (HR=2.18, 95% CI 1.75 to 2.71) in patients with RCC. These findings were robust when stratified by study region, sample size, therapeutic intervention, types of RCC and study quality. However, it differed significantly by assessment of the cut-off value defining ‘elevated NLR’ in RFS/PFS (p=0.004). The heterogeneity in our meta-analysis was mild to moderate.ConclusionsElevated NLR indicates a poorer prognosis for patients with RCC. NLR should be monitored in patients with RCC for rational risk stratification and treatment individualisation.
What the public knows and wants to know about medicines research and development: a survey of the general public in six European countries
Authors: Parsons Suzanne , Starling Bella , Mullan-Jensen Christine , Tham Su-Gwan , Warner Kay , Wever Kim 
Published: April 2015

ObjectivesTo explore public knowledge of, and interest in, learning more about medicines R&D in six European countries.DesignOnline survey of 6931 members of the public across Europe.MethodsThe survey formed part of a public omnibus survey. A quota sampling approach was used with quotas set according to national census data on age, gender and government region. The survey explored the public's knowledge and awareness of medicines R&D, their interest in learning more and the perceived influences on this.ResultsThe survey was completed by 6931 members of the public, over 75% of whom reported having no or less than good knowledge of medicines R&D. Males were more likely than females to report good knowledge (17% vs 15%), and knowledge appeared to decrease with age. Those who were currently or had previously been involved in medical research were almost five times more likely to report good knowledge of medicines R&D overall (43% vs 13%). Participants reported good knowledge of medicines safety and clinical trials but little knowledge of pharmacoeconomics. They were most interested in learning more about medicines safety and personalised and predictive medicine and least interested in pharmacoeconomics. Older people, women and respondents with current good knowledge of medicines R&D were most interested in learning more about medicines R&D.ConclusionsExperience of medical research appears to play a key role in increasing public awareness of and future interest in medicines R&D. Some groups may need to be specifically targeted to increase their awareness of medicines R&D, for example, women expressed great interest in learning more but reported less knowledge than men. It may be useful to explore further the views of those who are currently uninterested in learning more.
Hydrogen sulfide and traffic-related air pollutants in association with increased mortality: a case-crossover study in Reykjavik, Iceland
Authors: Finnbjornsdottir Ragnhildur Gudrun , Oudin Anna , Elvarsson Bjarki Thor , Gislason Thorarinn , Rafnsson Vilhjalmur 
Published: April 2015

ObjectivesTo study the association between daily mortality and short-term increases in air pollutants, both traffic-related and the geothermal source-specific hydrogen sulfide (H2S).DesignPopulation-based, time stratified case-crossover. A lag time to 4 days was considered. Seasonal, gender and age stratification were calculated. Also, the best-fit lag when introducing H2S >7 µg/m3was selected by the Akaike Information Criterion (AIC).SettingThe population of the greater Reykjavik area (n=181 558) during 2003–2009.ParticipantsCases were defined as individuals living in the Reykjavik capital area, 18 years or older (N=138 657), who died due to all natural causes (ICD-10 codes A00-R99) other than injury, poisoning and certain other consequences of external causes, or cardiovascular disease (ICD-10 codes I00-I99) during the study period.Main outcome measurePercentage increases in risk of death (IR%) following an interquartile range increase in pollutants.ResultsThe total number of deaths due to all natural causes was 7679 and due to cardiovascular diseases was 3033. The interquartile range increased concentrations of H2S (2.6 µg/m3) were associated with daily all natural cause mortality in the Reykjavik capital area. The IR% was statistically significant during the summer season (lag 1: IR%=5.05, 95% CI 0.61 to 9.68; lag 2: IR%=5.09, 95% CI 0.44 to 9.97), among males (lag 0: IR%=2.26, 95% CI 0.23 to 4.44), and among the elderly (lag 0: IR%=1.94, 95% CI 0.12 to 1.04; lag 1: IR%=1.99, 95% CI 0.21 to 1.04), when adjusted for traffic-related pollutants and meteorological variables. The traffic-related pollutants were generally not associated with statistical significant IR%s.ConclusionsThe results suggest that ambient H2S air pollution may increase mortality in Reykjavik, Iceland. To the best of our knowledge, ambient H2S exposure has not previously been associated with increased mortality in population-based studies and therefore the results should be interpreted with caution. Further studies are warranted to confirm or refute whether H2S exposure induces premature deaths.
A cross sectional study of surgical training among United Kingdom general practitioners with specialist interests in surgery
Authors: Ferguson H J M , Fitzgerald J E F , Reilly J , Beamish A J , Gokani V J 
Published: April 2015

ObjectivesIncreasing numbers of minor surgical procedures are being performed in the community. In the UK, general practitioners (family medicine physicians) with a specialist interest (GPwSI) in surgery frequently undertake them. This shift has caused decreases in available cases for junior surgeons to gain and consolidate operative skills. This study evaluated GPwSI's case-load, procedural training and perceptions of offering formalised operative training experience to surgical trainees.DesignProspective, questionnaire-based cross-sectional study.Setting/participantsA novel, 13-item, self-administered questionnaire was distributed to members of the Association of Surgeons in Primary Care (ASPC). A total 113 of 120 ASPC members completed the questionnaire, representing a 94% response rate. Respondents were general practitioners practising or intending to practice surgery in the community.ResultsRespondents performed a mean of 38 (range 5–150) surgical procedures per month in primary care. 37% (42/113) of respondents had previously been awarded Membership or Fellowship of a Surgical Royal College; 22% (25/113) had completed a surgical certificate or diploma or undertaken a course of less than 1 year duration. 41% (46/113) had no formal British surgical qualifications. All respondents believed that surgical training in primary care could be valuable for surgical trainees, and the majority (71/113, 63%) felt that both general practice and surgical trainees could benefit equally from such training.ConclusionsThere is a significant volume of surgical procedures being undertaken in the community by general practitioners, with the capacity and appetite for training of prospective surgeons in this setting, providing appropriate standards are achieved and maintained, commensurate with current standards in secondary care. Surgical experience and training of GPwSI's in surgery is highly varied, and does not yet benefit from the quality assurance secondary care surgical training in the UK undergoes. The Royal Colleges of Surgery and General Practice are well placed to invest in such infrastructure to provide long-term, high-quality service and training in the community.
CareTrack Kids—part 1. Assessing the appropriateness of healthcare delivered to Australian children: study protocol for clinical indicator development
Authors: Wiles Louise K , Hooper Tamara D , Hibbert Peter D , White Les , Mealing Nicole , Jaffe Adam , Cowell Christopher T , Harris Mark F , Runciman William B , Goldstein Stan , Hallahan Andrew R , Wakefield John G , Murphy Elisabeth , Lau Annie , Wheaton Gavin , Williams Helena M , Hughes Clifford , Braithwaite Jeffrey 
Published: April 2015

IntroductionDespite the widespread availability of clinical guidelines, considerable gaps remain between the care that is recommended (appropriate care) and the care provided. This protocol describes a research methodology to develop clinical indicators for appropriate care for common paediatric conditions.Methods and analysisWe will identify conditions amenable to population-level appropriateness of care research and develop clinical indicators for each condition. Candidate conditions have been identified from published research; burden of disease, prevalence and frequency of presentation data; and quality of care priority lists. Clinical indicators will be developed through searches of national and international guidelines, and formatted with explicit criteria for inclusion, exclusion, time frame and setting. Experts will review the indicators using a wiki-based approach and modified Delphi process. A formative evaluation of the wiki process will be undertaken.Ethics and disseminationHuman Research Ethics Committee approvals have been received from Sydney Children's Hospital Network, Children's Health Queensland Hospital and Health Service, and the Women's and Children's Health Network (South Australia). Applications are under review with Macquarie University and the Royal Australian College of General Practitioners. We will submit the results of the study to relevant journals and offer national and international presentations.
CareTrack Kids—part 2. Assessing the appropriateness of the healthcare delivered to Australian children: study protocol for a retrospective medical record review
Authors: Hooper Tamara D , Hibbert Peter D , Mealing Nicole , Wiles Louise K , Jaffe Adam , White Les , Cowell Christopher T , Harris Mark F , Runciman William B , Goldstein Stan , Hallahan Andrew R , Wakefield John G , Murphy Elisabeth , Lau Annie , Wheaton Gavin , Williams Helena M , Hughes Clifford , Braithwaite Jeffrey 
Published: April 2015

IntroductionAustralian and international clinical practice guidelines are available for common paediatric conditions. Yet there is evidence that there are substantial variations between the guidelines, recommendations (appropriate care) and the care delivered. This paper describes a study protocol to determine the appropriateness of the healthcare delivered to Australian children for 16 common paediatric conditions in acute and primary healthcare settings.Methods and analysisA random sample of 6000–8000 medical records representing a cross-section of the Australian paediatric population will be reviewed for appropriateness of care against a set of indicators within three Australian states (New South Wales, Queensland and South Australia) using multistage, stratified sampling. Medical records of children aged <16 years who presented with at least one of the study conditions during 2012 and 2013 will be reviewed.Ethics and disseminationHuman Research Ethics Committee approvals have been received from the Sydney Children's Hospital Network, Children's Health Queensland Hospital and Health Service and Women's and Children's Hospital Network (South Australia). An application is under review for the Royal Australian College of General Practitioners. The authors will submit the results of the study to relevant journals and offer oral presentations to researchers, clinicians and policymakers at national and international conferences.
Left ventricular diastolic reserve in patients with type 2 diabetes mellitus
Authors: Leung Melissa , Phan Victoria , Whatmough Melinda , Heritier Stephane , Wong Vincent W , Leung Dominic Y 
Published: April 2015

AimsDiastolic reserve is the ability of left ventricular filling pressures to remain normal with exercise. Impaired diastolic reserve may be an early sign of diabetic cardiomyopathy. We aimed to determine whether diastolic reserve differs in type 2 diabetes (DM) compared with non-DM, and to identify clinical, anthropological, metabolic and resting echocardiographic correlates of impaired diastolic reserve in patients with DM.Methods and results237 patients (aged 53±11 years, 133 DM, ejection fraction 68±9%) underwent rest and exercise echocardiography. Mitral E and septal e′ were measured at rest, immediately post, and 10 min into recovery. Analysis of covariance (ANCOVA) and binary regression with continuous outcomes were used to model e′ and E/e′ changes with exercise to identify impaired diastolic reserve defined as post-exercise E/e′ ≥15.After adjusting for baseline differences, patients with DM immediately post-exercise had a lower septal e′, a lower Δe′ (1.2 vs 2.3 cm/s, p=0.006) and a higher Δ septal E/e′ (1.7 vs 0.08, p<0.001) than patients without DM. In patients with normal resting E/e′ of ≤8 (n=130), DM had a significantly higher post-exercise septal E/e′ and a higher Δseptal E/e′ (2.63 vs 0.50, p<0.001). E/e′ in patients with DM remained significantly elevated up to 10 min post-exercise. Hypertension, longer duration of insulin therapy, poorer glycaemic control, worse renal function, larger left atrial volume and lower septal e′ were independent correlates of impaired diastolic reserve in patients with DM.ConclusionsPatients with DM have impaired diastolic reserve manifest as a blunted e′ response with exercise, persisting into recovery. Clinical, anthropometric, metabolic and echocardiographic correlates of impaired diastolic reserve in patients with DM were identified. An impaired LV diastolic reserve may be the underlying pathophysiological mechanism in patients with DM with unexplained exertional dyspnoea and may allow earlier detection of DM cardiomyopathy.
Estimating the monetary value of the annual productivity gained in patients with early rheumatoid arthritis receiving etanercept plus methotrexate: interim results from the PRIZE study
Authors: Zhang Wei , Bansback Nick , Sun Huiying , Pedersen Ronald , Kotak Sameer , Anis Aslam H 
Published: April 2015

ObjectiveTo measure and value the impact of combined etanercept (ETN) and methotrexate (MTX) therapy on work productivity in patients with early rheumatoid arthritis (RA) over 52 weeks.MethodsMTX- and biological-naïve patients with RA (symptom onset ≤12 months; Disease Activity Score based on a 28-joint count (DAS28) >3.2) received open-label ETN50/MTX for 52 weeks. The Valuation of Lost Productivity (VOLP) questionnaire, measuring paid and unpaid work productivity impacts, was completed approximately every 13 weeks. Bootstrapping methods were used to test changes in VOLP outcomes over time. One-year productivity impacts were compared between responders (DAS28 ≤3.2) at week 13 and non-responders using zero-inflated models for time loss and two-part models for total costs of lost productivity.Results196 patients were employed at baseline and had ≥1 follow-up with VOLP. Compared with baseline, at week 52, patients gained 33.4 h per 3 months in paid work and 4.2 h per week in unpaid work. Total monetary productivity gains were €1322 per 3 months. Over the 1-year period, responders gained paid (231 h) and unpaid work loss (122 h) compared with non-responders, which amounted to a gain of €3670 for responders.ConclusionsThis is the first clinical trial to measure and value the impact of biological treatment on all the labour input components that affect overall productivity. Combination therapy with ETN50/MTX was associated with a significant productivity gain for patients with early RA who were still observed at week 52. Over the 1-year treatment period, responders at week 13 suffered significantly less productivity loss than non-responders suggesting this gain was related to treatment response.Trial registration numberClinicalTrials.gov numberNCT00913458
Tumor-Induced Pressure in the Bone Microenvironment Causes Osteocytes to Promote the Growth of Prostate Cancer Bone Metastases
Authors: Sottnik Joseph L. , Dai Jinlu , Zhang Honglai , Campbell Brittany , Keller Evan T. 
Published: April 2015

Abstract
Cross-talk between tumor cells and their microenvironment is critical for malignant progression. Cross-talk mediators, including soluble factors and direct cell contact, have been identified, but roles for the interaction of physical forces between tumor cells and the bone microenvironment have not been described. Here, we report preclinical evidence that tumor-generated pressure acts to modify the bone microenvironment to promote the growth of prostate cancer bone metastases. Tumors growing in mouse tibiae increased intraosseous pressure. Application of pressure to osteocytes, the main mechanotransducing cells in bone, induced prostate cancer growth and invasion. Mechanistic investigations revealed that this process was mediated in part by upregulation of CCL5 and matrix metalloproteinases in osteocytes. Our results defined the critical contribution of physical forces to tumor cell growth in the tumor microenvironment, and they identified osteocytes as a critical mediator in the bone metastatic niche. Cancer Res; 75(11); 2151–8. ©2015 AACR.
Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer
Authors: Fang Lekun , Yang Zihuan , Zhou Junyi , Tung Jung-Yu , Hsiao Chwan-Deng , Wang Lei , Deng Yanhong , Wang Puning , Wang Jianping , Lee Mong-Hong 
Published: April 2015

Abstract
Biomarkers for predicting chemotherapy response are important to the treatment of colorectal cancer patients. Cryptochrome 2 (CRY2) is a circadian clock protein involved in cell cycle, but the biologic consequences of this activity in cancer are poorly understood. We set up biochemical and cell biology analyses to analyze CRY2 expression and chemoresistance. Here, we report that CRY2 is overexpressed in chemoresistant colorectal cancer samples, and CRY2 overexpression is correlated with poor patient survival. Knockdown of CRY2 increased colorectal cancer sensitivity to oxaliplatin in colorectal cancer cells. We also identify FBXW7 as a novel E3 ubiquitin ligase for targeting CRY2 through proteasomal degradation. Mechanistic studies show that CRY2 is regulated by FBXW7, in which FBXW7 binds directly to phosphorylated Thr300 of CRY2. Furthermore, FBXW7 expression leads to degradation of CRY2 through enhancing CRY2 ubiquitination and accelerating the CRY2's turnover rate. High FBXW7 expression downregulates CRY2 and increases colorectal cancer cells' sensitivity to chemotherapy. Low FBXW7 expression is correlated with high CRY2 expression in colorectal cancer patient samples. Also, low FBXW7 expression is correlated with poor patient survival. Taken together, our findings indicate that the upregulation of CRY2 caused by downregulation of FBXW7 may be a novel prognostic biomarker and may represent a new therapeutic target in colorectal cancer. Mol Cancer Ther; 14(6); 1476–87. ©2015 AACR.