bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Pharmacokinetics of Bevacizumab in Children with Osteosarcoma: Implications for Dosing
Authors: Turner David C. , Navid Fariba , Daw Najat C. , Mao Shenghua , Wu Jianrong , Santana Victor M. , Neel Michael , Rao Bhaskar , Willert Jennifer Reikes , Loeb David M. , Harstead K. Elaine , Throm Stacy L. , Freeman Burgess B. , Stewart Clinton F. 
Published: March 2014

AbstractPurpose: To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes.Experimental Design: Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression.Results: Bevacizumab concentration–time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults, with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space, 49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure, as body mass index percentile was significantly (P &lt; 0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure before primary tumor resection was associated with increased risk of major wound healing complications after surgery (P &lt; 0.05).Conclusion: A population pharmacokinetic model for bevacizumab was developed, which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications. Clin Cancer Res; 20(10); 2783–92. ©2014 AACR.
Dual Promoter Usage as Regulatory Mechanism of let-7c Expression in Leukemic and Solid Tumors
Authors: Pelosi Andrea , Careccia Silvia , Sagrestani Giulia , Nanni Simona , Manni Isabella , Schinzari Valeria , Martens Joost H.A. , Farsetti Antonella , Stunnenberg Hendrik G. , Gentileschi Maria Pia , Del Bufalo Donatella , De Maria Ruggero , Piaggio Giulia , Rizzo Maria Giulia 
Published: March 2014

Abstract
Let-7c, an intronic microRNA (miRNA) embedded in the long non-coding gene LINC00478, can act as a tumor suppressor by targeting oncogenes. Previous studies indicated that in acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia (AML) bearing the leukemia promoting PML/RARα fusion protein, let-7c expression seems to be controlled by the host gene promoter, in which canonical Retinoic Acid Responsive Elements (RAREs) are bound by PML/RARα in an all transretinoic acid (ATRA)–sensitive manner. Here, let-7c transcriptional regulation was further investigated and a novel intronic promoter upstream of the pre-miRNA was identified. This new promoter has transcriptional activity strongly indicating that at least two promoters need to be considered for let-7c transcription: the distal host gene and the proximal intronic promoter. Therefore, epigenetic modifying enzymes and histone acetylation and methylation status were analyzed on both let-7c promoters. It was demonstrated that ATRA treatment leads to let-7c upregulation inducing a more open chromatin conformation of the host gene promoter, with an enrichment of epigenetic marks that correlate with a more active transcriptional state. Conversely, the epigenetic marks on the intronic promoter are not significantly affected by ATRA treatment. Interestingly, in solid tumors such as prostate and lung adenocarcinoma it was found that both host and intronic promoters are functional. These data suggest that while the host gene promoter may control let-7c expression in AML, in a nonleukemic tumor context instead the intronic promoter contributes or preferentially regulates let-7c transcription.
Implications: Alternative promoter usage represents a regulatory mechanism of let-7c expression in different tissues. Mol Cancer Res; 12(6); 878–89. ©2014 AACR.
Endothelial Cell–Specific Liver Kinase B1 Deletion Causes Endothelial Dysfunction and Hypertension in Mice In Vivo
Authors: Zhang Wencheng , Wang Qilong , Wu Yue , Moriasi Cate , Liu Zhaoyu , Dai Xiaoyan , Wang Qiongxin , Liu Weimin , Yuan Zu-Yi , Zou Ming-Hui 
Published: March 2014

Background—
Liver kinase B1 (LKB1), a tumor suppressor, is a central regulator of cell polarity and energy homeostasis. The role of LKB1 in endothelial function in vivo has not been explored.

Methods and Results—

Endothelium-specific LKB1 knockout (
LKB1

endo−/−

) mice were generated by cross-breeding
LKB1

flox/flox

mice with VE-Cadherin-Cre mice.
LKB1

endo−/−

mice exhibited hypertension, cardiac hypertrophy, and impaired endothelium-dependent relaxation.
LKB1

endo−/−

endothelial cells exhibited reduced endothelial nitric oxide synthase activity and AMP kinase (a downstream enzyme of LKB1) phosphorylation at Thr172 compared with wild-type (WT) cells. In addition, the levels of caveolin-1 were higher in the endothelial cells of
LKB1

endo−/−

mice, and knockdown of caveolin-1 by siRNA normalized endothelial nitric oxide synthase activity. Human antigen R bound with the adenylate-uridylate-rich elements of caveolin-1 mRNA 3′ untranslated region, resulting in the increased stability of caveolin-1, and genetic knockdown of human antigen R decreased the expression of caveolin-1 in LKB1-deficient endothelial cells. Finally, adenoviral overexpression of constitutively active AMP kinase, but not green fluorescent protein, decreased caveolin-1, lowered blood pressure, and improved endothelial function in
LKB1

endo−/−

mice in vivo.

Conclusions—
Our findings indicate that endothelial LKB1 regulates endothelial nitric oxide synthase activity, endothelial function, and blood pressure by modulating AMP kinase–mediated caveolin-1 expression.
STARTS-2
Authors: Barst Robyn J. , Beghetti Maurice , Pulido Tomas , Layton Gary , Konourina Irina , Zhang Min , Ivy D. Dunbar 
Published: March 2014

Background—
The double-blind, placebo-controlled Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study assessed sildenafil in pediatric patients with pulmonary arterial hypertension; improved hemodynamics and exercise capacity occurred in medium- and high-dose groups. STARTS-2 was the extension study.

Methods and Results—
In STARTS-1, 234 children ≥8 kg were randomly assigned to low-, medium-, or high-dose sildenafil or placebo orally thrice daily; within-group dose depended on weight. In STARTS-2, sildenafil-treated patients continued STARTS-1 dosing; placebo-treated patients were randomized to 1 of the 3 sildenafil dose groups. Patients requiring additional pulmonary arterial hypertension–specific therapy discontinued study treatment; survival follow-up was attempted. As of August 2011, all children received ≥3 years of treatment (unless discontinued) from STARTS-1 baseline; 37 deaths were reported (26 on study treatment), 1 of which occurred within the first year of treatment. Most patients who died (28/37) had idiopathic/heritable pulmonary arterial hypertension (76% versus 33% overall) and baseline functional class III/IV disease (38% versus 15% overall); patients who died had worse baseline hemodynamics. Kaplan-Meier estimated 3-year survival rates from start of sildenafil were 94%, 93%, and 88% for patients randomized to low-, medium-, and high-dose sildenafil, respectively; 87%, 89%, and 80% were known to be alive at 3 years. Hazard ratios for mortality were 3.95 (95% confidence interval, 1.46–10.65) for high versus low and 1.92 (95% confidence interval, 0.65–5.65) for medium versus low dose; however, multiple analyses raised uncertainty about the survival/dose relationship.

Conclusions—
Although children randomized to higher compared with lower sildenafil doses had an unexplained increased mortality, all sildenafil dose groups displayed favorable survival for children with pulmonary arterial hypertension.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov/ct2/show/NCT00159874
(extension study of NCT00149913). Unique identifier: NCT00159874.
Resisting governmental control: how semi-autonomous agencies use strategic resources to challenge state coordination
Authors: Overman Sjors , van Thiel Sandra , Lafarge François 
Published: March 2014

Institutional pressure caused by public sector reform leads to strategic reactions from semi-autonomous agencies. Agencies in the Netherlands and France only complied with a selection of imposed reforms. Other rules were manipulated, not complied with, or compromises were made. The degree of compliance with reforms is not only dependent on structural aspects, but also on resources and power distributions between the actors. A comparison is made between the introduction of the Dutch Kaderwet ZBO and the French Révision Générale des Politiques Publiques. These agency reforms are contested between ministries, rather than between agency and parent ministry alone. Parent ministries tend to side with their agencies in both countries. In the Netherlands, power-related issues were most debated, whereas in France money-related issues caused most disagreement. Points for practitioners Reforms targeted at agencies are likely to meet resistance if agencies do not agree with the proposed rules, especially if they alter existing power relations. Some agencies possess certain resources which they can apply strategically to offer resistance to reforms. Parent ministries tend to side with agencies in their sector and try to protect them from other ministries.
The reform of the Belgian federal administration 10 years on: what balance has been achieved between operational autonomy of top managers and the supervision carried out by the horizontal ministerial departments?
Authors: de Visscher Christian , Randour François 
Published: March 2014

In the wake of the Copernic reform, Belgium’s senior federal civil servants are now appointed for a fixed term and guided on performance via management plans. This article sets out to assess the impact of the introduction of the fixed-term system on the autonomy of senior civil servants with regard to the horizontal departments responsible for the budget, on the one hand, and human resources, on the other hand, within Belgium’s federal administration. Based on the so-called ‘inconsistencies’ approach, the article focuses briefly on three inconsistencies: internal, discursive and contextual. An analysis of these inconsistencies confirms one of the forms of ‘cheating’ in the relationship between ministers and senior civil servants formulated by Hood and Lodge (2006), namely that the first can be inclined to reduce the margin of discretion of the latter by maintaining formal or informal mechanisms to exercise control over the provision of resources. Points for practitioners Greater managerial autonomy for senior civil servants, as advocated by NPM, cannot succeed without a transformation of the traditional modes of operation of the political-administrative relationship accompanying structural reforms. The low degree of autonomy of senior civil servants does not stem so much from the introduction of a ‘contractual’ relationship, but from the lack of support shown by the latter in the implementation of such reforms. In the case studied, senior civil servants can only be made more accountable and given greater autonomy if the ‘pyramid’ of control is reformed and internal audit activities developed.
All motivated by public service? The links between hierarchical position and public service motivation
Authors: Desmarais Céline , Gamassou Claire Edey 
Published: March 2014

Research into public service motivation (PSM) is currently witnessing exponential growth. However, the universal application of the concept to all categories of public employees raises questions. Indeed, the origins of the concept, which can be traced back to political science studies in the United States, may suggest that the concept applies mainly to senior management but much less to other types of employee, whose motivations seem more instrumental. Research into the antecedents of PSM has thus shown that high hierarchical levels were associated with employee profiles with a high level of PSM (Bright, 2005; Camilleri, 2007). Some authors go as far as to consider that the concept does not apply at all to blue-collar jobs (Gabris and Simo, 1995). The purpose of this article is therefore to analyse the differences between the public service motivation of operatives and that of other categories of employees. To do so, we draw on two empirical studies, one quantitative ( n = 2868), conducted among the public employees of cities in 12 countries, and the other qualitative, conducted among public employees working in the technical service of a French town. Our results show that the level of PSM is not lower among blue-collar workers but that, on the other hand, it is different in nature and dimensions. Points for practitioners The issue of the PSM of blue-collar public employees takes on a managerial dimension. Indeed, it has potential policy implications for human resource management policies to be implemented and on the segmentation of the public employees in the light of these policies. Our results thus argue for the mainstreaming of the public service dimension in the management of executives and would suggest that it is in the interest of public organizations to encourage the public service motivation of their employees by designing tasks in such a way that public employees can better appreciate the result of their work among customers and users.
‘Public on the outside, private on the inside’: the organizational hybridization, sense of belonging and identity strategies of the employees of a public unemployment insurance fund in Switzerland
Authors: Buffat Aurélien 
Published: March 2014

A number of studies show that New Public Management reforms have altered the current identity benchmarks of public officials, particularly by hybridizing values or management practices. However, existing studies have largely glossed over the sense of belonging of officials when their organization straddles the concerns of public service and private enterprise, so that the boundary between public and private sector is blurred. The purpose of this article is precisely to explore this sense of belonging in the context of organizational hybridization. It does so by drawing on the results of research conducted among the employees of a public unemployment insurance fund in Switzerland. On the one hand, the analysis shows how much their markers of belonging are hybrid, multiple and constructed in negative terms (with regard to the State), while indicating that the working practices of the employees point to an identity that is nevertheless closely bound with the public sector. On the other hand, the analysis shows that the organization plays strategically with its State status, by exploiting either its private or public identity in line with the needs related to its external image. The article concludes with a discussion of the results highlighting the strategic functionality of the hybrid identity of the actors. Points for practitioners The article is of particular interest to practitioners who are questioning the effects on identity of the increasingly hybrid organizational context which organizations are faced with today – straddling a public service rationale and that of a private enterprise. While the organizational hybridity brought about by NPM is making matters increasingly complex for practitioners – especially with regard to the proliferation of expectations made of them – the article nevertheless notes that it is this very same hybridity that provides actors with multiple identity-related markers of belonging which practitioners are likely to exploit strategically to adapt to this growing spectrum of demands. The idea of playing alternately with the public or private identity of the organization according to context has the potential of giving an extra margin of manoeuvre to practitioners and managers working in a hybrid environment.
What happens after the passage of reform initiatives? Two dimensions of social policy reform in Korea
Authors: Lee Jooha 
Published: March 2014

This article aims to present a comprehensive analysis of social policy reform, encompassing its two dimensions, that is, reform decision-making and implementation, with reference to Korea’s new social assistance programme. In the social policy reform after the economic crisis of 1997, less was delivered locally than decided centrally. First, there were decision deficits centrally, which became visible locally. This was considerably attributable to the fact that the decision-making process after ‘framework legislation’ was passed showed more active involvement of conservative forces ‘from above’ – despite the new-found importance of pro-welfare forces ‘from below’. Second, there were implementation deficits locally. This article explains the reasons why legislated policy was not implemented as designed in the light of three barriers to implementation. Although a powerful government may be able to steer reform through central decision making, it is not necessarily in control of effective implementation at the local level. Points for practitioners Today’s decision making in a lately democratized country such as Korea reflects the increase of power resources available to societal groups, but state officials play a more pivotal role, especially during the enforcement preparation process (the second round of decision making). Attention needs to be paid to the interplays between them, which may be particular to time and place. Changes in policy goals and contents at the central decision-making level do not always result in intended changes in implementation. The analysis of decision making should thus be followed by an investigation of implementation, which is rarely performed in the international literature on welfare reform.
Energy-saving-oriented group-elevator dispatching strategy for multi-traffic patterns
Authors: Zhang Jinglong , Zong Qun 
Published: March 2014

Energy-saving elevator dispatching has been recognized as a challenging issue in building transportation, and we develop a novel energy-saving dispatching strategy for regenerative group-elevator system. Group-elevator dispatching is a typical combinatorial optimization problem, and three keys of the dispatching optimization are optimization method, objective, and model. The three keys of energy-saving-oriented elevator dispatching are studied in this paper. First, robust optimization method is introduced to handle dispatching optimization under uncertain elevator traffic flows; uncertain flows influence energy-saving dispatching seriously. Second, dispatching energy-objective function for regenerative group-elevator system is derived both schedule energy for four traffic patterns (up-peak, down-peak, up/down-mixed, and night) and return energy for two peak patterns (up-peak and down-peak) are considered. Third, four robust optimization-dispatching models for four traffic patterns are built, and optimization objectives of four models are minimizing the energy-objective function. Moreover, because we cannot solve robust optimization models with uncertain parameters directly, model counterpart transformation is studied. Finally, we solve the four transformed models by Linear Interactive and General Optimizer software and obtain robust optimization-dispatching solutions. In practice, four energy-saving-dispatching robust optimization models are switched according to real-time traffic patterns, and elevators are dispatched based on the dispatching solutions. We reduce elevator system-energy consumption effectively and keep average waiting time of the passengers acceptable under multi-traffic patterns. Simulation results demonstrate the validity of our strategy. Practical application: Group-elevator system spends much unnecessary energy because of the uncertainty of elevator passenger-traffic flows. This paper develops an energy-saving elevator-dispatching optimization strategy, which is immune to the uncertainty of four typical traffic flows. In practice, we update the group-elevator controller by our algorithm to realize energy-saving dispatching of regenerative group-elevator system under multi-traffic patterns.
Imminence of death among hospital inpatients: Prevalent cohort study
Authors: Clark David , Armstrong Matthew , Allan Ananda , Graham Fiona , Carnon Andrew , Isles Christopher 
Published: March 2014

Background: There is a dearth of evidence on the proportion of the hospital population at any one time, that is in the last year of life, and therefore on how hospital policies and services can be oriented to their needs. Aim: To establish the likelihood of death within 12 months of a cohort of hospital inpatients on a given census date. Design: Prevalent cohort study. Participants: In total, 10,743 inpatients in 25 Scottish teaching and general hospitals on 31 March 2010. Results: In all, 3098 (28.8%) patients died during follow-up: 2.9% by 7 days, 8.9% by 30 days, 16.0% by 3 months, 21.2% by 6 months, 25.5% by 9 months and 28.8% by 12 months. Deaths during the index admission accounted for 32.3% of all deaths during the follow-up year. Mortality rose steeply with age and was three times higher at 1 year for patients aged 85 years and over compared to those who were under 60 years (45.6% vs 13.1%; p < 0.001). In multivariate analyses, men were more likely to die than women (odds ratio: 1.18, 95% confidence interval: 0.95–1.47) as were older patients (odds ratio: 4.99, 95% confidence interval: 3.94–6.33 for those who were 85 years and over compared to those who were under 60 years), deprived patients (odds ratio: 1.17, 95% confidence interval: 1.01–1.35 for most deprived compared to least deprived quintile) and those admitted to a medical specialty (odds ratio: 3.13, 95% confidence interval: 2.48–4.00 compared to surgical patients). Conclusion: Large numbers of hospital inpatients have entered the last year of their lives. Such data could assist in advocacy for these patients and should influence end-of-life care strategies in hospital.