Highlights • No large study has systematically explored predictors of telomere length and telomere attrition. • Sociodemographic, lifestyle, and psychosocial, metabolic and physiological stressors ...linked with telomere length. • 6-year telomere attrition almost completely predicted by baseline telomere length. • We suggest a strong internal homeostasis in the telomeric system. • Identified determinants may be targets of future studies to promote telomere maintenance and healthy aging.
Executive Compensation in the Netherlands Swagerman, Dirk; Terpstra, Erik
Problems and Perspectives in Management,
2007, Volume:
5, Issue:
3 continued
Journal Article
Peer reviewed
Open access
This paper shows the recent developments in the structure of Dutch executive pay contracts. An empirical study based on remuneration data on the executive board members of 71 Dutch listed companies ...over the period of 2002-2004 has revealed a number of clear trends in this area. This paper demonstrates that the political interference in compensation practices, for example in the form of corporate governance guidelines, has had a great impact on the design of compensation structures, but often at the expense of the economical efficiency of these arrangements. The main objective of this study is to increase insights into Dutch executive compensation arrangements and the way in which these have evolved under the influence of corporate governance requirements. Adapted from the source document.
U ovom se radu opisuju trendovi u dizajniranju ugovora o plaćanju nizozemskih top menadžera. Da bi se unaprijedilo poznavanje ovog problema, analizirani su podaci o kompenzacijama izvršnih članova ...odbora direktora 71 nizozemske korporacije uvrštene na tržište kapitala u periodu od 2002. do 2004. godine. Rad polazi od premise da specifični režim korporacijskog upravljanja i uvjeti u okruženju presudno utječu na ugovore o kompenzacijama. Na temelju teorijskog istraživanja, u kojem se kombiniraju empirijski rezultati i pregled literature, ustvrđuje se da se optimalni pristup
kompenzacijama postiže kompromisom između poštovanja standarda korporacijskog upravljanja (na temelju kojeg se optimiziraju potencijalni poticaji i smanjuju negativni poticaji menadžmentu) i težnje za ponudom konkurentnog paketa kompenzacija. Čini se da se ovaj kompromis razlikuje u svakom poduzeću, kao i u vremenu u kojem se promatra. Relevantnost ove studije je dvostruka: prvo, njezini rezultati bi mogli pomoći u oblikovanju javne debate o plaćanju top menadžmenta u Nizozemskoj. Nadalje, ona može poslužiti kao nacrt za buduća istraživanja na temu kompenzacija top menadžmenta u specifičnom kontekstu nizozemskog sustava korporacijskog upravljanja, kao i pomoći u kreiranju optimalnih kompenzacijskih paketa.
This article describes the trends in Dutch executive pay contracts. To increase our insight into this subject area, we conducted an empirical study on the basis of remuneration data provided by the ...executive board members of 71 Dutch listed companies over the period 2002-2004. The study starts from the premise that the characteristics of a unique corporate governance regime, together with the environmental context, shape compensation arrangements. Based on a theoretical research study, which combines our empirical research results with a literature overview, we argue that an optimal compensation arrangement is a trade-off among complying with corporate governance standards, optimizing potential incentives, preventing perverse incentives and offering a competitive pay package. It appears that this trade-off differs with each company at any moment in time. The relevance of this study may be threefold. First, its results can help shape the public debate about the pay of top executives in the Netherlands. Second, it could serve as a blueprint for future research on executive compensation in the specific context of the Dutch governance system. Furthermore, it could help remuneration committees in designing optimal compensation packages. PUBLICATION ABSTRACT
Executive pay in the Netherlands has risen sharply in recent years as equity-based compensation grows and boards increasingly adopt the pay-for-performance approach.
Diagnosing post-transplant lymphoproliferative disorder (PTLD) is challenging and often requires invasive procedures. Analyses of cell-free DNA (cfDNA) isolated from plasma is minimally invasive and ...highly effective for genomic profiling of tumors. We studied the feasibility of using cfDNA to profile PTLD and explore its potential to serve as a screening tool. We included seventeen patients with monomorphic PTLD after solid organ transplantation in this multi-center observational cohort study. We used low-coverage whole genome sequencing (lcWGS) to detect copy number variations (CNVs) and targeted next-generation sequencing (NGS) to identify Epstein-Barr virus (EBV) DNA load and somatic single nucleotide variants (SNVs) in cfDNA from plasma. Seven out of seventeen (41%) patients had EBV-positive tumors, and 13/17 (76%) had stage IV disease. Nine out of seventeen (56%) patients showed CNVs in cfDNA, with more CNVs in EBV-negative cases. Recurrent gains were detected for 3q, 11q, and 18q. Recurrent losses were observed at 6q. The fraction of EBV reads in cfDNA from EBV-positive patients was 3-log higher compared to controls and EBV-negative patients. 289 SNVs were identified, with a median of 19 per sample. SNV burden correlated significantly with lactate dehydrogenase levels. Similar SNV burdens were observed in EBV-negative and EBV-positive PTLD. The most commonly mutated genes were TP53 and KMT2D (41%), followed by SPEN, TET2 (35%), and ARID1A, IGLL5, and PIM1 (29%), indicating DNA damage response, epigenetic regulation, and B-cell signaling/NFkB pathways as drivers of PTLD. Overall, CNVs were more prevalent in EBV-negative lymphoma, while no difference was observed in the number of SNVs. Our data indicated the potential of analyzing cfDNA as a tool for PTLD screening and response monitoring.
Survival of CLL cells critically depends on heterotypic communication with benign bystanders cells in micro-environmental niches such as lymph node (LN) tissue. Here, mesenchymal stromal cells and ...macrophages, in concert with CD40L expressing T cells, are thought to participate in the dialog with the neoplastic B cells, but the mechanisms of this intricate interplay remain largely unknown. Moreover, whether CLL cells actively participate in shaping their prosurvival niche is poorly understood. We aimed to study 1) whether CD40 stimulation initiates active recruitment of monocytes by CLL cells, 2) whether CLL cells are able to differentiate these monocytes towards a supporting phenotype and 3) by which mechanism macrophages induce CLL survival.
We first studied the chemokinome of CLL cells after T cell stimulation using both microarray and Luminex techniques. Co-culture of autologous activated T cells with CLL cells resulted in induction of mRNA expression of CCL2,3,4,5,22 and IL10, which are known chemo-attractants for monocytes. These effects could be mimicked by CD40 activation of CLL cells. Protein screens of supernatants of CD40 activated CLL cells by Luminex assays confirmed increased protein expression of these chemo-attractants. Indeed, transwell assays showed enhanced migration of primary monocytes towards supernatants of CD40L stimulated CLL cells. Inhibitor experiments furthermore showed that the migratory effects of these chemokines was largely governed via the CCR2 and CCR3 receptors.
We next examined and compared polarization patterns of monocytes after differentiation with serum derived from CLL patients (N=25) or pooled healthy donor serum and found that CLL serum was able to differentiate macrophages towards a tumor supporting M2 phenotype. This finding was confirmed ex vivo by IHC, as M2 marker CD206 co-localizes with CD68 cells in CLL LNs, while the majority of macrophages in non-CLL derived LNs are CD80+ (M1 type).
Lastly, we examined how these macrophages exert their pro-survival effect on CLL. From a variety of Bcl-2 family proteins investigated, only Mcl-1 protein expression levels increased after interaction with macrophages. The relevance of Mcl-1 upregulation was verified by MCL-1 siRNA interference studies. The mechanism of induction of Mcl-1 was independent on NF-κB signaling, Mcl-1 mRNA transcription levels or protein stability, but rather unexpectedly appeared as a result of recruitment of polysomes to Mcl-1 mRNA, resulting in an increase in translation. This increase was accompanied by an increased phosphorylation of the rate-limiting translation initiation factor 4E-BP1 and ribosomal protein S6. The increase in Mcl-1 translation could be attributed to macrophage-induced Akt signaling.
In conclusions, these studies shed light on reciprocal cellular interactions in the CLL LN that shape pro-tumor differentiation of supporting cells, that in turn cause survival by changing the apoptotic balance. These interactions can be targeted at different levels, creating new treatment venues for this still incurable disease.
No relevant conflicts of interest to declare.
The mammalian
in vivo micronucleus assay is widely used as part of the genotoxicity testing battery required during the development of new drugs. As such, the
in vivo micronucleus assay has been used ...in a battery of assays for the assessment of cigarette ingredients or design modifications to help ensure that there is no increase in risk or any new risk introduced by these additions or modifications. The present series of studies was conducted to optimize and evaluate this assay for the assessment of the effects of mainstream smoke on the micronucleus frequency in the bone marrow and peripheral blood of rats. In a first experiment, the optimal conditions for performing the micronucleus assay in these tissues were determined. This was done by use of two compounds known for their micronucleus-inducing activity, i.e., the clastogen cyclophosphamide and the aneugen colchicine. In a second experiment, the effects of tube restraint on untreated control rats were investigated. In a third experiment, the optimal conditions were used to assess the clastogenic/aneugenic activity of cigarette smoke in Sprague-Dawley rats. The rat micronucleus assay in both bone marrow and peripheral blood is able to detect clastogenic and aneugenic activity. The flow cytometric determination of micronucleated cells in rat blood is at least as sensitive as determinations in bone marrow. No statistically significant differences were observed in micronucleus frequencies between rats with and without the additional stress of tube restraint; however, the cautious approach would be to use a fresh-air-exposed group (with tube restraint) as the negative control in inhalation experiments. Using the conditions identified as optimal in the above-mentioned experiments, the micronucleus assay was not able to detect effects induced by smoke from conventional cigarettes. Nevertheless, the micronucleus assay will remain a valuable tool as part of a testing battery used to investigate possible adverse effects related to product modifications.
