1,592 publications from this institution
<title>Abstract</title> Oncogenic mutations in otherwise normal tissue are common in many adult tissues <sup>1,2</sup> . This suggests multiple events need to converge to drive tumourigenesis and that many processes such as tissue differentiation may be protective against carcinogenesis. Within the liver Wnt/β-catenin signalling maintains zonal differentiation during liver homeostasis <sup>3,4</sup> . However, the <italic>CTNNB1</italic> oncogene—encoding β-catenin—is also frequently mutated in hepatocellular carcinoma, resulting in aberrant Wnt signalling that promotes cell growth <sup>5,6</sup> . Here we investigated the antagonistic interplay between Wnt-driven growth and differentiation in zonal hepatocyte populations during liver tumorigenesis. We found that β-catenin mutants transiently stimulated growth in zone-1 and -2 hepatocytes within the Wnt-low region of the liver lobule – before inducing a differentiated zone-3 fate. One key feature lacking within the differentiated zone-3 hepatocytes that is often upregulated in human cancer was MYC which can synergise with β-catenin to initiate HCC in mice. When mutant β-catenin and <italic>MYC</italic> were expressed cell-agnostically across the liver lobule, a subset of mutant hepatocytes were proliferative and tumorigenic. These exhibited a selective upregulation of the zone-2 factors IGFBP2, cyclin D1, and mTOR and a reduction in the levels of Wnt signalling when compared to non-proliferative Wnt-high single cell clones. Inhibition of mTOR signalling with Rapamycin blocked tumourigenesis. Furthermore, restricting β-catenin and <italic>MYC</italic> mutations with Lgr5-Cre to zone-3 hepatocytes suppressed tumourigenesis. This was associated with high Wnt signalling and the lack of zone-2 factors permissive to growth. Importantly other oncogenic-drivers could promote tumourigenesis from zone-3 hepatocytes but tumours that arose had all lost their zone 3 features. Therefore we propose that zonal identity dictates hepatocyte susceptibility to Wnt-driven tumorigenesis and that escaping Wnt-induced differentiation is essential for liver cancer.
The overall address of the present thesis is the relationship between being ‘on fire’ and burning out. More specifically, the thesis focused largely on two representations of involvement in work (work engagement and Type A behavior) and their respective relationships to burnout. Another pervasive theme was construct validity in assessing burnout and work engagement. These themes were addressed in four empirical studies, conducted in a sample of health-care workers (Study I) and a sample of information communication technology consultants (Studies II, III, and IV). Study I aimed to extend the previously preliminary support for the construct validity of the Swedish version of the Maslach Burnout Inventory (MBI). The objective of Study II was the discriminant validity of the Utrecht Work engagement Scale (UWES) against the theoretically adjacent constructs job involvement and organizational commitment. Another objective was the translation and evaluation of a Swedish version of the UWES. In Study III, the aim was to investigate (cross-sectional) association between Type A behavior, work engagement and burnout. Study III had two foci: 1) whether Type A behavior interacts with job factors to affect burnout and work engagement, and 2) the associations between the main components of Type A behavior (achievement-striving and irritability/impatience) and burnout as well as work engagement. Study IV concerned the longitudinal relationships between Type A behavior and burnout, and between work engagement and burnout. The results presented in this dissertation supported the construct validity of Swedish versions of the MBI and the UWES. It was further indicated that emotional exhaustion and depersonalization (or cynicism) constitute the core aspects of burnout, and that work engagement was more prominently associated with lack of health complaints than job involvement and organizational commitment. Type A behavior was found to be associated with burnout and work engagement in cross-sectional data, however different aspects of Type A behavior appeared to have somewhat different association with burnout and work engagement respectively. The achievement-striving aspect of Type A behavior was related primarily to work engagement, whereas irritability was associated with less engagement and more burnout complaints. No indications of an interaction between Type A behavior and job stress were found. The most important finding of Study IV was that change in Type A behavior was unrelated to change in burnout across time (one-year interval). Furthermore, Study IV supported the notion that work engagement and burnout are bipolar opposites and constitute a work well-being continuum. To conclude, the present thesis suggests that burnout should be viewed as an erosion of intrinsic, affective engagement in work occurring when intrinsic motivation is frustrated by job stress. To avoid conceptual confusion, burnout should be distinguished form exhaustion syndrome however it should be acknowledged that burnout may have negative impact on health. The present study indicated that Type A behavior is unrelated to the specific burnout reaction, a finding that needs to be replicated before generalizability can be assumed. However, it was assumed that Type A behavior represents an instrumental approach to work, further corroborating that burnout is a specific construct referring to the draining of a specific energetic and affective state. This does not imply that Type A behavior is unrelated to health deterioration – most plausibly, Type A behavior generates exhaustion and fatigue from over-exertion of energy. Both research and practice would benefit from exploring how work engagement may best be enhanced using job redesign.
This article proposes a theoretical perspective on teacher burnout that is based on the principles of social exchange. More specifically, it is argued that burnout results from a
The dimensionality and validity of the BM (Burnout Measure) is investigated in Dutch samples of human services professionals and white‐collar workers (total N = 2190). Results show that, in contrast to the presumed dimensions ‘physical exhaustion’, ‘emotional exhaustion’ and ‘mental exhaustion’, the factors of the BM are ‘demoralization’, ‘exhaustion’, and ‘loss of motive’. The factorial structure is not affected by using different time frames although an unrestricted time frame results in significantly higher mean scores. A BM version with a seven‐point Likert scale results in more reliable subscales than a five‐point scale. The factor ‘loss of motive’ is substantially affected by inconsistent answering patterns of the respondents. The three‐factor model of the BM fits equally well in samples of professionals with and without patient contact. The BM subscales correlate highly with fatigue and with the dimension ‘emotional exhaustion’ of the Maslach‐Burnout‐Inventory (MBI) but cannot be distinguished from psychological strain and psychosomatic complaints. Problems in the conceptualization of burnout and its operationalization are discussed. It is concluded that the BM captures only a particular aspect of burnout and is rather a measure of general well‐being. Recommendations for further use of a modified BM are given.
No abstract is provided for this article.
Additional file 7.
Abstract Over the last few years several studies led to a significant change in the field of ovarian cancer and it is currently believed that the fallopian tube and not the ovary surface epithelium (OSE) is the main origin of high-grade serous ovarian cancer (HG-SOC). Nevertheless, due to the lack of unique markers and adequate model systems the relative contribution of each tissue is not yet clear and the notion that OSE has a role in HG-SOC development was not cast aside altogether. In this work we have established novel organoid systems derived from both mouse OSE and oviduct (Ovi, the equivalent of human fallopian tube). These systems recapitulate their tissue of origin and demonstrate differences in medium requirements as well as gene expression. To establish comparable tumor progression models for both OSE and Ovi we used CRISPR-Cas9 technique and targeted commonly mutated genes in ovarian cancer (Trp53, Brca1, Nf1 and Pten). Thus, we were able to establish clones with different combinations of mutations. Histological, metaphase spread and gene expression analysis of the mutated organoid clones from both OSE and Ovi demonstrated different degrees of deviation from their wild type counterpart. This deviation became more evident as the amount of introduced mutations increased. Preliminary transplantation experiments showed that only triple mutants gave rise to tumors (Trp53, Brca1 and Pten or Trp53, Brca1 and Nf1). Moreover, Ovi mutant clones were more prone to grow into tumors in comparison to OSE as no tumors have been detected in mice transplanted with the OSE equivalent clones so far. Taken together, in this study we present the first comparable Ovi/OSE research platform that enables addressing questions related to origin and early stages of HG-SOC development. Citation Format: Kadi Lõhmussaar, Oded Kopper, Hans C. Clevers. BUILDING AN ORGANOID-BASED MODEL FOR OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-039.
Purpose The purpose of this paper is to examine the main and interaction effects of self-rated promotion and prevention regulatory focus on self-rated work performance, emotional exhaustion and sickness absence for managers and non-managers separately. The authors expected that promotion focus relates positively to performance and negatively to sickness absence, while prevention focus relates positively to exhaustion and sickness absence, both for managers and non-managers. Furthermore, the authors expected that promotion focus relates positively to performance but also to exhaustion and sickness absence when prevention focus is high, only for managers (i.e. a manager’s dual regulatory focus can be an effective but also exhausting leadership strategy). Design/methodology/approach The authors tested the hypotheses via moderated regression analyses among two independent groups, managers ( n =241) and non-managers ( n =415). Findings Promotion focus was positively related to managers’ and non-managers’ performance and negatively to non-managers’ sickness absence, while prevention focus did not have any main effects. As expected, managers’ promotion focus was positively related to managers’ sickness absence when managers’ prevention focus was high (i.e. dual regulatory focus). Furthermore, managers’ promotion focus negatively related to managers’ performance when managers’ prevention was high, failing to support the hypothesis. Practical implications Promotion focus should be enhanced by organizations among leaders and employees. The authors also cautiously discuss the possibility of interventions comparing a promotion focus with dual-focus training. Originality/value The authors contribute to the literature by examining the joint (rather than main) effects of promotion and prevention focus on work behavior and the authors address these links among managers and non-managers.
