http://repub.eur.nl/res/aut/11149/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39870/ 2013-04-01T00:00:00Z Purpose: The miRNA-regulating enzymes Dicer and Drosha exhibit aberrant expression in several cancer types. Dicer and Drosha play a crucial role during the angiogenetic process in vitro and, for Dicer, in vivo. We aimed to investigate the potential role of Dicer and Drosha in predicting response to Bevacizumab-based therapy in advanced colorectal cancer (CRC) patients. Methods: Dicer and Drosha mRNA levels were analysed in formalin-fixed paraffin-embedded specimens from patients affected by advanced CRC treated with or without Bevacizumab-containing regimens (n = 116 and n = 50, respectively) and from patients with diverticulosis as control group (n = 20). The experimental data were obtained using qRT-PCR, analysed comparing Dicer and Drosha expression levels in tumour samples versus normal mucosa and then compared to clinical outcome. Results: The tumour samples from Bevacizumab-treated patients showed a significantly higher Drosha expression (P <.001) versus normal mucosa, while Dicer levels did not differ. Intriguingly, we found that low Dicer levels predicted a longer progression-free survival (PFS) (P <.0001) and overall survival (OS) (P =.009). In addition, low Dicer levels were associated with better response to Bevacizumab-based treatments versus high Dicer levels (1.7% complete responses and 53.4% partial responses versus 0% and 32.7%, respectively; P =.0067). Multivariate analysis identified three independent predictors of improved OS: high performance status (PS) (relative risk (RR) 1.45; P =.011), lower organs involvement (RR 0.79; P =.034) and low Dicer expression (RR 0.71; P =.008). Conversely, Drosha levels were not associated with prognosis and outcome associated with treatment. In non-Bevacizumab-treated patients, Dicer and Drosha expression did not correlate with outcome. Conclusion: These findings suggest that low Dicer mRNA levels seem to be independent predictors of favourable outcome and response in patients affected by advanced CRCs treated with Bevacizumab-based therapy. http://repub.eur.nl/res/pub/25705/ 2011-05-13T00:00:00Z Background: Receptor activator of NFkB (RANK), its ligand (RANKL) and the decoy receptor of RANKL (osteoprotegerin, OPG) play a pivotal role in bone remodeling by regulating osteoclasts formation and activity. RANKL stimulates migration of RANK-expressing tumor cells in vitro, conversely inhibited by OPG. Materials and Methods: We examined mRNA expression levels of RANKL/RANK/OPG in a publicly available microarray dataset of 295 primary breast cancer patients. We next analyzed RANK expression by immunohistochemistry in an independent series of 93 primary breast cancer specimens and investigated a possible association with clinicopathological parameters, bone recurrence and survival. Results: Microarray analysis showed that lower RANK and high OPG mRNA levels correlate with longer overall survival (P = 0.0078 and 0.0335, respectively) and disease-free survival (P = 0.059 and 0.0402, respectively). Immunohistochemical analysis of RANK showed a positive correlation with the development of bone metastases (P = 0.023) and a shorter skeletal disease-free survival (SDFS, P = 0.037). Specifically, univariate analysis of survival showed that "RANK-negative" and "RANK-positive" patients had a SDFS of 105.7 months (95% CI: 73.9-124.4) and 58.9 months (95% CI: 34.7-68.5), respectively. RANK protein expression was also associated with accelerated bone metastasis formation in a multivariate analysis (P = 0.029). Conclusions: This is the first demonstration of the role of RANK expression in primary tumors as a predictive marker of bone metastasis occurrence and SDFS in a large population of breast cancer patients. http://repub.eur.nl/res/pub/6872/ 2001-03-30T00:00:00Z This paper analyses the market transformations in heritage tourism destinations when excessive tourism demand determines the emergence of a class of excursionists among visitors. Building on the approach of Keane (1997) and Shapiro (1983), our model highlights some important dimensions of sustainable tourism development. The lesser capacity of excursionists to learn the true quality of the tourist goods increases the convenience for producers to cut back on quality. To continue to serve high quality goods and keep up the reputation of the destination as demand continues to grow, producers need to gain a mark-up on price that might not be sustained in a competitive market. Hence the decline in “high-paying” demand segments which are increasingly susbstituted by visitors with lesser quality expectations. In the end, the dynamics explained with this approach are consistent with – and represent an economic reinterpretation of – the class of evolutionary models known as “destination life cycle”, when they are applied to heritage cities. The regulator achieves a sustainable growth if it could enforce quality or information standards. However, the process should be managed at a spatial level that is rarely matched by formal administrative competencies. Traditional tourism strategies are seldom successful when they try to prevent excessive growth by discouraging daily visits. This model helps to identify alternative and more appropriate policy instruments.