Pharmacogenetics of sunitinib in metastatic renal cell carcinoma

Sunitinib treatment requires a personalized approach, since patients can respond very differently to this drug. Pharmacogenetics may improve our ability to provide a tailored therapy by studying how genetic variations could influence drug response. The objective of this thesis was to find genetic markers that can predict toxicity and efficacy of sunitinib in patients with metastatic renal cell carcinoma. This research builds upon previous findings from candidate gene studies by testing a selection of SNPs based on plausible involvement in pharmacokinetics or pharmacodynamics of the drug of interest. We observed that SNPs located in genes involved in metabolism and drug absorption (CYP3A4, CYP3A5, and ABCB1) are potentially associated with the clearance of sunitinib and its active metabolite. In analogy to this, we confirmed SNP associations from previous studies for SNPs in CYP3A5 and ABCB1 that predict the need for dose reductions and improvement of PFS on sunitinib. Sunitinib-induced toxicity is possibly related to SNPs in CYP3A4 and CYP3A5, and in interleukin genes IL8 and IL13. VEGFR-2 (KDR) rs34231037 G-allele variant carriers were potentially associated with a favorable response to sunitinib. A GWAS learned us that SNPs in chromosome 21 are involved in sunitinib efficacy, probably by influencing drug resistance mechanisms. The research presented in this thesis was performed at the department of Clinical Pharmacy and Toxicology of Leiden University Medical Center, Leiden, The Netherlands. Financial support for the publication of this thesis was provided by Afdelingsfonds Klinische Farmacie & Toxicologie The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 259939.LUMC / Geneeskund

Europees aanhoudingsbevel: een onderzoek naar de gevolgen voor de rechtspositie van de opgeeiste Nederlander

in deze scriptie wordt onderzoek gedaan naar de vraag wat de gevolgen zijn van de invoering van de Overlevingswet voor de rechtspositie van de opgeeiste Nederlander

Multicomponent Reaction Based Synthesis of 1-Tetrazolylimidazo[1,5- a]pyridines

A series of unprecedented tetrazole-linked imidazo[1,5- a]pyridines are synthesized from simple and readily available building blocks. The reaction sequence involves an azido-Ugi-deprotection reaction followed by an acetic anhydride-mediated N-acylation-cyclization process to afford the target heterocycle. Furthermore, the scope of the methodology was extended to diverse R3-substitutions by employing commercial anhydrides, acid chlorides, and acids as an acyl component. The scope for the postmodification reactions are explored and the usefulness of the synthesis is exemplified by an improved three-step synthesis of a guanylate cyclase stimulator

Low-achieving adolescent students' perspectives on their interactions with classmates. An exploratory study to inform the implementation of a social emotional learning program in prevocational education

Social and Emotional Learning programs, designed to enhance adolescents’ social and emotional skills, are implemented in schools worldwide. One of these programs is Skills4Life (S4L), for students in Dutch secondary education. To strengthen this program and adapt it to students’ needs, we conducted an exploratory study on their perspectives on their own social-emotional development, focusing on low-achieving students in prevocational education. We interviewed eleven boys and eleven girls in five focus groups on (1) their general school life experiences, (2) their perceptions and experiences regarding interactions with peers, the problems they encountered in these interactions, and (3) the strategies and skills they used to solve these problems. Driven by findings in related studies initial thematic analyzes were extended using a three-step approach: an inductive, data-driven process of open coding; axial coding; and selective coding, using the social-emotional skills comprised in an often-used SEL framework as sensitizing concepts. Overall, students were satisfied with their relationships with classmates and teachers and their ability to manage their daily interaction struggles. Their reflections on their interactions indicate that the skills they preferred to use mirror the social-emotional skills taught in many school programs. However, they also indicated that they did not apply these skills in situations they experienced as unsafe and uncontrollable, e.g., bullying and harassment. The insights into adolescents’ social-emotional skills perceptions and the problems they encountered with peers at school presented here can contribute to customizing school-based skills enhancement programs to their needs. Teacher training is required to help teachers gain insight into students’ perspectives and to use this insight to implement SEL programs tailored to their needs.</p

Low-achieving adolescent students' perspectives on their interactions with classmates. An exploratory study to inform the implementation of a social emotional learning program in prevocational education

Social and Emotional Learning programs, designed to enhance adolescents’ social and emotional skills, are implemented in schools worldwide. One of these programs is Skills4Life (S4L), for students in Dutch secondary education. To strengthen this program and adapt it to students’ needs, we conducted an exploratory study on their perspectives on their own social-emotional development, focusing on low-achieving students in prevocational education. We interviewed eleven boys and eleven girls in five focus groups on (1) their general school life experiences, (2) their perceptions and experiences regarding interactions with peers, the problems they encountered in these interactions, and (3) the strategies and skills they used to solve these problems. Driven by findings in related studies initial thematic analyzes were extended using a three-step approach: an inductive, data-driven process of open coding; axial coding; and selective coding, using the social-emotional skills comprised in an often-used SEL framework as sensitizing concepts. Overall, students were satisfied with their relationships with classmates and teachers and their ability to manage their daily interaction struggles. Their reflections on their interactions indicate that the skills they preferred to use mirror the social-emotional skills taught in many school programs. However, they also indicated that they did not apply these skills in situations they experienced as unsafe and uncontrollable, e.g., bullying and harassment. The insights into adolescents’ social-emotional skills perceptions and the problems they encountered with peers at school presented here can contribute to customizing school-based skills enhancement programs to their needs. Teacher training is required to help teachers gain insight into students’ perspectives and to use this insight to implement SEL programs tailored to their needs.</p