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1 Cover Page The handle holds various files of this Leiden University dissertation. Author: Bronkhorst, Inge Title: The inflammatory microenvironment of uveal melanoma Issue Date:
2 Acknowledgements (Dankwoord)
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4 Acknowledgements 231 Direct na mijn afsluitend co-schap stond er nog een wetenschappelijke stage gepland. Ik had nooit verwacht dat dit zou leiden tot een promotieonderzoek, maar gaandeweg merkte ik dat ik naar iets toewerkte en kreeg gelukkig de kans om dit voort te zetten. Naast alle patiënten die bereid waren mee te werken, mijn mede auteurs en subsidiegevers wil ik iedereen bedanken, die mij de afgelopen jaren heeft geholpen, met en tijdens mijn onderzoek. Mijn promotor, prof. dr. Luyten, dank voor het vertrouwen en voor het feit dat ik vrij ben gelaten in het realiseren van mijn wetenschappelijke ambities. Dr. Jager, beste Martine, als ik weer eens het tempo had opgeschroefd, werden mijn manuscripten door jou vaak binnen een dag nagekeken en voorzien van waardevolle opmerkingen. Jij hebt voor mij de mogelijkheid gecreëerd om me te ontwikkelen en ik ben je hier ontzettend dankbaar voor. Ik heb een leuke tijd gehad op het Lab Oogheelkunde en samenwerkende afdelingen. Herbert, dank voor je gezelschap tijdens congressen in o.a. Fort Lauderdale en Kreta, je cornea-monologen tijdens de melanoom labbesprekingen en voor je betrokkenheid tijdens mijn persoonlijke en werkgerelateerde ergernissen. Fijn dat je mijn paranimf wilt zijn! Pieter, altijd een scherpe kritische blik en een onbegrensde genetische kennis, ik waardeer het zeer dat je de tijd hebt genomen om mij vanalles uit te leggen en mij aan het PCRen wist te zetten. Mijn voorgangers: Long, Mariam en Willem, al jullie inzet in het melanoom onderzoek heeft ervoor gezorgd dat ik op een rijdende trein kon stappen. Hopelijk dendert deze nog lang voort. Mijn naaste (dagelijkse) wetenschapscollega s: ladies first, Mieke dank voor de logistieke ondersteuning, Arlette, Gwyneth, Khanh, de expats Nisha en Tina, werkmodus buurman/dj Mark, Sake in de vissenkom, Sizar, Cao en vele studenten. Dank voor alle leuke momenten op het lab/p3-21 en natuurlijk de gezellige labuitjes! Vele uren heb ik bij de afdeling pathologie doorgebracht. Katja, toen ik als medischstudente bij je aankwam wist je me meteen in het lab aan het werk te zetten en ik kon altijd met vragen bij je terecht. Frans, bedankt voor je hulp bij het maken van de scans met de confocaal microscoop. Mijn dank gaat tevens uit naar alle aanwezigen bij de labmeetings van Tumor Immunology and Clinical Oncology. Bedankt voor de mogelijkheid om mijn onderzoeksdata te presenteren. Jullie kritisch commentaar op de studies heb ik erg gewaardeerd. In het bijzonder, Sjoerd en Thorbald, jullie hulp bij het immunologische deel van mijn onder-
5 232 Acknowledgements zoek is van grote waarde geweest. Ik heb veel van jullie geleerd. Dank aan Bart, voor de tussendoor samenwerking aan het BAP1 project, wat hopelijk nog een mooi vervolg krijgt. Moniek en Eveline, ik ben enorm blij dat dankzij jullie de differentiatie assays mogelijk waren, dank voor jullie flexibiliteit. Geert, hartelijk dank voor je hulp, je hebt mij erg geholpen om statistische methoden te begrijpen en toe te passen. A special thanks to dr. Chen and all the people from the Chen Lab at Schepens Eye Research Institute in Boston, USA. A completely different research field than I was used to, but you have taught me a lot about the retinal ganglion cells. I really enjoyed the scientific environment in and around your lab. Alle collegae van de afdeling Oogheelkunde. De overgang van het lab naar de kliniek was even wennen; bedankt voor jullie begrip en support. Lieve vrienden vaak ver weg maar toch dichtbij ik wil jullie bedanken voor de fijne avonden, weekenden of vakanties en alle andere momenten waar dan ook. Altijd gezellig om weer samen te zijn, wat voor mij de stress van het werk haalt. Myriam, jij mag vandaag mijn paranimf zijn. Een ambitieuze dame in Bruxelles, en je weet me altijd weer te inspireren door je optimisme. Jolien, Manon en Sara, ik vind het heel bijzonder dat we van jongs af aan vriendinnen zijn. Dank voor jullie eeuwige interesse. Lieve familie, dank voor jullie steun. Lieve Papa en Mama, en mijn zusje Karen samen met Peter, en mijn altijd attente Oma. Jullie staan altijd voor me klaar. Dat geldt natuurlijk ook voor mijn schoonfamilie Jan en Ans, Marjolein en Albert, heel erg bedankt voor jullie betrokkenheid. Sjon, jij bent er altijd voor mij en bent mijn allerliefste. Ik kijk ernaar uit om de wereld samen met jou verder te ontdekken.
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8 Curriculum Vitae Inge Bronkhorst was born on the 5th of August, 1985, in Drunen, the Netherlands. After graduating from the Stedelijk Gymnasium in s-hertogenbosch in 2003 she started her medical training at the Radboud University Nijmegen. In 2009, the author completed her clinical rotations with a program for student doctors in low-income countries at the Diponegoro University in Semarang, Indonesia. Back in the Netherlands, she moved to Den Haag, and started with a three months scientific training on M2 macrophages in uveal melanoma at the department of Ophthalmology of the Leiden University Medical Center (LUMC) under supervision of Dr. Martine J. Jager. After receiving her M.D. degree in 2010, a MD/PhD-trajectory position supported by the Board of Directors LUMC created the opportunity to continue this work as her research project. In the first year she was awarded the Dutch Association for Research in Vision and Ophthalmology (ARVO) Chapter Affiliate travel grant for the best presentation at the ARVO-NED day in Groningen amongst young researchers in the Netherlands. At the 2012 first Dutch Ophthalmology PhD-Students (DOPS) conference in Nijmegen, she received the award for best presentation content. During her PhD training, the author presented her work in Europe, South-America, and the United States. An awarded Nelly Reef Fund grant created the opportunity to visit and participate in a research project regarding the role of the immune system in retinal ganglion cell loss at the Schepens Eye Research Institute/ Harvard Medical School, United States. The author commenced her residency in Ophthalmology under the supervision of Prof. Dr. Gré P.M. Luyten in November 2012.
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10 List of publications 1. Ly LV, Bronkhorst IH, van Beelen E, Vrolijk J, Taylor AW, Versluis M, Luyten GP, Jager MJ. Inflammatory cytokines in eyes with uveal melanoma and relation with macrophage infiltration. Invest Ophthalmol Vis Sci Nov; 51(11): Bronkhorst IH, Ly LV, Jordanova ES, Vrolijk J, Versluis M, Luyten GP, Jager MJ. Detection of M2-macrophages in uveal melanoma and relation with survival. Invest Ophthalmol Vis Sci Feb 3; 52(2): Dennaoui J, Bronkhorst IH, Ly LV, de Wolff-Rouendaal D, Keunen JE, Schalij-Delfos NE, Jager MJ. Changes in immunological markers and influx of macrophages following trans-scleral thermotherapy of uveal melanoma. Acta Ophthalmol May; 89(3): Bronkhorst IH, Maat W, Jordanova ES, Kroes WG, Schalij-Delfos NE, Jager MJ. Effect of heterogeneous distribution of monosomy 3 on prognosis in uveal melanoma. Arch Pathol Lab Med Aug; 135(8): Bronkhorst IH and Jager MJ. Uveal Melanoma: The Inflammatory Microenvironment. J Innate Immun. 2012; 4(5 6): Van Essen TH, Bronkhorst IH, Maat W, Verduyn W, Roelen DL, Luyten GP, Jager MJ. A comparison of HLA genotype with inflammation in uveal melanoma. Invest Ophthalmol Vis Sci May 4; 53(6): Bronkhorst IH, Vu THK, Jordanova ES, Luyten GPM, van der Burg SH, Jager MJ. Different subsets of tumor-infiltrating lymphocytes correlate with macrophage influx and monosomy 3 in uveal melanoma. Invest Ophthalmol Vis Sci Aug 9; 53(9): Nagarkatti-Gude N, Bronkhorst IH, van Duinen SG, Luyten GPM, Jager MJ. Cytokines and chemokines in the vitreous fluid of eyes with uveal melanoma. Invest Ophthalmol Vis Sci Oct 1; 53(11): Vu TH, Bronkhorst IH, Versluis M, Marinkovic M, van Duinen SG, Vrolijk J, Luyten GPM, Jager MJ. Analysis of inflammatory cells in uveal melanoma after prior irradiation. Invest Ophthalmol Vis Sci Jan 14; 54(1):
11 238 List of publications 10. Bronkhorst IH, Jager MJ. Inflammation in uveal melanoma. Eye (Lond) Feb; 27(2): Jager MJ, Bronkhorst IH. Chapter Cancer Immunology. Section 1 Basic Principles. Eds. Singh and Damato: Clinical Ophthalmic Oncology, 2nd Edition El Filali M, Versluis M, Bronkhorst IH, Baghat A, Luyten GP, Jager MJ, van der Velden PA. ERK activation and monosomy 3 are associated with Src expression in uveal melanoma and may serve as biomarkers for Dasatinib treatment. Article submitted 13. Razzaq L, Versluis M, Bronkhorst IH, Marinkovic M, Luyten GP, de Keizer R, de Gruijl F, Jager MJ, van der Velden PA. GNAQ and GNA11 mutation distribution in uveal melanoma points to light dependent and light independent mutation mechanisms. Article submitted 14. Van Essen TH, van Pelt S, Bronkhorst IH, Versluis M, Luyten GP, van den Elsen PJ, van der Velden PA, Jager MJ. HLA expression in uveal melanoma is not influenced by gain of chromosome 6p. Article submitted
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Acknowledgements (Dankwoord)
Acknowledgements (Dankwoord) Na 3 jaar hard zwoegen op het laboratorium van de oogheelkunde is het boekje eindelijk af. In het begin waren er wat moeilijkheden, omdat ik vanaf nul moest beginnen. Allereerst
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