In this thesis, we used genetically engineered mouse models and a variety of cell-culture based assays to identify genes and pathways that are involved in the development and treatment of invasive... Show moreIn this thesis, we used genetically engineered mouse models and a variety of cell-culture based assays to identify genes and pathways that are involved in the development and treatment of invasive lobular carcinoma (ILC). To identify novel genes and pathways involved in the development of ILCs we employed a Sleeping Beauty (SB)-based insertional mutagenesis screen in conditional Cdh1 knockout mice. We show that active transposon mutagenesis drives ILC formation and analysis of common insertion sites in SB-induced tumors identified a mutually exclusive group of four genes (MYH9, MYPT1/2 and ASPP2), three of which are frequently altered in human ILCs. We then went on to show that these hits not only drive ILC development but also do so through a shared mechanism. We identified that all four hits result in actomyosin relaxation which enables E-cadherin deficient mammary epithelial cells to invade into the mammary stroma and initiate tumor development. In addition, we show that mammary epithelial cells that lose E-cadherin expression can survive in the fibrous stroma directly surrounding the mammary ducts through interactions with components of the basement membrane. Lastly, we used active mobilization of transposons to identify resistance mechanisms to the FGFR inhibitor AZD4547. Show less
ABSTRACT: BACKGROUND: Limited data exist on the impact of living kidney donation on the donor-recipient relationship. Purpose of this study was to explore motivations to donate or accept a (living... Show moreABSTRACT: BACKGROUND: Limited data exist on the impact of living kidney donation on the donor-recipient relationship. Purpose of this study was to explore motivations to donate or accept a (living donor) kidney, whether expected relationship changes influence decision making and whether relationship changes are actually experienced. METHODS: We conducted 6 focus groups in 47 of 114 invited individuals (41%), asking retrospectively about motivations and decision making around transplantation. We used qualitative and quantitative methods to analyze the focus group transcripts. RESULTS: Most deceased donor kidney recipients had a potential living donor available which they refused or did not want. They mostly waited for a deceased donor because of concern for the donors health (75%). They more often expected negative relationship changes than living donor kidney recipients (75% vs. 27%, p = 0.01) who also expected positive changes. Living donor kidney recipients mostly accepted the kidney to improve their own quality of life (47%). Donors mostly donated a kidney because transplantation would make the recipient less dependent (25%). After transplantation both positive and negative relationship changes are experienced. CONCLUSION: Expected relationship changes and concerns about the donors health lead some kidney patients to wait for a deceased donor, despite having a potential living donor available. Further research is needed to assess whether this concerns a selected group. Show less
