Understanding the meaning of the human genome codes is one of the keys to unlock the secrets of life. Despite having a fairly good grasp of the sequences of the human genome, we are still far from... Show moreUnderstanding the meaning of the human genome codes is one of the keys to unlock the secrets of life. Despite having a fairly good grasp of the sequences of the human genome, we are still far from understanding the functions of most parts of the genome and their involvement in diseases. The application of the CRISPR-Cas9 genome-editing systems revolutionized the way to study the function of the genome, not only the coding genes but also the non-coding genome. In this thesis, multiple CRISPR screening systems were designed and used to study the transport of chemotherapeutic drugs and the functions of non-coding regulatory elements in distinct biological pathways. Using the CRISPR screening systems, we identified previously known drug exporters such as ABCB1 and ABCG2 and a new doxorubicin importer gene SLC2A3 (GLUT3). We used an innovative dual-CRISPR system to study the functions of noncoding regulatory elements (NCREs) in their endogenous genomic environment. We provide the broad research community with a new tool to study the functions of NCREs in different biological aspects, and it is expected many more important NCREs will be discovered in the future, which would not only be relevant to fundamental biology but also to human diseases. Show less
In conclusion, this thesis proposes a new approach for reconstruction of coronary artery and the implanted BRS by fusion of OCT and X-ray angiography to analyze intracoronary ESS in vivo. The... Show moreIn conclusion, this thesis proposes a new approach for reconstruction of coronary artery and the implanted BRS by fusion of OCT and X-ray angiography to analyze intracoronary ESS in vivo. The studies conducted in this thesis demonstrate the feasibility of the proposed approach to analyze the detailed local coronary hemodynamics in patients, including the SS patterns after BRS implantation in coronary bifurcations. We observed that in vivo assessment of ESS was closely related to: (1) reconstruction of the side branches; (2) reconstruction of the BRS; (3) patient-specific flow; (4) post-processing portion size in which ESS was calculated. Based on these findings, we propose the following standard analysis procedures for assessment of intracoronary ESS in vivo: (1) reconstruct both the main vessel and its side branches to create a more accurate geometric model. (2) reconstruct BRS in naturally-bent shape and include it in the CFD analysis for assessment of ESS after BRS implantation; (3) use patient-specific coronary flow in the CFD analysis to have more accurate boundary condition; (4) set the proportion size according to the interrogated region of interest for quantification of the ESS in portions. Show less
In this thesis, we identify and/or analyse a couple of regulators of the TGF-β and Wnt signal transduction pathways that play important roles in breast cancer. Our aim was to understand how these... Show moreIn this thesis, we identify and/or analyse a couple of regulators of the TGF-β and Wnt signal transduction pathways that play important roles in breast cancer. Our aim was to understand how these regulators affect the different steps of these pathways, including receptor activation, post-translational modification of other transducing molecules, target gene transcription, as well as crosstalk with other cell signaling pathways. Insight in these mechanisms is expected to help to design strategies for therapeutic intervention in TGF-β and Wnt mediated breast cancer progression. Show less