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thesisAbstract.txt

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+Hepatocellular carcinoma (HCC) is the most common form of liver cancer, which is the second most prevalent cause of cancer mortalities worldwide. 
+The current standard of care for non-resectable HCC is to combine immunotherapy with targeted therapy, yet the median overall survival is only 19 months. 
+A reasonable question is whether survival could be increased if drugs developed for other purposes were repositioned to support HCC therapy. 
+The Broad Institute�s Connectivity Map (CMap) provides an approach to drug repositioning, essentially translating between diseases, drug compounds, and cellular components. 
+Given a gene signature of a disease, CMap scores compounds within its databases to identify drugs that would most effectively oppose it.
+Most CMap studies are based on disease signatures derived from either bulk tissue or cell lines. 
+Bulk tissue studies co-mingle signals from various cell types, obfuscating the underlying complexity and contributions of the tumor microenvironment (TME), which contains a wide variety of stromal and immune cells. 
+Cell line studies present difficulty in modeling the TME�s full range of signals over time. 
+Drug resistance often challenges therapy, and has been attributed to the dynamic complexity of the TME. 
+CMap could yield more insightful results if applied in the context of single-cell RNA-sequencing (scRNA-seq). 
+Single-cell analysis allows characterization of cell identity and function by attributing details of both malignant cells and the TME to their specific lineages. 
+The impact of this attribution is to isolate the TME�s tumor-supporting and tumor-suppressing mechanisms from the malignancy itself.
+Using previously published scRNA-seq data from 13 HCC patients and a normal tissue donor, the current study identifies 12 key cell types, recognizing both inter- and intra-tumor heterogeneity. 
+When surgical tumor sections are contrasted with sections of healthier tissue, 6428 unique genes are differentially expressed. 
+Requirements of CMap online processing, together with inference of the desirable direction of drug action, reduce these 6428 targets to a core set of 1529 for drug screening. 
+This screening results in a set of 425 compounds for which the drug�s disease-suppressing mechanisms of one cell type appear to be unopposed by disease-promoting mechanisms of others. 
+Using both CMap and scRNA-seq, the current study demonstrates a proof-of-concept for drug discovery tools based on in silico analysis, identifying drugs as candidates for further study.