Theses and Dissertations

Hepatocellular Carcinoma (HCC) is one of the main types of liver cancer accounting for 75% of cases and is the second deadliest cancer worldwide. Chronic Hepatitis B (HBV) and Hepatitis C (HCV) remain one of the most important global risk factors and account for 80% of all HCC cases. HCC also exhibits sex-differences with significantly higher incidence and worse prognosis in males. The mechanistic basis of these sex-differences is poorly understood. To identify genes and pathways that are sex-differentially expressed in viral-mediated HCC, we performed differential expression analysis on tumor vs. tumor adjacent samples that were stratified based on sex, viral etiology, and both. The differentially expressed genes were then used in a pathway enrichment analysis to identify potential pathways of interest. We found differentially expressed genes in both sexes and both etiologies. 65 genes were unique to females and 184 genes unique to males. 381 genes are unique to HBV and 195 genes are unique to HCV. We also found pathways that were significantly enriched by the differentially expressed genes. Ten pathways unique to the female tumor tumor-adjacent comparison and a majority of those pathways were a part of the cell cycle. Four enriched pathways unique to male tumor tumor-adjacent and three of them were a part of the immune system. There were no pathways unique to either etiology, but seven pathways shared by both etiologies. Two were a part of the cell cycle and one involved lipid metabolism. These differentially expressed genes and significant pathways are potential targets for individualized therapeutics and diagnostics for HCC.

Obesity has reached epidemic proportions all around the world, and it has doubled in prevalence in both adults and children in over 70 countries from 1980 to 2015 (Afshin et al., 2017). Excessive weight gain in this proportion has been shown to negatively affect human cognition, reward neurocircuitry, stress responsiveness, and quality of life (Morris et al., 2015). Obesity is an example of a complex interaction between the environment (i.e., high-fat diets) and heredity (i.e., polygenic patterns of inheritance). The overconsumption of a high-fat diet (HFD) is an environmental factor that commonly induces weight gain (Hariri & Thibault, 2010). Two dietary-induced phenotypes have been observed in rats as a bimodal distribution of weight gain: obesity-prone (OP) and obesity-resistant (OR). Levin et al. (1997) investigated male and female HFD-fed Sprague-Dawley rats designated as OR when their weight gains were less than the heaviest chow-fed controls, and OP when their weight gains were greater than the heaviest chow-fed controls. OP rats showed greater weight gain, similar energy intake (EI), and similar feed efficiency (FE) compared to OR rats. Pagliassotti et al. (1997) designated male HFD-fed Wistar rats as OP and OR based on upper and lower tertiles of weight gain. OP rats displayed greater weight gain and EI than OR rats. These investigations highlight a predicament regarding rodent research in obesity: independent variables such as rat age, gender, strain, distribution of dietary macronutrients, and fatty acid composition of HFD and chow vary considerably, making it challenging to generalize data. Our experiment utilized outbred male Sprague-Dawley rats (5-6 weeks) administered a chow diet (19% energy from fat; 3.1 kcal/g) and a lard-based HFD (60% energy from fat; 5.24 kcal/g) over eight weeks. Separate rat populations were examined over three consecutive years (2017-2020), and independent obesogenic environmental variables were controlled. We investigated the persistence of weight gain, EI, and FE in HFD-fed rats inclusive of a population of designated OP and OR rats based on tertiles of weight gain. We define persistence as being p > 0.05. We hypothesize that the profiles (periodic data) of the dependent variables (weight gain, EI, FE) will be similar and persistent throughout the three separate years, but the magnitudes (cumulative data) of the dependent variables will differ. Our findings demonstrate that HFD, OP, and OR groups were persistent for periodic and cumulative weight gain, along with FE across the three consecutive independent years. Our findings also demonstrate impersistence for periodic EI in all groups, along with impersistence in cumulative EI for CHOW, OP, and OR groups. Therefore, our results allude to an inconsistent relationship between EI and weight gain, indicating that EI does not completely explain weight gain. Thus, the weakness between EI and weight gain relationship may be attributed to a polygenic pattern of inheritance, possibly signaling a weight setpoint regardless of EI.

Obesity has reached epidemic proportions all around the world, and it has doubled in prevalence in both adults and children in over 70 countries from 1980 to 2015 (Afshin et al., 2017). Excessive weight gain in this proportion has been shown to negatively affect human cognition, reward neurocircuitry, stress responsiveness, and quality of life (Morris et al., 2015). Obesity is an example of a complex interaction between the environment (i.e., high fat diets) and heredity (i.e., polygenic patterns of inheritance). The overconsumption of a high-fat diet (HFD) is an environmental factor that commonly induces weight gain (Hariri & Thibault, 2010). Two dietary-induced phenotypes have been observed in rats as a bimodal distribution of weight gain: obesity-prone (OP) and obesity-resistant (OR). Levin et al. (1997) investigated male and female HFD-fed Sprague-Dawley rats designated as OR when their weight gains were less than the heaviest chow-fed controls, and OP when their weight gains were greater than the heaviest chow-fed controls. OP rats showed greater weight gain, similar energy intake (EI), and similar feed efficiency (FE) compared to OR rats. Pagliassotti et al. (1997) designated male HFD-fed Wistar rats as OP and OR based on upper and lower tertiles of weight gain. OP rats displayed greater weight gain and EI than OR rats. These investigations highlight a predicament regarding rodent research in obesity: independent variables such as rat age, gender, strain, distribution of dietary macronutrients, and fatty acid composition of HFD and chow vary considerably, making it challenging to generalize data. Our experiment utilized outbred male Sprague-Dawley rats (5-6 weeks) administered a chow diet (19% energy from fat; 3.1 kcal/g) and a lard-based HFD (60% energy from fat; 5.24 kcal/g) over eight weeks. Separate rat populations were examined over three consecutive years (2017-2020), and independent obesogenic environmental variables were controlled. We investigated the persistence of weight gain, EI, and FE in HFD-fed rats inclusive of a population of designated OP and OR rats based on tertiles of weight gain. We define persistence as being p > 0.05. We hypothesize that the profiles (periodic data) of the dependent variables (weight gain, EI, FE) will be similar and persistent throughout the three separate years, but the magnitudes (cumulative data) of the dependent variables will differ. Our findings demonstrate that HFD, OP, and OR groups were persistent for periodic and cumulative weight gain, along with FE across the three consecutive independent years. Our findings also demonstrate impersistence for periodic EI in all groups, along with impersistence in cumulative EI for CHOW, OP, and OR groups. Therefore, our results allude to an inconsistent relationship between EI and weight gain, indicating that EI does not completely explain weight gain. Thus, the weakness between EI and weight gain relationship may be attributed to a polygenic pattern of inheritance, possibly signaling a weight setpoint regardless of EI.