VictorJuiz/thesis huggingface dataset:
Overcoming Resistance to EZH2 Inhibition in Diffuse Large B-cell Lymphoma

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common non-Hodgkin lymphoma subtype, with relapse occurring in 30-40% of patients associated with increased resistance to chemotherapy. Gain of function mutations in EZH2, a gene encoding a histone methyltransferase, is common in DLBCL (~22%), yet response rates to tazemetostat, a selective small molecular inhibitor of EZH2, is low (17%). We had previously found that DOT1L knockout sensitizes EZH2 inhibitor-resistant cells to the effect of tazemetostat. Hence, we postulated that inhibition of DOT1L with a small molecule inhibitor (pinometostat) might increase the sensitivity of DLBCL to the effect of tazemetostat. Herein, we observed synergistic drug effects with combination therapy across multiple DLBCL cell lines. Moreover, we observed that DOT1L, with or without EZH2 inhibition, results in upregulation of genes involved in interferon signalling and B-cell differentiation. Our results thus far support a novel approach to overcoming resistance to EZH2 inhibition in DLBCL.

Keywords: Cancer
Combination Therapy
DNA
Epigenetics
Lymphoma
Relapse
Advisor: Kridel, Robert N
Aortic Pulse Wave Velocity and Kinetic Energy Loss as Biomarkers for Aortic Dissection Risk

Ascending aortic tissue biomechanics have been shown to reflect the histopathology of aneurysmal tissue and dissection risk. Accurate in vivo assessment of biomechanics may therefore improve current methods of evaluating dissection risk. Five in vivo imaging-based biomechanical parameters were investigated in this thesis as potential indicators of dissection risk: distensibility, compliance, arterial stiffness index (ASI), aortic pulse wave velocity (aPWV) and kinetic energy loss (KEL). Patients at higher risk of aortic dissection were identified based on comparison of ex vivo stiffness, energy loss and delamination strength between aneurysm and control populations. aPWV and KEL classified higher vs. lower risk patients with higher accuracy, greater sen- sitivity, and lower coefficient of variation than distensibility, compliance, and ASI. Thus, of the parameters assessed, aPWV and KEL best reflect tissue biomechanics and show potential as in vivo indicators of dissection risk.

Advisor: Simmons, Craig
Chung, Jennifer
Reaching across the Aisle: An Investigation of Inter-political Group Contact

According to the contact hypothesis (Allport, 1954), social interactions and relationships between members of opposing groups can reduce prejudice. This project explores contact between political groups with a meta-analysis of the contact effect on affective polarization and a survey study that examines intergroup anxiety as a barrier to inter-political group contact. Compiling 21 effects from 15 samples, the meta-analysis found a significant but small negative relationship between contact and prejudice towards the political outgroup (r = -.16, p

Keywords: Intergroup contact
Political psychology
Advisor: Page-Gould, Elizabeth
Improving the Efficacy of Double-negative T-Cells (DNTs) Against Lung Cancer: Chimeric Antigen Receptor-transduced DNTs as a Potential Treatment

Lung cancer is the leading cause of cancer-related mortalities, and better treatments are required. Double-negative T-cells (DNTs) are CD3+CD4-CD8- T-cells with potential as an off-the-shelf cellular therapy. They exhibit antitumor activity against lung cancer, but are not curative. Existing DNT potency can thus be improved, such as by the addition of a chimeric antigen receptor (CAR). CAR T-cell therapy is highly effective for hematological malignancies but shows limited success in solid tumors. In this study, anti-CD19 CAR (CAR19)-DNTs were significantly more cytotoxic than non-transduced (NT)-DNTs against A549 lung cancer cells modified to express CD19. CAR19-DNTs safely and effectively inhibited A549-CD19 tumor growth in a xenograft model and displayed increased tumor infiltration compared to NT-DNTs. We demonstrated for the first time that DNT cytotoxicity against lung cancer can be enhanced by a CAR, and CAR-DNTs may be an effective treatment for solid tumors if the cancer expresses an appropriate target antigen.

Keywords: Adoptive cellular therapy
CAR T-cell therapy
Double-negative T-cells
Immunotherapy
Lung cancer
Advisor: Zhang, Li
Elucidating the Role of Extracellular Vesicles during Spinal Development

Idiopathic scoliosis (IS) is a three dimensional curvature of the spine making up majority of scoliosis cases, yet with unknown etiology. Studying this condition has been difficult due to the genetic variability of those with IS as well as the lack of faithful animal models to recapitulate the natural progression of curvature formation. Our zebrafish models of IS have cerebrospinal fluid (CSF) flow defects as well as upregulation of immune and complement genes. Although the link between CSF flow defects and neuroinflammation remains unknown, it is suggested that a signalling factor secreted into CSF is not being properly distributed and modulating inflammation levels. Previous work has shown that extracellular vesicles (EVs), more particularly exosomes and ectosomes, can mediate inflammatory signals. I investigated the potential role of these vesicles in scoliosis pathogenesis by establishing zebrafish models to examine EV dynamics in vivo, possibly revealing more insight to the mechanism of IS.

Advisor: Ciruna, Brian
The Effect of Important Food Sources of Fructose-containing Sugars and Strategies to Reduce Sugar-sweetened Beverages on Markers of Non-alcoholic Fatty Liver Disease

Whether the effects of fructose-containing sugars on non-alcoholic fatty liver disease (NAFLD) is mediated by the food matrix is unclear. We thus conducted a systematic review and meta-analysis, where sixty-seven trial comparisons (n=1877) were included for analysis. The evidence indicates that excess energy as sugar-sweetened beverages (SSBs) leads to an increase intrahepatocellular lipid (IHCL) and alanine aminotransferase. Since SSBs are a viable health target, the best strategy to reduce SSB intake is needed. We therefore conducted a sub-study within the STOP Sugars NOW trial to evaluate the effect of non-nutritive sweetened beverages (NSBs) and water to reduce SSBs in 30 overweight and obese participants over 4 weeks on NAFLD measures. Using water to replace SSBs significantly decreased IHCL, but this was not seen when NSBs replaced SSBs or NSBs were compared to water. Energy control and food source appear to be mediators of the effect of fructose-containing sugars on NAFLD.

Keywords: food sources
fructose
non-alcoholic fatty liver disease
sugars
Advisor: Sievenpiper, John L
Constructing Hypomorphic and Null-suppressed Alleles of Human Essential Genes to Map Genetic Interactions

The current limitation in mapping all pairwise genetic interactions (GIs) in a model human cell line is that the number of measurements required is an order of magnitude greater than budding yeast, the only organism to-date where all pairwise GIs have been mapped systematically. This problem of scale for a human cell model requires the prioritization of query genes. In yeast, essential genes were found to represent GI hubs, demonstrating that essential genes are a good way to prioritize genes for surveying GIs. However, there is no method of creating human essential gene ‘queries’ without causing the cells to die. My overarching goal is to develop a method for generating essential gene queries in a model human cell line. I constructed hypomorphic alleles for four core essential genes (TUBB, POLR2A, CCT3 and TCP1), validated partial loss-of-function phenotypes, and demonstrated the effectiveness of hypomorphs for exploring GIs in essential genes.

Keywords: CRISPR
essntial gene
genetic interactions
Advisor: Boone, Charles
Moffat, Jason
Development of an Oligomeric Injectable Polyether-Polyester-Urethane-Urea Adhesive to Deliver Non-steroidal Anti-inflammatory Drugs for Osteoarthritic Patients

Osteoarthritis is the most common form of arthritis, resulting in inflammation of the joints. The field’s focus is on therapeutic interventions with intra-articular injections receiving increasing attention. A challenging limitation has been the short retention of these therapeutics, thereby requiring frequent injections. To overcome this disadvantage, the thesis investigates a novel amphiphilic adhesive thermoresponsive gel comprised of polyethylene glycol and polycaprolactone backbone with terminal adhesive domains linked with di-isocyanates as a drug delivery vehicle. It had comparable compressive moduli to the human meniscus, stable wet mass over 21 days, and the presence of chemical crosslinking. Celecoxib was encapsulated into the vehicle in which greater than 60% cumulative release was observed in vitro over 42 days. Lastly, a leaching experiment assessed the gel’s biocompatibility, metabolically active chondrocytes were shown when supplemented with catalase for seven days. This work demonstrates the use of an oligomeric thermoresponsive gel as a drug delivery vehicle.

Keywords: Dopamine
Drug Delivery
Polymer Chemistry
Thermoresponsive Hydrogel
Advisor: Santerre, Paul
Sone, Eli
Cognition and Estrogens: A Qualitative Exploration of Cognitive Change in BRCA1/2 Carriers Post-Oophorectomy

Estradiol (E2) deprivation accompanying menopause is a risk factor for Alzheimer’s Disease (AD). Early life bilateral-salpingo oophorectomy (BSO; ovarian and fallopian tube removal) results in an immediate cessation of E2 and confers a compounded risk of AD in later life. Yet how women experience cognitive changes following BSO is unknown. Subjective cognitive decline (SCD) is considered a harbinger of AD, thus I wondered if women with BSO experienced SCD. Moreover, given that SCD, by definition, is subjective I wanted to know how it is experienced. Therefore, I interviewed 14 women post-BSO which revealed rich descriptions of cognitive changes. Women also endorsed older subjective ages due to their physical symptoms and the cultural baggage of entering menopause at a young age. This study is the first to provide women’s own experiences of their cognitive health after early life BSO, providing insights into the oft-overlooked impact of BSO on women’s brain health.

Keywords: Alzheimer's disease
BRCA
Menopause
Oophorectomy
Qualitative
Subjective cognitive decline
Advisor: Einstein, Gillian
"The Average Counsellor Wouldn't Know": Exploring How General Health Practitioners Understand and Respond to Domestic Violence

Individuals experiencing and perpetrating domestic violence are frequently in contact with general health and mental health services, which must be prepared to respond. Through interviews with general service providers (n=17), including psychologists and nurses, the present study uncovered ways in which domestic violence-related risks are, and are not, recognized and responded to within general health and mental health practice. Qualitative analysis revealed that service providers possess basic knowledge of risk factors but frequently lack the organizational direction required for effective follow-up. Implications for future research and practice include further examination of system-level practices and ensuring the fundamental organizational conditions to allow providers to address domestic violence confidently and effectively.

Keywords: domestic violence
health care
intimate partner violence
mental health
risk assessment
safety planning
Advisor: Scott, Katreena L
Genes, Environments, and Drosophila Social Behaviour

Drosophila melanogaster behaviour is influenced by the social environment. Under high-density conditions larvae will cooperatively forage by aggregating into clusters and digging into food media. I investigated whether the foraging (for) gene contributes to variation in cooperative foraging behaviour. Two allelic variants of for, known as rover (forR) and sitter (forS), differ in their degree of larval cooperation, with rovers forming significantly fewer feeding clusters than sitters. Genetic analysis using a complete null mutant (for0) showed that for influences larval cooperative foraging. Altering the dosage of for provided evidence that for expression levels mediate cooperation in a non-linear fashion. I discuss the significance of genetic variation in cooperation from the perspectives of the relative fitness of rover and sitter variants, the ecology of Drosophila populations in nature, and the evolution of eusocial species.

Keywords: behaviour
cooperation
Drosophila
foraging
genetics
larvae
Advisor: Sokolowski, Marla B
Ketamine Mitigates Persistent Recognition and Spatial Memory Deficits after Sevoflurane Anesthesia in Mice

Postoperative delirium is a common complication in older adults, yet there are no effective pharmacological treatments. Several studies have found that ketamine, administered intraoperatively at a subanesthetic dose, attenuates postoperative cognitive impairments. However, other studies have found no such effects. Notably, ketamine prevents an anesthetic-induced sustained increase in α5GABAA receptor activity, and this increase has been associated with persistent memory impairments in mice. Given these results, we hypothesize that ketamine prevents memory deficits after general anesthesia in mice. We tested two general anesthetic drugs: the inhalational anesthetic sevoflurane and the injectable anesthetic etomidate. Using behavioral assays, we show that ketamine mitigates sevoflurane-induced sustained recognition and spatial memory deficits in mice. However, etomidate did not result in persistent impairments in recognition memory, so the effects of ketamine on etomidate anesthesia were not studied. Our study provides preclinical data which supports ketamine’s cognitive sparing properties against general anesthetic drugs.

Keywords: Etomidate
Ketamine
Mice
Recognition Memory
Sevoflurane
Spatial Memory
Advisor: Orser, Beverley A
Hardware-efficient Accelerators for Mask Generation in Coded-exposure Cameras

A Coded-Exposure-Pixel image sensor is an advanced image sensor with the programmability of the exposure per pixel, using codes ”mask data,” for various applications such as autonomous driving,3D imaging; mask data rate reaches 64Gbpsfor FHD cameras. The state-of-the-art camera system generates and stores the mask data into off-chip DRAM to be shipped to the camera; the current system suffers from high energy consumption, limited input bandwidth, and requires a high input data rate. This thesis presents two approaches for mask generation: on-chip mask generation and shipping compressed mask data to be decoded on-chip. The on-chip mask generation is proposed through a custom hardware accelerator and RISC-V subsystem. The second approach is introduced through a novel Huffman decompression accelerator. The aforementioned solutions outperform the current system in energy consumption, input bandwidth, and input data rate. These solutions are fabricated in 65nmtechnology as a stacked System-On-Chip to the Coded-Exposure cameras.

Keywords: Camera
Coded-exposure
Custom accelerators
Huffman encoding
RISC-V
System-on-chip
Advisor: Genov, Roman
Identification of Novel Genes associated with an Increased Risk of Breast Cancer

Genetic susceptibility plays an important role in the etiology of breast cancer. Currently, all known breast cancer susceptibility genes account for approximately 50% of familial cases; the rest of the genes are unknown. The purpose of this study was to identify novel breast cancer genes in a cohort of BRCA1 and BRCA2 negative Bahamian breast cancer patients. Primarily, we conducted whole-exome sequencing of germline DNA of 96 Bahamian breast cancer patients to identify candidate genes. These genes were further analyzed in a cohort of 387 Bahamian cases and 653 matched controls. We detected an association between 4 genes and breast cancer development. The gene DCLRE1C is involved in DNA repair via non-homologous end joining, RAD51C and XRCC3 are involved in homologous-recombination repair pathways, and DDX19B plays a key role in mRNA regulation These findings can enhance screening for people at risk and offering them preventive measures.

Keywords: Breast cancer
Cancer
Gene disovery
Genetics
Hereditary breast cancer
Molecular genetics
Advisor: Akbari, Mohammad R
Social Inequalities in Student Occupational Expectations in Canada, England, and the United States

As student occupational expectations have been found to predict adult occupational outcomes, the disproportionately low rates of occupational attainment among low SES and minoritized groups raise concern. This research compares the levels of social inequality in student occupational expectations in Canada, England, and the United States of America. Using the 2018 Programme for International Student Assessment, the outcome is measured by students expected occupational status, and the key independent variable used to measure SES is parental occupational status. This study has found that the correlation between student occupational expectations and parental occupational status vary in strength across the three countries. Canada shows a stronger relationship than England and the United States, after controlling for other independent variables, including parental education, home possessions, gender, immigration status, and academic achievement. The study intends to investigate the influences of such correlation and explain away the outcomes in a country-specific context.

Advisor: Chmielewski, Anna K
Evaluating Novel Biomarkers for Ovarian Cancer Diagnosis

Ovarian cancer is the deadliest gynecological cancer. Efficient diagnosis of ovarian cancer is challenging due to the limitations of current biomarkers, including CA125’s low specificity. We investigated arresten and two ovarian cancer specific glycoforms of CA125 alongside the current biomarker CA125 in plasma samples of 413 cases and 394 controls. Four biomarker concentrations were combined with age and menopausal status to make a diagnostic model based on the XGBoost machine learning algorithm. The multivariate model produced a sensitivity of 88.1% and a specificity of 93.3%, outperforming CA125 alone with a sensitivity and specificity of 87.2% and 79.0%, respectively. Focusing on the deadlier type II ovarian tumours that present in stage II and higher improved the model further, with a sensitivity of 91.1% and a specificity of 99.0%. The multivariate model showed promising results, with the possibility of further development into a point of care (POC) test for easier access.

Keywords: Arresten
Biomarker
CA125
Diagnostic
Epithelial Ovarian Cancer
Glycoform
Advisor: Akbari, Mohammad Reza MRA
Satellite-Based Exposure Model for Predicting Fine Particulate Matter (PM2.5) to Assess its Role on the Incidence of Acute Lower Respiratory Infections (ALRI) in Infants of Rural Bangladesh

Ambient fine particulate matter (PM2.5) has been shown to increase the risk of Acute Lower Respiratory Infections (ALRI), the burden for which is much higher in children of low-and middle-income countries (LMICs) such as Bangladesh where poor air quality is a significant public health concern. One challenge in assessing health effects associated with PM2.5 in LMICs is quantifying exposures for affected populations as measurement data are sparse. To address this issue, spatiotemporal regression and machine learning models that leveraged satellite observations of Aerosol Optical Depth (AOD) and meteorology to predict daily PM2.5 exposures between 2017 and 2021 at the georeferenced residential locations of children that were part of the Bangladesh Cook Stove Pregnancy Cohort Study (BCSPCS) were developed. The eXtreme Gradient Boosting (XGB) Machine Learning Model showed superior predictive performance in validation tests. Predicted exposures linked to the BCSPCS revealed that children having ALRI were exposed to statistically significantly higher PM2.5 than those without ALRI. This thesis demonstrates the feasibility of using satellite-AOD derived PM2.5 exposures to study health effects in LMICs and shows that poor air quality is a significant risk factor for the development of childhood ALRI.

Advisor: Franklin, Meredith MF
Phylogenetic Analysis of the in vitro Protein-Protein interactions between the PDZ domain of Rab3-interacting molecule (RIM), and the extreme C-terminus (CT) of Voltage-gated Calcium (CaV2) Channels

Neurotransmitter release relies on Ca2+ influx through voltage-gated calcium channels (CaV2), triggered by action potentials. Reliable release necessitates CaV2 localization near primed synaptic vesicles (SV). Rab3-interacting molecule (RIM) anchors CaV2 within nanometers to SVs, via interactions between the RIM PDZ domain and the C-terminus (CT; (i.e., DDWC-COOH-like motif)) of CaV2. Recently, a novel RIM paralog (RIM-II) with identical domains to the canonical RIM (RIM-I), was discovered, yet its functions remain undetermined.While this interaction is verified in vitro in mammals, I investigated its conservation in representative species across phyla. Directed Yeast 2-Hybrid screens indicated that this interaction is retained in basal-chordates, arthropods, brachiopods, and molluscs, revealing its presence in non-mammalian metazoans. Eliminating the last four residues on CaV2 CT notably reduced interactions with RIM-I PDZ domains, highlighting their importance for RIM-CaV2 interactions. However, RIM-II did not exhibit the same interactions across phyla, suggesting functional differences between RIM-I/-II PDZ domains.

Keywords: Calcium Channel
PDZ domain
Phylogenetics
Protein-protein interactions
RIM protein
Synaptic Vesicle
Advisor: Senatore, Adriano
The Quantification of Fibrosis Using Clinically-Indicated Magnetic Resonance Imaging for Head and Neck Cancer Patients

Patients with head and neck cancer (HNC) undergoing radiotherapy (RT) often develop fibrosis-related dysphagia (difficulty swallowing) over time post-RT. There is no method to objectively measure fibrosis, however magnetic resonance imaging (MRI) has potential. This study aimed to quantify fibrosis volume over time post RT using MRIs rated by neuroradiologists, and compared these findings with objective measures of swallowing impairment, captured speech-language pathologists using videofluoroscopy (VFS). Eligible participants were adults with HNC treated with RT who received more than one MRI and VFS up to one-year post-RT. Fibrosis volume was independently contoured in batches using post-processing software (VitreaTM). Inter-rater reliability was assessed, and training was done between batches. Quantifying fibrosis can result in earlier identification of fibrosis and better inform targeted rehabilitation treatment strategies for this population. This study demonstrated a reliable capture of fibrosis volume, and offers a pragmatic method for early detection of fibrosis and concomitant dysphagia.

Keywords: dysphagia
head and neck cancer
magnetic resonance imaging
radiation fibrosis
reliability
speech-language pathology
Advisor: Martino, Rosemary
The Outcome and Predictive Variables of Endodontic Microsurgery: A Retrospective Cohort Study

Outcome studies are critical to evidence-based endodontics. This study evaluated the rates and predictors of radiographic periapical healing and survival to reintervention of endodontic microsurgery (EMS). Prognostic factors were assessed using logistic and Cox regression analyses (P<.05). After an average follow-up of 54.9± 38.6 months, the overall radiographic healing for 128 eligible teeth was 82.8% and was associated with lack of periodontal involvement (OR: 2.8, CI: 1.1-7.7, P=0.045) and root-end filling depth >2mm (OR: 3.5, CI: 1.2-9.6, P=0.014). Among 186 eligible teeth, the overall survival rate was 88.2% after a mean follow-up of 50.3±37.2 months. Among these, 86.6% (n=161/186) survived without reintervention, while 1.6% (n=3/186) required further intervention. Survival to reintervention was significantly lower in patients aged ≤45 years (HR: 3.7, CI: 1.4-9.8, P=0.007) and cases where root-end filling depth was ≤2mm (HR: 4.3, CI: 1.7-10.8, P=0.002). Radiographic healing and survival to reintervention after EMS were very good.

Keywords: Apical Periodontitis
Cohort Study
Endodontic Microsurgery
Survival
Treatment Outcome
Advisor: Azarpazhooh, Amir