VictorJuiz/thesis huggingface dataset:
Preclinical Evaluation of Synergistic Drug Combinations in Acute Myeloid Leukemia
Keywords: Acute myeloid leukemia
Drug screening

The FDA-approved Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has significantly improved patient outcomes in B-cell malignancies, where BTK signaling is implicated in disease progression. Documented expression of constitutively active BTK in AML cells has generated interest in evaluating the potential therapeutic role of ibrutinib in the treatment of AML. We investigated the role of ibrutinib in AML by screening this drug against libraries of approved drugs in AML cell lines, identifying the poly(ADP-ribose) glycohydrolase inhibitor ethacridine lactate as a profoundly synergistic hit. This drug combination was preferentially cytotoxic to patient-derived AML cells over normal controls, and synergistic cell death was preceded by reactive oxygen species (ROS) production. Ibrutinib similarly synergized with current first-line AML chemotherapy agent daunorubicin. Interestingly, neither ethacridine, nor daunorubicin’s synergy with ibrutinib appeared to be BTK-dependent. Further study with the epidermal growth factor receptor (EGFR) inhibitor erlotinib—which also has preclinical anti-AML activity—revealed equally profound EGFR-independent synergy with ethacridine, with an increase in ROS that paralleled that induced by the ibrutinib-ethacridine combination. We determined that erlotinib-mediated potentiation of ethacridine accumulation was responsible for this combination’s synergistic cytotoxicity, and hypothesize that ibrutinib and ethacridine likely synergize via the same mechanism. In summary, we have identified a novel BTK-independent role for ibrutinib in AML, and for the first time, report a potential role for PARG inhibition as a combination candidate for AML therapy.
Infectious Agent Evolution in Bornean Orangutans
Keywords: Co-Evolution
Evolution
Orangutans
Plasmodium
Simian Foamy Virus
Simian T-Cell Lymphotropic Virus 1

In this thesis I provide among the first detailed studies of orangutan host/parasite co-evolution by bridging the disciplines of molecular virology/parasitology and biological anthropology. I used the tools of both disciplines to study the evolution of three infectious agents: simian foamy virus (SFV), simian T-lymphotropic virus 1 (STLV-1), and the protozoan parasite, Plasmodium, in orangutans Genus Pongo. Key to my thesis is the importance placed on the use of accurate calibration dates informed by archaeological and fossil data. Using this approach, I examine the evolutionary history of these infectious agents, including an estimation of the ages of divergence. The results suggest that SFV is the oldest of these infectious agents in orangutans, dating to >4 million years ago. My results challenge a previous hypothesis surrounding the appearance of a unique cladistic pattern for orangutan SFV based on the Mount Toba supervolcanic eruption at ~73 kya. The results of the present research suggest that the events leading to the development of this clade pattern is ~1.6 million years old, which rules out the Toba supereruption. My results also showed that there is a statistically significant level of host-virus coevolution in orangutans. My thesis research indicates the Plasmodium parasites in orangutans are much younger than previously thought. Finally, I estimate the origins of PTLV-1 in orangutans to between 7-343.7 kya. Overall, my thesis shows that the Pleistocene was an important period for the evolution of these infectious agents in orangutans and that it is at least possible that some of this evolution occurred on the Indochinese mainland before orangutans reached the islands of Sumatra and Borneo.
The Delivery of Pharmaceutical Health Care in Nunavut, Canada: Language, Culture and Policy
Keywords: Circumpolar
Indigenous
Inuit
Language Translation
Pharmaceutical Policy
Pharmacy Health Care

Pharmaceuticals are an essential component of modern health care as their therapeutic properties are often required to achieve optimal health outcomes. The pharmaceutical market is also a significant contributor to health care expenditures, with global sales exceeding US$300 billion and expenditures predicted to increase. These global factors necessitate the development of pharmaceutical policies that are adaptive to local contexts and address the complexities of purchasing, distribution, prescribing and administration practices that best suit the needs of local populations. Through multi-method research, my doctoral thesis explores three areas of pharmacy health care in Nunavut, Canada: policy and practice, discordance in health models, and language translation. First, this research examines the pharmacy policy currently serving remote communities in Nunavut, a territory affected by weather-related access issues, scarce human resources and complex financial allocations. Current policies are often in conflict with patient-centred care and result in significant pharmaceutical waste. Revised policies may better support health providers, and address distribution issues to optimize financial expenditures. Second, pharmaceutical health care is part of biomedicine, which offers sharp contrast to the more holistic Inuit wellness model. In Nunavut, although the majority of inhabitants are Inuit, biomedical health care is delivered primarily by Qallunaat (non-Inuit) health providers. This research uses a comparative framework to contrast these two health models to explain how multiple levels of cultural discordance layered with postcolonial inequalities may influence patient-provider relationships and patient adherence to pharmacotherapy. Third, this research considers language discordance in pharmacy health care in Nunavut, where pharmacy services are delivered in English to predominantly Inuit language speaking patients. Pharmacy language discordance can result in adverse drug events and serious patient harm. This situation is currently in transition as language legislation in Nunavut will soon require pharmacy services to be available in Inuit languages and efforts are underway to standardize Inuit-language pharmaceutical terminology. Together, these three issues influence the quality of pharmacy health care in Nunavut and this thesis contributes to a greater understanding of issues which hold the potential to direct future endeavours towards the optimization of pharmacy health care in Nunavut.
Group Decision Making and Preference Learning on Social Networks
Keywords: Group Decision Making
Preference Learning
Recommendation
Social Choice
Social Networks

This thesis focuses on exploiting the dynamics and correlations of preferences over social networks for developing efficient group decision making systems. One of the main challenges in any group decision problem is learning the individual preferences upon which decisions are based. It is the position of this thesis that social networks---by capturing preference correlations across individuals induced by social interactions---provide a natural and informative platform for preference learning. By mathematical modelling of preference dynamics and correlations over social networks, we focus on developing efficient algorithms for group decision making and recommendations, with less required user data, and lower cognitive and communication burden. We introduce empathetic frameworks in which individuals derive utility based on both their own intrinsic preferences (or happiness) and empathetic preferences, determined by the satisfaction of their acquaintances. After theoretically analysing this framework, we develop a scalable algorithm for group recommendation, and empirically demonstrate its performance. To capture the correlation of preference rankings on social networks, we introduce a network formation model called ranking networks in which the similarity of two individuals' rankings determines the chance they are connected to each other. After a thorough theoretical analysis, we use a special instance that we call preference-oriented social networks, for group decision making when faced with missing preferences. We develop algorithms to predict unknown individual preferences given known preferences of others in the social network and to make effective group decisions with partial preferences. Our empirical results demonstrate that incorporating social ties can significantly improve predictions and group decision making.
Photo-thermal Nanosystems for Diseased Cell Treatment
Keywords: Antibacterial
Cancer therapy
Nanohyperthemia
Nanomedicine
Nanosystems
Photo-thermal

The prevalence of cancer and infectious disease demands for development of more effective treatment technologies. Current standard chemo- and radiotherapy for cancer offer only relative therapeutic efficacy at the cost of significant side-effects. On the other hand, resistance of microbes to current antibiotics has raised serious concern in public health sectors such as hospitals. Thermal therapy is an alternative technique that employs high temperatures to treat diseased cells via direct and indirect heat effects. Owing to its nature, this technique can offer enhanced therapeutic efficacy in local diseased regions via either mono- or combinatorial platforms and very minimal side-effects. However, existing bulk heating systems are limited in providing selective and controlled temperature rise in the desired region at tissue/cellular scales. This compromises the therapeutic efficacy of the treatment and increases the risk of off-target heating in healthy tissues. In this thesis, we propose the use of heat-generating nanoparticles to precisely target heat into small regions and study how they can be applied in cancer and bacteria treatment. Our model nanoparticle system generates heat by light stimulation. Different nanosystems based on this particle are developed and their thermal effects on therapeutic distribution are explored at tumor tissue and cellular scales. In addition, the thermal effect of these nanoparticles is utilized to overcome microbial resistance. By mechanistic understanding of nanoparticle thermal effects at different length scales, this research helps to rationalize proper design and development of heat- generating nanomedicine for cancer and microbial treatments.
The Role of Fatigue in Osteoarthritis and its Potential Overlap with Pain and Depression
Keywords: depression
fatigue
osteoarthritis
pain

Background: Although not routinely assessed, individuals with osteoarthritis (OA) have identified fatigue as a key concern and research priority. Current conceptualizations of fatigue include multiple types, with physical and mental components. Pain and depression are two of the strongest fatigue predictors; however there are challenges to disentangling these symptoms. Purpose: To better understand the role of fatigue in OA, considering the potential of multiple types of fatigue and examining whether fatigue is a construct distinct from pain and depression. Methods: Two surveys, one-year apart, were administered via telephone interviews to an established population-based cohort (n =806) of older adults (64+ years) with hip and knee OA in two regions of Ontario, Canada. Descriptive analyses examined the amount of fatigue experienced and its variation across socio-demographics, health status variables and levels of pain and depression. Confirmatory factors analyses (CFA) were conducted to examine whether fatigue, pain and depression represent separate constructs. Results: Findings from descriptive analyses indicated that participants experienced notable general fatigue, although scores for specific types of fatigue were very low especially for mental fatigue. Fatigue intensity increased over time and was greater in women, older participants and those with less education. Fatigue was higher with increasing levels of co-morbidity, especially with reporting fibromyalgia, as well as levels of pain and depression. CFA models suggested that although related, fatigue did not overlap with either pain or depression. Evidence that there are two types of OA pain (“Pain on Activity”, “Pain at Rest”) was found; the latter of these overlapped with somatic depression symptoms, particularly restless sleep. A new variable (“Disturbed Rest”), created to account for this overlap, correlated moderately with pain on activity and related differently to depression and fatigue. Conclusion: Findings suggest individuals with OA experience a salient amount of general fatigue, and this is a construct distinct from both pain and depression. Pain experienced at rest and restless sleep were also found to form a unique construct, distinct from pain due to activity. Further research is warranted to examine similarities and differences in the characteristics of these symptoms in OA, as well as their impacts on disability.
An Institutional Ethnographic Investigation of College Professors' Experiences Constructing Course Outlines
Keywords: college teachers
course outlines
institutional ethnography
market economics
social relations
textual power

Institutional ethnography is the ontology and methodology that supports this investigation into the problematic of college teachers, officially known as professors, having more and more of their teaching energy being devoted to supporting the interests of market economics rather than the interests of students, college teachers, society, and the environment. I take the standpoint of college teachers and use interviews from college teachers who were about to use course outlines for the first time along with my own insider perspective as the entry point into an investigation of the social relations involved with college course outline work. I place my informants' experiences of teaching without course outlines in analytical contrast to the general way that another college orchestrates college teachers' work through the course outline construct. I do this by producing an extended Turner-style (2003) mapping of the local and extra-local web-like textual power that mediates college teachers' work at one particular community college. I argue that there are four nesting layers to the ruling relations power over college teachers' work with students. The first layer emphasizes the ideological work that college employees do to support global-finance capital. The second describes the managerial work done to set up the operational/production planning of teacher, course, class, and course outline work. The third reveals how faculty members are complicit in doing textual work to set up their own ruling. The fourth identifies the performance work that faculty members do to execute the textual rules of their prescriptive course outline commodity work. Additionally, I used a textual and discourse analysis of four union negotiation-related documents to reveal the way that texts interlock concepts from one to another to shrink teachers' professional autonomy. I find market economic ruling relations power embedded in a web of texts, work sequences, and work discourse connected to college course outlines. This power has the effect of deskilling college professors by both increasing the supervision and standardization of their work and decreasing opportunities for academic freedom. My textual mapping identifies places where opportunities for effective teaching and learning had been deleted and could be reclaimed.
Genes Underlying Social Influence on D. melanogaster Clocks
Keywords: Behaviour
Cell and Molecular
Circadian
Clocks
Genetics
Social

Social influence on an individual is found in many species. The mediation of such effects is based on communication, involving the generation, receipt, and integration of signals that modulate an organism's behaviour. The fruit fly Drosophila melanogaster has played a significant role in understanding the mechanisms underlying social influences. One emerging theme is that an individual's circadian system is highly responsive to the social surroundings and could mediate such influence. Yet a systematic search for genes underlying social cues that affect an individual's internal state, has been hampered by the lack of a reliable and robust `social screen'. In this study, the known aspects of social influence were assimilated to create an assay which monitors circadian gene expression in a focal fly when interacting with a partner (stimulus fly). The stimulus fly was either wild-type, or harbored an unknown (forward genetics) or known (reverse genetics) mutation. Deviations in the circadian signal of the focal fly were used to identify novel genes in the stimulus fly that underlie social interactions. Through the forward genetic approach, 2552 chemically mutagenized lines were established, of which 10 novel mutations affected social interactions. Through the reverse genetic approach, several candidate genes altered social interactions, one of which is homologous to a mammalian limbic associated membrane gene. This limbic-homologue and an EMS mutant were further characterized to identify potential pathways through which social effects are manifested. Along with altered locomotor activity, both displayed significantly altered hydrocarbon profiles. This suggests that social influence likely operates through multiple pathways, including olfaction and the clock system. Despite the assay being conducted in a light-dark environment, phase shifts, changes in expression levels, and/or changes in the rhythmicity index were all detected. This suggests that social effect on the circadian system is a potent modulator, even when operating within the confines of a much stronger Zeitgebers such as light. The implications of the assay and collected data were discussed. A model framework through which the mechanisms of social interactions can be further studied was also synthesized.
The Founding Act of the People: Democratic Theory and the Problem of Founding
Keywords: Constituent power
Constitutional democracy
Constitution-making
Founding
Paradox of founding
Popular sovereignty

How does democracy get off the ground? Is it possible to begin democratically where there is no democracy before? What is the significance of founding moments, if any, for the project of constitutional democracy? This dissertation explores the problem of founding from the standpoint of its relation to democratic theory. The central claim is that a democratic constitution is not only supposed to set up the institutions of self-government, but it is also supposed to be made, as much as possible, democratically. In other words, how the constitution is made is as significant as what it prescribes. I offer two arguments in support of this claim. The first one is a normative argument about the meaning of popular sovereignty. Under contemporary conditions of diversity and pluralism, constitutional claims of popular sovereignty would have little purchase unless they have a strong foothold in what citizens themselves have to say in their own voices on the form and principles of their own political organization. Secondly, I also draw attention to the role of founding moments in setting the course of democratic politics over time. In this register, the basic idea is that how we begin (or begin anew) makes a difference in our future prospects. The effects of founding as a crucial historical experience are woven --both for better and for worse-- into the very fabric of the political community, lingering in its institutions, practices and identity.
Dysphagia Following Endotracheal Intubation: Frequency, Risk Factors and Characteristics
Keywords: adult
cardiovascular surgery
deglutition
dysphagia
endotracheal intubation
extubation

Oropharyngeal dysphagia following endotracheal intubation occurs frequently, however, both the incidence and associated risk factors vary across the literature. This dissertation is comprised of three studies that investigate the frequency, associated risk factors and characteristics of post-extubation dysphagia along with the relation between intubation duration and swallowing outcomes with a focus on CV surgery. First, we conducted a systematic review in order to determine dysphagia frequency according to patient diagnoses and the association between dysphagia and intubation time. We conducted searches using fourteen electronic databases along with manual searching of journals and grey literature. Our critical appraisal utilized the Cochrane Risk of Bias Assessment and GRADE tools. Our second study assessed dysphagia frequencies according to four intubation duration strata on consecutive patients following CV surgery: I (
Regulation of Cellular Oxygen Sensing Pathways by VHL
Keywords: Erythropoiesis
Hypoxia
Ubiquitin

Erythropoiesis represents a vital physiologic process that can be adjusted to combat compromised oxygen availability, otherwise known as hypoxia. The canonical response to adapt to hypoxia is mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1). When oxygen is available HIFalpha subunits are hydroxylated by prolyl hydroxylase enzymes (PHD1-3) to allow for binding to the von Hippel-Lindau (VHL) tumour suppressor protein, which serves as the substrate recognition subunit of an E3-ubiquitin ligase complex that ultimately targets proteins for proteasome-mediated degradation. The work presented in this thesis demonstrates a novel role of VHL in recruiting DCNL1 to initiate E3-ubiquitin ligase enzymatic activity which, in essence, allows for the degradation of HIFalpha to commence. In hypoxia, hydroxylation does not take place and as a result HIFalpha can promote the transactivation of a repertoire of genes that aid in adaptation to hypoxia including one which encodes the glycoprotein hormone erythropoietin (EPO). EPO binds to EPO receptor (EPOR) expressed on erythroid progenitor cells to promote their proliferation and differentiation into red blood cells. An erythroid specific oxygen sensing pathway is elucidated in this thesis wherein EPOR is hydroxylated by PHD3 to promote VHL-mediated degradation in a manner analogous to HIFalpha. Combined, these findings build upon our fundamental understanding of how cells detect and counter hypoxic stress.
Neurophysiologic Studies of Human Subcallosal Cingulate Regions and its Modulation of the Dorsal Raphe in Depression
Keywords: Cellular firing
Deep brain stimulation
Dorsal raphe
Evoked field potentials
Medial prefrontal cortex
Serotonin

Depression is the most common of all psychiatric disorders and has a lifetime prevalence of 16% (Kessler et al., 2003). In this work I employ in vivo electrophysiological techniques to investigate key regions in a complex pathway implicated in emotional regulation. First I characterize the neurophysiology of the subcallosal cingulate (SCC) region in treatment resistant depression patients (TRD) undergoing surgery for the placement of deep brain stimulating (DBS) electrodes. In the same study, I show suppression of the locally evoked field potential in the SCC following high frequency stimulation (HFS), possibly indicating impaired plasticity in this cohort of patients. In the second part of this thesis I examine the effects of HFS in the medial prefrontal cortex (mPFC), a rodent homologue of the SCC, on the activity of neurons in the serotonin-rich dorsal raphe (DR) nucleus in the midbrain. In the same study, I also show that mPFC-HFS stimulates GABA interneurons in the DR, inhibiting cellular firing. In the last chapter of this thesis, I demonstrate unequivocal characterization of 5-HT neurons using optical stimulation in transgenic mice. I also use this optogenetic model to show that mPFC-HFS exerts a non-selective inhibitory effect on both 5-HT and non-5-HT neurons. Lastly, I use fast scan cyclic voltammetry to show that 5-HT can be evoked following short high-amplitude stimulation of the mPFC and that 5-HT reuptake is accelerated following a long mPFC-HFS train. Clinically, this strong effect of long-train HFS on the 5-HT reuptake system may explain the efficacy of SCC-DBS in patients that are refractory to SSRIs. Overall, the findings in this thesis demonstrate that HFS induces both local (mPFC/SCC) and distal (DR) effects on the serotonergic projections in the human and animal brain.