VictorJuiz/thesis huggingface dataset:
EGFR in Early Non-small Cell Lung Cancer: Tyrosine Kinase Inhibition in a Neoadjuvant Trial
Keywords: lung cancer
NSCLC
neoadjuvant
EGFR
EGFR TKI
response
histopathological response
molecular response
Intratumoural heterogeneity
ischemia

EGFR TKIs are standard therapy for advanced NSCLC. In order to define their role in early disease, we implemented a phase II trial of neoadjuvant gefitinib in clinical stage I NSCLC. Tumour shrinkage was seen in 43% of patients, with 11% achieving RECIST partial response (PR). Analysis of molecular markers showed EGFR TKD mutations in 17% of cases, being the only associated with PR. For the first time we defined the histopathological response of NSCLC to these agents, characterized by reduction in tumour cellularity and proliferative index as well as presence of non-mucinous BAC histology. Clinical PR tumours also presented large areas of stromal fibrosis with presence of focal residual tumour. In a characterization of intracellular signalling response, EGFR dephosphorylation in the residues Y1068 and Y1173 was not concordant and only the former was significantly reduced. pAkt Ser473/Akt and Thr308/Akt ratios were significantly reduced but observed among both, clinical responders and resistant patients. Interestingly, reduction in pEGFR Y1068 was significantly associated with increase in tumour cellularity (p=0.047), Ki-67 index (p=0.018) and tumour growth (p=0.019) with a residual perinuclear localization been detected, suggesting a novel mechanism of resistance involving receptor internalization. Finally, we determined that the EGFR protein remains stable up to one hour of post resection ischemia but two to three tumour samples are necessary for an adequate tumour representation. Furthermore, EGFR cytoplasmic compartment presented the best association with clinical response in our cohort. Taking all together, we were able to generate the first clinical trial exploring the use of an EGFR TKI in early NSCLC, characterizing for the first time the histopathological and signalling responses to these agents with an evidence of a potential novel mechanism of resistance. Finally, we observed that multiple samples collection for an adequate tumour representation, and assessment of the cytoplasmic compartment, are warrant.
Postprandial Metabolic Responses to Macronutrient in Healthy, Hyperinsulinemic and Type 2 Diabetic Subjects
Keywords: insulin resistance
insulinemic index

The literature comparing macronutrient metabolism in healthy and diabetic subjects is abundant; however, little data exists on how non-diabetic subjects with insulin resistance handle macronutrient. We did two studies to investigate the postprandial responses to macronutrient in healthy, hyperinsulinemic and type 2 diabetic (T2DM) subjects. In the first study, twenty-five healthy, non-diabetic subjects [9 with fasting serum insulin (FSI) <40pmol/L; 8 with 40 ≤ FSI < 70pmol/L; and 8 with FSI ≥ 70 pmol/L] were fed eleven test meals (50g oral glucose with 0-30g doses of canola oil or whey protein) after an overnight fast. There were no significant FSI × fat (p=0.19) or FSI × protein (p=0.08) interaction effects on glucose response, suggesting that the effects of fat or protein on glycemia were independent of FSI of the subjects. In addition, the changes in relative glucose response per gram of fat (r = -0.05, p = 0.82) or protein (r = 0.08, p = 0.70) were not related to FSI of the subjects. In the second study, Healthy (FSI < 40pmol/L), Hyperinsulinemic (FSI ≥ 40pmol/L), and T2DM were fed five foods with 50g available carbohydrate. Among the subject-groups, the Glycemic Index (GI) values were not significantly different for each food, and the mean (±SEM) GI values of all foods were not significantly different (p>0.05). However, the mean (±SEM) Insulinemic Index of the foods was higher in T2DM (100±7, n=10) than those of Healthy (78±5, n=9) and Hyperinsulinemic subjects (70±5, n=12) (p=0.05). The Insulinemic Index was inversely associated with insulin sensitivity (r=-0.66, p<0.0001), positively related to fasting- and postprandial-glucose (both r=0.68, p<0.0001) and hepatic insulin extraction (r=0.62, p=0.0002). The oral-glucose data were pooled from the two studies to investigate whether there was any relationship between GLP-1 and insulin sensitivity, β-cell function and hepatic insulin extraction. No significant correlation was observed (p>0.05). The results suggest that the glucose-lowering effect of fat and protein is not affected by insulin sensitivity. GI is independent of the metabolic status of the subjects; however, unlike GI, Insulinemic Index is influenced by the metabolic status of the subjects, and thus may have limited clinical utility.
Light and Soul
Keywords: Light
Soul

The lotus is a divine symbol in Asian traditions representing virtues of purity and non-attachment. "Light and Soul," is a work for orchestra with a duration of thirteen minutes, uses the growth of the lotus as a model for formal construction and musical development. The roots of a lotus are in the mud, the stem grows up through the water, basking in the sunlight. This pattern of growth signifies the progress of the soul from the primeval mud of materialism, through the waters of experience, and into the bright sunshine of enlightenment. In Buddhism, the heart of the human being is like an unopened lotus. When the virtues of the Buddha develop therein, the lotus blossoms, and that is why the Buddha sits on a lotus bloom. Confucian scholar Zhou Dunyi's short essay, "On the Love of the Lotus," points out there are many lovable flowers of grasses and trees both upon the water and on the land. In the Jin Dynasty, Tao Yuanming loved only the chrysanthemum. Since the Tang Dynasty, people of the world have loved the peony very much. However, Zhou Dunyi especially loves the lotus because while growing from the mud, it is unstained. Then he further lists out the reasons that he loves the lotus and comments that the lotus is a gentleman among the chrysanthemum and peony. The musical means of conveying this spiritual metaphor of the lotus in "Light and Soul" are primarily timbral, although there is a rigorous application of intervalic and scalar development in the music which gives it consistency and a sense of unfolding over the length of its duration.
Essays on the Economics of Organization
Keywords: Information and Communication Technology
Workplace Organization
Competition
Management Practices
Capital Structure

This thesis consists of three empirical studies on the economics of organization using novel data on organizations for analysis. Chapter 1 uses the longitudinal and nationally representative data from Statistics Canada's Workplace and Employee Survey to examine the distinct effects of Information and Communication Technology (ICT) on decentralization of decision rights. Using a sample of workplaces from different sectors and controlling for unobserved workplace-level heterogeneity, I find that decentralization (defined as the case when workers can plan work for themselves) is more likely when database software is used (which reduces learning cost) but is less likely when communication system is used (which reduces communication cost). These results are consistent with the predictions of the organizational model by Garicano (2000). Chapter 2 also uses the data from Workplace and Employee Survey and examines the impact of competition on the quality of the middle management in terms of the use of Human Resources Management (HRM) practices. I find that increased competition leads to an improvement in managerial quality, proxied by the use of HRM practices. These results complement the industry-specific evidence documented in the literature. Chapter 3, co-authored with Professor Varouj A. Aivazian, uses the management score of Bloom and Van Reenen (2007) as a proxy for managerial quality to examine the extent to which market structure interacts with capital structure. We find that leverage is negatively related to competition (measured by Import Penetration Ratio, Lerner Index, and Herfindahl-Hirschman Index). Besides, we find that competition is positively associated with managerial quality, and that managerial quality is in turn negatively related to leverage. We conclude that managerial quality explains the impact of competition on leverage which suggests that managerial quality serves as an important link between capital structure and market structure.
DETs in the Functional Syntax of Greek Nominals
Keywords: Syntax of determiners
definiteness

In this dissertation, I explore the formal mechanisms underlying restrictive modification by nominals (RMN). The central claim is that RMN is dependent on how definiteness is encoded in a given language. In Greek, RMN is exemplified by extra definite determiners followed by bare adjectives, as shown in (1) below. These may precede or follow the matrix nominal. Syntactically, I argue that the determiner and the adjective may form either a restrictive or non-restrictive nominal depending on their structural position. Focusing on restrictive nominals, I argue that they are adjuncts to nP, which raise to FocP when focused. These adjuncts are small nominals, consisting of acategorial roots and n. A look at the structure of the matrix noun reveals that adjectives adjoin to NumP, as they are always prenominal. A look at genitives also suggests that Greek nouns move as high as NumP. Central to this thesis is the question of what licenses RMN. Previous analyses have correlated it with rich morphology (Lekakou and Szendrői, 2007, 2008, 2010). For them, the determiner is the spell-out of inflection, but is otherwise a semantic expletive. To these claims, I counter-argue that RMN is best viewed as being dependent on how definiteness is encoded and that the definite determiner is simply underspecified for definiteness. Assuming that definiteness consists of two components, familiarity and uniqueness, and based on data from Standard English and Scottish English, I propose that definite determiners spelling out one component, familiarity, are predicted to exhibit RMN. Familiarity and uniqueness can thus be mapped into two syntactic projections, FamP and ιP, respectively. I then propose a syntactico-semantic mechanism that derives these constructions. Hence, this research offers a modern cross-linguistic account of RMN, while it also provides us with new insights about how definiteness can be encoded cross-linguistically.
Cyclic Deformation Behaviour and the Related Micro-mechanisms of F.C.C. Metals Processed by Accumulative Roll-bonding
Keywords: Cyclic Deformation
Ultra-fine grain
Fatigue
Microstructural Mechanisms
Accumulated Roll-Bonding
Mechanical Behaviour
Annealing Characteristics

The improvement in mechanical strength offered by ultra fine- (UF) and nanocrystalline (NC) sized grains is very attractive for potential applications of structural metals. Accumulative Roll-Bonding (ARB) is one of the promising new techniques for producing bulk UF grained metals. There are numerous reports on the monotonic mechanical behavior of various ARBed metals, however there are few, if any, on the cyclic deformation behavior of such metals. The primary objective of this study is to investigate the cyclic deformation behaviour and the related micro-mechanisms of ARBed metals from a fundamental perspective. To achieve this, the microstructure and the deformation behavior of commercial purity aluminum, OFHC copper, and DLP copper after ARB processing have been systematically characterized. The as-ARBed microstructure is found to be composite natured, with constituents of different grain sizes. The three constituents are: (i)UF grained matrix, (ii)NC primary discontinuities, and (iii)conventional sized pre-existing coarse grains. Due to this composite nature, three different cyclic strain accommodation mechanisms were found in the ARBed OFHC copper: (i)conventional dislocation patterns in the large grains, (ii)reactivation of pre-existing shear bands, and (iii)stress/strain driven grain coarsening at sites of strain localization. The order of activation of the mechanisms can be described with a composite approach based on activation energy. The occurrence of grain coarsening is the major contributor to the cyclic softening response observed in OFHC copper. Conversely, the lesser extent of cyclic softening in the other two metals is likely due to the higher microstructure stability of the initial as-ARBed materials. The microstructure stability is believed to be the primary influencing factor for the extent of grain coarsening and cyclic softening. The applied cyclic plastic strain is a secondary influencing factor, although this is generally overshadowed by the limitation of grain coarsening due to the short cyclic lifespan of these metals. The occurrences of shear banding and grain coarsening reported in the present ARBed metals are similarly reported for UF grained metals from other processes, e.g. ECAPed metals. Thus, its relationship to the cyclic deformation response and governing factors are believed to be applicable for UF grained metals in general.
Vector Specific Tolerance Induction for Airwary Gene Therapy
Keywords: Dendritic Cells
Tolerance
Adenovirus
Gene Therapy

The success of adenoviral mediated airway gene therapy is hindered by host immune responses against adenoviral vectors. Helper-dependent adenoviral vectors (HD-Ad) are devoid of viral coding sequences and have an improved safety profile compared to earlier generation adenoviral vectors. However, intranasal delivery of HD-Ad vectors potentiates a pulmonary adaptive immune response, described in chapter 2, which is a barrier to gene therapy. One of the ways to reduce the immunogenicity of HD-Ad vectors is to increase the efficiency of HD-Ad mediated gene transfer to the airways, which would lessen the immunogen availability, limiting immune response against HD-Ad vectors. In chapter 3, a viral formulation strategy using Nacystelyn and DEAE-Dextran to substantially increase the efficacy of adenoviral mediated gene transfer to the airways is described. To further reduce the immune response to HD-Ad vectors, I have developed two novel strategies to induce vector-specific tolerance. The first strategy, described in chapter 4, involves the use of dendritic cells (DCs) differentiated in presence of IL-10, which are refractory to HD-Ad induced maturation and instead prime generation of regulatory T cells which suppress HD-Ad induced T cell proliferation. Delivery of these DCs pulsed with HD-Ad vectors to mice results in induction of immunological tolerance along with sustained gene expression following multiple rounds of HD-Ad readministrations. The second strategy, described in chapter 5, involves delivery of apoptotic DCs followed by delivery of antigen towards which tolerance needs to be generated. Apoptotic DCs are readily taken up by viable DCs, which suppresses DC maturation and induces TGF-β1 secretion, driving generation of regulatory T cells towards the delivered antigen. This strategy has shown remarkable success in achieving tolerance towards ovalbumin. Therefore, these strategies can be used to induce immunological tolerance towards gene therapy vectors which will likely allow for sustained and long term therapeutic transgene expression.
Understanding Reports to Child Welfare from the Education System: Challenges and Opportunities for Supporting Vulnerable Children
Keywords: child maltreatment
child welfare
education
school
education system
child abuse
child abuse reporting
teachers
children's aid
mandatory reporting
social policy
Canada

Educators play a crucial role in the detection of child abuse, but there is limited research understanding the role of teachers in responding to maltreatment concerns. The purpose of this dissertation was to utilise three sequential studies, with multiple methodologies, to understand how Canadian educators are situated to detect, respond, and report suspected child abuse. In the first study, a national Canadian database was utilised to compare educator reported cases of child maltreatment to reports from all other professionals. In study two, 245 teachers completed a questionnaire examining their experiences of reporting child abuse, attitudes and beliefs, and perceived barriers and supports in reporting. Lastly, in the third study, semi-structured qualitative interviews were conducted with seven teachers who had recently reported child abuse. In integrating the results from these studies, three conclusions were drawn regarding the role of educators within the child welfare system. These included; 1) Teachers are well-positioned to detect and advocate for the needs of maltreated children; 2) Teachers have a need for greater confidence, and an increased ability to cope with uncertainty, when responding to child abuse; and 3) There is often a mismatch between the goals of teachers in the education system and the perceived response of the child welfare system. Three recommendations were then presented; 1) Educators are a key resource in supporting early detection and intervention initiatives to address child abuse and their role in these initiatives should be further explored; 2) Teachers should be provided with additional strategies to address perceived barriers in reporting child abuse; and 3) Initiatives to promote increased communication between the education and child welfare systems are required. Overall, results supported the unique child-centred perspective of educators in reporting child maltreatment. Study limitations and areas for future research were then discussed.
Compassion in Schools: Life Stories of Four Holistic Educators
Keywords: compassion
holistic education
connection and relationship
interconnection and interdependence
divinity within, God, Buddha nature within, or the Self
spirituality
heart
caring
empathy
love
contemplation
mindfulness
meditation
moral education through storytelling
social environment
authenticity
teacher's presence
transformation
self-directed learning
happiness

In this study the author investigates the nature of compassion, ways of developing compassion within ourselves, and ways of bringing compassion into schools. The author sees an imbalance and disconnection in the current Ontario public school system, between education of the mind (to have) and education of the heart (to be). This is demonstrated in the heightening violence in schools, because violence in schools means that students do not feel connected to and are not happy in their schools. To accomplish this purpose, the author explores the different ways we can connect—within ourselves, with classroom subjects, with students in the school, and with the community at large—through life stories of four holistic educators, including herself. Three have taught in Buddhist, Waldorf, and Montessori schools, which all foster compassion not only through empathy, caring, and love, but also through emotional and moral components of heart education, such as intuition, creativity, imagination, joy (Miller, 2006), and moral education (Noddings, 1992). The enquiry uses qualitative research and narrative method that includes portraiture and arts-based enquiry. The findings in the participants’ narratives reveal that compassion comprises spirituality, empathy, and caring. We can develop compassion through contemplation in an awareness of interconnection between the I and the Other. In conclusion, we can foster compassion in schools if we use holistic education’s basic principles of balance, inclusion, and connection (Miller, 1981, 1993, 1994, 1999, 2000, 2006, 2007, 2010), and if we bring in different ways of fostering compassion that the author has explored through four holistic teachers’ narratives in this study. By nurturing and connecting to students’ hearts, rather than forcing knowledge into their heads, it is possible to create schools where students are happy and feel connected to their learning.
Molecular Dynamics of Biomolecules at Interfaces: Insulin-insulin Interactions
Keywords: insulin dimer dissociation
molecular dynamics
force spectroscopy

Understanding the intermolecular forces and dynamics of insulin self-assembly is crucial for devising formulations for the treatment of insulin-dependent diabetes. Insulin must dissociate from its hexameric storage form, through an intermediate dimer form, to the bioactive monomer before receptor binding. Specifically, the dimer dissociation is a pivotal step to control insulin dynamics and self-assembly. Steered molecular dynamics simulations were performed on native insulin to provide molecular insight into the insulin dissociation force spectroscopy experiment. Our simulation results of force-induced dimer dissociation revealed that the dimer dissociation occurs near the limit of extensibility of the B-chain with significant conformational changes to the monomer(s). These long-range interactions, consistent with our experiments, are due to stronger inter-monomer interactions across the anti-parallel β-sheet interface than any other intra-monomer interaction. Novel atomistic data played an important role in detailed structural characterization of multiple unfolding and dissociation pathways that depend on the relative strength of the inter-monomer interactions and the intra-monomer interactions. Comparative simulations of two rapid-acting insulin analogues (LysB28ProB29, AspB28) to native insulin were performed to investigate the effect of sequence on the dimer dissociation. The hypothesis is that site-specific alterations to the dimer-forming surface of two rapid-acting analogues will result in a weakening of the inter-monomer interactions, which would be reflected during force-induced dimer dissociation. The results revealed that these analogues dissociates with lower probability of long-range interactions and a corresponding reduction in B-chain extension. B-chain extensibility is thus a characteristic marker of inter-monomer interactions and multiple unfolding pathways. These data agree with the design strategies of sequence modifications to the weakened inter-monomer interface applied to the synthesis of rapid-acting insulin analogues. In contrast, the ligand-induced alteration to the strengthened inter-monomer interactions through a specific GluB13s-zinc bridge contributed to the unique unfolding force curves, so it can be applicable as design strategy to the development of a novel long-acting analogue. Overall, our force spectroscopy studies on insulin native and analogues have successfully provided atomistic insights into the dimer dissociation characteristics and control strategies of self-assembly. In addition, this study would provide a framework for the structure-dynamics-function relationships of insulin-insulin receptor binding.