VictorJuiz/thesis huggingface dataset:
Distribution of Anti-cancer Drugs within Solid Tumours and Normal Tissues and its Potential for Modification to Improve Therapeutic Index
Keywords: Drug distribution
solid tumours
doxorubicin

Anti-cancer drugs gain access to solid tumors via the blood, and must penetrate tissue to reach all viable cancer cells. This thesis aims to compare the distribution of anticancer drugs in normal tissues and tumours, to examine whether drug distribution is modifiable and quantifiable in solid tumours, and to determine whether extracellular drug distribution can be improved by modifying intracellular drug distribution. The time-dependent spatial distribution of three anticancer drugs, doxorubicin, mitoxantrone and topotecan, were studied in normal tissues and tumours. Ten minutes after drug administration, there was fairly uniform distribution in the heart, kidney and liver whereas drug distribution within tumours was limited to perivascular regions. Doxorubicin distribution in P-glycoprotein (PgP) over-expressing tumours was compared to that in wild-type tumours and changes in distribution were evaluated with the use of PgP inhibitors. There was better doxorubicin distribution in PgP-over-expressing tumours compared to wild-type tumours, and pretreatment of PgP-over-expressing tumours with PgP inhibitors decreased doxorubicin distribution. These data suggest that reduced uptake of drug into cells may enhance extracellular drug distribution, and the dual effects of PgP inhibitors (increased drug uptake in proximal cells, but poorer drug distribution) may explain, in part, why these agents have not provided clinical benefit. The effect of the proton pump inhibitor pantoprozole on intracellular and extracellular drug distribution was determined. Pantoprazole increased endosomal pH in cells, leading to less sequestration of doxorubicin within them, and increased the toxicity of doxorubicin for cultured cells. In wild-type MCF7 tumours, pretreatment with pantoprazole enhanced doxorubicin distribution and tumour growth delay without apparent increase in toxicity. These studies have led to initiation of a phase I clinical trial of pantoprazole and doxorubicin for patients with solid tumours. The work completed in this thesis demonstrates that drug distribution can be modified and that these changes can be quantified, and may correlate with improved anti-tumour effects. Improving drug distribution through the use of proton pump inhibitors may be an effective strategy to improve chemotherapeutic efficacy.
Urban Dirty Work: Labour Strategies, Environmental Health, and Coping Among Informal Recyclers in Buenos Aires, Argentina
Keywords: informal recycling
Buenos Aires, Argentina
environmental health
urban inequality

This dissertation investigates informal waste recycling practices in the modern urban centre of Buenos Aires, Argentina. My research sets a baseline for the living and working conditions of the approximately 9,000 informal recyclers (cartoneros) in the city, focusing on their health, socio-economic status, and access to social and material resources. The research methods included a survey (n = 397) and interviews (n = 30) with cartoneros, as well as key informant interviews and an analysis of newspaper articles addressing informal recycling in the city. My findings indicate that Buenos Aires’ cartoneros, while not the poorest of the poor, are of a relatively low socio-economic status. Their health outcomes and determinants of health are poor compared to others in the Greater Buenos Aires region, and these workers are often stigmatized and discriminated against because of their associations with waste. Cartoneros’ experiences of the city are characterized by a series of social, political, and physical exclusions, revealing a state of urban inequality in Buenos Aires. I argue that municipal agendas of neoliberal urban development are implicated in both the symbolic and physical marginalization of these workers. Cartoneros draw upon many resources in coping with the multiple vulnerabilities that they face (particularly social resources and assets derived from their labour). They also occasionally engage with urban processes of exclusion through collective action and rhetorical redefinitions of their role in society. These workers are therefore active agents in their own destinies, and potential actors for social change. The municipal government of Buenos Aires has recently implemented a formalization plan for some of the city’s cartoneros; the dissertation includes an assessment of these plans, as well as recommendations for other policy-based interventions to informal recycling practices.
Contribution of Activated Coagulation Factor XII to Hypertension in Chronic Renal Failure: Investigation Involving Dialysis Patients and the 5/6 Nephrectomized Uremic Rat
Keywords: Coagulation Factor XII
FXIIa
hypertension
chronic renal failure
kinin-kallikrein system
sympathoadrenal

Activated coagulation Factor XII (FXIIa) elevates blood pressure (BP) acutely by stimulating adrenomedullary catecholamine (CA) release in Brown Norway (BN) bioassay rats. These effects are absent in kininogen-deficient BN Katholiek (BNK) bioassay rats, indicating that these FXIIa-induced responses require an intact kallikrein-kinin system (KKS). In three hypertensive anephric pediatric patients, ΔFXIIa concentrations tracked peri-dialytic ΔBP. We hypothesized that FXIIa exerts a vasoconstrictor pro-hypertensive action, via the KKS, particularly evident in chronic renal failure (CRF). In CRF patients (n=11) receiving conventional hemodialysis, mean plasma FXIIa concentrations were 3-fold (p<0.05) greater than in healthy controls. Although conversion from conventional to nocturnal hemodialysis did not change mean FXIIa concentrations there was intra-session variation within individuals, such that ΔFXIIa concentrations correlated with changes in mean arterial pressure (MAP, r=0.66, p=0.026) and total peripheral resistance (TPR, r=0.75, p=0.007). In normotensive BN rats, FXIIa infusion (85 ng/min/kg for 60 mins) increased MAP (10±1 mmHg), TPR (0.5±0.1 Units), and CA, whilst left-ventricular end-diastolic volume (LVEDV) and heart rate decreased (all p<0.05). After adrenalectomy, FXIIa infusion decreased MAP (5±1 mmHg), did not raise CA or induce sustained vasoconstriction, and caused a greater fall in LVEDV (all p<0.05). In the 5/6 nephrectomized (NX) rodent CRF model, MAP and TPR were significantly greater in BN NX (n=16) than in BNK NX (n=15) (147±4 vs. 133±2 mmHg, 2.8±0.2 vs. 2.3±0.2 Units; all p<0.05). Plasma FXIIa measured using our semi-quantitive ELISA was 3-fold higher in both BN NX and BNK NX than in controls (p<0.01), but only correlated with MAP (r=0.48, p=0.01) in the BN NX. Plasma CA were elevated in the BN NX (p<0.05) but not in BNK NX. Infusion of a specific FXIIa inhibitor into BN NX decreased MAP (-12 mmHg) and TPR (-0.5 Units) proportionally to baseline FXIIa (ΔMAP: r=-0.72, p=0.002; ΔTPR: r=-0.57, p=0.021), and plasma CA fell by 40-67% (all p<0.05). No such changes occurred in the BNK NX. In summary, a significant component of the hypertension of CRF can be attributed to FXIIa-induced vasoconstriction mediated via the KKS and stimulated CA release. In normal rats, FXIIa appears also to directly or indirectly decrease preload and heart rate.
Influence of Alkaline Copper Quat (ACQ) Solution Parameters on Copper Complex Distribution and Leaching
Keywords: Alkaline copper quat
ACQ
wood preservative
quaternary ammonium
DDAC
copper amine
copper ammonia
monoethanolamine
ammonia
tetramethylethylenediamine
copper leaching
copper speciation
copper distribution
MINTEQA2

The effects of ACQ solution parameters such as copper to quat ratio, pH and copper to ligand ratio on distribution of copper complexes in solution and insoluble precipitates, and on fixation and leaching of copper in treated wood were evaluated. The distribution of ionic complexes, predicted by equilibrium speciation model (MINTEQA2), was related to laboratory fixation and leaching results at controlled ACQ solution parameters. A decrease in the relative proportion of copper in the ACQ formulation from a copper oxide (CuO) to didecyldimethylammonium carbonate (DDACb) ratio of 2:1 to 1:1 and 1:2 resulted in lower copper retention in the treated samples and substantially decreased the amount of copper leached per unit area. For monoethanolamine (Mea) based ACQ, solution parameters which favour a higher proportion of monovalent cationic complex, which consume one reactive site in wood, and the presence of insoluble carbonate precipitate of copper in wood during preservative treatment resulted in higher leach resistance compared to the neutral copper complex present at higher pH. Ammonia (NH3) based ACQ can fix more copper at high pH as there is no chelated neutral complex as in Mea based ACQ; however divalent copper-NH3 complexes may consume two sites to fix in wood. Addition of NH3 in Mea based ACQ at Cu:Mea:NH3 ratio of 1:4:6 at pH 10.6 significantly reduced copper leaching compared to 1:4:0 (without ammonia) at pH 9 due to increased divalent copper-ammonia complexes and decreased neutral copper amine complex at elevated pH. Ammonia addition with a lower proportion of Mea (1:2.5:4 at pH 10.5-10.7), significantly reduced copper leaching compared to 1:4:0 at pH 9; no reduction was observed for ammonia addition in ACQ with a higher proportion of Mea (1:4:4 at pH 10.45). The lower copper leaching from 1:2.5:4 resulted from the higher amount of divalent copper-NH3 complexes at higher pH without compromising the amount of copper precipitated at lower pH. The higher percent copper leached from tetramethylethylenediamine (Tmed) based ACQ compared to Mea and NH3 based ACQ suggested that highly stable complexes tend to stay in solution and do not result in leach resistant copper in the wood.
Burn for Full Orchestra
Keywords: Composition
Orchestra

As the title of the work suggests, Burn brings to mind the qualities, characteristics and properties of fire: its volatile, destructive and unpredictable nature, and its often-overlooked sublime and evanescent states. Although I did not set out to programmatically depict the element in Burn, fire provides a metaphor for the compositional process. My objective was to compose a work that is harmonically and motivically rich, and where colour and character are of absolute importance. In turn, the work is explosive and unrelenting, with contrasting moments of subtler music. The complex and volatile personality of fire takes form right from the dramatic and combustible opening of Burn, through to the kaleidoscopic and mercurial textures of its developmental sections, its slow but catastrophic middle section, and its remorseless ending. And like the prodigiously agile nature of this element, I wanted to write a work that is engaging and virtuosic for its players. Burn is a single-movement work cast in three dramatic sections. The opening, spanning from mm. 1-24, establishes the musical material and sets the tone for the work. The music of the introduction gives way, at m. 25, to a developmental section, where varied forms of the introduction appear as structural delineators: mm. 68-71 to close the first part of the development, mm. 98-106 and mm. 131-136. The outer sections of Burn, mm. 1-136 and mm. 188-291, are fast and furious, colourful and nimble, and are similar to each other in character and content. The contrasting middle section, mm. 137-187, gives way to a different music, one that is slow and intense but shares motivic and harmonic attributes with the outer sections. The music climaxes at the return of the Tempo Primo, mm.166-187, with the defining motif of the outer sections superimposed at its original speed over the broad music of the middle section. Burn closes at the end of the third section with a varied return of the introduction.
Magneto-hydrodynamics Simulation in Astrophysics
Keywords: Magneto-hydrodynamics
simulation

Magnetohydrodynamics (MHD) studies the dynamics of an electrically conducting fluid under the influence of a magnetic field. Many astrophysical phenomena are related to MHD, and computer simulations are used to model these dynamics. In this thesis, we conduct MHD simulations of non-radiative black hole accretion as well as fast magnetic reconnection. By performing large scale three dimensional parallel MHD simulations on supercomputers and using a deformed-mesh algorithm, we were able to conduct very high dynamical range simulations of black hole accretion of Sgr A* at the Galactic Center. We find a generic set of solutions, and make specific predictions for currently feasible observations of rotation measure (RM). The magnetized accretion flow is subsonic and lacks outward convection flux, making the accretion rate very small and having a density slope of around – 1. There is no tendency for the flows to become rotationally supported, and the slow time variability of the RM is a key quantitative signature of this accretion flow. We also provide a constructive numerical example of fast magnetic reconnection in a three-dimensional periodic box. Reconnection is initiated by a strong, localized perturbation to the field lines and the solution is intrinsically three-dimensional. Approximately 30% of the magnetic energy is released in an event which lasts about one Alfvén time, but only after a delay during which the field lines evolve into a critical configuration. In the co-moving frame of the reconnection regions, reconnection occurs through an X-like point, analogous to the Petschek reconnection. The dynamics appear to be driven by global flows rather than local processes. In addition to issues pertaining to physics, we present results on the acceleration of MHD simulations using heterogeneous computing systems [83]. We have implemented the MHD code on a variety of heterogeneous and multi-core architectures (multi-core x86, Cell, Nvidia and ATI GPU) using different languages (FORTRAN, C, Cell, CUDA and OpenCL). Initial performance results for these systems are presented, and we conclude that substantial gains in performance over traditional systems are possible. In particular, it is possible to extract a greater percentage of peak theoretical performance from some heterogeneous systems when compared to x86 architectures.
The Public Dimension of Meaning
Keywords: Philosophy
Language
Mind
Meaning
Social Externalism

The philosophical discussion of conceptual content and linguistic meaning in the 20th century has been dominated by two contrasting approaches - the descriptive-internalist approach, and the causal-externalist approach. Recent semantic models, for example the two-dimensional semantics of Jackson and Chalmers, attempt to integrate these two approaches. In this dissertation I explore a series of puzzles that highlight points at which the resources of these two approaches combined fall short. Particularly, the dissertation is an argument for the claim that facts about a linguistic community can affect the conceptual and linguistic content of individual members of that community, developing insights of theorists such as Quine, Wittgenstein, Kripke, Lewis and Davidson. The study proceeds along two lines simultaneously, as an investigation into puzzles concerning conceptual content on the one hand, and concerning linguistic meaning on the other. The centerpiece of the investigation into linguistic meaning is a proposal for an irreducibly social aspect of linguistic meaning, which I call the ‘public content’ of linguistic terms. This proposal is motivated by the identification of some points at which neither individualist models of linguistic meaning nor the ‘social’ models of meaning currently available give convincing accounts. Drawing on recent developments in social epistemology, I argue that this aspect of meaning is determined by what speakers engaged in discourse would agree on under an ideal process of collective reasoning as the meaning of the terms they use. In the last chapter I attempt to reconcile this model of meaning with the two-dimensional semantic model, arguing for a three-dimensional model of meaning that includes internal, external, and public dimensions. Alongside the discussion of linguistic meaning I explore a series of related puzzles that arise for conceptual content, particularly a new puzzle of referential indeterminacy, and the problem of conceptual error or normativity. I propose and defend solutions to these puzzles that lean heavily on the rational resources of individuals, focusing on the ‘personal level’ contents of thought to resolve puzzles in this domain, and rejecting models that lean on ‘sub-personal’ states such as neuronal, historical, or dispositional states of thinkers.
Just a Beginning: Computers and Celestial Mechanics in the Work of Wallace J. Eckert
Keywords: history of computing
history of astronomy

This thesis details and analyzes the interaction between computers and science in a particular case. The case is the career of Wallace J. Eckert (1902-1971). Eckert was a professor of astronomy at Columbia University and scientific researcher for IBM. He has received some attention in the history of computing for his significant work in machine computation in the 1930s and 1940s and was the foremost expert on lunar theory for much of his life. First the existing secondary literature on the subject is discussed. Eckert's work has rarely been the focus of sustained historical scrutiny, but the question of the relation of science and the computer has received more scholarship in the history, philosophy and sociology of science. The main narrative of the thesis begins with the history of the various mathematical techniques and external aids to computation used over the course of the history of celestial mechanics. Having set the context, Eckert's early life and career is detailed up until 1945. Here, before the modern computer as such was developed, Eckert innovated by adapting IBM punched card machines to astronomical applications. Next Eckert's time as a scientific researcher employed by IBM after 1945 is detailed. Here he helped establish a culture of scientific research at IBM, demonstrated the value of IBM's products for science, aided in the development of new more complex machine designs including electronic systems and continued his own astronomical research. Eckert's major projects on electronic machines are described, especially those in lunar theory, with explanation of how his astronomical methods remained the same or were modified and expanded by later electronic machines and how he innovated with the machines at his disposal. In the conclusion, after summarizing later developments in celestial mechanics, broader questions about the modern computer's role in science are engaged. Continuity between pre and post computer methods is well illustrated by Eckert's work. His work also shows that while the computer was a force for change in celestial mechanics, the form of that change depended on the choices, resources and practices of the people using it.
L-arginine Metabolism Regulates Airways Responsiveness in Asthma and Exacerbation by Air Pollution
Keywords: arginase
asthma
air pollution
particulate matter
ozone
nitric oxide
nitric oxide synthase
airways hyperresponsiveness
polyamines
spermine
ADMA
inflammation

Asthma is a chronic respiratory disease with a high prevalence in Western countries, including Canada, and increased exacerbations have been associated with ambient air pollution. The maintenance of airways tone is critically dependent on the endogenous bronchodilator, nitric oxide (NO). The nitric oxide synthase (NOS) isoenzymes produce NO from the amino acid, L-arginine, and competition for substrate with the arginase isoenzymes can limit NO production. Imbalances between these pathways have been implicated in the airways hyperresponsiveness (AHR) of asthma. The overall objective of this work was to determine whether arginase and downstream polyamine metabolites are functionally involved in airways responsiveness in animal models of asthma and the adverse responses of allergic animals to air pollution. To this purpose, the expression profiles of proteins involved in L-arginine metabolism were determined in lung tissues from human asthmatics and murine models of ovalbumin (OVA)-induced airways inflammation. Expression of arginase 1 was increased in human asthma and animal models. Competitive inhibition of arginase attenuated AHR in vivo. The roles of the downstream metabolites of arginase, the polyamines (putrescine, spermidine and spermine) were examined by administering them via inhalation to anaesthetized mice. It was demonstrated that spermine increases methacholine responsiveness in normal and allergic mice. Additionally, inhibition of polyamine synthesis improved AHR in a murine model. Thus, arginase and downstream polyamine metabolites contribute to AHR in asthma. Finally, the potential role of arginase in the exacerbation of asthma by air pollution was investigated. For this purpose, murine sub-acute and chronic murine models of allergic airways inflammation were employed, which exhibit inflammatory cell influx and remodeling/AHR, respectively, to determine the role of arginase in the response to concentrated ambient fine particles plus ozone. Allergic mice that were exposed to air pollution exhibited increased arginase activity and expression, compared to filtered air-exposed controls. Furthermore, inhibition of arginase attenuated the air pollution-induced AHR. Thus, the studies of the arginase pathway and downstream metabolites described in this thesis indicate that arginase inhibition may be a therapeutic target in asthma and may also protect susceptible populations against the adverse health effects of air pollution.