Cancer Cell Mechanics in Chemoresistance and Chemotherapeutic Drug Exposure

Cancer remains a problem worldwide as one of the leading causes of morbidity and mortality. Many cancer patients experience recurrence and ultimately death due to treatment failure or the development of chemoresistance. The concept of chemoresistance however is complex, recent studies have highlighted that cellular structure and extra-cellular composition, mechanics and structure play a role in the development of chemoresistance. The mechanical properties of cells impact their architecture, migration patterns, intracellular trafficking and many other cellular functions. Studies have also revealed that cellular mechanical properties are modified during cancer progression. We investigated these mechanical properties and changes to them by using a malignant melanoma cell line (WM1158) and a chemoresistant malignant melanoma cell line (SK-MEL29). Malignant melanoma was the cell line of choice as it is one of the most prominent types of cancer known to develop chemoresistance. The aim of this study was to identify the effects of chemotherapeutic drug exposure on the mechanical properties and cytoskeletal composition of drug sensitive and drug resistant malignant melanoma cells. To achieve this, a combination of Multiple particle tracking microrheology (MPTM), quantitative RT-PCR and Western blotting techniques were utilised to demonstrate changes in cytoskeletal elements that are responsible for cellular mechanics. MPTM was developed as an approach to map intracellular mechanical properties of living cells and track the intracellular particles by Brownian motion to establish a viscoelastic model and compare it with the power-law approach. A quantification of the MPTM allowed capturing of the cell stiffness using the mean squared displacement (MSD) of cell under different conditions. The cytoskeletal elements actin and β-tubulin were analysed in qRT-PCR and Western blot as they form the key elements governing a cell’s mechanical stability and response to mechanical stimuli. The findings from this study revealed cell stiffness decreases as cancer progress, thereby cells become stiffer. The same pattern was evident for chemoresistant malignant cells and revealed that they had a loss of elasticity in comparison to their counter non-resistant malignant cells. With regards to protein levels and mRNA expression, the chemotherapeutic drug affected the cytoskeleton causing cells to undergo morphological changes which, however, was not seen in chemoresistant cells. The results from this study indicated that measuring mechanical properties of cells provides an efficient marker for cancer diagnosis and deeper understanding of cancer mechanobiology

The relationship between Saskatchewan's co-operative community clinics and the government of Saskatchewan : toward a new understanding

This dissertation is a study of the public policy-making process, the role of ideas and relationships in this process, and their effect on social economy enterprises, in particular co-operatives. It is concerned with a central problem in all social economy organizations today: understanding the impact of public policy on funding, decision-making and strategy. The relationship between Saskatchewan’s co-operative Community Clinics and the provincial government is of particular interest. In spite of a seeming congruence between the goals of the Community Clinics and the government, the Clinics have not been allowed to play a significant role in reforming the delivery of health care services in the province. The dissertation draws on models and concepts from the literatures on business–government relations, public policy and the policy-making process, the role of ideas and ideology in public policy, the social economy and public policy, and government–co-operative relations. A case study of the Community Clinics is elaborated through key informant interviews and supported by examination of primary and secondary literature. This research shows that the Community Clinics are unique organizations and that a new understanding can be developed if the Clinics are viewed as hybrids – some combination of co-operative, public, and perhaps even private organizations. The ambiguity in the relationship arises at least in part from the differing and conflicting ways that the Community Clinics have been conceptualized by the politicians, government officials, the health regions, and even the Clinics themselves. The research also shows that the dominant idea at play in the health care policy domain in Saskatchewan remains that of private medical practice, with fee-for-service remuneration, and that the conditions necessary for a major policy change with respect to the role of the Community Clinics do not exist

An experimental study on the effects of blade row interactions on aerodynamic loss mechanisms in a multistage compressor

While the gas turbine engine has existed for nearly 80 years, much of the complex aerodynamics which governs compressor performance is still not well understood. The unsteady flow field consists of periodic blade row interactions from the wakes and potential fields of each blade and vane. Vane clocking is the relative circumferential indexing of adjacent vane rows with the same vane count, and it is one method to change blade row interactions. Though the potential of performance benefits with vane clocking is known, the driving flow physics have yet to be identified. ^ This research examines the effects of blade row interactions on embedded stator total pressure loss and boundary layer transition in the Purdue 3-stage axial compressor. The inlet guide vane, Stator 1, and Stator 2 all have 44 vanes which enable vane clocking of the embedded stage, while the rotors have different blade counts producing amplitude modulation of the unsteady interactions. ^ A detailed investigation of corrected conditions is presented to establish repeatable, compressor performance year-round in a facility utilizing ambient inlet conditions. Without proper humidity accounting of compressor corrected conditions and an understanding of the potential for inlet temperature changes to affect clearances due to thermal growth, measurements of small performance changes in detailed research studies could be indiscernible. ^ The methodology and implementation of a powder-paint flow visualization technique along with the illuminated flow physics are presented in detail. This method assists in understanding the loss development in the compressor by highlighting stator corner separations and endwall flow patterns. Effects of loading condition, rotor tip clearance height, and stator wake and rotor tip leakage interactions are shown with this technique. ^ Vane clocking effects on compressor performance were quantified for nine loading conditions and six clocking configurations - the largest vane clocking dataset in the open literature. These data show that vane clocking effects are small at low loading conditions, including peak efficiency operation, but become stronger as loading increases, and then eventually lessen at near stall operation. Additionally, stator wake profiles and flow visualization reveal that total pressure loss changes are due to a corner separation modulation between clocking configurations. ^ To further address these clocking trends, high-frequency response data were acquired at the Stator 2 inlet and along the Stator 2 surface. The unsteadiness at the Stator 2 inlet was quantified with detailed radial traverses for the different clocking configurations. These data show the effects of interactions between the Stator 1 wake and Rotor 2 tip leakage flow, which result in significantly different inlet flow conditions for Stator 2. The high unsteadiness and blockage region formed by the rotor tip leakage flow changes in size and shape between clocking configurations. Finally, measurements of the Stator 2 surface flows were acquired to investigate the vane clocking effects on unsteady surface pressures and boundary layer transition. These data reveal that Stator 2 performance is influenced by blade row interactions including rotor-rotor interactions, stator wake-rotor tip leakage flow interactions, and vane clocking

Instilling an Entrepreneurial Mindset in Department of Defense (DoD) Organizations: Evidence from Entrepreneurial Organizations in the Private Sector

Calls for transforming government and creating entrepreneurial cultures in non-profit motivated organizations are everywhere today. The primary method proposed for instilling an entrepreneurial mindset is to institute best practices or lessons learned from commercial firms that have characteristics similar to those of large government organizations. While the similarities between the private and public sector organizations are many, the differences (e.g. legal restrictions, missions, and motivation of members of the organization) are also notable. This exploratory study seeks to more clearly define the commonalities between the experiences of private sector firms and how those experiences can be captured to help DoD organizations to transform themselves to better execute their mission

Caesarean section and risk of unexplained stillbirth in subsequent pregnancy

Background Caesarean section is associated with an increased risk of disorders of placentation in subsequent pregnancies, but effects on the rate of antepartum stillbirth are unknown. We aimed to establish whether previous caesarean delivery is associated with an increased risk of antepartum stillbirth. Methods We linked pregnancy discharge data from the Scottish Morbidity Record (1980–98) and the Scottish Stillbirth and Infant Death Enquiry (1985–98). We estimated the relative risk of antepartum stillbirth in second pregnancies using time-to-event analyses. Findings For 120 633 singleton second births, there were 68 antepartum stillbirths in 17 754 women previously delivered by caesarean section (2–39 per 10 000 women per week) and 244 in 102879 women previously delivered vaginally (1·44; p<0·001). Risk of unexplained stillbirth associated with previous caesarean delivery differed significantly with gestational age (p=0·04); the excess risk was apparent from 34 weeks (hazard ratio 2·23 [95% Cl 1·48–3·36]). Risk was not attenuated by adjustment for maternal characteristics or outcome of the first pregnancy (2·74 [1·74–4·30]). The absolute risk of unexplained stillbirth at or after 39 weeks' gestation was 1·1 per 1000 women who had had a previous caesarean section and 0·5 per 1000 in those who had not. The difference was due mostly to an excess of unexplained stillbirths among women previously delivered by caesarean section. Interpretation Delivery by caesarean section in the first pregnancy could increase the risk of unexplained stillbirth in the second. In women with one previous caesarean delivery, the risk of unexplained antepartum stillbirth at or after 39 weeks' gestation is about double the risk of stillbirth or neonatal death from intrapartum uterine rupture

Constructing the Liminal: La Portentosa Vida de la Muerte

Written in 1792 by Fr. Joaquin Bolanos, the rare book, La portentosa vida de la muerte, chronicles the life and exploits of Death. She appears neither as deity nor human, but as a skeletal personification with attributes of both man and woman. The constructed view of Death as a physical being in the prints that accompany the text offers the opportunity to explore artistic problems with respect to depicting the ambiguous. Within this thesis, I will use the conceptual framework of liminality to interrogate the boundaries of such constructed categories as art, ornament, trademark, gender and genre. Original research also centers the discovery of a vast array of watermarks that appear specifically in the Gilcrease Museum's copy of the book.Art Histor

Addressing the challenges of establishing quality wastewater or non- sewered sanitation-based surveillance, including laboratory and epidemiological considerations, in Malawi

Learning from clinical laboratories, wastewater or environmental (including non-sewered sanitation) environmental microbiology laboratories can be established in resource-limited settings that focus on pathogen detection and pandemic prevention. Transparent discussions on the laboratory challenges and adaptations required for this can help meet the future requirements of health research and surveillance. This report aims to describe the challenges encountered when setting up a wastewater or environmental laboratory for multipathogen surveillance in Malawi, a resource-limited setting, as well as the lessons learnt. We identified nine unifying themes: what to monitor, human resource capacity, indicators of data quality, equipment availability, supply of consumable goods, ongoing operation and maintenance of the laboratory, application of localised guidelines for laboratory operations, lack of real-time clinical correlation for calibration and localised ethical considerations. Over our 6-month timeline, only Salmonella typhi, Vibrio cholerae and severe acute respiratory syndrome coronavirus 2 analyses were set-up. However, we were unable to set-up measles and tuberculosis analyses owing largely to supply delays. By establishing this system at a public higher education academic laboratory in Malawi, we have ensured that ongoing capacity building and piloting of public health work is conducted in the country, rather than relying on non-governmental organisations or reference laboratory support beyond national borders. This work is not intended to replace clinical testing but rather demonstrates the potential for adapting higher education academic laboratory infrastructure to add wastewater or environmental (including non-sewered sanitation) samples, where appropriate, as additive epidemiological data for better pandemic preparedness

Estimating sewage flow rate in Jefferson County, Kentucky, using machine learning for wastewater-based epidemiology applications

Direct measurement of the flow rate in sanitary sewer lines is not always feasible and is an important parameter for the normalization of data used in wastewater-based epidemiology applications. Machine learning to estimate past wastewater influent flow rates supporting public health applications has not been studied. The aim of this study was to assess wastewater treatment plant influent flow rates when compared with weather data and to retrospectively estimate flow rates in Louisville, Kentucky (USA), based on other data types using machine learning. A random forest model was trained using a range of variables, such as feces-related indicators, weather data that could be associated with dilution in sewage systems, and area demographics. The developed algorithm successfully estimated the flow rate with an accuracy of 91.7%, although it did not perform as well with short-term (1-day) high flow rates. This study suggests using variables such as precipitation (mm/day) and population size are more important for wastewater flow estimation. The fecal indicator concentration (cross-assembly phage and pepper mild mottle virus) was less important. Our study challenges currently accepted opinions by showing the important public health potential application of artificial intelligence in wastewater treatment plant flow rate estimation for wastewater-based epidemiological applications