Triple-negative breast cancer (TNBC) accounts for 15% of all diagnosed breast cancers nationally and affects African-American women 3 times more likely than any other ethnic group. Locally, African-American women in the New Orleans area see higher incidence of TNBC cases versus African-American women from the rest of the state of Louisiana, which represents an area of heightened public health interest for the metropolitan area. TNBC is a highly metastatic disease, and targeted therapies such as tamoxifen and herceptin are ineffective due to the lack of estrogen receptor (ER) and HER2/neu target expression in TNBC tumors. Chemotherapy remains the only effective drug therapy in TNBC cases. Evaluating new classes of drugs for clinical use against TNBC as well as furthering our understanding of underlying regulatory mechanisms in TNBC is a priority. Pan-deacetylase inhibitors (DACi), like panobinostat, have shown promise in clinical trials as therapies in other cancers. Pre-clinical data of panobinostat treatment in TNBC cell lines published by this lab has been positive so far, exhibiting a reduction in TNBC metastatic potential. DACi can alter multiple signaling pathways and are known to restore dysregulated microRNA (miRNA) expression patterns (miRnome) in cancers. MiRNA are a relatively new class of non-protein coding regulatory biomolecules that exhibit a variety of cancer-related properties, many still unknown in TNBC. Pan-DACi treatment combined with miRnome analysis in TNBC cell lines can be used to identify previously unknown miRNA cancer-related properties in TNBC. The specific aim of this project consists of using DACi treatment on TNBC cell lines in conjunction with miRnome analysis to identify previously undescribed anti-cancer miRNAs and elucidate their cancer-related properties in TNBC while uncovering affected cancer pathways, detecting miRNA targets, and revealing affected downstream components. Initial miRNA expression analysis of MDA-MB-231 TNBC cells treated with panobinostat or trichostatin A versus controls produced a list of potential anti-cancer miRNA candidates for further study. Among them, investigations into miR-203 and miR-335 produced unclear results as these were theorized to have anti-metastatic properties in TNBC yet enhanced cancer properties in our models and assays. Overexpression of mir-215 (a tumor suppressor in other cancers) unexpectedly enhanced tumor growth five fold in SCID mice xenografted with lentivirally-transduced MDA-MB-231 breast cancer cells stably overexpressing miR-215 (231/215+). Further qPCR analysis of 231/215+ cells uncovered upregulation of the breast cancer-associated lncRNA, HOTAIR; the breast cancer-associated miRNA, miR-196a; as well as the entire HOXC cluster in which they reside. This represents a previously unidentified regulatory mechanism of the HOXC cluster in humans. Additionally, miR-200b overexpression in MDA-MB-231 cells induced a change in cell morphology to an epithelial-like phenotype, reduced migration by 50%, and re-expressed the epithelial marker CDH1. This demonstrates a partial reversal of epithelial-mesenchymal transition (EMT), which indicates a reduction in metastatic potential by miR-200b overexpression in MDA-MB-231 cells. Additionally, these cells exhibited increased estrogen receptor alpha and related signaling pathways while also being susceptible to reduced proliferation with the anti-estrogen drug fulvestrant at high doses. Using pan-DACi treatment of TNBC cells to analyze changes in the miRnome for unknown cancer-related miRNA candidates suitable for further investigation in TNBC, we identified miR-215 overexpression in MDA-MB-231 cells as an oncogenic event that enhances tumor growth, cell proliferation, and HOXC cluster transcription while miR-200b is an anti-metastatic miRNA that partially reverses EMT and reduces fulvestrant resistance through re-expression of estrogen receptor signaling. / acase@tulane.edu

Therapeutics targeting the PI3K (phosphatidylinositol 3-kinase) and the Ras/MAPK (mitogen-activated protein kinases) pathways have potential as non-toxic treatments for triple-negative breast cancer due to their frequent over-activation in several forms of cancer. Interestingly, the PI3K and Ras/MAPK pathways have been shown to incite cancer dormancy behavior individually and tumorigenic behavior in unison when induced in healthy breast epithelial cells (MCF-10A) in vivo. Tumorigenesis and metastasis are heavily reliant on the specific mechanical and adhesive properties of cells, including decreased stiffness, increased mechanosensitivity, and decreased adhesion. However, the describe cellular behaviors are poorly understood for dormant cancer phenotypes. Understanding the mechanical and adhesive behaviors of MCF-10A cells as a function of PI3K and/or Ras/MAPK pathway over-activation further explores the cross-talk enabling unique dormant and tumorigenic characteristics. Cellular viscoelasticity and adhesion were measured for MCF-10A cells with PTEN (phosphatase and tensin homolog) knockout and activated KRAS (Kristen rat sarcoma viral oncogene homolog) overexpression to activate the PI3K and Ras/MAPK pathways respectively with atomic force microscopy. PTEN knockout alone has no observable influence on cell adhesion but resulted in softer cells with less organized cytoskeleton. Activated KRAS overexpression increased cell stiffness and cell adhesion regardless of PTEN expression level. Moreover, the overexpression of activated KRAS enhanced the sensitivity of cells to the substrate stiffness. The findings suggest that the cancer-associated pathways PI3K and Ras/MAPK regulate cell adhesion and mechanics to promote tumor formation and metastasis. More importantly, the results that signify mutations of different molecular pathways associated with cancer dormancy regulate cell mechanics differently suggests that cell stiffness is a biomarker that detects and differentiates different types of dormant cancers.

This dissertation explores the physics of droplet impingement on superhydrophobic surfaces. The research is divided in three categories. First, the effect of a slip boundary condition on droplet spreading/retracting is considered. A model is developed based on energy conservation to evaluate spreading rates on surfaces exhibiting isotropic and anisotropic slip. The results show that larger slip causes the droplet to spread out farther owing to reduced friction at the interface for both slip scenarios. Furthermore, effects of slip become magnified for large Weber numbers due to the larger solid-liquid contact area during the process. On surfaces with anisotropic slip, droplets adopt an elliptical shape following the azimuthal contour of the slip on the surface. It is common for liquid to penetrate into the cavities at the superhydrophobic interface following droplet impact. Once penetrated, the flow is said to be in the Wenzel state and many superhydrophobic advantages, such as self-cleaning and drag-reduction, become negated. Transition from the Wenzel to the Cassie state (liquid resides above the texture) is referred to as dewetting and is the focus of the second piece of this dissertation. Micro-pillar pitch, height and temperature play a role on dewetting dynamics. The results show that dewetting rates increase with increasing pillar height and increasing surface temperature. A scaling model is constructed to obtain an explanation for the experimental observations and suggests that increasing pillar height increasing the driving dewetting force, while increasing surface temperature decreases dissipation. The last piece of work of this dissertation entails droplet impingement on superheated surfaces (100°C - 400°C). We find that the Leidenfrost point (LFP) occurs at a lower temperature on a hydrophobic surface than a hydrophilic one, where the LFP refers to the lowest temperature at which secondary atomization ceases to occur. This behavior is attributed to the manner in which vapor bubbles grow at the solid-liquid interface. Also in this work, high-speed photographs reveal that secondary atomization can be significantly suppressed on a superhydrophobic surface owing to the micro-pillar forest which allows vapor to escape hence minimizing bubble formation within the droplet. However, a more in-depth study into different superhydrophobic texture patterns later reveals that atomization intensity can significantly increase for small pitch values given the obstruction to vapor flow presented by the increased frequency of the pillars.

Urban water utilities in the United States face challenges due to a combination of external drivers. These include urbanization and population growth, which are stressing a system of aging infrastructure. Compliance with increasing regulations is also a challenge in a fiscally-constrained economic environment. A changing climate threatens infrastructure and past assumptions for water supply and quality. Urban utilities provide clean water and sanitation services to over 80% of the country’s population and its industrial centers. Therefore, the sustainability of these water utilities are crucial to the country’s and the public’s well-being. New operating models are emerging for a “utility of the future.” Future utilities will recover resources, reduce their overall environmental impact, partner in the local economy, and deliver watershed-wide benefits to improve quality of life. These are all elements of a sustainable utility, but the sector has not agreed upon an applicable definition of sustainability, which intuitively incorporates an inter-generational approach to utility operations. For the purposes of this research, a sustainable utility is defined as one that will provide its crucial services for current and future generations, protect public and environmental health, and enable economic growth, all while minimizing resource consumption. Previous research provided little guidance on the most important sustainable practices for U.S. urban water utilities or the key attributes of those utilities that enable the shift toward sustainability. Additionally, the practice of sustainability measurement, and the closely-related practice of performance measurement, has not been widely adopted in the U.S. water sector. This research program addressed the challenge of providing guidance on, and measurement of, sustainability by developing a framework to quickly and quantitatively assess a utility’s sustainability and key organizational attributes. A mixed methods approach to this research used qualitative and quantitative methodologies. The approach utilized accepted anthropological methods to assess engineering and business concepts at water utilities. Data originated from semi-structured interviews of an external advisory committee of 12 widely-recognized, progressive, U.S. water utility leaders along with online surveys of water utility professionals. The analyzed data revealed the most important sustainable practices for sustainable utilities and organizational attributes that enable the shift toward sustainable operations. Practices are actionable, quantitative, and in some cases, unique to the water sector. Attributes are generally qualitative; largely controlled by internal decisions and actions; and influence a utility’s ability to operate sustainably. Datasets for sustainable practices and organizational attributes were generated using the techniques of discourse analysis on the semi-structured interview transcripts and freelisting on the online survey results. Top results from each dataset were cross-compared to generate the final, consolidated list of top practices and attributes. A sustainability index was developed from the top eight sustainable practices, measured via a total of 14 indicators. Indices were tailored to water, wastewater, and combined utilities. The top sustainable practices were: Education and Communication; Financial Management; Green Infrastructure; Habitat/Watershed Protection; Long-term Resource Plan; Resource Recovery; and Water Conservation. These eight practices provided sufficient coverage of the economic, social, environmental, and infrastructure components of the triple bottom line-plus concept used to frame sustainability for this research. This research also established the top six organizational attributes that enable the shift toward sustainability. These attributes were: Board Support / Political Will; Flexible Staff; Innovative Culture; Leadership; Organizational Commitment; and Staff Training / Development. These six attributes were assessed via a total of seven indicators, with guidance and scaling similar to the practices for ease of use by the end user. Current sustainability and performance measurement frameworks were analyzed for indicators and measurement approaches that matched the top practices and attributes. Some of the practices and only one of the six attributes matched an existing framework. When there was a match, the existing assessment was used to help with ease of use. In other cases, new indicators, guidance, and scaling (for assessment) were developed. Practices and attributes without a match suggests these aspects of sustainable utilities are relatively new to the sector, or at least, measurement of these practices and attributes is not widespread. The practices and attributes were combined into the final framework, a survey tool, which was pilot tested with three water utilities. The pilot testing demonstrated that the survey was comprehensive, yet at the same time, concise enough that it could be completed in under two hours by a limited number of utility staff. The application of this framework to a representative sample of U.S. urban water utilities can generate data to establish which attributes correlate to sustainable utilities. This will help utilities focus their limited resources on attributes which are shown to enable the shift toward sustainability.

The electron-electron coincidence (e,2e) technique yields complete kinematical information about the electron impact ionization process. The (e,2e) technique has been widely used to study dynamical effects in ionizing collisions with atomic targets, however studies of molecular ionization using this technique have been very limited. Recently further experimental studies of small molecules have been proposed, as the cross sections of small molecules are now computable using sophisticated theoretical approaches [77, 24]. This thesis presents dynamical investigations for the electron impact ionization of the molecular targets H2O and H2, employing the (e,2e) technique to experimentally measure the triple differential cross section (TDCS). The TDCS is defined as the probability that a bound electron will be ejected from the target atom or molecule (into a particular direction with a defined energy) and the initial electron will be scattered into a particular direction with a particular energy. All TDCSs presented within this thesis were performed using an electron coincidence spectrometer in the coplanar asymmetric geometry at intermediate incident electron energies. This thesis presents the electron impact ionization TDCSs of H2O. A series of measurements were performed using H2O in the vapour form. Measurements of the TDCS are presented for the 2a1 atomic-like orbital and the 1b2, 3a1 and 1b1 molecular orbitals at a common incident electron energy of 250eV, ejected electron energy of 10eV and scattering angle of -15o. The experimental TDCSs are compared with theoretical cross sections that were calculated by Champion et al [25, 26] using a distorted wave Born approach (DWBA). TDCS measurements for the single ionization of the hydrogen molecule, H2 were performed as in recent years there has been evidence that indicates the ejected electron angular distribution is perturbed due to Young-type interference effects. The oscillatory structure which is predicted in the cross section is due to the two-centred nature of the molecule [27, 29]. This thesis presents experimental TDCSs for the ionization of H2 which are compared to TDCSs of helium. A series of measurements for the TDCSs of H2 and He are presented at a common incident electron energy of 250eV and scattering angle of -15o, for a range of ejected electron energies between 10eV and 100eV. The experimental TDCSs are compared with two types of theoretical calculations.

Drug use and misuse among young people in Australia has caused concern throughout the community and has prompted nationwide action to address the problem. One component of intervention strategies with young people is drug education. Drug education in Australia represents an international philosophy of prevention and takes a harm minimisation approach to intervention. One strategy that has had international success in the area of drug education with young people, and that has been used effectively in health education in Australia since the 1970s, is peer education. Peer drug education involves young people conducting drug education sessions with their peers. An example of peer drug education in Australia is the Teenagers Teaching Teenagers' (Triple T) program, conducted in the Australian Capital Territory (ACT). Evaluations and descriptions of peer drug education programs tend to focus more on outcomes pertaining to program recipients and fail to explore in detail the specific experience of peer leaders. Existing research on the experience of peer leadership does not explore in detail the personal experience of leaders, that being the effect of peer leadership training and duties on leaders' personal perceptions of drugs, their behaviour with drugs and their own feelings and skills. This thesis explores the personal experience of a group of peer leaders who participated in the Triple T program in 1994. It considers their perceptions of the program at the time of training and then goes on to explore the impact of this experience on their formulation of ideas about drugs to the present day. The thesis is a qualitative project which utilises in-depth interviewing and focus groups to gather data and then presents a thematic analysis of participant response. The thesis asks two research questions, 1. What do young men and women involved in the Triple T program take from the experience of peer leadership training and duties? 2. In what way does the Triple T' experience appear to contribute to the development of drug related ideas of these young people in the two years following involvement in the program? The findings suggest that the participants gained information, skills and personal development from the training and generally found it to be a positive experience. However, participants distanced themselves personally from a substantial amount of the training content and did not personally reflect on the training content to any great extent at the time of training. Training processes and some aspects of leadership duties more personally affected them, although again there was personal distancing from this part of the program. In exploring the findings there was difficulty determining the influence of the training experience due to participant reluctance to attribute influence to any one source on the formulation of ideas. Instead, participants describe a complex interaction of influences on the formulation of ideas about drugs and a process which involves maintaining control, upholding the notion of informed choice and incorporating ideas about drugs into the formation of an adult identity. Influences on these ideas include the training, actual experiences with drugs and observations of others. The thesis exploration suggests that being involved in peer drug education does impact on peer leaders but this experience was not personalised to any great degree at the time of training. However, in the following two years, participants called on the training information as well as other influences as they formed their ideas about drugs. The thesis raises some issues of how to maximise leaders' personal connection to the peer drug education process, if this is in fact a desired outcome of peer education. It also suggests the need for further research into the experience of peer leaders who seem to have remained the least considered party in the peer education movement.

Social pressure for sustainability has become a significant factor in Australian business. Made popular by a variety of diverse social movements that employ various tactics, sustainability is increasingly being debated in boardrooms and work areas of both large and small businesses. In this research, sustainability issues are treated as a set of a wider range of obligatory and externally imposed (OEI) issues that are increasingly confronting contemporary business. Of interest to this research is how senior managers deal with sustainability issues. While some businesses excel in dealing with OEI issues, others prevaricate. This research focuses on those businesses that appear to excel in resolving sustainability issues to explore how senior managers deal with sustainability issues. Such understanding is essential for contemporary practising senior managers, as it provides guidance for management behaviour that will enable sustainability and other OEI issues to be dealt with. The author's effort to understand how senior managers deal with sustainability issues has led to the first business context application of Harré's positioning theory. A social constructionist approach, positioning theory is concerned with ordinary conversations, and presumes that these are the building blocks of all other discursive phenomena. The resulting theory builds on positioning theory and provides a point of departure to conduct related research on other organizations that excel in dealing with OEI issues and those that prevaricate. With positioning theory it has been shown that, in dealing with sustainability issues, senior managers engage in a range of positioning of themselves and others. In doing so, power and knowledge have been considered in the light of Foucault's unique and penetrating concepts. This has led to the proposed augmentation of positioning theory to include a concept of social flux, which is put forward as an indication of social order or culture. Through this development, it has shown how senior managers confront opposition and reinforce support to enable them to achieve and preserve sustainability objectives. In practical terms, senior managers alter four components of the social order to align the culture with the issues that need to be dealt with. These components - rights, duties, morals and actions - are parameters that senior managers tune or level when they deal with sustainability issues. When the social order is appropriately tuned or levelled, it is aligned with the issues that need to be dealt with. That alignment enables issues to be resolved in a way appropriate for the organization.

L'acier grade 91 serait un candidat approprié pour des éléments de structures du circuit secondaire et du générateur de vapeur des réacteurs nucléaires de génération IV. Leur durée de vie sera prolongée jusqu'à 60 ans. Cela nécessite de considérer les mécanismes actifs durant de très longs temps de fluage afin de proposer des prédictions de durées de vie plus fiable que de simples extrapolations. La striction est le mécanisme de ruine principal pour des durées de vie jusqu'à 160 kh à 500°C et 94 kh à 600°C. Une simulation de la striction tenant compte de l'adoucissement du matériau conduit à deux lois de bornes qui encadrent les durées de vie expérimentales d'un grand nombre d'aciers martensitiques revenus jusqu'à 200 kh à température 500-700°C. Des cavités intergranulaires observées en FEG-SEM à deux durées de vie longues affectent faiblement la vitesse de déformation. Une prédiction du développement des cavités permettrait d'extrapoler les durées de vie hors du domaine expérimental. Leur germination et croissance, supposées associées à la diffusion des lacunes, sont modélisées grâce à deux modèles classiques. Le premier tient compte d'une germination instantanée (Raj et Ashby) et le second d'une germination continue - Dyson. Le second, plus stable par rapport à ses paramètres que le premier, conduit à des prédictions des tailles finales de cavités en accord raisonnable avec les mesures en FEG-SEM. La vitesse de germination identifiée expérimentalement est requise dans ce modèle. La germination continue des cavités par diffusion est modélisée grâce au modèle classique de Raj. Ce modèle ne permet pas des prédictions de densité de cavités en accord avec les mesures, même en tenant compte de la germination aux interfaces matrice / précipités, observée au MEB-FEG et d'un facteur maximal de concentration de contrainte locale de 2. Ce dernier a été obtenu grâce à des calculs par éléments finis en déformations planes du fluage de microstructures simulées ou réelles, comprenant des points triples ou des précipités/phases de Laves. L'utilisation de la loi de germination de Dyson permet de proposer des prédictions au-delà de 200kh. La durée de vie prédite par le modèle de Riedel d'un essai à basse contrainte semble être en accord avec la durée expérimentale estimée de l'essai (toujours en cours) et actuellement en stade tertiaire, basée sur la fraction de la durée de vie habituellement consommée par le stade tertiaire.

<p>Syftet är att utifrån GRI:s riktlinjer undersöka ICA:s hållbarhetsredovisning samt jämföra den med den generella uppfattningen som intressentgruppen leverantörer har om hållbarhetsredovisningar.</p><p>ICA tar GRI:s riktlinjer på stort allvar vid tillämpning av dessa vid upprättandet av sin hållbarhetsredovisning. Leverantörernas intresse påverkar ett flertal resultatindikatorer som ICA inte har definierat som resultatindikatorer valda utifrån leverantörernas intresse.</p>

EURISOL sera la source de prochaine génération pour la production de faisceaux intenses d'ions exotiques. Son complexe accélérateurs se compose d'un linac primaire, des ensembles cibles et sources et d'un linac de post-accélération qui fournit les ions radioactifs aux différentes aires expérimentales. L'étude menée dans ce mémoire concerne l'accélérateur primaire : un linac RF supraconducteur capable d'accélérer plusieurs types d'ions (D+, 3He2+ et H