Microarray analysis of tamoxifen resistance in breast cancer.

PhDTamoxifen remains a widely used hormone therapy for pre and postmenopausal women with hormone receptor positive breast cancer in both adjuvant and metastatic disease settings. Resistance to this well tolerated and cost-effective drug limits its use. Only an improved understanding of the mechanisms of tamoxifen resistance will provide the basis for overcoming this phenomenon. Expression profiles from tamoxifen-resistant and sensitive MCF7 derived breast cancer cell lines were prepared, using Affymetrix HG_U133A cDNA microarrays. The data generated was analysed to identify novel pathways and genes associated with tamoxifen resistance or sensitivity. Selected genes, whose expression correlates with response to tamoxifen, were validated using RT-PCR in cell lines and following this, in situ hybridisation and immunohistochemistry on cell lines. Functional analyses of these genes were carried out: genes that were down-regulated in tamoxifen resistant MCF7 cells (HRASLS3, CTSD, CAXII) were selectively knocked down using RNA interference. Cell lines stably over-expressing genes upregulated in the tamoxifen resistant MCF7s (ATP1B1, SOCS2, NR4A2) were selected. These manipulated cells were subsequently tested for their response to anti-oestrogen treatment. Another major marker in breast cancer is the ERBB2 proto-oncogene; overexpressed in 20% of breast carcinomas, it is associated with poor prognosis and hormone resistance. The transcriptional deregulation of ERBB2 in breast cancer may in part be mediated by the transcription factors AP-2 and . Previous studies have shown that ERBB2 expression is repressed by oestrogen activated oestrogen receptor and that AP-2 binding sites within the ERBB2 promoter and the intronic enhancer are required for this oestrogenic repression. Using RNA interference, AP-2 and were successfully knocked down in breast cancer cell lines MCF7, T47D and ZR75-1. These have been used to investigate the effect of AP-2 loss on ERBB2 expression in hormonally manipulated cells

Classifying videogames as art and why it matters now

This dissertation analyses the idea that videogames can be considered art in order to argue that wide ranging benefits could be seen if the institution recognised them as such. I have explored the idea that the institution is the key to progress the notion of videogames as art and both art museums and universities alike must be behind the progression of what is considered the artistic canon in order to create new opportunities in the field of making art. I have reviewed popular arguments for and against the inclusion of videogames in the institutional artistic canon and then considered videogames in the light of several theorist's ideas of what art is. Primarily I have looked at the ideas behind cluster theory and the theory of mass art as a way of justifying videogames as art. I have followed this with case studies of This War of Mine (2014) and the developer Sam Barlow who has produced many videogames including Aisle (1999), Silent Hill: Shattered Memories (2009), and Her Story (2015). Lastly I have considered what might be the long-term benefits of classifying videogames as art within the institution, primarily the enfranchisement of young women artists. I do this by reviewing the new National Curriculum in computer programming and considering how, in the light of Virginia Woolf's A Room of One's Own, this new education area will empower young women to be able to create art despite pressures that still persist with regards to the "proper" role of a woman in our society. It is my suggestion that all you need to create a work of videogame art is a basic computer, a standard UK education, and a room of your own - but only if the art institution recognises videogames as a legitimate form of art

'The dilemma of councillors': The history of local government in Kenya, c. 1945 - 2010

This thesis examines the history of local government in Kenya from the late-colonial period up to the passage of Kenya's new constitution in 2010. The development of local government was a hallmark of the Colonial Office's policy for Africa in the post-war period. In spite of this, scholarship on post-colonial Kenya has tended to overlook local authorities. The 2010 constitution devolves power to forty-seven new county governments; in light of this, this thesis considers how the local state has historically functioned in practice. In doing so, it contributes to the literature on decentralisation, neo-patrimonialism and the state in Africa. Historiography of modern Kenya has focused on elite politics and the political dynamics of the highly centralised state. The prevailing narrative of local government in Kenya has been a story of formal decline. By reading the narrative of the Kenyan state from the bottom-up, this thesis explores the development of competing ideas of government in Kenya, and the way this has shaped the practices of state institutions and those who hold local office. It draws on three case study councils - Nakuru Municipal, Kilifi and Kakamega County Councils - to critique the popular depiction of corrupt and self-serving local leaders. Contrary to this, the moral world of councillors is presented as one that was full of challenging and competing demands yet was not devoid of an ethos of civic responsibility. Despite the many financial and institutional weaknesses of local authorities, councillors retained a level of legitimacy within their communities through their roles as patrons and clients in local and national political networks. The thesis thus explores the interplay between 'elite' and 'deep' politics, arguing that the pressure on politicians to distribute patronage and provide welfare support was particularly acute for councillors. By examining these pressures, this thesis studies the tension between official policy and the everyday practices of local government

An investigation into age-associated undernutrition

Loss of appetite is frequently observed during ageing; termed the ‘anorexia of ageing’. Some evidence suggests that with advancing age there is an increase in satiety hormones, such as CCK and PYY, and a decrease in the hunger hormone ghrelin which may contribute to the anorexia of ageing. However, not all studies agree, emphasising the need for more in depth research to clarify age related changes. My first study developed a rat model to replicate the hormonal responses observed in humans. However, the results of this study did not replicate human studies; there were no alterations gastrointestinal hormones. I then designed a human study to examine more comprehensively, the effect of ageing on gastrointestinal peptide hormone release. Healthy human volunteers aged 20 to 92 years were studied in fasting and post-prandial conditions. The results demonstrated an increase in PYY concentrations post-prandially in older volunteers. In order to understand the mechanism behind this, I followed this study with an investigation looking at the changes in gastrointestinal hormones in ageing mice colons. The data produced results conflicting with the human study, since no increase in PYY levels was observed. Dietary manipulation provides a good opportunity to alter gastrointestinal appetite hormone release, since release differs depending on the macronutrient content of the food consumed. My final studies focused on high protein diets. Results demonstrated that older volunteers were insensitive to the satiating effect of protein, where younger volunteers ate less following a high protein test meal but the older volunteers food intake did not change. Gastrointestinal appetite hormones concentrations did not change significantly between the high and low protein meals in the older and younger adults. These results suggest that age-associated reductions in appetite could be due to a resultant increase in the satiety hormone PYY. More studies need to be conducted to understand the role of protein on appetite and food intake in older adults

Effects of the COVID-19 Pandemic on Rates of Cyberbullying in a University Sample

Purpose and Originality Cyberbullying refers to when an individual or group harasses, mistreats, or mocks an individual or group using an electronic device in a way in which the victim(s) do not feel capable of responding or defending themselves (Whittaker & Kowalski, 2014). Cyberbullying is associated with symptoms of depression, anxiety, suicidal ideation, substance use, delinquency, and poor academic performance (Zalaquett & Chatters, 2014). The purpose of this study was to investigate the possible impact the COVID-19 pandemic may have had on cyberbullying. This study not only adds to the limited information concerning cyberbullying among college students, but also whether cyberbullying may have been impacted by increased utilization of online learning platforms during the pandemic. Method Between March and April 2021, participants (n = 135) were recruited from a mid-sized public university in the Rocky Mountain region of the United States using the university’s research recruitment system (SONA). The 47-item survey was administered remotely using Qualtrics – an online survey platform – and included items inspired from previous works including the self-report Participant Role Questionnaire (PRQ; Bushard, 2013), the Revised Olweus Bully/Victim Questionnaire (OBVQ; Olweus, 1996), and the Cyberbullying Experiences Survey (Doane et al., 2013). The survey took approximately 10 minutes to complete and asked participants about their age, race/ethnicity, gender, class standing, involvement in student groups, experiences with cyberbullying, perceived rates of cyberbullying since the pandemic, and their personal participation in cyberbullying. Results and Significance As expected, the sample endorsed much higher levels of overall online activity since university classes went to an online format in April 2020. However, on average, participants did not believe that changing to online platforms led to a general increase in cyberaggression, did not personally perceive an increase in cyberaggression during this period, nor was there an increase in endorsements of personal involvement in cyberbullying as either the aggressor or victim. The variable with the strongest relationship to cyberaggressing during the pandemic (since April 2020) was endorsement of being cybervictimized (r =.735, p = r = 0.373, p = n = 36, 28%), “Classmates who are not friends” (n = 32, 25%), and “I don’t know” (n = 27, 21%). In summary, our results suggest that most participants did not view increased online learning as a catalyst for cyberaggression, though participants with personal histories with cyberaggression appeared sensitized to, or further engaged in, the phenomena. Further research should seek to shed light on the actions and perceptions related to cyberbullying in this important subgroup