Investigation of the Tumour Promoting Effects of Cellular Senescence During Pituitary and Lung Tumourigenesis

This thesis involves understanding the role that cellular senescence plays during the early stages of adamantinomatous craniopharyngioma (ACP) and non-small cell lung cancer (NSCLC) tumourigenesis using genetically engineered mouse models. The host laboratory has previously shown that when pituitary stem cells are targeted with oncogenic β-catenin, they form clusters of stem cells that show non-cell autonomous tumour inducing potential. Using immunohistochemical and transcriptomic approaches, here I show that cluster cells are molecularly analogous in mouse and human ACP and share a signature of senescence with concomitant activation of the senescence associated secretory phenotype (SASP). I reveal that the tumour-inducing potential of the cluster cells requires a robust SASP. This is evidenced by targeting pituitary stem cells of aged mice (older than 6 months) with oncogenic β -catenin, which results in reduced SASP and decreased tumourigenesis. This suggests that a robust SASP is the likely driver of paracrine tumourigenesis in the pituitary. Further to this, the role of activated MAPK signalling during pituitary development was explored by driving the expression of oncogenic Kras (KrasG12D) and Braf (BrafV600E) in either pituitary progenitors or postnatal adult pituitary stem cells. By demonstrating a cell-autonomous expansion of the embryonic pituitary stem cells compartment with impaired differentiation potential, this study provided insight into the pathogenesis of another pituitary tumour, papillary craniopharyngioma. Finally, during oncogenic Kras-driven (KrasG12D) NSCLC progression in mice, it is observed that the adenoma phase of the tumour does not show a high level of senescence, however senescent cells are found outside and in association with the growing tumours in agreement with the concept of paracrine senescence. To study these senescent cells in vivo a new genetically engineered mouse model (p16FDR) was developed which allows for their visualisation, pharmacogenetic ablation and lineage tracing. Ablation of these senescent cells using p16FDR mice was found to reduce tumour burden and proliferation significantly. Together, these data suggest that senescence can have paracrine pro-tumourigenic properties and their therapeutic ablation may be clinically beneficial

Hot Topic: Interest Rate Set at 7.25 Percent Effective July 1, 2011, on Delinquent Taxes Collected or Administered by the State of Tennessee

The rate of interest effective July 1, 2011, through June 30, 2012, has been set at 7.25 percent, which is the same as for the current year (FY 2011)

Hot Topic: Interest Rate Set at 7.25 Percent Effective July 1, 2010, on Delinquent Taxes Collected or Administered by the State of Tennessee

The rate of interest effective July 1, 2010, through June 30, 2011, has been set at 7.25 percent, which is the same as for the current year (FY 2011)

A tale of two states: a comparative study of higher education reform and its effects on economic growth in East and West Germany 1945 - 1989

The hypothesis at the heart of this thesis is that long-term economic growth depends on the discovery and development of new ideas and technologies which enable innovation resulting in increased productivity. As technological innovation generally results from research processes instigated and performed by those with higher levels of education, it becomes important to analyse higher education as an economic actor as well as a symbolic institution of cultural and elite reproduction. The thesis compares the development of higher levels of human capital in East and West Germany over the period 1945 – 1990: states with two very different and competing myths of democratic legitimacy and radically opposed social, political and economic systems but both convinced that human capital development held the key to reconstruction and economic growth. In highlighting the imperatives for reform and outlining the main changes which took place in higher education within the strictures imposed by competing ideologies, the thesis assesses the effectiveness of human capital investment in terms of the success of the economic objectives identified by both countries. The thesis finds that the initial hypothesis is proven, albeit that its effectiveness was mitigated by a number of external economic shocks and internal social and political factors which, in the end, led to the demise of the East German regime

Stem cell biology and drug discovery

There are many reasons to be interested in stem cells, one of the most prominent being their potential use in finding better drugs to treat human disease. This article focuses on how this may be implemented. Recent advances in the production of reprogrammed adult cells and their regulated differentiation to disease-relevant cells are presented, and diseases that have been modeled using these methods are discussed. Remaining difficulties are highlighted, as are new therapeutic insights that have emerged

Teacher Beliefs and Subject Matter Boundaries: The Struggle for Curricular Transformation Among Teachers of Adults

Teachers of adult learners in formal settings are increasingly exploring more integrated approaches to curriculum and teaching. One location for such work is the community college. Among these teachers, however, who are traditionally content experts, an integrated approach often represents a paradigmatic shift in their understanding of what is most worth knowing. Little is known about how these teachers\u27 beliefs influence, change, and are changed by participation in such curriculum efforts. This study reports on the beliefs and meaning and perspectives of one group of teachers attempting to bring about more curricular coherence and integration within four different disciplines of developmental education

Planning the Next BRAC: Redevelopment Alternatives for Dobbins Air Reserve Base and Air Force Plant No. 6

For nearly 75 years, Dobbins Air Reserve Base (Dobbins) and Air Force Plant No. 6 (AFP #6) have been key military installations supporting Americaﾒs national security. Some fear that shifting budgetary trends and mission goals may jeopardize the future of these two facilities (Trubey 2015). The future of Dobbins will be determined through a Base Realignment and Closure (BRAC) process. The Department of Defense (DOD) uses the BRAC process to assess the costs and benefits of each base and their capacity to support current and future missions. The DOD then recommends for the realignment or closure of bases deemed too costly to maintain or inessential to maintaining national security. The next BRAC round could potentially occur in 2019 (21 Century Partnership 2016). When this happens, the DOD could recommend for Dobbins to stay at the same capacity, realign and expand its responsibilities, realign and lose some responsibilities, or to close entirely. While AFP #6 is recognized as a separate institution, some fear that if Dobbins closes entirely, Lockheed Martin, who leases AFP #6, may independently choose to terminate its lease and consolidate its operations to other Lockheed Martin operated facilities across the country. Both Dobbins and Lockheed Martin are huge economic drivers for Cobb County and the metro Atlanta region. Aware of the negative economic shock of a closed base, Cobb County officials, regional representatives, and military advocates have been lobbying to keep Dobbins open and to be a gaining facility in the next BRAC round. While the work of this lobbying group is important, there has been little planning conducted for scenarios in which Dobbinsﾒ responsibilities shrink or evaporate. This document will make the case that officials also need to plan for these alternate scenarios. It will also explore the economic recovery of three formerly closed bases to suggest a superior redevelopment route for Cobb County officials to pursue