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Systemic chemotherapy is the primary treatment modality for metastatic colorectal carcinoma (MCRC). However, both conventional and novel chemotherapeutic drugs produce only modest improvements in outcome despite the introduction of predictive biomarkers. It is postulated that genomic heterogeneity within MCRC may be responsible for poor therapeutic response, but a comprehensive analysis of disseminated disease has not been performed. This thesis provides in-depth analysis of the clinicopathological and genomic features within a cohort of fatal MCRC cases recruited via the ‘Gift’ research autopsy project. Material sampled at autopsy was analysed at the allelic and chromosomal level using targeted and whole genome sequencing (WGS); the pattern of genomic change within and between deposits was correlated with that of any resected disease and the clinical data for each donor. The insights from this cohort were further explored within a series of locally advanced CRC using micro-dissection of intravascular, intraperitoneal and intranodal tumour deposits. Initial analysis demonstrated that mutation status at therapeutically predictive genomic loci is virtually homogenous within cases of disseminated MCRC. Phylogenetic analysis of WGS data documented the evolutionary and clonal complexity within MCRC, showing that, whilst clonal distribution may correlate with disease distribution, multiple clones from the same primary tumour may converge on the same metastatic site and demonstrate dissemination via similar metastatic routes. It was also demonstrated that most key genomic events arise early within the development of MCRC and when putative ‘driver’ events occur within established disease they do not appear to produce dominant metastatic clones. Therefore, it is concluded that, if a tumour has the capacity to metastasise, this characteristic is present across many or all subclones within a tumour and the likely determinant of the pattern of metastatic spread is a combination of the core biology of a tumour and the regional features of the surrounding bowel.

The slip-spring model introduced by Likhtman (Macromolecules 38, 6128-6139 (2005)) simulates a single chain entangled within a polymer melt. Single-chain models such as the slip-spring model allow the rheology of polymers to be studied without requiring the use of expensive multiple-chain molecular dynamics simulations. This study investigates the slip-spring model in the context of a single entanglement and compares it to a two-chain entanglement model. A better understanding of the mechanisms involved in an entanglement is obtained, through the properties of stress relaxation and mean squared displacement, but also through analysis of the bead positions and bond vectors involved. Flaws are identified within the slip-spring model, for which modifications to the model are suggested, including the addition of a non-isotropic spring-constant and the replacement of the slip-spring by a slip-chain. This examination of the simple case is carried out, so that the knowledge gained may be later applied to the multiple-entanglement slip-spring model. During the course of this study, the generic polymer simulation (GPS) package was con- structed by the Reading Theoretical Polymer Physics Group. GPS provides an object-orientated simulation framework, designed to keep simulations organised and make new simulations faster to create. An overview of the concepts involved is included in this thesis. Another tool encountered within this study is maximum likelihood estimation, a statistical technique that, when applied to polymer models such as the slip-spring model, allows the estimation of model parameters. Such a fitting is not only useful for finding the best parameters, but also prevents the model flaws from being obscured by incorrect parameter fitting.

It is now well-established that many hormones regulate the metabolism of target cells by binding to receptors which can interact with specific members of a family of guanine nucleotide-binding regulatory proteins (G-proteins) which can in turn control the activity of various intracellular effector enzymes and ion channels. One such effector enzyme is adenylate cyclase which is controlled by stimulatory (Gs) and inhibitory (Gi) proteins. Both of these proteins are heterotrimers consisting of alpha-, beta- and gamma-subunits, with the alpha-subunits conferring the abilities to interact with particular receptors and effectors. There are at least three members of the Gialpha-subunit family of proteins, termed Gialpha-1, Gialpha-2 and Gialpha-3. The functional significance of this multiplicity is unknown although it has been suggested that Gialpha-2 may be responsible for mediating the inhibition of adenylate cyclase activity in certain systems and that each of these proteins can regulate K+ channel opening.

This thesis examines John Calvin's concept of the Kingdom of God. There are four basic terms for this concept: regnum Dei, regnum Christi, regnum caelorum and regnum caeleste. All of these terms are more or less interchangeable. With the Christian church Calvin recognizes that one aspect of the Kingdom of God is its transcendent, heavenly, eternal dimension. This is the unique meaning of regnum caeleste. Yet most of Calvin's discourse on the Kingdom refers to the presence of God's Kingdom or rule on earth. The term regnum can mean either kingdom or reign. Regnum Dei therefore refers to God's reign or his Kingdom, or in many cases both aspects together. There are two dimensions to his reign: the general rule over the world and the special redemptive rule through his Word and Spirit. In the broader sense, the regnum Dei is basically equivalent to God's providence. The special, redemptive dimension of God's reign is the Kingdom of Christ or the regnum Christi. The regnum Christi is the rule of Christ from the time of his ascension up to the time of the Last Judgement, at which time Christ will hand back the reign to the Father. The product of Christ's reign is the church, which is Christ's Kingdom. Calvin uses the concept of the regnum Christi to interpret some important prophetic passages in the Old Testament. Many Old Testament prophecies are seen by Calvin to point forward to the New Testament age when Christ will rule. There is also an individual dimension to the Kingdom of God in Calvin's theology. The Kingdom of God is often the life of sanctification which is found in the individual believer. But collectively, as we have seen, the Kingdom of God on earth often refers to the church. Although Calvin urges princes and rulers to submit to the rule of Christ, it is perhaps inconsistent when he does not include 'lq Christian political institutions in his concept of the Kingdom of God. Thus in respect to the city of Geneva, over which he exerted so much influence, Calvin sees the church in that city as a part of Christ's Kingdom, but the city as a whole is not considered to be Christ's Kingdom.

At present, no documentation pertaining to the factors influencing utilization of research into clinical practice by Certified Registered Nurse Anesthetists (CRNAs) exists. An investigation was undertaken to determine perceptions of CRNAs regarding factors within the context of the work setting, which may serve to influence their utilization of research in their clinical practice. A descriptive quantitative study provided information based upon data acquired from a 32-item questionnaire (Barriers to Research Utilization Scale, BRUS) electronically distributed to a random sample of 2500 CRNAs residing within the United States. From the CRNAs responding to the questionnaire, the five greatest barriers to research utilization were: 1. Research is not generalizable to own setting. 2. Research is not reported clearly or readably. 3. The CRNA does not see the value of research for practice 4. Conclusions drawn from the research are unjustified. 5. The amount of research is overwhelming. Recommendations for future research include distribution of the questionnaire to the stakeholder groups comprised of (a) A larger national sample of CRNAs, (b) CRNAs from various geographic regions, and (c) CRNAs in either medically or non-medically- directed practice settings. The BRUS can be modified to conduct a Delphi study in university-based graduate programs in nurse anesthesia to broaden the understanding of the professional practice factors that influence research utilization by CRNAs. This information will be useful in contributing towards the design of academic and clinical curricula preparing entry-level nurse anesthetists for contextual realities in professional practice. The questionnaire may also be useful for investigating demographic factors (e.g., age, gender, academic and clinical preparation for entry-level practice, tenure in practice) that may influence the values and attitudes of practicing CRNAs toward translational research. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]