HIF-1alpha role in oxygen-dependent radio- and chemosensitivity

Poor oxygenation (hypoxia) is a common characteristic of human solid tumours, and is associated with cell survival, metastasis and resistance to radio- and chemotherapies. Hypoxia-induced stabilisation of hypoxia-inducible factor-1α (HIF-1α) leads to changes in expression of various genes associated with growth, vascularisation and metabolism. However whether HIF-1α plays a causal role in promoting hypoxic resistance to antitumour therapies remains unclear. In this study we used pharmacological and genetic methods to investigate the HIF-1α contribution to radio- and chemoresistance in four cancer cell lines derived from cervical, breast, prostate and melanoma human tumours. Under normoxia or hypoxia (<0.2% or 0.5% oxygen) the cells were exposed to either a standard irradiation dose (6.2 Gy) or chemotherapeutic drug (cisplatin), and subsequent cell proliferation (after 7 days) was measured in terms of resazurin reduction. Oxygen-dependent radio- and chemosensitivity was evident in all wild type whereas it was reduced or abolished in HIF-1α (siRNA) knockdown cells. The effects of HIF-1α-modulating drugs (EDHB, CoCl2, deferoxamine to stabilise and R59949 to destabilise it) reflected both HIF-1α-dependent and independent mechanisms. Collectively the data show that HIF-1α played a causal role in our in vitro model of hypoxia-induced radioresistance whereas its contribution to oxygendependent sensitivity to cisplatin was less clear-cut. Although this behavior is likely to be conditioned by further biological and physical factors operating in vivo, it is consistent with the hypothesis that interventions directed at HIF-1α may improve the clinical effectiveness of tumour treatments.

The Ford administration, Angola and the perception of Post-Vietnam US credibility, 1974-1976

This thesis is a study of how the Gerald Ford administration struggled to address a perceived loss of US credibility after the collapse of Vietnam, with a focus on the role of Secretary of State Henry Kissinger in the formulation, implementation and subsequent defence of US Angolan policy. By examining the immediate post-Vietnam period, this thesis shows that Vietnam had a significant impact on Kissinger’s actions on Angola, which resulted in an ill conceived covert operation in another third world conflict. In 1974, Africa was a neglected region in Cold War US foreign policy, yet the effects of the Portuguese revolution led to a rapid decolonization of its African territories, of which Angola was to become the focus of superpower competition. After South Vietnam collapsed in April 1975, Kissinger became fixated on restoring the perceived loss of US prestige, Angola provided the first opportunity to address this. Despite objections from his advisors, Kissinger methodically engineered a covert program to assist two anti-Marxist guerrilla groups in Angola. As the crisis escalated, the media discovered the operation and the Congress decided to cease all funding. A period of heated tensions ensued, resulting in Kissinger creating a new African policy to outmanoeuvre his critics publicly, while privately castigating them to foreign leaders. This thesis argues that Kissinger’s dismissal of internal dissent and opposition from the Congress was influenced by what he perceived as bureaucrats being affected by the Vietnam syndrome, and his obsession with restoring US credibility. By looking at the private and public records – as expressed in government meetings and official reports, US newspaper and television coverage and diplomatic cables – this thesis addresses the question of how the lessons of Vietnam failed to influence Kissinger’s actions in Angola, but the lessons of Angola were heavily influential in the construction of a new US-African policy.

Rallying to a cause: the plays of Zakes Mda 1979-1989

Zakes Mda, dubbed one of South Africa's most prolific playwrights, produced his richest and most powerful theatre work during the 70s and 80s. Ironically, it is only in the 90s that he has been acknowledged in his own country as one of its foremost dramatists - ironic since he has recently moved away from drama into the realms of fiction. Fortunately Mda has accumulated a worthy canon of dramatic works, spanning radio and film, as well as theatre, and there is no reason to believe that he will not return to play writing. Mda has worked extensively in theatre in various capacities but most notably in the area of theatre-for-development. For example, he worked as director with Maratholi Travelling Theatre in Lesotho, an experience which contributed, in part, towards his book "When People Play People: Development Communication Through Theatre". Mda's plays have been produced in the United States, Britain, Spain, France and Russia as well as in southern Africa. "The Nun's Romantic Story" has been translated into Castilian and Catalan and "We Shall Sing for the Fatherland" and "Dark Voices Ring" have both been translated into Russian and French. In South Africa he won the Merit Award of the Amstel Playwright of the Year Society for "We Shall Sing for the Fatherland" in 1978 and in 1979 he was Amstel Playright of the Year for "The Hill". For his novel "She Plays with the Darkness", he won the Sanlam Literary Award in 1995.

Repairing wireless sensor network connectivity in damaged environments

A wireless sensor network can become partitioned due to node failure, requiring the deployment of additional relay nodes in order to restore network connectivity. This introduces an optimisation problem involving a tradeoff between the number of additional nodes that are required and the costs of moving through the sensor field for the purpose of node placement. This tradeoff is application-dependent, influenced for example by the relative urgency of network restoration. In addition, minimising the number of relay nodes might lead to long routing paths to the sink, which may cause problems of data latency. This data latency is extremely important in wireless sensor network applications such as battlefield surveillance, intrusion detection, disaster rescue, highway traffic coordination, etc. where they must not violate the real-time constraints. Therefore, we also consider the problem of deploying multiple sinks in order to improve the network performance. Previous research has only parts of this problem in isolation, and has not properly considered the problems of moving through a constrained environment or discovering changes to that environment during the repair or network quality after the restoration. In this thesis, we firstly consider a base problem in which we assume the exploration tasks have already been completed, and so our aim is to optimise our use of resources in the static fully observed problem. In the real world, we would not know the radio and physical environments after damage, and this creates a dynamic problem where damage must be discovered. Therefore, we extend to the dynamic problem in which the network repair problem considers both exploration and restoration. We then add a hop-count constraint for network quality in which the desired locations can talk to a sink within a hop count limit after the network is restored. For each new problem of the network repair, we have proposed different solutions (heuristics and/or complete algorithms) which prioritise different objectives. We evaluate our solutions based on simulation, assessing the quality of solutions (node cost, movement cost, computation time, and total restoration time) by varying the problem types and the capability of the agent that makes the repair. We show that the relative importance of the objectives influences the choice of algorithm, and different speeds of movement for the repairing agent have a significant impact on performance, and must be taken into account when selecting the algorithm. In particular, the node-based approaches are the best in the node cost, and the path-based approaches are the best in the mobility cost. For the total restoration time, the node-based approaches are the best with a fast moving agent while the path-based approaches are the best with a slow moving agent. For a medium speed moving agent, the total restoration time of the node-based approaches and that of the path-based approaches are almost balanced.

Experimental impulse radio IEEE 802.15.4a UWB based wireless sensor localization technology: Characterization, reliability and ranging

Ultra Wide Band (UWB) transmission has recently been the object of considerable attention in the field of next generation location aware wireless sensor networks. This is due to its fine time resolution, energy efficient and robustness to interference in harsh environments. This paper presents a thorough applied examination of prototype IEEE 802.15.4a impulse UWB transceiver technology to quantify the effect of line of sight (LOS) and non line of sight (NLOS) ranging in real indoor and outdoor environments. Results included draw on an extensive array of experiments that fully characterize the 802.15.4a UWB transceiver technology, its reliability and ranging capabilities for the first time. A new two way (TW) ranging protocol is proposed. The goal of this work is to validate the technology as a dependable wireless communications mechanism for the subset of sensor network localization applications where reliability and precision positions are key concerns.