Built for Extraction: Dependence, Sovereignty and Development in Timor-Leste

In 2002, Timor-Leste was granted membership to the United Nations (UN) making it the first new State of the twenty-first century. By accepting the authority of the UN and allowing the international development and aid architecture to take over the country, Timor-Leste entered into a relationship of dependency on foreign aid in order to become independent. Today, the country is still pursuing sovereignty on the final frontier of the Timor Sea. Using the overarching notion of ‘extraction’, this thesis argues that Timor-Leste’s path towards self-determination has served the interests of third-party actors who benefit from the development processes of the country while many citizens suffer in poverty. Through an integrated analysis that uses both qualitative and quantitative data, this thesis draws upon scholarship on dependency theory, post-coloniality, and international political economy to explain Timor-Leste’s uneven pattern of development. While these literatures are useful in understanding elements of what has happened in Timor-Leste, they fall short when looking comprehensively at the country’s experience and troubled history. To expand the picture, the thesis further draws upon and applies academic debates on ‘extractivism’ and ‘neo-extractivism’ as they have emerged in Latin American development studies literature. With this focus on extraction, the thesis explains the ongoing ways in which the spoils of development in Timor-Leste remain in the hands of a few. Informed by research spanning eleven months in-country in 2013, and a return period of intensive field work in 2015, this thesis draws from the insights provided by over 50 formal and informal interviews conducted with a large cross section of local and international populations including donors, politicians, activists, students, academics, development workers and everyday citizens. Collectively these sources tell the story of a country that has matured out of a persistent struggle against outside control. Tracing the colonial history of Timor-Leste from the Portuguese traders of the eighteenth century to the Indonesian military rulers of the twentieth century to the intergovernmental aiders of the twenty-first century, the thesis unpacks the country’s ongoing dependency relationships. It demonstrates how the state has increased its revenues and its hold on power due to the presence of natural resources in the country. Applying the notion of an ‘oil complex’ rather than a ‘resource curse’ conceptual framework to analyse Timor-Leste’s resource wealth, this thesis demonstrates that the components of this phenomena are intrinsically linked with Timor-Leste’s fight for sovereignty by the country’s political elite. This effort to assert state sovereignty is made evident through its investment in the petroleum processing infrastructural mega-project ‘Tasi Mane’, an undertaking of dubious benefit for everyday East Timorese. Finally, the thesis argues that there is a dire need for Timor-Leste to diversify its economy, but to achieve this diversification the country and its people will have to overcome past and present dependency relationships in the pursuit of national sovereignty. Taken as a whole, the discussion offers a timely addition to recent debates on development in Timor-Leste, while also providing a useful contribution to critical development studies.Thesis (Ph.D.) -- University of Adelaide, School of Social Sciences, 202

Positive allosteric modulation of CD11b as a novel therapeutic strategy against lung cancer

Lung cancer is one of the leading causes of cancer-related deaths in the United States. A major hurdle for improved therapies is immune suppression mediated by the tumor and its microenvironment. The lung tumor microenvironment (TME) contains large numbers of tumor-associated macrophages (TAMs), which suppress the adaptive immune response, increase neo-vascularization of the tumor, and provide pro-tumor factors to promote tumor growth. CD11b is highly expressed on myeloid cells, including TAMs, where it forms a heterodimeric integrin receptor with CD18 (known as CD11b/CD18, Mac-1, CR3, and αMβ2), and plays an important role in recruitment and biological functions of these cells, and is a validated therapeutic target. Here, we describe our pre-clinical studies targeting CD11b in the context of lung cancer, using pharmacologic and genetic approaches that work via positive allosteric modulation of CD11b function. GB1275 is a novel small molecule modulator of CD11b that is currently in Phase 1/2 clinical development. We assess GB1275 treatment effects on tumor growth and immune infiltrates in the murine Lewis Lung Carcinoma (LLC) syngeneic tumor model. Additionally, as an orthogonal approach to determine mechanisms of action, we utilize our recently developed novel CD11b knock-in (KI) mouse that constitutively expresses CD11b containing an activating isoleucine to glycine substitution at residue 332 in the ligand binding CD11b A-domain (I332G) that acts as a positive allosteric modulator of CD11b activity. We report that pharmacologic modulation of CD11b with GB1275 significantly reduces LLC tumor growth. CD11b KI mice similarly show significant reduction in both the size and rate of LLC tumor growth, as compared to WT mice, mimicking our observed treatment effects with GB1275. Tumor profiling revealed a significant reduction in TAM infiltration in GB1275-treated and in CD11b KI mice, increase in the ratio of M1/M2-like TAMs, and concomitant increase in cytotoxic T cells. The profiling also showed a significant decrease in CCL2 levels and a concomitant reduction in Ly6

Integrin CD11b activation drives anti-tumor innate immunity

Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression. Recruitment of these cells is regulated by integrins, a family of adhesion receptors that includes integrin CD11b. Here we report that, unexpectedly, integrin CD11b does not regulate myeloid cell recruitment to tumors but instead controls myeloid cell polarization and tumor growth. CD11b activation promotes pro-inflammatory macrophage polarization by stimulating expression of microRNA Let7a. In contrast, inhibition of CD11b prevents Let7a expression and induces cMyc expression, leading to immune suppressive macrophage polarization, vascular maturation, and accelerated tumor growth. Pharmacological activation of CD11b with a small molecule agonist, Leukadherin 1 (LA1), promotes pro-inflammatory macrophage polarization and suppresses tumor growth in animal models of murine and human cancer. These studies identify CD11b as negative regulator of immune suppression and a target for cancer immune therapy

Current health and economic burden of chronic diabetic osteomyelitis.

INTRODUCTION: Diabetic foot ulcer (DFU) prevalence is as high as 25% and 40-80% of DFUs become infected (DFI). About 20% of infected ulcers will spread to bone causing diabetic foot osteomyelitis (DFO). DFU costs Medicare $9-13 billion/year. The most expensive costs associated with DFU are inpatient costs and hospital admissions. DFO costs are driven mostly by surgical procedures. DFU patients have a 3-year cumulative mortality rate of 28% and rates approaching 50% in amputated patients. AREAS COVERED: This review will summarize the current health and economic burden of DFO covering management, epidemiology, and copious costs associated with DFO. The review began by searching PubMed and Cochrane databases for various terms including, \u27diabetic osteomyelitis costs,\u27 \u27diabetic foot infection,\u27 and \u27diabetes and antibiotics.\u27 Additionally, references from retrieved publications were reviewed. The global burden of DFU calls for investigating new therapeutic options. EXPERT OPINION: For DFI, anti-biofilm agents have had success because they directly deliver antimicrobials to the infection site. For DFO, intraosseous (I/O) antibiotic therapy similarly bypasses the issue of vascular disease, will likely have improved therapeutic efficacy, and reduced costs for DFO patients. I/O antibiotic therapy has had clinical success in one case report already, and may significantly improve the lives of those afflicted with DFO