691 research outputs found
The identification of therapeutic targets in metastatic melanoma
No full textMetastatic melanoma, a cancer historically refractory to chemotherapeutic strategies, has a poor prognosis and accounts for the majority of skin cancer related mortality. Although the recent approval of two new drugs combating this disease, Ipilimumab and Vemurafenib (PLX4032), has demonstrated for the first time in decades an improvement in overall survival; the clinical efficacy of these drugs has been marred by severe adverse immune reactions and acquired drug resistance in patients, respectively. Thus, understanding the etiology of metastatic melanoma will contribute to the improvement of current therapeutic strategies while leading to the development of novel drug approaches.\ud
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In order to identify recurrently mutated genes of therapeutic relevance in metastatic melanoma, a panel of stage III local lymph node melanomas were extensively characterised using high-throughput genomic technologies. This led to the identification of mutations in TFG in 5% of melanomas from a candidate gene sequencing approach using SNP array analysis, 24% of melanomas with mutations in MAP3K5 or MAP3K9 though unbiased whole-exome sequencing strategies, and inactivating mutations in NF1 in BRAF/NRAS wild type tumours though pathway analysis. Lastly, this thesis describes the development of a melanoma specific mutation panel that can rapidly identify clinically relevant mutation profiles that could guide effective treatment strategies through a personalised therapeutic approach.\ud
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These findings are discussed in respect to a number of important issues raised by this study including the current limitation of next-generation sequencing technology, the difficulty in identifying ‘driver’ mutations critical to the development of melanoma due to high carcinogenic exposure by UV radiation, and the ultimate application of mutation screening in a personalised therapeutic setting. In summary, a number novel genes involved in metastatic melanoma have been identified that may have relevance for current therapeutic strategies in treating this disease
Whole genome and exome sequencing of melanoma
No full textMelanoma has historically been refractive to traditional therapeutic approaches. As such, the development of novel drug strategies has been needed to improve rates of overall survival in patients with melanoma, particularly those with late stage or disseminated disease. Recent success with molecularly based targeted drugs, such as Vemurafenib in BRAF-mutant melanomas, has now made “personalized medicine” a reality within some oncology clinics. In this sense, tailored drugs can be administered to patients according to their tumor “mutation profiles.” The success of these drug strategies, in part, can be attributed to the identification of the genetic mechanisms responsible for the development and progression of metastatic melanoma. Recently, the advances in sequencing technology have allowed for comprehensive mutation analysis of tumors and have led to the identification of a number of genes involved in the etiology of metastatic melanoma. As the methodology and costs associated with next-generation sequencing continue to improve, this technology will be rapidly adopted into routine clinical oncology practices and will significantly impact on personalized therapy. This review summarizes current and emerging molecular targets in metastatic melanoma, discusses the potential application of next-generation sequencing within the paradigm of personalized medicine, and describes the current limitations for the adoption of this technology within the clinic
Ken Wilber's Spectrum Model: Identifying Alternative Soteriological Perspectives
No full textI identify two problematic strands of Wilber's transpersonal theory. First, I question Wilber's claim that his spectrum model is supported by the materials of all the world's major mystical traditions. I argue that his integral, hierarchical perspective privileges some traditions but distorts others. Drawing heavily upon Andrew Rawlinson's recent, taxonomic study of mystical traditions, which identifies four authentic routes to spiritual emancipation (Cool Structured, Cool Unstructured, Hot Structured and Hot Unstructured), I argue that while Wilber's model, itself Cool (the source of spiritual liberation lies within oneself) and Structured (developmental, hierarchical), provides a valuable cartography of transpersonal structures and states of consciousness, it cannot adequately handle the materials of the alternative, soteriological paths of Hot traditions (emphasizing the numinous, and as other than oneself) and Unstructured traditions (affirming that there can be no gradual, or progressive, spiritual development at all). Second, and more cursorily, I argue that it is Wilber's Cool Structured perspective that informs his categorisation of Jung as an elevationist. I try to demonstrate that Jung's psychic model of the conjunction of opposites is a Hot Structured one, which provides an alternative, soteriological path for persons whose spiritual needs are different from those addressed by Wilber
Understanding drug resistance of targeted BRAF inhibitors in late-stage melanoma
No full textLate-stage melanoma is an aggressive skin cancer for which traditional treatment strategies such as chemotherapy are ineffective. Recently, a new class of targeted drugs (BRAF inhibitors) has become the standard of care for a subset of melanoma patients; however, long term treatment success is complicated by drug resistance. This study will identify the causes of resistance with the purpose to improve targeted drug strategies and increase survival rates for late-stage melanoma patients.$355,028.00Early Career FellowshipsCJ Martin Biomedical EC
Evaluation of cation-exchanged zeolite adsorbents for post-combustion carbon dioxide capture
No full textA series of zeolite adsorbents has been evaluated for potential application in post-combustion CO₂ capture using a new high-throughput gas adsorption instrument capable of measuring 28 samples in parallel. Among the zeolites tested, Ca-A exhibits the highest CO₂ uptake (3.72 mmol g⁻¹ and 5.63 mmol cm⁻³) together with an excellent CO₂ selectivity over N₂ under conditions relevant to capture from the dry flue gas stream of a coal-fired power plant. The large initial isosteric heat of adsorption of −58 kJ mol⁻¹ indicates the presence of strong interactions between CO₂ and the Ca-A framework. Neutron and X-ray powder diffraction studies reveal the precise location of the adsorption sites for CO₂ in Ca-A and Mg-A. A detailed study of CO₂ adsorption kinetics further shows that the performance of Ca-A is not limited by slow CO₂ diffusion within the pores. Significantly, Ca-A exhibited a higher volumetric CO₂ uptake and CO₂/N₂ selectivity than Mg₂(dobdc) (dobdc⁴⁻ = 1,4-dioxido-2,5-benzenedicarboxylate; Mg-MOF-74, CPO-27-Mg), one of the best performing adsorbents. The exceptional performance of Ca-A was maintained in CO₂ breakthrough simulations.Tae-Hyun Bae, Matthew R. Hudson, Jarad A. Mason, Wendy L. Queen, Justin J. Dutton, Kenji Sumida, Ken J. Micklash, Steven S. Kaye, Craig M. Brown and Jeffrey R. Lon
Fostering a cybersecurity mindset
No full textWhat precisely is the meaning of the concept of cybersecurity – and who is responsible for its implementation? Guest author William Dutton argues that challenges in this area might require a certain mindset among internet users. Is this indeed a significant shift in thinking about cybersecurity
A Vietnamese Moses : Philiphê Bỉnh and the geographies of early modern Catholicism /
No full text"A Vietnamese Moses is the story of Philiphê Binh, a Vietnamese Catholic priest who in 1796 traveled from Tonkin to the Portuguese court in Lisbon to persuade its ruler to appoint a bishop for his community of ex-Jesuits. Based on Binh's surviving writings from his thirty-seven-year exile in Portugal, this book examines how the intersections of global and local Roman Catholic geographies shaped the lives of Vietnamese Christians in the early modern era. The book also argues that Binh's mission to Portugal and his intense lobbying on behalf of his community reflected the agency of Vietnamese Catholics, who vigorously engaged with church politics in defense of their distinctive Portuguese-Catholic heritage. George E. Dutton demonstrates the ways in which Catholic beliefs, histories, and genealogies transformed how Vietnamese thought about themselves and their place in the world. This sophisticated exploration of Vietnamese engagement with both the Catholic Church and Napoleonic Europe provides a unique perspective on the complex history of early Vietnamese Christianity"--Publisher.Includes bibliographical references (pages 281-326) and index.Philiphê Bỉnh and the Catholic geographies of Tonkin -- A Catholic community in crisis -- Journeys : Macao, Goa, and Lisbon -- Arrival in Lisbon and first encounters -- Invoking the Padroado : Bỉnh and Prince Dom João -- Waiting for Bỉnh in Tonkin and Macao -- Life in Lisbon and the Casa do Espirito Santo, 1807-1833 -- The tales of Philiphê Bỉnh."A Vietnamese Moses is the story of Philiphê Binh, a Vietnamese Catholic priest who in 1796 traveled from Tonkin to the Portuguese court in Lisbon to persuade its ruler to appoint a bishop for his community of ex-Jesuits. Based on Binh's surviving writings from his thirty-seven-year exile in Portugal, this book examines how the intersections of global and local Roman Catholic geographies shaped the lives of Vietnamese Christians in the early modern era. The book also argues that Binh's mission to Portugal and his intense lobbying on behalf of his community reflected the agency of Vietnamese Catholics, who vigorously engaged with church politics in defense of their distinctive Portuguese-Catholic heritage. George E. Dutton demonstrates the ways in which Catholic beliefs, histories, and genealogies transformed how Vietnamese thought about themselves and their place in the world. This sophisticated exploration of Vietnamese engagement with both the Catholic Church and Napoleonic Europe provides a unique perspective on the complex history of early Vietnamese Christianity"--Publisher.JSTO
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