Alterations to sphingolipid metabolism are associated with increased pulmonary inflammation, but the impact of inflammatory mediators, such as neutrophil elastase (NE), on airway sphingolipid homeostasis remains unknown. NE is a protease associated CF lung disease progression, and can be found in up to micromolar concentrations in patient airways. While sphingolipids have been investigated in the context of CF, the focus has been on loss of cystic fibrosis transmembrane conductance regulator (CFTR) function. Here, we present a novel observation: oropharyngeal aspiration of NE increases airway ceramides in mice. Using a previously characterized mouse model of NE-induced inflammation, we demonstrate that NE increases de novo ceramide production, which is likely mediated via increased SPTLC2 levels. Inhibition of de novo sphingolipid synthesis using myriocin, an SPT inhibitor, decreases airway ceramide as well as the release of pro-inflammatory signaling molecules induced by NE. Furthermore, in a retrospective study of the sphingolipid content of CF sputum—the largest of its type in this patient cohort to date, we investigated the association between NE and sphingolipids. There were linear correlations between the concentration of active NE and ceramide, sphingomyelin, and monohexosylceramide moieties as well as sphingosine-1-phosphate. The presence of Methicillin-resistant Staphylococcus aureus (MRSA) positive culture and female gender both strengthened the association of NE and sphingolipids, but higher FEV1 % predicted weakened the association, and Pseudomonas aeruginosa had no effect on the association between NE and sphingolipids. These data suggest that NE may increase sphingolipids in CF airways as it did in our in vivo model, and that this association is stronger in patients that have worse lung function, are female, and whose lungs are colonized with MRSA. Modulating sphingolipid homeostasis could provide novel pharmacological approaches for alleviating pulmonary inflammation.

Because of the aerobic nature of cellular metabolism in mammalian organisms, a continuous supply of oxygen is necessary to maintain normal physiological function. As organisms age, their metabolic rates generally decline and there are accompanying alterations in the structure and function of the microcirculation, as this part of the cardiovascular system is especially important for oxygen exchange. The overall Oxygen Transport System can be considered as being composed of two complementary components: one for Oxygen Demand and one for Oxygen Supply. The purpose of the current work is to describe the age-dependent changes in both oxygen demand and oxygen supply at the level of the microcirculation, using intravital microscopic observations of the rat spinotrapezius muscle, along with optical techniques to delineate the structural, hemodynamic and oxygenation variables needed to characterize the Oxygen Transport System in this tissue. A summary of the findings is that basal oxygen consumption gradually declined with age (from 2 to 12 months) and there were corresponding decreases in tissue blood flow, blood hemoglobin concentration and capillary surface area for oxygen exchange, so that oxygen supply and demand were generally well-matched.

The EWSR1-FLI1 t(11;22)(q24;q12) translocation is the pathognomonic genomic alteration in 85% of the Ewing Family of Tumors (EWFT) a malignancy of the bone and the surrounding tissue, predominantly affecting children and adolescents. This translocation results in the formation of a chimeric oncoprotein which acts as an aberrant transcription factor that is currently not pharmaceutically druggable, driving the need for more effective targeted therapies. The EWSR1-FLI1 translocation induces a variety of changes including dysregulation of the epigenome and altered gene expression to drive tumorigenesis, and consequently contributes to the hypersensitivity of EWFT to several classes of chemotherapeutics. We sought to exploit these intrinsic sensitivities by employing a matched pair of cell lines derived from the same patient with Ewing sarcoma prior to and following chemotherapy, a panel of Ewing sarcoma cell lines, and several patient-derived xenografts (PDX) collected at the time of relapse or autopsy, which led us to the development of two novel combination targeted therapies for EWFT. In our matched pair of EWFT cell lines, we found sensitivity to the Poly(ADP-ribose Polymerase (PARP) inhibitor olaparib was diminished following chemotherapy, despite a predicted sensitivity. In addition, we discovered increased expression of the antiapoptotic protein BCL-2 in the chemotherapy-resistant cells, conferring apoptotic resistance to olaparib. We found that EWS-FLI1 increases BCL-2 expression; however, inhibition of BCL-2 alone is insufficient to sensitize EWFT cells to olaparib, revealing a dual necessity for BCL-2 and BCL-XL (BCL2L1) in EWFT survival. These data reveal BCL-2 and BCL-XL act together to drive olaparib mediated apoptotic resistance in Ewing sarcoma and identify a novel, rational combination therapy using olaparib and the BCL-2/BCL-XL inhibitor navitoclax. In addition, using high throughput drug screening we have identified a novel epigenetic susceptibility in EWFT to GSK-J4 (GlaxoSmithKline), an inhibitor of lysine 27 of histone 3 (H3K27) demethylases: ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) and Jumonji D3 (JMJD3). Treatment with GSK-J4 leads to a decrease in H3K27 acetylation (H3K27ac) and ultimately, the silencing of EWS-FLI1 gene targets. We sought to sensitize GSK-J4-mediated inhibition of EWS-FLI1 targets by blocking RNA polymerase II activity using the Cyclin Dependent Kinase 7 (CDK7) inhibitor THZ1. By targeting CDK7-mediated transcription we were able to sensitize EWFTs to H3K27 demethylase inhibition. We therefore propose co-targeting of H3K27 demethylases and CDK7 acts as a surrogate EWS-FLI1 inhibitor. Given the difficulties targeting EWS-FLI1, these strategies may present viable clinical therapies.

Source: Masters Abstracts International, Volume: 47-06, page: 3373. Advisers: Kelly Volcik; Sarah Baraniuk. Includes bibliographical references.

Thesis (M.N.(Clinical))--Victoria University of Wellington, 2009. / Includes bibliographical references.

Thesis (M.Sc.)--University of Alberta, 2010. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science in Clinical Epidemiology, Department of Public Health Sciences. Title from pdf file main screen (viewed on February 23, 2010). Includes bibliographical references.

In most of the studies, face to face interviews are required with individuals for data collection and hence to apply questionnaires. There are two methods for applying the questionnaire / the paper-based and the electronic method. The paper-based method takes time and is of a high cost to the researchers. Because of writing/reading based errors, this method may cause inaccuracy in collected data. On the contrary, conducting questionnaires in electronic environment procures savings in cost and time, improves data accuracy, gives faster results, and increases efficiency. However, in this method some problems may arise in surveys conducted in urban areas, i.e. problems related to communication and network infrastructure. Nevertheless, advances in Information Technologies provide mobile data collection and computing, and hence they have become a significant place in every part of our life. Many researchers have begun to prefer using these developing technologies in their studies since using mobile devices in conducting health surveys is more useful and economical than the paper-based questionnaires. In this thesis, we have developed a mobile device-based questionnaire, which is an adaptation of the one used by the National Cancer Institute of USA in paper-based form. In other words, in this work the &ldquo / Health Habits and History Questionnaire&rdquo / has been adopted to the pocket PCs. It is planned to be used for an ongoing epidemiological study in &Ccedil / ukurova region. We hope that this study will be an example for the similar studies in the future.

Research Doctorate - Doctor of Philosophy (PhD) / Privacy of personal information is becoming a major problem in health care, in the light of coming implementation of electronic health record (EHR)systems. There is evidence of increasing public concern over privacy of personal health information that is to be stored in EHRs and widely used within the interconnected systems. The issues for the health care system include inadequate legislation for privacy in health care, as well as deficiency of effective technical and security measures. The work in the thesis is part of a larger project which aims to offer a comprehensive set of new techniques for protection of confidential individual's health data used for statistical purposes. The research strategy is to explore concerns about privacy in relation to legislation, attitudes to health care and technical protections in statistical databases. It comprised two different approaches: * content analysis of legal frameworks addressing protection of privacy in Australian health care, and * social research to explore privacy concerns in health care by Australians 18 years and over. This thesis presents a new multi-stage research to explore privacy concerns in health care raised by the development of EHR systems. Stage one involved 23 participants within four focus groups. Stage two was a national sample survey conducted with 700 respondents 18 years and over. The results of analysis are presented. They are compared with the results of other studies. The main findings of this thesis are: * revealing the main inadequacies in the Australian legal system for protecting privacy of health information in electronic health records; * determining characteristics of people who have concerns about the privacy of their health information; * identifying items of a health record which have to be protected and some reasons for that. The findings of the study will assist with the decision and solution for appropriate technical measures in statistical databases as well as issues of inadequacy in the existing privacy legislation. Furthermore, the work in this thesis confirmed a low awareness of public in relation to statistical use of personal health information and a low level of trust to automated systems of electronic health records which are initiated by the government. In conclusion, attitude towards privacy depends on individual's characteristics but also on existing legislation, public's awareness of this legislation,the means of resolving complaints, and awareness of technical means for privacy protection. Therefore, it is important to educate public in order for EHR system function to the full of its potential and the future innovations of information technology to strengthen health care and medical research.

Thesis (Ph. D.)--University of Texas Health Science Center at Houston, School of Public Health, 2008. / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0972. Adviser: Benjamn C. Amick, III. Includes bibliographical references.

Thesis (Ph. D.)--University of California, San Diego, 2002. / Vita. Includes bibliographical references (leaves 367-392).