In the age of big data, thoughtful management and harmonization of clinical metadata and sample processing in translational research is a critical for effective data generation, integration, and analysis. These steps enable the cutting edge discoveries and enhance overall conclusions that may come from complex multi-omic translational research studies. The focus of my thesis has been on harmonizing the clinical metadata collected as part of the lung Pre Cancer Genome Atlas (PCGA) in addition to expanding the use of banked samples. The lung PCGA study included longitudinal collected samples and data from participants in a high-risk lung cancer-screening program at Roswell Park Comprehensive Cancer Center (Roswell) in Buffalo, NY. Clinical metadata for this study was collected over many years at Roswell and subsets of this data were shared with Boston University Medical Campus (BUMC) for the lung PCGA study. During the study, additional clinical metadata was acquired and shared with BUMC to complement the analysis of genomic profiling of DNA and RNA, as well as protein staining of tissue. With regards to the PCGA study, my thesis has two aims: 1) Curate the clinical metadata from received from Roswell during the PCGA study to enhance both its accessibility to current investigators and collaborators and reproducibility of results 2) Test methods to isolate DNA from remnant samples to expand the use of banked samples for genomic profiling. We hypothesized that the accomplishment of these goals would allow for increased use of the clinical metadata, enhanced reproducibility of the results, and expansion of samples available for DNA sequencing The clinical metadata received from Roswell was consolidated into a singular source that is continually updated and available for export for future research use. These metadata management efforts led to increased use among the members of our laboratory and collaborators working with the lung PCGA cohort. Additionally, the curation of metadata has allowed for improved analysis, reproducibility, and increased awareness of the current inventory of remaining samples. During the process of lung PCGA clinical metadata curation, physical inventory of the remaining samples revealed remnant organic phase samples. Therefore, in addition to my work associated with clinical metadata, the second goal of my thesis focuses on DNA isolation from remnant banked biological samples from the lung PCGA cohort. In the first phase of the lung PCGA, nucleic acid isolation of RNA was intended to be collected exclusively from fresh frozen endobronchial biopsy samples, and formalin-fixed paraffin embedded (FFPE) biopsy samples were to be used for DNA isolation. DNA isolation from the FFPE samples was unsuccessful. However, from the RNA isolation, the remaining organic phase was banked and could potentially serve as a source of DNA. The organic phase of this isolation contained cell debris, proteins, and, as previously mentioned, DNA. We hypothesized that current protocols for organic phase DNA isolation might yield adequate quantities of DNA for genomic profiling. Utilizing immortalized cell culture lines to establish methodology, numerous organic phase DNA isolation protocols were tested. During subsequent validation using the remaining organic phase samples from the lung PCGA cohort, the protocol yielded varied results, suggesting that further optimization to increase DNA purity is required. The ability to isolate DNA from these valuable samples will enhance progress in the lung PCGA study. The aims of this thesis involving curation of clinical metadata and generation of additional DNA samples for DNA profiling has had significant impact on the PCGA study and future expansions of this work.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22362号 / 医博第4603号 / 新制||医||1043(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 稲垣 暢也, 教授 竹内 理 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Thesis (M.Sc. (Biochemistry)) -- University of Limpopo, 2020 / Despite major advancements in the development of various chemotherapuetic agents, treatment for lung cancer remains costly, ineffective, toxic to neighbouring normal noncancerous cells and still hampered by high level of remissions (Wistuba et al., 2018; Tana et al., 2016; Schiller et al., 2002). Synthesis of novel quinoxalines with a wide spectrum of biological activities has recently received considerable attention with promising anticancer drug activity since most of them do not affect non-cancerous cells and are derived from readily available less costly raw materials (Srivastava et al., 2014). Since combination treatment has been shown to augment and improve single drug treatment, trace elements were employed in this study in combination with quinoxalines derivatives (Gomez et al., 2016; Kocdor et al., 2015; Ku et al., 2012; John et al., 2010; Killile and Killilea, 2007). Zinc is an essential element that is integral to many proteins and transcription factors which regulate key cellular functions such as the response to oxidative stress, DNA replication, DNA damage repair, cell cycle progression, and apoptosis (Dhawan and Chadha, 2010). Owing to the importance of these two approaches, the aim of this study was to provide in vitro preliminary anticancer activity data on A549 lung cancer cells using combination of zinc and quinoxaline derivatives. An assessment of the quinoxaline derivatives ferric reducing power and DPPH free radical scavenging activity was performed. The cytotoxic and anti-proliferation activity of these derivatives and zinc on cancer cell lines was determined using the MTT assay. The ability of the quinoxaline derivatives and zinc to modulate oxidative stress was evaluated using the H2DCFDA fluorescence assay. Cell cycle arrest stages were analysed by flow cytometry through propidium iodide cell cycle analyses. The ability of the quinoxaline derivatives to induce apoptosis in cancer cells was assessed using DAPI/PI, Acridine Orange/Ethidium Bromide (AO/EB) and Annexin V-FITC/Dead Cell assays. Western blot was used to investigate the Bcl/Bax expression ratios in A549 lung cancer cells after treatment with quinoxaline derivatives, zinc and in combination. Of the four quinoxaline derivatives tested, 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate (LA-39B) and 3-(quinoxaline-3-yl) prop-2-yn-1-ol (LA-55) produced significant anticancer properties against A549 lung cancer cells at minimal concentrations of 25μM. Both quinoxaline derivatives displayed antioxidant properties and did not induce cell death in non-cancerous Raw 267.4 macrophage cells. Cytotoxicity was observed in A549 lung cancer, HeLa cervical cancer and MCF-7 breast cancer cells albeit inhibition was more pronounced in A549 lung cancer cells. Treatment of cancer cells with zinc also resulted in pronounced cytotoxicity at a minimal concentration of 25μM. Although reduced oxidative stress was observed in Raw 264.7 macrophages, in A549 lung cancer cells both compounds were able to increase ROS production which was accompanied by high levels of apoptosis when treated with derivatives and zinc alone but when in combination an improved higher level of apoptosis is observed. The improved anti-cancer activity of this drug combination treatment was further accompanied by lower Bcl/Bax expression ratios with upregulation of Bax in A549 lung cancer cells. The results of the study suggest that 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate and 3-(quinoxaline-3-yl) prop- 2-yn-1-ol are potential candidates drug for treatment of lung cancer. The use of these quinoxaline derivatives in combination with zinc can offer alternative treatment options for lung cancer. / National Research Foundation (NRF)

Air and saline P-V curves were run on the excised lungs of rats starved 1-4 days. Stability estimates based on % of maximum volume retained on deflation tended toward decreases, but atelectasis was not increased according to buoyancy measurements. Compliance was not significantly affected, with whatever trend existed being toward increases. Average air P-V curves for day 3 and 4 of starvation were essentially superimposable on control curves. Surface tension of lung lavage fluid was measured (Surfactometer) during cyclic compression and expansion of the film. Min and max γ were elevated, and the activity index (s) depressed, but the area of the hysteresis loop was relatively unchanged. It is concluded that despite increases in γ of lung washings, pulmonary mechanics was little affected by 1-4 days of food deprivation. The effects on surface tension may be due to a decrease in quantity of surfactant extractable, without any change in composition.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Symptom research with advanced lung cancer patients has primarily focused on symptom severity, frequency, and distress; yet, little is known about advanced lung cancer patients’ priorities and success criteria for symptom improvement. To address these gaps in the literature, this study examined these outcomes using a modified Patient Centered Outcomes Questionnaire (PCOQ), which has largely been used with adults with chronic pain. Advanced lung cancer patients (N = 102) were recruited from the Indiana University Simon Cancer Center to participate in a one-time self-report survey, including demographic and medical questionnaires, symptom treatment history, standardized measures of symptom severity and quality of life, and the modified PCOQ focused on eight common symptoms in advanced lung cancer. Cancer information was collected from medical records. My primary aim was to evaluate the construct validity of the PCOQ. As hypothesized, symptom severity ratings on the PCOQ were positively correlated with standardized assessments of the same symptoms as well as functional status. Greater severity of most symptoms on the PCOQ was also correlated with worse quality of life, and greater severity of four symptoms was correlated with having more medical comorbidities. Positive, moderate correlations were found between the severity and importance of seeing improvement in cough, fatigue, sleep problems, and pain on the PCOQ. Patients considered low levels of symptom severity to be acceptable following symptom treatment; no differences were found across the eight symptoms. Latent profile analysis identified four patient subgroups based on the importance of seeing improvement in each of the symptoms: (1) those who rated all symptoms as low in importance (n = 12); (2) those who rated bronchial symptoms and sleep problems as low in importance and all other symptoms as moderately important (n = 29); (3) those who rated nausea and emotional distress as low in importance and all other symptoms as moderately important (n = 23); and (4) those who rated all symptoms as highly important (n = 33). These subgroups were unrelated to demographic and clinical factors, except for functional status. Findings suggest that symptom severity and importance are related yet distinct aspects of the advanced lung cancer symptom experience. Furthermore, patients have heterogeneous priorities for symptom management, which has implications for tailoring treatment.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18155号 / 医博第3875号 / 新制||医||1002(附属図書館) / 31013 / 京都大学大学院医学研究科医学専攻 / (主査)教授 上本 伸二, 教授 平岡 眞寛, 教授 安達 泰治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19173号 / 医博第4015号 / 新制||医||1010(附属図書館) / 32165 / 京都大学大学院医学研究科医学専攻 / (主査)教授 木村 剛, 教授 福田 和彦, 教授 小池 薫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19556号 / 医博第4063号 / 新制||医||1012(附属図書館) / 32592 / 京都大学大学院医学研究科医学専攻 / (主査)教授 小池 薫, 教授 福田 和彦, 教授 三嶋 理晃 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

リポジトリの登録にあたっては、Peer reviewされた最終版のみ可能であり、その際には下記の出版社のウェブサイトのアドレスを記載することが求められる。当該論文は2014年6月の出版であり、12ヶ月を経過していることから、公開には差し支えはない。http://clincancerres.aacrjournals.org/content/20/12/3087.full / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19617号 / 医博第4124号 / 新制||医||1015(附属図書館) / 32653 / 京都大学大学院医学研究科医学専攻 / (主査)教授 小川 誠司, 教授 野田 亮, 教授 伊達 洋至 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM