IUPUI / Fatty acid synthase (FASN) over-expression has been associated with poor prognosis and recurrence in cancer patients. In addition, it has also been found that overexpression of FASN causes resistance to DNA-damaging treatments by up-regulating the non-homologous end joining (NHEJ) repair of DNA double-strand break. Proton pump inhibitors (PPIs), were originally designed to decrease gastric acid production by binding irreversibly with gastric hydrogen potassium ATPase. PPIs have recently been reported to reduce drug resistance in cancer cells when used in combination with other chemotherapeutics, although the mechanism of resistance reduction is uncertain. In our lab, previous investigation showed that PPIs decreased FASN thioesterase (TE) domain activity and cancer cell proliferation in a dose-dependent manner. In this study, I tested the hypothesis that PPIs sensitize breast cancer cells to doxorubicin and ionizing radiation (IR) treatments by inhibiting FASN. When administered to breast cancer cells as single-agent, lansoprazole exhibited the highest potency in inhibiting both FASN activity and breast cancer cell proliferation, among four PPIs tested. In addition, treatment of breast cancer cells with lansoprazole decreased the mRNA and protein levels of poly (ADP-ribose) polymerase-1 (PARP-1) and NHEJ activity, accompanied by elevated γ-H2AX expression. Following a 3-day treatment with lansoprazole, a dose-dependent disruption in cell cycle disruption and increased apoptosis were also detected. Combination of lansoprazole with either doxorubicin or IR caused profoundly higher levels of DNA damage accumulation than doxorubicin or IR treatment alone, suggesting synergistic effects. Taken together, our observations suggest that PPIs synergistically suppress breast cancer cells in combination with DNA damaging treatments by inhibiting FASN. These findings may provide a potential route to overcome resistance to DNA-damaging chemo/radiation treatments in refractory breast cancers.

京都大学 / 0048 / 新制・論文博士 / 博士(理学) / 乙第12887号 / 論理博第1545号 / 新制||理||1580(附属図書館) / 31641 / 京都大学大学院理学研究科 / (主査)教授 林 重彦, 教授 松本 吉泰, 教授 谷村 吉隆 / 学位規則第4条第2項該当 / Doctor of Science / Kyoto University / DGAM

No description available.

No description available.

The society is going through transformations in several dimensions at the same time. The energy system is moving towards renewables and reduced resource intensity. Market structures are gradually changing, and new actors emerge to compete with incumbents. Digitization creates fundamentally new conditions for everyone. Cities are being reimagined and are driving much of the transformation. Energy optimization becomes a heated topic for the whole society. This thesis research collaborated with the company SWECO Energy Strategies group investigates one part of energy optimization: proposing different possible scenarios of combining different types of buildings in a city block to urban designers and real estate company. The objective of this research is to find out the suitable combinations leading to an evener and lower demand profile from the perspectives of energy supply and the grid. This thesis project will try different methods to identify the most promising combination of various functioned buildings and develop a new methodology to solve the similar cases. A city block with either several types of building or single type of building can have an even and low energy profile. Moreover, there isn’t a definite relationship between the flatness of energy profile and the correlated amount of total demand. In this project, different scenarios are created and tested by the assistance of Python programing language and Solver installed in Excel. Through a series of tests and analysis, the best case is found with the most area of residential buildings. Qualitatively economic analysis is done, proving that an even energy profile is conducive to the cost-saving. Through the conducted case study, a general methodology is developed, which facilitates urban designers to design similar projects to some extent in the future.

The purpose of this thesis is to investigate the reversibility of the adverse effects of combination inhaled corticosteroids (ICs) on vocal fold health as part of a five-year study. This pilot study tested the hypothesis that the adverse effects of ICs may be induced and then reversed, using a benchtop model and rabbit larynges measuring sustained subglottic pressure and airflow. Eighteen rabbits were assigned randomly to 5 subgroups, including baseline, induction experimental, induction control, reversibility experimental, and reversibility control. Baseline rabbits did not receive any treatment. Both experimental groups, induction and reversibility, were administered Advair until visual-perceptual ratings were noted. Their paired control groups were administered nebulized saline in the same dosage levels. Induction groups were immediately sacrificed, while reversibility groups entered a withdrawal phase until visual-perceptual ratings showed a return to baseline. Larynges were dissected and mounted on a benchtop model for phonation trials. Dependent variables included sustained phonatory pressure (cm/H2O) and sustained phonatory airflow (L/min). The results of phonation trials indicate that sustained pressure and flow were higher for both induction and reversibility experimental groups when compared to baseline and control groups. The reversibility experimental group had lower sustained pressure and flow than the induction experimental group. These results indicate a reduction of signs after a period of rest. These findings suggest that voice symptoms may be reversible to a degree after combination IC use. These are important preliminary data that support future studies with larger sample sizes to confirm findings.

No description available.

The gross domestic product (GDP) is an essential measure of the state of economic activity and serves as a crucial tool for policymakers, investors, or businesses. However, the official GDP estimate in the Czech Republic is only available with a lag of approximately 60 days, and the Czech National Bank (CNB) announces its GDP forecast once in each quarter. This thesis focuses on predicting GDP growth in the current quarter, referred to as nowcasting. I employ several methods to nowcast the real GDP growth in the Czech Republic in a pseudo-real-time setting and compare their performance. Additionally, I investigate the possibility of creating an ensemble model by using a weighted average of several nowcasting models. The results suggest that the Dynamic Factor Model (DFM) performs best in the GDP nowcasting task, and its predictive accuracy is comparable with the official CNB nowcast. Furthermore, the model averaging process yields accuracy close to the best individual model while addressing model uncertainty. The GDP nowcast of the DFM will be made available to the public in real-time on a website and updated with a daily frequency.

Indiana University-Purdue University Indianapolis (IUPUI) / Breast cancer is the second most common cancer among women in the US after skin cancer. While early detection and improved therapy has led to an overall decline in breast cancer mortality, metastatic disease remains largely incurable, indicating a need for improved therapeutic options for patients. Telomeres are repetitive (TTAGGG)n DNA sequences found at the end of chromosomes that protect the ends from recombination, end to end fusions, and recognition as damaged DNA. The enzyme telomerase acts to stabilize short telomeres, preventing apoptosis or senescence due to genomic instability. Telomerase is active in 85-90% of cancers, and inactive in most normal cells, making telomerase an attractive target for cancer therapy. Use of the telomerase-specific, lipidated oligonucleotide GRN163L can antagonize telomerase activity and telomere maintenance in cancer cells by preventing telomerase from binding to telomeres. GRN163L has been shown by our laboratory to inhibit breast cancer cell growth and metastasis in animal models. However, the mechanisms of cancer cell growth and metastatic inhibition via GRN163L are not completely understood. The overall goal of this research project was to further elucidate the role of telomerase in breast cancer cell survival by: 1) determining the effects of combining telomere dysfunction induced by GRN163L with a DNA damage inducer (irradiation); 2) elucidating the mechanisms underlying the cellular response to GRN163L and the effect of combination therapy with the mitotic inhibitor paclitaxel; and 3) testing the hypothesis that a telomerase inhibitor can augment the effects of trastuzumab in breast cancer cells with HER2 amplification. Results support the central hypothesis that the telomere dysfunction, structural and proliferative changes in breast cancer cells induced by GRN163L can synergize with irradiation, paclitaxel, and trastuzumab to inhibit the tumorigenicity of breast cancer cells both in vitro and in vivo. Furthermore, GRN163L can restore sensitivity of therapeutically resistant breast cancer cells to trastuzumab. These results provide insight into the role of telomerase in cancer cell growth. Additionally, implications of this research support GRN163L as an important part of therapeutic regimens for primary tumors, recurrence, and metastatic disease.

No description available.