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The objective of this thesis is to examine the relationship between CAIX (a biomarker for insufficient oxygen in tumor microenvironment) and CD8+ T cells (the immune cells for killing cancer cells) for ovarian cancer. We approach the problem from two perspectives. The first approach is to set up count models such as Poisson, negative binomial, and zero-inflated Poisson models to examine the cell counts between CAIX and CD8+ T cells in the tumor microenvironment. The second approach is to apply the cross-K function, which is a second-order property of the point pattern process. We find that the tissue microarray (TMA), which is a technique to assemble hundreds of tissue samples on one TMA block, has a fixed effect on the CD8+ T cell counts. There are two TMA blocks A2 and B1. The relationship between CAIX and CD8+ T cells highly depends on TMAs. On TMA B1 stroma, a negative relationship between CAIX and CD8+ T cell counts is observed in the negative binomial models. When taking the spatial domain into account and comparing the estimated cross-K function of CAIX and CD8+ T cells to the simulated envelopes generated by a homogeneous Poisson process, we find that CAIX and CD8+ T cells are regulated and repel each other on TMA B1. Tissue category also plays an influential role in analyzing the relationship. The estimated cross-K function of CAIX and CD8 + T cells is more dispersed on tumors than on stroma. / Graduate

Ovarian cancer results in more deaths per year than any other cancer of the female reproductive system. The low survival rate is partly due to the lack of early detection and the susceptibility to relapse. The AKT serine threonine kinase plays a pivotal role in hallmark cellular processes for the progression of ovarian cancer, including tumor cell growth and migration. Therapeutic targeting of pan-AKT has been problematic, in part due to feedback mechanisms and crosstalk with other pathways. The hypothesis for this study is that AKT 1, -2 and -3 isoforms may have different roles and regulate cell processes in uniquely varied ways. A transgenic mouse model that expresses the SV40 T-antigen viral oncogene and is known to have dramatically increased susceptibility to ovarian cancer was utilized, and it had genetic inactivation of either AKT1 or AKT2 through targeted deletion of the individual genes because these isoforms have been implicated in this cancer. Primary ovarian tumor cell cultures were established and found to exhibit different morphology, proliferation and migration that may indicate a different role for the AKT1 and AKT2 isoforms in these contexts. Ovarian tumor cells with absence of AKT1 predominantly exhibited reduced cell migration when compared to cells with retention of AKT1 and absence of AKT2. Since AKT is known to be important for epithelial-mesenchymal transition (EMT), a process potentially associated with tumor cell metastasis, the expression of transcription factors implicated in EMT was assessed by real-time array analysis in ovarian tumor cells knocked-out for either AKT1 or AKT2. Twist1, one of the major players in EMT, was not detectable in the cells missing the AKT1 isoform. Results indicate an association of Twist1 with AKT1 in EMT and migration of ovarian tumors cells. This finding is significant because AKT2 has been implicated as the major player of cell migration in human breast cancer iv cells. Collectively, these findings support a tissue specific role of the AKT isoforms, and may provide insights regarding the most useful cell context in order to target components of the AKT signaling pathway indirectly affecting EMT in order to prevent tumor progression in patients with ovarian and perhaps other types of cancers

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24195号 / 医博第4889号 / 新制||医||1060(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 戸井 雅和, 教授 藤田 恭之, 教授 伊藤 貴浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23801号 / 医博第4847号 / 新制||医||1058(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 小林 恭, 教授 竹内 理, 教授 金子 新 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The intrauterine environment induces developmental adaptations that impact health and disease risk later in life. Reproductive abnormalities are now included in the long list of health complications seen in offspring exposed to early life adversity including poor prenatal nutrition. Previous work has shown using a rat model, that offspring born to mothers that were nutrient restricted (UN) during pregnancy are growth restricted, enter puberty early, and as adults, display characteristics of early ovarian aging with reduced follicle number. This present study aimed to investigate whether key proteins involved in ovarian follicle recruitment and growth, including the PI3K/Akt pathway, may be impaired as a result of early life nutritional adversity. Maternal UN resulted in irregular estrous cyclicity due to persistent estrus, a significant decrease in young adult ovarian antral follicles, corpora lutea, and a significant increase in atretic follicles. A decrease in growing follicles in UN offspring appears to be due to lowered expression of granulosa-cell secreted growth factor IGF-1 in antral follicles, and increased expression of pro-apoptotic factor Casp3 in secondary follicles of young adult offspring born to UN dams. Changes in follicle signalling pathways were apparent before observing altered ovarian function. In UN prepubertal offspring, expression levels of IGF1-R and FSHR were lowered in secondary and antral follicles respectively. These growth factors may contribute to a decrease in PI3K/Akt activation as immunohistochemical staining revealed a decrease in pAkt immunolocalization in prepubertal antral follicles. Moreover, neonatal ovaries of UN offspring show decreased levels of immunopositive staining for AMHRII, a regulatory receptor of the ovarian reserve. This study demonstrates that maternal UN during pregnancy impacts ovarian function in female offspring as early as P65. Findings from this study provides a model of understanding mechanisms of follicle loss and reproductive dysfunction as a result of nutrient restriction during fetal life. / Thesis / Master of Science (MSc)

Polycystic Ovarian Syndrome (PCOS) is common among women of reproductive age (ages 15-49), and it can put patients at higher risk for diseases such as type II diabetes or coronary heart disease. While the mechanisms behind PCOS are poorly understood, it is diagnosed using two characteristics: hyperandrogenism and anovulation. Once diagnosed, many patients are also tested for insulin resistance (IR). While IR is thought of as a symptom of PCOS, this study will examine the effects of treatment of IR to manage symptoms of PCOS rather than treatment of hyperandrogenism. This meta-analysis used data from studies previously published by searching for them using key words such as "polycystic ovarian syndrome," "insulin resistance," "hyperandrogenism," and "medication." These data were organized by symptoms studied, and coded. Information extracted was the title, author(s), date of publication, sample size, group characteristics, interventions, and outcomes of each study. This meta-analysis found that the use of insulin sensitizers as treatment for PCOS did not have a greater effect on symptom management than traditional PCOS medications, such as oral contraceptives. These results are useful in the search for a comprehensive and effective treatment of PCOS and may be useful in a clinical setting for treatment guidance purposes.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is one of the most common endocrine dysfunction problems among women of the reproductive age, with a global prevalence of 4-20%, causing 430,000 associated DALYs. Initial treatment of PCOS is mainly focused on diet and exercise and, if left untreated, PCOS can lead to many complications including, but not limited to, diabetes, metabolic syndrome, cardiovascular disease and endometrial cancer. In India, one out of five women are found to have PCOS with the numbers increasing with every year, according to a 2015 study done by Metropolis Healthcare. Some studies done in other parts of the country have shown that there is very limited knowledge about PCOS. Currently there is no data about the knowledge, attitudes and practices about PCOS in Kerala, India, which is an area known to have the highest rates of diabetes in India as well as an area having a high rate of infertility. PROPOSED PROJECT AND SIGNIFICANCE: This study is proposed to assess the knowledge, attitudes and practices of PCOS among women of reproductive age (18-45 years) in urban and rural areas of Thrissur, Kerala, India. This will help in understanding if there are any barriers to treatment and highlight the best preventive measures, as well as treatment strategies in this population, that might reduce its health burden. CONCLUSION: This will be a pilot study assessing perceptions of PCOS in Kerala, India. If this study demonstrates a low understanding of PCOS as shown in other parts of India, this will provide help in understanding the reasons why the prevalences of PCOS as well as diabetes and infertility, are increasing in the state of Kerala.

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