Orientador: Marilza Vieira Cunha Rudge / Resumo: The mild gestational hyperglycemia (MGH) and gestational diabetes mellitus (GDM), referred as gestational hyperglycemia in this study, have important consequences for the mother, fetus and newborn. The association between gestational hyperglycemia and urinary incontinence is scarce in the literature. Our academic research group "Diabetes and Pregnancy - Clinical and Experimental", from Botucatu Medical School, UNESP, has studied the translational aspects of gestational hyperglycemia related to urinary incontinence in females and in animal models. The results help to elucidate the pathophysiological mechanisms that lead to female pelvic floor disorders in women with GDM and HGL, but there is need for further research to expand the understanding of the phenomena that result in better care for patients. Whereas monocyte chemotactic protein-3 (CCL7) is an important factor for the recovery mechanism of urinary incontinence, our hypothesis was that patients with GDM or HGL present changes in the CCL7 levels and this would retard/prevent the migration of mesenchymal stem cells to the site of injury caused by IU, causing consequences in the postpartum period. Thus, the purpose of this study was to determine the CCL7 levels profile in hyperglycemic pregnant women with urinary incontinence since the beginning of pregnancy up to the first year postpartum and to examine the correlation between the progression of UI and serum levels of CCL7. This identification may indicate CCL7 as a poss... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24284号 / 医博第4900号 / 新制||医||1061(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 羽賀 博典, 教授 上野 英樹, 教授 髙折 晃史 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Cancer is still one of the most common causes of death world-wide and in parallel there is a need to update the repertoire of therapies that withstand resistance of recurrent cancers. Since the introduction of antibody therapies as anti-cancer pharmaceuticals, recognized as immunotherapy in health care, it has been an increasing field in cancer therapy, as a more targeted treatment compared to chemotherapy. Despite the great success, immunotherapy rely on parenteral administration, partly due to poor tissue penetration. If the treatment is administered intravenously, specialized personnel is required, in addition to that it can be inconvenient for the patient. Also, pharmaceuticals based on antibodies often require costly production steps which yields a high-priced treatment. To approach this problem, researchers have developed small affinity domains with the aim to increase tissue penetration while keeping a high specificity to its target. Albumin Binding Domain Derived Affinity Protein (ADAPT) is an example of a small affinity domain of only 7 kDa, which is based on albumin binding domain (ABD) from the streptococcal protein G. Recently, it was shown that the ADAPTs can be further engineered to bind albumin and another relevant target protein of interest simultaneously, which suggests a tolerable half-life in patient serum, alternative administration routes and lower production costs compared to antibody treatments. Furthermore, less side effects are expected due to higher specificity compared to chemotherapy. This work presents the characterization of novel ADAPT proteins that the target the cancer relatedproteins C-C motif ligand 7 (CCL7), vascular endothelial growth factor A (VEGF-A) and carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5). The new constructs were produced recombinantly in Escherichia coli (E. coli) and purified using affinity chromatography. Moreover, the results demonstrate bispecific binding with high affinity towards serum albumin and CCL7 and CEACAM5 respectively, while the ADAPT variants targeting VEGF-A remain to be further developed. Lastly, the importance of different amino acids for structural and binding properties of one CEACAM5 binder are stated. It reveals that the target binding relies on hydrophobic interactions which also can be connected to its poor structural attributes. Accordingly, this project adds new insights about the ADAPTs which can be useful in research towards future clinical applications aimed to improve cancer treatments.