Class of 2017 Abstract / Objectives: The specific aims of this project were to evaluate the incidence of carboplatin HSR in patients with the BRCA1 or BRCA2 mutations compared to those without these mutations. Secondary objectives were to identify carboplatin cycles where reactions occurred, grade of reaction, and treatment outcomes. Methods: This retrospective chart review included 167 ovarian, fallopian tube, and primary peritoneal cancer patients at the University of Arizona Cancer Center who underwent a regimen with carboplatin from 2013-2015. Results: 126 out of 167 patients were analyzed. HSR occurred in 4 patients with BRCA mutations, and in 9 patients without mutations, though incidence was not significant with respect to the groups (3.1% versus 17.4%, P=0.5291). Overall, there were 11 grade 1 reactions, 14 grade 2 reactions, and 16 grade 3 reactions to carboplatin. Conclusions: Presence of a BRCA1/2 mutation was not associated with a higher incidence of HSR in carboplatin. More studies are needed to clarify the impact of BRCA mutations on developing carboplatin HSR.

Visceral leishmaniasis (VL) causes fatal life-threatening disease, if left untreated. The current drugs have various limitations; hence, natural products from medicinal plants are being focused in search of new drugs to treat leishmaniasis. The aim of the present study was to evaluate the antileishmanial and immunomodulatory activities of F5 and F6 alcoholic fractions from Withania somnifera leaves and purified withaferin-A in Leishmania donovani-infected peritoneal macrophages and BALB/c mice. We observed that F5 (15 mu g/mL), F6 (10 mu g/mL), and withaferin-A (1.5 mu M) reduce amastigote count in peritoneal macrophages and induce reactive oxygen species and significant decrease in IL-10 mRNA expression compared to control upon treatment. Subsequently, in vivo study mice were treated with F5 (25 and 50 mg/kg b.wt.), F6 (25 and 50 mg/kg b.wt.) orally, and withaferin-A (2 mg/kg b.wt.) intraperitoneally for 10 consecutive days and a drastic reduction in parasite burden in both spleen and liver were observed. The treatment resulted in the reduction in IL-10, IL-4, and TGF-beta mRNA expression and a significant increase in IFN-gamma /IL-10 expression ratio in the treated group compared to control. The humoral response of these alcoholic fractions and withaferin-A shows increased IgG2a levels when compared with IgG1 in treated mice. Taken together, our result concludes that withanolides in alcoholic fractions demonstrate a potent antileishmanial and immunomodulatory activities in experimental VL.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21997号 / 医博第4511号 / 新制||医||1037(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 武藤 学, 教授 妹尾 浩, 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

Background: Bone and mineral metabolism disorders are common among end-stage renal disease (ESRD) patients, which could lead to hip fracture. It is unclear whether the hip fracture risk is different among patients on hemodialysis (HD) versus peritoneal dialysis (PD). This meta-analysis was conducted to evaluate the hip fracture risk in ESRD patients on HD, when compared to PD. Methods: A literature review was conducted in EMBASE, MEDLINE, and Cochrane databases through January 31, 2018 to identify studies that appraised the rate or risk of hip fracture among patients on HD, when compared to PD. Effect estimates from the individual studies were derived and consolidated utilizing random-effect, generic inverse variance approach of DerSimonian and Laird. Results: Five cohort studies with 1 276 677 ESRD patients were enrolled. HD status was associated with a significantly higher risk of hip fracture with the pooled odds ratio (OR) of 1.61 (95% confidence interval [CI] 1.50-1.73, I2 = 10.0%), compared with PD. When the analysis was limited to studies with confounder-adjusted analysis, the pooled OR of hip fracture among HD patients was 1.57 (95% CI 1.43-1.72, I2 = 13.6%). Funnel plots and Egger's regression test demonstrated no significant publication bias in our meta-analysis. Conclusions: Among ESRD patients, HD status is associated with a 61% higher risk of hip fracture compared to PD.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第17813号 / 医博第3811号 / 新制||医||999(附属図書館) / 30628 / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙折 晃史, 教授 武藤 学, 教授 杉田 昌彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

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Chronic peritonitis contributes to technique failure in peritoneal dialysis (PD), an effective replacement therapy for chronic kidney failure. Staphylococcus aureus infection is one of the most common causes of peritonitis in PD. Interestingly, mice deficient in the cell surface heparan sulfate proteoglycan, syndecan-1, were reported to clear S. aureus corneal infection more effectively than wild-type mice. The objectives of this study were to examine the protein expression and role of syndecan-1 in leukocyte recruitment, chemokine presentation and S. aureus infection in the microcirculation underlying the parietal peritoneum in wild-type and syndecan-1-/- mice. Immunofluorescence intravital microscopy (IVM) of the parietal peritoneum microcirculation revealed that syndecan-1 was localized to the subendothelial region of venules and the mesothelial layer but does not regulate leukocyte recruitment and is not necessary for presentation of the chemokine MIP-2 in peritoneal venules. IVM was also used to study the effects of a conventional PD solution injected through a peritoneal catheter in a mouse PD model. After 6 weeks of dialysis, the peritoneal catheter implant increased leukocyte rolling and extravasation, fibrosis and angiogenesis in the parietal peritoneum independently from the dialysis solution treatment. Furthermore, the role of syndecan-1 was examined using a 4 week PD model. Four hours after infection with S. aureus through the dialysis catheter or intraperitoneal injection, the dialyzed syndecan-1-/- mice were more susceptible to S. aureus infection than undialyzed syndecan-1-/- controls and wild-type animals. IVM showed that in S. aureus infection, syndecan-1 was removed from the subendothelial surface of peritoneal venules but syndecan-1 deficiency did not affect leukocyte recruitment during S. aureus infection. This study indicates that syndecan-1 in the peritoneum and microcirculation is not a regulator of inflammatory responses but is crucial for providing a barrier to S. aureus infection, which may have important implications for susceptibility to S. aureus infections in PD. / Dissertation / Doctor of Philosophy (Medical Science)

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