家族性卵巣機能不全原因遺伝子FOXL2による核内受容体エストロゲンレセプターβの転写制御機構の解明

学位の種別: 課程博士審査委員会委員 : (主査)東京大学教授 井上 聡, 東京大学教授 栗原 裕基, 東京大学准教授 北中 幸子, 東京大学准教授 河野 博隆, 東京大学准教授 住谷 昌彦University of Tokyo(東京大学

A Study on Project-Based Learning from the Viewpoint of Organizational Knowledge Creation Theory

アクティブラーニングの1 つとしてPBL（problem/project-based learning）がある。PBL には問題解決学習（problem based learning）とプロジェクト学習（project based learning）の2 つがある。これまでPBL を対象とする研究は着実に蓄積されてきたが，PBL の理論的枠組みは未だ脆弱であることが指摘されている。そこで，本研究ではこの問題を克服するために，大学教育でのプロジェクト学習について，組織的知識創造理論から考察する。本研究の第1 の目的は，組織的知識創造理論がプロジェクト学習においても適用できることを確認することである。第2 の目的は，プロジェクト学習における教員の役割について，組織的知識創造理論から示唆を得ることである。本研究では，以下の3 ステップを踏む。まず，本研究の鍵概念である組織的知識創造理論を紹介する。次に，3 つのプロジェクト学習の事例を紹介し，組織的知識創造理論から分析する。最後に，組織的知識創造理論がプロジェクト学習においても適用できることについて，また，示唆されたプロジェクト学習における教員の役割について議論する。One form of active learning is PBL. There are two types of PBL: “problem-based learning” and “project-based learning.” Although a large number of studies have been on PBL, few studies have been conducted using surveys based on academic theories. Therefore, this paper discusses “project-based learning” from the viewpoint of organizational knowledge creation theory. The primary objective of this study is to apply organizational knowledge creation theory in the field of “project-based learning.” The secondary objective is to recommend teachers’ roles in “project-based learning” from the standpoint of organizational knowledge creation theory. The analysis includes three steps: first, a review of organizational knowledge creation theory; second, an examination of three case studies; and finally, a discussion on applying the theory to “project-based learning”, and suggesting teachers’ roles from this viewpoint

Resveratrol promotes expression of SIRT1 and StAR in rat ovarian granulosa cells: an implicative role of SIRT1 in the ovary

<p>Abstract</p> <p>Background</p> <p>Resveratrol is a natural polyphenolic compound known for its beneficial effects on energy homeostasis, and it also has multiple properties, including anti-oxidant, anti-inflammatory, and anti-tumor activities. Recently, silent information regulator genes (Sirtuins) have been identified as targets of resveratrol. Sirtuin 1 (SIRT1), originally found as an NAD⁺-dependent histone deacetylase, is a principal modulator of pathways downstream of calorie restriction, and the activation of SIRT1 ameliorates glucose homeostasis and insulin sensitivity. To date, the presence and physiological role of SIRT1 in the ovary are not known. Here we found that SIRT1 was localized in granulosa cells of the human ovary.</p> <p>Methods</p> <p>The physiological roles of resveratrol and SIRT1 in the ovary were analyzed. Immunohistochemistry was performed to localize the SIRT1 expression. SIRT1 protein expression of cultured cells and luteinized human granulosa cells was investigated by Western blot. Rat granulosa cells were obtained from diethylstilbestrol treated rats. The cells were treated with increasing doses of resveratrol, and subsequently harvested to determine mRNA levels and protein levels. Cell viability was tested by MTS assay. Cellular apoptosis was analyzed by caspase 3/7 activity test and Hoechst 33342 staining.</p> <p>Results</p> <p>SIRT1 protein was expressed in the human ovarian tissues and human luteinized granulosa cells. We demonstrated that resveratrol exhibited a potent concentration-dependent inhibition of rat granulosa cells viability. However, resveratrol-induced inhibition of rat granulosa cells viability is independent of apoptosis signal. Resveratrol increased mRNA levels of SIRT1, LH receptor, StAR, and P450 aromatase, while mRNA levels of FSH receptor remained unchanged. Western blot analysis was consistent with the results of quantitative real-time RT-PCR assay. In addition, progesterone secretion was induced by the treatment of resveratrol.</p> <p>Conclusions</p> <p>These results suggest a novel mechanism that resveratrol could enhance progesterone secretion and expression of luteinization-related genes in the ovary, and thus provide important implications to understand the mechanism of luteal phase deficiency.</p

Case report: Posterior reversible encephalopathy syndrome, an adverse effect of lenvatinib and pembrolizumab combination therapy, in a patient with advanced endometrial cancer

BackgroundLenvatinib-pembrolizumab combination (LEAP) is an approved therapy in Japan for advanced endometrial cancer, based on the data from the KEYNOTE-775 clinical trial. We report a case of posterior reversible encephalopathy syndrome (PRES) in a patient who received LEAP therapy for advanced endometrial cancer.Case presentationA 53-year-old patient with stage IVB endometrial cancer having rectal metastases, after four cycles of paclitaxel-carboplatin therapy, was found to have increased rectal invasion, peritoneal dissemination, and multiple paraaortic lymph node metastases. She was treated with LEAP therapy and discharged on day 12 without adverse events, except for mild anemia on day 11 of treatment. She was carefully managed in the outpatient department, but on day 18, she was admitted to the emergency department with severely impaired consciousness and generalized seizures. Computed tomography of the head and lumbar tap showed no abnormal findings, and the seizures resolved with anticonvulsant medication alone. Based on a thorough physical examination and findings on magnetic resonance imaging (MRI), which showed high signal intensity in the left occipital lobe, encephalopathy, rather than encephalitis, was the likely diagnosis. Symptomatic improvement was observed, and pembrolizumab monotherapy was resumed.ConclusionsIf consciousness is impaired during LEAP treatment, it is necessary to differentiate between immunogenic encephalitis caused by pembrolizumab or encephalopathy caused by lenvatinib. MRI and lumbar tap can help in distinguishing between the two and diagnosing the responsible drug

Antireflux Transoral Incisionless Fundoplication Using EsophyX: 12-Month Results of a Prospective Multicenter Study

BACKGROUND: A novel transoral incisionless fundoplication (TIF) procedure using the EsophyX system with SerosaFuse fasteners was designed to reconstruct a full-thickness valve at the gastroesophageal junction through tailored delivery of multiple fasteners during a single-device insertion. The safety and efficacy of TIF for treating gastroesophageal reflux disease (GERD) were evaluated in a prospective multicenter trial. METHODS: Patients (n = 86) with chronic GERD treated with proton pump inhibitors (PPIs) were enrolled. Exclusion criteria included an irreducible hiatal hernia > 2 cm. RESULTS: The TIF procedure (n = 84) reduced all hiatal hernias (n = 49) and constructed valves measuring 4 cm (2-6 cm) and 230 degrees (160 degrees -300 degrees ). Serious adverse events consisted of two esophageal perforations upon device insertion and one case of postoperative intraluminal bleeding. Other adverse events were mild and transient. At 12 months, aggregate (n = 79) and stratified Hill grade I tight (n = 21) results showed 73% and 86% of patients with >or=50% improvement in GERD health-related quality of life (HRQL) scores, 85% discontinuation of daily PPI use, and 81% complete cessation of PPIs; 37% and 48% normalization of esophageal acid exposure; 60% and 89% hiatal hernia reduction; and 62% and 80% esophagitis reduction, respectively. More than 50% of patients with Hill grade I tight valves had a normalized cardia circumference. Resting pressure of the lower esophageal sphincter (LES) was improved significantly (p < 0.001), by 53%. EsophyX-TIF cured GERD in 56% of patients based on their symptom reduction and PPI discontinuation. CONCLUSION: The 12-month results showed that EsophyX-TIF was safe and effective in improving quality of life and for reducing symptoms, PPI use, hiatal hernia, and esophagitis, as well as increasing the LES resting pressure and normalizing esophageal pH and cardia circumference in chronic GERD patients.Journal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Activation of Nrf2/Keap1 pathway by oral Dimethylfumarate administration alleviates oxidative stress and age-associated infertility might be delayed in the mouse ovary

Abstract Background Age-associated infertility is a problem worldwide, and management of oxidative stress is known to be essential. Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway works as an essential defense mechanism against oxidative stress, and an oral drug Dimethylfumarate (DMF) is known to activate the pathway. Methods We tested the hypothesis that oral DMF could alleviate oxidative stress in the ovary, resulting in salvation of age-associated infertility in a mouse model of reproductive age, and we examined the effects of DMF administration. 20 mg/kg DMF was administrated to female mice from 32 to 48 weeks, and Nrf2 levels, antioxidant levels, ovarian reserve, DNA damage, and oxidative stress were examined. Results DMF administration resulted in elevated mRNA and protein levels of Nrf2, antioxidants, and telomere, and serum levels of Nrf2 and anti-mullerian hormone were also elevated. Results of TUNEL assay and Immunohistochemistry of mice ovarian tissues showed that DNA damage and oxidative stress were decreased by DMF administration, and significantly more oocytes were collected along with preservation of 60% more primordial follicles. Conclusions Our data suggest that DMF administration activates the Nrf2/Keap1 pathway, elevate levels of antioxidants, and decrease DNA damage and oxidative stress, resulting in improved ovarian reserve in the mouse ovary