オメガ3脂肪酸の最終代謝産物であるレゾルビンE3とその前駆物質18-Hydroxyeicosapentaenoic acidによる早産予防と炎症制御メカニズムに関する研究

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 岡 明, 東京大学准教授 藤代 準, 東京大学准教授 平池 修, 東京大学准教授 春名 めぐみ, 東京大学講師 松崎 政代University of Tokyo(東京大学

Purkinje cells originate from cerebellar ventricular zone progenitors positive for Neph3 and E-cadherin

AbstractGABAergic Purkinje cells (PCs) provide the primary output from the cerebellar cortex, which controls movement and posture. Although the mechanisms of PC differentiation have been well studied, the precise origin and initial specification mechanism of PCs remain to be clarified. Here, we identified a cerebellar and spinal cord GABAergic progenitor-selective cell surface marker, Neph3, which is a direct downstream target gene of Ptf1a, an essential regulator of GABAergic neuron development. Using FACS, Neph3+ GABAergic progenitors were sorted from the embryonic cerebellum, and the cell fate of this population was mapped by culturing in vitro. We found that most of the Neph3+ populations sorted from the mouse E12.5 cerebellum were fated to differentiate into PCs while the remaining small fraction of Neph3+ cells were progenitors for Pax2+ interneurons, which are likely to be deep cerebellar nuclei GABAergic neurons. These results were confirmed by short-term in vivo lineage-tracing experiments using transgenic mice expressing Neph3 promoter-driven GFP. In addition, we identified E-cadherin as a marker selectively expressed by a dorsally localized subset of cerebellar Neph3+ cells. Sorting experiments revealed that the Neph3+ E-cadherinhigh population in the embryonic cerebellum defined PC progenitors while progenitors for Pax2+ interneurons were enriched in the Neph3+ E-cadherinlow population. Taken together, our results identify two spatially demarcated subregions that generate distinct cerebellar GABAergic subtypes and reveal the origin of PCs in the ventricular zone of the cerebellar primordium

SOD1 Is Essential for the Viability of DT40 Cells and Nuclear SOD1 Functions as a Guardian of Genomic DNA

Reactive oxygen species (ROSs) are produced during normal cellular metabolism, particularly by respiration in mitochondria, and these ROSs are considered to cause oxidative damage to macromolecules, including DNA. In our previous paper, we found no indication that depletion of mitochondrial superoxide dismutase, SOD2, resulted in an increase in DNA damage. In this paper, we examined SOD1, which is distributed in the cytoplasm, nucleus, and mitochondrial intermembrane space. We generated conditional SOD1 knockout cells from chicken DT40 cells and analyzed their phenotypes. The results revealed that SOD1 was essential for viability and that depletion of SOD1, especially nuclear SOD1, increased sister chromatid exchange (SCE) frequency, suggesting that superoxide is generated in or near the nucleus and that nuclear SOD1 functions as a guardian of the genome. Furthermore, we found that ascorbic acid could offset the defects caused by SOD1 depletion, including cell lethality and increases in SCE frequency and apurinic/apyrimidinic sites

Protective roles of ascorbic acid in oxidative stress induced by depletion of superoxide dismutase in vertebrate cells.

Superoxide dismutases (SODs) are antioxidant proteins that convert superoxide to hydrogen peroxide. In vertebrate cells, SOD1 is mainly present in the cytoplasm, with small levels also found in the nucleus and mitochondrial intermembrane space, and SOD2 is present in the mitochondrial matrix. Previously, the authors conditionally disrupted the SOD1 or SOD2 gene in DT40 cells and found that depletion of SOD1 caused lethality, while depletion of SOD2 led to growth retardation. The observations from previous work showed that the lethality observed in SOD1-depleted cells was completely rescued by ascorbic acid. Ascorbic acid is a water-soluble antioxidant present in biological fluids; however, the exact target for its antioxidant effects is not known. In this study, the authors demonstrated that ascorbic acid offset growth defects observed in SOD2-depleted cells and also lowered mitochondrial superoxide to physiological levels in both SOD1- or SOD2-depleted cells. Moreover, depletion of SOD1 or SOD2 resulted in the accumulation of intracellular oxidative stress, and this increased oxidative stress was reduced by ascorbic acid. Taken together, this study suggests that ascorbic acid can be applied as a nontoxic antioxidant that mimics the functions of cytoplasmic and mitochondrial SODs

Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan: one-year clinical outcomes (RECONFIRM-2)

Biologics targeting TNF have brought about a paradigm shift in the treatment of rheumatoid arthritis (RA) and infliximab, anti-TNF-α chimeric monoclonal antibody, was marketed in 2003 in Japan. We previously reported on the RECONFIRM study, a retrospective clinical study on the efficacy of infliximab therapy in a RA management group in Japan, where we evaluated the clinical response after 22 weeks of the therapy in 258 patients. The study reported here was aimed at reconfirming the clinical efficacy of the infliximab therapy and demographic factors related to the efficacy over a 54-week study period in 410 RA patients in the same study group. Infliximab was infused according to the domestically approved method, and the clinical response was evaluated following 54 weeks of infliximab therapy using the European League Against Rheumatism (EULAR) response criteria. Disease activity was assessed by DAS28-CRP (Disease Activity Score including a 28-joint count/C-reactive protein). Infliximab was discontinued in 24.4% of the 410 patients at 54 weeks and 9.3% and 8.1% discontinued the therapy due to adverse events and inefficiency, respectively. Average DAS28-CRP decreased from 5.5 at week 0 to 3.1 at week 54 after the therapy. Patients in remission and those showing low-, moderate-, and high-disease activity changed from 0.0, 1.0, 9.0 and 90.0%, respectively, at the start of the study to 27.6, 11.7, 34.4 and 26.3%, respectively, at week 54. Younger age, RF-negativity and low scores of DAS28-CRP showed significant correlations with remission at week 54. EULAR response criteria—good, moderate, and no response to infliximab—were 37.0, 41.7 and 21.2%, respectively. In conclusion, we reconfirmed the clinical efficacy of infliximab and demographic factors related to the efficacy over a 54-week study period in 410 Japanese patients with RA using DAS28-CRP and EULAR response criteria

Factors that contribute to long-term survival in patients with leukemia not in remission at allogeneic hematopoietic cell transplantation

<p>Abstract</p> <p>Background</p> <p>There has been insufficient examination of the factors affecting long-term survival of more than 5 years in patients with leukemia that is not in remission at transplantation.</p> <p>Method</p> <p>We retrospectively analyzed leukemia not in remission at allogeneic hematopoietic cell transplantation (allo-HCT) performed at our institution between January 1999 and July 2009. Forty-two patients with a median age of 39 years received intensified conditioning (n = 9), standard (n = 12) or reduced-intensity conditioning (n = 21) for allo-HCT. Fourteen patients received individual chemotherapy for cytoreduction during the three weeks prior to reduced-intensity conditioning. Diagnoses comprised acute leukemia (n = 29), chronic myeloid leukemia-accelerated phase (n = 2), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (n = 10) and plasma cell leukemia (n = 1). In those with acute leukemia, cytogenetic abnormalities were intermediate (44%) or poor (56%). The median number of blast cells in bone marrow (BM) was 26.0% (range; 0.2-100) before the start of chemotherapy for allo-HCT. Six patients had leukemic involvement of the central nervous system. Stem cell sources were related BM (7%), related peripheral blood (31%), unrelated BM (48%) and unrelated cord blood (CB) (14%).</p> <p>Results</p> <p>Engraftment was achieved in 33 (79%) of 42 patients. Median time to engraftment was 17 days (range: 9-32). At five years, the cumulative probabilities of acute graft-versus-host disease (GVHD) and chronic GVHD were 63% and 37%, respectively. With a median follow-up of 85 months for surviving patients, the five-year Kaplan-Meier estimates of leukemia-free survival rate and overall survival (OS) were 17% and 19%, respectively. At five years, the cumulative probability of non-relapse mortality was 38%. In the univariable analyses of the influence of pre-transplant variables on OS, poor-risk cytogenetics, number of BM blasts (>26%), MDS overt AML and CB as stem cell source were significantly associated with worse prognosis (p = .03, p = .01, p = .02 and p < .001, respectively). In addition, based on a landmark analysis at 6 months post-transplant, the five-year Kaplan-Meier estimates of OS in patients with and without prior history of chronic GVHD were 64% and 17% (p = .022), respectively.</p> <p>Conclusion</p> <p>Graft-versus-leukemia effects possibly mediated by chronic GVHD may have played a crucial role in long-term survival in, or cure of active leukemia.</p

Prominent IgM Deposition in Glomerulus Is Associated with Severe Proteinuria and Reduced after Combined Treatment of Tonsillectomy with Steroid Pulse Therapy in Patients with IgA Nephropathy

IgA nephropathy (IgAN) is characterized by mesangial deposition of IgA, C3, and often IgM. We examined the relationship among IgM deposition, clinical features, and renal outcome in IgAN patients who underwent combined treatment of tonsillectomy with steroid pulse therapy (Tx-SP). We retrospectively reviewed 73 IgAN patients treated with Tx-SP from March 2006 to March 2014. The patients were divided into those with moderate (2+) to severe (3+) mesangial IgM deposition (Prominent IgM-positive patients, P-Group) and those with negative (−) to faint (1+) deposition (the “Other” patients, O-Group). Using propensity scores to minimize confounding factors, 11 propensity score-matched patients with O-Group (mO-Group) were compared to 11 P-Group patients. The study outcome was defined as urinary protein grade by urine test strip before Tx-SP and one year after Tx-SP. P-Group patients exhibited an increased severity of proteinuria compared to O-Group (p=0.018) and mO-Group patients (p=0.009) before Tx-SP. After Tx-SP, proteinuria was significantly ameliorated in the P-Group, reaching the same severity recorded in the O-Group (p=0.007) and mO-Group (p=0.021). No significant differences were noted between P-Group and mO-Group in microhematuria, serum creatinine level, and histological severity. Prominent IgM deposition is associated with severe proteinuria in IgAN. However, Tx-SP induces a sufficient reduction in the severity of proteinuria in IgM-positive IgAN

Ca' Foscari Japanese Studies 7, Arts and Literature 2, Rethinking Nature in Japan from Tradition to Modernity

It is a pleasure for us to present this book, with the contributions of the Inter- national Symposium Rethinking Nature in Japan: from Tradition to Modernity held at Ca’ Foscari University of Venice in the Auditorium Santa Margherita. This was the Second International Conference organized in Venice: in 2013 we celebrated the first Symposium Rethinking Nature in Contemporary Japan. Science, Economics, Politics, published by Edizioni Cafoscari in 2014. The aim of the Symposium was the analysis of Japanese society and the international relationships after the accident at Fukushima nuclear plant in March 2011. Its wide-ranging consequences on everyday life of Japanese citizens brought into the limelight issues such as the protection of the environment, the man- agement of natural resources, and food safety, both within the country and abroad, as fundamental challenges to our globalised society. In 2013, the participation of scholars from Europe, Japan and United States helped us to achieve a deeper insight into this multifaceted issue, combining several disciplines under a multidisciplinary and comparative approach. At the root of all these problems stand the basic theme of the relation between man and nature. Historically, Japan has developed through the centuries an extremely rich tradition on this complex topic, in the intel- lectual field as well as in terms of material culture. That is the reason why we decided to choose as the theme of this Sym- posium in 2014 the cultural representations of the idea of Nature in the transition from tradition to modernity. This Symposium, “Rethinking Nature in Japan: From Tradition to Mo- dernity”, was centered on Fine Arts, Religion and Thought, Literature, Theatre and Cinema. We had four panel sessions: “Nature and Environment in Japanese Fine Arts: from Tradition to Modernity”, in Japanese Literature, in Japanese Thought and in Performing Arts. First of all, as a representative of Ca’ Foscari University and of our colleagues, we would like to thank all students, guests and colleagues for their presence at the Symposium, and thank also our special guests from Japan, from the United State, from Europe and from Italy for their (pre- cious) contributions. We believe for all the participants [students, scholars, lecturers, for you and for us] our Symposium was very interesting and fruitful and we hope that the same will be also for this book We would like to thank the representatives of our University, the Rector of Ca’ Foscari University, prof. Carlo Carraro and prof. Tiziana Lippiello, Director of the Department of Asian and North African Studies for their constant support. We are much indebeted to the Director Matsunaga Fumio and to the Japan Foundation for their special attention to the Japanese Studies Sec- tion of our Department. As for our sponsors, we would like to express our thanks to SAGA [School of Asian Studies and Business Management] for the generous financial support. We are also grateful to the artist Miyayama Hiroaki who painted the wisteria branch in the poster of the program and generously allowed us to use it as the logo of our Symposium, and prof. Caterina Virdis Limentani of Padua University who organized the exhibition: Splendori dal Giappone, Le storie del principe Genji nella tradizione Edo e nelle incisioni di Miyayama Hiroaki and the relation between this work and Miyayama’s prints in Padua at Palazzo Zuckermann from March 1st to 31st, 2014. Last but not least, we would thank again all the students who attended the Symposium, the speakers/contributors from Japan, United State, Eu- rope, Italy, the student staff, all our colleagues of the Japanese Section, our young researchers, the organizing committee: Paolo Calvetti, Massimo Raveri, Luisa Bienati, Aldo Tollini, Marcella Mariotti, Giovanni Bulian, Ca- terina Mazza, Toshio Miyake, Andrea Revelant and Pierantonio Zanotti, to all the administration st