Structure–activity relationship study on senktide for development of novel potent neurokinin-3 receptor selective agonists

Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate neurokinin-3 receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties

環境デザインに関する国際教育プログラムの構築について（その2）/二つのワークショップの比較考察

本研究は、神戸芸術工科大学紀要「芸術工学2013」に掲載した「環境デザインに関する国際教育プログラムの構築について」の継続研究であり、本稿では前稿で取り上げた活動以降の2013年度に実施した内容について報告する。本研究で注目しているのは、環境デザイン分野における現地集中開催型の国際ワークショップである。2013年度は2012年度に引き続き、5月にイタリアのサルデーニャで開催されたLandWorks に参加し、インスタレーションを現地で実際に制作することを特色とするこのワークショップ特有の運営面での工夫等に関して、さらに詳細な情報収集を行った。また、9月にフランスのノルマンディー地方で開催されたEMiLA（EuropeanMasters in Landscape Architecture）サマースクールのワークショップに参加し、より広域的な課題への取り組み手法と、国が異なる5 大学の共通プログラムという、教育の国際化を考える上でたいへん興味深い教育制度の仕組みについて情報収集した。本稿では、これら2つのワークショップの概要について説明した後、実施運営面および教育制度面という2つの観点からの比較考察を行い、両者の相違点を明確にした上で、国際ワークショップの企画運営、ならびに、それを教育プログラムに組み入れる上での、主要な検討項目について整理する。This paper further develops the research topic discussed in "Investigation for International Education Programs in the Field of Environmental Design" published in 2013 on this Bulletin of Kobe Design University.During the academic year 2013, we participated in two international workshops: LandWorks Sardina in Italy, and the workshop of EMiLA (European Masters in Landscape Architecture) Summer School held in France. While the LandWorks focus on the realization of on-site projects, the EMiLA workshop deals with the problems of wider areas. The unique educational system of EMiLA as the common program of 5 schools from different countries in Europe is also investigated.In this paper, after the explanation of the two workshops mentioned above, a comparative analysis is made from the viewpoints of the administration and the relation to the educational systems. The differences of the two workshops provide a range of possibilities regarding the organization of similar international workshops and the incorporation of them into the exisiting educational systems

環境デザインに関する国際教育プログラムの構築について

本研究では、環境デザインに関する新たな国際教育プログラムの構築をめざして海外の先行事例に関する情報を収集し、それらに関する分析考察を行う。なかでも短期集中型で実施されるワークショップ形式の国際教育プログラムに注目する。本学ではこれまで2回にわたって、ユネスコの景観と環境デザインに関する講座、CUPEUM1)が主催する国際ワークショップ、WAT2)に参加し、その実施運営についてのノウハウを蓄積すると共に、このような国際ワークショップの教育上の意義と可能性について検討してきた。これらの経験を基礎として、2012年度はイタリアのサルデーニャ島で開催されたLandworks3)のワークショップに参加し、ランドスケープ分野の国際ワークショップという共通性は有しつつも、テーマ設定、組織、運営等において、WATとは異なる方式のワークショップについての情報収集と比較考察を行った。また、フィンランドのヘルシンキで開催されたCumulus4)大会およびフランスのサンテティエンヌ5)で開催されたデザインビエンナーレへの参加を通して、環境デザインを取り巻く世界の動向を把握した。さらに、ランドスケープの教育機関として著名なフランスのENSP6)を訪問して情報交換を行い、今後の連携の可能性に関して検討を行った。In this paper, the possibilities of international education programs in the field of environmental design are investigated. We particularly focus on the intensive international workshop programs.So far Kobe Design University participated in two international workshops named WAT, organized by CUPEUM (Chaire UNESCO en paysage et environnement de l\u27université de Montréal). Through these experiences, we have reviewed the educational significances of the workshops as well as technical matters for administration.In 2012, we participated in another workshop Landworks Sardinia in Italy. Through comparison, we further examined the possibilities of design topics, organization, and administration of the international workshops.We also participated in the Cumulus conference in Helsinki in Finland and the Saint-Étienne Design Biennale in France in order to grasp the global situation of environmental design. On the visit to ENSP, a well-known school of landscape architecture in France, several possibilities for international cooperation in the future were also discussed

環境デザインの国際ワークショップ開催に向けた坂出市に関する基礎調査

本研究では、近年中の実施を予定している環境デザインの国際ワークショップの準備を兼ねて、その開催候補地である坂出市の将来構想の策定とまちづくり戦略の立案に役立てるための基礎調査を行う。　古くから瀬戸内海の海上交通の要所として、また、瀬戸大橋開通後は、陸上交通における四国の玄関口として発展してきた坂出市であるが、人口減少時代を迎えて社会構造と産業構造が大きく転換しつつある今、市内では様々な問題が各所で顕在化している。その一方、島嶼部や山域部の美しい自然、平野部に広がる農地、市街地内の歴史文化資源等については、それらの価値や潜在力が、これまで十分に活用されてきたとは言い難い。　今回の調査においては、最初に地域の特色を広域的な観点から把握し、地勢的な特質から坂出市域を4つのゾーン（抱護ゾーン、中核ゾーン、臨海ゾーン、島嶼ゾーン）に区分した。その上で、現地調査および関係者へのヒアリングを通して、ゾーンごとの様々な課題ならびに多様な地域資源の分布に関する把握整理を行った。　結果として、場所ごとの多くの課題と今後の利活用がのぞまれる豊富な地域資源の存在が明らかになった。今後、新しい時代の戦略的なまちづくりの方策づくりに向けて、これらの成果を生かしていきたい。This research aims to acquire and sort out basic information about the city of Sakaide, as a preparatory work for an international workshop of environmental design which is to be held in the following years. The city of Sakaide has been developed since ancient times as a strategic place of sea traffic being located at the middle of Seto Inland Sea. The importance of the city further augmented when the construction of the Seto Ohashi Bridge was completed in 1988. However, now in the age of depopulation, with the drastic change of social and industrial conditions, many problems have emerged in different areas in the city. In this research, the city area is divided into four zones according to the geographical features, namely enclosure zone, central zone, waterfront zone, and island zone. Various problems and local resources are recognized through field survey and interviews. The result of this research will be applied not only to the following workshop but also to draw up a strategic city vision of Sakaide in the new age

Enhanced antitumor efficacy of fiber‐modified, midkine promoter‐regulated oncolytic adenovirus in human malignant mesothelioma

Oncolytic virotherapy using adenoviruses has potential for therapeutic benefits in malignant mesothelioma. However, the downregulation of coxsackie virus/adenovirus receptor (CAR) expression is frequently a critical rate-limiting factor that impedes the effectiveness of adenovirus serotype 5 (Ad5)-based vectors in many cancer types. We evaluated CAR (Ad5 receptor) and CD46 (adenovirus serotype 35 [Ad35] receptor) expression in six human malignant mesothelioma cell lines. Very low CAR expression was observed in MSTO-211H and NCI-H2052 cells, whereas the other cell lines showed strong expression. In contrast, CD46 was highly expressed in all mesothelioma cell lines. On this basis, we replaced the CAR binding sequence of Ad5 with the CD46 binding sequence of Ad35 in the replication-defective adenoviruses and the tumor-specific midkine promoter-regulated oncolytic adenoviruses. By this fiber modification, the infectivity, virus progeny production, and in vitro cytocidal effects of the adenoviruses were significantly enhanced in low CAR-expressing MSTO-211H and NCI-H2052 cells, also resulting in similar or even higher levels in high CAR-expressing mesothelioma cell lines. In MSTO-211H xenograft models, the fiber-modified oncolytic adenovirus significantly enhanced antitumor effect compared to its equivalent Ad5-based vector. Our data demonstrate that Ad35 fiber modification of binding tropism in a midkine promoter-regulated oncolytic Ad5 vector confers transductional targeting to oncolytic adenoviruses, thereby facilitating more effective treatment of malignant mesothelioma

Enhanced antitumor efficacy of fiber-modified, midkine promoter-regulated oncolytic adenovirus in human malignant mesothelioma

Oncolytic virotherapy using adenoviruses has potential for therapeutic benefits in malignant mesothelioma. However, the downregulation of coxsackie virus/adenovirus receptor (CAR) expression is frequently a critical rate-limiting factor that impedes the effectiveness of adenovirus serotype 5 (Ad5)-based vectors in many cancer types. We evaluated CAR (Ad5 receptor) and CD46 (adenovirus serotype 35 [Ad35] receptor) expression in six human malignant mesothelioma cell lines. Very low CAR expression was observed in MSTO-211H and NCI-H2052 cells, whereas the other cell lines showed strong expression. In contrast, CD46 was highly expressed in all mesothelioma cell lines. On this basis, we replaced the CAR binding sequence of Ad5 with the CD46 binding sequence of Ad35 in the replication-defective adenoviruses and the tumor-specific midkine promoter-regulated oncolytic adenoviruses. By this fiber modification, the infectivity, virus progeny production, and in vitro cytocidal effects of the adenoviruses were significantly enhanced in low CAR-expressing MSTO-211H and NCI-H2052 cells, also resulting in similar or even higher levels in high CAR-expressing mesothelioma cell lines. In MSTO-211H xenograft models, the fiber-modified oncolytic adenovirus significantly enhanced antitumor effect compared to its equivalent Ad5-based vector. Our data demonstrate that Ad35 fiber modification of binding tropism in a midkine promoter-regulated oncolytic Ad5 vector confers transductional targeting to oncolytic adenoviruses, thereby facilitating more effective treatment of malignant mesothelioma

The Progression of Severe Aplastic Anemia to Hypoplastic Leukemia in a Long-Term Observation after the Administration of Pegylated rHuMGDF

Thrombopoietin (TPO) is a critical regulator of hematopoiesis. We previously reported that a severe aplastic anemia (SAA) who received a short-term administration of pegylated recombinant human megakaryocyte growth and development factor (rHuMGDF). A trilineage hematologic response was induced, however the patient was diagnosed with leukemia after nine years and eight months from administration of rHuMGDF. In recent reports, somatic mutations in myeloid cancer candidate genes were present in one-third of the AA. A mutant clone may be expanded by rHuMGDF in our patient. The long-term safety of patients treated with TPO and eltrombopag remains unknown. Careful observations are warranted hereafter