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Pradimicin A (PRM-A) and its derivatives comprise a unique family of antibiotics that show antifungal, antiviral, and antiparasitic activities through binding to d-mannose (Man)-containing glycans of pathogenic species. Despite their great potential as drug leads with an exceptional antipathogenic action, therapeutic application of PRMs has been severely limited by their tendency to form water-insoluble aggregates. Recently, we found that attachment of 2-aminoethanol to the carboxy group of PRM-A via amide linkage significantly suppressed the aggregation. Here, we prepared additional amide derivatives (2–8) of PRM-A to examine the possibility that the amide formation of PRM-A could suppress its aggregation propensity. Sedimentation assay and isothermal titration calorimetry experiment confirmed that all amide derivatives can bind Man without significant aggregation. Among them, hydroxamic acid derivative (4) showed the most potent Man-binding activity, which was suggested to be derived from the anion formation of the hydroxamic acid moiety by molecular modeling. Derivative 4 also exhibited significant antifungal activity comparable to that of PRM-A. These results collectively indicate that amide formation of PRM-A is the promising strategy to develop less aggregative derivatives, and 4 could serve as a lead compound for exploring the therapeutic application of PRM-A.

Pradimicin A (PRM-A) is an actinomycete-derived antibiotic that shows antifungal activity through binding to d-mannose (Man)-containing glycans of fungi. Despite its unique mode of antifungal action, therapeutic application of PRM-A has been severely limited by the aggregate-forming property. In this study, we demonstrated that C4′-N-formyl PRM-A and the dexylosylated derivative of C4′-N-acetyl PRM-A showed significant Man-binding and antifungal activities without any aggregation or precipitation. The presented results provide a promising modification strategy for exploring the therapeutic application of PRM-A.

Pradimicin A (PRM-A) and related compounds constitute an exceptional family of natural pigments that show Ca^2+-dependent recognition of d-mannose (Man). Although these compounds hold great promise as research tools in glycobiology, their practical application has been severely limited by their inherent tendency to form water-insoluble aggregates. Here, we demonstrate that the 2-hydroxyethylamide derivative (PRM-EA) of PRM-A shows little aggregation in neutral aqueous media and retains binding specificity for Man. We also show that PRM-EA stains glycoproteins in dot blot assays, whereas PRM-A fails to do so, owing to severe aggregation. Significantly, PRM-EA is sensitive to glycoproteins carrying high mannose-type and hybrid-type N-linked glycans, but not to those carrying complex-type N-linked glycans. Such staining selectivity has never been observed in conventional dyes, suggesting that PRM-EA could serve as a unique staining agent for the selective detection of glycoproteins with terminal Man residues.

Research team head, Research team member, Publisher, 多くの神経膠腫は未だに根治困難であり, さらなる分子分類と治療の最適化が必要である。我々は, 術前化学療法(neoadjuvant chemotherapy)戦略の神経膠腫における有用性を検討し, 1p/19q codelやMGMTメチル化 をもつ神経膠腫に対しては, 化学療法による腫瘍縮小後のsecond-look resectionにより予後が改善される可能性を示し, また術前画像所見の組み合わせから, 分子マーカーを予測するスコアシステムを開発した。さらに, ロゼット形成性グリア神経細胞腫瘍の遺伝学的背景及び1p/19q codel神経膠腫の予後や膠芽腫長期生存に関わる因子を明らかにした。 The majority of diffuse gliomas is not curable yet, and the development of the personalized treatments according to molecular characteristics is indispensable. The main aims of this study were to establish the personalized therapies and to explore the utility of the neoadjuvant chemotherapy for chemo-sensitive gliomas. The prospective study for the diffuse gliomas with 1p/19q codeletion or MGMT promoter methylation suggested that upfront chemotherapy and subsequent resection for initial incomplete resections might be superior to chemotherapy and observation strategy. To preoperatively design the neoadjuvant strategy, we established the scoring systems to predict 1p/19q codeletion and MGMT methylation based on imaging features. Moreover, we have elucidated the molecular background of the rosette-forming glioneuronal tumor, molecular-pathological prognostic factors in 1p/19q-codeleted gliomas, and the factors favorably associated with long-term survival in glioblastoma patients., 研究種目 : 基盤研究(C)(一般) 研究期間 : 2015～2017 課題番号 : 15K10343 研究分野 : 脳腫瘍

In recent years, the success of Japanese firms in the global market has prompted efforts to understand the sources of their competitive advantage. It has been suggested that one such source is the Japanese firms' management accounting systems, and a number of articles have claimed that important differences do exist between U.S. and Japanese firms in this area. However, the claims have tended to be supported by anecdotal rather than systematic, evidence. The objective of this article is to contribute further insights into similarities and differences between U.S. and Japanese firms' management accounting practice. Exhaustive search of published surveys in the U.S. and Japanese literatures (much of which is in Japanese) provided the basis for U.S. - Japan comparisons on six aspects of management accounting practices. In turn, these comparisons were used for deriving implications for future research. Two major limitations of extant research and, thus, directions for future research are identified. First, future research needs to go beyond the simple use or non-use of techniques to investigate more detailed aspects of technique use. Second, since management accounting is only one component of a firm's total management system, attention also needs to be devoted to the organization's context, process, and goals of a firm's management accoutning practices.