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Nishijima, Yoshinori ; 西嶋, 義憲
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金沢大学人間社会研究域経済学経営学系<br />Persons or objects on signs seem to have a culturally preferred direction of facing (Kumakura, 1
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990). Is such a difference in direction also true of pictures on traffic signs between Japan and Germany? People in Japan and Germany drive on the left and the right side of the road, respectively. In this respect, a question arises: Does the difference between left-hand and right-hand traffic in these two countries influence the way the pictures on traffic signs face? The aim of this study is threefold: 1) to collect functionally equivalent traffic signs in Japan and Germany; 2) to compare the pictures on the signs between these countries with respect to their facing directions; and 3) to try to clarify whether and to what extent differences in facing directions are found on the traffic signs. The results are expected to contribute to the study of the relationship between writing directions and facing directions of pictures.
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Nishijima, Yoshinori ; 西嶋, 義憲
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金沢大学人間社会研究域経済学経営学系<br />This study focuses on functionally equivalent, but semantically different sign expressions in Ja
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panese and German, such as o-nori-no-sai-wa tesuri-ni o-tsukamarikudasai [Literally, “when steping on, please grip handrail”], kiiroi-sen-no uchigawani o-tachi-kudasai [please stand inside yellow line], oriru sai-wa o-oashimoto-ni gochūi-kudasai [“when getting off, please pay attention to under foot”], and o-ko-sama tsure-no kata-wa o-ko-sama-no te-o totte o-nori-kudasai [“person with child is asked to ride on taking child’s hand”] in Japanese versus its German counterpart Benutzung auf eigene Gefahr [“using at your own risk”], which are posted near escalators. This example tells us that the Japanese sign consists of four concrete sentences whereas the German one presents a simple and abstract sentence. Such correspondents cannot be adequately explained from only construal and politeness perspectives. In this study, such corresponding expressions in Japanese and German will be contrasted to find out what information is relevant to each society. The results will reveal what communicative behaviors are expected in corresponding situations between Japan and Germany, which can contribute to efficient intercultural communication.
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Nishijima, Yoshinori ; 西嶋, 義憲
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金沢大学人間社会研究域経済学経営学系<br />By comparing some functionally equivalent routine formulas in Japaneseand German in correspondin
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g situations, it is hypothesized that different strategies arereflected in formulation patterns of routine formulas in both languages. For example,different expressions are used by parents in Japanese and German if their childbumps into a post. The two expressions are often used in corresponding situations inboth Japan and Germany and can therefore be regarded as functionally equivalent,although the used strategies differ, i.e., the Japanese expression is based on sharing thedangerous situation between the parent and the child, whereas the German one focuseson providing an appropriate direction to the child. Comparing such functionallyequivalent routine formulas suggests that they reflect different strategies, includingpoliteness, in corresponding situations. This study tested this hypothesis by comparingfunctionally equivalent routine formulas uttered in corresponding apologetic situationsin the socialization process of controlling children’s social behavior in Japan andGermany. The results confirm the hypothesis and suggest that the difference in strategy influences the communicative behaviors of Japanese and German speakers. Concerning politeness, the results reveal the aspects considered polite in corresponding routineformulas of the two languages. Furthermore, the communicative normality of each language is also reflected in its respective routine formulas and focus of attention in interactions. This information may be applied toward more efficient foreign language teaching.
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Nishijima, Yoshinori ; 西嶋, 義憲
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金沢大学人間社会研究域経済学経営学系<br />The aim of this paper is twofold: (1) to compare functionally equivalent English, German, and Ja
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panese sign expressions in public spaces with respect to politeness and (2) to reveal whether and how politeness is formulated in sign expressions in each language in relation to explicitness. A total of 208 Japanese and 198 German sign expressions were collected through fieldwork. Among them, 35 functionally equivalent correspondence pairs between the two languages were confirmed, and they were compared, along with their English equivalents, with respect to politeness. The results showed that English signs tend to use explicit expressions, whereas Japanese signs frequently contain honorific items, and German signs use infinitive phrases to avoid mentioning personal relationships. Based on these findings, it is pointed out that each language has its preferred styles of politeness, even for sign expressions, which are expected to give relevant information or instructions to passengers in a clear, direct manner.
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Nishijima, Yoshinori ; 西嶋, 義憲
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金沢大学人間社会研究域経済学経営学系<br />Interest in the linguistic study of perspectives from which linguistic expressions are formulate
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d has been revived in the past 20 years, due to the recent development of cognitive linguistics. Among the many contributions to the study of such perspectives, Ikegami (2000) clearly showed that Japanese differs from English, through a comparison of a Japanese literary text with its English translation. However, there has been little discussion on the methods employed for comparison in the studies on this topic. The purpose of the present paper is threefold: (1) to describe what methodological problems are recognized in previous contrastive studies on the perspectives, especially in the field of cognitive linguistics; (2) in order to avoid methodological problems, to propose an alternative method for a more objective comparison of the perspectives between two languages; and (3) to demonstrate the validity of the proposed method for contrasting formulation patterns in terms of their perspective by some of the data obtained.
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Nishijima, Yoshinori ; 西嶋, 義憲
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金沢大学人間社会研究域経済学経営学系<br />The present paper discusses the different perspectives from which Japanese and German speakers f
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ormulate utterances. It was hypothesized that these different perspectives are reflected not only in evaluating concepts of communicative behavior, but also in routine formulas for controlling communicative behavior in Japanese and German. This hypothesis was examined by comparing two pairs of functionally equivalent routine formulas in Japanese and German. Furthermore, a questionnaire was administered to compare other Japanese and German routine formulas possibly used in corresponding situations. The results confirmed that in Japanese, linguistic formulation patterns relate to the empathy felt by the speaker toward an interlocutor, arising from the perspective of their situation, whereas in German, these tend to depend on an opposition between the participants involved, characterized by a perspective external to their situation. Because the data employed in the present study are limited, the hypothesis should be verified using extensive data. The results of this study helps clarify the possible misunderstandings between Japanese and German speakers, owing to the different linguistic formulation patterns employed, and could promote more efficient foreign language teaching.
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Nishijima, Yoshinori ; 西嶋, 義憲
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金沢大学人間社会研究域経済学経営学系<br />Research on the perspectives from which linguistic expressions are formulated has increased in t
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he past 20 years due to the development of cognitive linguistics. For example, Ikegami (2000) showed that Japanese and English speakers employ different perspectives by comparing the opening sentence of a Japanese literary text with its English translation. Similarly, Narita (2009) compared sentences from literary texts with their translations in Japanese and German. However, these studies analyzing literary text translations contain little discussion on the validity of the translation-based comparison method, particularly in terms of comparability and objectivity. This paper has three purposes: (1) to claim that the original and translation-based methods are not always appropriate for perspective studies; (2) to propose, as an alternative method, comparing functionally equivalent formulas used on public signs, i.e., Watch your step, Keep out, and Out of Service; and (3) to show how Japanese differs from German in the perspectives from which corresponding expressions in the two languages are formulated. Expressions were collected from signs on buses, trains, and railway stations in Japan and Germany. Examples include Haire-masen/Kein Eingang (‘No entrance’), Senro-ni orite-wa ike-masen/Ausstieg verboten (‘Do not go down to the railway track’), and ishitsubutsu-gakari/Fundbüro (‘Lost and found’). Functionally equivalent expressions were selected for the analysis. For example, a formula telling bus passengers that the bus will stop at the next station is Tsugi tomari-masu (next.TOP stop.HON) in Japanese and Wagen hält (vehicle.NOM stop.PRES) in German. These corresponding expressions can be compared syntactically and semantically. The former has no surface-level subject; it conveys that “I” and “we” or the bus will stop at the next station. The scene is described from the perspective inside the situation, i.e., from within the bus. The latter has a third-person subject, Wagen, signifying that the bus is observed from the perspective outside the situation. These different perspectives and their occurrence distributions are shown through the comparison of corresponding sign expressions. The analysis reveals that Japanese tends to formulate expressions from a perspective inside the scene where the event occurs, whereas German expresses sentences from the perspective outside the scene.<br />19th International Congress of Linguists(19 ICL), 21-27 July 2013 Geneva
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Mukaida, Naofumi ; Nakamoto, Yasunari ; 向田, 直史 ; 中本, 安成
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金沢大学がん進展制御研究所<br />Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen
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presenting cells (APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma (HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC. © The Author(s) 2018.<br />Supported by (in part) Research Programs on the Innovative Development and Application for New Drugs for Hepatitis B (No. 17fk0310116h0001) from the Japan Agency for Medical Research and Development (AMED) and Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University.
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Mukai, Kanae ; Komatsu, Emi ; Nakajima, Yukari ; Urai, Tamae ; Nasruddin ; Sugama, Junko ; Nakatani, Toshio ; 向井, 加奈恵 ; 中島, 由加里 ; 須釜, 淳子 ; 中谷, 壽男
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金沢大学医薬保健研究域保健学系<br />Cutaneous wound healing is delayed by protein malnutrition (PM). On the other hand, estrogen promot
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es cutaneous wound healing by its anti-inflammatory and cell proliferation effects. Therefore, we hypothesized that estrogen administration in protein-malnourished ovariectomized (OVX) female mice might improve the inflammatory response and promote cutaneous wound healing as well as normal nutrition. To test this hypothesis, we used full-thickness excisional wounds in Control SHAM, PM SHAM, PM OVX and PM OVX+17β-estradiol mice. The Control diet included 200 g/kg protein and the PM diet included 30 g/kg protein. The ratio of wound area in the Control SHAM group was significantly smaller than those in the three PM groups. In addition, microscopic findings also showed that the ratio of collagen fibers, the ratio of myofibroblasts and the number of new blood vessels in the Control SHAM group were significantly greater than those in the three PM groups. However, the number of Ym1-positive cells as an anti-inflammatory M2-like macrophage marker in the PM OVX+17β-estradiol group was significantly higher than those in the other three groups. These results indicate that the appearance of anti-inflammatory M2-like macrophages was promoted by estrogen administration; however, it could not promote cutaneous wound healing upon a low-protein diet. Therefore, it may be confirmed that nutrition is more important for promoting cutaneous wound healing than estrogen administration.
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Ikeya, Noriyuki ; Tanaka, Gengo ; Tsukagoshi, Akira ; 田中, 源吾
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金沢大学国際基幹教育院GS教育系
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Tanaka, Gengo ; Ikeya, Noriyuki ; 田中, 源吾
概要:
金沢大学国際基幹教育院GS教育系<br />Eighty-five fossil and Recent species of the genus Loxoconcha (Crustacea : Ostracoda) from East As
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ia are systematically reexamined. On the basis of carapace morphology, the genus Loxoconcha from East Asia is divided into five species groups : L. pulchra, L. optima, L. japonica, L. uranouchiensis and L. japonica species groups. The migration and speciation patterns of four species of the L. japonica species group are as follows. In Late Miocene, L. lilljeborgii and L. tumulosa were distributed over the Paleo-Indian Ocean. In Early Pliocene time, these species migrated to the Western Pacific and L. japonica evolved from populations of L. tumulosa by peramorphic evolution. In the Middle Pleistocene, L. shanhaiensis evolved from populations of L. japonica in the Ryukyu Islands by paedomorphic evolution.
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Tanaka, Gengo ; Seto, Koji ; Mukuda, Takao ; Nakano, Yusuke ; 田中, 源吾
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金沢大学国際基幹教育院GS教育系<br />Thirty-five ostracod species belonging to 18 genera are recognized from the Middle Miocene Fujina
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Formation (ca. 14-12 Ma), 3km southwest of Matsue City, Shimane Prefecture, Japan. Most of these species are part of the recent Japan Sea proper water fauna; they are also classified into 4 categories, circumpolar, cryophilic, endemic cool-temperate and temperate species. These ostracod assemblages indicate that the Fujina Formation was deposited under a cold-water environment. Ten new species, Ambtonia shimanensis, A. takayasui, Acanthocythereis fujinaensis, A. izumoensis, Cluthia tamayuensis, C. subjaponica, Kotoracythere tsukagoshii, Laperousecythere ikeyai, Palmoconcha irizukii, and Robertsonites yatsukanus are described.
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Tanaka, Gengo ; 田中, 源吾
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金沢大学国際基幹教育院GS教育系<br />島根県,出雲市菅沢の大森層より26属42種の介形虫化石を抽出し,2つの介形虫群(Ambostracon-Argilloecia-Cytheropteron群集およびPaijenborchella-
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Palmoconcha-Urocythereis pohangensis群集)を認めた.これらの群集は冷温〜温暖な公海の下浅海環境を示唆する.大森層および布志名層からの介形虫化石群の主成分分析は,その堆積環境が上部層準に向かってしだいに深くなっていったことを示唆する.5新種(Cytheropteron shimanense, Loxoconcha izumoensis, Paradoxostoma yakumotatsunus, Schizocythere sakanoueiおよびUrocythereis sugesawensis)を記載した.<br />Ostracods from the Omori Formation in Sugesawa (Izumo City, Shimane Prefecture) comprise 42 species belonging to 26 genera. Five new species, Cytheropteron shimanense, Loxoconcha izumoensis, Paradoxostoma yakumotatsunus, Schizocythere sakanouei and Urocythereis sugesawensis are described. Two ostracod assemblages (Ambostracon-Argilloecia-Cytheropteron assemblage and Paijenborchella-Palmoconcha-Urocythereis pohangensis assemblage) are recognized. These assemblages indicate that the uppermost of the Omori Formation was deposited under the environments from cool to warm open sublittoral condition. Principal components analysis of ostracod assemblages from the Omori and Fujina Formations indicates that, in general, the depositional environment becomes deeper and deeper towards the upper horizon.
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Tanaka, Gengo ; Nakase, Hajime ; Yamashita, Shota ; Arai, Kazuno ; 田中, 源吾
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金沢大学国際基幹教育院GS教育系<br />In Rikuzentakata City, Ostracode assemblages in sediment deposited by the Tohoku‐Oki earthquake an
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d tsunami of 11 March 2011 revealed that the sediment was derived from the seafloor from at least 9 m water depth, and was transported inland more than 1 km. The tsunami wave height at this location was higher than 10 m. Four hundred fifty seven modern ostracode assemblages were used in the modern analogue technique to estimate the depth source of the tsunami deposited assemblages. The application of this method to paleo‐tsunami deposits may provide insight into past tsunami wave height and potentially earthquake slip and magnitude.<br />Embargo Period 6 months
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Tanaka, Gengo ; 田中, 源吾
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Sanyuania cuneata Zhao & Whatley, 1992 was reported initially from Late Pleistocene core samples from the northern part
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of the Yellow Sea and Recent sediments collected from supra tidal pools (17 practical salinity unit (psu)) in Xiangshangang Bay, East China Sea (Zhao & Whatley, 1992). Later, specimens were discovered, but not identified, in Lake Nakaumi, Shimane Prefecture, SW Japan (Fig. 1) (as Cytheridae gen. et. sp. indet. by Tanaka et al. (1998) and Sanyuania sp. by Seto et al. (1999)). Further examination of these Japanese specimens has clarified that they are conspecific with the Chinese specimens. This has provided an opportunity to review the distribution (Fig. 1) and potential environmental significance of Sanyuania cuneata and, for the first time, to describe its appendages (Fig. 2).Specimens figured herein were recovered from Lake Nakaumi (35°26′ 50″ N, 133°07′50″ E) at a depth of 0.3–6.0 m and salinity of 8–17 psu on 9 September 1998. The surface of the sediment was covered by the byssus of the mussel Musculista senhousia (Benson, 1842).Sanyuania cuneata is probably endemic to the East China Sea and the southwestern part of the Sea of Japan and is a potentially useful palaeoenvironmental indicator of brackish (steno-haline) environments in the area. By using the oxygen isotopic data from planktonic foraminifers and the estimated value of salinity flowing into the Japan Sea, Matsui et al. (1998) approximated that the salinity of the surface water of Japan Sea declined to about 20 psu during the Last Glacial Maximum . . .
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Tanaka, Gengo ; Parker, Andrew R. ; Hasegawa, Yoshikazu ; Siveter, David J. ; Yamamoto, Ryoichi ; Miyashita, Kiyoshi ; Takahashi, Yuichi ; Ito, Shosuke ; Wakamatsu, Kazumasa ; Mukuda, Takao ; Matsuura, Marie ; Tomikawa, Ko ; Furutani, Masumi ; Suzuki , Kayo ; Maeda, Haruyoshi ; 田中, 源吾
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金沢大学国際基幹教育院GS教育系<br />Vision, which consists of an optical system, receptors and image-processing capacity, has existed
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for at least 520 Myr. Except for the optical system, as in the calcified lenses of trilobite and ostracod arthropods, other parts of the visual system are not usually preserved in the fossil record, because the soft tissue of the eye and the brain decay rapidly after death, such as within 64 days and 11 days, respectively. The Upper Carboniferous Hamilton Formation (300 Myr) in Kansas, USA, yields exceptionally well-preserved animal fossils in an estuarine depositional setting. Here we show that the original colour, shape and putative presence of eumelanin have been preserved in the acanthodii fish Acanthodes bridgei. We also report on the tissues of its eye, which provides the first record of mineralized rods and cones in a fossil and indicates that this 300 Myr-old fish likely possessed colour vision.<br />This work was supported by the Science Research of Education and Science Government of Japan (grant no. 24540501 to G.T. and no. 24340129 to H.M.).
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Tanaka, Gengo ; Smith, Robin J. ; Siveter, David J. ; Parker, Andrew R. ; 田中, 源吾
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金沢大学国際基幹教育院GS教育系<br />Compound eyes are common in decapod crustaceans. Decapods have an abundant post-Palaeozoic fossil
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record, but hitherto morphological information about their eyes has been mainly restricted to Recent material. Here we report the discovery of compound eyes recovered from acetic acid residues of two fish-bearing nodules from the Cretaceous Santana Formation of Brazil; they include what are identified as decapod larval compound eyes. The fossil eyes are comparable to phyllosoma larval eyes because of the following characters: the hemispherical visual surface on a stalked eye; the relatively small-size of the visual surface of the eye; rounded facets are arranged in square arrays in the anterior region; the fact that the neighboring ommatidia are bounded by ridges and/ or grooves; and the more convex inner surface of the cornea lens. This report represents the first description of a three-dimensionally preserved fossil decapod eye. We conclude that the eyes probably represent palinuroid phyllosoma larval eyes and were an adaptation to a planktonic lifestyle. © 2009 Zoological Society of Japan.
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Kobayashi, Mio ; Kakuda, Yuko ; Harada, Kenichi ; Sato, Yasunori ; Sasaki, Motoko ; Ikeda, Hiroko ; Terada, Mitsuhiro ; Mukai, Munenori ; Kaneko, Shuichi ; Nakanuma, Yasuni ; 小林, 水緒 ; 原田, 憲一 ; 佐藤, 保則 ; 佐々木, 素子 ; 池田, 博子 ; 金子, 周一 ; 中沼, 安二
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金沢大学医薬保健研究域医学系<br />AIM: To investigate histological and immunohistochemical differences in hepatitis between autoimmune
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hepatitis (AIH) and primary biliary cirrhosis (PBC) with AIH features. METHODS: Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were examined. The activity of periportal and lobular inflammation was scored 0 (none or minimal activity) to 4 (severe), and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored 0-3. The infiltration of mononuclear cells positive for CD20, CD38, CD3, CD4, and CD8 and positive for immunoglobulins (IgG, IgM, and IgA) at the periportal areas (interface hepatitis) and in the hepatic lobules (lobular hepatitis) were semiquantitatively scored in immunostained liver sections (score 0-6). Serum aspartate aminotransferase (AST), immunoglobulins, and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual lesions. RESULTS: Lobular hepatitis, hepatitic rosette formation, and emperipolesis were more extensive and frequent in AIH than in PBC. CD3+, CD4+, and CD8+ cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in PBC. The degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC, but to a lesser degree in AIH. CD20+ cells were mainly found in the portal tracts and, occasionally, at the interface in both diseases. Elevated AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration, specifically CD38+ cells in PBC. No correlation existed between autoantibodies and inflammatory cell infiltration in PBC or AIH. While most AIH cases were IgG-predominant at the interface, PBC cases were divided into IgM-predominant, IgM/IgGequal, and IgG-predominant types, with the latter sharing several features with AIH. CONCLUSION: These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
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Okazaki, Mitsuyoshi ; Makino, Isamu ; Kitagawa, Hirohisa ; Nakanuma, Shinichi ; Hayashi, Hironori ; Nakagawara, Hisatoshi ; Miyashita, Tomoharu ; Tajima, Hidehiro ; Takamura, Hiroyuki ; Ohta, Tetsuo ; 岡崎, 充善 ; 牧野, 勇 ; 北川, 裕久 ; 中沼, 伸一 ; 林, 泰寛 ; 中川原, 寿俊 ; 宮下, 知治 ; 田島, 秀浩 ; 高村, 博之 ; 太田, 哲生
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金沢大学医薬保健研究域医学系<br />We herein report a case of anaplastic carcinoma of the pancreas with remarkable intraductal tumor gr
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owth into the main pancreatic duct. A 76-year-old male was referred to our hospital for treatment of a pancreatic tumor. Preoperative examinations revealed a poorly defined tumor in the main pancreatic duct in the body of the pancreas, accompanied with severe dilatation of the main pancreatic duct, which was diagnosed as an intraductal papillary-mucinous neoplasm. We performed distal pancreatectomy and splenectomy. The pathological examination revealed that the tumor consisted of a mixture of anaplastic carcinoma (giant cell type) and adenocarcinoma in the pancreas. There was a papillary projecting tumor composed of anaplastic carcinoma in the dilated main pancreatic duct. The patient is now receiving chemotherapy because liver metastasis was detected 12 mo after surgery. In this case, we could observe a remarkable intraductal tumor growth into the main pancreatic duct. We also discuss the pathogenesis and characteristics of this rare tumor with specific tumor growth. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
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Sato, Hirohide ; Sato, Yasunori ; Harada, Kenichi ; Sasaki, Motoko ; Hirano, Katsuyasu ; Nakanuma, Yasuni ; 佐藤, 保則 ; 原田, 憲一 ; 佐々木, 素子 ; 中沼, 安二
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金沢大学医薬保健研究域医学系<br />A 77-year-old woman complained of epigastralgia, and a tumor (5 cm in diameter) of the gallbladder n
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eck was detected by image analysis. Following cholecystectomy, the tumor was pathologically diagnosed as intraductal papillary neoplasm (IPN), gastric type, with associated invasive carcinoma. About 10 mo later, intraluminal multiple masses (3 foci, up to 1.8 cm) were noted in the extrahepatic bile duct, and the resected specimen showed that all tumors had similar gross and microscopic features as seen in gallbladder IPN without invasion, and they were synchronous multiple lesions. This case showed a papillary tumor of the gallbladder of gastric phenotype, and confirmed that the gallbladder is a target of IPN in addition to the bile ducts. © 2013 Baishideng. All rights reserved.
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Onishi, Ichiro ; Kitagawa, Hirohisa ; Harada, Kenichi ; Maruzen, Syogo ; Sakai, Seisyo ; Makino, Isamu ; Hayashi, Hironori ; Nakagawara, Hisatoshi ; Tajima, Hidehiro ; Takamura, Hiroyuki ; Fujimura, Takashi ; Kayahara, Masato ; Ikeda, Hiroko ; Ohta, Tetsuo ; Nakanuma, Yasuni ; 北川, 裕久 ; 原田, 憲一 ; 牧野, 勇 ; 林, 泰寛 ; 中川原, 寿俊 ; 田島, 秀浩 ; 高村, 博之 ; 藤村, 隆 ; 萱原, 正都 ; 池田, 博子 ; 太田, 哲生 ; 中沼, 安二
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金沢大学医薬保健研究域医学系<br />We present the first case of an intraductal papillary neoplasm of the bile duct (IPNB) accompanying
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a mixed adenoneuroendocrine carcinoma (MANEC). A 74-yearold woman presented with fever of unknown cause. Laboratory data revealed jaundice and liver injury. Contrast-enhanced computed tomography revealed a 20 mm polypoid tumor in the dilated distal bile duct, which exhibited early enhancement and papillary growth. Upper gastrointestinal endoscopy revealed mucus production from the papilla of Vater, characterized by its protruding and dilated orifice. Endoscopic ultrasonography visualized the polypoid tumor in the distal bile duct, but no invasive region was suggested by diagnostic imaging. Therefore, the initial diagnosis was IPNB. After endoscopic nasobiliary drainage, a pylorus-preserving pancreaticoduodenectomy was performed. Pathological examination of the resected bile duct revealed papillary proliferation of biliary-type cells with nuclear atypia, indicating pancreaticobiliary-type IPNB. In addition, solid portions comprised of tumor cells with characteristic salt-and-pepper nuclei were evident. Immunohistochemistry revealed expression of the neuroendocrine marker synaptophysin in this solid component, diagnosing it as a neuroendocrine tumor (NET). Furthermore, the MIB-1 proliferation index of NET was higher than that of IPNB, and microinvasion of the NET component was found, indicating neuroendocrine carcinoma (NET G3). This unique case of MANEC, comprising IPNB and NET, provides insight into the pathogenesis of biliary NET. © 2013 Baishideng. All rights reserved.
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| 22.
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Hattori, Yuki ; Gabata, Toshifumi ; Matsui, Osamu ; Mochizuki, Kentaro ; Kitagawa, Hirohisa ; Kayahara, Masato ; Ohta, Tetsuo ; Nakanuma, Yasuni ; 蒲田, 敏文 ; 松井, 修 ; 北川, 裕久 ; 萱原, 正都 ; 太田, 哲生 ; 中沼, 安二
概要:
金沢大学医薬保健研究域医学系<br />Aim: To evaluate retrospectively the correlation between enhancement patterns on dynamic computed to
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mography (CT) and angiogenesis and fibrosis in pancreatic adenocarcinoma. Methods: Twenty-three patients with pancreatic adenocarcinoma underwent dynamic CT and tumor resection. In addition to the absolute and relative enhanced value that was calculated by subtracting the attenuation value on pre-contrast from those on contrast-enhanced CT in each phase, we defined one parameter, "tumor-aorta enhancement ratio", which was calculated by dividing enhancement of pancreatic cancer by enhancement of abdominal aorta in each phase. These enhancement patterns were correlated with the level of vascular endothelial growth factor (VEGF), microvessel density (MVD), and extent of fibrosis. Results: The absolute enhanced value in the arterial phase correlated with the level of VEGF and MVD (P = 0.047, P = 0.001). The relative enhanced value in arterial phase and tumor-aorta enhancement ratio (arterial) correlated with MVD (P = 0.003, P = 0.022). Tumor-aorta enhancement ratio (arterial) correlated negatively with the extent of fibrosis (P = 0.004). The tumors with greater MVD and higher expression of VEGF tended to show high enhancement in the arterial dominant phase. On the other hand, the tumors with a larger amount of fibrosis showed a negative correlation with the grade of enhancement during the arterial phase. Conclusion: Enhancement patterns on dynamic CT correlated with angiogenesis and may be modified by the extent of fibrosis. © 2009 The WJG Press and Baishideng. All rights reserved.
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| 23.
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Sasaki, Motoko ; Araki, Ichiro ; Yasui, Toshiaki ; Kinoshita, Masaru ; Itatsu, Keita ; Nojima, Takayuki ; Nakanuma, Yasuni ; 佐々木, 素子 ; 野島, 孝之 ; 中沼, 安二
概要:
金沢大学医薬保健研究域医学系<br />We report a case of primary localized malignant biphasic mesothelioma of the liver in a 66-year-old
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man associated with asbestosis. The tumor was detected as a hepatic nodule, 4 cm in diameter, in the right lobe (S8 segment) on CT scan. Histopathological examination demonstrated an intrahepatic tumor with central necrosis consisting of a papillary epithelioid pattern on the surface of the liver, microcystic (microglandular or adenomatoid) pattern mainly in the subcapsular area and sarcomatoid pattern intermingled with microcystic pattern in the major part of the hepatic nodular tumor. Tumor cells, especially of epithelioid type, showed distinct immunoreactivity for mesothelial markers (WT-1, calretinin, D2-40, CK5/6, mesothelin, thrombomodulin) and no immunoreactivity for epithelial (adenocarcinoma) markers (CEA, CD15, BerEP4, BG8, MOC31). P53 immunoreactivity was detected focally in papillary epithelioid tumor cells and extensively in microcystic and sarcomatoid components, suggesting that the papillary epithelioid mesothelioma arose on the surface of the liver, and tumor cells showing microcystic and sarcomatoid patterns invaded and grew into the liver. To date, this is the first case of primary localized malignant biphasic mesothelioma of the liver, since all three primary hepatic mesotheliomas reported so far were epithelioid type. © 2009 The WJG Press and Baishideng. All rights reserved.
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| 24.
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Yoshikawa, Seiichi ; Zen, Yoh ; Fujii, Takahiko ; Sato, Yasunori ; Ohta, Tetsuo ; Aoyagi, Yutaka ; Nakanuma, Yasuni ; 全, 陽 ; 佐藤, 保則 ; 太田, 哲生 ; 中沼, 安二
概要:
金沢大学医薬保健研究域医学系<br />AIM: To reveal the characteristics of CD133+ cells in the liver. METHODS: This study examined the hi
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stological characteristics of CD133 + cells in non-neoplastic and neoplastic liver tissues by immunostaining, and also analyzed the biological characteristics of CD133 + cells derived from human hepatocellular carcinoma (HCC) or cholangiocarcinoma cell lines. RESULTS: Immunostaining revealed constant expression of CD133 in non-neoplastic and neoplastic biliary epithelium, and these cells had the immunophenotype CD133+/CK19+/HepPar -1-. A smal l number of CD133+/CK19-/HepPar-1+ cells were also identified in HCC and combined hepatocellular and cholangiocarcinoma. In addition, small ductal structures, resembling the canal of Hering, partly surrounded by hepatocytes were positive for CD133. CD133 expression was observed in three HCC (HuH7, PLC5 and HepG2) and two cholangiocarcinoma cell lines (HuCCT1 and CCKS1). Fluorescence-activated cell sorting (FACS) revealed that CD133+ and CD133-cells derived from HuH7 and HuCCT1 cells similarly produced CD133+ and CD133- cells during subculture. To examine the relationship between CD133+ cells and the side population (SP) phenotype, FACS was performed using Hoechst 33342 and a monoclonal antibody against CD133. The ratios of CD133+/CD133-cells were almost identical in the SP and non-SP in HuH7. In addition, four different cellular populations (SP/CD133+, SP/CD133-, non-SP/CD133+, and non-SP/CD133-) could similarly produce CD133+ and CD133- cells during subculture. CONCLUSION: This study revealed that CD133 could be a biliary and progenitor cell marker in vivo. However, CD133 alone is not sufficient to detect tumor-initiating cells in cell lines. © 2009 The WJG Press and Baishideng. All rights reserved.
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| 25.
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Fujimura, Takashi ; Ohta, Tetsuo ; Oyama, Katsunobu ; Miyashita, Tomoharu ; Miwa, Koichi ; 藤村, 隆 ; 太田, 哲生 ; 尾山, 勝信 ; 宮下, 知治 ; 三輪, 晃一
概要:
金沢大学医薬保健研究域医学系<br />Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were developed as one of the anti-inflammatory
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drugs to avoid the various side effects of non-steroidal anti-inflammatory drugs (NSAIDs). However, coxibs also have an ability to inhibit tumor development of various kinds the same way that NSAIDs do. Many experimental studies using cell lines and animal models demonstrated an ability to prevent tumor proliferation of COX-2 inhibitors. After performing a randomized study for polyp chemoprevention study in patients with familial adenomatous polyposis (FAP), which showed that the treatment with celecoxib, one of the coxibs, significantly reduced the number of colorectal polyps in 2000, the U.S. Food and Drug Administration (FDA) immediately approved the clinical use of celecoxib for FAP patients. However, some coxibs were recently reported to increase the risk of serious cardiovascular events including heart attack and stroke. In this article we review a role of COX-2 in carcinogenesis of gastrointestinal tract, such as the esophagus, stomach and colorectum, and also analyze the prospect of coxibs for chemoprevention of gastrointestinal tract tumors. © 2006 The WJG Press. All rights reserved.
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| 26.
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Nakanuma, Shinichi ; Miyashita, Tomoharu ; Hayashi, Hironori ; Tajima, Hidehiro ; Takamura, Hiroyuki ; Makino, Isamu ; Oyama, Katsunobu ; Nakagawara, Hisatoshi ; Fushida, Sachio ; Ohta, Tetsuo ; 中沼, 伸一 ; 宮下, 知治 ; 高村, 博之 ; 林, 泰寛 ; 田島, 秀浩 ; 牧野, 勇 ; 尾山, 勝信 ; 中川原, 寿俊 ; 伏田, 幸夫 ; 太田, 哲生
概要:
金沢大学附属病院肝胆膵・移植外科<br />Objectives: Continuous thrombocytopenia after liver transplant is associated with a less favorable
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prognosis, but this pathogenesis remains unclear. We focused on the consumption of platelets in the allograft. We assessed platelet consumption in allografts, and evaluated the pathology of platelet aggregation in an allograft tissue and its involve-ment in clinical outcomes.Materials and Methods: We took biopsy specimens from 20 patients. To examine the localization of platelet aggregation, CD42b was assayed immuno-histochemically, and its level of expression correlated with clinical data and outcomes.Results: Platelet aggregation in zone 3 was 70%, compared with 30% in zone 1 and 50% in zone 2. Platelets were found mainly as extravasated platelet aggregates in local microenvironments. Patients were stratified according to the extent of extravasated platelet aggregates in zone 3 into extravasated platelet aggregate-negative and -positive groups. Graft weight/recipient body weight ratio with the extravasated platelet aggregate-positive group was significantly lower than that of the extravasated platelet aggregate-negative group. Platelet count after surgery was lower, while total bilirubin and prothrombin time/international normalized ratio were higher in the extravasated platelet aggregate-positive than they were in the extravasated platelet aggregate-negative group.Conclusions: Extravasated platelet aggregates in the zone 3 of allograft tissue cause the consumption of platelets and continuous thrombocytopenia after transplant, and may be the clinical marker for deterioration of graft function. Platelet activation and degranulation following the release by platelets of some negative regulators may be involved partially in liver damage.
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| 27.
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Nakanuma, Shinichi ; Takamura, Hiroyuki ; Shoji, Masatoshi ; Hayashi, Hironori ; Tajima, Hidehiro ; Nakagawara, Hisatoshi ; Miyashita, Tomoharu ; Kitagawa, Hirohisa ; Tani, Takashi ; Ohta, Tetsuo ; 中沼, 伸一 ; 高村, 博之 ; 林, 泰寛 ; 田島, 秀浩 ; 中川原, 寿俊 ; 宮下, 知治 ; 北川, 裕久 ; 太田, 哲生
概要:
金沢大学附属病院肝胆膵・移植外科<br />Liver transplant is a treatment for familial amyloid polyneuropathy. Few cases of ABO-incompatible
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living-donor liver transplant for familial amyloid polyneuropathy exist. The outcome of an ABO-incompatible living-donor liver transplant has improved recently, using local infusion therapy and rituximab prophylaxis. Here, we describe a successful ABO-incompatible living-donor liver transplant in a patient with familial amyloid polyneuropathy in whom disease progression ceased at 2 years’ follow-up. Additionally, no evidence of acute or chronic rejection, or adverse events of the immuno-suppressive therapy, was seen. As a postoperative complication, fatty changes in the grafted liver because of malnutrition or adverse events of corticosteroids were confirmed by a liver biopsy taken early after transplant. The main cause of malnutrition was considered to be gastrointestinal dysfunction caused by familial amyloid poly-neuropathy. Therefore, before deterioration of digestive function, liver transplants should be considered for familial amyloid polyneuropathy. This case suggests that an ABO-incompatible living-donor liver transplant may provide greater opportunities for familial amyloid polyneuropathy patients.
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| 28.
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Saito, Motonobu ; Goto, Akiteru ; Abe, Noriko ; Saito, Katsuharu ; Maeda, Daichi ; Ohtake, Tohru ; Murakami, Yoshinori ; Takenoshita, Seiichi ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Cell adhesion molecule (CADM) genes encode immunoglobulin superfamily molecules, which are involved
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in cell-cell adhesion in a number of human epithelia. Through the maintenance of epithelia, CADM genes protect against malignant conversion and metastasis. Whilst numerous in vitro studies have investigated the molecular characteristics of CADM1 and CADM4 and in vivo studies have investigated CADM1 and CADM4 expression in a number of tumor types, the roles of CADM1 and CADM4 have yet to be elucidated. Therefore, in the present study, CADM1 and CADM4 expression levels were evaluated using immunohistochemistry staining in 208 patients with breast cancer and compared with clinicopathological factors. CADM1 and CADM4 expression levels were negative in 160 (76.9%) and 166 (79.8%) of the 208 cases, respectively. The lack of expression in these cases was associated with advanced tumor stage, suggesting that inactivation of CADM1 and CADM4 promotes breast cancer development. The prognostic role of CADM1 and CADM4 in breast cancer was also evaluated and the expression of CADM1 and CADM4 were not associated with cancer-specific survival or overall survival rate in the cohort of patients in the present study. Whilst these results suggested that CADM1 and CADM4 possess tumor suppressive roles, further functional experiments are required to address the important mechanisms involving CADM1 and CADM4. © 2018, Spandidos Publications. All rights reserved.
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| 29.
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Ikeda, Yuji ; Oda, Katsutoshi ; Hiraike-Wada, Osamu ; Koso, Takahiro ; Miyasaka, Aki ; Kashiyama, Tomoko ; Tanikawa, Michihiro ; Sone, Kenbun ; Nagasaka, Kazunori ; Maeda, Daichi ; Kawana, Kei ; Nakagawa, Shunsuke ; Fukayama, Masashi ; Tetsu, Osamu ; Fujii, Tomoyuki ; Yano, Tetsu ; Kozuma, Shiro ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Cyclin D1 is an important regulator of cell cycle progression. Phosphorylation of cyclin D1 at Thr28
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6 by GSK3β triggers its nuclear export and cytoplasmic proteolysis via the 26S proteasome. Cyclin D1 overexpression is a common event in various types of human cancers; however, reports of mutations are extremely rare. We analyzed mutations of the cyclin D1 gene, CCND1, in 88 endometrial cancer tissue specimens and detected mutations in 2 cases (2.3%). Both were unreported mutations with substitution of threonine to isoleucine at codon 286 (T286I). These two tumors harbored coexisting mutations in K-ras, PIK3CA and/or PTEN and showed accumulation of cyclin D1 in the nucleus by immunohistochemistry. Furthermore, we analyzed the functions of mutant cyclin D1 (T286I) by luciferase assays, immunofluorescence, western blotting and clonogenic cell survival assays in HEK-293T cells. We found that exogenous mutant cyclin D1 (T286I) accumulated in the nuclei in HEK-293T cells, and that it inhibited the expression of pRb. Additionally, the number of colonies was increased by introduction of mutant cyclin D1 (T286I) compared to that of wild-type cyclin D1. In conclusion, we identified an unreported CCND1 mutation (T286I) in two endometrial cancers and revealed that the mutation was functional for inducing cell proliferation in human cells.
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| 30.
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Ohmatsu, Hanako ; Sugaya, Makoto ; Fujita, Hideki ; Miyagaki, Tomomitsu ; Kadono, Takafumi ; Maeda, Daichi ; Takazawa, Yutaka ; Fukayama, Masashi ; Tamaki, Kunihiko ; Sato, Shinichi ; 前田, 大地
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金沢大学医薬保健研究域医学系
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| 31.
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Suzuki, Kensuke ; Nagasaka, Kazunori ; Oda, Katsutoshi ; abe, Hiroyuki ; Maeda, Daichi ; Matsumoto, Yoko ; Arimoto, Takahide ; Kawana, Kei ; Fukayama, Masashi ; Osuga, Yutaka ; Fujii, Tomoyuki ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Background: Lymphangioleiomyomatosis (LAM) is a rare idiopathic disorder that occurs in women of chi
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ldbearing age, and consists of a diffuse proliferation of abnormal smooth muscle cells along the thoracic and abdominal lymphogenous route. Case presentation: We experienced a case of a 47-yo woman with recent history of systemic lupus erythematosus (SLE) diagnosed with endometrial cancer, initially suspected to have metastasized to pelvic and para-aortic lymph nodes based on preoperative diagnostic imaging. Subsequent pathological diagnosis revealed stage IB endometrial cancer without evidence of lymph node involvement. Instead, enlarged pelvic and para-aortic lymph nodes were found to be due to extrapulmonary LAM, from a primary lesion found inside the uterine myometrium. SLE improved after surgery. Conclusion: This is the first reported case of comorbid endometrial cancer, SLE, and aggressive LAM metastasizing to regional lymph nodes, and strengthens the clinical evidence for a common role of mTOR pathway hyperactivity and estrogen responsiveness in the pathophysiology of metastasizing lesions of the genital tract. © 2016 The Author(s).
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| 32.
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Seiki, Takayuki ; Nagasaka, Kazunori ; Kranjec, Christian ; Kawana, Kei ; Maeda, Daichi ; Nakamura, Hiroe ; Taguchi, Ayumi ; Matsumoto, Yoko ; Arimoto, Takahide ; Wada-Hiraike, Osamu ; Oda, Katsutoshi ; Nakagawa, Shunsuke ; Yano, Tetsu ; Fukayama, Masashi ; Banks, Lawrence ; Osuga, Yutaka ; Fujii, Tomoyuki ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Background: The high risk Human Papillomavirus (HPV) E6 oncoproteins play an essential role in the d
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evelopment of cervical malignancy. Important cellular targets of E6 include p53 and the PDZ domain containing substrates such as hScrib and Dlg. We recently showed that hScrib activity was mediated in part through recruitment of protein phosphatase 1γ (PP1γ). Methods: Expression patterns of hScrib and PP1γ were assessed by immunohistochemistry of HPV-16 positive cervical intraepithelial neoplasm (CIN), classified as CIN1 (n=4), CIN2 (n=8), CIN3 (n=8), cervical carcinoma tissues (n=11), and HPV-negative cervical tissues (n=8), as well as by subfractionation assay of the HPV-16 positive cervical cancer cell lines, CaSki and SiHa. To explore the effects of the HPV-16 oncoproteins, we have performed siRNA knockdown of E6/E7 expression, and monitored the effects on the expression patterns of hScrib and PP1γ. Results: We show that PP1γ levels in HPV-16 positive tumour cells are reduced in an E6/E7 dependent manner. Residual PP1γ in these cells is found mostly in the cytoplasm as opposed to the nucleus where it is predominantly found in normal cells. We have found a striking concordance with redistribution in the pattern of expression (9/11; 81.8%) and loss of PP1γ expression in HPV-16 positive cervical tumours (2/11; 18.2%). Furthermore, this loss of PP1γ expression and redistribution in the pattern of expression occurs progressively as the lesions develop (8/8; 100%). Conclusion: Together, these results suggest that PP1γ may be a novel target of the HPV-16 oncoproteins and indicate that it might be a potential novel biomarker for HPV-16 induced malignancy. © Seiki et al.
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| 33.
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Oda, Katsutoshi ; Ikeda, Yuji ; Maeda, Daichi ; Arimoto, Takahide ; Kawana, Kei ; Fukayama, Masashi ; Osuga, Yutaka ; Fujii, Tomoyuki ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Background: Surgical site infections are potential complications following open myomectomy. These in
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fections usually develop immediately after the surgery, and are most often located in the myometrium. Pyogenic cervical cysts are rare and have not been previously reported to occur at the site of myomectomy.Case presentation: A 41-year-old nulligravida Japanese woman was referred to our hospital with a large cervical cyst (>15 cm in diameter). She had undergone a myomectomy 13 years previously, and the surgical site had extended to the endocervical gland. Standard blood tests did not show any evidence of inflammation. The patient underwent a total abdominal hysterectomy, which revealed that the cyst contained multiple components, including Escherichia coli, old blood, and evidence of endometriosis. A pathological review did not show malignant cells within the cyst. The pyogenic cyst originated from the upper anterior cervix, which was one of the sites involved in the previous myomectomy.Conclusion: We reported a huge pyogenic cervical cyst exhibiting signs of endometriosis, in the vicinity of the uterine scar from the open myomectomy. The previous surgery and endometriosis might have contributed to the formation of this rare pyogenic cyst. © 2014 Oda et al.; licensee BioMed Central Ltd.
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| 34.
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Inoue, Tomoko ; Oda, Katsutoshi ; Arimoto, Takahide ; Samejima, Taiki ; Takazawa, Yutaka ; Maeda, Daichi ; Fukayama, Masashi ; Kawana, Kei ; Osuga, Yutaka ; Fujii, Tomoyuki ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Background: Xanthogranulomatous inflammation is an uncommon form of chronic inflammation that is des
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tructive to the normal tissue of affected organs. Although xanthogranulomatous endometritis and xanthogranulomatous salpingitis of the female genital tract has been described previously, to the best of our knowledge, this is the first report of xanthogranulomatous inflammation with infiltration into the uterine myometrium from the perimetrium without endometritis.Case presentation: A 68-year-old Japanese woman with intermittent lower abdominal pain and low-grade fever who was initially treated with antibiotics underwent hysterectomy due to abscess formation in the posterior wall of the myometrium and perimetrium (the outer serosal layer of the uterus). Histopathological findings revealed that the abscess was caused by xanthogranulomatous inflammation with the granulation tissue and chronic inflammatory cells that consisted of focal and sheets of foam cells. The inflammation destroyed the perimetrial elastic lamina, and the myometrium was deeply infiltrated by the xanthoma cells. Neither endometritis nor salpingitis was coexistent with the xanthogranulomatous inflammation.Conclusion: The patient was diagnosed as xanthogranulomatous inflammation, most likely arising from the perimetrium. Our findings suggest that the perimetrium, as well as the endometrium and adnexae, is one of the origins of xanthogranulomatous inflammation in female genital tract. © 2014 Inoue et al.; licensee BioMed Central Ltd.
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| 35.
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Matsumoto, Yoko ; Miyamoto, Yuichiro ; Cabral, Horacio ; Matsumoto, Yu ; Nagasaka, Kazunori ; Nakagawa, Shunsuke ; Yano, Tetsu ; Maeda, Daichi ; Oda, Katsutoshi ; Kawana, Kei ; Nishiyama, Nobuhiro ; Kataoka, Kazunori ; Fujii, Tomoyuki ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Treatment of recurrent or advanced cervical cancer is still limited, and new therapeutic choices are
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needed for improving prognosis and quality of life of patients. Because human papilloma virus (HPV) infection is critical in cervical carcinogenesis, with the E6 and E7 oncogenes of HPV degrading tumor suppressor proteins through the ubiquitin proteasome system, the inhibition of the ubiquitin proteasome system appears to be an ideal target to suppress the growth of cervical tumors. Herein, we focused on the ubiquitin proteasome inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) as an anticancer agent against cervical cancer cells, and physically incorporated it into micellar nanomedicines for achieving selective delivery to solid tumors and improving its in vivo efficacy. These MG132-loaded polymeric micelles (MG132/m) showed strong tumor inhibitory in vivo effect against HPV-positive tumors from HeLa and CaSki cells, and even in HPV-negative tumors from C33A cells. Repeated injection of MG132/m showed no significant toxicity to mice under analysis by weight change or histopathology. Moreover, the tumors treated with MG132/m showed higher levels of tumor suppressing proteins, hScrib and p53, as well as apoptotic degree, than tumors treated with free MG132. This enhanced efficacy of MG132/m was attributed to their prolonged circulation in the bloodstream, which allowed their gradual extravasation and penetration within the tumor tissue, as determined by intravital microscopy. These results support the use of MG132 incorporated into polymeric micelles as a safe and effective therapeutic strategy against cervical tumors. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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| 36.
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Nishimura, Riki ; Takita, Junko ; Sato-Otsubo, Aiko ; Kato, Motohiro ; Koh, Katsuyoshi ; Hanada, Ryoji ; Tanaka, Yukichi ; Kato, Keisuke ; Maeda, Daichi ; Fukayama, Masashi ; Sanada, Masashi ; Hayashi, Yasuhide ; Ogawa, Seishi ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Rhabdomyosarcoma (RMS) is a common solid tumor in childhood divided into two histological subtypes,
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embryonal (ERMS) and alveolar (ARMS). The ARMS subtype shows aggressive clinical behavior with poor prognosis, while the ERMS subtype has a more favorable outcome. Because of the rarity, diagnostic diversity and heterogeneity of this tumor, its etiology remains to be completely elucidated. Thus, to identify genetic alterations associated with RMS development, we performed single nucleotide polymorphism array analyses of 55 RMS samples including eight RMS-derived cell lines. The ERMS subtype was characterized by hyperploidy, significantly associated with gains of chromosomes 2, 8 and 12, whereas the majority of ARMS cases exhibited near-diploid copy number profiles. Loss of heterozygosity of 15q was detected in 45.5% of ARMS that had been unrecognized in RMS to date. Novel amplifications were also detected, including IRS2 locus in two fusion-positive tumors, and KRAS or NRAS loci in three ERMS cases. Of note, gain of 13q was significantly associated with good patient outcome in ERMS. We also identified possible application of an ALK inhibitor to RMS, as ALK amplification and frequent expression of ALK were detected in our RMS cohort. These findings enhance our understanding of the genetic mechanisms underlying RMS pathogenesis and support further studies for therapeutic development of RMS. © 2013 Japanese Cancer Association.
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| 37.
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Hiraike, Haruko ; Wada-Hiraike, Osamu ; Nakagawa, Shunsuke ; Saji, Shigehira ; Maeda, Daichi ; Miyamoto, Yuichiro ; Sone, Kenbun ; Tanikawa, Michihiro ; Oda, Katsutoshi ; Nakagawa, Keiichi ; Yano, Tetsu ; Fukayama, Masashi ; Taketani, Yuji ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />DBC1/KIAA1967 (deleted in breast cancer 1) is a putative tumor-suppressor gene cloned from breast ca
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ncer specimens and is reported to regulate p53-dependent apoptosis through its specific inhibition of SIRT1 deacetylase. Although SIRT1 plays a pivotal role in carcinogenesis by regulating cellular proliferation, survival and death, its role in breast cancer remains controversial. Therefore, we aimed to investigate the expression status and clinicopathological significance of DBC1 and SIRT1 in breast cancer tissues. We evaluated the expression of DBC1 and SIRT1 in breast core-needle biopsy specimens from 48 primary breast cancer patients between 2005 and 2008. These patients were treated with primary systemic chemotherapy and subsequent surgical resection of the lesions. Immunohistochemical expression scores of DBC1 and SIRT1 were evaluated, and the relationship between their expression levels and clinicopathological features of breast cancer was analyzed. The expression was observed exclusively in the nuclei of normal and neoplastic ductal cells. In breast biopsy specimens, positive expression of DBC1 and SIRT1 was noted in 85 and 98% of patients, respectively. Expression of DBC1 was significantly associated with the tumor nuclear grade (P=0.019). DBC1 and SIRT1 expression was inversely correlated with HER2 expression (P=0.026 and 0.003, respectively). Lower expression of DBC1 and SIRT1 indicated a tendency for a favorable pathological response to chemotherapy, although this was not statistically significant. Our results reveal that the expression of DBC1 and SIRT1 in breast tissues is associated with tumor characteristics. © 2011 Spandidos Publications Ltd.
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| 38.
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Uni, Masahiro ; Yoshimi, Akihide ; Maki, Hiroaki ; Maeda, Daichi ; Nakazaki, Kumi ; Nakamura, Fumihiko ; Fukayama, Masashi ; Kurokawa, Mineo ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />We report here a 47-year-old male with the diagnosis of high-grade B-cell lymphoma and hemophagocyto
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sis accompanying disseminated intravascular coagulation (DIC). Lymphoma-associated hemophagocytic syndrome (LAHS) is a life-threatening disorder, and LAHS secondary to B-cell lymphoma is relatively rare compared to that secondary to T- or NK/T-cell lymphoma in Western countries. T- or NK/T-cell LAHS is sometimes combined with DIC, which makes patients' outcomes even worse, but few reports of B-cell LAHS accompanying DIC has been published so far. We successfully treated a patient with this condition with recombinant thrombomodulin (rTM), a novel agent for DIC. We believe that rTM is a therapeutic option in cases with B-cell LAHS accompanying DIC.
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| 39.
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Maeda, Daichi ; Tsui-Lien, Mao ; Fukayama, Masashi ; Nakagawa, Shunsuke ; Yano, Tetsu ; Taketani, Yuji ; Shih, Ie-Ming ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Recent genome-wide analysis has demonstrated that somatic mutations in ARID1A (BAF250) are the most
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common molecular genetic changes in ovarian clear cell carcinoma (OCCC). ARID1A mutations, which occur in approximately half of OCCC cases, lead to deletion of the encoded protein and inactivation of the putative tumor suppressor. In this study, we determined the significance of loss of ARID1A immunoreactivity with respect to several clinicopathological features in a total of 149 OCCCs. First, we demonstrated that ARID1A immunohistochemistry showed concordance with the mutational status in 91% of cases with 100% sensitivity and 66% specificity. Specifically, among 12 OCCC cases for which ARIDA mutational status was known, ARIDIA immunoreactivity was undetectable in all 9 cases harboring ARID1A mutations and was undetectable in one of 3 cases with wild-type ARID1A. With respect to the entire cohort, ARID1A immunoreactivity was undetectable in 88 (59%) of 149 OCCCs. There was no significant difference between ARID1A negative and positive cases in terms of histopathologic features, age, clinical stage, or overall survival. In conclusion, this study provides further evidence that mutations in ARID1A resulted in loss of ARID1A protein expression in OCCC, although no significant differences between ARID1A positive and negative cases were observed with respect to any clinicopathological features examined. © 2010 by the authors.
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| 40.
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Shiraishi, Kouya ; Okada, Yukinori ; Takahashi, Atsushi ; Kamatani, Yoichiro ; Momozawa, Yukihide ; Ashikawa, Kyota ; Kunitoh, Hideo ; Matsumoto, Shingo ; Takano, Atsushi ; Shimizu, Kimihiro ; Goto, Akiteru ; Tsuta, Koji ; Watanabe, Shun-ichi ; Ohe, Yuichiro ; Watanabe, Yukio ; Goto, Yasushi ; Nokihara, Hiroshi ; Furuta, Koh ; Yoshida, Akihiko ; Goto, Koichi ; Hishida, Tomoyuki ; Tsuboi, Masahiro ; Tsuchihara, Katsuya ; Miyagi, Yohei ; Tanaka, Kazumi ; Nakayama, Haruhiko ; Yokose, Tomoyuki ; Nagashima, Toshiteru ; Ohtaki, Yoichi ; Maeda, Daichi ; Imai, Kazuhiro ; Minamiya, Yoshihiro ; Sakamoto, Hiromi ; Saito, Akira ; Shimada, Yoko ; Sunami, Kuniko ; Saito, Motonobu ; Inazawa, Johji ; Nakamura, Yusuke ; Yoshida, Teruhiko ; Yokota, Jun ; Matsuda, Fumihiko ; Matsuo, Keitaro ; Daigo, Yataro ; Kubo, Michiaki ; Kohno, Takashi ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Lung adenocarcinoma driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than
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in European/Americans (10-20%). Here we investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA class II at 6p21.32 (rs2179920; P =5.1 × 10 '17, per-allele OR=1.36) and 6p21.1 (FOXP4) (rs2495239; P=3.9 × 10 '9, per-allele OR=1.19) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma. This study indicates that multiple genetic factors underlie the risk of lung adenocarcinomas with EGFR mutations.
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| 41.
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Oki, Shinya ; Sone, Kenbun ; Oda, Katsutoshi ; Hamamoto, Ryuji ; Ikemura, Masako ; Maeda, Daichi ; Takeuchi, Makoto ; Tanikawa, Michihiro ; Mori-Uchino, Mayuyo ; Nagasaka, Kazunori ; Miyasaka, Aki ; Kashiyama, Tomoko ; Ikeda, Yuji ; Arimoto, Takahide ; Kuramoto, Hiroyuki ; Wada-Hiraike, Osamu ; Kawana, Kei ; Fukayama, Masashi ; Osuga, Yutaka ; Fujii, Tomoyuki ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />The histone methyltransferase EZH2, a key epigenetic modifier, is known to be associated with human
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tumorigenesis. However, the physiological importance of EZH2 and its clinical relevance in endometrial cancer remain unclear. Hence, in the present study, we investigated the expression and function of EZH2 in endometrial cancer. In a quantitative real-time PCR analysis of 11 endometrial cancer cell lines and 52 clinical endometrial cancer specimens, EZH2 was significantly overexpressed in cancer cells and tissues compared to that in corresponding normal control cells and tissues. Kaplan-Meier survival analysis using data of the TCGA RNA-seq database and tissue microarrays (TMAs) indicated that EZH2 overexpression is associated with endometrial cancer prognosis. In addition, knockdown of EZH2 using specific siRNAs resulted in growth suppression and apoptosis induction of endometrial cancer cells, accompanied by attenuation of H3K27 trimethylation. Consistent with these results, treatment with GSK126, a specific EZH2 inhibitor, suppressed endometrial cancer cell growth and decreased the number of cancer cell colonies. Furthermore, GSK126 showed additive effects with doxorubicin or cisplatin, which are conventional drugs for treatment of endometrial cancer. Further studies should explore the therapeutic potential of inhibiting EZH2 in patients with endometrial cancer. © Oki et al.
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| 42.
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Goto, Akiteru ; Masamitsu, Tanaka ; Yoshida, Makoto ; Umakoshi, Michinobu ; Nanjo, Hiroshi ; Shiraishi, Kouya ; Saito, Motonobu ; Kohno, Takashi ; Kuriyama, Sei ; Konno, Hayato ; Imai, Kazuhiro ; Hajime, Saito ; Minamiya, Yoshihiro ; Maeda, Daichi ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Purpose miR-451 is a tumor suppressive microRNA with several target genes, including Macrophage migr
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ation inhibitory factor (MIF). As little is known about the expression and clinicopathological significance of mir-451 in NSCLC, we performed a clinicopathological study of 370 NSCLC cases to clarify them. Cell biological experiments were also performed on NSCLC cell lines to confirm the tumor-suppressive role of miR-451 and whether or not MIF is targeted by miR-451. Methods We analyzed 370 NSCLC cases for the miR-451 expression by quantitative real-time polymerase chain reaction and the MIF expression by immunohistochemistry. Eighty-four background lung tissue samples were also evaluated for the miR-451 expression. The clinicopathological and genetic factors surveyed were the disease-free survival, smoking status, histological type, disease stage, EGFR gene mutations and ALK rearrangements. In 286 adenocarcinoma cases, the invasive status (adenocarcinoma in situ, minimally invasive adenocarcinoma and invasive adenocarcinoma) was also evaluated. Five NSCLC cell lines (H23, H441, H522, H1703, and H1975) were cultured and evaluated for their miR-451 and MIF expression. The cell lines with lower miR-451 and higher MIF expressions were then selected and transfected with miR-451-mimic to observe its effects on MIF expression, Akt and Erk status, cell proliferation, and cell migration. Results The miR-451 expression was down-regulated in cancer tissues compared with background lung tissues (P<0.0001). Factors such as advanced disease stage, positive pleural invasion and nodal status and being a smoker were significantly correlated with a lower expression of miR-451 (P<0.05 each), while EGFR gene mutations and ALK rearrangements were not. In adenocarcinoma, invasive and minimally invasive adenocarcinoma showed lower expression of miR-451 than adenocarcinoma in situ (P<0.0005, respectively). A survival analysis showed that a lower expression of miR-451 was an independent predictor of a poor prognosis for NSCLC (P<0.05). The MIF expression was inversely correlated with the miR-451 expression. Out of 5 NSCLC cell lines examined, H441 and H1975 showed higher MIF and lower miR-451 expressions. After the transfection of miR-451-mimic, the MIF expression and phosphorylated Akt expression of these cell lines was suppressed, as were cell proliferation and cell migration. Conclusion This clinicopathological study of 370 NSCLC cases and the cell biological studies of NSCLC cell lines clarified the tumor-suppressive role of miR-451 and its prognostic value. We also validated MIF as a target of miR-451 in NSCLC. © 2017 Goto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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| 43.
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Kito, Masahiko ; Maeda, Daichi ; Kudo-Asabe, Yukitsugu ; Sato, Naoki ; Ie-Ming, Shih ; Wang, Tian-Li ; Tanaka, Masamitsu ; Terada, Yukihiro ; Goto, Akiteru ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />In Table 1, the values in the Case column should be listed from 1 to 18. Please see the corrected Ta
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ble 1 here. © 2016 Kito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />Correction to: PLoS ONE https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156069
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| 44.
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Kito, Masahiko ; Maeda, Daichi ; Kudo-Asabe, Yukitsugu ; Sato, Naoki ; Ie-Ming, Shih ; Wang, Tian-Li ; Tanaka, Masamitsu ; Terada, Yukihiro ; Goto, Akiteru ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />There is a growing body of evidence regarding cell competition between normal and mutant mammalian c
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ells, which suggest that it may play a defensive role in the early phase of carcinogenesis. In vitro study in the past has shown that overexpression of vimentin in normal epithelial cells at the contact surface with transformed cells is essential for the cell competition involved in epithelial defense against cancer. In this study, we attempted to examine cell competition in human tissue in vivo by investigating surgically resected human fallopian tubes that contain p53 signatures and serous tubal intraepithelial lesions (STILs), a linear expansion of p53-immunopositive/TP53 mutant tubal epithelial cells that are considered as precursors of pelvic high grade serous carcinoma. Immunofluorescence double staining for p53 and the cell competition marker vimentin was performed in 21 sections of human fallopian tube tissue containing 17 p53 signatures and 4 STILs. The intensities of vimentin expression at the interface between p53-positive cells at the end of the p53 signature/STIL and adjacent p53-negative normal tubal epithelial cells were compared with the background tubal epithelium. As a result, the average vimentin intensity at the interfaces relative to the background intensity was 1.076 (95% CI, 0.9412-1.211 for p53 signature and 0.9790 (95% CI, 0.7206-1.237) for STIL. Thus, it can be concluded that overexpression of the cell competition marker vimentin are not observed in human tissue with TP53 alterations. © 2016 Kito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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| 45.
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Maeda, Daichi ; Yoshiyuki, Akiyama ; Morikawa, Teppei ; Kunita, Akiko ; Ota, Yasunori ; Katoh, Hiroto ; Niimi, Aya ; Nomiya, Akira ; Ishikawa, Shumpei ; Goto, Akiteru ; Igawa, Yasuhiko ; Fukayama, Masashi ; Homma, Yukio ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Interstitial cystitis (IC) is a chronic bladder disease with urinary frequency, bladder discomfort o
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r bladder pain of unknown etiology. Based on cystoscopic findings, patients with IC are classified as either Hunner-type/classic IC (HIC), presenting with a specific Hunner lesion, or non-Hunner-type IC (NHIC), presenting with no Hunner lesion, but post-hydrodistension mucosal bleeding. Inflammatory cell infiltration, composed predominantly of lymphocytes, plasma cells and epithelial denudation, has in the past been documented as a major pathological IC finding. However, the significance of the pathological evaluation of IC, especially with regard to the difference between HIC and NHIC, has been downplayed in recent years. In this study, we performed immunohistochemical quantification of infiltrating T-lymphocytes, B-lymphocytes and plasma cells, and measured the amount of residual epithelium in urinary bladder biopsy specimens taken from patients with HIC and NHIC, and those with no IC, using image analysis software. In addition, in situ hybridization of the light chains was performed to examine clonal B-cell expansion. Lymphoplasmacytic infiltration was significantly more severe in HIC specimens than in NHIC specimens (P <0.0001). Substantial lymphoplasmacytic inflammation (≥200 cells/mm2) was observed in 93% of HIC specimens, whereas only 8% of NHIC specimens were inflamed. Plasmacytic infiltration was more prominent in HIC specimens compared with NHIC and non-IC cystitis specimens (P <0.005). Furthermore, expansion of light-chain-restricted B-cells was observed in 31% of cases of HIC. The amount of residual epithelium was decreased in HIC specimens compared with NHIC specimens and non-IC cystitis specimens (P <0.0001). These results suggest that NHIC and HIC are distinct pathological entities, with the latter characterized by pancystitis, frequent clonal B-cell expansion and epithelial denudation. An abnormality in the B-cell population may be involved in the pathogenesis of HIC. © 2015 Maeda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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| 46.
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Uehara, Yuriko ; Oda, Katsutoshi ; Ikeda, Yuji ; Koso, Takahiro ; Tsuji, Shingo ; Yamamoto, Shogo ; Asada, Kayo ; Sone, Kenbun ; Kurikawa, Reiko ; Makii, Chinami ; Hagiwara, Otoe ; Tanikawa, Michihiro ; Maeda, Daichi ; Hasegawa, Kosei ; Nakagawa, Shunsuke ; Wada-Hiraike, Osamu ; Kawana, Kei ; Fukayama, Masashi ; Fujiwara, Keiichi ; Yano, Tetsu ; Osuga, Yutaka ; Fujii, Tomoyuki ; Aburatani, Hiroyuki ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Correction to: PLoS ONE https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128066
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| 47.
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Uehara, Yuriko ; Oda, Katsutoshi ; Ikeda, Yuji ; Koso, Takahiro ; Tsuji, Shingo ; Yamamoto, Shogo ; Asada, Kayo ; Sone, Kenbun ; Kurikawa, Reiko ; Makii, Chinami ; Hagiwara, Otoe ; Tanikawa, Michihiro ; Maeda, Daichi ; Hasegawa, Kosei ; Nakagawa, Shunsuke ; Wada-Hiraike, Osamu ; Kawana, Kei ; Fukayama, Masashi ; Fujiwara, Keiichi ; Yano, Tetsu ; Osuga, Yutaka ; Fujii, Tomoyuki ; Aburatani, Hiroyuki ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Ovarian clear cell carcinoma (CCC) is generally associated with chemoresistance and poor clinical ou
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tcome, even with early diagnosis; whereas high-grade serous carcinomas (SCs) and endometrioid carcinomas (ECs) are commonly chemosensitive at advanced stages. Although an integrated genomic analysis of SC has been performed, conclusive views on copy number and expression profiles for CCC are still limited. In this study, we performed single nucleotide polymorphism analysis with 57 epithelial ovarian cancers (31 CCCs, 14 SCs, and 12 ECs) and microarray expression analysis with 55 cancers (25 CCCs, 16 SCs, and 14 ECs). We then evaluated PIK3CA mutations and ARID1A expression in CCCs. SNP array analysis classified 13% of CCCs into a cluster with high frequency and focal range of copy number alterations (CNAs), significantly lower than for SCs (93%, P < 0.01) and ECs (50%, P = 0.017). The ratio of whole-arm to all CNAs was higher in CCCs (46.9%) than SCs (21.7%; P < 0.0001). SCs with loss of heterozygosity (LOH) of BRCA1 (85%) also had LOH of NF1 and TP53, and LOH of BRCA2 (62%) coexisted with LOH of RB1 and TP53. Microarray analysis classified CCCs into three clusters. One cluster (CCC-2, n = 10) showed more favorable prognosis than the CCC-1 and CCC-3 clusters (P = 0.041). Coexistent alterations of PIK3CA and ARID1A were more common in CCC-1 and CCC-3 (7/11, 64%) than in CCC-2 (0/10, 0%; P < 0.01). Being in cluster CCC-2 was an independent favorable prognostic factor in CCC. In conclusion, CCC was characterized by a high ratio of whole-arm CNAs; whereas CNAs in SC were mainly focal, but preferentially caused LOH of well-known tumor suppressor genes. As such, expression profiles might be useful for sub-classification of CCC, and might provide useful information on prognosis. © 2015 Uehara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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| 48.
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Ito, Yukinobu ; Yoshida, Makoto ; Maeda, Daichi ; Takahashi, Masato ; Nanjo, Hiroshi ; Masuda, Hirotake ; Gopto, Akiteru ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Arteriovenous malformations consist of tangles of arteries and veins that are often connected by a f
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istula. The causes and mechanisms of these clinical entities are not fully understood. We discovered that suturing an arterial patch into the common jugular vein of rabbits led to spontaneous neovascularization, the formation of an arteriovenous fistula and the development of an arteriovenous shunt. An arterial patch excised from the common carotid artery was sutured into the common jugular vein. Within a month, a dense nidus-like neovasculature formed around the patch. Angiography and pulse-oximeter analyses showed that the blood flowing into the neovasculature was arterial blood. This indicated that an arteriovenous shunt had formed. Fluorescence in situ hybridization with a Y chromosome probe in female rabbits that received an arterial patch from male rabbits showed that the vessels close to the graft bore the Y chromosome, whereas the vessels further away did not. Enzyme-linked immunosorbent assays and cDNA microarray analysis showed that multiple angiogenic factors were upregulated after patch transplantation. This is the first in vivo model of spontaneous arteriovenous fistula formation. Further research on these differences may help to improve understanding of human vascular anomaly diseases and the basic principles underlying vasculogenesis and/or angiogenesis. © 2018 The Author(s).
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Takahashi, Kenichi ; Mashima, Hirosato ; Miura, Kouichi ; Maeda, Daichi ; Goto, Akiteru ; Gotio, Takashi ; Sun-Wada, Ge-Hong ; Wada, Yoh ; Ohnishi, Hirohide ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Although aberrations of intracellular vesicle transport systems towards lysosomes including autophag
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y and endocytosis are involved in the onset and progression of acute pancreatitis, the molecular mechanisms underlying such aberrations remain unclear. The pathways of autophagy and endocytosis are closely related, and Rab7 plays crucial roles in both. In this study, we analyzed the function of Rab7 in acute pancreatitis using pancreas-specific Rab7 knockout (Rab7Δpan) mice. In Rab7Δpan pancreatic acinar cells, the maturation steps of both endosomes and autophagosomes were deteriorated, and the lysosomal functions were affected. In experimental models of acute pancreatitis, the histopathological severity, serum amylase concentration and intra-pancreatic trypsin activity were significantly higher in Rab7Δpan mice than in wild-type mice. Furthermore, the autophagy process was blocked in Rab7Δpan pancreas compared with wild-type mice. In addition, larger autophagic vacuoles that colocalize with early endosome antigen 1 (EEA1) but not with lysosomal-associated membrane protein (LAMP)-1 were much more frequently formed in Rab7Δpan pancreatic acinar cells. Accordingly, Rab7 deficiency exacerbates the severity of acute pancreatitis by impairing the autophagic and endocytic pathways toward lysosomes.
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| 50.
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Akiyama, Yoshiyuki ; Morikawa, Teppei ; Maeda, Daichi ; Shintani, Yukako ; Niimi, Aya ; Nomiya, Akira ; Nakayama, Atsuhito ; Igawa, Yasuhiko ; Fukayama, Masashi ; Homma, Yukio ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />An up-regulated CXCR3 pathway and affluent plasma cell infiltration are characteristic features of H
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unner type interstitial cystitis (HIC). We further examined these two features using bladder biopsy samples taken from 27 patients with HIC and 15 patients with non-IC cystitis as a control. The number of CD3-positive T lymphocytes, CD20-positive B lymphocytes, CD138-positive plasma cells, and CXCR3-positive cells was quantified by digital image analysis. Double-immunofluorescence for CXCR3 and CD138 was used to detect CXCR3 expression in plasma cells. Correlations between CXCR3 positivity and lymphocytic and plasma cell numbers and clinical parameters were explored. The density of CXCR3-positive cells showed no significant differences between HIC and non-IC cystitis specimens. However, distribution of CXCR3-positivity in plasma cells indicated co-localization of CXCR3 with CD138 in HIC specimens, but not in non-IC cystitis specimens. The number of CXCR3-positive cells correlated with plasma cells in HIC specimens alone. Infiltration of CXCR3-positive cells was unrelated to clinical parameters of patients with HIC. These results suggest that infiltration of CXCR3-positive plasma cells is a characteristic feature of HIC. The CXCR3 pathway and specific immune responses may be involved in accumulation/retention of plasma cells and pathophysiology of the HIC bladder.
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| 51.
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Tsuda, Takeaki ; 津田, 武明
概要:
金沢大学先端科学・社会共創推進機構<br />One-dimensional flow equations were derived for non-Newtonian fluids in slot coating and a simple
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numerical method was proposed to solve the equations. We investigated non-Newtonian effects on coating performance and coating quality in slot coating. In some cases, computational results and experimental data were compared and both agreed well. A series of numerical computations showed that the one-dimensional approach can describe non-Newtonian flow under lips in a few minutes and that a pressure field equation proposed by Higgins can determine the location of an upstream meniscus. Moreover, it was found that the non-Newtonian characteristics of coating liquids affect both coating performance and coating quality. Because each non-Newtonian effect is quite different, we should optimize the conditions of slot coating and die geometries according to the target problem. © 2010 The Society of Rheology, Japan.
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Asano, Tetsuo ; Bose, Prosenjit ; Carmi, Paz ; Maheshwari, Anil ; Shu, Chang ; Smid, Michiel H. M. ; Wuhrer, Stefanie ; 浅野, 哲夫
概要:
金沢大学<br />The distance preserving graph embedding problem is to embed vertices of a given weighted graph into points in
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2-dimensional Euclidean space so that for each edge the distance between their corresponding endpoints is as close to the weight of the edge as possible. If the given graph is complete, that is, if distance constraints are given as a full matrix, then principal coordinate analysis can solve it in polynomial time. A serious disadvantage is its quadratic space requirement. In this paper we develop linear-space algorithms for this problem. A key idea is to partition a set of n objects into disjoint subsets (clusters) of size O(√n) such that the minimum inter cluster distance is maximized among all possible such partitions.<br />CCCG2007 The 19th Canadian Conference on Computational Geometry, August 20-22, 2007
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Asano, Tetsuo ; Mulzer, Wolfgang ; Wang, Yajun ; 浅野, 哲夫
概要:
金沢大学<br />Constant-work-space algorithms model computation when space is at a premium: the input is given as a read-only
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array that allows random ac- cess to its entries, and the algorithm may use constantly many additional registers of O(logn) bits each, where n denotes the input size. We present such algorithms for two restricted variants of the shortest path problem. First, we describe how to report a simple path between two arbitrary nodes in a given tree. Using a technique called "computing instead of storing", we obtain a naive algorithm that needs quadratic time and a constant number of additional registers. We then show how to improve the running time to linear by applying a technique named "simulated parallelization". Second, we show how to compute a shortest geodesic path between two points in a simple polygon in quadratic time and with constant work-space.
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Asano, Tetsuo ; Demaine, Erik D. ; Demaine, Martin L. ; Uehara, Ryuhei ; 浅野, 哲夫
概要:
金沢大学<br />Kaboozle is a puzzle consisting of several square cards, each annotated with colored paths and dots drawn on b
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oth sides and holes drilled. The goal is to join two colored dots with paths of the same color (and fill all holes) by stacking the cards suitably. The freedoms here are to reflect, rotate, and order the cards arbitrarily, so it is not surprising that the problem is NP-complete (as we show). More surprising is that any one of these freedoms-reflection, rotation, and order-is alone enough to make the puzzle NP-complete. Furthermore, we show NP-completenessof a particularly constrained form of Kaboozle related to 1D paper folding. Specifically, we suppose that the cards are glued together into a strip, where each glued edge has a specified folding direction (mountain or valley). This variation removes the ability to rotate and reflect cards, and restricts the order to be a valid folded state of a given 1D mountain-valley pattern. © 2012 Information Processing Society of Japan.
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Higuchi, Akihiro ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />Dry eye syndrome is a multifactorial condition on the tear and ocular surface. Autologous serum e
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ye drop is an effective method for treating dry eye. Autologous serum eye drops are now widely used by specialists since a first report in 1975. The results of a systematic study showed that the efficacy of autologous serum eye drops remains ambiguous because its preparation methods and clinical application have not been standardized. To elucidate the efficacy of autologous serum eye drops, well-designed, large-scale, high-quality randomized controlled trials need to be conducted with standardized treatment and use. Since serum components are partially similar to tear components, autologous serum eye drops improve dry eye by supplying tear components such as growth factors, proteins, and vitamins. Adding to the evidence based on the treatment of dry eye, we have found a new treatment candidate from serum: selenoprotein P (SeP). The efficacy of SeP as a treatment for dry eye was revealed by applying SeP eye drops to a dry eye rat model. Compared with phosphate-buffered saline treatment, SeP eye drops significantly reduced the fluorescein score of the cornea and suppressed the oxidative stress in the cornea, which is related to onset of dry eye, leading to improved corneal disorder. We have developed a new dry eye model caused by oxidative stress that will be used to screen candidate molecules for antioxidative activity. © 2018 The Authors.
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Higuchi, Akihiro ; Erina Oonishi ; Kawakita, Tetsuya ; Tsubota, Kazuo ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />Purpose: 2-hydroxy estradiol (2-OHE2) is a catechol derivative of 17β -Estradiol (E2) and it is s
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ynthesized from E2 catalyzed by cytochrome P4501A1. Previous studies reported that 2-OHE2 is a physiologic antioxidant in lipoproteins, liver microsomes, and the brain. Catechol derivatives show an anti-inflammatory effect through the inhibition of prostaglandin endoperoxide synthase (PGS) activity. Corneal erosion caused by dry eye is related to an increase in oxidative stress and inflammation in ocular surface cells. We investigated the therapeutic effects of 2-OHE2 on corneal damage caused by dry eye. Methods: Steroidal radical scavenging activity was confirmed through the electron spin resonance (ESR) method. PGS activity was measured using the COX Fluorescent Activity Assay Kit. To evaluate the effect of 2-OHE2 on the treatment for dry eye, 2-OHE2 was applied as an eye drop experiment using dry eye model rats. Results: 2-OHE2 scavenged tyrosyl radical and possibly suppressed oxidative stress in corneal epithelial cells. In addition, 2-OHE2 inhibited PGS activity, and 2-OHE2 is probably a competitive inhibitor of PGS. Corneal PGS activity was upregulated in the dry eye group. Therefore, 2-OHE2 eye drops improved corneal erosion in dry eye model rats. Conclusions: 2-OHE2 is a candidate for the treatment of dry eye through the suppression of inflammation and oxidative stress in the cornea. © 2016 Molecular Vision.
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| 57.
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Higuchi, Akihiro ; Kawakita, Tetsuya ; Tsubota, Kazuo ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />Purpose: To investigate the effect of desiccation on secretion of inflammatory cytokines in corne
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al epithelial cells and in the rat desiccation model. Methods: A human corneal epithelial cell line (CEPI) was grown in keratinocyte growth medium 2 (KGM2) to approximately 80% confluence. The medium was aspirated and dishes were left for 0 to 30 min with the cover left open to dry the cells (short-term desiccation). After desiccation, KGM2 was added to the dishes and collected from the dishes 15 min later to measure the concentrations of cytokines in the medium by sandwich enzyme immunoassay (ELISA). Viability of the cells was estimated with alamer blue. To study the effect of long-term desiccation, cultivated cells on transwells were used. After dessiccation for up to 8 h, the viability of the cells and levels of cytokines in the culture medium were examined. The expression of cytokines in the cornea of the dry eye model rat was measured by real-time PCR. Results: Short-term dessication of CEPI cells significantly increased the interleukin (IL)-6 level and slightly increased the tumor necrosis factor (TNF)-α level. Anti-IL-6 antibody partially suppressed cell death caused by desiccation. Upon long-term desiccation, IL-6 and IL-8 levels were increased. In the dry eye model rats, the IL-6 mRNA level in the cornea significantly increased, whereas TNF-α mRNA level slightly increased. Conclusions: Desiccation induced IL-6 expression in corneal epithelial cells, suggesting that IL-6 participates in desiccation-induced cell death. © 2011 Molecular Vision.
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| 58.
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Higuchi, Akihiro ; Inoue, Hiroyoshi ; Kawakita, Tetsuya ; Ogishima, Tadashi ; Tsubota, Kazuo ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />The ocular surface is strongly affected by oxidative stress, and anti-oxidative systems are maint
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ained in corneal epithelial cells and tear fluid. Dry eye is recognized as an oxidative stress-induced disease. Selenium compound eye drops are expected to be a candidate for the treatment of dry eye. We estimated the efficacy of several selenium compounds in the treatment of dry eye using a dry eye rat model. All of the studied selenium compounds were uptaken into corneal epithelial cells in vitro. However, when the selenium compounds were administered as eye drops in the dry eye rat model, most of the selenium compounds did not show effectiveness except for Se-lactoferrin. Se-lactoferrin is a lactoferrin that we prepared that binds selenium instead of iron. Se-lactoferrin eye drops suppressed the up-regulated expression of heme oxygenase-1, cyclooxygenase-2, matrix metallopeptidase-9, and interleukin-6 and also suppressed 8-OHdG production in the cornea induced by surgical removal of the lacrimal glands. Compared with Se-lactoferrin, apolactoferrin eye drops weakly improved dry eye in high dose. The effect of Se-lactoferrin eye drops on dry eye is possibly due to the effect of selenium and also the effect of apolactoferrin. Se-lactoferrin is a candidate for the treatment of dry eye via regulation of oxidative stress in the corneal epithelium. © 2012 Higuchi et al.
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| 59.
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Higuchi, Akihiro ; Takahashi, Kazuhiko ; Hirashima, Masaki ; Kawakita, Tetsuya ; Tsubota, Kazuo ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />The ocular surface is always attacked by oxidative stress, and cornea epithelial cells are suppos
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ed to have their own recovery system against oxidative stress. Therefore we hypothesized that tears supply key molecules for preventing oxidative stress in cornea. The potential target key molecule we focused is selenoprotein P (SeP). SeP is a carrier of selenium, which is an essential trace element for many animals, for oxidative stress metabolism in the organism, and was extremely expressed in lacrimal gland. An experiment was performed with SeP eye drops in a rat dry eye model, prepared by removing the lacrimal glands. The anticipated improvement in corneal dry eye index and the suppression of oxidative stress markers were observed in SeP eye drop group. Furthermore, the concentration of SeP was significantly higher in dry eye patients compared with normal volunteers. Collectively, we concluded that tear SeP is a key molecule to protect the ocular surface cells against environmental oxidative stress. © 2010 Higuchi et al.
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| 60.
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Higuchi, Akihiro ; Inoue, Hiroyoshi ; Kaneko, Yoshio ; Oonishi, Erina ; Tsubota, Kazuo ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />The ocular surface is strongly affected by oxidative stress, which causes many ocular diseases in
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cluding dry eye. Previously, we showed that selenium compounds, e.g., selenoprotein P and Se-lactoferrin, were candidates for treatment of dry eye. This paper shows the efficacy of Se-lactoferrin for the treatment of dry eye compared with Diquas as a control drug using two dry eye models and incorporation of lactoferrin into corneal epithelial cells via lactoferrin receptors. We show the efficacy of Se-lactoferrin eye drops in the tobacco smoke exposure rat dry eye model and short-term rabbit dry eye model, although Diquas eye drops were only effective in the short-term rabbit dry eye model. These results indicate that Se-lactoferrin was useful in the oxidative stress-causing dry eye model. Se-lactoferrin was taken into corneal epithelium cells via lactoferrin receptors. We identified LRP1 as the lactoferrin receptor in the corneal epithelium involved in lactoferrin uptake. Se-lactoferrin eye drops did not irritate the ocular surface of rabbits. Se-lactoferrin was an excellent candidate for treatment of dry eye, reducing oxidative stress by a novel mechanism. © 2016 The Author(s).
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| 61.
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Yamaguchi, Naoya ; Ishii, Fumiyuki ; 山口, 直也 ; 石井, 史之
概要:
金沢大学ナノマテリアル研究所<br />We investigate the effect of tensile strain on spin splitting at the n-type interface of LaAlO3/SrTi
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O3 in terms of spin–orbit coupling coefficient α and spin texture in the momentum space using first-principles density-functional calculations. Our results show that α could be controlled by the tensile strain, and can be enhanced by up to 5 times for a tensile strain of 7%, and the effect of the tensile strain leads to a persistent spin helix, which has a long spin lifetime. The strain effect on the LaAlO3/SrTiO3 interface is important for various applications such as spin field-effect transistors and spin-to-charge conversion.
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| 62.
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Naito, Hisamichi ; Takara, Kazuhiro ; Wakabayashi, Taku ; Kawahara, Hiroki ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />It is widely accepted that blood vessels in the tumor microenvironment are immature because mural ce
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ll (MC) adhesion to endothelial cells (ECs) is broadly lacking. Hyperpermeability of the tumor vasculature then results in interstitial hypertension that mitigates against penetration of anticancer drugs into the depths of the tumor. It has been suggested that treatment with angiogenesis inhibitors normalizes blood vessels, resulting in restoration of normal permeability and improved drug delivery. However, recent reports suggest that cancer cell invasion is induced from the edge of the tumor into peripheral areas after treatment with angiogenesis inhibitors. Therefore, it is important to assess the status of blood vessels in the fibrous cap at the tumor rim after antiangiogenesis therapy. In the present study, we found that mature blood vessels in which ECs are covered with MCs are present in the fibrous cap. After treatment with angiogenesis inhibitors, immature blood vessels were destroyed and vascular function was significantly improved, but maturing blood vessels in which ECs were covered with MCs remained visible. These maturing blood vessels showed a less dilated character after treatment with the angiogenesis inhibitors. It is widely accepted that well-matured blood vessels are sheathed in extracellular matrix (ECM) and that cancer cells migrate along tracks made of ECM collagen fibers. Therefore, our data indicate the importance of destroying maturing blood vessels outside the tumor parenchyma to prevent cancer cell invasion. © 2011 Japanese Cancer Association.
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| 63.
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Iba, Tomohiro ; Naito, Hisamichi ; Shimizu, Shota ; Rahmawati, Fitriana Nur ; Wakabayashi, Taku ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
Background: During sprouting angiogenesis, stalk cells, localized behind tip cells, generate endothelial cells (ECs) for
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the elongation of new vessels. We hypothesized that stalk cells may have endothelial progenitor cell properties because of their highly proliferative ability. We conducted Hoechst dye DNA staining in ECs of preexisting blood vessels from hind limb muscle and found that endothelial-side population (E-SP) cells, which efflux Hoechst rapidly with abundant ABC transporters, show highly producing ability of ECs. We previously showed the existence of E-SP cells in hind limb muscle, retina, and liver, but not in other tissues such as adipose tissue, skin, and placenta. Methods: We investigated the existence of E-SP cells and analyzed their proliferative ability among CD31+CD45- ECs from adipose tissue, skin, and placenta of adult mice. We also analyzed the neovascular formation of E-SP cells from adipose tissue in vivo. Results: We detected E-SP cells in all tissues examined. However, by in vitro colony formation analysis on OP9 cells, we found that E-SP cells from adipose tissue and skin, but not from placenta, have highly proliferative ability. Moreover, E-SP cells from adipose tissue could contribute to the neovascular formation in hind limb ischemia model. Conclusion: The adipose tissue and skin are available sources to obtain endothelial stem cells for conducting therapeutic angiogenesis in regenerative medicine. © 2019 The Author(s).
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| 64.
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Wakabayashi, Taku ; Naito, Hisamichi ; Takara, Kazuhiro ; Kidoya, Hiroyasu ; Sakimoto, Susumu ; Oshima, Yusuke ; Nishida , Kohji ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
Purpose. The neovascular form of age-related macular degeneration (AMD) is characterized by the growth of abnormal new b
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lood vessels from the choroid, termed choroidal neovascularization (CNV). The origin of the new vessels in CNV, however, has not been elucidated fully to our knowledge. The purpose of this study is to identify vascular endothelial side population (SP) cells in the preexisting choroidal vessels, and investigate their potential role in AMD. Methods. We made single cell suspensions of freshly isolated mouse choroidal, retinal, and brain tissue by enzymatic digestion. Vascular endothelial SP cells were isolated using flow cytometry based on the ability to efflux the DNA-binding dye, Hoechst 33342, via ATP-binding cassette (ABC) transporters. Results. In the choroid, 2.8% of CD31+CD45- vascular endothelial cells (ECs) showed a typical SP staining pattern. They were not bone marrow-derived and possessed high colony-forming capacity in vitro. They proliferated during laser-induced CNV in vivo. In contrast, stereotypic SP staining pattern was not observed in retinal and brain ECs. Retinal and brain EC-SP cells included increased SP populations with less colony-forming capacity within the SP compartment, because they contained cells with and without proliferative potential. The latter still could efflux the dye due to high levels of ABC transporters, such as ABCB1a, ABCC4, and ABCC6. Conclusions. The EC-SP cells in the choroid may represent vessel-residing endothelial stem/progenitor cells contributing mainly to angiogenesis, and may be useful for augmenting vascular regeneration or for developing new antiangiogenic therapy in AMD. © 2013 The Association for Research in Vision and Ophthalmology, Inc.
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| 65.
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Yamakawa, Daishi ; Kidoya, Hiroyasu ; Sakimoto, Susumu ; Jia, Weizhen ; Naito, Hisamichi ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />Tie2 is a receptor tyrosine kinase expressed on vascular endothelial cells (ECs). It has dual roles
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in promoting angiogenesis and stabilizing blood vessels, and it has been suggested that Tie2 forms dimers and/or oligomers in the absence of angiopoietin-1 (Ang1); however, the mechanism of ligand-independent dimerization of Tie2 and its biological significance have not been clarified. Using a bimolecular fluorescence complementation assay and a kinase-inactive Tie2 mutant, we show here that ligand-independent Tie2 dimerization is induced without Tie2 phosphorylation. Moreover, based on the fact that Tie1 never forms heterodimers with Tie2 in the absence of Ang1 despite having high amino acid sequence homology with Tie2, we searched for ligand-independent dimerization domains of Tie2 by reference to the difference with Tie1. We found that the YIA sequence of the intracellular domain of Tie2 corresponding to the LAS sequence in Tie1 is essential for this dimerization. When the YIA sequence was replaced by LAS in Tie2 (Tie2YIA/LAS), ligand-independent dimer was not formed in the absence of Ang1. When activation of Tie2YIA/LAS was induced by a high dose of Ang1, phosphorylation of Tie2 was limited compared with wild-type Tie2, resulting in retardation of activation of Erk downstream of Tie2. Therefore, these data suggest that ligand-independent dimerization of Tie2 is essential for a strong response upon stimulation with high dose Ang1. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.
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| 66.
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Kidoya, Hiroyasu ; Muramatsu, Fumitaka ; Shimamura, Teppei ; Jia, Weizhen ; Satoh, Takashi ; Hayashida, Yumiko ; Naito, Hisamichi ; Kunisaki, Yuya ; Arai, Fumio ; Seki, Masahide ; Suzuki, Yutaka ; Osawa , Tsuyoshi ; Akira , Shizuo ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />The balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSP
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Cs) maintains hematopoietic homeostasis, failure of which can lead to hematopoietic disorder. HSPC fate is controlled by signals from the bone marrow niche resulting in alteration of the stem cell transcription network. Regnase-1, a member of the CCCH zinc finger protein family possessing RNAse activity, mediates post-transcriptional regulatory activity through degradation of target mRNAs. The precise function of Regnase-1 has been explored in inflammation-related cytokine expression but its function in hematopoiesis has not been elucidated. Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA. In addition, we found that dysfunction of Regnase-1 leads to the rapid onset of abnormal hematopoiesis. Thus, our data reveal that Regnase-1-mediated post-transcriptional regulation is required for HSPC maintenance and suggest that it represents a leukemia tumor suppressor. © 2019, The Author(s).
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| 67.
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Kawahara, Hiroki ; Naito, Hisamichi ; Takara, Kazuhiro ; Wakabayashi, Taku ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />Background:A drug delivery system specifically targeting endothelial cells (ECs) in tumors is requir
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ed to prevent normal blood vessels from being damaged by angiogenesis inhibitors. The purpose of this study was to investigate whether apelin, a ligand for APJ expressed in ECs when angiogenesis is taking place, can be used for targeting drug delivery to ECs in tumors.Methods and Results:Uptake of apelin via APJ stably expressed in NIH-3T3 cells was investigated using TAMRA (fluorescent probe)-conjugated apelin. Both long and short forms of apelin (apelin 36 and apelin 13) were taken up, the latter more effectively. To improve efficacy of apelin- liposome conjugates, we introduced cysteine, with its sulfhydryl group, to the C terminus of apelin 13, resulting in the generation of apelin 14. In turn, apelin 14 was conjugated to rhodamine-encapsulating liposomes and administered to tumor-bearing mice. In the tumor microenvironment, we confirmed that liposomes were incorporated into the cytoplasm of ECs. In contrast, apelin non-conjugated liposomes were rarely found in the cytoplasm of ECs. Moreover, non-specific uptake of apelin-conjugated liposomes was rarely detected in other normal organs.Conclusions:ECs in normal organs express little APJ; however, upon hypoxic stimulation, such as in tumors, ECs start to express APJ. The present study suggests that apelin could represent a suitable tool to effectively deliver drugs specifically to ECs within tumors. © 2013 Kawahara et al.
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| 68.
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Sakimoto, Susumu ; Kidoya, Hiroyasu ; Kamei, Motohiro ; Naito, Hisamichi ; Yamakawa, Daishi ; Sakaguchi, Hirokazu ; Wakabayashi, Taku ; Nishida, Kohji ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />Purpose: Adrenomedullin (ADM) has been shown to take part in physiological and pathological angiogen
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esis. The purpose of this study was to investigate whether ADM signaling is involved in choroidal neovascularization (CNV) using a mouse model. Methods and Results: CNV was induced by laser photocoagulation in 8-week-old C57BL/6 mice. ADM mRNA expression significantly increased following treatment, peaking 4 days thereafter. The expression of ADM receptor (ADM-R) components (CRLR, RAMP2 and RAMP 3) was higher in CD31+CD45- endothelial cells (ECs) than CD31-CD45- non-ECs. Inflammatory stimulation upregulated the expression of ADM not only in cell lines but also in cells in primary cultures of the choroid/retinal pigment epithelium complex. Supernatants from TNFα-treated macrophage cell lines potentiated the proliferation of ECs and this was partially suppressed by an ADM antagonist, ADM (22-52). Intravitreous injection of ADM (22-52) or ADM neutralizing monoclonal antibody (mAb) after laser treatment significantly reduced the size of CNV compared with vehicle-treated controls (p<0.01). Conclusions: ADM signaling is involved in laser-induced CNV formation, because both an ADM antagonist and ADM mAb significantly inhibited it. Suppression of ADM signaling might be a valuable alternative treatment for CNV associated with age-related macular degeneration. © 2013 Sakimoto et al.
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| 69.
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Ryu Kanzaki, ; Naito, Hisamichi ; Kise, Kazuyoshi ; Takara, Kazuhiro ; Eino, Daisuke ; Minami, Masato ; Shintani, Yasushi ; Funaki, Soichiro ; Kawamura, Tomohiro ; Kimura, Toru ; Okumura, Meinoshin ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />Alterations to the tumor stromal microenvironment induced by chemotherapy could influence the behavi
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or of cancer cells. In the tumor stromal microenvironment, cancer-associated fibroblasts (CAFs) play an important role. Because the receptor tyrosine kinase Axl and its ligand Gas6 could be involved in promoting non-small cell lung cancer (NSCLC), we investigated the role of Gas6 secreted by CAFs during chemotherapy in NSCLC. In a murine model, we found that Gas6 expression by CAFs was upregulated following cisplatin treatment. Gas6 expression might be influenced by intratumoral hypoperfusion during chemotherapy, and it increased after serum starvation in a human lung CAF line, LCAFhTERT. Gas6 is associated with LCAFhTERT cell growth. Recombinant Gas6 promoted H1299 migration, and conditioned medium (CM) from LCAFhTERT cells activated Axl in H1299 cells and promoted migration. Silencing Gas6 in LCAFhTERT reduced the Axl activation and H1299 cell migration induced by CM from LCAFhTERT. In clinical samples, stromal Gas6 expression increased after chemotherapy. Five-year disease-free survival rates for patients with tumor Axl- and stromal Gas6-positive tumors (n = 37) was significantly worse than for the double negative group (n = 12) (21.9% vs 51.3%, p = 0.04). Based on these findings, it is presumed that Gas6 derived from CAFs promotes migration of Axl-expressing lung cancer cells during chemotherapy and is involved in poor clinical outcome. © 2017 The Author(s).
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Yoshida, Mari ; Ishioka, Yukichi ; Ozawa, Takamasa ; Okuyama, Hirohisa ; Iguchi, Motofumi ; Ota, Takeshi ; Ito, Takaomi ; Nagira, Morio ; Morita, Atsushi ; Tanaka, Hidekazu ; Naito, Hisamichi ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />Partner of sld five 1 (PSF1) is an evolutionary conserved DNA replication factor involved in DNA rep
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lication in lower species, which is strongly expressed in normal stem cell populations and progenitor cell populations. Recently, we have investigated PSF1 functions in cancer cells and found that PSF1 plays a significant role in tumour growth. These findings provide initial evidence for the potential of PSF1 as a therapeutic target. Here, we reveal that PSF1 contains an immunogenic epitope suitable for an antitumour vaccine. We analysed PSF1 peptides eluted from affinity-purified human leukocyte antigen (HLA) by mass spectrometry and identified PSF179-87 peptide (YLYDRLLRI) that has the highest prediction score using an in silico algorithm. PSF179-87 peptide induced PSF1-specific cytotoxic T lymphocyte responses such as the production of interferon-γ and cytotoxicity. Because PSF1 is expressed in cancer cell populations and highly expressed in cancer stem cell populations, these data suggest that vaccination with PSF179-87 peptide may be a novel therapeutic strategy for cancer treatment. © 2017 The Author(s).
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| 71.
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Matsushita, Jun ; Inagaki, Shigenori ; Nishie, Tomomi ; Sakasai, Tomoki ; Tanaka, Junko ; Watanabe, Chisato ; Mizutani, Ken-ichi ; Miwa, Yoshihiro ; Matsumoto, Ken ; Takara, Kazuhiro ; Naito, Hisamichi ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; Nagai, Takeharu ; Takahashi, Satoru ; Ema, Masatsugu ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />Angiogenesis is important from normal development as well as from tumour growth. However, the molecu
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lar and cellular mechanisms underlying angiogenesis are not fully understood, partly because of the lack of a good animal model from imaging. Here, we report the generation of a novel transgenic (Tg) mouse that expresses a bioluminescent reporter protein, Nano-lantern, under the control of Fetal liver kinase 1 (Flk1). Flk1-Nano-lantern BAC Tg mice recapitulated endogenous Flk1 expression in endothelial cells and lymphatic endothelial cells during development and tumour growth. Importantly, bioluminescence imaging of endothelial cells from the aortic rings of Flk1-Nano-lantern BAC Tg mice enabled us to observe endothelial sprouting from 18 hr without any detectable phototoxicity. Furthermore, Flk1-Nano-lantern BAC Tg mice achieved time-lapse luminescence imaging of tumour angiogenesis in freely moving mice with implanted tumours. Thus, this transgenic mouse line contributes a unique model to study angiogenesis within both physiological and pathological contexts.
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| 72.
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Yamane, Keitaro ; Naito, Hisamichi ; Wakabayashi, Taku ; Yoshida, Hironori ; Muramatsu, Fumitaka ; Iba, Tomohiro ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />SLD5 is a member of the GINS complex, essential for DNA replication in eukaryotes. It has been repor
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ted that SLD5 is involved in early embryogenesis in the mouse, and cell cycle progression and genome integrity in Drosophila. SLD5 may be involved in malignant tumor progression, but its relevance in human cancer has not been determined. Here, we found strong SLD5 expression in both human bladder cancer tissues from patients and cell lines. Knockdown of SLD5 using small interfering RNA resulted in reduction of cell growth both in vitro and an in vivo xenograft model. Moreover, we found that high levels of SLD5 in bladder cancer cells result from downregulation of microRNA (miR)-370 that otherwise suppresses its expression. High level expression of DNA-methyltransferase (DNMT) 1 and IL-6 were also observed in bladder cancer cells. Knockdown of IL-6 led to downregulation of DNMT1 and SLD5 expression, suggesting that IL-6-induced overexpression of DNMT1 suppresses miR-370, resulting in high SLD5 expression. Our findings could contribute to understanding tumorigenic processes and progression of human bladder cancer, whereby inhibition of SLD5 could represent a novel strategy to prevent tumor growth.
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| 73.
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Sakimoto, Susumu ; Kidoya, Hiroyasu ; Naito, Hisamichi ; Kamei, Motohiro ; Sakaguchi, Hirokazu ; Goda, Nobuhito ; Fukamizu, Akiyoshi ; Nishida , Kohji ; Takakura, Nobuyuki ; 内藤, 尚道 ; 高倉, 伸幸
概要:
金沢大学医薬保健研究域医学系<br />Interactions between astrocytes and endothelial cells (ECs) are crucial for retinal vascular formati
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on. Astrocytes induce migration and proliferation of ECs via their production of vascular endothelial growth factor (VEGF) and, conversely, ECs induce maturation of astrocytes possibly by the secretion of leukemia inhibitory factor (LIF). Together with the maturation of astrocytes, this finalizes angiogenesis. Thus far, the mechanisms triggering LIF production in ECs are unclear. Here we show that apelin, a ligand for the endothelial receptor APJ, induces maturation of astrocytes mediated by the production of LIF from ECs. APJ (Aplnr)- and Apln-deficient mice show delayed angiogenesis; however, aberrant overgrowth of endothelial networks with immature astrocyte overgrowth was induced. When ECs were stimulated with apelin, LIF expression was upregulated and intraocular injection of LIF into APJ-deficient mice suppressed EC and astrocyte overgrowth. These data suggest an involvement of apelin/APJ in the maturation process of retinal angiogenesis. © 2012. Published by The Company of Biologists Ltd.
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| 74.
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Nagao, Seiya ; Kanamori, Masaki ; Ochiai, Shinya ; Tomihara, S. ; Fukushi, Keisuke ; Yamamoto, Masayoshi ; 長尾, 誠也 ; 落合, 伸也 ; 福士, 圭介 ; 山本, 政儀
概要:
金沢大学環日本海域環境研究センター<br />At stations on the Natsui River and the Same River in Fukushima Prefecture, Japan, effects of a h
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eavy rain event on radiocesium export were studied after Typhoon Roke during 21-22 September 2011, six months after the Fukushima Dai-ichi Nuclear Power Plant accident. Radioactivity of 134Cs and 137Cs in river waters was 0.009-0.098 Bq L-1 in normal flow conditions during July-September 2011, but it increased to 0.85 Bq L -1 in high flow conditions because of heavy rains occurring with the typhoon. The particulate fractions of 134Cs and 137Cs were 21-56% of total radiocesium in the normal flow condition, but were close to 100% after the typhoon. These results indicate that the pulse input of radiocesium associated with suspended particles from land to coastal ocean occurred because of the heavy rain event. Export flux of 134Cs and 137Cs attributable to the heavy rain accounts for 30-50% of the annual radiocesium flux from inland to coastal ocean region in 2011. Results show that rain events are one factor contributing to the transport and dispersion of radiocesium in river watersheds and coastal marine environments. © 2013 Author(s).
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| 75.
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Murata, Yoshimasa ; Muroyama, Toshiharu ; Kawabata, Yoshiko ; Yamamoto, Masayoshi ; Komura, Kazuhisa ; 山本, 政儀 ; 小村, 和久
概要:
金沢大学環日本海域環境研究センター<br />Specific activities (Bq/g-element) of residual neutron-induced radionuclides by the JCO criticali
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ty accident were measured for soil, concrete block and chemical reagent samples collected in the JCO campus. Induced radionuclides such as 24Na, 46Sc, 54Mn, 59Fe, 60Co, 65Zn, 82Br, 122Sb, 134Cs and 140La were detected in the samples, depending on the ground distance from the accident point and the sampling date. Apparent thermal, epi-thermal and fast neutron fluences, which reached the sample at each point, were roughly estimated from the specific activities and cross sections of the target nuclides taken from a literature. The present data are believed to be important as validation data for a three-dimensional neutron transport model calculation.
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| 76.
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Konagaya, Matsuo ; Asano, Tetsuo ; 浅野, 哲夫
概要:
金沢大学<br />This paper presents an efficient algorithm for reporting all intersections among n given segments in the plane
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using work space of arbitrarily given size. More exactly, given a parameter s which is between Ω(1) and O(n) specifying the size of work space, the algorithm reports all the segment intersections in roughly O(n2/√s+K) time using O(s) words of O(log n) bits, where K is the total number of intersecting pairs. The time complexity can be improved to O((n2/s)log s+K) when input segments have only some number of different slopes.
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| 77.
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Asano, Tetsuo ; Kumar, Revant ; 浅野, 哲夫
概要:
金沢大学<br />Given a binary image I and a threshold t, the size-thresholded binary image I(t) defined by I and t is the bin
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ary image after removing all connected components consisting of at most t pixels. This paper presents space-efficient algorithms for computing a size-thresholded binary image for a binary image of n pixels, assuming that the image is stored in a read-only array with random-access. With regard to the problem, there are two cases depending on how large the threshold t is, namely, Relatively large threshold where t=Ω(√n), and Relatively small threshold where t=O(√n). In this paper, a new algorithmic framework for the problem is presented. From an algorithmic point of view, the problem can be solved in O(n) time and O(n) work space. We propose new algorithms for both the above cases which compute the size-threshold binary image for any binary image of n pixels in O(n log n) time using only O(√n) work space.
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| 78.
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Bekki, Kanae ; Toriba, Akira ; Ning, Tang ; Kameda, Takayuki ; Hayakawa, Kazuichi ; 戸次, 加奈江 ; 鳥羽, 陽 ; 唐, 寧 ; 亀田, 貴之 ; 早川, 和一
概要:
金沢大学理工研究域自然システム学系<br />Polycyclic aromatic hydrocarbons (PAHs) are included in various environmental pollutants such as
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airborne particles and have been reported to induce a variety of toxic effects. On the other hand, PAH derivatives are generated from PAHs both through chemical reaction in the atmosphere and metabolism in the body.PAH derivatives have become known for their specific toxicities such as estrogenic/antiestrogenic activities and oxidative stress, and correlations between the toxicities and structures of PAH derivatives have been shown in recent studies. These studies are indispensable for demonstrating the health effects of PAH derivatives, since they would contribute to the comprehensive toxicity prediction of many kinds of PAH derivatives.<br />多環芳香族炭化水素類（PAHs）は大気粉塵などの多種類の環境汚染物質に含まれ，長年の研究によって多様な生体影響を引き起こすことが知られている．一方で，PAHsは生体内での代謝反応や，大気中での化学反応によって多種多様な誘導体を生成することが知られている．近年では，PAHだけでなくPAH誘導体の毒性影響が着目されており，エストロゲン様/抗エストロゲン作用，酸化ストレス反応など，PAHとは異なる誘導体独自の毒性影響の存在が報告されている．また，生成するPAH誘導体には多くの構造異性体が存在するが，PAH誘導体が示す毒性作用と構造との間に相関性，いわゆる構造活性相関があることが示されている．以上の研究は，環境中に存在するPAH 誘導体の生体影響を解明する上で重要な研究であるとともに，多種多様なPAH誘導体の総合的な毒性影響予測に貢献できると考えられる．
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| 79.
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Aida, Mammadova ; アイーダ, ママードヴァ
概要:
We created the training course towards Sustainable Development Goals (SDGs) in Kanazawa City, and observed the challenge
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s and opportunities of SDGs in the practice. Field destinations were divided into water, energy, agricultural, fishery, and forestry sectors. Fieldwork showed the strong interconnection between each sector and their sustainable cooperation was clearly observed. However, we have faced several challenges and questions while conducting the course. For example, not all SDGs were related and appropriate to the region, as well as inability to encompass all the SDGs in one course, and also whether the sustainable city model of Kanazawa City can be implemented in developing countries. To address these questions, in our future studies we are going to develop an integrated educational framework towards SDGs.<br />この研究では，金沢市で持続可能な開発目標(SDGs)に向けて集中コースを作成した。市の環境・社会経済分野を視察することにより，この目標の課題をフィールドワークで実地学習した。フィールドの目的地は，水，エネルギー，農業，林業，漁業，工芸と教育分野に分かれている。各分野は強い相対的な関連性を示し，持続可能な協力が明確になった。しかし，コースを作成する際，次のような課題と直面した；すべてのSDGsは地域に適切ではないこと，また各SDGsは相対的に関連し，個別な目標として考えられない。金沢市から学んだ持続可能な教育モデルは教育実習や途上国の教育モデルとして採用できるかなどを次の研究で調査する予定である。
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| 80.
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佐藤, 正英 ; 三浦, 均 ; 上羽, 牧夫 ; Sato, Masahide ; Miura, Hitoshi ; Uwaha, Makio
概要:
金沢大学総合メディア基盤センター<br />We carry out a phase field simulation to study the formation of a comb–like step pattern induced b
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y a straight adatom source advancing in front of a step. The asymmetry of the suface diffusion field induced by the adatom source causes step wandering and small protrusions are formed. The step pattern is changed by the velocity of the adatom soruce, Vp. When Vp is larger than a critical value Vpc, the step cannot follow the adatom source. A seaweed-like pattern is formed with small ϵ4 and a dendritic pattern is formed with large ϵ4, where ϵ4 represents the strength of the anisotropy of step stiffness. When Vp < Vpc, the protrusions follow the adatom source: the comb-like pattern with straight finger-like protrusions, which is induced by step wandering triggered by noise, is formed. For a small Vp, the period of protrusions depends on the strength of noise, but the dependence of the period on the noise strength is week when Vp is near Vpc. The relation between the period and Vp approaches to that between the width of a channel and the velocity of a needle-like step in the free growth in a channel.<br />Embargo Period 12 months
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| 81.
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Sato, Shuichi ; 佐藤, 秀一
概要:
We consider Littlewood-Paley functions associated with a non-isotropic dilation group on ℝn. We prove that certain Littl
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ewood-Paley functions defined by kernels with no regularity concerning smoothness are bounded on weighted Lp spaces, 1 < p < 1, with weights of the Muckenhoupt class. This, in particular, generalizes a result of N. Rivière (1971).
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| 82.
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Suga, Takuya ; Shimizu, Shoma ; Ukaji, Yutaka ; 菅, 拓也 ; 宇梶, 裕
概要:
金沢大学理工研究域物質化学系<br />A concise method to directly generate benzyl radicals from benzyl alcohol derivatives has been devel
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oped. The simple and inexpensive combination of TiCl4(collidine) (collidine = 2,4,6-collidine) and manganese powder afforded a low-valent titanium reagent, which facilitated homolytic cleavage of benzylic C–OH bonds. The application to radical conjugate addition reactions demonstrated the broad scope of this method. The reaction of various benzyl alcohol derivatives with electron-deficient alkenes furnished the corresponding radical adducts.<br />Embargo Period 12 months
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| 83.
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Mammadova, Aida
概要:
Kanazawa University International Student Center
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| 84.
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Arasuna, Akane ; Kigawa, Masahito ; Fujii, Shunsuke ; Endo, Takatsugu ; Takahashi, Kenji ; Okuno, Masayuki ; 荒砂, 茜 ; 髙橋, 憲司 ; 奥野, 正幸
概要:
金沢大学理工研究域自然システム<br />The nanostructure (atomic-scale structure) and water species in the body frame and spicules of the
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marine glass sponge, Euplectella aspergillum, collected from the sea floor around Cebu Island was characterized in detail by thermogravimetric differential thermal analysis, nuclear magnetic resonance spectroscopy, Raman and infrared spectroscopies, and X-ray diffraction method. The structural features of the nanostructure in the body frame and spicules were essentially similar to each other, although these were different from those of inorganic amorphous silica materials, such as silica gel and silica glass. In addition, the averaged short and medium range structures of the sponge may be similar to those of tridymite. The water content and water species included in the body frame and spicules were almost the same. More than half of the contained water was physisorbed water molecules, and the rest was attributed to Q3 and Q2 silanol groups. Most of the water species may be present at the surface and involved in hydrogen bonding.
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| 85.
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Sawada, Takeshi ; Yamamoto, Eiichiro ; Yamano, Hiro-o ; Nojima, Masanori ; Harada, Taku ; Maruyama, Reo ; Ashida, Masami ; Aoki, Hironori ; Matsushita, Hiro-o ; Yoshikawa, Kenjiro ; Harada, Eiji ; Tanaka, Yoshihito ; Wakita, Shigenori ; Niinuma, Takeshi ; Kai, Masahiro ; Eizuka, Makoto ; Sugai, Tamotsu ; Suzuki, Hiromu ; 澤田, 武
概要:
金沢大学医薬保健学総合研究科先進的地域医療研究講座 = Department of Advanced Research in Community Medicine<br />To clarify the molecular and clin
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icopathological characteristics of colorectal serrated lesions, we assessed the DNA methylation of cancer-associated genes in a cohort of BRAF-mutant precancerous lesions from 94 individuals. We then compared those results with the lesions’ clinicopathological features, especially colorectal subsites. The lesions included hyperplastic polyps (n = 16), traditional serrated adenomas (TSAs) (n = 15), TSAs with sessile serrated adenomas (SSAs) (n = 6), SSAs (n = 49) and SSAs with dysplasia (n = 16). The prevalence of lesions exhibiting the CpG island methylator phenotype (CIMP) was lower in the sigmoid colon and rectum than in other bowel subsites, including the cecum, ascending, transverse and descending colon. In addition, several cancer-associated genes showed higher methylation levels within lesions in the proximal to sigmoid colon than in the sigmoid colon and rectum. These results indicate that the methylation status of lesions with BRAF mutation is strongly associated with their location, histological findings and neoplastic pathways. By contrast, no difference in aberrant DNA methylation was observed in normal-appearing background colonic mucosa along the bowel subsites, which may indicate the absence of an epigenetic field defect.
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| 86.
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Sato, Masahide ; 佐藤, 正英
概要:
金沢大学総合メディア基盤センター<br />Covering nanoparticles with DNA strands is one of the useful methods of controlling the interactio
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n between particles because DNA strands can be easily designed according to our specifications. Obtaining an idea from the two-dimensional structures formed by the nanoparticles covered with DNA strands, which we call DNA nanoparticles, we carry out Brownian dynamics simulations and study the formation of two-dimensional structures in a binary system. We assume that the different types of particles attract each other with Morse potential, which is minimum when their distance is σ'. When the types of particles are the same and their distance is smaller than σ, the particles are repulsive. The mixture of both square and triangular lattices is formed when σ'/σ = 1. With decreasing σ'/σ, a square lattice, a honeycomb lattice, and string-shaped clusters are formed. The coexistence of both square and triangular lattices with large σ'/σ and the formation of stringlike clusters with small σ'/σ occur because we neglect the attraction between the same types of particles and use a short-range attraction between different types of particles.<br />Embargo Period 12 months
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| 87.
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Takayama, Yuki ; 髙山, 雄貴
概要:
金沢大学理工研究域地球社会基盤学系 Institute of Science and Engineering<br />This study develops a model in which heterogeneous commuters
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choose their residential locations and departure times from home in a monocentric city with a bottleneck located at the entrance to the central business district (CBD). We systematically analyze the model by utilizing the properties of complementarity problems. This analysis shows that, although expanding the capacity of the bottleneck generates a Pareto improvement when commuters do not relocate, it can lead to an unbalanced distribution of benefits among commuters: commuters residing closer to the CBD gain and commuters residing farther from the CBD lose. Furthermore, we reveal that an optimal time-varying congestion toll alters the urban spatial structure. We then demonstrate through examples that (a) if rich commuters are flexible, congestion tolling makes cities denser and more compact; (b) if rich commuters are highly inflexible, tolling causes cities to become less dense and to spatially expand; and (c) in both cases, imposing a toll helps rich commuters but hurts poor commuters.<br />working paper
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| 88.
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Tada, Hayato ; Nomura, Akihiro ; Nohara, Atsushi ; Inazu, Akihiro ; Mabuchi, Hiroshi ; YAMAGISHI, Masakazu ; Kawashiri, Masa-aki ; 多田, 隼人 ; 野村, 章洋 ; 野原, 淳 ; 稲津, 明広 ; 馬淵, 宏 ; 山岸, 正和 ; 川尻, 剛照
概要:
金沢大学附属病院循環器内科<br />Aim: We aimed to clarify post-prandial accumulation of remnant-like particles (RLP) in patients with
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sitosterolemia.\nMethods: Oral fat tolerance test cream (Jomo Shokuhin, Takasaki, Japan) 50 g was given per body surface area (m2); blood sampling was performed at 2 h intervals up to 6 h. Plasma lipoprotein fractions and RLP fractions were determined in four sitosterolemic subjects with double mutations in ATP-binding cassette (ABC) sub-family G member 5 or member 8 (ABCG5 or ABCG8) gene (mean age=18 yr, median low-density lipoprotein cholesterol [LDL-C]=154 mg/dL), six heterozygous carriers (mean age=31 yr, median LDL-C=105 mg/dL), and five subjects with heterozygous familial hypercholesterolemia (FH, mean age=32 yr, median LDL-C=221 mg/dL). The incremental area under curve (iAUC) of lipids, including LDL-C, apolipoprotein B-48 (apoB48), RLP cholesterol (RLP-C), and RLP triglyceride (RLP-TG) were evaluated.\nResults: After oral fat load, there was no significant difference of the iAUC of LDL-C between sitosterolemia and heterozygous FH, whereas the iAUC of apoB48 was significantly larger in the sitosterolemic subjects compared with that of heterozygous FH (2.9 µg/mL×h vs. 1.3 µg/mL×h, p＜0.05). Under these conditions, the iAUCs of RLP-C and RLP-TG levels were significantly larger in the sitosterolemic subject compared with those of heterozygous FH (9.5 mg/dL×h vs. 5.7 mg/dL×h, p＜0.05; 149 mg/dL×h vs. 40 mg/dL×h, p＜0.05, respectively), whereas those of heterozygous carriers were comparable with those with heterozygous FH.\nConclusions: Post-prandial lipoprotein metabolism in sitosterolemia appeared to be impaired, leading to their elevation in serum sterol levels. (UMIN Clinical Trials Registry number, UMIN000020330)<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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| 89.
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Tada, Hayato ; Nohara, Atsushi ; Inazu, Akihiro ; Sakuma, Nagahiko ; Mabuchi, Hiroshi ; Kawashiri, Masa-aki ; 多田, 隼人 ; 野原, 淳 ; 稲津, 明広 ; 馬淵, 宏 ; 川尻, 剛照
概要:
金沢大学附属病院循環器内科<br />Sitosterolemia is a rare inherited disease characterized by increased levels of plant sterols, such a
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s sitosterol. The cause of this disease is ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively) gene mutations. Recent advances in genetics have revealed that the prevalence of subjects with deleterious mutations in ABCG5 and/or ABCG8 genes could be more than 1 in ~200,000 individuals among the general population. Furthermore, accumulated evidence, including infantile cases exhibiting progression/regression of systemic xanthomas associated with LDL cholesterol levels, have shown that the elevation of LDL cholesterol seems to be the major cause of development of atherosclerosis and not the elevation of sitosterol. Regarding therapies, LDL apheresis, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, could be useful for sitosterolemia, in addition to ezetimibe and/or colestimide. In this study, we provide the current understanding and future perspectives of sitosterolemia, which is currently considered an extremely rare disorder but is expected to be much more prevalent in clinical settings.<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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| 90.
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Nakahashi, Takuya ; Tada, Hayato ; Sakata, Kenji ; Nomura, Akihiro ; Ohira, Miho ; Mori, Mika ; Takamura, Masayuki ; Hayashi, Kenshi ; Yamagishi, Masakazu ; Kawashiri, Masa-aki ; 多田, 隼人 ; 坂田, 憲治 ; 野村, 章洋 ; 大平, 美穂 ; 森, 三佳 ; 高村, 雅之 ; 林, 研至 ; 山岸, 正和 ; 川尻, 剛照
概要:
金沢大学附属病院循環器内科<br />Aim: To assess whether combining measurements obtained from carotid ultrasonography in addition to th
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e age, creatinine, and ejection fraction (ACEF) score would improve the predictive ability of outcome in patients with acute coronary syndrome (ACS).\nMethods: We examined 264 patients with ACS (194 men; mean age: 68±11 years) who underwent percutaneous coronary intervention. The carotid plaque score (cPS) and intima–media thickness (cIMT) were determined by carotid ultrasonography. The modified ACEF score was calculated using the following formula: (age/left ventricular ejection fraction) ＋1 point for every 10 mL/min reduction in creatinine clearance below 60 mL/min per 1.73 m2. The endpoint of this study was major adverse cardiovascular and cerebrovascular events (MACEs), defined as all-cause death, myocardial infarction, stoke, and target vessel revascularization.\nResults: During the median 4-year follow-up, there were 121 incidents of MACEs. Multivariate Cox proportional hazard regression analysis revealed that cPS ≥9.8 (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.01–2.31) and ACEF score ≥1.20 (HR, 1.62; 95% CI, 1.11–2.39) were significantly associated with MACEs, whereas cIMT was not. When the new combined risk score was calculated by multiplying the cPS by the modified ACEF score, the freedom from MACEs at 5 years was 71% and 31% for the lower and higher scores, respectively (p＜0.001). The area under the receiver-operating characteristic curve for MACEs for the ACEF score, cPS, and combined risk score were 0.65, 0.66, and 0.71, respectively (p＜0.05).\nConclusion: The cPS offers an incremental predictive value when combined to the simple ACEF score in ACS.<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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| 91.
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Nomura, Akihiro ; Tada, Hayato ; Nohara, Atsushi ; Kawashiri, Masa-aki ; Yamagishi, Masakazu ; 野村, 章洋 ; 多田, 隼人 ; 野原, 淳 ; 川尻, 剛照 ; 山岸, 正和
概要:
金沢大学附属病院先端医療開発センター<br />Aim: Sitosterolemia is an extremely rare, autosomal recessive disease characterized by high plas
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ma cholesterols and plant sterols because of increased absorption of dietary cholesterols and sterols from the intestine, and decreased excretion from biliary tract. Previous study indicated that sitosterolemic patients might be vulnerable to post-prandial hyperlipidemia, including high remnant-like lipoprotein particles (RLP) level. Here we evaluate whether a loading dietary fat increases a post-prandial RLP cholesterol level in sitosterolemic patients compared to heterozygous familial hypercholesterolemic patients (FH).\nMethods: We recruit total of 20 patients: 5 patients with homozygous sitosterolemia, 5 patients with heterozygous sitosterolemia, and 10 patients with heterozygous FH as controls from May 2015 to March 2018 at Kanazawa University Hospital, Japan. All patients receive Oral Fat Tolerance Test (OFTT) cream (50 g/body surface area square meter, orally only once, and the cream includes 34% of fat, 74 mg of cholesterol, and rich in palmitic and oleic acids. The primary endpoint is the change of a RLP cholesterol level after OFTT cream loading between sitosterolemia and FH. We measure them at baseline, and 2, 4, and 6 hours after the oral fat loading.\nResults: This is the first study to evaluate whether sitosterolemia patients have a higher post-prandial RLP cholesterol level compared to heterozygous FH patients.\nConclusion: The result may become an additional evidence to restrict dietary cholesterols for sitosterolemia. This study is registered at University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000020330).<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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| 92.
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Tada, Hayato ; Kawashiri, Masa-aki ; Nohara, Atsushi ; Inazu, Akihiro ; Kobayashi, Junji ; Yasuda, Kenji ; Mabuchi, Hiroshi ; Yamagishi, Masakazu ; Hayashi, Kenshi ; 多田, 隼人 ; 川尻, 剛照 ; 野原, 淳 ; 稲津, 明広 ; 小林, 淳二 ; 馬淵, 宏 ; 山岸, 正和 ; 林, 研至
概要:
金沢大学附属病院循環器内科<br />Aim: The Japan Atherosclerosis Society (JAS) guidelines for the prevention of atherosclerotic disease
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s 2012 (JAS2012) proposed lipid management targets; however, less data is available regarding the attainment rates of each target in community-based settings. Therefore, we assessed the attainment rates of lipid management targets among subjects who underwent Japanese specific health checkups.\nMethods: A total of 85,716 subjects (male=29,282, 34.2%) aged 40–74 years who underwent specific health checkups from 2012 to 2014 in Kanazawa city, Japan, were included in this study. We evaluated the attainment rates of the lipid management targets according to the JAS2012 guideline and investigated the clinical characteristics of the subjects without achieving the targets.\nResults: The target for LDL cholesterol (LDL-C) was the least attained in all risk categories, 89, 72, 50, and 34% for category I, II, III, and secondary prevention, respectively, in 2014. In addition, these rates inversely correlated with the grade of risk categories (p-value for trends ＜0.001). Attainment rate of the LDL-C target in the suspected chronic kidney disease (CKD) group was significantly lower than in the groups with diabetes, stroke, or absolute risk in category III (49.2, 60.3, 63.5, 54.4%, respectively, p-value ＜0.001 for each). Moreover, the attainment rate of the LDL-C target was significantly lower in subjects that did not receive lipid-lowering therapy than in those who received it in the secondary prevention (27.7 and 40.6%, respectively, p-value ＜0.001).\nConclusions: Lipid management is inadequate in community-based settings, particularly, in subjects with CKD and secondary prevention.<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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| 93.
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Tada, Hayato ; Kawashiri, Masa-aki ; Yamagishi, Masakazu ; 多田, 隼人 ; 川尻, 剛照 ; 山岸, 正和
概要:
金沢大学附属病院循環器内科<br />We have learned that low-density lipoprotein (LDL) cholesterol is the cause of atherosclerosis from v
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arious aspects, including a single case with familial hypercholesterolemia, other cases with different types of Mendelian dyslipidemias, large-scale randomized controlled trials using LDL cholesterol lowering therapies, and Mendelian randomization studies using common as well as rare variants associated with LDL cholesterol levels. There is no doubt that determinations of genotypes in lipid-associated genes have contributed not only to the genetic diagnosis for Mendelian dyslipidemias but also to the discoveries of novel therapeutic targets. Furthermore, recent studies have shown that such genetic information could provide useful clues for the risk prediction as well as risk stratification in general and in particular population. We provide the current understanding of genetic analyses relating to plasma lipids and coronary artery disease.<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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| 94.
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Doui-Ota, Misato ; 太田(堂井), 美里
概要:
金沢大学医薬保健研究域薬学系<br />中国では， 目的とする薬効の向上や副作用低減を目的に， 大黄には主に酒製や蒸製の修治が施されてきた。 現在の 『中華人民共和国薬典』 には， 「酒大黄」 と称する酒炒 （酒を吹きかけた後に炙る） 品，
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「熟大黄」 と称する酒蒸 （酒を吹きかけた後に蒸す） 品が収載されているが， 修治による効能変化についてはこれまで充分に研究されてこなかった。 本稿では， 本草考証研究と成分研究により熟大黄と酒大黄の本質を調査した。 熟大黄については， 本草考証研究によると， 解毒作用を期待した大黄は酒製の後に蒸したものではなく単に蒸したものであった。 一方， 成分研究から十分量の酒に浸した後に蒸したものは解毒作用が期待できると考えられる。 更に本修治により瀉下作用が低下すると判断できる。 次に酒大黄については， 金元代以降から酒炒品は駆血作用を期待して用いていたと考えられる。 本作用を有する修治大黄は酒を吹きかけた後に加熱して製するべきである。<br />In China, rhubarb has been mainly processed with liquor or by steaming to increase its medicinal effects or decrease its side effects. The modern Chinese Pharmacopoeia describes frying rhubarb after spraying with liquor as shu-daiou and steaming rhubarb after spraying with liquor as jyuku-daiou; however pharmacologic significance of processing has not been elucidated. In this article, the author examines jyuku-daiou and shu-daiou in herbological and chemical studies. As for jyuku-daiou, in herbological study, the rhubarb which used as a remedy against poison was not steamed after liquor processed one but simply steamed one. However in chemical study, the rhubarb which soaked in a sufficient amount of liquor before being steamed expects to be used as a remedy against poison. In addition, the rhubarb is considered to have a decreased purgative effect. Then as for shu-daiou, frying rhubarb after processed with liquor has been used to improve blood stasis since the Jin and Yuan Dynasties in China. The rhubarb with the effect should be processed as follows; sprayed with liquor before being heated. © 2013, Medical and Pharmaceutical Society for WAKAN-YAKU. All rights reserved.
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| 95.
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Doui, Misato ; Mikage, Masayuki ; Kawahara, Nobuo ; 堂井, 美里 ; 御影, 雅幸
概要:
金沢大学医薬保健研究域薬学系<br />日本では， ショウガの乾燥品を 「生姜」， 湯煎または蒸製品を 「乾姜」 としているが， これらの品質は加工方法の違いに影響される。 我々はショウガの色彩の変化は加熱方法により異なり， その変化は 6
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-shogaol の 6-gingerol に対する割合 （［S/G］） と相関していることを明らかにした。 すなわち， 蒸製品の a* 値 （赤み） と 6-shogaol の 6-gingerol に対する割合 （［S/G］） の間に正の相関が認められたが， 湯煎品では成分比によらず a* 値はほぼ一定であった。 また， 180℃での加熱品では ［S/G］ と a* 値に対数曲線上の相関が認められた。 本研究では， 上述の結果を応用して市場品 「生姜」， 「乾姜」 の品質評価を行なった。 その結果， 大半の 「生姜」 の a* 値は ［S/G］ と対数曲線上の相関が認められたが， 表面に白味を帯びた検体の a* 値は 2 以下となり， 曲線と離れた場所に位置した。 一方 「乾姜」 の a* 値と ［S/G］ の関係は， 正の相関を成すもの， ［S/G］ に関わらず a* 値が 9 付近のもの， a* 値が 8 以下のものの 3 パターンに分かれた。 これらの調製法は順に蒸製， 湯煎， 低温での湯煎品であると判断した。 以上， 色彩と ［S/G］ の値から調製法が予測できることを明らかにした。<br />In Japan, dried ginger is called shokyo, and ginger dried after soaked in hot water or steamed is called kankyo. The quality of processed ginger might be affected by the processing methods. Previously, we reported that the heating method used to process fresh ginger affected the color of the resultant product and how its color was correlated with its 6-shogaol to 6-gingerol ratio ([S/G]); i.e., the a* value (indicating redness) of steamed ginger positively correlated with its [S/G], the a* value of ginger soaked in hot water remained constant regardless of its [S/G], and the a* value of ginger heated at 180°C displayed a logarithmic correlation with [S/G]. In this paper, we used the above results to evaluate the quality of shokyo and kankyo products on the market. As a result, we found that the a* values of most shokyo products logarithmically correlated with their [S/G]. However, shokyo products with whitish surfaces displayed a* values of less than + 2, and their a* values and [S/G] showed no correlations. Meanwhile, kankyo products were divided into 3 groups by the relationships between the a* values and [S/G]; i.e., samples whose a* values correlated with their [S/G], those with a* values around + 9, and those with a* values less than + 8. These kankyo samples might be produced by steaming, soaking in hot water, and soaking in warm water, respectively. Therefore, we confirmed that the combination of color values and [S/G] could be used to infer processing methods of ginger products. © 2013, Medical and Pharmaceutical Society for WAKAN-YAKU. All rights reserved.
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| 96.
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Fukazawa, Ayako ; Yamaguchi, Masaya ; Takano, Fumihide ; Mikage, Masayuki ; 御影, 雅幸
概要:
金沢大学医薬保健研究域薬学系<br />Jatyadi Taila(J)はアーユルヴェーダ（インド伝統医学）で用いられる薬用オイルであり，特に薬線Kshara Sutraを用いた痔瘻手術の際に用いられている。この手術方法は日本へも導入されて
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いるが，Jについては薬理作用，毒性および術後処置について未だ明らかにされていない。そこで本研究では，培養ヒト表皮角化細胞におけるケモカイン・インターロイキン（IL）-8の産出および細胞増殖作用に対するJの効果を調査した。さらにJの代替品として紫雲膏および中黄膏を構成する生薬に基づいたオイルを調製することを試みた。JはTPAで共刺激された角化細胞中のIL-8 産出に影響を及ぼさなかったが，強い細胞毒性を示した。鬱金で作ったオイルは角化細胞中のIL-8産出および細胞毒性を示した。鬱金および黄柏で作ったオイルはIL-8産出を抑える傾向を示した。Jのメタノール画分は細胞毒性を示さずIL-8産出を抑制した。ゴマ油や紫根で作ったオイルのメタノール画分は有意に角化細胞を増殖させたが，IL-8産出に影響を及ぼさなかった。以上よりJは角化細胞の炎症反応の調節を通じて皮膚炎を抑制する可能性があることが示された。紫雲膏や中黄膏に基づいたオイルがKshara Sutraによる手術を受けた患者に役立つ可能性がある。<br />An Ayurvedic medicated oil, Jatyadi Taila (J), is known to be used in Ayurveda (Indian traditional medicine), especially for anal fistula surgery involving the medicated thread Kshara Sutra. Although this surgical method has been introduced into Japan, the pharmacological efficacy, toxicity and postoperative care for J remain unclear. In this study, we investigated the effects of this oil on production of the chemokine interleukin (IL)-8 as well as cell proliferation in cultured human epidermal keratinocytes. We also attempted to create an oil for Kshara Sutra based on Kampo ointments such as shiunko and chuoko, instead of J. J itself did not affect IL-8 production in keratinocytes co-stimulated with TPA, but showed a strong cytotoxicity toward this cell line. Among the tested oils, oil of turmeric resulted in suppression of not only IL-8 production but also cell growth in cultured keratinocytes. Oil of turmeric and Phellodendri Cortex showed a tendency to suppress IL-8 production under the same condition. The methanol-eluted fractions of J suppressed IL-8 production without any significant cytotoxicity. The methanol fraction of the oil from sesame or Lithospermi Radix significantly enhanced the proliferation of keratinocytes without IL-8 production. These findings indicate that the Ayurvedic oil J may have potential for suppression of skin inflammation through regulation of the keratinocyte inflammatory response. It is further proposed that Japanese Taila based on shiunko and chuoko might be useful for Kshara Sutra surgery in patients. © 2012, Medical and Pharmaceutical Society for WAKAN-YAKU. All rights reserved.
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| 97.
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Han, Yan ; Kitaoka, Fumiyo ; Mano, Masumi ; Sasaki, Yohei ; Mikage, Masayuki ; 御影, 雅幸
概要:
金沢大学医薬保健研究域薬学系<br />漢方生薬 「威霊仙」 はキンポウゲ科のセンニンソウ属植物の地下部に由来する。 近年の生薬市場には多数の原植物に由来する威霊仙が見られるが， 日・中の薬局方では原植物を Clematis hexapet
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ala, C. mandshurica および C. chinensisの 3 種であると規定している。 現在日本， 中国及び韓国市場の威霊仙の原植物を明らかにする目的で， 東アジアに産するセンニンソウ属植物のうち関連する 9 分類群について， 分子生物学的に ITS 領域を検討した。 その結果， ITS 全領域の塩基配列を検討することにより， 9 分類群を区別することができた。 以上の結果から， 現在市場で入手した11サンプルの威霊仙を分子遺伝学的に同定することができた。 すなわち， 日本市場品は 4 サンプルのうち 3 つは C. mandshurica で， 1 つは C. chinensis であった。 中国市場品 4 サンプルのうち 2 つは C. mandshurica で， 他の 2 つは C. brachyura であった。 韓国産 3 サンプルのうち 2 つは C. mandshurica で， 他の 1 つは C. terniflora var. robusta であった。<br />Clematidis Radix (Wei Ling Xian in Chinese and Ireisen in Japanese) is a crude drug used in traditional Chinese medicine and is derived from the underground parts of Clematis plants, which belong to the family Ranunculaceae. The Clematidis Radix sold in modern markets is derived from a variety of botanical origins, whereas the Chinese and Japanese pharmacopoeias state that Clematidis Radix should be produced from Clematis hexapetala, C. mandshurica, or C. chinensis. To clarify the botanical origin of this crude drug, 9 closely related taxa of the genus Clematis growing in East Asia were subjected to molecular biological studies of their internal transcribed spacer (ITS) regions. We found that the ITS region nucleotide sequences of the 9 taxa had diverged. As a result, the 9 taxa could be successfully differentiated by comparing their whole ITS region sequences. Based on this result, 11 Clematidis Radix samples obtained from modern Japanese, Chinese, and Korean markets were genetically identified as follows: Of the samples from Japanese markets, 3 out of 4 were categorized as C. mandshurica, and one as C. chinensis. Among the samples from Chinese markets, 2 out of 4 were identified as C. mandshurica, and the other two as C. brachyura. Meanwhile, of the 3 samples from Korean markets, two were identified as C. mandshurica, and the other as C. terniflora var. robusta. © 2013, Medical and Pharmaceutical Society for WAKAN-YAKU. All rights reserved.
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| 98.
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Okutsu, Kayu ; Kurotani, Arisa ; Sasaki, Yohei ; Mikage, Masayuki ; 御影, 雅幸
概要:
金沢大学医薬保健研究域薬学系<br />アーユルヴェーダではアリシュタという薬酒が広く利用されている。 日本の薬酒が酒に生薬を浸漬し作られるチンキ剤であるのに対し， アリシュタは生薬の煎液をアルコール発酵させて作られる。 発酵による生薬の成
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分変化が， チンキ剤にはないアリシュタ独自の効能に寄与していると予想される。 本研究では， アリシュタとチンキ剤の相違点を明らかにすることを目的とし， 生姜， 大棗， ヒハツから製造したアリシュタ及びチンキ剤のピペリン及び [6]-ジンゲロール含量を HPLC により比較した。 アリシュタ中のピペリン含量はチンキ剤より高く14.6 mg/l であり， 製造過程で大きな変化は見られなかった。 一方アリシュタ中の [6]-ジンゲロール含量は11.3 mg/l とチンキ剤の50%以下であり， 製造過程において [6]-ジンゲロールが減少していた。 そこで [6]-ジンゲロールを添加した酵母培養液を LC-MS/MS 分析し， 酵母によるジンゲロールの代謝物を調べた。 その結果， ジンゲロールが酵母により [6]-ショウガオールなど 4 つの化合物に代謝されていることが示唆され， 同様の化合物がアリシュタにも含まれることが明らかになった。<br />In Ayurveda, practitioners use a herbal liquor called Arishta to treat patients suffering with emaciation or indigestion. Arishta is produced by decocting various herbs and then subjecting the resultant liquid to alcoholic fermentation. During the alcoholic fermentation stage, the constituents of Arishta change chemically, which would also alter the medicinal effects of Arishta. In order to characterize the components of Arishta, we investigated the differences between the compositions of Arishta and a tincture (an alcohol-soaked herbal liquor). First, we attempted to prepare Arishta in our laboratory from ginger, jujube, and long pepper and compared the piperine and [6]-gingerol contents of Arishta with those of the abovementioned tincture using HPLC. The alcohol content of the laboratory-made Arishta (LM-Arishta) was 15%, which was almost the same as that of the Arishta sold in Sri Lanka. The piperine content of the LM-Arishta was 14.6 mg/l, which was slightly higher than that of the tincture. It seems that decoction is more effective way to extract piperine than ethanol immersion. However, [6]-gingerol content of the LM-Arishta was 11.3 mg/l, which was less than 50% of that of the tincture. Subsequently, we incubated [6]-gingerol with yeast in culture medium to search [6]-gingerol metabolites. LC-MS/MS analysis suggested that [6]-gingerol is transformed to 4 metabolites such as [6]-shogaol and 3 or 5 acetoxy-[6]-gingerdiol during alcoholic fermentation. These metabolites were also detected in LM-Arishta and thus, it was suggested that [6]-gingerol was metabolized during LM-Arishta making. © 2013, Medical and Pharmaceutical Society for WAKAN-YAKU. All rights reserved.
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| 99.
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Shi, Wen ; Kitaoka, Fumiyo ; Doui, Misato ; Miyake, Katsunori ; Sasaki, Yohei ; Kakiuchi, Nobuko ; Mikage, Masayuki ; 堂井, 美里 ; 垣内, 信子 ; 御影, 雅幸
概要:
金沢大学医薬保健研究域薬学系<br />日本薬局方ではアカネ科 Uncaria sinensis Havil., U. rhynchophylla Miq. 及び U. macrophylla Wall. の鉤を釣藤鉤として規定している。
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釣藤鉤には異なる薬効を示すインドール及びオキシインドールアルカロイドが含まれているが， これらの組成は原植物の違いにより特徴的に異なるとされる。 しかし， Uncaria 属植物のアルカロイド組成に影響を与える要因については報告されていない。 本研究では， 広域で採集した Uncaria 属植物の種を DNA 塩基配列により正確に同定した後に， アルカロイド （rhynchophylline, geissoschizine methyl ether 及び hirsutine） 含量を HPLC 法により測定した。 その結果， 降水量が低い地域に生育する U. rhynchophyllaの鉤及び茎にアルカロイド含量が高い傾向が認められた。 また， 同一種であっても， 栽培品と野生品のアルカロイド組成は異なり， 市場品 「釣藤鉤」 には rhynchophylline 優位のタイプと geissoschizine methyl ether と hirsutine 優位のタイプの 2 種が確認された。 加えて， 釣藤鉤の原植物を正確に同定するために， DNA 塩基配列解析及び PCR-RFLP 法を用いた分子系統学的手法を確立した。<br />The Japanese Pharmacopoeia states that the crude drug Chotoko is composed of the hooks of Uncaria rhynchophylla Miq., U. sinensis Havil., and U. macrophylla Wall., all of which belong to the Rubiaceae family. It has been reported that the indole and oxindole type alkaloids contained in Chotoko have different pharmacological effects, and Chotoko products derived from different species are composed of different alkaloids. However, there are no reports about the factors affecting the chemical compositions of Uncaria plants. In this study, we analyzed the alkaloid contents (the rhynchophylline, geissoschizine methyl ether, and hirsutine contents) of Uncaria samples collected from a broad range of sites by HPLC after identifying their species by DNA sequence analysis. As a result, we found that the hooks and small stems of U. rhynchophylla grown in habitats with lower annual precipitation levels tended to display higher alkaloid contents. We also found that the alkaloid compositions of cultivated Uncaria plants were different from those of wild plants, even those belonging to the same species, and crude Chotoko products displayed two types of alkaloid profile, the rhynchophylline-rich type and the geissoschizine methyl ether and hirsutine-rich type. Moreover, in order to accurately identify the botanical origin of Chotoko, we established a method involving molecular genetics techniques; i.e., DNA sequence analysis and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). © 2012, Medical and Pharmaceutical Society for WAKAN-YAKU. All rights reserved.
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| 100.
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Tatsukawa, Sanae ; Mikage, Masayuki ; 御影, 雅幸
概要:
金沢大学医薬保健研究域薬学系<br />漢薬 「木通」 は， 日局でその基源がアケビ科のアケビ又はミツバアケビの蔓性の茎であると規定され， わが国での国内需要のすべては国内野生品でまかなわれている。 日本に分布する本属植物は主にアケビ， ミ
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ツバアケビ及びこれらの雑種とされているゴヨウアケビの 3 分類群であるが， 生薬について種の区別はなされておらず， ゴヨウアケビ由来のものも流通している可能性が高い。 また， アケビとミツバアケビについて薬理作用や成分に差が認められ， 同属植物内でも種による使い分けの必要性が示唆されている。 しかし， 日本産については生薬の形態から原植物の鑑別は不可能であるとされてきた。 そこで， 日本産本属植物3分類群の木質茎の形態学的特徴を検討し， 市場品の基源鑑別法の確立を試みた。 その結果， 木質茎表面の色， コルク組織の構造及び茎の半径とコルク層の厚みの関係において相違が認められ， 90 % 以上の精度で 3 分類群を識別できる検索表を作成した。 これにより， 日本産 「木通」 について原植物の識別がほぼ可能になり， 日本産 「木通」 の主産地である信越及び四国産にゴヨウアケビ由来品が流通していることが示唆された。<br />The Japanese Pharmacopoeia Fifteenth Edition prescribes Akebiae Caulis, Mokutsu in Japanese, should be the woody stem of Akebia quinata Decaisne and A. trifoliata Koidzumi of the family Lardizabalaceae. We examined morphologically the woody stems of 3 wild Akebia taxa growing in Japan, A. quinata, A. trifoliata, and A. × pentaphylla Makino, for the purpose of finding morphological criteria to discriminate them and for identifying Mokutsu in the market. We found that the 3 taxa could be distinguished by a combination of surface color of stem, inner morphologies of stone cells and sclerenchyma cells, etc. with an accuracy of more than 90%, though it had been reported that A. quinata and A. trifoliata could not be distinguished by only stem anatomy. Using these criteria, we found that the woody stems of all 3 Akebia taxa were circulated equally in the Japanese market. This is the first record that the stem of A. × pentaphylla is circulating in the market as Mokutsu. © 2007, Medical and Pharmaceutical Society for WAKAN-YAKU. All rights reserved.
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