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1. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial

Author

Mercuri, Eugenio Maria, Deconinck, N., Mazzone, Elena Stacy, Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, Giovanni, Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W. Y., Martin, Craig, Fontoura, P., Day, J. W., Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Fuerst-Recktenwald, S., Marquet, A., Mulhardt, N., Trundell, D., Daron, A., Delstanche, S., Romain, B., Dal Farra, F., Schneider, O., Balikova, I., Delbeke, P., Joniau, I., Tahon, V., Wittevrongel, S., De Vos, E., Casteels, I., De Waele, L., Cassiman, C., Prove, L., Kinoo, D., Vancampenhout, L., Van Den Hauwe, M., Van Impe, A., Prufer de Queiroz Campos Araujo, A., Chacon Pereira, A., Nardes, F., Haefeli, L., Rossetto, J., Almeida Pereira, J., Ferreira Rebel, M., Campbell, C., Sharan, S., Mcdonald, W., Scholtes, C., Mah, J., Sframeli, M., Chiu, A., Hagel, J., Beneish, R., Pham, C., Toffoli, D., Arpin, S., Turgeon Desilets, S., Wang, Y., Hu, C., Huang, J., Qian, C., Shen, L., Xiao, Y., Zhou, Z., Li, H., Wang, S., Xiong, H., Chang, X., Dong, H., Liu, Y., Sang, T., Wei, C., Wen, J., Cao, Y., Lv, X., Zhao, J., Li, W., Qin, L., Barisic, N., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Gidaro, T., Seferian, A., De Lucia, Sara Sofia, Barreau, E., Mnafek, N., Momtchilova, M. M., Peche, H., Valherie, C., Grange, A., Lilien, C., Milascevic, D., Tachibana, S., Ravelli, C., Cardas, R., Vanden Brande, L., Davion, J. -B., Coopman, S., Bouacha, I., Debruyne, P., Defoort, S., Derlyn, G., Leroy, F., Danjoux, L., Guilbaud, J., Desguerre, I., Barnerias, C., Semeraro, M., Bremond-Gignac, D., Bruere, L., Rateaux, M., Deladriere, E., Germa, V., Pereon, Y., Magot, A., Mercie, S., Billaud, F., Le Goff, L., Letellier, G., Portefaix, A., Fontaine, S., De-Montferrand, C., Le-Goff, L., Saidi, M., Bouzid, N., Barriere, A., Tinat, M., Dreesbach, M., Lagreze, W., Michaelis, B., Molnar, F., Seger, D., Vogt, S., Bertini, Enrico Silvio, D'Amico, Adele, Petroni, S., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Priolo, E., Rao, G., Morando, S., Tacchetti, P., Zuffi, A., Comi, G. P., Brusa, R., Corti, Serafino, Daniele, V., Govoni, A., Magri, F., Minorini, V., Osnaghi, S. G., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Meneri, M., Zoppas, F., Parente, V., Masson, R., Bianchi Marzoli, Stefania, Santarsiero, Rocco Domenico, Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Zanin, Renata, Amorelli, Giulia Maria, Barresi, C., D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, Haginoya, K., Kato, A., Morishita, Y., Kira, R., Akiyama, K., Goto, M., Mori, Y., Okamoto, M., Tsutsui, S., Takatsuji, Y., Tanaka, A., Komaki, H., Suzuki, I., Takeuchi, M., Todoroki, D., Watanabe, S., Omori, M., Matsubayashi, T., Inakazu, E., Nagura, H., Suzuki, A., Osaka, H., Ohashi, M., Ishikawa, N., Harada, Y., Fudeyasu, K., Hirata, K., Michiue, K., Ueda, K., Yashiro, S., Seki, M., Sano, N., Uemura, A., Fukuyama, K., Matsumoto, Y., Miyazaki, H., Shibata, M., Kobayashi, K., Nakamura, Y., Takeshima, Y., Kuma, M., Fraczek, A., Jedrzejowska, M., Lusakowska, A., Czeszyk-Piotrowicz, A., Hautz, W., Rakusiewicz, K., Burlewicz, M., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Mazurkiewicz-Beldzinska, M., Lemska, A., Modrzejewska, S., Koberda, M., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Steinborn, B., Dalz, M., Grabowska, J., Hajduk, W., Janasiewicz-Karachitos, J., Klimas, M., Stopa, M., Gajewska, E., Pusz, B., Vlodavets, D., Melnik, E., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Milic Rasic, V., Brankovic, V., Kosac, A., Djokic, O., Jaksic, V., Pepic, A., Martinovic, J., Munell Casadesus, F., Tizzano, E., Martin Begue, N., Wolley Dod, C., Subira, O., Planas Pascual, B., Toro Tamargo, E., Madruga Garrido, M., Medina Romero, J. D., Salinas, M. P., Nascimento Osorio, A., Diaz Cortes, A., Jimenez Ganan, E., Suh, S. D., Medina Cantillo, J., Moya, O., Padros, N., Roca Urraca, S., Gonzalez Valdivia, H., Pascual Pascual, S., de Manuel, S., Noval Martin, S., Burnham, P., Espinosa Garcia, S., Martinez Moreno, M., Topaloglu, H., Oncel, I., Eroglu Ertugrul, N., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Ayse Karaduman, A., Tunca Yilmaz, O., Bilgin, N., Sari, S., Chiriboga, C., Kane, S., Lee, J., Rome-Martin, D., Beres, S., Duong, T., Gee, R., Dunaway Young, S., Mercuri E. (ORCID:0000-0002-9851-5365), Mazzone E. S., Baranello G., Martin C., De Lucia S., Bertini E., D'Amico A., Corti S., Bianchi Marzoli S., Santarsiero D., Zanin R., Amorelli G. M., D'Amico G., Orazi L., Coratti G. (ORCID:0000-0001-6666-5628), Mercuri, Eugenio Maria, Deconinck, N., Mazzone, Elena Stacy, Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, Giovanni, Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W. Y., Martin, Craig, Fontoura, P., Day, J. W., Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Fuerst-Recktenwald, S., Marquet, A., Mulhardt, N., Trundell, D., Daron, A., Delstanche, S., Romain, B., Dal Farra, F., Schneider, O., Balikova, I., Delbeke, P., Joniau, I., Tahon, V., Wittevrongel, S., De Vos, E., Casteels, I., De Waele, L., Cassiman, C., Prove, L., Kinoo, D., Vancampenhout, L., Van Den Hauwe, M., Van Impe, A., Prufer de Queiroz Campos Araujo, A., Chacon Pereira, A., Nardes, F., Haefeli, L., Rossetto, J., Almeida Pereira, J., Ferreira Rebel, M., Campbell, C., Sharan, S., Mcdonald, W., Scholtes, C., Mah, J., Sframeli, M., Chiu, A., Hagel, J., Beneish, R., Pham, C., Toffoli, D., Arpin, S., Turgeon Desilets, S., Wang, Y., Hu, C., Huang, J., Qian, C., Shen, L., Xiao, Y., Zhou, Z., Li, H., Wang, S., Xiong, H., Chang, X., Dong, H., Liu, Y., Sang, T., Wei, C., Wen, J., Cao, Y., Lv, X., Zhao, J., Li, W., Qin, L., Barisic, N., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Gidaro, T., Seferian, A., De Lucia, Sara Sofia, Barreau, E., Mnafek, N., Momtchilova, M. M., Peche, H., Valherie, C., Grange, A., Lilien, C., Milascevic, D., Tachibana, S., Ravelli, C., Cardas, R., Vanden Brande, L., Davion, J. -B., Coopman, S., Bouacha, I., Debruyne, P., Defoort, S., Derlyn, G., Leroy, F., Danjoux, L., Guilbaud, J., Desguerre, I., Barnerias, C., Semeraro, M., Bremond-Gignac, D., Bruere, L., Rateaux, M., Deladriere, E., Germa, V., Pereon, Y., Magot, A., Mercie, S., Billaud, F., Le Goff, L., Letellier, G., Portefaix, A., Fontaine, S., De-Montferrand, C., Le-Goff, L., Saidi, M., Bouzid, N., Barriere, A., Tinat, M., Dreesbach, M., Lagreze, W., Michaelis, B., Molnar, F., Seger, D., Vogt, S., Bertini, Enrico Silvio, D'Amico, Adele, Petroni, S., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Priolo, E., Rao, G., Morando, S., Tacchetti, P., Zuffi, A., Comi, G. P., Brusa, R., Corti, Serafino, Daniele, V., Govoni, A., Magri, F., Minorini, V., Osnaghi, S. G., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Meneri, M., Zoppas, F., Parente, V., Masson, R., Bianchi Marzoli, Stefania, Santarsiero, Rocco Domenico, Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Zanin, Renata, Amorelli, Giulia Maria, Barresi, C., D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, Haginoya, K., Kato, A., Morishita, Y., Kira, R., Akiyama, K., Goto, M., Mori, Y., Okamoto, M., Tsutsui, S., Takatsuji, Y., Tanaka, A., Komaki, H., Suzuki, I., Takeuchi, M., Todoroki, D., Watanabe, S., Omori, M., Matsubayashi, T., Inakazu, E., Nagura, H., Suzuki, A., Osaka, H., Ohashi, M., Ishikawa, N., Harada, Y., Fudeyasu, K., Hirata, K., Michiue, K., Ueda, K., Yashiro, S., Seki, M., Sano, N., Uemura, A., Fukuyama, K., Matsumoto, Y., Miyazaki, H., Shibata, M., Kobayashi, K., Nakamura, Y., Takeshima, Y., Kuma, M., Fraczek, A., Jedrzejowska, M., Lusakowska, A., Czeszyk-Piotrowicz, A., Hautz, W., Rakusiewicz, K., Burlewicz, M., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Mazurkiewicz-Beldzinska, M., Lemska, A., Modrzejewska, S., Koberda, M., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Steinborn, B., Dalz, M., Grabowska, J., Hajduk, W., Janasiewicz-Karachitos, J., Klimas, M., Stopa, M., Gajewska, E., Pusz, B., Vlodavets, D., Melnik, E., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Milic Rasic, V., Brankovic, V., Kosac, A., Djokic, O., Jaksic, V., Pepic, A., Martinovic, J., Munell Casadesus, F., Tizzano, E., Martin Begue, N., Wolley Dod, C., Subira, O., Planas Pascual, B., Toro Tamargo, E., Madruga Garrido, M., Medina Romero, J. D., Salinas, M. P., Nascimento Osorio, A., Diaz Cortes, A., Jimenez Ganan, E., Suh, S. D., Medina Cantillo, J., Moya, O., Padros, N., Roca Urraca, S., Gonzalez Valdivia, H., Pascual Pascual, S., de Manuel, S., Noval Martin, S., Burnham, P., Espinosa Garcia, S., Martinez Moreno, M., Topaloglu, H., Oncel, I., Eroglu Ertugrul, N., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Ayse Karaduman, A., Tunca Yilmaz, O., Bilgin, N., Sari, S., Chiriboga, C., Kane, S., Lee, J., Rome-Martin, D., Beres, S., Duong, T., Gee, R., Dunaway Young, S., Mercuri E. (ORCID:0000-0002-9851-5365), Mazzone E. S., Baranello G., Martin C., De Lucia S., Bertini E., D'Amico A., Corti S., Bianchi Marzoli S., Santarsiero D., Zanin R., Amorelli G. M., D'Amico G., Orazi L., and Coratti G. (ORCID:0000-0001-6666-5628)

Abstract

Background: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. Methods: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2–25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing. Findings: Between Oct 9, 2017, and Sept 4, 2018, 180 patients were rand

Published
2022

3. Granular thin films with high RF permeability

Author

Shimada, Yutaka, Yamaguchi, Masahiro, Ohnuma, Sigehiro, Itoh, Tetsuo, Li, Wei Dong, Ikeda, Sinji, Kim, Ki Hyeon, and Nagura, H.

Subjects
Thin films -- Research, Dielectric films -- Research, Business, Electronics, Electronics and electrical industries
Abstract

Owing to high resistivity and high inplane uniaxial anisotropy, granular films are known to exhibit high permeability at radio frequencies. But this granular resistivity is not high enough to suppress eddy current when they are used at gigahertz frequencies. Recent developments to solve this problem are described. One is patterning the granular films. It is effective to control the inplane anisotropy and to suppress inplane eddy current. Another is deposition of granular films by evaporation. A peculiar fiber structure is formed for which very high resistivity and anisotropy are realized. Finally, a study of using these films as near-field electromagnetic noise absorbers is described, and it is demonstrated that they have high potential as micrometer-scale noise absorbing elements in the gigahertz frequency range. Index Terms--EMC, granular films, patterned film, permeability.

Published
2003

24. Proceedings of the international session of the 26th annual meeting October 18–20, 1984—Chiba, Japan

Author

Kato, Y., Miyamori, H., Unoura, M., Ohmizo, N., Tanaka, N., Kobayashi, K., Hattori, N., Arakawa, Y., Amaki, S., Shikata, T., Liu, Bang-Hyun, Kanai, K., Morioka, S., Nishida, M., Noto, H., Takahashi, K., Matsushita, K., Beasley, R. Palmer, Hwang, Lu-Yu, Yano, M., Shima, M., Tsunoda, E., Koga, M., Minamino, T., Tsuji, T., Kagawa, K., Okuno, T., Takino, T., Kurihara, Takeshi, Obata, Hiroshi, Beasley, R. Palmer, Okita, K., Konishi, T., Kado, Y., Yokosuka, O., Omata, M., Imazeki, F., Ryuu, M., Okuda, K., Mitamura, Keiji, Chen, D. S., Sung, J. L., Lai, M. Y., Sheu, J. C., Hsu, H. C., Nakamura, T., Morizane, T., Tsuchiya, M., Kobayashi, K., Unoura, M., Okawa, K., Kobayashi, K., Kitano, A., Kuwajima, S., Hashimura, H., Matsumoto, T., Hiki, M., Yamamoto, S., Kinoshita, Y., Nagura, H., Shioda, Y., Tsutsumi, Y., Hasegawa, H., Watanabe, K., Kanoh, T., Nishida, O., Uchino, H., Miyake, T., Hishitani, Y., Bhargava, D. K., Shriniwas, B. N. Tandon, Kapur, B. M. L., Chawla, T. C., Kiran, Usha, Gupta, J. P., Jain, A. K., Agrawal, B. K., Gupta, Saroj, Chiba, M., Sasaki, M., Konn, M., Yamanaka, Y., Morita, T., Hashizume, T., Nara, K., Odagiri, H., Fujii, M., Ono, K., Nio, Y., Tsuchitani, T., Inamoto, T., Kodama, H., Tobe, T., Shi, Z. R., Kim, Y. S., Yamaoka, H., Nishiyama, K., Tajima, S., Fukushima, T., Tsuchiya, S., Kuroe, K., Kimura, A., Suwa, Y., Furukawa, H., Miyake, T., Watanabe, M., Yoshida, T., Aiso, S., Asakura, H., Tsuchiya, M., Miura, M., Hiwatashi, N., Fujiyama, Y., Kobayashi, K., Bamba, T., Hosoda, S., Benno, Y., Wakashin, Y., Wakashin, M., Mori, T., Ueda, S., Yoshida, H., Mori, Y., Okuda, K., You, Li, Wei-Fa, Ye, Yang, Guang-Xao, Ye, Wei-Fa, Nelwan, R. H. H., Gandhi, B. M., Gupta, H., Irshad, M., Chawla, T. C., Tandon, B. N., Cho, Mong, Liu, Bang-Hyun, Wu, Xie-ning, Tandon, Rakesh K., Srivastava, A. K., Kapur, B. M. L., Misra, R. K., Jiang, Shi-hu, Lin, Yan-zun, Liu, Bang-Hyun, Abdurachman, S. A., Hadi, Sujono, Bhargava, D. K., Agrawal, B. K., Bhat, K. R., Baoen, Wang, Madanagopalan, N., Solomon, V., Jayanthi, V., Raghuram, K., Kandasamy, I., Annapoorani, S., Gajarai, A., Panchanadam, M., Joshi, Y. K., Gandhi, B. M., Tandon, B. N., Hassan, A., Guntur, H., Soemarto, R., Rahardja, S. H., Soemarto, W., Baoen, Wang, Park, Keun-Soo, Liu, Bang-Hyun, Yao, G. B., Zhang, L. M., Wu, M. F., Tong, S. T., Tian, Y. F., Iwai, N., Kaneda, H., Tsuto, T., Yanagihara, J., Takahashi, T., Jinkun, Zhang, Jinkun, Zhang, Durrani, Hamid A., Gupta, J. P., Jain, A. K., Govil, A. K., Tripathi, V. N. P., Baoen, Wang, Shi, Z. R., Yin, D. Y., Wen, F. Q., Zhang, Jinkun, Panchanadam, M., Balasubramania, V. C., Are, P. S., Thyagarajan, S. P., Mahadevan, S., Dravidamani, S., Nigam, Pranesh, Agrawal, A. K., Kapoor, K. K., Lesmana, L., Sidharta, H., Marwoto, W., Akbar, N., Sulaiman, A., Sjaifoellah Noer, H. M., Gupta, J. P., Tantry, B. V., Jain, A. K., Sheu, J. C., Chen, D. S., Sung, J. L., Chuang, C. N., Yang, P. M., Lin, J. T., Hsu, H. C., Sheu, J. C., Lin, Y. H., Chen, D. S., Lee, C. S., Beasley, R. P., Hwang, L. Y., Nigam, Pranesh, Kapoor, K. K., and Gupta, A. K.

Published
1985
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29. Analysis of cell damage and proliferation in Helicobacter pylori-infected human gastric mucosa from patients with gastric adenocarcinoma

Author

Yabuki, N., Sasano, H., Tobita, M., Imatani, A., Hoshi, T., Kato, K., Ohara, S., Asaki, S., Toyota, T., and Nagura, H.

Subjects
Male, Helicobacter pylori, Pancreatic Elastase, Adenocarcinoma, Middle Aged, Immunohistochemistry, digestive system diseases, Helicobacter Infections, Ki-67 Antigen, Gastric Mucosa, Stomach Neoplasms, Humans, Female, Cell Division, Research Article, Aged, DNA Damage
Abstract

Helicobacter pylori (HP) infection, a cause of multifocal atrophic gastritis, is considered an important factor related to the evolution of the human gastric mucosa from normal to intestinal-type adenocarcinoma. We examined cell proliferation and both double and single strand DNA damage in situ in 35 patients undergoing gastrectomy for adenocarcinoma with HP-infected gastric mucosa by immunolocalization of Ki-67, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, and in situ nick translation. We also studied the distribution of intraepithelial neutrophils by elastase immunolocalization. HP infection was confirmed in all cases by serum anti-HP antibodies, ureas testing, and histopathological examination. HP-infected gastric mucosa was classified according to the degree of inflammation and intestinal metaplasia. Ki-67, terminal deoxynucleotidyl transferase-mediated labeling, in situ nick translation, and intraepithelial neutrophil indices all increased with the progression of gastritis and were highest in glands with incomplete intestinal metaplasia. All indices were lowest in gastric glands with complete intestinal metaplasia. Significant positive correlations were observed among these markers. Increased proliferative activity in HP-associated chronic gastritis in response to cell damage or injury was clearly demonstrated, suggesting that both HP-associated toxins and intraepithelial neutrophils are important in HP-related gastric epithelial injury. Increased cell turnover associated with incomplete intestinal metaplasia may result in DNA instability and subsequent development of intestinal-type gastric adenocarcinoma in HP-infected mucosa.

Published
1997

30. Immunohistochemical study of DNA topoisomerase II in human gastric disorders

Author

Yabuki, N., Sasano, H., Kato, K., Ohara, S., Toyota, T., Nagura, H., Miyaike, M., Nozaki, N., and Kikuchi, A.

Subjects
Research Article
Abstract

Topoisomerase II (topo II) separates chromosomes at the end of mitosis and is also the target for various chemotherapeutic agents. Expression of this enzyme has been demonstrated to increase rapidly at the end of the S to G2/M phase and decrease after the completion of mitosis. We immunolocalized topo II in specimens of both normal and neoplastic human gastric mucosas to evaluate expression of this enzyme. Three different antibodies were used for the immunostaining of topo II (anti-topo II alpha isoform, anti-topo II beta isoform and anti-topo II alpha and -beta isoforms). There were no significant differences in topo II labeling index (LI) between frozen and paraffin-embedded tissue sections obtained from the same cases. Topo II LI was significantly correlated with Ki67 LI in all of the specimens examined. The area of cells positive for Topo II was much narrower than that of Ki67 in the normal gastric glands, and the pattern of Topo II immunolocalization in both adenomas and adenocarcinomas was also essentially the same as that of Ki67. The topo II LI values (positive cells/1000 cells) for normal gastric gland, adenoma, intestinal-type adenocarcinoma, and diffuse-type adenocarcinoma were 114.7 +/- 2.2, 266.7 +/- 18.8, 277.6 +/- 19.2, and 324.5 +/- 5.3, respectively. Significant differences in topo II LI and topo II/Ki67 index were observed between normal and neoplastic mucosas (P < 0.0001) and between adenomas or intestinal-type adenocarcinoma and diffuse-type adenocarcinoma (P < 0.001 and P < 0.01, respectively). Simultaneous measurement of topo II alpha and nuclear DNA content by two-parameter flow cytometry revealed that the Jurkat cell line established from acute lymphocytic leukemia cells expressed the enzyme in cells at other than S and G2/M phases of the cell cycle whereas topo-II alpha-positive cells were predominantly observed in S and G2/M phases of the cell cycle in the cells from normal lymph nodes. These findings suggest that dys-regulation or qualitative changes of topo II alpha expression are associated with malignancy. Topo II immunostaining can thus detect proliferating cells in routinely processed tissue sections and can indicate the altered topo II alpha expression in human cancers, which may be related to the sensitivity to topo-II-targeted chemotherapeutic agents.

Published
1996

31. Immunophenotypic characterization of Epstein-Barr virus-associated gastric carcinoma: massive infiltration by proliferating CD8+ T-lymphocytes

Author

Saiki Y, Ohtani H, Naito Y, Masaaki Miyazawa, and Nagura H

Subjects
Herpesvirus 4, Human, Cell Count, Herpesviridae Infections, CD8-Positive T-Lymphocytes, Flow Cytometry, Immunohistochemistry, Immunophenotyping, Tumor Virus Infections, Antigens, CD, Stomach Neoplasms, Biomarkers, Tumor, Humans, Neoplasm Invasiveness, Microscopy, Immunoelectron, Cell Adhesion Molecules, Cell Division, In Situ Hybridization
Abstract

A subset of gastric carcinoma carries Epstein-Barr virus (EBV). The immunophenotypic features of EBV-associated (EBV+) gastric carcinoma, which we have analyzed using 25 EBV+ cases, remain unclear. Frozen tissue samples were stained with antibodies to various immune cell markers. To evaluate the proliferative activity of CD8+ cells, we performed CD8/Ki-67 double staining on paraffin-embedded sections. The results were compared with those in EBV-negative (EBV-) gastric carcinomas. All EBV+ and EBV- gastric carcinoma cells expressed major histocompatibility complex class I, whereas major histocompatibility complex class II expression in tumor cells was more prominent in EBV+ cases. Intercellular adhesion molecule-1 and Fas/APO-1 expression was largely restricted to EBV+ cases. The lymphocytes that infiltrated EBV+ tumor nests were predominantly CD8+ T cells, many of which expressed perforin. Immunoelectron microscopy confirmed a close cell to cell contact between these CD8+ cells and carcinoma cells. CD8+ cells were CD11a+ and CD11b- by flow cytometry performed in one case. The labeling index of Ki-67, the proliferation-associated antigen, in CD8+ cells was 4 times higher in EBV+ cases than in EBV- cases. Our data suggest that these CD8+ cells, which bear a cytotoxic phenotype, are actively proliferating in close contact with EBV+ tumor cells and that the specificity of the CD8+ cells may be directed to EBV and/or cellular antigens expressed by the tumor. This is consistent with a generally favorable prognosis of EBV+ gastric carcinoma. Because the observed T-cell infiltration is insufficient to eradicate the tumor cells, certain immunosuppressive factors were speculated to allow the essentially immunogenic carcinoma cells to establish a macroscopic lesion.

Published
1996

32. Immunoelectron microscopic localization of transforming growth factor beta 1 and latent transforming growth factor beta 1 binding protein in human gastrointestinal carcinomas: qualitative difference between cancer cells and stromal cells

Author

Mizoi T, Ohtani H, Miyazono K, Masaaki Miyazawa, Matsuno S, and Nagura H

Subjects
Microscopy, Macrophages, Intracellular Signaling Peptides and Proteins, Fibroblasts, Immunohistochemistry, Latent TGF-beta Binding Proteins, Transforming Growth Factor beta, Granulation Tissue, Humans, Protein Precursors, Carrier Proteins, Microscopy, Immunoelectron, Digestive System, Gastrointestinal Neoplasms, Subcellular Fractions
Abstract

Transforming growth factor beta 1 (TGF-beta 1) is secreted as an inactive complex associated with latent TGF-beta 1 binding protein (LTBP). Tissue localization of these proteins has not been fully understood in human pathological conditions. We examined the immunohistochemical localization of TGF-beta 1 precursor (proTGF-beta 1) and LTBP in carcinomas and granulation tissue in the human gastrointestinal tract at the light and electron microscopic levels. In normal tissue, endothelial cells and granulocytes sporadically showed immunoreactivity for proTGF-beta 1, while epithelial cells were all negative. In cancer tissue, both cancer cells and stromal cells (fibroblasts, macrophages, and endothelial cells) were positive for proTGF-beta 1, more frequently in diffuse-type gastric carcinomas than in differentiated-type adenocarcinomas. Immunoelectron microscopy revealed that proTGF-beta 1 was localized in rough endoplasmic reticulum and perinuclear cisternae in fibroblasts, macrophages, and endothelial cells in cancer stroma and in fibrous granulation tissue. In contrast, the intracellular localization of proTGF-beta 1 in carcinoma cells was predominantly observed in the cytosol (cytoplasmic matrix). This finding suggests disarranged or blocked intracellular transportation of proTGF-beta 1 in cancer cells. The immunoreactivity for LTBP was not observed in the normal epithelial cells. It was localized in cancer stroma, not in cancer cells. Ultrastructurally, LTBP was located in the extracellular matrix around fibroblasts and smooth muscle cells. The intracellular immunoreactivity for LTBP was observed in rough endoplasmic reticulum of fibroblasts and smooth muscle cells, the same as in granulation tissue. These results suggest that gastrointestinal carcinoma cells produce no or a small amount of LTBP in vivo. Our investigation suggests that extensive fibrosis in both cancer stroma and granulation tissues may be promoted by TGF-beta 1 mainly secreted from stromal cells.

Published
1993

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