37 results on '"Baasanjav B."'
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2. 295 EFFECT OF TREHALOSE DURING IN VITRO MATURATION OF PIG OOCYTES ON OOCYTE MATURATION AND EMBRYONIC DEVELOPMENT AFTER PARTHENOGENESIS
- Author
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Jeon, Y., primary, Baasanjav, B., additional, Jeong, Y. I., additional, Jeong, Y. W., additional, Kim, Y. W., additional, Hyun, S. H., additional, Yang, I. S., additional, and Hwang, W. S., additional
- Published
- 2015
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3. Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study
- Author
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Labeau, Sonia O, Afonso, Elsa, Benbenishty, Julie, Blackwood, Bronagh, Boulanger, Carole, Brett, Stephen J, Calvino-Gunther, Silvia, Chaboyer, Wendy, Coyer, Fiona, Deschepper, Mieke, François, Guy, Honore, Patrick M, Jankovic, Radmilo, Khanna, Ashish K, Llaurado-Serra, Mireia, Lin, Frances, Rose, Louise, Rubulotta, Francesca, Saager, Leif, Williams, Ged, Blot, Stijn I, Dritan, Muzha, Antoni Margarit Ribas, Fernando, Lipovesty, Cecilia, Loudet, Fiona, Coyer, Philipp, Eller, Nafseen, Mostafa, Patrick, M Honoré, Vanesa Mercado Telleria, Jasmina, Smajic, Paula Cristina Nogueira, Khalid Mahmood Khan Nafees, Romuald, Hentchoya, Louise, Rose, Javiera, Soledad, Frances, Lin, Yenny, Cardenas, Amylkar Garay Reyes, Alan, Sustic, Meropi, Mpouzika, Tamas, Vymazal, Hanne Irene Jensen, Hernan, Aguirre-Bermeo, Liivi, Maddison, Maija, Valta, Silvia, Calvino-Gunther, Frank, Bloos, Faustina Excel Adipa, Vasilios, Koulouras, Judy, Enamorado, Zsuzsann, Ágoston, Hrönn, Birgisdóttir, Amit, Gupta, Mohan, Gurjar, Bram, Kilapong, Seyed Mohammadreza Hashemian, Ignacio, Martin-Loeches, Julie, Benbenishty, Andrea, Cortegiani, Kelly, Fletcher, Yoshiro, Hayashi, Wangari, Waweru-Siika, Khalid, Abidi, Sang-Min, Lee, Burhan, Hadri, Mihails, Dolgusevs, Fayez François Abillama, Tomas, Jovaisa, Cyril, Thix, Muhammed, Elhadi, Basri Mat Nor, Shanti, Ratnam, Mohd Zulfakar Mazlan, Sundaresan, Maiyalagan, Luis, Sánchez-Hurtado, Adrian, Belii, Mendsaikhan, Naranpurev, Prabha, Gautam, Dylan De Lange, Rachael, Parke, Rose Ekama Ilesanmi, Mirjana, Shosholcheva, Antonija, Petosic, Ranveig, Lind, Madiha Hashmi Ffarcsi, Javier, Bogarin, Aaron Mark Hernandez, Malgorzata, Mikaszewska-Sokolewicz, Bruno, Sousa, Dana, Tomescu, Dorel, Sandesc, Theogene, Twagirumugabe, Vitaly, Gusarov, Maie, Ebaid, Radmilo, Jankovic, Gari, Slobodianiuk, Andrea, Martonova, Rihard, Knafelj, Mervyn, Mer, Emilio, Maseda, Bernardo, Panka, Joerg, C Schefold, Eva, Joelsson-Alm, Konlawij, Trongtrakul, Lorna, Merritt-Charles, Lamia Ouanes Besbes, Yalım, Dikmen, Lesia, Zgrzheblovska, Mark, Fielding, Francesca, Rubulotta, Ashish, K Khanna, Leif, Saager, Ingrid von der Osten, Alban, Greca, Alma, Cani, Nordian, Xhindi, Genci, Hyska, Antonio Margarit Ribas, Susana, Pinto, Paulo, Alves, Romina, Esposito, Emanuel, Valgolio, John Thomas Sanchez Minope, Antonio, Abdala, Maria, Ayala, Silvina, Bravo, Ana, Bantar, Patricia, Delgado, Gustavo, Badariotti, Fernando, Lipovestky, Ana, Diaz, Pablo, Saul, Mariano, Setten, Alejandra, Aucapina, Ysica, Acosta, Victor, Gonzalez, Luis, Camputaro, Fernando, Baccaro, Robert, Villa, Marcela, Mastantuono, Emiliano, Dean, Oscar Fernández Rostello, Patricia, Brizuela, Julio Ricardo Bartoli, Matias, Guereschi, Cristian, Quiroga, Sofia, Putruele, Paula, Villegas, Veronica, Curilen, Ruben, Fernandez, Mariangeles Gabriela Nocheretti, Rosana Gabriela Escalante, Cecilia Inés Loudet, Silvia, Fernandez, Ana Laura Gonzalez, Gustavo Andres Alvarez, Federico, Iglesias, Silvia, Chaparro, Graciela, Zakalik, Gonzalo, Pagella, Matías, Baini, Pierina Arias Campos, Ignacio, Sabbag, Armando, Schmukler, Imelda Perdomo Fonseca, Gonzalo Martín Alvarez, Mario, Ramirez, Fernando, Tapia, Carlos Alejandro Bascary, Graciela Del Valle Gimenez, Fernando Pablo Bertoletti, Esteban, Milioto, Pablo Julio Maldonaldo Bonsignore, Maria Alejandra Fernandez, Julie, Smith, Tim, Chimunda, Lorraine, Thompson, Teena, Maguire, Wendy, Chaboyer, Stacey, Watts, Marion, Mitchell, Madeleine, Powell, India, Lye, Leanne, Parsons, Nerilee, Baker, Claire, Reynolds, Amy, Thompson, Kristy, Masters, Kellie, Sosnowski, Lynette, Morrison, Gavin, D Leslie, Ramanathan, Lakshmanan, Alexis, Tabah, Wendy, Brown, Sharon, McDowell-Skaines, Andrea, Mclucas, Chris, Smith, Mandy, Tallot, Sarah, Jones, Michelle, Barakat-Johnson, Thomas, Leong, Rand, Butcher, Kerrie, Martin, Philipp, Douschan, Dirk von Lewinski, René, Schmutz, Uta, Kolussi, Fatema, Salman, Zainab, Ateya, Koen De Decker, Niels Van Regenmortel, Anita, Jans, Patricia, Wijnands, Stefano, Coremans, Patrick, M Honore, David De Bels, Tanja, Depuydt, Caroline, Paillet, Luc-Marie, Jacquet, Walter, Swinnen, Francis, Hannes, Matthia, Mergeay, Stijn Van de Velde, Silvie, Allaert, Pieter, Hoste, Christophe, Borin, Sandrine, Balon, Vincent, Fraipont, Patrick, Biston, Nicolas De Schryver, Thierry, Dugernier, Ilse Van Cotthem, Angelica Olivetto de Almeida, Silvia Angelica Jorge, Delmiro, Becker, Raysa Cristina Schmidt, Evellyn, Oliveira, Aline, Ramalho, Eliane, Mazocoli, Audrey, Fioretti, Elaine, Barros, Leticia, Serpa, Suzana, Bianchini, Ticiane, Campanili, Taís, Pantaleao, Paulo Carlos Garcia, Ana Lucia Vitti Ronchini, Rayanne, Santos, Nurulhuda Binti, A Manap, Sean, Bagshaw, Dominic, Carney, Jon, Davidow, Ella, Rokosh, Andréa Maria Laizner, Samantha, Smith, Megan, Mcquirter, Betty Star Kampayana, René, Favre, Martin, Sills, Julie, Dallaire, Cathy, Becker, Sherissa, Microys, Bonnie, Bowes, Jennifer, Lajeunesse, Rishi, Ghosh, Jacqueline, Baptiste-Savoie, Rose, Raizman, Gabriel, Suen, Noushin, Taghavi, Orla, Smith, Clare, Fielding, Julieta, Canales, Pia, Molina, Javiera, Chaparro, Maria Idalia Sepulveda, Matias Jesús Flamm Zamorano, Pamela, Rocha, Ximena, Villanueva, Paola, Araya, Meneses, Dayan, Fernando, Avalos, Xiaohan, Li, Liu, Yu, Xinxia, Li, Xiaoyan, Chen, Zhixia, Jiang, Jing, Yang, Jingfang, Chen, Lei, Yang, Kefang, Wang, Jie, Gao, Xiuhua, Fang, Ronghua, Zhao, Xinhua, Xia, Hongmei, Liu, Jing, Li, Haiyan, Wang, Gen, Meng, Yanhong, Di, Damei, Wang, Rong Hua Zhao, Li Ping Hu, Peipei, Xu, Qing Feng Jiao, Hai Yun Wang, Chun Jie Xia, Yan, Liu, Mei, Ye, Yan, Wan, Wenmei, Wang, Yajun, Ding, Aiua, Ren, Yan, Gao, Qi, Li, Guifang, Du, Yanling, Shen, Yanming, Ding, Ning, Li, Cui, Yuan, Lei, Tan, Qiang, Lin, Hailing, Guo, Howe, Yan, Xiao, Xu, Wei, Zhang, Jinxian, Liang, Libing, Zhang, Eryun, Tian, Qian, Zhao, Lin, Insu, Jingwen, Dong, Yanmei, Gu, Ying, Liu, Lina, Zhao, Wei, Wang, Hongmei, Qiao, Lili, Tuo, Mengmeng, Lv, Jin Yu Zhu, Jifen, Zhu, Ying, Wei, Man, Liu, Yin, He, Jiyin, Cheng, Jin, Liu, Jia, Na, Dongfang, Wei, Qing, Li, Xiaoying, Wu, Huan, Duan, Dongliang, Lin, Qiong, Liang, Xiaofang, Luo, Yunfeng, Xiong, Rong Fen Huang, Jing, Fu, Tao, Zan, Man, Ye, Zeya, Shi, Yanfei, Long, Yang, Lei, Xiaodi, Liu, Chen, Yumei, Lingling, Wang, Yali, Zhang, Yan, Xu, Cheng, Wang, Zhijuan, Chengxia, Sun, Jinhui, Song, Yingli, Wang, Xiumei, Liu, Yupeng, Liu, Yuxia, Yuan, Qingping, Huang, Fengling, Yang, Yun, Wu, Xianping, Luo, Xiaowu, Bai, Hong, Zheng, Min, Song, Yue, Sun, Zhangshuangzi, Li, Feifei, Luo, Miao, Liu, Li Chuntang Li, Xinjian, Li, Guiping, Zhang, Lina, Xiao, Tingting, Yu, Guangyuan, Gao, Wei, Wei, Fanglan, Wang, Ting, Han, Tingting, Li, Zeng, Qi, Jing Mei Zeng, Yan, Long, Fuqun, Pan, Jing, Wang, Guoxue, He, Haiyan, Chen, Feifei, Zhang, Chao, Yu, Gao, Chunhua, Xiuying, Yao, Dongmei, Bai, Liu, Lu, Xuelian, Xu, Yan, Wang, Xuejuan, Liang, Zhang, Na, Aizhi, Zhang, Xiaochun, Hu, Hui, Zhang, Ruixia, Wang, Poon Shing Tak, Sung Wai Ho, Qun Xia Jiang, Xinran, Ding, Liu, Hong, Limei, Miao, Zhaoxia, Feng, Liping, Huang, Juan, Wu, Yuping, Wang, Jiye, Guo, Baoke, Zhang, Chaoqun, Ma, Han, Yu, Congcong, Liu, Min, Ding, Linlin, Luan, Jing, Zheng, Shanshan, Lv, Shumin, Jiang, Wenzhen, Cao, Xiujuan, Xue, Guangyan, Liu, Xiyan, Wei, Youru, Jiang, Zhiru, Yao, Gao, Li, Jinhua, Li, Wenwen, Zhao, Mei, Jiang, Junping, Hao, Jing, Zhang, Caiju, Song, Feifei, Chen, Shuhui, Wang, Lili, Hu, Deyan, Cao, Jianhong, Wan, Xiaomin, Wang, Hongyan, Shao, Zhenxia, Zhang, Xia, Cui, Jingyu, Liu, Lijuan, Zhao, Xingguo, Li, Limei, Fan, Ling, Zhang, Min, Yu, Biyan, Li, Chunxia, Li, Ling, Liu, Xuelian, Liu, Wenmin, Chen, Yan, Li, Zhang, Zhigang, Yuchen, Wu, Chenghau, Mu, Guoyan, Zhu, Fan, Yang, Qi, Bo, Ling, Li, Meili, Chen, Jing Hua Jiang, Hai, Yin, Xuelian, Pang, Yue Ying Gong, Shunzhu, Yang, Xiaoli, Yan, Xianhong, Zheng, Dehong, Lei, Lei, Lei, Yinhua, Guo, Lihong, Liu, Jing, Yu, Wei, Sun, Aiping, Bi, Weiwei, Li, Yang, Wu, Ji, Li, Dongshu, Ni, Zijing, Wu, Bing, Song, Qin, Fei, Yang, Xiaoyan, Qiong, Ran, Xixi, Li, Xueping, Jiao, Hua, Ji, Sun, Zhiping, Hong, Ma, Jianhong, Mu, Yanhua, Hao, Yin, Li, Ying, Wang, Caihong, Hui, Wenjie, Ju, Yuxia, Huo, Yuxia, Wang, Lei, Chen, Yan, Yan, Qingli, Zhao, Hongjuan, Chen, Guijun, Bao, Ying, Cao, Hong, Li, Hong, Zhang, Ying, Zhang, Lina, Xu, Jia, Guixiang, Ying, Li, Hui Min Zhao, Xia, Huang, Zhaoxing, Dai, Yanman, Jian, Hongsu, Zhang, Zhixia, Tian, Zu Qing Cao, Miao, Li, Yang, Liu, Fei, Ouyang, Fuying, Ma, Wangyan, Jin, Liuyan, Ge, Shifen, Wu, Weilian, Yuan, Tianfei, Chen, Guanxiu, Shi, Zhihong, Chen, Kewei, Liu, Xue, Lin, Yuemen, Ly, Sun, Lijuan, Xiao Fang Tian, Shuo, Wang, Zhangxia, Feng, Xiaozhe, Liu, Yunchun, Dong, Jundi, Zhang, Nie, Bocui, Guoxian, Wang, Yingjuan, Zhao, Xiaojun, Wu, Qiao, Yang, Rongjun Ling Hu, Xue Qin Li, Zhu Jun Yu, Yanlan, Yao, Xiaoqiong, Deng, Yan, Xiao, Yan, Xie, Yanping, Yang, Huai, Yang, Yuming, Zhou, Zhuqing, Li, Min, Xiao, Yongxia, Yang, Yani, Tian, Luz Marina Silva Gama, Juan Sebastian Hernandez, Nestor, Caicedo, Jorge, Marin, Maria-Elena, Ochoa, Monica, Gomez, José, Rojas-Suarez, Jeniffer, Gonzalez, Amylkar José Garay Reyes, Edwin, Chapeta, Estefania, Orozco, Ina, Filipović-Grčić, Anita, Vuković, Suzana, Pečenković, Aleksandar, Šuput, Gordana, Zivanovic-Posilovic, Armanda, Bozena, Nikolina, Udiljak, Morena, Milic, Renata Curic Radivojevic, Slobodan, Mihaljevic, Marijana, Matas, Dinko, Tonkovic, Hemena, Čuljak, Ivana, Herceg, Gordana, Pavlisa, Milena, Dobric, Tatjana, Beker, Višnja Nesek Adam, Tanja, Goranovic, Chrysanthos, Markoulias, Mina, Mathaios, Maria, Mylordou, Eleni, Achilleos, Pavlina, Kleanthous, Veronika, Kotanidi, Maria, Foka, Iwy, Charalabous, Anna, Alexandrou, Marios, Georgiou, Artemis, Patsalos, Sofia, Zepoy, Constantina, Constantinou, Petr, Piza, Tomas, Vymazal, Elisabeth, Wiborg, Louise, Bruhn, Karin, Kaasby, Karin Rehnholt Pedersen, Sanne, Mikkelsen, Marie, Collet, Anne, Langvad, Hanne, Andresen, Susanne, Fischer, Inger Ebbesen Kjærgård, Britta, Jepsen, Birthe, Husted, Morten, Bestle, Anne Marie Kodal, Tina Charlotte Bitsch Hansen, Anne Sofie Bomholt Pedersen, Tina Damgaar Thomsen, Anisette, Hoegenhaven, Mette, From, Tine Melgaard Frandsen, Grit, Henning, Anja, Hansen, Inger Abildgaard Bliksted, Luis Mario Tamayo, Pedro, Mogrovejo, Carolina, Palaez, Diego Rolando Morocho Tutillo, Cintia Valencia Hurtado, Maria Fernanda García, Diana, Alvarez, Fausto, Guerrero, Alexandra, Vasquez, Martin, Kütimets, Kadri, Tamme, Eneli, Anvelt, Lomangisi, Dlamini-Sserumaga, Carita, Löfqvist, Virpi, Lusenius, Outi, Kauppi, Jenni-Katarina, Sakki, Tarja, Tervo-Heikkinen, Ulla, Kesti, Merja, Merilainen, Elina, Karjula, Minna, Peltomaa, Auli, Palmu, Maarit, Ahtiala, Maija Anniina Valta, Hervé, Mentec, Gaëtan, Plantefève, Guillaume, Besch, Sébastien, Pili-Floury, Stanislas, Ledochowski, Marc Danguy des Déserts, Christophe, Giacardi, Cédric, Daubin, Audrey, Massard, Yann Le Guen, Agnès, Blanc, Simon, Mandaroux, Silvia Calvino Günther, Prune, Avogadro, Anthony, Radavidson, Jean, Turc, Sébastien, Jochmans, Hervé, Quintard, Laetitia, Boyer, Cédric, Bruel, François, Philippart, Philippe, Montravers, Enora, Atchade, Nadine, Flessel, Benoît, Chinardet, Léa, Soulisse, Cindy, Pillard, Delphine, Ngo, Benjamin, Bongiorno, Nathalie, Heitzler, Virginie, Souppart, Nathalie, Gautheret, Jean-Francois, Timsit, Fatiha, Essardy, Muriel, Fartoukh, Daisy, Mehay, Fabienne, Etourneau, Jean-Christophe, Farkas, Pascal, Beuret, Gabriel, Preda, Etienne De Montmollin, Vincent, Castelain, Ulrich, Jaschinski, Monika, Rothenfusser, Detlef, Kindgen-Milles, Thomas, Dimski, Christine, Fiedler, Tobias, Heinicke, Patrick, Meybohm, Tobias, Schulze, Marc, Bota, Sabrina, Pelz, Tobias, Odenthal, Martin, Christ, Kathrin, Bösl, Achilleas, Chovas, Sebastian, Stehr, Philipp, Simon, Sarah, Grotheer, Sebastian, Schüppel, Stefan, Schaller, Lea, Albrecht, Andeas, Stübner, Stephan, Graeser, Nina, Kolbe, Martina, Lausch, Anja, Diers, Ulf, Guenther, Reimer, Riessen, Martin, Roller, Irene Pearl Osei, Anita-Chrysolyte, Kusi-Appiah, Yakubu, H Yakubu, Belinda, Guadi-Gosh, Christos, Dragoumanis, Christos, Christofis, Nikolaos, Kazakos, Styliani, Bastani, Charalampos, Martinos, Vasileios, Bekos, Metaxia, Papanikolaou, Theonymfi, Papavasilopoulou, Anna, Efthymiou, Vasiliki, Chantziara, Anna, Kyriakoudi, Nikolaos, Kakaras, Chrisi, Diakaki, Aikaterini, Flevari, Charikleia, Nikolaou, Kounougeri, Katerina, Lamprini, Avramopoulou, Kyriaki, Tsikritsaki, Georgios, Gkiokas, Eirini, Pantiora, Chrysostomos, Katsenos, Eirini-Chysovalanto, Patsiou, Paraskevi, Alexandropoulou, Ioannis, Koutsodimitropoulos, Epaminontas, Farmakis, Konstantina, Nestora, Marinos, Chatzis, Eumorfia, Kondili, Stella, Soundoulounaki, Ourania, Mousafiri, Dimitra, Lepida, Antonia, Liarmakopoulou, Georgios, Papathanakos, Mrina, Oikonomou, Panagiotis, Ioannides, Dimitrios, Papadopoulos, Ioannis, Staikos, Maria, Stafylaraki, Bogdan, Raitsiou, Konstantinos, Mandis, Ifigenia, Ravani, Styliani, Kourelea, Aikaterini, Efthimiou, Giannoula, Thoma, Apostolos, Bakas, Konstantinos, Psarulis, Souzana, Anisoglou, Eirini, Papageorgiou, Evangelia, Michailidou, Thomai, Tholioti, Athena, Lavrentieva, Evdokia, Sourla, Anastasia, Spyropoulou, Nikolaos, Pantelas, Kristina Mariana Matei Stalika, Ioannis, Georgakas, Antigoni, Karathanou, Syragoula, Tsikriki, Aikaterini, Dimoula, Sofia, Kanakaki, Aristeidis, Vakalos, Konstantinos, Pagioulas, Judy Enamorado Enamorado, Gabor, Nardai, Fatime, Hawchar, Asbjorn, Blondal, Brynja, Rygvadottir, Rannveig, J Jonasdottir, Hrönn, Birgisdottir, Bhagyesh, Shah, Shuchi, Kaushik, Swagata, Tripathy, Mukta, Singh, Sonika, Agarwal, Manish, Gupta, Meraj, Ahmad, Kishore, Mangal, Vaibhav, Bhargava, Vilas, Kushare, Simant, Jha, Lakshay, Bhakhtiani, Manoj, Kamal, Arvind, Baronia, Ade, Susanti, Mayang Indah Lestari, Zulkifli, Zulkifli, Windu, Baskoro, Farid, Zand, Fatemeh, Zarei, Ata, Mahmoodpoor, Farshad, Heidari, Fateme, Jafaraghaee, Aidan, O'Shea, Fiona, O'Shea, Caroline, O'Donnell, Geraldine, Craig, Gerry, Fitzpatrick, Lisa, Dunne, Jennifer, Hastings, Brian, Marsh, Caitriona, Cody, Elizabeth, Campbell, Deirdre, Doyle, Michelle, Pacturanan, Christine, Sheehan, Annette, Carey, Charlotte, Carter, Regina, Mulvey, Damien O'Connell Rosemary Finn, Catherine, Motherway, Amy, Walsh, Jennifer, Kehoe, Shella, Delossantos, Jennifer, Lalor, Siobhan, O'Nuallain, Helena, Behan, Sandra, Mcpherson, Ailesh, Corcoran, Patricia, Gordon, Glenda, Rooney, Dassy, Levy, Mazal, Azencot, Vladimir, Gurevich, Alinoy, Lavy, Valentina, Bendelari, Romina, Marconi, Antonio, Barone, Chiara, Gatti, Andrea, Giampaoletti, Cinzia, Borgognoni, Davide Massimo Ghioldi, Arena, Raimondo, Giacomo, Castiglione, Anna Vita Bruno, Giorgia, Rubulotta, Antonella, Mo, Amalia, Corso, Salvatore, Girianni, Andrea, Bruni, Eugenio, Garofalo, Salvatore Maurizio Maggiore, Alessandro Di Risio, Italo, Calamai, Rosario, Spina, Savino, Spadaro, Carlo Alberto Volta, Antonella, Cotoia, Lucia, Mirabella, Laura, Maulicino, Giancarlo, Abregal, Maria, Donvito, Paolo, D'Ambrosio, Filipo, Binda, Ileana, Adamina, Alessandro, Galazzi, Alessandra, Negro, Rosanna, Vaschetto, Fabio, Capuzzi, Margherita, Boschetto, Lucia, Stivanello, Luciano, Bonaccorso, Chiara, Megna, Pasquale, Iozzo, Antonino, Rizzo, Giovanni, Scire, Maria Rosa Taibi, Francesca Paola Tranello, Antonio, Manzo, Lidia, Traina, Beatrice, Pastore, Attilio, Quaini, Gian Domenico Giusti, Gloria, Montaldi, Federica, Piergentili, Federica, Mancini, Simona, Casaioli, Francesco, Uccelli, Fabio, Guarracino, Adriana, Onelli, Valentina Di Gravio, Maria, Cossu, Oliva, Matrona, Monica, Rocco, Daniela, Alampi, Federica, Dellafiore, Flavia, Ranalli, Matteo, Bossolasco, Elisabetta, Brizio, Pina, Migliorino, Paolo, Cortellazi, Moris, Rosati, Francesco, D'Ambrosio, Catia, Quagliotto, Erik, Roman-Pognuz, Alberto, Peratoner, De Rosa, Silvia, Marina Alessandra Martin, Francesca De Sanctis, Paolo, Ciorba, Patrick, Toppin, Hyacinth, Harding-Goldson, Shunsuke, Taito, Nobuaki, Shime, Ryohey, Yamamoto, Fumiya, Kanda, Akemi, Hirao, Moritoki, Egi, Ayako, Noguchi, Satoru, Hashimoto, Umeda, Aya, Hideaki, Sakuramoto, Akira, Ohuchi, Jun, Kataoka, Kumi, Maruyama, Izumi, Nakayama, Yoshimasa, Nishime, Koji, Fujimoto, Kenji, Takahashi, Mayumi, Tsujimoto, Masako, Shimizu, Eunice, Tole, Malcolm, C Correia, Je Hyeong Kim, Sunghoon, Park, Kyung Chan Kim, Jonghyun, Baek, Jung-Min, Bae, So Young Park, Tai Sun Park, Heung Bum Lee, Seung Yong Park, Jisoo, Park, Lee, Yeon-Joo, Cho, Young-Jae, Sang-Miin, Lee, Kyeongman, Jeon, Seok Chan Kim, Jongmin, Lee, Hyun Keun Chee, Jin Won Huh, Yun Su Sim, Junghyun, Kim, Youjin, Chang, Jong-Joon, Ahn, Byung Ju Kang, Won-Yeon, Lee, Seok Jeong Lee, Nehat, Baftiu, Ivasr, Krastins, Sonia, Stiban, Michel El Feghaly, Elie, Gharios, Marie, Merheb, Mohamed, Benlamin, Ala, Khaled, Wesal Ali Belkhair, Majd, Tabib, Firas, Ashour, Ahmed, Elhadi, Osama Wanees Emhemid Tababa, Taha, Khaled, Soad Imhmed, R Alkhumsi, Abdualhamid, I Alshrif, Ahmed Ali Aboufray, Aya, Alabuzidi, Ahmed Ramadan Triki, Mala, Elgammudi, Hajer Ben Zahra, Enas, Soula, Maram Milud Said Al-Alawi, Hazem, Ahmed, Mohamed Abdurazzag Ali Ghula, Saulius, Vosylius, Lucie, Mouton, Touraj, Rastegar, Claude, Sertznig, Gilles, Martin, Christian, Theisen, Christian, Ferretti, Fränk, Gils, Marc, Gallion, Asmah, Zainudin, Laila Kamaliah Kamalul Bahrin, Shanti Rudra Deva, Azmin Huda Abdul Rahim, Sherliza, Wahab, W Nazaruddin, W Hassan, Wan Nasrudin Wan Ismail, Mohd Nazri Ali, Tien Meng Khoo, Noryani Mohd Samat, Jenny May Geok Tong, Nik Azman Nik Adib, Mohd Basri Mat Nor, Shanthi, Ratnam, Nahla, Ismail, Siti Rohayah Sulaiman, Kit Weng Foong, Anita, Alias, Ngu Pei Hua, Jorge Macias Zermeno, Daniel, Blanco, Karely, Duran, Claudia Lizbeth Lopez Nava, San Juan Roman Nandyelly, Luis Alejandro Sanchez-Hurtado, Brigitte, Tejeda-Huezo, Mario Del Moral Armengol, Luis Pedro Ambriz Nava, Jorge Guerra Herrera, Gilberto Felipe Vazquez de Anda, Humberto, Gallegos-Perez, Nancy, Hernandez-Sanchez, Lucia, Hernandez-Ponce, Luis, Gorordo-Delsol, Marcos, Hernandez-Romero, Saira, Gomez, Fernando, Molinar, Silvio, A Ñamendys-Silva, Juan, P Romero-Gonzalez, Daira, Gonzalez, Antonio, Landaverde, Miguel Ángel Sosa, Berenice, Navarro, José Ivan Rodriguez de Molina Serrano, Sergio Reyes Iburrigarro, Alejandro, Ibarra, Joaquin, Aguirre, Mayra, Martinez-Gonzalez, Nayeli Rocio Cañas Padilla, Ana Alícia Velarde Pineda, Missael Vladimir Espinoza Villafuerte, María Ocotlan Gonzalez Herrera, Battsetseg, Baasanjav, Abdelhamid, Hachimi, Mina, Elkhayari, Tarek, Dendane, Nisha Bhandari Subedi, Sabina Dhakal Pathak, Meena, Manandhar, Laura Van Gulik, Mark Van Den Brink, Peter Van Vliet, Benjamin, Gerretsen, Lettie Van Den Berg, Marina De Haan, Binny, Tuinstra, Paul, Kuijpers, Jennifer, Reijntjens, Jan Wytze Vermeijden, Martin, Rinket, Margijske, Vanroest, Auke, Reidinga, Bert, Loef, Willem, Dieperink, Marisa, Onrust, Tom, Dormans, Laura, Bormans, Matty, Koopmans, Rik, T Gerritsen, Arlette Van Den Elst, Mirjam, Evers, Oscar, Oiting, Rob, Wilting, Bart, Ramaker, Mark van der Kuil, Jan-Willem, Fijen, Lenneke, Haas, Jasper, Haringman, Lynette, Newby, Eileen, Gilder, Danielle, Hacking, Rica, Dagooc, Rima, Song, Hansjoerg, Waibel, Frances, Dawn, Jackie, Rapley, Llesley, Chadwick, Carmel, Chapman, Petra, Crone, Jonathan, Albrett, Peter, Marko, Jennifer, Goodson, Troy, Browne, Richard, Whitticase, Cheryl, Davidson, Harriet, Judd, Daniel, Owens, Tonia, Onyeka, Innocent, Ugwu, Rose, Ilesanmi, Prisca Olabisi Adejumo, Afolabi, Owojuyigbe, Anthony, Adenekan, Stella, Uba, Christiana, Chime, Deborah, Jibrin, Babangida John Sankey, Oyebola, Adekola, Simeon, Olanipekun, Mirjana, Shosolcheva, Vanja, Gievski, Andrijan, Kartalov, Filip, Naumovski, Biljana, Kuzmanovska, Angela, Trposak, Zaneta, Bogoevska-Miteva, Rodney, Rosalia, Brita Fosser Olsen, Britt, Sjobo, Karianne Dale Jensen, Drammen, Sykehus, Birgitte Fosser Johansen, Esben, Straede, Edda, Johansen, Inger Johanne Finnstrom, Annette, Toellefsen, Hege, Ostenjo, Hege, Bjorgen, Bjorn, Bratsberg, Elin, Kristoffersen, Elin Mari Skorstad, Siri, Hansen, Sylvi, Vullum, Gro Anne Lunde, Wenche, Arntsen, Mette, Lund, Gro Ringstad Akselsen, Kristina Reinertsen Monstad, Ane, Stenset, Hanne, Haugom, Bjoern, Monsen, Lisa, Høgvall, Siw, Trudvang, Britt, Galaaen, Siv Karin Malmin, Marit Hildegunn Andersen, Rita Foss Hargott, Yvonne, Andersen, Elin, Steffenak, Marit, Nyhus, Barbro, Meland, Madiha, Hashmi, Noelia, Rivas, Elizabeth, Maidana, Alberto de Jesús Ortiz, Dolly Mabel Bordon Cabral, Marcelo, Simi, Cesar, Aponte, Juan Carlos Rivas, Sirley, Gill, Amilcar, Garcia, Gloria, Alvarenga, Laura, Cespedes, Hugo, Perez, Maria Liz Moreira, Fidelina, Canete, Roberto, Gonzalez, Natalia, Monges, Mary, Coman, Marcelo, Pederzani, Natalia, Franco, Ferdinand, Aganon, Regina, Martinez, Debbie, Noblezada-Uy, Chris Gerome Ellazar, Franklin Dean Cerezo, Jose Emmanuel Palo, Cristal April Jane Aperocho, Michael, Isanan, Marta, Tubacka, Przemyslaw, Jasiewicz, Miroslaw, Czuczwar, Michal, Borys, Aleksandra, Gutysz-Wojnicka, Lidia, Glinka, Ryszard, Gawda, Jan, Bilawicz, Paula, Cabrita, João, Vieira, Margarida Ferreira Figueiredo, Cristiana Mota Pinheiro, Nelson, Antunes, Laura, Pedro, Fatima, Ferreira, Isabel, Parente, Maria, Varela, Fatima, Fernandes, Claudia, Martins, Abel, Viveiros, Raquel, Cavaco, Clara Santa Rita, Sofia, Dias, Ana Margarida Feranandes, Pedro, Silva, Catarina, Nunes, João, Cabral, Filpe, Pires, Hilaryano, Ferreira, Jacinta, Santos, Vitor Manuel Vaz Pinto, Bruno Miguel Bispo, Amelia, Ferreira, Elena, Molinos, Estevão, Lafuente, Ricardo, Gregorio, Humberto, Costa, Ângela, Lima, Susana, Ferreira, Vanda, Seromenho, Eulália, Luis, Idália, Valerio, Helena, Cesar, Ana, Tavares, Ahmed Subhy Alsheikhly, Saeed, Mahmood, Catalin Traian Guran, Alida, Moise, Daniela Carmen Filipescu, Mihail, Luchian, Mihai, Popescu, Monica Adriana Scutariu, Cristina, Petrisor, Natalia, Hagau, Ioana, Grigoras, Tatiana, Patrichi, Vitaly, Gusarev, Alexandra, Pivkina, Vladimir, Kulakov, Olga, Ignatenko, Julia, Kovaleva, Trina, Zhivotneva, Marina, Zhedaeva, Nikita, Matiushkov, Olga, Ershova, Natalya, Egorova, Victoria, Khoronenko, Danil, Baskakov, Dmitry, Sergeev, Michael, Piradov, Liudmila, Grishina, Marat, Magomedov, Evgeniy, Zuev, Uri, Gorokhovatsky, Anna, Leonova, Liudmila, Fadeeva, Vladislav, Belskiy, Dmitriy, Galishevskiy, Nadezhda, Zubareva, Maksim, Tribulev, Oksana, Zueva, Alexander, Kiselev, Nikolaj, Kamenshchikov, Ekaterina, Tokareva, Maxim, Petrushin, Irina, Starchenko, Isaac, Nshimyumuremyi, Jerome, Muhizi, Egide, Buregeya, Josue, Nzarora, Amer, Assiri, Maie Salem Ebaid, Ghaleb, Almekhlafi, Yasser, Mandourah, Jelena, Velickovic, Dejan, Veličković, Bojan, Jovanovic, Adi, Hadzibegovic, Branislava, Stefanovic, Vanja, Misic, Vesna, Bumbasirevic, Marija, Rajković, Milena, Stojanovic, Srđan, Gavrilovic, Maja, Stanojević, Aktham, Yaghi, Anton, Turčan, Peter, Firment, Garri, Slobodianiuk, Daria, Rabarova, Danca, Lančaričová, Janko, Vlaovic, Matjaž, Groznik, Milica, Lukic, Janja, Perme, Maja, Sostaric, Nejc, Umek, Tomislav, Mirkovic, Simon, Dolenc, Misa, Fister, Nika, Zorko, Andrej, Markota, Nomhle Princess Yeni, Phumele, Jali, Shelley, Schmollgruber, Muhommed Ridwaan Syed, Nivisha, Parag, Robert, Wise, Maria, Galiana, José Alejandro Navarro, Ana María De Pablo, Patricia, Albert, Pilar, Martinez, Yolanda, Mendiara, Barbara, Garcia, Ana Alabart Llinas, Marilyn, Riveiro, Elisabet, Gallart, Alba, Riera, Miquel, Sanz, Swagotika, Salo, Miguel Angel Gimenez Lajara, Montserrat Venturas Nieto, Rosa, Garcia, José Manuel Garcia Pena, Maria Carmen Gorgolas, Maria Aranzazu Isasi, Rafael, Sierra, Federico, Gordo, Isabel, Conejo, Vicent, Salvà-Costa, Carolina, Garzón-Tovar, Sara, Lospitao, Rafael, Gonzalez, Pedro, Gutierrez, Mercè, Girona, Jordi, Adamuz, Pablo Garcia Olivares, José Peral Gutierrez de Ceballos, Celia, Tirado, Irene De Wit, Ana Belén Curto Polo, Maria Del Mar Diaz Salcedo, Javier, Ripolles-Melchor, Eugenio, Martinez-Hurtado, Jorge Duerto Alvarez, María Luisa Bravo Arcas, Juan Ignacio Torres Gonzalez, Ana Belén Sánchez de la Ventana, Pablo Lopez-Arcas Calleja, Raquel Garcia Alvarez, Purificacion Sanchez Zamora, Alvaro Ortega Guerrero, Rosario, Cosano, Jonathan, Perez-Vacas, Margarita, Campos-Perez, Emma Moreno Barreiro, Losune Cano Sanchez, Monica Garcia Diaz, Raquel, Jimenez, Lorena Del Rio Cabajo, Daniel Sancho Muriel, Helena Fernandez Alonso, Ana Wensell Fernández, Isabel Santín Piñan, Guillermo Muñiz Albaiceta, Maria Cristina Iglesias Fernandez, Francisco Javier Saenz Abos, Pablo, Monedero, Ramon Molina Chueca, Lydia Gallego Aguirre, Silvia Call Manosa, Carmen Partera Luque, Neus, Calpe, Monica Recio Losilla, Meritxell Tapia Fores, Olga, Farre, Oscar, Fernandez, M Del Rosario Villar Redondo, Donaldo, S Arteta Arteta, Maria Angeles Hurtado Sanchez, Cristina Paños Espinosa, Laura Martinez Reyes, Laura Claramunt Domenech, Carmen Velasco Guillén, Josep Trenado Alvarez, Mercedes Del Cotillo, Jesus Emilio Barrueco-Francioni, Belen Burgos Conde, Maria Pilar Sogues Blanco, Maria Luisa Blasco, Ana Isabel Clement, Clara, Hurtado, Luz Coronado Sanz, David, Perez-Torres, Estefanía, Prol-Silva, Jorge, Pereira, Iván Areán González, Anastasio Espejo Cano, Cesar Rodriguez Nuñez, Inmaculada Lorenzo Fernadez, Alejandra Azahara Marguello Fernandez, Rosa Del Bosque Diez, Badiola, Hilario, Begoña, Zalba-Etayo, Ana, Pascual-Bielsa, Preveen, Banwarie, Dick, Nahar, Alisha van Axel, Naraindath, N Boedjawan, Erika Backlund Jansson, Ann-Sofie, Malvemyr, Lotta, Johansson, Ulla, Sandberg, Catarina, Tingsvik, Gunilla, Mattsson, Gun, Löf, Martin, Spångfors, Mona, Ringdal, Sebastian, Geijer, Lotti, Orvelius, Mia, Hylen, Caroline, Lagerhäll, Eva, Åkerman, Viveca Hamback Hellkvist, Ulrica, Mickelsson, Ewa, Wahlbom, Ing-Marie, Larsson, Ewa, Wallin, Filippo, Boroli, Solenne, Ory, Margaret Lynn Jong, Alexander, Dullenkopf, Martin, Lang, Yvan, Fleury, Marianne, Maus, Nawfel, Ben-Hamouda, Anne, Fishman, Mei Yu Hsu, Shu Chuan Chang, Konlawij, Trongtratul, Chaiwut, Sawawiboon, Sunthiti, Morakul, Bodin, Khwannimit, Keevan, Singh, Dale, Ventour, Dianne, Figaro-Barclay, Sasha, Sankar-Maharaj, Mhamed Sami Mebazaa, Salma, Kamoun, Souheil, Elatrous, Lamia, Besbes, Fekri, Abroug, Walid, Naija, Youssef Zied Elhechmi, Walid, Sellami, Zied, Hajjej, Takoua, Merhabene, Imen, Talik, Ozlem Ozkan Kuscu, Ozcengiz, Dilek, Avşar, Zerman, Hayriye Cankar Dal, Sema, Turan, Semih, Aydemir, Hakan, Yilmaz, Duygu Kayar Calili, Seval, İzdes, Melike, Cengiz, Ayça, Gümüş, Banu, Taşdemir, Ali, Kağnıcı, Mustafa, Ay, Serap Avcı Ay, Gulbahar, Caliskan, Turkay, Akbas, Abidin Oner Balbay, Serdar, Efe, Volkan, Inal, Gülseren, Elay, Pınar, Karabacak, Boğaç, Özserezli, Evren, Şentürk, Oktay, Demirkiran, Suha, Bozbay, Elif, Erdogan, Mustafa, Akker, Nebia, Peker, Asu, Ozgultekin, Sibel Ocak Serin, Can, Turan, Gulsah, Karaoren, Senay, Goksu, Sait, Karakurt, Huseyin, Arikan, Fethi, Gül, İsmail, Cinel, Iskender, Kara, Hasan Nabi Undar, Yesim Serife Bayraktar, Jale Bengi Çelik, Murat Emre Tokur, Demet Tok Aydin, İsmail, Yildiz, Beysim, Özcan, Başar, Erdivanli, Ahmet, Eroglu, Devrim, Akdağ, Nurdan, Ünlü, Adonis, Dungca, Ashwaq, Ali, Bindu, Thankamma, Paul Eric Reyes, Sini, John, Ajitha, Rajendran, Fatima Kasem El Ahmad, Kathleen Ann Smiley, Susanna, Hojden, Mia Thorning Miller, Vishnu Das Sasidharan Nair, Maria Gracia San Antonio, Khaled Al Qawasmeh, Sabah Abu Shawish, Hilary, Twiggs, Ines, Rosado, Volodymyr, Babych, Faye, Morren, Charlotte, Young, Nicola, Vaughan-Jones, Stephanie, Harris, Karen, Burns, Carmel, Georgiev, Rosina, Shayamano, Ian, Kerslake, Peter, Creber, Ana, Vochin, Catherine, O'Brien, Paul, Caddell, Samantha, Hagan, Mandy, Hughes, Tomasz, Torlinski, James, Sherwin, Santhana, Kannan, Amber, Markham, Richard, Lebon, Jason, Cupitt, Julius, Cranshaw, Nigel, White, Victoria, Marriott, Wendy, Milner, Casiano Barrera Groba, Joao, Azoia, Petra, Polgarova, Shaly, George, Ritoo, Kapoor, Ceri, Lynch, Nathalie, Fox, Karen, Cranmer, Natalie, Fox, Thomas, Llewellym, Kelly, Matthews, Louise, Maltby, Jowena, Ibao, Karen, Boulton, Rachel, Jarman, Karen, Baxter, Ashok Sundai Raj, Arif, Moghal, Joanne, White, Suzanne, Barrowcliffe, Mark, Pulletz, Vaarisan, Ganeshalingam, Rosaleen, Baruah, Carole, Boulanger, Helen, Baker, Justin, Woods, Poe Poe Ei, Vongayi, Ogbeide, Paul, Hayden, Jennifer, Hughes, Madhu, Balasubramanian, Armorel, Salberg, Rajnish, Saha, Dagmar, Holmquist, Claire, Derbyshire, Neil, Smith, Elizabeth, Stones, Jane, Ademokun, Monica, Popescu, Maria Schofield Legorburo, Samantha, North, Carole, Brett, Helen, Jaundoo, Jayne, Craig, Simon, Whiteley, Clare, Howcroft, Liz, Wilby, Peter, Delve, David, Shaw, Karen, Williams, Ingeborg, D Welters, Jane, Mcmullen, Stephen, Brett, Leah, Flores, Treiza, Trueman-Dawkins, Mae, Templeton, John, Adams, Catherine, Smith, John, Prowle, Heather, Byers, Andrea, Mcdonnell, Bernd Oliver Rose, Rosie, Reece-Anthony, Luis, Mendes, Marcela, Vizcaychipi, Rhian, Bull, Grace, Lacaden, Eleanor, Santiago, Carlos Castro Delgado, Sarah, Farnell-Ward, Elaine, Thorpe, Justine, Somerville, Anne, Williams, Donna, Cummings, Helen, Derrick, Sarah, Brumwell, Claire, Randell, Nicola, Mccann, Emma, Aves, Gillian, Berry, Tamas, Szakmany, Una, Gunter, Paul, Pulak, Nikki, Sarkar, Kerry, Wright, Vitor, Gomes, Jones, Jo, Ruth, Palfrey, Julie, Camsooksai, Abby, Lewis, Antony, Eneas, Ascanio, Tridente, Louise, Barr, Beverley, Thomas, Emma, Parkin, Daniel, Horner, Christian, Frey, Suzanne, Bench, Rachel, Baumber, Phil, Broadhurst, Matthew, Jackson, Lynne, Williams, Michele, Clark, Jonathan, Paddle, Sarah, Bean, Sarah, Buckley, Christopher, Palfreeman, Sophie, Liu, Nicola, Allison, Ben, Attwood, Penny, Parsons, Victoria, Houghton, Sarah Jane Turner, David, Higgins, Egidija, Bielskute, Nicola, Horrigan, Reni, Jacob, Karen, Habgood, Ahmed, Zaki, Amy, Collins, Jenny, Lord, Charalice, Ramiro, Agnieszka, 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European Society of Intensive Care Medicine (ESICM) Trials Group Collaborators, Muzha, D., Ribas, A.M., Lipovesty, F., Loudet, C., Coyer, F., Eller, P., Mostafa, N., Honoré, P.M., Telleria, V.M., Smajic, J., Nogueira, P.C., Nafees, KMK, Hentchoya, R., Rose, L., Soledad, J., Lin, F., Cardenas, Y., Reyes, A.G., Sustic, A., Mpouzika, M., Vymazal, T., Jensen, H.I., Aguirre-Bermeo, H., Maddison, L., Valta, M., Calvino-Gunther, S., Bloos, F., Adipa, F.E., Koulouras, V., Enamorado, J., Ágoston, Z., Birgisdóttir, H., Gupta, A., Gurjar, M., Kilapong, B., Hashemian, S.M., Martin-Loeches, I., Benbenishty, J., Cortegiani, A., Fletcher, K., Hayashi, Y., Waweru-Siika, W., Abidi, K., Lee, S.M., Hadri, B., Dolgusevs, M., Abillama, F.F., Jovaisa, T., Thix, C., Elhadi, M., Nor, B.M., Ratnam, S., Mazlan, M.Z., Maiyalagan, S., Sánchez-Hurtado, L., Belii, A., Naranpurev, M., Gautam, P., De Lange, D., Parke, R., Ilesanmi, R.E., Shosholcheva, M., Petosic, A., Lind, R., Ffarcsi, M.H., Bogarin, J., Hernandez, 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A.S., Goller, S., Afonso, E., Larina, E., Labeau, Sonia O. [0000-0003-3863-612X], Afonso, Elsa [0000-0003-0873-0852], Benbenishty, Julie [0000-0002-8488-9649], Blackwood, Bronagh [0000-0002-4583-5381], Boulanger, Carole [0000-0002-1392-6633], Brett, Stephen J. [0000-0003-4545-8413], Calvino-Gunther, Silvia [0000-0003-3586-7205], Chaboyer, Wendy [0000-0001-9528-7814], Coyer, Fiona [0000-0002-8467-0081], Deschepper, Mieke [0000-0001-6797-3147], Honore, Patrick M. [0000-0002-6697-4890], Jankovic, Radmilo [0000-0003-0742-8686], Khanna, Ashish K. [0000-0002-9083-891X], Llaurado-Serra, Mireia [0000-0002-5123-0581], Lin, Frances [0000-0001-8735-5469], Rose, Louise [0000-0003-1700-3972], Rubulotta, Francesca [0000-0001-8644-1728], Saager, Leif [0000-0003-3416-4727], Williams, Ged [0000-0002-7481-2445], Blot, Stijn I. [0000-0003-2145-0345], Apollo - University of Cambridge Repository, Critical Care, Labeau S.O., Afonso E., Benbenishty J., Blackwood B., Boulanger C., Brett S.J., Calvino-Gunther S., Chaboyer W., Coyer F., Deschepper M., Francois G., Honore P.M., Jankovic R., Khanna A.K., Llaurado-Serra M., Lin F., Rose L., Rubulotta F., Saager L., Williams G., Blot S.I., Muzha D., Ribas A.M., Lipovesty F., Loudet C., Eller P., Mostafa N., Telleria V.M., Smajic J., Nogueira P.C., Nafees K.M.K., Hentchoya R., Soledad J., Cardenas Y., Reyes A.G., Sustic A., Mpouzika M., Vymazal T., Jensen H.I., Aguirre-Bermeo H., Maddison L., Valta M., Bloos F., Adipa F.E., Koulouras V., Enamorado J., Agoston Z., Birgisdottir H., Gupta A., Gurjar M., Kilapong B., Hashemian S.M., Martin-Loeches I., Cortegiani A., Fletcher K., Hayashi Y., Waweru-Siika W., Abidi K., Lee S.-M., Hadri B., Dolgusevs M., Abillama F.F., Jovaisa T., Thix C., Elhadi M., Nor B.M., Ratnam S., Mazlan M.Z., Maiyalagan S., Sanchez-Hurtado L., Belii A., 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N.N., Jansson E.B., Malvemyr A.-S., Johansson L., Sandberg U., Tingsvik C., Mattsson G., Lof G., Spangfors M., Ringdal M., Geijer S., Orvelius L., Hylen M., Lagerhall C., Akerman E., Hellkvist V.H., Mickelsson U., Wahlbom E., Larsson I.-M., Wallin E., Boroli F., Ory S., Jong M.L., Dullenkopf A., Lang M., Fleury Y., Maus M., Ben-Hamouda N., Fishman A., Hsu M.Y., Chang S.C., Trongtratul K., Sawawiboon C., Morakul S., Khwannimit B., Singh K., Ventour D., Figaro-Barclay D., Sankar-Maharaj S., Mebazaa M.S., Kamoun S., Elatrous S., Besbes L., Abroug F., Naija W., Elhechmi Y.Z., Sellami W., Hajjej Z., Merhabene T., Talik I., Kuscu O.O., Dilek O., Zerman A., Dal H.C., Turan S., Aydemir S., Yilmaz H., Calili D.K., Izdes S., Cengiz M., Gumus A., Tasdemir B., Kagnici A., Ay M., Ay S.A., Caliskan G., Akbas T., Balbay A.O., Efe S., Inal V., Elay G., Karabacak P., Ozserezli B., Senturk E., Demirkiran O., Bozbay S., Erdogan E., Akker M., Peker N., Ozgultekin A., Serin S.O., Turan C., Karaoren G., Goksu S., Karakurt S., Arikan H., Gul F., Cinel I., Kara I., Undar H.N., Bayraktar Y.S., Celik J.B., Tokur M.E., Aydin D.T., Yildiz I., Ozcan B., Erdivanli B., Eroglu A., Akdag D., Unlu N., Dungca A., Ali A., Thankamma B., Reyes P.E., John S., Rajendran A., Ahmad F.K.E., Smiley K.A., Hojden S., Miller M.T., Das Sasidharan Nair V., Antonio M.G.S., Qawasmeh K.A., Shawish S.A., Twiggs H., Rosado I., Babych V., Morren F., Young C., Vaughan-Jones N., Harris S., Burns K., Georgiev C., Shayamano R., Kerslake I., Creber P., Vochin A., O'Brien C., Caddell P., Hagan S., Hughes M., Torlinski T., Sherwin J., Kannan S., Markham A., Lebon R., Cupitt J., Cranshaw J., White N., Marriott V., Milner W., Groba C.B., Azoia J., Polgarova P., George S., Kapoor R., Lynch C., Fox N., Cranmer K., Llewellym T., Matthews K., Maltby L., Ibao J., Boulton K., Jarman R., Baxter K., Raj A.S., Moghal A., White J., Barrowcliffe S., Pulletz M., Ganeshalingam V., Baruah R., Baker H., Woods J., Ei P.P., Ogbeide V., Hayden P., Hughes J., Balasubramanian M., Salberg A., Saha R., Holmquist D., Derbyshire C., Smith N., Stones E., Ademokun J., Legorburo M.S., North S., Brett C., Jaundoo H., Craig J., Whiteley S., Howcroft C., Wilby L., Delve P., Shaw D., Williams K., Welters I.D., McMullen J., Brett S., Flores L., Trueman-Dawkins T., Templeton M., Adams J., Prowle J., Byers H., McDonnell A., Rose B.O., Reece-Anthony R., Mendes L., Vizcaychipi M., Bull R., Lacaden G., Santiago E., Delgado C.C., Farnell-Ward S., Thorpe E., Somerville J., Williams A., Cummings D., Derrick H., Brumwell S., Randell C., McCann N., Aves E., Berry G., Szakmany T., Gunter U., Pulak P., Sarkar N., Wright K., Gomes V., Jones J., Palfrey R., Camsooksai J., Lewis A., Eneas A., Tridente A., Barr L., Thomas B., Parkin E., Horner D., Frey C., Bench S., Baumber R., Broadhurst P., Jackson M., Williams L., Clark M., Paddle J., Bean S., Buckley S., Palfreeman C., Liu S., Allison N., Attwood B., Parsons P., Houghton V., Turner S.J., Higgins D., Bielskute E., Horrigan N., Jacob R., Habgood K., Zaki A., Collins A., Lord J., Ramiro C., Kubisz-Pudelko A., Kotze M., Williams H., Iovenko I., Tsarev A., Briva A., Mendez G., Napolitano L., Teig M., Rodriguez G.E., Ben-Jacob T., Potestio C., Eng T., Mahanes D., Khanna A., Duggal A., Nananmori M., Lois M., Karamchandani K., Bealer C., Barefield C., Terry D., Fivecoat P., Idowu O., Cata J., Clesi T., Peterson J., Hatton K., Dhaliwal J., Mueller D., Tao J., Eltorai A.S., Pastores S.M., Remor N., Salazar J., Barkas D., Joffe A., Barnes C., Sona C., Schallom M., Short J., Lorenzo J., Von Der Osten I., Borkowska M., Demarre L., Pleitinckx V., Xing C., Debue A.-S., Goller S., Larina E., Labeau, S. O., Blackwood, B., Brett, S. J., Deschepper, M., Francois, G., Honore, P. M., Khanna, A. K., Williams, G., Blot, S. I., Ribas, A. M., Telleria, V. M., Nogueira, P. C., Nafees, K. M. K., Reyes, A. G., Jensen, H. I., Adipa, F. E., Agoston, Z., Hashemian, S. M., Lee, S. -M., Abillama, F. F., Nor, B. M., Mazlan, M. Z., Sanchez-Hurtado, L., De lange, D., Ilesanmi, R. E., Ffarcsi, M. H., Hernandez, A. M., Schefold, J. C., Besbes, L. O., Minope, J. T. S., Rostello, O. F., Bartoli, J. R., Nocheretti, M. G., Escalante, R. G., Loudet, C. I., Gonzalez, A. L., Alvarez, G. A., Campos, P. A., Fonseca, I. P., Alvarez, G. M., Bascary, C. A., del Valle Gimenez, G., Bertoletti, F. P., Bonsignore, P. J. M., Fernandez, M. A., Leslie, G. D., Mclucas, A., Jacquet, L. -M., de Almeida, A. O., Jorge, S. A., Schmidt, R. C., Garcia, P. C., Ronchini, A. L. V., Manap, N. B. A., Laizner, A. M., Mcquirter, M., Kampayana, B. S., Sepulveda, M. I., Zamorano, M. J. F., Zhao, R. H., Hu, L. P., Jiao, Q. F., Wang, H. Y., Xia, C. J., Insu, L., Zhu, J. Y., Zhu, J. F., Huang, R. F., Wang, L. L., Song, J. H., Liu, X. M., Li, Z. S., Li, L. C., Zeng, J. M., Hu, X. C., Wang, R. X., Tak, P. S., Ho, S. W., Jiang, Q. X., Huang, L. P., Liu, X. L., Jiang, J. H., Gong, Y. Y., Lei, D. H., Bi, A. P., Zhao, H. M., Cao, Z. Q., Wu, S. F., Tian, X. F., Feng, Z. X., Liu, X. Z., Jiang, Z. X., Wang, G. X., Hu, R. L., Li, X. Q., Yu, Z. J., Yang, Y. X., Gama, L. M. S., Hernandez, J. S., Ochoa, M. -E., Reyes, A. J. G., Filipovic-Grcic, I., Vukovic, A., Pecenkovic, S., Suput, A., Radivojevic, R. C., Culjak, H., Adam, V. N., Pedersen, K. R., Kjaergard, I. E., Kodal, A. M., Hansen, T. C. B., Pedersen, A. S. B., Thomsen, T. D., Frandsen, T. M., Bliksted, I. A., Tamayo, L. M., Tutillo, D. R. M., Hurtado, C. V., Garcia, M. F., Kutimets, M., Lofqvist, C., Sakki, J. -K., Valta, M. A., Plantefeve, G., Deserts, M. D., Gunther, S. C., Timsit, J. -F., Farkas, J. -C., Bosl, K., Schuppel, S., Stubner, A., Osei, I. P., Kusi-Appiah, A. -C., Yakubu, Y. H., Patsiou, E. -C., Stalika, K. M. M., Enamorado, J. E., Jonasdottir, R. J., Lestari, M. I., Finn, D. O. C. R., Mcpherson, S., Ghioldi, D. M., Bruno, A. V., Maggiore, S. M., Volta, C. A., Taibi, M. R., Tranello, F. P., Giusti, G. D., Martin, M. A., Correia, M. C., Kim, J. H., Kim, K. C., Bae, J. -M., Park, S. Y., Park, T. S., Lee, H. B., Kim, S. C., Chee, H. K., Huh, J. W., Sim, Y. S., Ahn, J. -J., Kang, B. J., Lee, W. -Y., Lee, S. J., Feghaly, M. E., Belkhair, W. A., Tababa, O. W. E., Alkhumsi, S. I. R., Alshrif, A. I., Aboufray, A. A., Triki, A. R., Zahra, H. B., Al-Alawi, M. M. S., Ghula, M. A. A., Bahrin, L. K. K., Deva, S. R., Rahim, A. H. A., Hassan, W. N. W., Ismail, W. N. W., Ali, M. N., Khoo, T. M., Samat, N. M., Tong, J. M. G., Adib, N. A. N., Nor, M. B. M., Sulaiman, S. R., Foong, K. W., Hua, N. P., Zermeno, J. M., Nava, C. L. L., Nandyelly, S. J. R., Sanchez-Hurtado, L. A., Nava, L. P. A., Herrera, J. G., de Anda, G. F. V., Namendys-Silva, S. A., Romero-Gonzalez, J. P., Sosa, M. A., de Molina Serrano, J. I. R., Iburrigarro, S. R., Padilla, N. R. C., Pineda, A. A. V., Villafuerte, M. V. E., Herrera, M. O. G., Subedi, N. B., Pathak, S. D., Vermeijden, J. W., Gerritsen, R. T., Fijen, J. -W., Adejumo, P. O., Sankey, B. J., Olsen, B. F., Jensen, K. D., Johansen, B. F., Finnstrom, I. J., Skorstad, E. M., Lunde, G. A., Akselsen, G. R., Monstad, K. R., Hogvall, L., Malmin, S. K., Andersen, M. H., Hargott, R. F., de Jesus Ortiz, A., Cabral, D. M. B., Rivas, J. C., Moreira, M. L., Ellazar, C. G., Cerezo, F. D., Palo, J. E., Aperocho, C. A. J., Figueiredo, M. F., Pinheiro, C. M., Rita, C. S., Feranandes, A. M., Pinto, V. M. V., Bispo, B. M., Lima, A., Alsheikhly, A. S., Guran, C. T., Filipescu, D. C., Scutariu, M. A., Ebaid, M. S., Velickovic, D., Rajkovic, M., Stanojevic, M., Turcan, A., Lancaricova, D., Yeni, N. P., Syed, M. R., Navarro, J. A., De Pablo, A. M., Llinas, A. A., Lajara, M. A. G., Nieto, M. V., Pena, J. M. G., Gorgolas, M. C., Isasi, M. A., Salva-Costa, V., Garzon-Tovar, C., Olivares, P. G., de Ceballos, J. P. G., Polo, A. B. C., del Mar Diaz Salcedo, M., Alvarez, J. D., Arcas, M. L. B., Gonzalez, J. I. T., de la Ventana, A. B. S., Calleja, P. L. -A., Alvarez, R. G., Zamora, P. S., Guerrero, A. O., Barreiro, E. M., Sanchez, L. C., Diaz, M. G., Muriel, D. S., Alonso, H. F., Fernandez, A. W., Pinan, I. S., Albaiceta, G. M., Fernandez, M. C. I., Abos, F. J. S., Chueca, R. M., Aguirre, L. G., Manosa, S. C., Luque, C. P., Losilla, M. R., Fores, M. T., del Rosario Villar Redondo, M., Arteta Arteta, D. S., Sanchez, M. A. H., Espinosa, C. P., Reyes, L. M., Domenech, L. C., Guillen, C. V., Alvarez, J. T., del Cotillo, M., Barrueco-Francioni, J. E., Conde, B. B., Blanco, M. P. S., Blasco, M. L., Clement, A. I., Sanz, L. C., Gonzalez, I. A., Cano, A. E., Nunez, C. R., Fernadez, I. L., Fernandez, A. A. M., Boedjawan, N. N., Jansson, E. B., Malvemyr, A. -S., Lof, G., Spangfors, M., Lagerhall, C., Akerman, E., Hellkvist, V. H., Larsson, I. -M., Jong, M. L., Hsu, M. Y., Chang, S. C., Mebazaa, M. S., Elhechmi, Y. Z., Kuscu, O. O., Dal, H. C., Calili, D. K., Izdes, S., Gumus, A., Tasdemir, B., Kagnici, A., Ay, S. A., Balbay, A. O., Ozserezli, B., Senturk, E., Serin, S. O., Gul, F., Cinel, I., Undar, H. N., Bayraktar, Y. S., Celik, J. B., Tokur, M. E., Aydin, D. T., Yildiz, I., Ozcan, B., Akdag, D., Unlu, N., Reyes, P. E., Ahmad, F. K. E., Smiley, K. A., Miller, M. T., Antonio, M. G. S., Qawasmeh, K. A., Shawish, S. A., Groba, C. B., Raj, A. S., Ei, P. P., Legorburo, M. S., Welters, I. D., Mcmullen, J., Mcdonnell, A., Rose, B. O., Delgado, C. C., Mccann, N., Turner, S. J., Rodriguez, G. E., Eltorai, A. S., Pastores, S. M., Demarre, L., and Debue, A. -S.
- Subjects
Male ,Original ,medicine.medical_treatment ,artificial ,Critical Care and Intensive Care Medicine ,Medical and Health Sciences ,Pressure ulcer ,law.invention ,Decubitus epidemiology ,ICU ,Morbidity ,Mortality ,Outcome ,Pressure injury ,Risk factors ,Adult ,Aged ,Hospital Mortality ,Humans ,Patient Discharge ,Prevalence ,Risk Factors ,Intensive Care Units ,Respiration, Artificial ,0302 clinical medicine ,decubitus epidemiology ,pressure injury ,pressure ulcer ,outcome ,risk factors ,morbidity ,mortality ,law ,Medicine and Health Sciences ,adults ,Medicine ,Simplified Acute Physiology Score ,icu ,ziekenhuissterfte ,Immunodeficiency ,intensive care ,European Society of Intensive Care Medicine (ESICM) Trials Group Collaborators ,mannen ,volwassenen ,COST ,Intensive care unit ,STATE ,ULCERS ,Underweight ,medicine.symptom ,Life Sciences & Biomedicine ,Human ,medicine.medical_specialty ,risicofactoren ,Decubitus epidemiology, ICU, Pressure injury, Pressure ulcer, Outcome, Risk factors, Morbidity, Mortality ,pressure injuries ,Intensive Care Unit ,prevalentie ,NO ,1117 Public Health and Health Services ,DecubICUs Study Team ,03 medical and health sciences ,Critical Care Medicine ,Anesthesiology ,General & Internal Medicine ,Health Sciences ,ouderen ,Mechanical ventilation ,Science & Technology ,business.industry ,decubitus ,Risk Factor ,030208 emergency & critical care medicine ,1103 Clinical Sciences ,Odds ratio ,medicine.disease ,Emergency & Critical Care Medicine ,Confidence interval ,030228 respiratory system ,Emergency medicine ,kunstmatige ademhaling ,RISK-FACTORS ,business ,respiration - Abstract
Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347, Funder: Flemish Society for Critical Care Nurses, Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score < 19, ICU stay > 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat.
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- 2021
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4. Sphingosine kinase 2 and p62 regulation are determinants of sexual dimorphism in hepatocellular carcinoma.
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Green CD, Brown RDR, Uranbileg B, Weigel C, Saha S, Kurano M, Yatomi Y, and Spiegel S
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- Animals, Female, Humans, Male, Mice, Cell Proliferation, Diet, High-Fat adverse effects, Lysophospholipids metabolism, Mice, Inbred C57BL, Mice, Knockout, Sphingosine analogs & derivatives, Sphingosine metabolism, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular genetics, Liver Neoplasms metabolism, Liver Neoplasms pathology, Liver Neoplasms genetics, Phosphotransferases (Alcohol Group Acceptor) metabolism, Phosphotransferases (Alcohol Group Acceptor) genetics, Sex Characteristics
- Abstract
Objective: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality, and its incidence is increasing due to endemic obesity. HCC is sexually dimorphic in both humans and rodents with higher incidence in males, although the mechanisms contributing to these correlations remain unclear. Here, we examined the role of sphingosine kinase 2 (SphK2), the enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in gender specific MASH-driven HCC., Methods: Male and female mice were fed a high fat diet with sugar water, a clinically relevant model that recapitulates MASH-driven HCC in humans followed by physiological, biochemical cellular and molecular analyses. In addition, correlations with increased risk of HCC recurrence were determined in patients., Results: Here, we report that deletion of SphK2 protects both male and female mice from Western diet-induced weight gain and metabolic dysfunction without affecting hepatic lipid accumulation or fibrosis. However, SphK2 deficiency decreases chronic diet-induced hepatocyte proliferation in males but increases it in females. Remarkably, SphK2 deficiency reverses the sexual dimorphism of HCC, as SphK2
-/- male mice are protected whereas the females develop liver cancer. Only in male mice, chronic western diet induced accumulation of the autophagy receptor p62 and its downstream mediators, the antioxidant response target NQO1, and the oncogene c-Myc. SphK2 deletion repressed these known drivers of HCC development. Moreover, high p62 expression correlates with poor survival in male HCC patients but not in females. In hepatocytes, lipotoxicity-induced p62 accumulation is regulated by sex hormones and prevented by SphK2 deletion. Importantly, high SphK2 expression in male but not female HCC patients is associated with a more aggressive HCC differentiation status and increased risk of cancer recurrence., Conclusions: This work identifies SphK2 as a potential regulator of HCC sexual dimorphism and suggests SphK2 inhibitors now in clinical trials could have opposing, gender-specific effects in patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier GmbH.)- Published
- 2024
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5. Comprehensive metabolic modulations of sphingolipids are promising severity indicators in COVID-19.
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Uranbileg B, Isago H, Nakayama H, Jubishi D, Okamoto K, Sakai E, Kubota M, Tsutsumi T, Moriya K, and Kurano M
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- Humans, Male, Female, Middle Aged, Adult, Sphingosine analogs & derivatives, Sphingosine metabolism, Aged, Biomarkers blood, Biomarkers metabolism, COVID-19 metabolism, COVID-19 blood, COVID-19 virology, Sphingolipids metabolism, Sphingolipids blood, SARS-CoV-2, Severity of Illness Index
- Abstract
The COVID-19 pandemic, caused by SARS-CoV-2, has had a significant worldwide impact, affecting millions of people. COVID-19 is characterized by a heterogenous clinical phenotype, potentially involving hyperinflammation and prolonged tissue damage, although the exact underlying mechanisms are yet to be fully understood. Sphingolipid metabolites, which govern cell survival and proliferation, have emerged as key players in inflammatory signaling and cytokine responses. Given the complex metabolic pathway of sphingolipids, this study aimed to understand their potential role in the pathogenesis of COVID-19. We conducted a comprehensive examination of sphingolipid modulations across groups classified based on disease severity, incorporating a time-course in serum and urine samples. Several sphingolipids, including sphingosine, lactosylceramide, and hexosylceramide, emerged as promising indicators of COVID-19 severity, as validated by correlation analyses conducted on both serum and urine samples. Other sphingolipids, such as sphingosine 1-phosphate, ceramides, and deoxy-dihydroceramides, decreased in both COVID-19 patients and individuals with non-COVID infectious diseases. This suggests that these sphingolipids are not specifically associated with COVID-19 but rather with pathological conditions caused by infectious diseases. Our analysis of urine samples revealed elevated levels of various sphingolipids, with changes dependent on disease severity, potentially highlighting the acute kidney injury associated with COVID-19. This study illuminates the intricate relationship between disturbed sphingolipid metabolism, COVID-19 severity, and clinical factors. These findings provide valuable insights into the broader landscape of inflammatory diseases., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
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- 2024
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6. Alzheimer's disease manifests abnormal sphingolipid metabolism.
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Uranbileg B, Isago H, Sakai E, Kubota M, Saito Y, and Kurano M
- Abstract
Introduction: Alzheimer's disease (AD) is associated with disturbed metabolism, prompting investigations into specific metabolic pathways that may contribute to its pathogenesis and pathology. Sphingolipids have garnered attention due to their known physiological impact on various diseases., Methods: We conducted comprehensive profiling of sphingolipids to understand their possible role in AD. Sphingolipid levels were measured in AD brains, Cerad score B brains, and controls, as well as in induced pluripotent stem (iPS) cells (AD, PS, and control), using liquid chromatography mass spectrometry., Results: AD brains exhibited higher levels of sphingosine (Sph), total ceramide 1-phosphate (Cer1P), and total ceramide (Cer) compared to control and Cerad-B brains. Deoxy-ceramide (Deoxy-Cer) was elevated in Cerad-B and AD brains compared to controls, with increased sphingomyelin (SM) levels exclusively in Cerad-B brains. Analysis of cell lysates revealed elevated dihydroceramide (dhSph), total Cer1P, and total SM in AD and PS cells versus controls. Multivariate analysis highlighted the relevance of Sph, Cer, Cer1P, and SM in AD pathology. Machine learning identified Sph, Cer, and Cer1P as key contributors to AD., Discussion: Our findings suggest the potential importance of Sph, Cer1P, Cer, and SM in the context of AD pathology. This underscores the significance of sphingolipid metabolism in understanding and potentially targeting mechanisms underlying AD., Competing Interests: The present study was a collaborative research project undertaken by The University of Tokyo and Nihon Waters Masayuki Kubota. ES is now an employee of Japan Waters Corporation. ES and MKb were employed by Nihon Waters K.K. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Uranbileg, Isago, Sakai, Kubota, Saito and Kurano.)
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- 2024
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7. Development of an advanced liquid chromatography-tandem mass spectrometry measurement system for simultaneous sphingolipid analysis.
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Uranbileg B, Sakai E, Kubota M, Isago H, Sumitani M, Yatomi Y, and Kurano M
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- Ceramides, Chromatography, Liquid, Sphingomyelins, Sphingosine, Sphingolipids metabolism, Tandem Mass Spectrometry methods
- Abstract
Mass spectrometry-based lipidomics approaches offer valuable tools for the detection and quantification of various lipid species, including sphingolipids. The present study aimed to develop a new method to simultaneously detect various sphingolipid species that applies to diverse biological samples. We developed and validated a measurement system by employing a single-column liquid chromatography-mass spectrometry system utilizing a normal-phase separation mode with positive ionization. The measurement system provided precision with a coefficient of variant below 20% for sphingolipids in all types of samples, and we observed good linearity in diluted serum samples. This system can measure the following sphingolipids: sphingosine 1-phosphate (S1P), sphingosine (Sph), dihydroS1P (dhS1P), dihydroSph (dhSph), ceramide 1-phosphate (Cer1P), hexosylceramide (HexCer), lactosylceramide (LacCer), dh-ceramide, deoxy-ceramide, deoxy-dh-ceramide, and sphingomyelin (SM). By measuring these sphingolipids in cell lysates where S1P lyase expression level was modulated, we could observe significant and dynamic modulations of sphingolipids in a comprehensive manner. Our newly established and validated measurement system can simultaneously measure many kinds of sphingolipids in biological samples. It holds great promise as a valuable tool for laboratory testing applications to detect overall modulations of sphingolipids, which have been proposed to be involved in pathogenesis processes in a series of elegant basic research studies., (© 2024. The Author(s).)
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- 2024
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8. Cerebrospinal Fluid Lysophosphatidylcholine Species for Distinguishing Narrowing of the Lumbar Spine.
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Sumitani M, Kimura A, Mochizuki T, Akiyama T, Uranbileg B, Takahashi T, Hirai T, Hayakawa K, Chikuda H, and Kurano M
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- Humans, Lumbar Vertebrae surgery, Lysophosphatidylcholines, Low Back Pain complications, Neuralgia complications, Spinal Stenosis etiology
- Abstract
Background: Reoperation, sometimes multiple, is common with progressively worse outcomes in patients with degenerative lumbar spine diseases. Lysophosphatidylcholine (LPC), a precursor of lysophosphatidic acid, in the cerebrospinal fluid (CSF) is a possible biomarker for neuropathic pain and discriminating neuropathic pain caused by lumbar spinal canal stenosis (LSCS) from other etiologies. This study aimed to explore this possible use of LPC species in the CSF., Methods: Patients with LSCS (n = 137) and persistent spinal pain syndrome (n = 22) were subjected in this multi-site observational study. The CSF was collected by lumbar puncture. Using liquid chromatography-tandem mass spectrometry, we measured 6 LPC species, (16:0), (18:0), (18:1), (18:2), (20:4), and (22:6), in the CSF. We compared the LPC values between the groups and determined the cutoff levels that could efficiently discriminate the groups with high accuracy., Results: The levels of all measured LPC species were significantly higher in the LSCS group than the persistent spinal pain syndrome group. Four LPC species demonstrated more than 0.80 area under the curve obtained from the receiver operating characteristic curve analysis. Although the specificity of cutoff levels for the 6 LPC species was low to moderate, their sensitivity was consistently high., Conclusions: The existing diagnostic protocols combining physical examinations and morphological imaging studies for lumbar spinal pain have limited sensitivity. Measuring LPC species in the CSF is a promising objective laboratory test and could be suitable for detecting the presence of lumbar spinal stenosis and can help indications for surgery., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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9. Understanding the modulations of glycero-lysophospholipids in an elastase-induced murine emphysema model.
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Isago H, Uranbileg B, Mitani A, and Kurano M
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- Mice, Humans, Animals, Pancreatic Elastase, Lysophospholipids metabolism, Pulmonary Emphysema chemically induced, Pulmonary Emphysema pathology, Pulmonary Disease, Chronic Obstructive pathology, Emphysema chemically induced
- Abstract
Background: Increasing evidence indicates that bioactive lipid mediators are involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Recently, glycero-lysophospholipids, such as lysophosphatidic acid (LysoPA) and lysophosphatidylserine (LysoPS), have been recognized as significant inflammation-related lipid mediators. However, their association with COPD remains unclear., Methods: We used an elastase-induced murine emphysema model to analyze the levels of lysophospholipids and diacyl-phospholipids in the lungs. Additionally, we assessed the expression of LysoPS-related genes and published data on smokers., Results: In the early phase of an elastase-induced murine emphysema model, the levels of LysoPS and its precursor (phosphatidylserine [PS]) were significantly reduced, without significant modulations in other glycero-lysophospholipids. Additionally, there was an upregulation in the expression of lysoPS receptors, specifically GPR34, observed in the lungs of a cigarette smoke-exposed mouse model and the alveolar macrophages of human smokers. Elastase stimulation induces GPR34 expression in a human macrophage cell line in vitro., Conclusions: Elastase-induced lung emphysema affects the LysoPS/PS-GPR34 axis, and cigarette smoking or elastase upregulates GPR34 expression in alveolar macrophages. This novel association may serve as a potential pharmacological target for COPD treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2024
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10. Apolipoprotein M bound sphingosine 1-phosphate suppresses NETosis through activating S1P1 and S1P4.
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Kurano M, Uranbileg B, and Yatomi Y
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- Animals, Mice, Apolipoproteins M, Mice, Knockout, Sphingosine, Extracellular Traps metabolism, Histones, Lysophospholipids
- Abstract
The pleiotropic effects of high-density lipoprotein (HDL), including its protective properties against sepsis, are attributed to the sphingosine 1-phosphate and apolipoprotein M (ApoM) that are carried on the lipoproteins. In this study, we attempted to elucidate the possible mechanisms underlying the sepsis coagulopathic state by considering the modulation of NETosis. Our results revealed that in a lipopolysaccharide-induced sepsis mouse model, the levels of NETosis markers, such as plasma DNA and histone, were elevated in ApoM-knockout (KO) mice and attenuated in ApoM-overexpressing mice. In ApoM-KO mice, the survival rate decreased and the occurrence rates of coagulopathy and organ injury increased following the administration of histone. Treatment with a conditioned medium of ApoM-overexpressing cells attenuated the observed NETosis in HL-60S cells that differentiated into neutrophils and were inhibited through the suppression of S1P1 or S1P4. The attenuation of PKCδ and PKCα/β by S1P1 and S1P4 activation may also be involved. In ApoM-overexpressing mice, coagulopathy and organ injuries were attenuated following an injection of histone; these effects were partially inhibited by S1P1, 3, S1P4, or S1P1 antagonists. Furthermore, the exogenous administration of ApoM protected ApoM-KO mice that were challenged with histone from developing NETosis. In conclusion, the ApoM/S1P axis protects against NETosis through the attenuation of PKC activation by S1P1 and S1P4. The development of drugs targeting the ApoM/S1P axis may be beneficial for the treatment of pathological conditions involving uncontrolled NETosis, such as sepsis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2023
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11. The Lysophospholipase PNPLA7 Controls Hepatic Choline and Methionine Metabolism.
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Harada S, Taketomi Y, Aiba T, Kawaguchi M, Hirabayashi T, Uranbileg B, Kurano M, Yatomi Y, and Murakami M
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- Animals, Humans, Mice, Glycerylphosphorylcholine metabolism, Liver metabolism, Methionine metabolism, S-Adenosylmethionine metabolism, Choline metabolism, Lysophospholipase metabolism
- Abstract
The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca
2+ -independent phospholipase A2 (iPLA2 ) family, as a key regulator of the production of glycerophosphocholine (GPC), a precursor of endogenous choline, whose methyl groups are preferentially fluxed into the methionine cycle in the liver. PNPLA7 deficiency in mice markedly decreases hepatic GPC, choline, and several metabolites related to choline/methionine metabolism, leading to various symptoms reminiscent of methionine shortage. Overall metabolic alterations in the liver of Pnpla7 -null mice in vivo largely recapitulate those in methionine-deprived hepatocytes in vitro. Reduction of the methyl donor S -adenosylmethionine (SAM) after methionine deprivation decreases the methylation of the PNPLA7 gene promoter, relieves PNPLA7 expression, and thereby increases GPC and choline levels, likely as a compensatory adaptation. In line with the view that SAM prevents the development of liver cancer, the expression of PNPLA7, as well as several enzymes in the choline/methionine metabolism, is reduced in human hepatocellular carcinoma. These findings uncover an unexplored role of a lysophospholipase in hepatic phospholipid catabolism coupled with choline/methionine metabolism.- Published
- 2023
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12. Modulations of bioactive lipids and their receptors in postmortem Alzheimer's disease brains.
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Kurano M, Saito Y, Uranbileg B, Saigusa D, Kano K, Aoki J, and Yatomi Y
- Abstract
Background: Analyses of brain samples from Alzheimer's disease (AD) patients may be expected to help us improve our understanding of the pathogenesis of AD. Bioactive lipids, including sphingolipids, glycerophospholipids, and eicosanoids/related mediators have been demonstrated to exert potent physiological actions and to be involved in the pathogenesis of various human diseases. In this cross-sectional study, we attempted to elucidate the associations of these bioactive lipids with the pathogenesis/pathology of AD through postmortem studies of human brains., Methods: We measured the levels of glycerophospholipids, sphingolipids, and eicosanoids/related mediators in the brains of patients with AD (AD brains), patients with Cerad score B (Cerad-b brains), and control subjects (control brains), using a liquid chromatography-mass spectrometry method; we also measured the mRNA levels of specific receptors for these bioactive lipids in the same brain specimens., Results: The levels of several species of sphingomyelins and ceramides were higher in the Cerad-b and AD brains. Levels of several species of lysophosphatidic acids (LPAs), lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine (LPE), lysophosphatidylinositol, phosphatidylcholine, phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol, and phosphatidylglycerol were especially high in the Cerad-b brains, while those of lysophosphatidylglycerol (LPG) were especially high in the AD brains. Several eicosanoids, including metabolites of prostaglandin E2, oxylipins, metabolites of epoxide, and metabolites of DHA and EPA, such as resolvins, were also modulated in the AD brains. Among the lipid mediators, the levels of S1P2, S1P5, LPA1, LPA2, LPA6, P2Y10, GPR174, EP1, DP1, DP2, IP, FP, and TXA2r were lower in the AD and/or Cerad-b brains. The brain levels of ceramides, LPC, LPI, PE, and PS showed strong positive correlations with the Aβ contents, while those of LPG showed rather strong positive correlations with the presence of senile plaques and neurofibrillary tangles. A discriminant analysis revealed that LPG is especially important for AD and the LPE/PE axis is important for Cerad-b., Conclusions: Comprehensive lipidomics, together with the measurement of lipid receptor expression levels provided novel evidence for the associations of bioactive lipids with AD, which is expected to facilitate future translational research and reverse translational research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kurano, Saito, Uranbileg, Saigusa, Kano, Aoki and Yatomi.)
- Published
- 2022
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13. Sphingosine 1-phosphate lyase facilitates cancer progression through converting sphingolipids to glycerophospholipids.
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Uranbileg B, Kurano M, Kano K, Sakai E, Arita J, Hasegawa K, Nishikawa T, Ishihara S, Yamashita H, Seto Y, Ikeda H, Aoki J, and Yatomi Y
- Subjects
- Chromatography, Liquid, Glycerophospholipids, Humans, Lysophospholipids, RNA, Messenger, Sphingolipids, Sphingosine analogs & derivatives, Tandem Mass Spectrometry, Carcinoma, Hepatocellular genetics, Colonic Neoplasms genetics, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Liver Neoplasms genetics
- Abstract
Background: In addition to potent agonist properties for sphingosine 1-phosphate (S1P) receptors, intracellularly, S1P is an intermediate in metabolic conversion pathway from sphingolipids to glycerolysophospholipids (glyceroLPLs). We hypothesized that this S1P metabolism and its products might possess some novel roles in the pathogenesis of cancer, where S1P lyase (SPL) is a key enzyme., Methods: The mRNA levels of sphingolipid-related and other cancer-related factors were measured in human hepatocellular carcinoma (HCC), colorectal cancer, and esophageal cancer patients' tumours and in their adjacent non-tumour tissues. Phospholipids (PL) and glyceroLPLs were measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In-vitro experiments were performed in Colon 26 cell line with modulation of the SPL and GPR55 expressions. Xenograft model was used for determination of the cancer progression and for pharmacological influence., Results: Besides high SPL levels in human HCC and colon cancer, SPL levels were specifically and positively linked with levels of glyceroLPLs, including lysophosphatidylinositol (LPI). Overexpression of SPL in Colon 26 cells resulted in elevated levels of LPI and lysophosphatidylglycerol (LPG), which are agonists of GPR55. SPL overexpression-enhanced cell proliferation was inhibited by GPR55 silencing. Conversely, inhibition of SPL led to the opposite outcome and reversed by adding LPI, LPG, and metabolites generated during S1P degradation, which is regulated by SPL. The xenograft model results suggested the contribution of SPL and glyceroLPLs to tumour progression depending on levels of SPL and GPR55. Moreover, the pharmacological inhibition of SPL prevented the progression of cancer. The underlying mechanisms for the SPL-mediated cancer progression are the activation of p38 and mitochondrial function through the LPI, LPG-GPR55 axis and the suppression of autophagy in a GPR55-independent manner., Conclusion: A new metabolic pathway has been proposed here in HCC and colon cancer, SPL converts S1P to glyceroLPLs, mainly to LPI and LPG, and facilitates cancer development., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
- Published
- 2022
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14. Inhibition of autotaxin activity ameliorates neuropathic pain derived from lumbar spinal canal stenosis.
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Uranbileg B, Ito N, Kurano M, Kano K, Uchida K, Sumitani M, Aoki J, and Yatomi Y
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- Animals, Behavior, Animal, Carbolines blood, Cerebrospinal Fluid metabolism, Disease Models, Animal, Female, Ganglia, Spinal metabolism, Humans, Lysophosphatidylcholines metabolism, Lysophospholipids pharmacology, Mice, Phosphodiesterase Inhibitors blood, Rats, Sprague-Dawley, Spinal Canal metabolism, Rats, Carbolines pharmacology, Neuralgia drug therapy, Phosphodiesterase Inhibitors pharmacology, Phosphoric Diester Hydrolases metabolism, Spinal Stenosis complications
- Abstract
Lumbar spinal canal stenosis (LSS) or mechanical compression of dorsal root ganglion (DRG) is one of the causes of low back pain and neuropathic pain (NP). Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator that is produced mainly from lysophosphatidylcholine (LPC) via autotaxin (ATX) and is known to induce NP via LPA
1 receptor signaling in mice. Recently, we demonstrated that LPC and LPA were higher in cerebrospinal fluid (CSF) of patients with LSS. Based on the possible potential efficacy of the ATX inhibitor for NP treatment, we used an NP model with compression of DRG (CD model) and investigated LPA dynamics and whether ATX inhibition could ameliorate NP symptoms, using an orally available ATX inhibitor (ONO-8430506) at a dose of 30 mg/kg. In CD model, we observed increased LPC and LPA levels in CSF, and decreased threshold of the pain which were ameliorated by oral administration of the ATX inhibitor with decreased microglia and astrocyte populations at the site of the spinal dorsal horn projecting from injured DRG. These results suggested possible efficacy of ATX inhibitor for the treatment of NP caused by spinal nerve root compression and involvement of the ATX-LPA axis in the mechanism of NP induction.- Published
- 2021
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15. The Multiple Faces of the Marmot: Associations with the Plague, Hunting, and Cosmology in Mongolia.
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Fijn N and Terbish B
- Abstract
Mongolians have long known of the association between marmots and the plague. We examine their understanding of the marmot not only as a biological species that can harbour the plague, but also from a cosmological perspective as a chimerical being with potential punishment on hunters who have transgressed ancient taboos. To do so we deconstruct the multiple image of the chimerical marmot in legends, stories, and beliefs. Many Mongolians believe that if the marmot is over-exploited and the population decimated through excessive hunting, hunting households may be punished with infections of the plague., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.)
- Published
- 2021
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16. Suppression of sphingosine 1-phosphate lyase retards the liver regeneration in mice after partial hepatectomy.
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Kageyama Y, Uranbileg B, Kusumoto Y, Sakai E, Ikeda H, Kurano M, and Yatomi Y
- Subjects
- Aldehyde-Lyases genetics, Animals, Cell Proliferation physiology, Hepatectomy, Liver surgery, Lysophospholipids metabolism, Male, Mice, Mice, Transgenic, Models, Animal, RNA, Small Interfering administration & dosage, Sphingosine analogs & derivatives, Sphingosine metabolism, Aldehyde-Lyases metabolism, Hepatocytes metabolism, Liver physiology, Liver Regeneration physiology
- Abstract
Background: Liver regeneration is an extremely complicated process that is regulated by a number of signaling pathways. Sphingosine 1-phosphate (S1P), a potent bioactive lipid mediator playing crucial roles in various cellular responses through its receptors, has been attracting attention in the fields of hepatology, where S1P lyase (SPL), an irreversibly degrading enzyme of S1P, reportedly has a stimulatory role in growth of hepatocellular carcinoma (HCC)., Aim of the Study: To examine whether SPL might play a stimulatory role in liver regeneration., Method: Using in-vivo siRNA technology, we inhibited SPL expression. Seventy percent of the liver was resected in mice as partial hepatectomy (PH). Liver tissue samples were collected and mRNA expression level of the SPL, IHC of the proliferating cell nuclear antigen (PCNA), protein levels of various proliferation factors and lipid measurements were performed in different groups., Results: The mRNA levels of SPL increased in PH mice on the third day after PH surgery. When we suppressed the expression of SPL by in-vivo siRNA, we observed a significant decline of the PCNA positive cell numbers. Furthermore, the Cyclin D1 expressions and phosphorylation of ERK also were decreased in the siSPL injected PH group., Conclusion: We verified the importance of the SPL in liver regeneration, using the mice PH model. SPL might be a potential target to facilitate liver regeneration., (© 2020 The Author(s).)
- Published
- 2020
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17. Identification of novel biomarkers of hepatocellular carcinoma by high-definition mass spectrometry: Ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry and desorption electrospray ionization mass spectrometry imaging.
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Nagai K, Uranbileg B, Chen Z, Fujioka A, Yamazaki T, Matsumoto Y, Tsukamoto H, Ikeda H, Yatomi Y, Chiba H, Hui SP, Nakazawa T, Saito R, Koshiba S, Aoki J, Saigusa D, and Tomioka Y
- Subjects
- Biomarkers, Tumor analysis, Biomarkers, Tumor metabolism, Carcinoma, Hepatocellular metabolism, Chromatography, High Pressure Liquid, Humans, Liver metabolism, Liver Neoplasms metabolism, Metabolome, Spectrometry, Mass, Electrospray Ionization, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Carcinoma, Hepatocellular diagnosis, Liver pathology, Liver Neoplasms diagnosis
- Abstract
Rationale: Hepatocellular carcinoma (HCC) is a highly malignant disease for which the development of prospective or prognostic biomarkers is urgently required. Although metabolomics is widely used for biomarker discovery, there are some bottlenecks regarding the comprehensiveness of detected features, reproducibility of methods, and identification of metabolites. In addition, information on localization of metabolites in tumor tissue is needed for functional analysis. Here, we developed a wide-polarity global metabolomics (G-Met) method, identified HCC biomarkers in human liver samples by high-definition mass spectrometry (HDMS), and demonstrated localization in cryosections using desorption electrospray ionization MS imaging (DESI-MSI) analysis., Methods: Metabolic profiling of tumor (n = 38) and nontumor (n = 72) regions in human livers of HCC was performed by an ultrahigh-performance liquid chromatography quadrupole time-of-flight MS (UHPLC/QTOFMS) instrument equipped with a mixed-mode column. The HCC biomarker candidates were extracted by multivariate analyses and identified by matching values of the collision cross section and their fragment ions on the mass spectra obtained by HDMS. Cryosections of HCC livers, which included both tumor and nontumor regions, were analyzed by DESI-MSI., Results: From the multivariate analysis, m/z 904.83 and m/z 874.79 were significantly high and low, respectively, in tumor samples and were identified as triglyceride (TG) 16:0/18:1(9Z)/20:1(11Z) and TG 16:0/18:1(9Z)/18:2(9Z,12Z) using the synthetic compounds. The TGs were clearly localized in the tumor or nontumor areas of the cryosection., Conclusions: Novel biomarkers for HCC were identified by a comprehensive and reproducible G-Met method with HDMS using a mixed-mode column. The combination analysis of UHPLC/QTOFMS and DESI-MSI revealed that the different molecular species of TGs were associated with tumor distribution and were useful for characterizing the progression of tumor cells and discovering prospective biomarkers., (© 2019 The Authors. Rapid Communications in Mass Spectrometry published by John Wiley & Sons Ltd.)
- Published
- 2020
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18. Possible involvement of PS-PLA1 and lysophosphatidylserine receptor (LPS1) in hepatocellular carcinoma.
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Uranbileg B, Kurano M, Sato M, Ikeda H, Ishizawa T, Hasegawa K, Kokudo N, and Yatomi Y
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- Aged, Carcinoma, Hepatocellular blood, Carcinoma, Hepatocellular genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Liver Neoplasms blood, Liver Neoplasms genetics, Lysophospholipids metabolism, Male, Middle Aged, Phospholipases A1 blood, RNA, Messenger genetics, RNA, Messenger metabolism, Carcinoma, Hepatocellular metabolism, Liver Neoplasms metabolism, Phospholipases A1 metabolism
- Abstract
Lysophosphatidylserine (LysoPS) is a lysophospholipid, its generating enzyme, phosphatidylserine-specific phospholipase A1 (PS-PLA1), reportedly plays roles in stomach and colon cancers. Here, we examined the potential roles of LysoPS in hepatocellular carcinoma (HCC). The ninety-seven HCC patients who underwent surgical treatment were enrolled in this study and approved by the institutional review board. Among LysoPS-related enzymes and receptors, increased PS-PLA1 or LysoPS receptor 1 (LPS1) mRNA was observed in HCC tissues compared to non-HCC tissues. PS-PLA1 mRNA in HCC was associated with no clinical parameters, while LPS1 mRNA in HCC was correlated inversely with tumor differentiation. Furthermore, higher serum PS-PLA1 was observed in HCC patients compared to healthy control and correlated with PS-PLA1 mRNA in non-HCC tissues and with serum AST or ALT. Additionally, serum levels of PS-PLA1 were higher in HCC patients with HCV-related liver injury than in those with HBV or non-HBV-, non-HCV-related liver diseases. In conclusion, among LysoPS-related enzymes and receptors, PS-PLA1 and LPS1 mRNA were increased in HCC. Based on the correlation between the serum PS-PLA1 and the mRNA level of PS-PLA1 in non-HCC tissues, the liver may be the main source of serum PS-PLA1, and serum PS-PLA1 levels may be a useful marker for liver injury.
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- 2020
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19. Alteration of the lysophosphatidic acid and its precursor lysophosphatidylcholine levels in spinal cord stenosis: A study using a rat cauda equina compression model.
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Uranbileg B, Ito N, Kurano M, Saigusa D, Saito R, Uruno A, Kano K, Ikeda H, Yamada Y, Sumitani M, Sekiguchi M, Aoki J, and Yatomi Y
- Subjects
- Animals, Constriction, Pathologic, Disease Models, Animal, Female, Gene Expression Regulation, Lysophosphatidylcholines blood, Lysophosphatidylcholines cerebrospinal fluid, Lysophospholipids blood, Lysophospholipids cerebrospinal fluid, Neuralgia metabolism, Neuralgia pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Sprague-Dawley, Receptors, Lysophosphatidic Acid genetics, Receptors, Lysophosphatidic Acid metabolism, Cauda Equina pathology, Lysophosphatidylcholines metabolism, Lysophospholipids metabolism, Spinal Cord pathology
- Abstract
Cauda equina compression (CEC) is a major cause of neurogenic claudication and progresses to neuropathic pain (NP). A lipid mediator, lysophosphatidic acid (LPA), is known to induce NP via the LPA
1 receptor. To know a possible mechanism of LPA production in neurogenic claudication, we determined the levels of LPA, lysophosphatidylcholine (LPC) and LPA-producing enzyme autotaxin (ATX), in the cerebrospinal fluid (CSF) and spinal cord (SC) using a CEC as a possible model of neurogenic claudication. Using silicon blocks within the lumbar epidural space, we developed a CEC model in rats with motor dysfunction. LPC and LPA levels in the CSF were significantly increased from day 1. Importantly, specific LPA species (16:0, 18:2, 20:4) were upregulated, which have been shown to produce by ATX detected in the CSF, without changes on its level. In SC, the LPC and LPA levels did not change, but mass spectrometry imaging analysis revealed that LPC was present in a region where the silicon blocks were inserted. These results propose a model for LPA production in SC and CSF upon neurogenic claudication that LPC produced locally by tissue damages is converted to LPA by ATX, which then leak out into the CSF.- Published
- 2019
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20. Genotypes of amyotrophic lateral sclerosis in Mongolia.
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Daria T, Müller K, Oidovdorj G, Baatar K, Boldbaatar P, Sarangerel J, Rentsenbat M, Turbat S, Yadamsuren E, Weydt P, Dambasuren B, Bosookhuu O, Banzrai C, Damchaa B, Pinkhardt EH, Rosenbohm A, Högel J, Andersen P, Borck G, Batmunkh M, Ludolph AC, and Weishaupt JH
- Subjects
- Adult, Asian People genetics, DNA Repeat Expansion genetics, Female, Genetic Predisposition to Disease genetics, Genotype, Humans, Male, Middle Aged, Mongolia, Pedigree, Polymorphism, Single Nucleotide genetics, Young Adult, Amyotrophic Lateral Sclerosis genetics, C9orf72 Protein genetics, RNA-Binding Protein FUS genetics, Superoxide Dismutase-1 genetics
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2019
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21. Lysophosphatidic acids and their substrate lysophospholipids in cerebrospinal fluid as objective biomarkers for evaluating the severity of lumbar spinal stenosis.
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Hayakawa K, Kurano M, Ohya J, Oichi T, Kano K, Nishikawa M, Uranbileg B, Kuwajima K, Sumitani M, Tanaka S, Aoki J, Yatomi Y, and Chikuda H
- Subjects
- Aged, Aged, 80 and over, Biomarkers cerebrospinal fluid, Female, Humans, Male, Middle Aged, Lumbar Vertebrae, Lysophospholipids cerebrospinal fluid, Spinal Stenosis cerebrospinal fluid
- Abstract
Lysophospholipids (LPLs) are known to have potentially important roles in the initiation and maintenance of neuropathic pain in animal models. This study investigated the association between the clinical severity of lumbar spinal stenosis (LSS) and the cerebrospinal fluid (CSF) levels of LPLs, using human samples. We prospectively identified twenty-eight patients with LSS and fifteen controls with idiopathic scoliosis or bladder cancer without neurological symptoms. We quantified LPLs from CSF using liquid chromatography-tandem mass spectrometry. We assessed clinical outcome measures of LSS (Neuropathic Pain Symptom Inventory (NPSI) and Zurich Claudication Questionnaire (ZCQ)) and categorized patients into two groups according to their severity. Five species of lysophosphatidic acid (LPA), nine species of lysophosphatidylcholine (LPC), and one species of lysophosphatidylinositol (LPI) were detected. The CSF levels of all species of LPLs were significantly higher in LSS patients than controls. Patients in the severe NPSI group had significantly higher LPL levels (three species of LPA and nine species of LPC) than the mild group. Patients in the severe ZCQ group also had significantly higher LPL levels (four species of LPA and nine species of LPC). This investigation demonstrates a positive correlation between the CSF levels of LPLs and the clinical severity of LSS. LPLs are potential biomarkers for evaluating the severity of LSS.
- Published
- 2019
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22. Lysophosphatidic acid is associated with neuropathic pain intensity in humans: An exploratory study.
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Kuwajima K, Sumitani M, Kurano M, Kano K, Nishikawa M, Uranbileg B, Tsuchida R, Ogata T, Aoki J, Yatomi Y, and Yamada Y
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Phosphoric Diester Hydrolases cerebrospinal fluid, Lysophospholipids cerebrospinal fluid, Neuralgia cerebrospinal fluid, Pain Management
- Abstract
The underlying mechanisms of neuropathic pain remain to be elucidated. Basic animal research has suggested that lysophosphatidic acids, which are bioactive lipids produced by autotaxin from lysophosphatidylcholine, may play key roles in the initiation and maintenance of neuropathic pain. Here, we investigated the clinical relevance of lysophosphatidic acids signaling on neuropathic pain in humans. Eighteen patients who had been diagnosed with neuropathic pain with varied etiologies participated in the study. Cerebrospinal fluid samples were obtained by lumbar puncture and the concentrations of 12 species of lysophosphatidic acids and lysophosphatidylcholine, autotaxin, and the phosphorylated neurofilament heavy subunit were measured. Pain symptoms were assessed using an 11-point numeric rating scale and the Neuropathic Pain Symptom Inventory regarding intensity and descriptive dimensions of neuropathic pain. The total lysophosphatidic acids were significantly associated with both pain intensity and symptoms. 18:1 and 20:4 lysophosphatidic acids in particular demonstrated the most correlations with dimensions of pain symptoms. Autotaxin and the phosphorylated neurofilament heavy subunit showed no association with pain symptoms. In conclusions, lysophosphatidic acids were significantly associated with pain symptoms in neuropathic pain patients. These results suggest that lysophosphatidic acids signaling might be a potential therapeutic target for neuropathic pain., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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23. Evidence Suggests Sphingosine 1-Phosphate Might Be Actively Generated, Degraded, and Transported to Extracellular Spaces With Increased S1P 2 and S1P 3 Expression in Colon Cancer.
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Uranbileg B, Nishikawa T, Ikeda H, Kurano M, Sato M, Saigusa D, Aoki J, Watanabe T, and Yatomi Y
- Subjects
- Aged, Extracellular Space, Female, Humans, Male, Middle Aged, Phosphotransferases (Alcohol Group Acceptor) metabolism, Receptors, Lysosphingolipid metabolism, Sphingosine metabolism, Colonic Neoplasms metabolism, Lysophospholipids metabolism, Sphingosine analogs & derivatives
- Abstract
Background: A pivotal role of sphingosine 1-phosphate (S1P) in cancer has been suggested based on the ceramide-S1P rheostat theory that the intracellular balance between prosurvival S1P and proapoptotic ceramide determines cell fate. Upregulation of S1P-generating sphingosine kinases (SKs) and downregulation of S1P-degrading S1P lyase (SPL) might increase intracellular S1P levels to exert a prosurvival effect in cancer in general, such as colon cancer. However, we recently observed a distinct S1P metabolism in hepatocellular carcinoma tissues that increased SPL mRNA levels with reduced S1P levels. Thus, we investigated S1P metabolism in colon cancer., Patients and Methods: We enrolled 26 consecutive colon cancer patients, who had undergone surgical treatment., Results: Not only SK, but also SPL, mRNA levels were increased in colon cancer tissues compared with the adjacent nontumorous tissues. Furthermore, the mRNA levels of another S1P degrading enzyme, S1P phosphatase 1, S1P transporters, spinster homolog 2, adenosine triphosphate-binding cassette subfamily C member 1, and S1P receptors, S1P
2 and S1P3 were also increased, but the S1P levels were not increased in the colon cancer tissues. The reduction of SPL expression by silencing led to reduced proliferation and invasion, and overexpression of SPL caused enhanced proliferation in colon cancer cell lines., Conclusion: In human colon cancer tissues, mRNA levels of S1P-generating and S1P-degrading enzymes, transporters from inside to outside the cells, and S1P receptors, S1P2 and S1P3 were elevated, suggesting active S1P metabolism and movement. This altered S1P metabolism might play a role in colon cancer pathophysiology., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2018
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24. Higher LPA2 and LPA6 mRNA Levels in Hepatocellular Carcinoma Are Associated with Poorer Differentiation, Microvascular Invasion and Earlier Recurrence with Higher Serum Autotaxin Levels.
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Enooku K, Uranbileg B, Ikeda H, Kurano M, Sato M, Kudo H, Maki H, Koike K, Hasegawa K, Kokudo N, and Yatomi Y
- Subjects
- Aged, Carcinoma, Hepatocellular blood, Carcinoma, Hepatocellular blood supply, Female, Humans, Liver Neoplasms blood, Liver Neoplasms blood supply, Male, Middle Aged, Carcinoma, Hepatocellular pathology, Cell Differentiation, Liver Neoplasms pathology, Neovascularization, Pathologic, Phosphoric Diester Hydrolases blood, RNA, Messenger metabolism, Receptors, Lysophosphatidic Acid genetics
- Abstract
Hepatocellular carcinoma (HCC) commonly develops in patients with liver fibrosis; in these patients, the blood levels of lysophosphatidic acid (LPA) and its generating enzyme autotaxin (ATX) increase with the liver fibrosis stage. We aimed to examine the potential relevance of ATX and LPA in HCC. Fifty-eight HCC patients who underwent surgical treatment were consecutively enrolled in the study. Among the LPA receptors in HCC, higher LPA2 mRNA levels correlated with poorer differentiation, and higher LPA6 mRNA levels correlated with microvascular invasion, which suggested a higher malignant potential of HCC with increased LPA2 and LPA6 expression. In patients with primary HCC, neither LPA2 nor LPA6 mRNA levels were associated with recurrence. However, when serum ATX levels were combined for analysis as a surrogate for plasma LPA levels, the cumulative intra-hepatic recurrence rate was higher in patients in whom both serum ATX levels and LPA2 or LPA6 mRNA levels were higher than the median. However, the mRNA level of phosphatidic acid-selective phospholipase A1ɑ, another LPA-generating enzyme, in HCC patients was not associated with pathological findings or recurrence, even in combination with the expression of LPA receptors. Higher LPA2 mRNA levels were associated with poorer differentiation, and higher LPA6 levels were associated with microvascular invasion in HCC; both became a risk factor for recurrence after surgical treatment when combined with increased serum ATX levels. ATX and LPA receptors merit consideration as therapeutic targets of HCC., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
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25. Sphingosine kinase-1, S1P transporter spinster homolog 2 and S1P2 mRNA expressions are increased in liver with advanced fibrosis in human.
- Author
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Sato M, Ikeda H, Uranbileg B, Kurano M, Saigusa D, Aoki J, Maki H, Kudo H, Hasegawa K, Kokudo N, and Yatomi Y
- Subjects
- Aged, Female, Humans, Liver pathology, Liver Cirrhosis pathology, Male, Sphingosine-1-Phosphate Receptors, Anion Transport Proteins biosynthesis, Gene Expression Regulation, Liver metabolism, Liver Cirrhosis metabolism, Phosphotransferases (Alcohol Group Acceptor) biosynthesis, RNA, Messenger biosynthesis, Receptors, Lysosphingolipid biosynthesis
- Abstract
The role of sphingosine 1-phosphate (S1P) in liver fibrosis or inflammation was not fully examined in human. Controversy exists which S1P receptors, S1P1 and S1P3 vs S1P2, would be importantly involved in its mechanism. To clarify these matters, 80 patients who received liver resection for hepatocellular carcinoma and 9 patients for metastatic liver tumor were enrolled. S1P metabolism was analyzed in background, non-tumorous liver tissue. mRNA levels of sphingosine kinase 1 (SK1) but not SK2 were increased in livers with fibrosis stages 3-4 compared to those with 0-2 and to normal liver. However, S1P was not increased in advanced fibrotic liver, where mRNA levels of S1P transporter spinster homolog 2 (SPNS2) but not S1P-degrading enzymes were enhanced. Furthermore, mRNA levels of S1P2 but not S1P1 or S1P3 were increased in advanced fibrotic liver. These increased mRNA levels of SK1, SPNS2 and S1P2 in fibrotic liver were correlated with α-smooth muscle actin mRNA levels in liver, and with serum ALT levels. In conclusion, S1P may be actively generated, transported to outside the cells, and bind to its specific receptor in human liver to play a role in fibrosis or inflammation. Altered S1P metabolism in fibrotic liver may be their therapeutic target.
- Published
- 2016
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26. Multicenter study of device-associated infection rates in hospitals of Mongolia: Findings of the International Nosocomial Infection Control Consortium (INICC).
- Author
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Ider BE, Baatar O, Rosenthal VD, Khuderchuluun C, Baasanjav B, Donkhim C, Batsuur B, Jambiimolom M, Purevdorj SE, Tsogtbaatar U, Sodnomdarjaa B, Gendaram B, Mendsaikhan N, Begzjav T, Narankhuu B, Ariungerel BE, Tumendemberel B, and Orellano PW
- Subjects
- Bacteria drug effects, Bacteria isolation & purification, Drug Resistance, Bacterial, Hospitals, Humans, Intensive Care Units, Mongolia epidemiology, Prevalence, Prospective Studies, Sepsis epidemiology, Urinary Tract Infections epidemiology, Catheter-Related Infections epidemiology, Cross Infection epidemiology, Pneumonia, Ventilator-Associated epidemiology
- Abstract
Background: To report the results of the International Nosocomial Infection Control Consortium (INICC) multicenter study conducted in Mongolia from September 2013-March 2015., Methods: A device-associated health care-associated infection prospective surveillance study in 3 adult intensive care units (ICUs) from 3 hospitals using the U.S. Centers for Disease Control and Prevention (CDC) and National Healthcare Safety Network (NHSN) definitions and INICC methods., Results: We documented 467 ICU patients for 2,133 bed days. The central line-associated bloodstream infection (CLABSI) rate was 19.7 per 1,000 central line days, the ventilator-associated pneumonia (VAP) rate was 43.7 per 1,000 mechanical ventilator days, and the catheter-associated urinary tract infection (CAUTI) rate was 15.7 per 1,000 urinary catheter days; all of the rates are higher than the INICC rates (CLABSI: 4.9; VAP: 16.5; and CAUTI: 5.3) and CDC-NHSN rates (CLABSI: 0.8; VAP: 1.1; and CAUTI: 1.3). Device use ratios were also higher than the CDC-NHSN and INICC ratios, except for the mechanical ventilator device use ratio, which was lower than the INICC ratio. Resistance of Staphylococcus aureus to oxacillin was 100%. Extra length of stay was 15.1 days for patients with CLABSI, 7.8 days for patients with VAP, and 8.2 days for patients with CAUTI. Extra crude mortality in the ICUs was 18.6% for CLABSI, 17.1% for VAP, and 5.1% for CAUTI., Conclusion: Device-associated health care-associated infection rates and most device use ratios in our Mongolian hospitals' ICUs are higher than the CDC-NSHN and INICC rates., (Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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27. Increased mRNA Levels of Sphingosine Kinases and S1P Lyase and Reduced Levels of S1P Were Observed in Hepatocellular Carcinoma in Association with Poorer Differentiation and Earlier Recurrence.
- Author
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Uranbileg B, Ikeda H, Kurano M, Enooku K, Sato M, Saigusa D, Aoki J, Ishizawa T, Hasegawa K, Kokudo N, and Yatomi Y
- Subjects
- Aldehyde-Lyases antagonists & inhibitors, Aldehyde-Lyases metabolism, Carcinoma, Hepatocellular blood supply, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular surgery, Cell Line, Tumor, Cell Movement, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Liver Neoplasms blood supply, Liver Neoplasms pathology, Liver Neoplasms surgery, Metabolome, Neoplasm Invasiveness, Neoplasm Recurrence, Local pathology, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors, Phosphotransferases (Alcohol Group Acceptor) metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Risk Factors, Sphingosine metabolism, Aldehyde-Lyases genetics, Carcinoma, Hepatocellular genetics, Cell Differentiation genetics, Liver Neoplasms genetics, Lysophospholipids metabolism, Neoplasm Recurrence, Local genetics, Phosphotransferases (Alcohol Group Acceptor) genetics, Sphingosine analogs & derivatives
- Abstract
Although sphingosine 1-phosphate (S1P) has been reported to play an important role in cancer pathophysiology, little is known about S1P and hepatocellular carcinoma (HCC). To clarify the relationship between S1P and HCC, 77 patients with HCC who underwent surgical treatment were consecutively enrolled in this study. In addition, S1P and its metabolites were quantitated by LC-MS/MS. The mRNA levels of sphingosine kinases (SKs), which phosphorylate sphingosine to generate S1P, were increased in HCC tissues compared with adjacent non-HCC tissues. Higher mRNA levels of SKs in HCC were associated with poorer differentiation and microvascular invasion, whereas a higher level of SK2 mRNA was a risk factor for intra- and extra-hepatic recurrence. S1P levels, however, were unexpectedly reduced in HCC compared with non-HCC tissues, and increased mRNA levels of S1P lyase (SPL), which degrades S1P, were observed in HCC compared with non-HCC tissues. Higher SPL mRNA levels in HCC were associated with poorer differentiation. Finally, in HCC cell lines, inhibition of the expression of SKs or SPL by siRNA led to reduced proliferation, invasion and migration, whereas overexpression of SKs or SPL enhanced proliferation. In conclusion, increased SK and SPL mRNA expression along with reduced S1P levels were more commonly observed in HCC tissues compared with adjacent non-HCC tissues and were associated with poor differentiation and early recurrence. SPL as well as SKs may be therapeutic targets for HCC treatment.
- Published
- 2016
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28. Cdc6 protein obstructs apoptosome assembly and consequent cell death by forming stable complexes with activated Apaf-1 molecules.
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Niimi S, Arakawa-Takeuchi S, Uranbileg B, Park JH, Jinno S, and Okayama H
- Published
- 2015
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29. Increased serum mitochondrial creatine kinase activity as a risk for hepatocarcinogenesis in chronic hepatitis C patients.
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Enooku K, Nakagawa H, Soroida Y, Ohkawa R, Kageyama Y, Uranbileg B, Watanabe N, Tateishi R, Yoshida H, Koike K, Yatomi Y, and Ikeda H
- Subjects
- Aged, Animals, Carcinoma, Hepatocellular complications, Female, Fibrosis, Hepatitis C, Chronic complications, Hepatocytes cytology, Humans, Liver pathology, Liver Neoplasms complications, Male, Mice, Mice, Inbred C57BL, Middle Aged, Platelet Count, Proportional Hazards Models, ROC Curve, Risk, Sensitivity and Specificity, Serum Albumin metabolism, Carcinoma, Hepatocellular blood, Creatine Kinase, Mitochondrial Form blood, Hepatitis C, Chronic blood, Liver Neoplasms blood
- Abstract
Serum mitochondrial creatine kinase (MtCK) activity was reportedly increased in cirrhotic patients although less prominent than that in hepatocellular carcinoma (HCC) patients. To elucidate the clinical significance of serum MtCK activity in chronic liver disease, 171 chronic hepatitis C patients were enrolled. Serum MtCK activity in study subjects was correlated with serum albumin, platelet counts, liver stiffness values and serum aspartate and alanine aminotransferase. In mouse fibrotic liver induced by bile duct ligation, ubiquitous MtCK mRNA and protein expressions were significantly enhanced and its immunoreactivity was increased, predominantly in hepatocytes. During the mean follow-up period of 2.7 years, HCC developed in 21 patients, in whom serum MtCK activity was significantly higher than that in patients without HCC development. Multivariate Cox regression analysis revealed that higher serum MtCK activity was a risk for HCC development. A cutoff value of MtCK for the prediction of HCC development was determined as 9.0 U/L on receiver operating characteristics analysis, where area under receiver operating characteristics curve was 0.754, with a sensitivity of 61.9%, a specificity of 92.8% and a high negative predictive value of 94.2%. Cumulative incidence of HCC was significantly higher in patients with serum MtCK activity of >9.0 U/L compared to those with serum MtCK activity of ≤ 9.0 U/L even in patients with elevated liver stiffness value, >15 kPa. In conclusion, serum MtCK activity may be increased correlatively with the stage of liver fibrosis and hepatocellular damage. Increased serum MtCK activity is an independent risk for hepatocarcinogenesis in chronic hepatitis C patients., (Copyright © 2014 UICC.)
- Published
- 2014
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30. Increased serum autotaxin levels in hepatocellular carcinoma patients were caused by background liver fibrosis but not by carcinoma.
- Author
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Kondo M, Ishizawa T, Enooku K, Tokuhara Y, Ohkawa R, Uranbileg B, Nakagawa H, Tateishi R, Yoshida H, Kokudo N, Koike K, Yatomi Y, and Ikeda H
- Subjects
- Aged, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular surgery, Catheter Ablation, Female, Gene Expression Regulation, Neoplastic, Humans, Liver Neoplasms pathology, Liver Neoplasms surgery, Male, Phosphoric Diester Hydrolases genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Tumor Burden, Carcinoma, Hepatocellular blood, Carcinoma, Hepatocellular complications, Liver Cirrhosis complications, Liver Neoplasms blood, Liver Neoplasms complications, Phosphoric Diester Hydrolases blood
- Abstract
Background: Controversy exists as to whether autotaxin (ATX) may be importantly associated with pathophysiology of hepatocellular carcinoma (HCC)., Methods: We evaluated serum ATX levels and its mRNA expression in consecutive 148 HCC patients treated with radiofrequency ablation (RFA) and 30 patients with hepatic resection., Results: Although increased serum ATX levels were observed in almost all the patients treated with RFA, they were not reduced after RFA. Furthermore, serum ATX levels were associated not with tumor burden but with the parameters predicting for liver fibrosis, such as liver stiffness values. Then, in surgically-treated patients, there was no significant correlation between serum ATX levels and ATX mRNA expression levels in HCC tissues. Notably, ATX mRNA expression levels in HCC tissues were not higher than those in peri-tumorous tissues. Finally, serum ATX levels in surgically-treated HCC patients were rather correlated with ATX mRNA expression levels in peri-tumorous tissues as well as with liver fibrosis stage., Conclusion: The increase in serum ATX levels in HCC patients may not be caused by abundant ATX production in HCC tissues but by fibrosis in the background livers., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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31. High ubiquitous mitochondrial creatine kinase expression in hepatocellular carcinoma denotes a poor prognosis with highly malignant potential.
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Uranbileg B, Enooku K, Soroida Y, Ohkawa R, Kudo Y, Nakagawa H, Tateishi R, Yoshida H, Shinzawa S, Moriya K, Ohtomo N, Nishikawa T, Inoue Y, Tomiya T, Kojima S, Matsuura T, Koike K, Yatomi Y, and Ikeda H
- Subjects
- Animals, Carcinoma, Hepatocellular mortality, Carcinoma, Hepatocellular pathology, Female, Humans, Immunoblotting, Liver Neoplasms mortality, Liver Neoplasms pathology, Male, Mice, Mice, Transgenic, Middle Aged, Prognosis, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Suppressor of Cytokine Signaling Proteins metabolism, Transfection, Carcinoma, Hepatocellular enzymology, Creatine Kinase, Mitochondrial Form metabolism, Liver Neoplasms enzymology
- Abstract
We previously reported the increased serum mitochondrial creatine kinase (MtCK) activity in patients with hepatocellular carcinoma (HCC), mostly due to the increase in ubiquitous MtCK (uMtCK), and high uMtCK mRNA expression in HCC cell lines. We explored the mechanism(s) and the relevance of high uMtCK expression in HCC. In hepatitis C virus core gene transgenic mice, known to lose mitochondrial integrity in liver and subsequently develop HCC, uMtCK mRNA and protein levels were increased in HCC tissues but not in non-tumorous liver tissues. Transient overexpression of ankyrin repeat and suppressor of cytokine signaling box protein 9 (ASB9) reduced uMtCK protein levels in HCC cells, suggesting that increased uMtCK levels in HCC cells may be caused by increased gene expression and decreased protein degradation due to reduced ASB9 expression. The reduction of uMtCK expression by siRNA led to increased cell death, and reduced proliferation, migration and invasion in HCC cell lines. Then, consecutive 105 HCC patients, who underwent radiofrequency ablation with curative intent, were enrolled to analyze their prognosis. The patients with serum MtCK activity >19.4 U/L prior to the treatment had significantly shorter survival time than those with serum MtCK activity ≤ 19.4 U/L, where higher serum MtCK activity was retained as an independent risk for HCC-related death on multivariate analysis. In conclusion, high uMtCK expression in HCC may be caused by hepatocarcinogenesis per se but not by loss of mitochondrial integrity, of which ASB9 could be a negative regulator, and associated with highly malignant potential to suggest a poor prognosis., (© 2013 UICC.)
- Published
- 2014
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32. Simultaneous Quantification of Sphingolipids in Small Quantities of Liver by LC-MS/MS.
- Author
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Saigusa D, Okudaira M, Wang J, Kano K, Kurano M, Uranbileg B, Ikeda H, Yatomi Y, Motohashi H, and Aoki J
- Abstract
Sph, S1P, and Cer, derived from the membrane sphingolipids, act as intracellular and intercellular mediators, involved in various (path) physiological functions. Accordingly, determining the distributions and concentrations of these sphingolipid mediators in body tissues is an important task. Consequently, a method for determination of sphingolipids in small quantities of tissue is required. Sphingolipids analysis has been dependent on improvements in mass spectrometry (MS) technology. Additionally, decomposition of sphingosine-1-phosphate (S1P) in the tissue samples before preparation for MS has hindered analysis. In the present study, a method for stabilization of liver samples before MS preparation was developed using a heat stabilizer (Stabilizor™ T1). Then, a LC-MS/MS method using a triple-quadrupole mass spectrometer with a C8 column was developed for simultaneous determination of sphingolipids in small quantities of liver specimens. This method showed good separation and validation results. Separation was performed with a gradient elution of solvent A (5 mmol L(-1) ammonium formate in water, pH 4.0) and solvent B (5 mmol L(-1) ammonium formate in 95% acetonitrile, pH 4.0) at 300 μL min(-1). The lower limit of quantification was less than 132 pmol L(-1), and this method was accurate (∼13.5%) and precise (∼7.13%) for S1P analysis. The method can be used to show the tissue distribution of sphingolipids.
- Published
- 2014
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33. Successive phosphorylation of p27(KIP1) protein at serine-10 and C terminus crucially controls its potency to inactivate Cdk2.
- Author
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Mohanty AR, Kan Q, Srivastava S, Uranbileg B, Arakawa-Takeuchi S, Fujita N, and Okayama H
- Subjects
- Animals, Binding Sites, Catalysis, Cell Cycle, Cell Cycle Proteins chemistry, Cell Line, Cell Proliferation, Histidine chemistry, Nuclear Proteins chemistry, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Rats, Recombinant Proteins chemistry, Cyclin-Dependent Kinase 2 chemistry, Cyclin-Dependent Kinase Inhibitor p27 chemistry, Serine chemistry
- Abstract
During the G(1)-S transition, the activity of Cdk2 is regulated by its association with p27(KIP1), which in rodent fibroblasts undergoes phosphorylation mainly at serine 10, threonine 187, and C-terminal threonine 197 by KIS, Cdk2, and Pim or ROCK, respectively. Recently Cdc6 the AAA+ ATPase, identified initially to assemble pre-replicative complexes on origins of replication and later to activate p21(CIP1)-inactivated Cdk2, was found also to activate p27-bound Cdk2 but only after the bound p27 is C-terminally phosphorylated. On the other hand, the biological significance of the serine 10 phosphorylation remains elusive aside from its involvement in the stability of p27 itself. We report here that serine 10 phosphorylation is required for efficient C-terminal phosphorylation of its own by PIM and ROCK kinases and critically controls the potency of p27 as a Cdk2 inhibitor. In vitro, PIM1 and active ROCK1 efficiently phosphorylated free as well as Cdk2-bound p27 but only when the p27 was phosphorylated at Ser-10 in advance. Consistently, a Ser-10 nonphosphorylatable mutant p27 protein was not phosphorylated at the C terminus in vivo. Furthermore, when double-phosphorylated, free p27 was no longer a potent inhibitor of Cdk2, and Cdk2-bound p27 could be removed by Cdc6 to reactivate the Cdk2. Thus, phosphorylation at these two sites crucially controls the potency of this CDK inhibitor in two distinct modes.
- Published
- 2012
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34. Cdc6 protein obstructs apoptosome assembly and consequent cell death by forming stable complexes with activated Apaf-1 molecules.
- Author
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Niimi S, Arakawa-Takeuchi S, Uranbileg B, Park JH, Jinno S, and Okayama H
- Subjects
- Adenosine Triphosphate metabolism, Animals, Caspase 9 metabolism, Cell Cycle Proteins metabolism, Cells, Cultured, Enzyme Activation, Hydrolysis, Mice, Nuclear Proteins metabolism, Apoptosomes, Apoptotic Protease-Activating Factor 1 metabolism, Cell Cycle Proteins physiology, Cell Death, Nuclear Proteins physiology
- Abstract
Cdc6 is the bifunctional AAA+ ATPase that assembles prereplicative complexes on origins of replication and activates p21(CIP1)- or p27(KIP1)-bound Cdk2. During the G(1)-S transition, the Cdc6 gene essential for chromosomal replication is activated by the E2F transcriptional factor. Paradoxically, Apaf-1 encoding the central component of the apoptosome is also activated at the same time and by E2F. Consequently, genes for antipodal life and death are regulated in the same manner by the same transcriptional factor. Here we report a striking solution to this paradox. Besides performing prereplicative complex assembly and Cdk2 activation, Cdc6 obstructed apoptosome assembly by forming stable complexes very likely with a monomer of cytochrome c-activated Apaf-1 molecules. This function depended on its own ATPase domain but not on the cyclin-binding motif. In proliferating rodent fibroblasts, Cdc6 continued to block apoptosome assembly induced by a non-cytochrome c or some other mechanism, suppressing seemingly unintended apoptosis when promoting cell proliferation. Thus, Cdc6 is an AAA+ ATPase with three functions, all working for life.
- Published
- 2012
- Full Text
- View/download PDF
35. Cdc6 protein activates p27KIP1-bound Cdk2 protein only after the bound p27 protein undergoes C-terminal phosphorylation.
- Author
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Uranbileg B, Yamamoto H, Park JH, Mohanty AR, Arakawa-Takeuchi S, Jinno S, and Okayama H
- Subjects
- Amino Acid Substitution physiology, Animals, Cell Cycle Proteins chemistry, Cell Cycle Proteins genetics, Cell Division physiology, Cells, Cultured, Cyclin D3 genetics, Cyclin D3 metabolism, Cyclin-Dependent Kinase Inhibitor p27 chemistry, Cytoskeleton physiology, Enzyme Activation physiology, Fibroblasts cytology, Humans, Mice, Monomeric GTP-Binding Proteins metabolism, Neuropeptides metabolism, Nuclear Proteins chemistry, Nuclear Proteins genetics, Phosphorylation physiology, Protein Binding physiology, Protein Structure, Tertiary physiology, RNA, Small Interfering pharmacology, Ras Homolog Enriched in Brain Protein, Rats, Threonine metabolism, rho-Associated Kinases metabolism, Cell Cycle Proteins metabolism, Cyclin-Dependent Kinase 2 metabolism, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Fibroblasts enzymology, Nuclear Proteins metabolism
- Abstract
In mammalian cells Cdk2 activity during the G(1)-S transition is mainly controlled by p27(KIP1). Although the amount and subcellular localization of p27 influence Cdk2 activity, how Cdk2 activity is regulated during this phase transition still remains virtually unknown. Here we report an entirely new mechanism for this regulation. Cdc6 the AAA+ ATPase, known to assemble prereplicative complexes on chromosomal replication origins and activate p21(CIP1)-bound Cdk2, also activated p27-bound Cdk2 in its ATPase and cyclin binding motif-dependent manner but only after the p27 bound to the Cdk2 was phosphorylated at the C terminus. ROCK, which mediates a signal for cell anchorage to the extracellular matrix and activates the mTORC1 cascade as well as controls cytoskeleton assembly, was partly responsible for C-terminal phosphorylation of the p27. In vitro reconstitution demonstrated ROCK (Rho-associated kinase)-mediated phosphorylation of Cdk2-bound p27 at the C terminus and subsequent activation of the Cdk2 by Cdc6.
- Published
- 2012
- Full Text
- View/download PDF
36. Mammalian target of rapamycin complex 1 signaling opposes the effects of anchorage loss, leading to activation of Cdk4 and Cdc6 stabilization.
- Author
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Arakawa-Takeuchi S, Kobayashi K, Park JH, Uranbileg B, Yamamoto H, Jinno S, and Okayama H
- Subjects
- Animals, Caspase 3 metabolism, Cell Cycle Proteins genetics, Cell Line, Chromosomal Proteins, Non-Histone genetics, Cyclin-Dependent Kinase 4 genetics, Cyclin-Dependent Kinase 6 genetics, Immunoblotting, Protein Stability, Rats, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors genetics, Ubiquitination physiology, Cell Cycle Proteins metabolism, Chromosomal Proteins, Non-Histone metabolism, Cyclin-Dependent Kinase 4 metabolism, Cyclin-Dependent Kinase 6 metabolism, Transcription Factors metabolism
- Abstract
When deprived of an anchorage to the extracellular matrix, fibroblasts arrest in the G(1) phase with inactivation of Cdk4/6 and Cdk2 and destruction of Cdc6, the assembler of prereplicative complexes essential for S phase onset. How cellular anchorages control these kinases and Cdc6 stability is poorly understood. Here, we report that in rat embryonic fibroblasts, activation of mammalian target of rapamycin complex 1 by a Tsc2 mutation or overexpression of a constitutively active mutant Rheb overrides the absence of the anchorage and stabilizes Cdc6 at least partly via activating Cdk4/6 that induces Emi1, an APC/C(Cdh1) ubiquitin ligase inhibitor., (Copyright 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
- Published
- 2010
- Full Text
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37. Surgery in Mongolia.
- Author
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Gunsentsoodol B, Nachin B, and Dashzeveg T
- Subjects
- Forecasting, General Surgery education, General Surgery trends, Humans, Mongolia, General Surgery organization & administration
- Abstract
Western-style medicine in Mongolia was introduced in 1922. Today the health service structure is well adapted to the needs of the country. Surgery in Mongolia is performed by more than 300 surgeons who serve a population of 2.5 million people. The differences in geographical and settlement conditions create significant disparities in health needs between rural and urban populations. In this report we give an overview of the development and current status of medical service, disease patterns, and medical educational systems, including surgical specialty training.
- Published
- 2006
- Full Text
- View/download PDF
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