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1.  Guidelines for the use and interpretation of assays for monitoring autophagy 
Klionsky, Daniel J. | Abdalla, Fabio C. | Abeliovich, Hagai | Abraham, Robert T. | Acevedo-Arozena, Abraham | Adeli, Khosrow | Agholme, Lotta | Agnello, Maria | Agostinis, Patrizia | Aguirre-Ghiso, Julio A. | Ahn, Hyung Jun | Ait-Mohamed, Ouardia | Ait-Si-Ali, Slimane | Akematsu, Takahiko | Akira, Shizuo | Al-Younes, Hesham M. | Al-Zeer, Munir A. | Albert, Matthew L. | Albin, Roger L. | Alegre-Abarrategui, Javier | Aleo, Maria Francesca | Alirezaei, Mehrdad | Almasan, Alexandru | Almonte-Becerril, Maylin | Amano, Atsuo | Amaravadi, Ravi K. | Amarnath, Shoba | Amer, Amal O. | Andrieu-Abadie, Nathalie | Anantharam, Vellareddy | Ann, David K. | Anoopkumar-Dukie, Shailendra | Aoki, Hiroshi | Apostolova, Nadezda | Arancia, Giuseppe | Aris, John P. | Asanuma, Katsuhiko | Asare, Nana Y.O. | Ashida, Hisashi | Askanas, Valerie | Askew, David S. | Auberger, Patrick | Baba, Misuzu | Backues, Steven K. | Baehrecke, Eric H. | Bahr, Ben A. | Bai, Xue-Yuan | Bailly, Yannick | Baiocchi, Robert | Baldini, Giulia | Balduini, Walter | Ballabio, Andrea | Bamber, Bruce A. | Bampton, Edward T.W. | Juhász, Gábor | Bartholomew, Clinton R. | Bassham, Diane C. | Bast, Robert C. | Batoko, Henri | Bay, Boon-Huat | Beau, Isabelle | Béchet, Daniel M. | Begley, Thomas J. | Behl, Christian | Behrends, Christian | Bekri, Soumeya | Bellaire, Bryan | Bendall, Linda J. | Benetti, Luca | Berliocchi, Laura | Bernardi, Henri | Bernassola, Francesca | Besteiro, Sébastien | Bhatia-Kissova, Ingrid | Bi, Xiaoning | Biard-Piechaczyk, Martine | Blum, Janice S. | Boise, Lawrence H. | Bonaldo, Paolo | Boone, David L. | Bornhauser, Beat C. | Bortoluci, Karina R. | Bossis, Ioannis | Bost, Frédéric | Bourquin, Jean-Pierre | Boya, Patricia | Boyer-Guittaut, Michaël | Bozhkov, Peter V. | Brady, Nathan R | Brancolini, Claudio | Brech, Andreas | Brenman, Jay E. | Brennand, Ana | Bresnick, Emery H. | Brest, Patrick | Bridges, Dave | Bristol, Molly L. | Brookes, Paul S. | Brown, Eric J. | Brumell, John H. | Brunetti-Pierri, Nicola | Brunk, Ulf T. | Bulman, Dennis E. | Bultman, Scott J. | Bultynck, Geert | Burbulla, Lena F. | Bursch, Wilfried | Butchar, Jonathan P. | Buzgariu, Wanda | Bydlowski, Sergio P. | Cadwell, Ken | Cahová, Monika | Cai, Dongsheng | Cai, Jiyang | Cai, Qian | Calabretta, Bruno | Calvo-Garrido, Javier | Camougrand, Nadine | Campanella, Michelangelo | Campos-Salinas, Jenny | Candi, Eleonora | Cao, Lizhi | Caplan, Allan B. | Carding, Simon R. | Cardoso, Sandra M. | Carew, Jennifer S. | Carlin, Cathleen R. | Carmignac, Virginie | Carneiro, Leticia A.M. | Carra, Serena | Caruso, Rosario A. | Casari, Giorgio | Casas, Caty | Castino, Roberta | Cebollero, Eduardo | Cecconi, Francesco | Celli, Jean | Chaachouay, Hassan | Chae, Han-Jung | Chai, Chee-Yin | Chan, David C. | Chan, Edmond Y. | Chang, Raymond Chuen-Chung | Che, Chi-Ming | Chen, Ching-Chow | Chen, Guang-Chao | Chen, Guo-Qiang | Chen, Min | Chen, Quan | Chen, Steve S.-L. | Chen, WenLi | Chen, Xi | Chen, Xiangmei | Chen, Xiequn | Chen, Ye-Guang | Chen, Yingyu | Chen, Yongqiang | Chen, Yu-Jen | Chen, Zhixiang | Cheng, Alan | Cheng, Christopher H.K. | Cheng, Yan | Cheong, Heesun | Cheong, Jae-Ho | Cherry, Sara | Chess-Williams, Russ | Cheung, Zelda H. | Chevet, Eric | Chiang, Hui-Ling | Chiarelli, Roberto | Chiba, Tomoki | Chin, Lih-Shen | Chiou, Shih-Hwa | Chisari, Francis V. | Cho, Chi Hin | Cho, Dong-Hyung | Choi, Augustine M.K. | Choi, DooSeok | Choi, Kyeong Sook | Choi, Mary E. | Chouaib, Salem | Choubey, Divaker | Choubey, Vinay | Chu, Charleen T. | Chuang, Tsung-Hsien | Chueh, Sheau-Huei | Chun, Taehoon | Chwae, Yong-Joon | Chye, Mee-Len | Ciarcia, Roberto | Ciriolo, Maria R. | Clague, Michael J. | Clark, Robert S.B. | Clarke, Peter G.H. | Clarke, Robert | Codogno, Patrice | Coller, Hilary A. | Colombo, María I. | Comincini, Sergio | Condello, Maria | Condorelli, Fabrizio | Cookson, Mark R. | Coombs, Graham H. | Coppens, Isabelle | Corbalan, Ramon | Cossart, Pascale | Costelli, Paola | Costes, Safia | Coto-Montes, Ana | Couve, Eduardo | Coxon, Fraser P. | Cregg, James M. | Crespo, José L. | Cronjé, Marianne J. | Cuervo, Ana Maria | Cullen, Joseph J. | Czaja, Mark J. | D'Amelio, Marcello | Darfeuille-Michaud, Arlette | Davids, Lester M. | Davies, Faith E. | De Felici, Massimo | de Groot, John F. | de Haan, Cornelis A.M. | De Martino, Luisa | De Milito, Angelo | De Tata, Vincenzo | Debnath, Jayanta | Degterev, Alexei | Dehay, Benjamin | Delbridge, Lea M.D. | Demarchi, Francesca | Deng, Yi Zhen | Dengjel, Jörn | Dent, Paul | Denton, Donna | Deretic, Vojo | Desai, Shyamal D. | Devenish, Rodney J. | Di Gioacchino, Mario | Di Paolo, Gilbert | Di Pietro, Chiara | Díaz-Araya, Guillermo | Díaz-Laviada, Inés | Diaz-Meco, Maria T. | Diaz-Nido, Javier | Dikic, Ivan | Dinesh-Kumar, Savithramma P. | Ding, Wen-Xing | Distelhorst, Clark W. | Diwan, Abhinav | Djavaheri-Mergny, Mojgan | Dokudovskaya, Svetlana | Dong, Zheng | Dorsey, Frank C. | Dosenko, Victor | Dowling, James J. | Doxsey, Stephen | Dreux, Marlène | Drew, Mark E. | Duan, Qiuhong | Duchosal, Michel A. | Duff, Karen E. | Dugail, Isabelle | Durbeej, Madeleine | Duszenko, Michael | Edelstein, Charles L. | Edinger, Aimee L. | Egea, Gustavo | Eichinger, Ludwig | Eissa, N. Tony | Ekmekcioglu, Suhendan | El-Deiry, Wafik S. | Elazar, Zvulun | Elgendy, Mohamed | Ellerby, Lisa M. | Eng, Kai Er | Engelbrecht, Anna-Mart | Engelender, Simone | Erenpreisa, Jekaterina | Escalante, Ricardo | Esclatine, Audrey | Eskelinen, Eeva-Liisa | Espert, Lucile | Espina, Virginia | Fan, Huizhou | Fan, Jia | Fan, Qi-Wen | Fan, Zhen | Fang, Shengyun | Fang, Yongqi | Fanto, Manolis | Fanzani, Alessandro | Farkas, Thomas | Farre, Jean-Claude | Faure, Mathias | Fechheimer, Marcus | Feng, Carl G. | Feng, Jian | Feng, Qili | Feng, Youji | Fésüs, László | Feuer, Ralph | Figueiredo-Pereira, Maria E. | Fimia, Gian Maria | Fingar, Diane C. | Finkbeiner, Steven | Finkel, Toren | Finley, Kim D. | Fiorito, Filomena | Fisher, Edward A. | Fisher, Paul B. | Flajolet, Marc | Florez-McClure, Maria L. | Florio, Salvatore | Fon, Edward A. | Fornai, Francesco | Fortunato, Franco | Fotedar, Rati | Fowler, Daniel H. | Fox, Howard S. | Franco, Rodrigo | Frankel, Lisa B. | Fransen, Marc | Fuentes, José M. | Fueyo, Juan | Fujii, Jun | Fujisaki, Kozo | Fujita, Eriko | Fukuda, Mitsunori | Furukawa, Ruth H. | Gaestel, Matthias | Gailly, Philippe | Gajewska, Malgorzata | Galliot, Brigitte | Galy, Vincent | Ganesh, Subramaniam | Ganetzky, Barry | Ganley, Ian G. | Gao, Fen-Biao | Gao, George F. | Gao, Jinming | Garcia, Lorena | Garcia-Manero, Guillermo | Garcia-Marcos, Mikel | Garmyn, Marjan | Gartel, Andrei L. | Gatti, Evelina | Gautel, Mathias | Gawriluk, Thomas R. | Gegg, Matthew E. | Geng, Jiefei | Germain, Marc | Gestwicki, Jason E. | Gewirtz, David A. | Ghavami, Saeid | Ghosh, Pradipta | Giammarioli, Anna M. | Giatromanolaki, Alexandra N. | Gibson, Spencer B. | Gilkerson, Robert W. | Ginger, Michael L. | Ginsberg, Henry N. | Golab, Jakub | Goligorsky, Michael S. | Golstein, Pierre | Gomez-Manzano, Candelaria | Goncu, Ebru | Gongora, Céline | Gonzalez, Claudio D. | Gonzalez, Ramon | González-Estévez, Cristina | González-Polo, Rosa Ana | Gonzalez-Rey, Elena | Gorbunov, Nikolai V. | Gorski, Sharon | Goruppi, Sandro | Gottlieb, Roberta A. | Gozuacik, Devrim | Granato, Giovanna Elvira | Grant, Gary D. | Green, Kim N. | Gregorc, Ales | Gros, Frédéric | Grose, Charles | Grunt, Thomas W. | Gual, Philippe | Guan, Jun-Lin | Guan, Kun-Liang | Guichard, Sylvie M. | Gukovskaya, Anna S. | Gukovsky, Ilya | Gunst, Jan | Gustafsson, Åsa B. | Halayko, Andrew J. | Hale, Amber N. | Halonen, Sandra K. | Hamasaki, Maho | Han, Feng | Han, Ting | Hancock, Michael K. | Hansen, Malene | Harada, Hisashi | Harada, Masaru | Hardt, Stefan E. | Harper, J. Wade | Harris, Adrian L. | Harris, James | Harris, Steven D. | Hashimoto, Makoto | Haspel, Jeffrey A. | Hayashi, Shin-ichiro | Hazelhurst, Lori A. | He, Congcong | He, You-Wen | Hébert, Marie-Josée | Heidenreich, Kim A. | Helfrich, Miep H. | Helgason, Gudmundur V. | Henske, Elizabeth P. | Herman, Brian | Herman, Paul K. | Hetz, Claudio | Hilfiker, Sabine | Hill, Joseph A. | Hocking, Lynne J. | Hofman, Paul | Hofmann, Thomas G. | Höhfeld, Jörg | Holyoake, Tessa L. | Hong, Ming-Huang | Hood, David A. | Hotamisligil, Gökhan S. | Houwerzijl, Ewout J. | Høyer-Hansen, Maria | Hu, Bingren | Hu, Chien-an A. | Hu, Hong-Ming | Hua, Ya | Huang, Canhua | Huang, Ju | Huang, Shengbing | Huang, Wei-Pang | Huber, Tobias B. | Huh, Won-Ki | Hung, Tai-Ho | Hupp, Ted R. | Hur, Gang Min | Hurley, James B. | Hussain, Sabah N.A. | Hussey, Patrick J. | Hwang, Jung Jin | Hwang, Seungmin | Ichihara, Atsuhiro | Ilkhanizadeh, Shirin | Inoki, Ken | Into, Takeshi | Iovane, Valentina | Iovanna, Juan L. | Ip, Nancy Y. | Isaka, Yoshitaka | Ishida, Hiroyuki | Isidoro, Ciro | Isobe, Ken-ichi | Iwasaki, Akiko | Izquierdo, Marta | Izumi, Yotaro | Jaakkola, Panu M. | Jäättelä, Marja | Jackson, George R. | Jackson, William T. | Janji, Bassam | Jendrach, Marina | Jeon, Ju-Hong | Jeung, Eui-Bae | Jiang, Hong | Jiang, Hongchi | Jiang, Jean X. | Jiang, Ming | Jiang, Qing | Jiang, Xuejun | Jiang, Xuejun | Jiménez, Alberto | Jin, Meiyan | Jin, Shengkan V. | Joe, Cheol O. | Johansen, Terje | Johnson, Daniel E. | Johnson, Gail V.W. | Jones, Nicola L. | Joseph, Bertrand | Joseph, Suresh K. | Joubert, Annie M. | Juhász, Gábor | Juillerat-Jeanneret, Lucienne | Jung, Chang Hwa | Jung, Yong-Keun | Kaarniranta, Kai | Kaasik, Allen | Kabuta, Tomohiro | Kadowaki, Motoni | Kågedal, Katarina | Kamada, Yoshiaki | Kaminskyy, Vitaliy O. | Kampinga, Harm H. | Kanamori, Hiromitsu | Kang, Chanhee | Kang, Khong Bee | Kang, Kwang Il | Kang, Rui | Kang, Yoon-A | Kanki, Tomotake | Kanneganti, Thirumala-Devi | Kanno, Haruo | Kanthasamy, Anumantha G. | Kanthasamy, Arthi | Karantza, Vassiliki | Kaushal, Gur P. | Kaushik, Susmita | Kawazoe, Yoshinori | Ke, Po-Yuan | Kehrl, John H. | Kelekar, Ameeta | Kerkhoff, Claus | Kessel, David H. | Khalil, Hany | Kiel, Jan A.K.W. | Kiger, Amy A. | Kihara, Akio | Kim, Deok Ryong | Kim, Do-Hyung | Kim, Dong-Hou | Kim, Eun-Kyoung | Kim, Hyung-Ryong | Kim, Jae-Sung | Kim, Jeong Hun | Kim, Jin Cheon | Kim, John K. | Kim, Peter K. | Kim, Seong Who | Kim, Yong-Sun | Kim, Yonghyun | Kimchi, Adi | Kimmelman, Alec C. | King, Jason S. | Kinsella, Timothy J. | Kirkin, Vladimir | Kirshenbaum, Lorrie A. | Kitamoto, Katsuhiko | Kitazato, Kaio | Klein, Ludger | Klimecki, Walter T. | Klucken, Jochen | Knecht, Erwin | Ko, Ben C.B. | Koch, Jan C. | Koga, Hiroshi | Koh, Jae-Young | Koh, Young Ho | Koike, Masato | Komatsu, Masaaki | Kominami, Eiki | Kong, Hee Jeong | Kong, Wei-Jia | Korolchuk, Viktor I. | Kotake, Yaichiro | Koukourakis, Michael I. | Flores, Juan B. Kouri | Kovács, Attila L. | Kraft, Claudine | Krainc, Dimitri | Krämer, Helmut | Kretz-Remy, Carole | Krichevsky, Anna M. | Kroemer, Guido | Krüger, Rejko | Krut, Oleg | Ktistakis, Nicholas T. | Kuan, Chia-Yi | Kucharczyk, Roza | Kumar, Ashok | Kumar, Raj | Kumar, Sharad | Kundu, Mondira | Kung, Hsing-Jien | Kurz, Tino | Kwon, Ho Jeong | La Spada, Albert R. | Lafont, Frank | Lamark, Trond | Landry, Jacques | Lane, Jon D. | Lapaquette, Pierre | Laporte, Jocelyn F. | László, Lajos | Lavandero, Sergio | Lavoie, Josée N. | Layfield, Robert | Lazo, Pedro A. | Le, Weidong | Le Cam, Laurent | Ledbetter, Daniel J. | Lee, Alvin J.X. | Lee, Byung-Wan | Lee, Gyun Min | Lee, Jongdae | lee, Ju-hyun | Lee, Michael | Lee, Myung-Shik | Lee, Sug Hyung | Leeuwenburgh, Christiaan | Legembre, Patrick | Legouis, Renaud | Lehmann, Michael | Lei, Huan-Yao | Lei, Qun-Ying | Leib, David A. | Leiro, José | Lemasters, John J. | Lemoine, Antoinette | Lesniak, Maciej S. | Lev, Dina | Levenson, Victor V. | Levine, Beth | Levy, Efrat | Li, Faqiang | Li, Jun-Lin | Li, Lian | Li, Sheng | Li, Weijie | Li, Xue-Jun | Li, Yan-Bo | Li, Yi-Ping | Liang, Chengyu | Liang, Qiangrong | Liao, Yung-Feng | Liberski, Pawel P. | Lieberman, Andrew | Lim, Hyunjung J. | Lim, Kah-Leong | Lim, Kyu | Lin, Chiou-Feng | Lin, Fu-Cheng | Lin, Jian | Lin, Jiandie D. | Lin, Kui | Lin, Wan-Wan | Lin, Weei-Chin | Lin, Yi-Ling | Linden, Rafael | Lingor, Paul | Lippincott-Schwartz, Jennifer | Lisanti, Michael P. | Liton, Paloma B. | Liu, Bo | Liu, Chun-Feng | Liu, Kaiyu | Liu, Leyuan | Liu, Qiong A. | Liu, Wei | Liu, Young-Chau | Liu, Yule | Lockshin, Richard A. | Lok, Chun-Nam | Lonial, Sagar | Loos, Benjamin | Lopez-Berestein, Gabriel | López-Otín, Carlos | Lossi, Laura | Lotze, Michael T. | Low, Peter | Lu, Binfeng | Lu, Bingwei | Lu, Bo | Lu, Zhen | Luciano, Fréderic | Lukacs, Nicholas W. | Lund, Anders H. | Lynch-Day, Melinda A. | Ma, Yong | Macian, Fernando | MacKeigan, Jeff P. | Macleod, Kay F. | Madeo, Frank | Maiuri, Luigi | Maiuri, Maria Chiara | Malagoli, Davide | Malicdan, May Christine V. | Malorni, Walter | Man, Na | Mandelkow, Eva-Maria | Manon, Stephen | Manov, Irena | Mao, Kai | Mao, Xiang | Mao, Zixu | Marambaud, Philippe | Marazziti, Daniela | Marcel, Yves L. | Marchbank, Katie | Marchetti, Piero | Marciniak, Stefan J. | Marcondes, Mateus | Mardi, Mohsen | Marfe, Gabriella | Mariño, Guillermo | Markaki, Maria | Marten, Mark R. | Martin, Seamus J. | Martinand-Mari, Camille | Martinet, Wim | Martinez-Vicente, Marta | Masini, Matilde | Matarrese, Paola | Matsuo, Saburo | Matteoni, Raffaele | Mayer, Andreas | Mazure, Nathalie M. | McConkey, David J. | McConnell, Melanie J. | McDermott, Catherine | McDonald, Christine | McInerney, Gerald M. | McKenna, Sharon L. | McLaughlin, BethAnn | McLean, Pamela J. | McMaster, Christopher R. | McQuibban, G. Angus | Meijer, Alfred J. | Meisler, Miriam H. | Meléndez, Alicia | Melia, Thomas J. | Melino, Gerry | Mena, Maria A. | Menendez, Javier A. | Menna-Barreto, Rubem F. S. | Menon, Manoj B. | Menzies, Fiona M. | Mercer, Carol A. | Merighi, Adalberto | Merry, Diane E. | Meschini, Stefania | Meyer, Christian G. | Meyer, Thomas F. | Miao, Chao-Yu | Miao, Jun-Ying | Michels, Paul A.M. | Michiels, Carine | Mijaljica, Dalibor | Milojkovic, Ana | Minucci, Saverio | Miracco, Clelia | Miranti, Cindy K. | Mitroulis, Ioannis | Miyazawa, Keisuke | Mizushima, Noboru | Mograbi, Baharia | Mohseni, Simin | Molero, Xavier | Mollereau, Bertrand | Mollinedo, Faustino | Momoi, Takashi | Monastyrska, Iryna | Monick, Martha M. | Monteiro, Mervyn J. | Moore, Michael N. | Mora, Rodrigo | Moreau, Kevin | Moreira, Paula I. | Moriyasu, Yuji | Moscat, Jorge | Mostowy, Serge | Mottram, Jeremy C. | Motyl, Tomasz | Moussa, Charbel E.-H. | Müller, Sylke | Muller, Sylviane | Münger, Karl | Münz, Christian | Murphy, Leon O. | Murphy, Maureen E. | Musarò, Antonio | Mysorekar, Indira | Nagata, Eiichiro | Nagata, Kazuhiro | Nahimana, Aimable | Nair, Usha | Nakagawa, Toshiyuki | Nakahira, Kiichi | Nakano, Hiroyasu | Nakatogawa, Hitoshi | Nanjundan, Meera | Naqvi, Naweed I. | Narendra, Derek P. | Narita, Masashi | Navarro, Miguel | Nawrocki, Steffan T. | Nazarko, Taras Y. | Nemchenko, Andriy | Netea, Mihai G. | Neufeld, Thomas P. | Ney, Paul A. | Nezis, Ioannis P. | Nguyen, Huu Phuc | Nie, Daotai | Nishino, Ichizo | Nislow, Corey | Nixon, Ralph A. | Noda, Takeshi | Noegel, Angelika A. | Nogalska, Anna | Noguchi, Satoru | Notterpek, Lucia | Novak, Ivana | Nozaki, Tomoyoshi | Nukina, Nobuyuki | Nürnberger, Thorsten | Nyfeler, Beat | Obara, Keisuke | Oberley, Terry D. | Oddo, Salvatore | Ogawa, Michinaga | Ohashi, Toya | Okamoto, Koji | Oleinick, Nancy L. | Oliver, F. Javier | Olsen, Laura J. | Olsson, Stefan | Opota, Onya | Osborne, Timothy F. | Ostrander, Gary K. | Otsu, Kinya | Ou, Jing-hsiung James | Ouimet, Mireille | Overholtzer, Michael | Ozpolat, Bulent | Paganetti, Paolo | Pagnini, Ugo | Pallet, Nicolas | Palmer, Glen E. | Palumbo, Camilla | Pan, Tianhong | Panaretakis, Theocharis | Pandey, Udai Bhan | Papackova, Zuzana | Papassideri, Issidora | Paris, Irmgard | Park, Junsoo | Park, Ohkmae K. | Parys, Jan B. | Parzych, Katherine R. | Patschan, Susann | Patterson, Cam | Pattingre, Sophie | Pawelek, John M. | Peng, Jianxin | Perlmutter, David H. | Perrotta, Ida | Perry, George | Pervaiz, Shazib | Peter, Matthias | Peters, Godefridus J. | Petersen, Morten | Petrovski, Goran | Phang, James M. | Piacentini, Mauro | Pierre, Philippe | Pierrefite-Carle, Valérie | Pierron, Gérard | Pinkas-Kramarski, Ronit | Piras, Antonio | Piri, Natik | Platanias, Leonidas C. | Pöggeler, Stefanie | Poirot, Marc | Poletti, Angelo | Poüs, Christian | Pozuelo-Rubio, Mercedes | Prætorius-Ibba, Mette | Prasad, Anil | Prescott, Mark | Priault, Muriel | Produit-Zengaffinen, Nathalie | Progulske-Fox, Ann | Proikas-Cezanne, Tassula | Przedborski, Serge | Przyklenk, Karin | Puertollano, Rosa | Puyal, Julien | Qian, Shu-Bing | Qin, Liang | Qin, Zheng-Hong | Quaggin, Susan E. | Raben, Nina | Rabinowich, Hannah | Rabkin, Simon W. | Rahman, Irfan | Rami, Abdelhaq | Ramm, Georg | Randall, Glenn | Randow, Felix | Rao, V. Ashutosh | Rathmell, Jeffrey C. | Ravikumar, Brinda | Ray, Swapan K. | Reed, Bruce H. | Reed, John C. | Reggiori, Fulvio | Régnier-Vigouroux, Anne | Reichert, Andreas S. | Reiners, John J. | Reiter, Russel J. | Ren, Jun | Revuelta, José L. | Rhodes, Christopher J. | Ritis, Konstantinos | Rizzo, Elizete | Robbins, Jeffrey | Roberge, Michel | Roca, Hernan | Roccheri, Maria C. | Rocchi, Stephane | Rodemann, H. Peter | Rodríguez de Córdoba, Santiago | Rohrer, Bärbel | Roninson, Igor B. | Rosen, Kirill | Rost-Roszkowska, Magdalena M. | Rouis, Mustapha | Rouschop, Kasper M.A. | Rovetta, Francesca | Rubin, Brian P. | Rubinsztein, David C. | Ruckdeschel, Klaus | Rucker, Edmund B. | Rudich, Assaf | Rudolf, Emil | Ruiz-Opazo, Nelson | Russo, Rossella | Rusten, Tor Erik | Ryan, Kevin M. | Ryter, Stefan W. | Sabatini, David M. | Sadoshima, Junichi | Saha, Tapas | Saitoh, Tatsuya | Sakagami, Hiroshi | Sakai, Yasuyoshi | Salekdeh, Ghasem Hoseini | Salomoni, Paolo | Salvaterra, Paul M. | Salvesen, Guy | Salvioli, Rosa | Sanchez, Anthony M.J. | Sánchez-Alcázar, José A. | Sánchez-Prieto, Ricardo | Sandri, Marco | Sankar, Uma | Sansanwal, Poonam | Santambrogio, Laura | Saran, Shweta | Sarkar, Sovan | Sarwal, Minnie | Sasakawa, Chihiro | Sasnauskiene, Ausra | Sass, Miklós | Sato, Ken | Sato, Miyuki | Schapira, Anthony H.V. | Scharl, Michael | Schätzl, Hermann M. | Scheper, Wiep | Schiaffino, Stefano | Schneider, Claudio | Schneider, Marion E. | Schneider-Stock, Regine | Schoenlein, Patricia V. | Schorderet, Daniel F. | Schüller, Christoph | Schwartz, Gary K. | Scorrano, Luca | Sealy, Linda | Seglen, Per O. | Segura-Aguilar, Juan | Seiliez, Iban | Seleverstov, Oleksandr | Sell, Christian | Seo, Jong Bok | Separovic, Duska | Setaluri, Vijayasaradhi | Setoguchi, Takao | Settembre, Carmine | Shacka, John J. | Shanmugam, Mala | Shapiro, Irving M. | Shaulian, Eitan | Shaw, Reuben J. | Shelhamer, James H. | Shen, Han-Ming | Shen, Wei-Chiang
Autophagy  2012;8(4):445-544.
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
doi:10.4161/auto.19496
PMCID: PMC3404883  PMID: 22966490
LC3; autolysosome; autophagosome; flux; lysosome; phagophore; stress; vacuole
2.  Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia 
Hosgood, H. Dean | Wang, Wen-Chang | Hong, Yun-Chul | Wang, Jiu-Cun | Chen, Kexin | Chang, I-Shou | Chen, Chien-Jen | Lu, Daru | Yin, Zhihua | Wu, Chen | Zheng, Wei | Qian, Biyun | Park, Jae Yong | Kim, Yeul Hong | Chatterjee, Nilanjan | Chen, Ying | Chang, Gee-Chen | Hsiao, Chin-Fu | Yeager, Meredith | Tsai, Ying-Huang | Wei, Hu | Kim, Young Tae | Wu, Wei | Zhao, Zhenhong | Chow, Wong-Ho | Zhu, Xiaoling | Lo, Yen-Li | Sung, Sook Whan | Chen, Kuan-Yu | Yuenger, Jeff | Kim, Joo Hyun | Huang, Liming | Chen, Ying-Hsiang | Gao, Yu-Tang | Kim, Jin Hee | Huang, Ming-Shyan | Jung, Tae Hoon | Caporaso, Neil | Zhao, Xueying | Huan, Zhang | Yu, Dianke | Kim, Chang Ho | Su, Wu-Chou | Shu, Xiao-Ou | Kim, In-San | Bassig, Bryan | Chen, Yuh-Min | Cha, Sung Ick | Tan, Wen | Chen, Hongyan | Yang, Tsung-Ying | Sung, Jae Sook | Wang, Chih-Liang | Li, Xuelian | Park, Kyong Hwa | Yu, Chong-Jen | Ryu, Jeong-Seon | Xiang, Yongbing | Hutchinson, Amy | Kim, Jun Suk | Cai, Qiuyin | Landi, Maria Teresa | Lee, Kyoung-Mu | Hung, Jen-Yu | Park, Ju-Yeon | Tucker, Margaret | Lin, Chien-Chung | Ren, Yangwu | Perng, Reury-Perng | Chen, Chih-Yi | Jin, Li | Chen, Kun-Chieh | Li, Yao-Jen | Chiu, Yu-Fang | Tsai, Fang-Yu | Yang, Pan-Chyr | Fraumeni, Joseph F. | Seow, Adeline | Lin, Dongxin | Zhou, Baosen | Chanock, Stephen | Hsiung, Chao Agnes | Rothman, Nathaniel | Lan, Qing
Human genetics  2012;131(7):10.1007/s00439-012-1144-8.
A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10−12); however, this association did not achieve genome-wide significance (p < 10−7) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10−8; allelic risk = 0.80, 95% confidence interval (CI) = 0.74–0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67–0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.
doi:10.1007/s00439-012-1144-8
PMCID: PMC3875137  PMID: 22367405
3.  Alcohol consumption in 0.5 million people from 10 diverse regions of China: prevalence, patterns and socio-demographic and health-related correlates 
Millwood, Iona Y | Li, Liming | Smith, Margaret | Guo, Yu | Yang, Ling | Bian, Zheng | Lewington, Sarah | Whitlock, Gary | Sherliker, Paul | Collins, Rory | Chen, Junshi | Peto, Richard | Wang, Hongmei | Xu, Jiujiu | He, Jian | Yu, Min | Liu, Huilin | Chen, Zhengming | Li, Liming | Chen, Zhengming | Chen, Junshi | Collins, Rory | Wu, Fan | Peto, Richard | Chen, Zhengming | Lancaster, Garry | Yang, Xiaoming | Williams, Alex | Smith, Margaret | Yang, Ling | Chang, Yumei | Millwood, Iona | Chen, Yiping | Zhang, Qiuli | Lewington, Sarah | Whitlock, Gary | Guo, Yu | Zhao, Guoqing | Bian, Zheng | Wu, Lixue | Hou, Can | Pang, Zengchang | Wang, Shaojie | Zhang, Yun | Zhang, Kui | Liu, Silu | Zhao, Zhonghou | Liu, Shumei | Pang, Zhigang | Feng, Weijia | Wu, Shuling | Yang, Liqiu | Han, Huili | He, Hui | Pan, Xianhai | Wang, Shanqing | Wang, Hongmei | Hao, Xinhua | Chen, Chunxing | Lin, Shuxiong | Hu, Xiaoshu | Zhou, Minghao | Wu, Ming | Wang, Yeyuan | Hu, Yihe | Ma, Liangcai | Zhou, Renxian | Xu, Guanqun | Dong, Baiqing | Chen, Naying | Huang, Ying | Li, Mingqiang | Meng, Jinhuai | Gan, Zhigao | Xu, Jiujiu | Liu, Yun | Wu, Xianping | Gao, Yali | Zhang, Ningmei | Luo, Guojin | Que, Xiangsan | Chen, Xiaofang | Ge, Pengfei | He, Jian | Ren, Xiaolan | Zhang, Hui | Mao, Enke | Li, Guanzhong | Li, Zhongxiao | He, Jun | Liu, Guohua | Zhu, Baoyu | Zhou, Gang | Feng, Shixian | Gao, Yulian | He, Tianyou | Jiang, Li | Qin, Jianhua | Sun, Huarong | Liu, Liqun | Yu, Min | Chen, Yaping | Hu, Zhixiang | Hu, Jianjin | Qian, Yijian | Wu, Zhiying | Chen, Lingli | Liu, Wen | Li, Guangchun | Liu, Huilin | Long, Xiangquan | Xiong, Youping | Tan, Zhongwen | Xie, Xuqiu | Peng, Yunfang
Background Drinking alcohol has a long tradition in Chinese culture. However, data on the prevalence and patterns of alcohol consumption in China, and its main correlates, are limited.
Methods During 2004–08 the China Kadoorie Biobank recruited 512 891 men and women aged 30–79 years from 10 urban and rural areas of China. Detailed information on alcohol consumption was collected using a standardized questionnaire, and related to socio-demographic, physical and behavioural characteristics in men and women separately.
Results Overall, 76% of men and 36% of women reported drinking some alcohol during the past 12 months, with 33% of men and 2% of women drinking at least weekly; the prevalence of weekly drinking in men varied from 7% to 51% across the 10 study areas. Mean consumption was 286 g/week and was higher in those with less education. Most weekly drinkers habitually drank spirits, although this varied by area, and beer consumption was highest among younger drinkers; 37% of male weekly drinkers (12% of all men) reported weekly heavy drinking episodes, with the prevalence highest in younger men. Drinking alcohol was positively correlated with regular smoking, blood pressure and heart rate. Among male weekly drinkers, each 20 g/day alcohol consumed was associated with 2 mmHg higher systolic blood pressure. Potential indicators of problem drinking were reported by 24% of male weekly drinkers.
Conclusion The prevalence and patterns of drinking in China differ greatly by age, sex and geographical region. Alcohol consumption is associated with a number of unfavourable health behaviours and characteristics.
doi:10.1093/ije/dyt078
PMCID: PMC3733702  PMID: 23918852
Alcohol; drinking; cohort study; descriptive analysis; China
4.  Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies 
Abnet, Christian C. | Wang, Zhaoming | Song, Xin | Hu, Nan | Zhou, Fu-You | Freedman, Neal D. | Li, Xue-Min | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Dawsey, Sanford M. | Liao, Linda M. | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Chung, Charles C. | Wang, Chaoyu | Wheeler, William | Yeager, Meredith | Yuenger, Jeff | Hutchinson, Amy | Jacobs, Kevin B. | Giffen, Carol A. | Burdett, Laurie | Fraumeni, Joseph F. | Tucker, Margaret A. | Chow, Wong-Ho | Zhao, Xue-Ke | Li, Jiang-Man | Li, Ai-Li | Sun, Liang-Dan | Wei, Wu | Li, Ji-Lin | Zhang, Peng | Li, Hong-Lei | Cui, Wen-Yan | Wang, Wei-Peng | Liu, Zhi-Cai | Yang, Xia | Fu, Wen-Jing | Cui, Ji-Li | Lin, Hong-Li | Zhu, Wen-Liang | Liu, Min | Chen, Xi | Chen, Jie | Guo, Li | Han, Jing-Jing | Zhou, Sheng-Li | Huang, Jia | Wu, Yue | Yuan, Chao | Huang, Jing | Ji, Ai-Fang | Kul, Jian-Wei | Fan, Zhong-Min | Wang, Jian-Po | Zhang, Dong-Yun | Zhang, Lian-Qun | Zhang, Wei | Chen, Yuan-Fang | Ren, Jing-Li | Li, Xiu-Min | Dong, Jin-Cheng | Xing, Guo-Lan | Guo, Zhi-Gang | Yang, Jian-Xue | Mao, Yi-Ming | Yuan, Yuan | Guo, Er-Tao | Zhang, Wei | Hou, Zhi-Chao | Liu, Jing | Li, Yan | Tang, Sa | Chang, Jia | Peng, Xiu-Qin | Han, Min | Yin, Wan-Li | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Yang, Liu-Qin | Zhu, Fu-Guo | Yang, Xiu-Feng | Feng, Xiao-Shan | Wang, Zhou | Li, Yin | Gao, She-Gan | Liu, Hai-Lin | Yuan, Ling | Jin, Yan | Zhang, Yan-Rui | Sheyhidin, Ilyar | Li, Feng | Chen, Bao-Ping | Ren, Shu-Wei | Liu, Bin | Li, Dan | Zhang, Gao-Fu | Yue, Wen-Bin | Feng, Chang-Wei | Qige, Qirenwang | Zhao, Jian-Ting | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Xu, Li-Yan | Wu, Zhi-Yong | Bao, Zhi-Qin | Chen, Ji-Li | Li, Xian-Chang | Zhuang, Xiang | Zhou, Ying-Fa | Zuo, Xian-Bo | Dong, Zi-Ming | Wang, Lu-Wen | Fan, Xue-Pin | Wang, Jin | Zhou, Qi | Ma, Guo-Shun | Zhang, Qin-Xian | Liu, Hai | Jian, Xin-Ying | Lian, Sin-Yong | Wang, Jin-Sheng | Chang, Fu-Bao | Lu, Chang-Dong | Miao, Jian-Jun | Chen, Zhi-Guo | Wang, Ran | Guo, Ming | Fan, Zeng-Lin | Tao, Ping | Liu, Tai-Jing | Wei, Jin-Chang | Kong, Qing-Peng | Fan, Lei | Wang, Xian-Zeng | Gao, Fu-Sheng | Wang, Tian-Yun | Xie, Dong | Wang, Li | Chen, Shu-Qing | Yang, Wan-Cai | Hong, Jun-Yan | Wang, Liang | Qiu, Song-Liang | Goldstein, Alisa M. | Yuan, Zhi-Qing | Chanock, Stephen J. | Zhang, Xue-Jun | Taylor, Philip R. | Wang, Li-Dong
Human Molecular Genetics  2012;21(9):2132-2141.
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
doi:10.1093/hmg/dds029
PMCID: PMC3315211  PMID: 22323360
5.  The 5p15.33 Locus Is Associated with Risk of Lung Adenocarcinoma in Never-Smoking Females in Asia 
PLoS Genetics  2010;6(8):e1001051.
Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10−7 or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30×10−11). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38×10−11). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60×10−20, allelic risk = 1.54, 95% Confidence Interval (CI) 1.41–1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40–1.87), and 2.35 (95% CI: 1.95–2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.
Author Summary
Worldwide, approximately 15% of lung cancer cases occur among nonsmokers. Genome-wide association studies (GWAS) of lung cancer conducted in populations of European background have identified three regions on chromosomes 5, 6, and 15 that harbor genetic variants that confer risk for lung cancer. Prior studies were conducted primarily in cigarette smokers, raising the possibility that the associations could be related to tobacco use, lung carcinogenesis, or both. A GWAS of lung cancer among never-smokers is an optimal setting to discover effects that are independent of smoking. Since most women in Asia do not smoke, we conducted a GWAS of lung adenocarcinoma among never-smoking females (584 cases, 585 controls) in Taiwan, and observed a region on chromosome 5 significantly associated with risk for lung cancer in never-smoking women. The finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls. To our knowledge, this study is the first reported GWAS of lung cancer in East Asian women, and together with the replication studies represents the largest genetic association study in this population. The findings provide insight into the genetic contribution of common variants to lung carcinogenesis.
doi:10.1371/journal.pgen.1001051
PMCID: PMC2916850  PMID: 20700438
6.  Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease 
Nature genetics  2012;44(8):890-894.
We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases with coronary artery disease and 5,019 controls, followed by de novo replication studies in 15,460 cases and 11,472 controls, all of Chinese Han descent. We successfully identified four new loci for coronary artery disease reaching genome-wide significance (P < 5 × 10−8), which mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (PHACTR1, TCF21, CDKN2A/B and C12orf51). These findings provide new insights into biological pathways for the susceptibility of coronary artery disease in Chinese Han population.
doi:10.1038/ng.2337
PMCID: PMC3927410  PMID: 22751097
7.  The Schistosoma japonicum genome reveals features of host-parasite interplay 
Nature  2009;460(7253):345-351.
Schistosoma japonicum is a parasitic flatworm that causes human schistosomiasis, a significant cause of morbidity in China and the Philippines. Here we present a draft genomic sequence for the worm, which is the first reported for any flatworm, indeed for the superphylum Lophotrochozoa. The genome provides a global insight into the molecular architecture and host interaction of this complex metazoan pathogen, revealing that it can exploit host nutrients, neuroendocrine hormones and signaling pathways for growth, development and maturation. Having a complex nervous system and a well developed sensory system, S. japonicum can accept stimulation of the corresponding ligands as a physiological response to different environments, such as fresh water or the tissues of its intermediate and mammalian hosts. Numerous proteinases, including cercarial elastase, are implicated in mammalian skin penetration and haemoglobin degradation. The genomic information will serve as a valuable platform to facilitate development of new interventions for schistosomiasis control.
doi:10.1038/nature08140
PMCID: PMC3747554  PMID: 19606140
8.  Genetic polymorphisms of nerve growth factor receptor (NGFR) and the risk of Alzheimer's disease 
Background
Loss of basal forebrain cholinergic neurons is attributable to the proapoptotic signaling induced by nerve growth factor receptor (NGFR) and may link to Alzheimer's disease (AD) risk. Only one study has investigated the association between NGFR polymorphisms and the risk of AD in an Italian population. Type 2 diabetes mellitus (DM) may modify this association based on previous animal and epidemiologic studies.
Methods
This was a case-control study in a Chinese population. A total of 264 AD patients were recruited from three teaching hospitals between 2007 to 2010; 389 controls were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected from NGFR to test the association between NGFR htSNPs and the risk of AD.
Results
Variant NGFR rs734194 was significantly associated with a decreased risk of AD [GG vs. TT copies: adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.20-0.95]. Seven common haplotypes were identified. Minor haplotype GCGCG was significantly associated with a decreased risk of AD (2 vs. 0 copies: adjusted OR = 0.39, 95% CI = 0.17-0.91). Type 2 DM significantly modified the association between rs2072446, rs741072, and haplotype GCTTG and GTTCG on the risk of AD among ApoE ε4 non-carriers (Pinteraction < 0.05).
Conclusion
Inherited polymorphisms of NGFR were associated with the risk of AD; results were not significant after correction for multiple tests. This association was further modified by the status of type 2 DM.
doi:10.1186/1477-5751-11-5
PMCID: PMC3362783  PMID: 22236693
NGFR; Alzheimer's disease; htSNP; haplotype
9.  Laboratory-Based Surveillance and Molecular Epidemiology of Influenza Virus in Taiwan 
Journal of Clinical Microbiology  2005;43(4):1651-1661.
A laboratory-based surveillance network of 11 clinical virological laboratories for influenza viruses was established in Taiwan under the coordination of the Center for Disease Control and Prevention (CDC), Taiwan. From October 2000 to March 2004, 3,244 influenza viruses were isolated, including 1,969 influenza A and 1,275 influenza B viruses. The influenza infections usually occurred frequently in winter in the northern hemisphere. However, the influenza seasonality in Taiwan was not clear during the four seasons under investigation. For example, the influenza A viruses peaked during the winters of 2001, 2002, and 2003. However, some isolated peaks were also found in the summer and fall (June to November) of 2001 and 2002. An unusual peak of influenza B also occurred in the summer of 2002 (June to August). Phylogenetic analysis shows that influenza A isolates from the same year were often grouped together. However, influenza B isolates from the year 2002 clustered into different groups, and the data indicate that both B/Victoria/2/87-like and B/Yamagata/16/88-like lineages of influenza B viruses were cocirculating. Sequence comparison of epidemic strains versus vaccine strains shows that many vaccine-like Taiwanese strains were circulating at least 2 years before the vaccine strains were introduced. No clear seasonality of influenza reports in Taiwan occurred in contrast to other more continental regions.
doi:10.1128/JCM.43.4.1651-1661.2005
PMCID: PMC1081360  PMID: 15814980
10.  A Meta-Analysis Identifies New Loci Associated with Body Mass index in Individuals of African Ancestry 
Monda, Keri L. | Chen, Gary K. | Taylor, Kira C. | Palmer, Cameron | Edwards, Todd L. | Lange, Leslie A. | Ng, Maggie C.Y. | Adeyemo, Adebowale A. | Allison, Matthew A. | Bielak, Lawrence F. | Chen, Guanji | Graff, Mariaelisa | Irvin, Marguerite R. | Rhie, Suhn K. | Li, Guo | Liu, Yongmei | Liu, Youfang | Lu, Yingchang | Nalls, Michael A. | Sun, Yan V. | Wojczynski, Mary K. | Yanek, Lisa R. | Aldrich, Melinda C. | Ademola, Adeyinka | Amos, Christopher I. | Bandera, Elisa V. | Bock, Cathryn H. | Britton, Angela | Broeckel, Ulrich | Cai, Quiyin | Caporaso, Neil E. | Carlson, Chris | Carpten, John | Casey, Graham | Chen, Wei-Min | Chen, Fang | Chen, Yii-Der I. | Chiang, Charleston W.K. | Coetzee, Gerhard A. | Demerath, Ellen | Deming-Halverson, Sandra L. | Driver, Ryan W. | Dubbert, Patricia | Feitosa, Mary F. | Freedman, Barry I. | Gillanders, Elizabeth M. | Gottesman, Omri | Guo, Xiuqing | Haritunians, Talin | Harris, Tamara | Harris, Curtis C. | Hennis, Anselm JM | Hernandez, Dena G. | McNeill, Lorna H. | Howard, Timothy D. | Howard, Barbara V. | Howard, Virginia J. | Johnson, Karen C. | Kang, Sun J. | Keating, Brendan J. | Kolb, Suzanne | Kuller, Lewis H. | Kutlar, Abdullah | Langefeld, Carl D. | Lettre, Guillaume | Lohman, Kurt | Lotay, Vaneet | Lyon, Helen | Manson, JoAnn E. | Maixner, William | Meng, Yan A. | Monroe, Kristine R. | Morhason-Bello, Imran | Murphy, Adam B. | Mychaleckyj, Josyf C. | Nadukuru, Rajiv | Nathanson, Katherine L. | Nayak, Uma | N’Diaye, Amidou | Nemesure, Barbara | Wu, Suh-Yuh | Leske, M. Cristina | Neslund-Dudas, Christine | Neuhouser, Marian | Nyante, Sarah | Ochs-Balcom, Heather | Ogunniyi, Adesola | Ogundiran, Temidayo O. | Ojengbede, Oladosu | Olopade, Olufunmilayo I. | Palmer, Julie R. | Ruiz-Narvaez, Edward A. | Palmer, Nicholette D. | Press, Michael F. | Rampersaud, Evandine | Rasmussen-Torvik, Laura J. | Rodriguez-Gil, Jorge L. | Salako, Babatunde | Schadt, Eric E. | Schwartz, Ann G. | Shriner, Daniel A. | Siscovick, David | Smith, Shad B. | Wassertheil-Smoller, Sylvia | Speliotes, Elizabeth K. | Spitz, Margaret R. | Sucheston, Lara | Taylor, Herman | Tayo, Bamidele O. | Tucker, Margaret A. | Van Den Berg, David J. | Velez Edwards, Digna R. | Wang, Zhaoming | Wiencke, John K. | Winkler, Thomas W. | Witte, John S. | Wrensch, Margaret | Wu, Xifeng | Yang, James J. | Levin, Albert M. | Young, Taylor R. | Zakai, Neil A. | Cushman, Mary | Zanetti, Krista A. | Zhao, Jing Hua | Zhao, Wei | Zheng, Yonglan | Zhou, Jie | Ziegler, Regina G. | Zmuda, Joseph M. | Fernandes, Jyotika K. | Gilkeson, Gary S. | Kamen, Diane L. | Hunt, Kelly J. | Spruill, Ida J. | Ambrosone, Christine B. | Ambs, Stefan | Arnett, Donna K. | Atwood, Larry | Becker, Diane M. | Berndt, Sonja I. | Bernstein, Leslie | Blot, William J. | Borecki, Ingrid B. | Bottinger, Erwin P. | Bowden, Donald W. | Burke, Gregory | Chanock, Stephen J. | Cooper, Richard S. | Ding, Jingzhong | Duggan, David | Evans, Michele K. | Fox, Caroline | Garvey, W. Timothy | Bradfield, Jonathan P. | Hakonarson, Hakon | Grant, Struan F.A. | Hsing, Ann | Chu, Lisa | Hu, Jennifer J. | Huo, Dezheng | Ingles, Sue A. | John, Esther M. | Jordan, Joanne M. | Kabagambe, Edmond K. | Kardia, Sharon L.R. | Kittles, Rick A. | Goodman, Phyllis J. | Klein, Eric A. | Kolonel, Laurence N. | Le Marchand, Loic | Liu, Simin | McKnight, Barbara | Millikan, Robert C. | Mosley, Thomas H. | Padhukasahasram, Badri | Williams, L. Keoki | Patel, Sanjay R. | Peters, Ulrike | Pettaway, Curtis A. | Peyser, Patricia A. | Psaty, Bruce M. | Redline, Susan | Rotimi, Charles N. | Rybicki, Benjamin A. | Sale, Michèle M. | Schreiner, Pamela J. | Signorello, Lisa B. | Singleton, Andrew B. | Stanford, Janet L. | Strom, Sara S. | Thun, Michael J. | Vitolins, Mara | Zheng, Wei | Moore, Jason H. | Williams, Scott M. | Zhu, Xiaofeng | Zonderman, Alan B. | Kooperberg, Charles | Papanicolaou, George | Henderson, Brian E. | Reiner, Alex P. | Hirschhorn, Joel N. | Loos, Ruth JF | North, Kari E. | Haiman, Christopher A.
Nature genetics  2013;45(6):690-696.
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
doi:10.1038/ng.2608
PMCID: PMC3694490  PMID: 23583978
11.  Baiji genomes reveal low genetic variability and new insights into secondary aquatic adaptations 
Nature Communications  2013;4:2708.
The baiji, or Yangtze River dolphin (Lipotes vexillifer), is a flagship species for the conservation of aquatic animals and ecosystems in the Yangtze River of China; however, this species has now been recognized as functionally extinct. Here we report a high-quality draft genome and three re-sequenced genomes of L. vexillifer using Illumina short-read sequencing technology. Comparative genomic analyses reveal that cetaceans have a slow molecular clock and molecular adaptations to their aquatic lifestyle. We also find a significantly lower number of heterozygous single nucleotide polymorphisms in the baiji compared to all other mammalian genomes reported thus far. A reconstruction of the demographic history of the baiji indicates that a bottleneck occurred near the end of the last deglaciation, a time coinciding with a rapid decrease in temperature and the rise of eustatic sea level.
Despite major conservation efforts, the Yangtze river dolphin, or baiji, is now recognised as functionally extinct. Here, Zhou et al. report a high quality draft baiji genome, as well as three re-sequenced genomes, and highlight evolutionary adaptations to aquatic life.
doi:10.1038/ncomms3708
PMCID: PMC3826649  PMID: 24169659
12.  Accuracy of faecal occult blood test and Helicobacter pylori stool antigen test for detection of upper gastrointestinal lesions 
BMJ Open  2013;3(10):e003989.
Objective
Highly sensitive guaiac-based faecal occult blood (Hemoccult SENSA) and Helicobacter pylori stool antigen testing might help detect upper gastrointestinal lesions when appended to a colorectal cancer screening programme with faecal immunochemical testing. We evaluated the diagnostic accuracies of two stool tests in detecting upper gastrointestinal lesions.
Design
Cross-sectional design.
Setting
Hospital-based and community-based screening settings.
Participants
A hospital-based deviation cohort of 3172 participants to evaluate test performance and a community-based validation cohort of 3621 to verify the findings.
Interventions
Three types of stool tests with bidirectional endoscopy as the reference standard.
Outcomes
Sensitivity, specificity and positive and negative likelihood ratios.
Results
For detecting upper gastrointestinal lesions in cases with negative immunochemical tests, the sensitivity, specificity, and positive and negative likelihood ratios of the guaiac-based and H pylori antigen tests were 16.3% (95% CI 13.3% to 19.8%), 90.1% (88.9% to 91.2%), 1.64 (1.31 to 2.07), and 0.93 (0.89 to 0.97), respectively, and 52.5% (48.1% to 56.9%), 80.6% (79.0% to 82.1%), 2.71 (2.41 to 3.04) and 0.59 (0.54 to 0.65), respectively. For detecting upper gastrointestinal lesions in cases with normal colonoscopy, the results of the guaiac-based and H pylori antigen tests were 17.9% (14.8% to 21.5%), 90.1% (88.9% to 91.2%), 1.81 (1.45 to 2.26) and 0.91 (0.87 to 0.95), respectively, and 53.1% (48.6% to 57.4%), 80.7% (79.1% to 82.2%), 2.75 (2.45 to 3.08) and 0.58 (0.53 to 0.64), respectively. Within the community, positive predictive values of the immunochemical and H pylori antigen tests were 36.0% (26.0% to 46.0%) and 31.9% (28.3% to 35.5%), respectively, for detecting lower and upper gastrointestinal lesions, which were similar to expected values.
Conclusions
The H pylori stool antigen test is more accurate than the guaiac-based test in the screening of upper gastrointestinal lesions in a population with high prevalence of H pylori infection and upper gastrointestinal lesions. It is applicable to add the H pylori antigen test to the immunochemical test for pan detection.
Trial registration
NCT01341197 (ClinicalTrial.gov).
doi:10.1136/bmjopen-2013-003989
PMCID: PMC3816242  PMID: 24176798
GASTROENTEROLOGY
13.  The Abundance and Diversity of Soil Fungi in Continuously Monocropped Chrysanthemum 
The Scientific World Journal  2013;2013:632920.
Chrysanthemum is an important ornamental plant which is increasingly being monocropped. Monocropping is known to affect both fungal abundance and species diversity. Here, quantitative PCR allied with DGGE analysis was used to show that fungi were more abundant in the rhizosphere than in the bulk soil and that the fungal populations changed during the growth cycle of the chrysanthemum. The majority of amplified fragments appeared to derive from Fusarium species, and F. oxysporum and F. solani proved to be the major pathogenic species which are built up by monocropping.
doi:10.1155/2013/632920
PMCID: PMC3821950  PMID: 24260019
14.  Genome-Wide Patterns of Genetic Variation in Two Domestic Chickens 
Genome Biology and Evolution  2013;5(7):1376-1392.
Domestic chickens are excellent models for investigating the genetic basis of phenotypic diversity, as numerous phenotypic changes in physiology, morphology, and behavior in chickens have been artificially selected. Genomic study is required to study genome-wide patterns of DNA variation for dissecting the genetic basis of phenotypic traits. We sequenced the genomes of the Silkie and the Taiwanese native chicken L2 at ∼23- and 25-fold average coverage depth, respectively, using Illumina sequencing. The reads were mapped onto the chicken reference genome (including 5.1% Ns) to 92.32% genome coverage for the two breeds. Using a stringent filter, we identified ∼7.6 million single-nucleotide polymorphisms (SNPs) and 8,839 copy number variations (CNVs) in the mapped regions; 42% of the SNPs have not found in other chickens before. Among the 68,906 SNPs annotated in the chicken sequence assembly, 27,852 were nonsynonymous SNPs located in 13,537 genes. We also identified hundreds of shared and divergent structural and copy number variants in intronic and intergenic regions and in coding regions in the two breeds. Functional enrichments of identified genetic variants were discussed. Radical nsSNP-containing immunity genes were enriched in the QTL regions associated with some economic traits for both breeds. Moreover, genetic changes involved in selective sweeps were detected. From the selective sweeps identified in our two breeds, several genes associated with growth, appetite, and metabolic regulation were identified. Our study provides a framework for genetic and genomic research of domestic chickens and facilitates the domestic chicken as an avian model for genomic, biomedical, and evolutionary studies.
doi:10.1093/gbe/evt097
PMCID: PMC3730349  PMID: 23814129
single nucleotide polymorphism; whole genome resequencing; genetic variation; CNVs; chicken
15.  MicroRNA-495 inhibits proliferation of glioblastoma multiforme cells by downregulating cyclin-dependent kinase 6 
Background
Glioblastoma multiforme (GBM) is the most aggressive type of glioma and carries the poorest chances of survival. There is therefore an urgent need to understand the mechanisms of glioma tumorigenesis and develop or improve therapeutics. The aim of this study was to assess the possible prognostic value of cyclin-dependent kinase 6 (CDK6) and the effects of microRNA-495 (miR-495) manipulation on CDK6 expression and cell survival in glioma cells.
Methods
Analyses of clinical specimens from GBM patients were used. Expression of CDK6 was analyzed by real-time polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry. Expression of CDK6 was also analyzed after over-expression of miR-495 in T98 cells; both cell proliferation and RB phosphorylation were examined. Cell proliferation, cell cycle distribution, and RB phosphorylation were also examined after knockdown of CDK6 in U87-MG and T98 cells.
Results
Analyses of clinical specimens from GBM patients identified that CDK6 is significantly expressed in gliomas. CDK6 antigen expression was higher in tumor cores and margins than in adjacent normal brain tissues, and higher levels of CDK6 expression in the tumor margin correlated with decreased survival. Over-expression of miR-495 in T98 cells downregulated the expression of CDK6 and inhibited retinoblastoma phosphorylation, and knockdown of CDK6 in U87-MG and T98 cells by siRNAs resulted in cell cycle arrest at the G1/S transition and inhibition of cell proliferation.
Conclusions
This study revealed miR-495 is down-regulated in glioma tissues. Furthermore, miR-495 regulated CDK6 expression and involved in glioma cell growth inhibition, which indicated the possible role of miR-495 in tumor progression.
doi:10.1186/1477-7819-11-87
PMCID: PMC3655862  PMID: 23594394
CDK6; Glioblastoma multiforme; MicroRNA-495; Tumor progression
16.  Docetaxel, Cisplatin and Fluorouracil (DCF) Regimen Compared with Non-Taxane-Containing Palliative Chemotherapy for Gastric Carcinoma: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(4):e60320.
Background
Gastric carcinoma (GC) is one of the highest cancer-mortality diseases with a high incidence rate in Asia. For surgically unfit but medically fit patients, palliative chemotherapy is the main treatment. The chemotherapy regimen of docetaxel, cisplatin and 5-fluorouracil (DCF) has been used to treat the advanced stage or metastatic GC. It is necessary to compare effectiveness and toxicities of DCF regimen with non-taxane-containing palliative chemotherapy for GC.
Methods
PubMed, EmBase, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure databases were searched to select relative randomized controlled trials (RCTs) comparing DCF to non-taxane-containing chemotherapy for patients with palliatively resected, unresectable, recurrent or metastatic GC. Primary outcome measures were 1-year and 2-year overall survival (OS) rates. Secondary outcome measures were median survival time (MST), median time to progression (TTP), response rate and toxicities.
Results
Twelve RCTs were eligible and 1089 patients were analyzed totally (549 in DCF and 540 in control). DCF regimen increased partial response rate (38.8% vs 27.9%, p = 0.0003) and reduced progressive disease rate (18.9% vs 33.3%, p = 0.0005) compared to control regimen. Significant improvement of 2-year OS rate was found in DCF regimen (RR = 2.03, p = 0.006), but not of 1-year OS rate (RR = 1.22, p = 0.08). MST was significantly prolonged by DCF regimen (p = 0.039), but not median TTP (p = 0.054). Both 1-year OS rate and median TTP had a trend of prolongation by DCF regimen. Chemotherapy-related mortality was comparable (RR = 1.23, p = 0.49) in both regimens. In grade I-IV toxicities, DCF regimen showed a major raise of febrile neutropenia (RR = 2.33, p<0.0001) and minor raises of leucopenia (RR = 1.25, p<0.00001), neutropenia (RR = 1.19, p<0.00001), and diarrhea (RR = 1.59, p<0.00001), while in other toxicities there were no significant differences.
Conclusion
DCF regimen has better response than non-taxane containing regimen and could potentially improve the survival outcomes. The chemotherapy-related toxicity of DCF regimen is acceptable to some extent.
doi:10.1371/journal.pone.0060320
PMCID: PMC3617226  PMID: 23593191
17.  Reversal of MRP7 (ABCC10)-Mediated Multidrug Resistance by Tariquidar 
PLoS ONE  2013;8(2):e55576.
Multidrug resistance protein 7 (MRP7, ABCC10) is a recently discovered member of the ATP-binding cassette (ABC) family which are capable of conferring resistance to a variety of anticancer drugs, including taxanes and nucleoside analogs, in vivo. MRP7 is highly expressed in non-small cell lung cancer cells, and Mrp7-KO mice are highly sensitive to paclitaxel, making MRP7 an attractive chemotherapeutic target of non-small cell lung cancer. However, only a few inhibitors of MRP7 are currently identified, with none of them having progressed to clinical trials. We used MRP7-expressing cells to investigate whether tariquidar, a third generation inhibitor of P-glycoprotein, could inhibit MRP7-mediated multidrug resistance (MDR). We found that tariquidar, at 0.1 and 0.3 µM, significantly potentiated the sensitivity of MRP7-transfected HEK293 cells to MRP7 substrates and increased the intracellular accumulation of paclitaxel. We further demonstrated that tariquidar directly impaired paclitaxel efflux and could downregulate MRP7 protein expression in a concentration- and time-dependent manner after prolonged treatment. Our findings suggest that tariquidar, at pharmacologically achievable concentrations, reverses MRP7-mediated MDR through inhibition of MRP7 protein expression and function, and thus represents a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.
doi:10.1371/journal.pone.0055576
PMCID: PMC3564796  PMID: 23393594
18.  Trends in Susceptibility of Vancomycin-Resistant Enterococcus faecium to Tigecycline, Daptomycin, and Linezolid and Molecular Epidemiology of the Isolates: Results from the Tigecycline In Vitro Surveillance in Taiwan (TIST) Study, 2006 to 2010 
Among the 219 vancomycin-resistant Enterococcus faecium isolates collected in 20 Taiwanese hospitals from 2006 to 2010, all were susceptible to linezolid and daptomycin, and 98.6% were susceptible to tigecycline. There was a shift toward higher tigecycline MIC values (MIC90s) from 2006-2007 (0.06 μg/ml) to 2008–2010 (0.12 μg/ml). The MIC90s of daptomycin and linezolid remained stationary. Although pulsotypes among the isolates from the 20 hospitals varied, intrahospital spreading of several clones was identified in 13 hospitals.
doi:10.1128/AAC.00533-12
PMCID: PMC3370810  PMID: 22491684
19.  Retinitis Pigmentosa Reduces the Risk of Proliferative Diabetic Retinopathy: A Nationwide Population-Based Cohort Study 
PLoS ONE  2012;7(9):e45189.
Purpose
To study the association between retinitis pigmentosa (RP) and the progression of diabetic retinopathy (DR).
Methods
Using the Longitudinal Health Insurance Database 2000 of Taiwan, we identified individuals with an initial diagnosis for RP during the period of 1997–2008. A non-RP comparison group, 10-fold frequency matched by sex, age, index year and the year of diabetes diagnosed, were randomly selected from the same database. The occurrence of DR was observed for all subjects until the end of 2009. The Kaplan-Meier curves were used to illustrate the cumulative probability of developing DR for the RP group and comparison groups. The hazard ratio (HR) of DR for the RP group relative to the comparison group was estimated using Cox proportional hazards model after adjusting for potential confounders.
Results
The Kaplan-Meier curves were not statistically significant different between the RP group and the comparison group. However, the RP group had a higher cumulative probability of developing DR during the first six to seven years. The cumulative probability kept increasing and became higher in the comparison group but remained unchanged in the RP group. The HR for the RP patients comparing with the comparison group was 0.96 (95% confidence interval (CI) = 0.43–2.14). Stratified by severity, RP was associated with a non-statistically significant reduced risk of proliferative DR (PDR) (HR = 0.70, 95% CI = 0.16–3.14). The HR for non-proliferative DR (NPDR) was 1.08 (95% CI = 0.40–2.86).
Conclusion
In this study, RP was not statistically significant associated with the incidence of DR.
doi:10.1371/journal.pone.0045189
PMCID: PMC3460977  PMID: 23028838
20.  Agreement Assessment of Tigecycline Susceptibilities Determined by the Disk Diffusion and Broth Microdilution Methods among Commonly Encountered Resistant Bacterial Isolates: Results from the Tigecycline In Vitro Surveillance in Taiwan (TIST) Study, 2008 to 2010 
The Tigecycline In Vitro Surveillance in Taiwan (TIST) study, initiated in 2006, is a nationwide surveillance program designed to longitudinally monitor the in vitro activity of tigecycline against commonly encountered drug-resistant bacteria. This study compared the in vitro activity of tigecycline against 3,014 isolates of clinically important drug-resistant bacteria using the standard broth microdilution and disk diffusion methods. Species studied included methicillin-resistant Staphylococcus aureus (MRSA; n = 759), vancomycin-resistant Enterococcus faecium (VRE; n = 191), extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (n = 602), ESBL-producing Klebsiella pneumoniae (n = 736), and Acinetobacter baumannii (n = 726) that had been collected from patients treated between 2008 and 2010 at 20 hospitals in Taiwan. MICs and inhibition zone diameters were interpreted according to the currently recommended U.S. Food and Drug Administration (FDA) criteria and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. The MIC90 values of tigecycline against MRSA, VRE, ESBL-producing E. coli, ESBL-producing K. pneumoniae, and A. baumannii were 0.5, 0.125, 0.5, 2, and 8 μg/ml, respectively. The total error rates between the two methods using the FDA criteria were high: 38.4% for ESBL-producing K. pneumoniae and 33.8% for A. baumannii. Using the EUCAST criteria, the total error rate was also high (54.6%) for A. baumannii isolates. The total error rates between these two methods were <5% for MRSA, VRE, and ESBL-producing E. coli. For routine susceptibility testing of ESBL-producing K. pneumoniae and A. baumannii against tigecycline, the broth microdilution method should be used because of the poor correlation of results between these two methods.
doi:10.1128/AAC.05879-11
PMCID: PMC3294924  PMID: 22155819
21.  Trends in the Susceptibility of Clinically Important Resistant Bacteria to Tigecycline: Results from the Tigecycline In Vitro Surveillance in Taiwan Study, 2006 to 2010 
The Tigecycline In Vitro Surveillance in Taiwan (TIST) study, a nationwide, prospective surveillance during 2006 to 2010, collected a total of 7,793 clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA) (n = 1,834), penicillin-resistant Streptococcus pneumoniae (PRSP) (n = 423), vancomycin-resistant enterococci (VRE) (n = 219), extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (n = 1,141), ESBL-producing Klebsiella pneumoniae (n = 1,330), Acinetobacter baumannii (n = 1,645), and Stenotrophomonas maltophilia (n = 903), from different specimens from 20 different hospitals in Taiwan. MICs of tigecycline were determined following the criteria of the U.S. Food and Drug Administration (FDA) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST-2011). Among drug-resistant Gram-positive pathogens, all of the PRSP isolates were susceptible to tigecycline (MIC90, 0.03 μg/ml), and only one MRSA isolate (MIC90, 0.5 μg/ml) and three VRE isolates (MIC90, 0.125 μg/ml) were nonsusceptible to tigecycline. Among the Gram-negative bacteria, the tigecycline susceptibility rates were 99.65% for ESBL-producing E. coli (MIC90, 0.5 μg/ml) and 96.32% for ESBL-producing K. pneumoniae (MIC90, 2 μg/ml) when interpreted by FDA criteria but were 98.7% and 85.8%, respectively, when interpreted by EUCAST-2011 criteria. The susceptibility rate for A. baumannii (MIC90, 4 μg/ml) decreased from 80.9% in 2006 to 55.3% in 2009 but increased to 73.4% in 2010. A bimodal MIC distribution was found among carbapenem-susceptible A. baumannii isolates, and a unimodal MIC distribution was found among carbapenem-nonsusceptible A. baumannii isolates. In Taiwan, tigecycline continues to have excellent in vitro activity against several major clinically important drug-resistant bacteria, with the exception of A. baumannii.
doi:10.1128/AAC.06053-11
PMCID: PMC3294947  PMID: 22203598
22.  Effects of Repetitive Hyperbaric Oxygen Treatment in Patients with Acute Cerebral Infarction: A Pilot Study 
The Scientific World Journal  2012;2012:694703.
The role of hyperbaric oxygen therapy (HBOT) in the treatment of acute ischemic stroke is controversial. This prospective study assessed the efficacy and safety of HBOT as adjuvant treatment on 46 acute ischemic stroke in patients who did not receive thrombolytic therapy. The HBOT group (n = 16) received conventional medical treatment with 10 sessions of adjunctive HBOT within 3–5 days after stroke onset, while the control group (n = 30) received the same treatment but without HBOT. Early (around two weeks after onset) and late (one month after onset) outcomes (National Institutes of Health Stroke Scale, NIHSS scores) and efficacy (changes of NIHSS scores) of HBOT were evaluated. The baseline clinical characteristics were similar in both groups. Both early and late outcomes of the HBOT group showed significant difference (P ≤ 0.001). In the control group, there was only significant difference in early outcome (P = 0.004). For early efficacy, there was no difference when comparing changes of NIHSS scores between the two groups (P = 0.140) but there was statistically significant difference when comparing changes of NIHSS scores at one month (P ≤ 0.001). The HBOT used in this study may be effective for patients with acute ischemic stroke and is a safe and harmless adjunctive treatment.
doi:10.1100/2012/694703
PMCID: PMC3415162  PMID: 22919348
23.  Genome-Wide Association Study of Treatment Refractory Schizophrenia in Han Chinese 
PLoS ONE  2012;7(3):e33598.
We report the first genome-wide association study of a joint analysis using 795 Han Chinese individuals with treatment-refractory schizophrenia (TRS) and 806 controls. Three loci showed suggestive significant association with TRS were identified. These loci include: rs10218843 (P = 3.04×10−7) and rs11265461 (P = 1.94×10−7) are adjacent to signaling lymphocytic activation molecule family member 1 (SLAMF1); rs4699030 (P = 1.94×10−6) and rs230529 (P = 1.74×10−7) are located in the gene nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); and rs13049286 (P = 3.05×10−5) and rs3827219 (P = 1.66×10−5) fall in receptor-interacting serine/threonine-protein kinase 4 (RIPK4). One isolated single nucleotide polymorphism (SNP), rs739617 (P = 3.87×10−5) was also identified to be associated with TRS. The -94delATTG allele (rs28362691) located in the promoter region of NFKB1 was identified by resequencing and was found to associate with TRS (P = 4.85×10−6). The promoter assay demonstrated that the -94delATTG allele had a significant lower promoter activity than the -94insATTG allele in the SH-SY5Y cells. This study suggests that rs28362691 in NFKB1 might be involved in the development of TRS.
doi:10.1371/journal.pone.0033598
PMCID: PMC3313922  PMID: 22479419
24.  Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma treatment 
Neuro-Oncology  2010;12(10):1050-1060.
Malignant glioma is a common and severe primary brain tumor with a high recurrence rate and an extremely high mortality rate within 2 years of diagnosis, even when surgical, radiological, and chemotherapeutic interventions are applied. Intravenously administered drugs have limited use because of their adverse systemic effects and poor blood–brain barrier penetration. Here, we combine 2 methods to increase drug delivery to brain tumors. Focused ultrasound transiently permeabilizes the blood–brain barrier, increasing passive diffusion. Subsequent application of an external magnetic field then actively enhances localization of a chemotherapeutic agent immobilized on a novel magnetic nanoparticle. Combining these techniques significantly improved the delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea to rodent gliomas. Furthermore, the physicochemical properties of the nanoparticles allowed their delivery to be monitored by magnetic resonance imaging (MRI). The resulting suppression of tumor progression without damaging the normal regions of the brain was verified by MRI and histological examination. This noninvasive, reversible technique promises to provide a more effective and tolerable means of tumor treatment, with lower therapeutic doses and concurrent clinical monitoring.
doi:10.1093/neuonc/noq054
PMCID: PMC3018928  PMID: 20663792
BCNU; glioma; magnetic nanoparticle; MRI; ultrasound
25.  A New Drug Design Targeting the Adenosinergic System for Huntington's Disease 
PLoS ONE  2011;6(6):e20934.
Background
Huntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed.
Methodology/Principal Findings
Here, we report a novel dual-function compound, N6-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A2AR and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A2AR and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A2AR knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A2AR in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD.
Conclusions/Significance
The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases.
doi:10.1371/journal.pone.0020934
PMCID: PMC3119665  PMID: 21713039

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