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1.  HLA-E–restricted regulatory CD8+ T cells are involved in development and control of human autoimmune type 1 diabetes  
The Journal of Clinical Investigation  2010;120(10):3641-3650.
A key feature of the immune system is its ability to discriminate self from nonself. Breakdown in any of the mechanisms that maintain unresponsiveness to self (a state known as self-tolerance) contributes to the development of autoimmune conditions. Recent studies in mice show that CD8+ T cells specific for the unconventional MHC class I molecule Qa-1 bound to peptides derived from the signal sequence of Hsp60 (Hsp60sp) contribute to self/nonself discrimination. However, it is unclear whether they exist in humans and play a role in human autoimmune diseases. Here we have shown that CD8+ T cells specific for Hsp60sp bound to HLA-E (the human homolog of Qa-1) exist and play an important role in maintaining peripheral self-tolerance by discriminating self from nonself in humans. Furthermore, in the majority of type 1 diabetes (T1D) patients tested, there was a specific defect in CD8+ T cell recognition of HLA-E/Hsp60sp, which was associated with failure of self/nonself discrimination. However, the defect in the CD8+ T cells from most of the T1D patients tested could be corrected in vitro by exposure to autologous immature DCs loaded with the Hsp60sp peptide. These data suggest that HLA-E–restricted CD8+ T cells may play an important role in keeping self-reactive T cells in check. Thus, correction of this defect could be a potentially effective and safe approach in the therapy of T1D.
doi:10.1172/JCI43522
PMCID: PMC2947239  PMID: 20877010
2.  Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) 
Klionsky, Daniel J | Abdelmohsen, Kotb | Abe, Akihisa | Abedin, Md Joynal | Abeliovich, Hagai | Acevedo Arozena, Abraham | Adachi, Hiroaki | Adams, Christopher M | Adams, Peter D | Adeli, Khosrow | Adhihetty, Peter J | Adler, Sharon G | Agam, Galila | Agarwal, Rajesh | Aghi, Manish K | Agnello, Maria | Agostinis, Patrizia | Aguilar, Patricia V | Aguirre-Ghiso, Julio | Airoldi, Edoardo M | Ait-Si-Ali, Slimane | Akematsu, Takahiko | Akporiaye, Emmanuel T | Al-Rubeai, Mohamed | Albaiceta, Guillermo M | Albanese, Chris | Albani, Diego | Albert, Matthew L | Aldudo, Jesus | Algül, Hana | Alirezaei, Mehrdad | Alloza, Iraide | Almasan, Alexandru | Almonte-Beceril, Maylin | Alnemri, Emad S | Alonso, Covadonga | Altan-Bonnet, Nihal | Altieri, Dario C | Alvarez, Silvia | Alvarez-Erviti, Lydia | Alves, Sandro | Amadoro, Giuseppina | Amano, Atsuo | Amantini, Consuelo | Ambrosio, Santiago | Amelio, Ivano | Amer, Amal O | Amessou, Mohamed | Amon, Angelika | An, Zhenyi | Anania, Frank A | Andersen, Stig U | Andley, Usha P | Andreadi, Catherine K | Andrieu-Abadie, Nathalie | Anel, Alberto | Ann, David K | Anoopkumar-Dukie, Shailendra | Antonioli, Manuela | Aoki, Hiroshi | Apostolova, Nadezda | Aquila, Saveria | Aquilano, Katia | Araki, Koichi | Arama, Eli | Aranda, Agustin | Araya, Jun | Arcaro, Alexandre | Arias, Esperanza | Arimoto, Hirokazu | Ariosa, Aileen R | Armstrong, Jane L | Arnould, Thierry | Arsov, Ivica | Asanuma, Katsuhiko | Askanas, Valerie | Asselin, Eric | Atarashi, Ryuichiro | Atherton, Sally S | Atkin, Julie D | Attardi, Laura D | Auberger, Patrick | Auburger, Georg | Aurelian, Laure | Autelli, Riccardo | Avagliano, Laura | Avantaggiati, Maria Laura | Avrahami, Limor | Awale, Suresh | Azad, Neelam | Bachetti, Tiziana | Backer, Jonathan M | Bae, Dong-Hun | Bae, Jae-sung | Bae, Ok-Nam | Bae, Soo Han | Baehrecke, Eric H | Baek, Seung-Hoon | Baghdiguian, Stephen | Bagniewska-Zadworna, Agnieszka | Bai, Hua | Bai, Jie | Bai, Xue-Yuan | Bailly, Yannick | Balaji, Kithiganahalli Narayanaswamy | Balduini, Walter | Ballabio, Andrea | Balzan, Rena | Banerjee, Rajkumar | Bánhegyi, Gábor | Bao, Haijun | Barbeau, Benoit | Barrachina, Maria D | Barreiro, Esther | Bartel, Bonnie | Bartolomé, Alberto | Bassham, Diane C | Bassi, Maria Teresa | Bast, Robert C | Basu, Alakananda | Batista, Maria Teresa | Batoko, Henri | Battino, Maurizio | Bauckman, Kyle | Baumgarner, Bradley L | Bayer, K Ulrich | Beale, Rupert | Beaulieu, Jean-François | Beck, George R. | Becker, Christoph | Beckham, J David | Bédard, Pierre-André | Bednarski, Patrick J | Begley, Thomas J | Behl, Christian | Behrends, Christian | Behrens, Georg MN | Behrns, Kevin E | Bejarano, Eloy | Belaid, Amine | Belleudi, Francesca | Bénard, Giovanni | Berchem, Guy | Bergamaschi, Daniele | Bergami, Matteo | Berkhout, Ben | Berliocchi, Laura | Bernard, Amélie | Bernard, Monique | Bernassola, Francesca | Bertolotti, Anne | Bess, Amanda S | Besteiro, Sébastien | Bettuzzi, Saverio | Bhalla, Savita | Bhattacharyya, Shalmoli | Bhutia, Sujit K | Biagosch, Caroline | Bianchi, Michele Wolfe | Biard-Piechaczyk, Martine | Billes, Viktor | Bincoletto, Claudia | Bingol, Baris | Bird, Sara W | Bitoun, Marc | Bjedov, Ivana | Blackstone, Craig | Blanc, Lionel | Blanco, Guillermo A | Blomhoff, Heidi Kiil | Boada-Romero, Emilio | Böckler, Stefan | Boes, Marianne | Boesze-Battaglia, Kathleen | Boise, Lawrence H | Bolino, Alessandra | Boman, Andrea | Bonaldo, Paolo | Bordi, Matteo | Bosch, Jürgen | Botana, Luis M | Botti, Joelle | Bou, German | Bouché, Marina | Bouchecareilh, Marion | Boucher, Marie-Josée | Boulton, Michael E | Bouret, Sebastien G | Boya, Patricia | Boyer-Guittaut, Michaël | Bozhkov, Peter V | Brady, Nathan | Braga, Vania MM | Brancolini, Claudio | Braus, Gerhard H | Bravo-San Pedro, José M | Brennan, Lisa A | Bresnick, Emery H | Brest, Patrick | Bridges, Dave | Bringer, Marie-Agnès | Brini, Marisa | Brito, Glauber C | Brodin, Bertha | Brookes, Paul S | Brown, Eric J | Brown, Karen | Broxmeyer, Hal E | Bruhat, Alain | Brum, Patricia Chakur | Brumell, John H | Brunetti-Pierri, Nicola | Bryson-Richardson, Robert J | Buch, Shilpa | Buchan, Alastair M | Budak, Hikmet | Bulavin, Dmitry V | Bultman, Scott J | Bultynck, Geert | Bumbasirevic, Vladimir | Burelle, Yan | Burke, Robert E | Burmeister, Margit | Bütikofer, Peter | Caberlotto, Laura | Cadwell, Ken | Cahova, Monika | Cai, Dongsheng | Cai, Jingjing | Cai, Qian | Calatayud, Sara | Camougrand, Nadine | Campanella, Michelangelo | Campbell, Grant R | Campbell, Matthew | Campello, Silvia | Candau, Robin | Caniggia, Isabella | Cantoni, Lavinia | Cao, Lizhi | Caplan, Allan B | Caraglia, Michele | Cardinali, Claudio | Cardoso, Sandra Morais | Carew, Jennifer S | Carleton, Laura A | Carlin, Cathleen R | Carloni, Silvia | Carlsson, Sven R | Carmona-Gutierrez, Didac | Carneiro, Leticia AM | Carnevali, Oliana | Carra, Serena | Carrier, Alice | Carroll, Bernadette | Casas, Caty | Casas, Josefina | Cassinelli, Giuliana | Castets, Perrine | Castro-Obregon, Susana | Cavallini, Gabriella | Ceccherini, Isabella | Cecconi, Francesco | Cederbaum, Arthur I | Ceña, Valentín | Cenci, Simone | Cerella, Claudia | Cervia, Davide | Cetrullo, Silvia | Chaachouay, Hassan | Chae, Han-Jung | Chagin, Andrei S | Chai, Chee-Yin | Chakrabarti, Gopal | Chamilos, Georgios | Chan, Edmond YW | Chan, Matthew TV | Chandra, Dhyan | Chandra, Pallavi | Chang, Chih-Peng | Chang, Raymond Chuen-Chung | Chang, Ta Yuan | Chatham, John C | Chatterjee, Saurabh | Chauhan, Santosh | Che, Yongsheng | Cheetham, Michael E | Cheluvappa, Rajkumar | Chen, Chun-Jung | Chen, Gang | Chen, Guang-Chao | Chen, Guoqiang | Chen, Hongzhuan | Chen, Jeff W | Chen, Jian-Kang | Chen, Min | Chen, Mingzhou | Chen, Peiwen | Chen, Qi | Chen, Quan | Chen, Shang-Der | Chen, Si | Chen, Steve S-L | Chen, Wei | Chen, Wei-Jung | Chen, Wen Qiang | Chen, Wenli | Chen, Xiangmei | Chen, Yau-Hung | Chen, Ye-Guang | Chen, Yin | Chen, Yingyu | Chen, Yongshun | Chen, Yu-Jen | Chen, Yue-Qin | Chen, Yujie | Chen, Zhen | Chen, Zhong | Cheng, Alan | Cheng, Christopher HK | Cheng, Hua | Cheong, Heesun | Cherry, Sara | Chesney, Jason | Cheung, Chun Hei Antonio | Chevet, Eric | Chi, Hsiang Cheng | Chi, Sung-Gil | Chiacchiera, Fulvio | Chiang, Hui-Ling | Chiarelli, Roberto | Chiariello, Mario | Chieppa, Marcello | Chin, Lih-Shen | Chiong, Mario | Chiu, Gigi NC | Cho, Dong-Hyung | Cho, Ssang-Goo | Cho, William C | Cho, Yong-Yeon | Cho, Young-Seok | Choi, Augustine MK | Choi, Eui-Ju | Choi, Eun-Kyoung | Choi, Jayoung | Choi, Mary E | Choi, Seung-Il | Chou, Tsui-Fen | Chouaib, Salem | Choubey, Divaker | Choubey, Vinay | Chow, Kuan-Chih | Chowdhury, Kamal | Chu, Charleen T | Chuang, Tsung-Hsien | Chun, Taehoon | Chung, Hyewon | Chung, Taijoon | Chung, Yuen-Li | Chwae, Yong-Joon | Cianfanelli, Valentina | Ciarcia, Roberto | Ciechomska, Iwona A | Ciriolo, Maria Rosa | Cirone, Mara | Claerhout, Sofie | Clague, Michael J | Clària, Joan | Clarke, Peter GH | Clarke, Robert | Clementi, Emilio | Cleyrat, Cédric | Cnop, Miriam | Coccia, Eliana M | Cocco, Tiziana | Codogno, Patrice | Coers, Jörn | Cohen, Ezra EW | Colecchia, David | Coletto, Luisa | Coll, Núria S | Colucci-Guyon, Emma | Comincini, Sergio | Condello, Maria | Cook, Katherine L | Coombs, Graham H | Cooper, Cynthia D | Cooper, J Mark | Coppens, Isabelle | Corasaniti, Maria Tiziana | Corazzari, Marco | Corbalan, Ramon | Corcelle-Termeau, Elisabeth | Cordero, Mario D | Corral-Ramos, Cristina | Corti, Olga | Cossarizza, Andrea | Costelli, Paola | Costes, Safia | Cotman, Susan L | Coto-Montes, Ana | Cottet, Sandra | Couve, Eduardo | Covey, Lori R | Cowart, L Ashley | Cox, Jeffery S | Coxon, Fraser P | Coyne, Carolyn B | Cragg, Mark S | Craven, Rolf J | Crepaldi, Tiziana | Crespo, Jose L | Criollo, Alfredo | Crippa, Valeria | Cruz, Maria Teresa | Cuervo, Ana Maria | Cuezva, Jose M | Cui, Taixing | Cutillas, Pedro R | Czaja, Mark J | Czyzyk-Krzeska, Maria F | Dagda, Ruben K | Dahmen, Uta | Dai, Chunsun | Dai, Wenjie | Dai, Yun | Dalby, Kevin N | Dalla Valle, Luisa | Dalmasso, Guillaume | D'Amelio, Marcello | Damme, Markus | Darfeuille-Michaud, Arlette | Dargemont, Catherine | Darley-Usmar, Victor M | Dasarathy, Srinivasan | Dasgupta, Biplab | Dash, Srikanta | Dass, Crispin R | Davey, Hazel Marie | Davids, Lester M | Dávila, David | Davis, Roger J | Dawson, Ted M | Dawson, Valina L | Daza, Paula | de Belleroche, Jackie | de Figueiredo, Paul | de Figueiredo, Regina Celia Bressan Queiroz | de la Fuente, José | De Martino, Luisa | De Matteis, Antonella | De Meyer, Guido RY | De Milito, Angelo | De Santi, Mauro | de Souza, Wanderley | De Tata, Vincenzo | De Zio, Daniela | Debnath, Jayanta | Dechant, Reinhard | Decuypere, Jean-Paul | Deegan, Shane | Dehay, Benjamin | Del Bello, Barbara | Del Re, Dominic P | Delage-Mourroux, Régis | Delbridge, Lea MD | Deldicque, Louise | Delorme-Axford, Elizabeth | Deng, Yizhen | Dengjel, Joern | Denizot, Melanie | Dent, Paul | Der, Channing J | Deretic, Vojo | Derrien, Benoît | Deutsch, Eric | Devarenne, Timothy P | Devenish, Rodney J | Di Bartolomeo, Sabrina | Di Daniele, Nicola | Di Domenico, Fabio | Di Nardo, Alessia | Di Paola, Simone | Di Pietro, Antonio | Di Renzo, Livia | DiAntonio, Aaron | Díaz-Araya, Guillermo | Díaz-Laviada, Ines | Diaz-Meco, Maria T | Diaz-Nido, Javier | Dickey, Chad A | Dickson, Robert C | Diederich, Marc | Digard, Paul | Dikic, Ivan | Dinesh-Kumar, Savithrama P | Ding, Chan | Ding, Wen-Xing | Ding, Zufeng | Dini, Luciana | Distler, Jörg HW | Diwan, Abhinav | Djavaheri-Mergny, Mojgan | Dmytruk, Kostyantyn | Dobson, Renwick CJ | Doetsch, Volker | Dokladny, Karol | Dokudovskaya, Svetlana | Donadelli, Massimo | Dong, X Charlie | Dong, Xiaonan | Dong, Zheng | Donohue, Terrence M | Doran, Kelly S | D'Orazi, Gabriella | Dorn, Gerald W | Dosenko, Victor | Dridi, Sami | Drucker, Liat | Du, Jie | Du, Li-Lin | Du, Lihuan | du Toit, André | Dua, Priyamvada | Duan, Lei | Duann, Pu | Dubey, Vikash Kumar | Duchen, Michael R | Duchosal, Michel A | Duez, Helene | Dugail, Isabelle | Dumit, Verónica I | Duncan, Mara C | Dunlop, Elaine A | Dunn, William A | Dupont, Nicolas | Dupuis, Luc | Durán, Raúl V | Durcan, Thomas M | Duvezin-Caubet, Stéphane | Duvvuri, Umamaheswar | Eapen, Vinay | Ebrahimi-Fakhari, Darius | Echard, Arnaud | Eckhart, Leopold | Edelstein, Charles L | Edinger, Aimee L | Eichinger, Ludwig | Eisenberg, Tobias | Eisenberg-Lerner, Avital | Eissa, N Tony | El-Deiry, Wafik S | El-Khoury, Victoria | Elazar, Zvulun | Eldar-Finkelman, Hagit | Elliott, Chris JH | Emanuele, Enzo | Emmenegger, Urban | Engedal, Nikolai | Engelbrecht, Anna-Mart | Engelender, Simone | Enserink, Jorrit M | Erdmann, Ralf | Erenpreisa, Jekaterina | Eri, Rajaraman | Eriksen, Jason L | Erman, Andreja | Escalante, Ricardo | Eskelinen, Eeva-Liisa | Espert, Lucile | Esteban-Martínez, Lorena | Evans, Thomas J | Fabri, Mario | Fabrias, Gemma | Fabrizi, Cinzia | Facchiano, Antonio | Færgeman, Nils J | Faggioni, Alberto | Fairlie, W Douglas | Fan, Chunhai | Fan, Daping | Fan, Jie | Fang, Shengyun | Fanto, Manolis | Fanzani, Alessandro | Farkas, Thomas | Faure, Mathias | Favier, Francois B | Fearnhead, Howard | Federici, Massimo | Fei, Erkang | Felizardo, Tania C | Feng, Hua | Feng, Yibin | Feng, Yuchen | Ferguson, Thomas A | Fernández, Álvaro F | Fernandez-Barrena, Maite G | Fernandez-Checa, Jose C | Fernández-López, Arsenio | Fernandez-Zapico, Martin E | Feron, Olivier | Ferraro, Elisabetta | Ferreira-Halder, Carmen Veríssima | Fesus, Laszlo | Feuer, Ralph | Fiesel, Fabienne C | Filippi-Chiela, Eduardo C | Filomeni, Giuseppe | Fimia, Gian Maria | Fingert, John H | Finkbeiner, Steven | Finkel, Toren | Fiorito, Filomena | Fisher, Paul B | Flajolet, Marc | Flamigni, Flavio | Florey, Oliver | Florio, Salvatore | Floto, R Andres | Folini, Marco | Follo, Carlo | Fon, Edward A | Fornai, Francesco | Fortunato, Franco | Fraldi, Alessandro | Franco, Rodrigo | Francois, Arnaud | François, Aurélie | Frankel, Lisa B | Fraser, Iain DC | Frey, Norbert | Freyssenet, Damien G | Frezza, Christian | Friedman, Scott L | Frigo, Daniel E | Fu, Dongxu | Fuentes, José M | Fueyo, Juan | Fujitani, Yoshio | Fujiwara, Yuuki | Fujiya, Mikihiro | Fukuda, Mitsunori | Fulda, Simone | Fusco, Carmela | Gabryel, Bozena | Gaestel, Matthias | Gailly, Philippe | Gajewska, Malgorzata | Galadari, Sehamuddin | Galili, Gad | Galindo, Inmaculada | Galindo, Maria F | Galliciotti, Giovanna | Galluzzi, Lorenzo | Galluzzi, Luca | Galy, Vincent | Gammoh, Noor | Gandy, Sam | Ganesan, Anand K | Ganesan, Swamynathan | Ganley, Ian G | Gannagé, Monique | Gao, Fen-Biao | Gao, Feng | Gao, Jian-Xin | García Nannig, Lorena | García Véscovi, Eleonora | Garcia-Macía, Marina | Garcia-Ruiz, Carmen | Garg, Abhishek D | Garg, Pramod Kumar | Gargini, Ricardo | Gassen, Nils Christian | Gatica, Damián | Gatti, Evelina | Gavard, Julie | Gavathiotis, Evripidis | Ge, Liang | Ge, Pengfei | Ge, Shengfang | Gean, Po-Wu | Gelmetti, Vania | Genazzani, Armando A | Geng, Jiefei | Genschik, Pascal | Gerner, Lisa | Gestwicki, Jason E | Gewirtz, David A | Ghavami, Saeid | Ghigo, Eric | Ghosh, Debabrata | Giammarioli, Anna Maria | Giampieri, Francesca | Giampietri, Claudia | Giatromanolaki, Alexandra | Gibbings, Derrick J | Gibellini, Lara | Gibson, Spencer B | Ginet, Vanessa | Giordano, Antonio | Giorgini, Flaviano | Giovannetti, Elisa | Girardin, Stephen E | Gispert, Suzana | Giuliano, Sandy | Gladson, Candece L | Glavic, Alvaro | Gleave, Martin | Godefroy, Nelly | Gogal, Robert M | Gokulan, Kuppan | Goldman, Gustavo H | Goletti, Delia | Goligorsky, Michael S | Gomes, Aldrin V | Gomes, Ligia C | Gomez, Hernando | Gomez-Manzano, Candelaria | Gómez-Sánchez, Rubén | Gonçalves, Dawit AP | Goncu, Ebru | Gong, Qingqiu | Gongora, Céline | Gonzalez, Carlos B | Gonzalez-Alegre, Pedro | Gonzalez-Cabo, Pilar | González-Polo, Rosa Ana | Goping, Ing Swie | Gorbea, Carlos | Gorbunov, Nikolai V | Goring, Daphne R | Gorman, Adrienne M | Gorski, Sharon M | Goruppi, Sandro | Goto-Yamada, Shino | Gotor, Cecilia | Gottlieb, Roberta A | Gozes, Illana | Gozuacik, Devrim | Graba, Yacine | Graef, Martin | Granato, Giovanna E | Grant, Gary Dean | Grant, Steven | Gravina, Giovanni Luca | Green, Douglas R | Greenhough, Alexander | Greenwood, Michael T | Grimaldi, Benedetto | Gros, Frédéric | Grose, Charles | Groulx, Jean-Francois | Gruber, Florian | Grumati, Paolo | Grune, Tilman | Guan, Jun-Lin | Guan, Kun-Liang | Guerra, Barbara | Guillen, Carlos | Gulshan, Kailash | Gunst, Jan | Guo, Chuanyong | Guo, Lei | Guo, Ming | Guo, Wenjie | Guo, Xu-Guang | Gust, Andrea A | Gustafsson, Åsa B | Gutierrez, Elaine | Gutierrez, Maximiliano G | Gwak, Ho-Shin | Haas, Albert | Haber, James E | Hadano, Shinji | Hagedorn, Monica | Hahn, David R | Halayko, Andrew J | Hamacher-Brady, Anne | Hamada, Kozo | Hamai, Ahmed | Hamann, Andrea | Hamasaki, Maho | Hamer, Isabelle | Hamid, Qutayba | Hammond, Ester M | Han, Feng | Han, Weidong | Handa, James T | Hanover, John A | Hansen, Malene | Harada, Masaru | Harhaji-Trajkovic, Ljubica | Harper, J Wade | Harrath, Abdel Halim | Harris, Adrian L | Harris, James | Hasler, Udo | Hasselblatt, Peter | Hasui, Kazuhisa | Hawley, Robert G | Hawley, Teresa S | He, Congcong | He, Cynthia Y | He, Fengtian | He, Gu | He, Rong-Rong | He, Xian-Hui | He, You-Wen | He, Yu-Ying | Heath, Joan K | Hébert, Marie-Josée | Heinzen, Robert A | Helgason, Gudmundur Vignir | Hensel, Michael | Henske, Elizabeth P | Her, Chengtao | Herman, Paul K | Hernández, Agustín | Hernandez, Carlos | Hernández-Tiedra, Sonia | Hetz, Claudio | Hiesinger, P Robin | Higaki, Katsumi | Hilfiker, Sabine | Hill, Bradford G | Hill, Joseph A | Hill, William D | Hino, Keisuke | Hofius, Daniel | Hofman, Paul | Höglinger, Günter U | Höhfeld, Jörg | Holz, Marina K | Hong, Yonggeun | Hood, David A | Hoozemans, Jeroen JM | Hoppe, Thorsten | Hsu, Chin | Hsu, Chin-Yuan | Hsu, Li-Chung | Hu, Dong | Hu, Guochang | Hu, Hong-Ming | Hu, Hongbo | Hu, Ming Chang | Hu, Yu-Chen | Hu, Zhuo-Wei | Hua, Fang | Hua, Ya | Huang, Canhua | Huang, Huey-Lan | Huang, Kuo-How | Huang, Kuo-Yang | Huang, Shile | Huang, Shiqian | Huang, Wei-Pang | Huang, Yi-Ran | Huang, Yong | Huang, Yunfei | Huber, Tobias B | Huebbe, Patricia | Huh, Won-Ki | Hulmi, Juha J | Hur, Gang Min | Hurley, James H | Husak, Zvenyslava | Hussain, Sabah NA | Hussain, Salik | Hwang, Jung Jin | Hwang, Seungmin | Hwang, Thomas IS | Ichihara, Atsuhiro | Imai, Yuzuru | Imbriano, Carol | Inomata, Megumi | Into, Takeshi | Iovane, Valentina | Iovanna, Juan L | Iozzo, Renato V | Ip, Nancy Y | Irazoqui, Javier E | Iribarren, Pablo | Isaka, Yoshitaka | Isakovic, Aleksandra J | Ischiropoulos, Harry | Isenberg, Jeffrey S | Ishaq, Mohammad | Ishida, Hiroyuki | Ishii, Isao | Ishmael, Jane E | Isidoro, Ciro | Isobe, Ken-ichi | Isono, Erika | Issazadeh-Navikas, Shohreh | Itahana, Koji | Itakura, Eisuke | Ivanov, Andrei I | Iyer, Anand Krishnan V | Izquierdo, José M | Izumi, Yotaro | Izzo, Valentina | Jäättelä, Marja | Jaber, Nadia | Jackson, Daniel John | Jackson, William T | Jacob, Tony George | Jacques, Thomas S | Jagannath, Chinnaswamy | Jain, Ashish | Jana, Nihar Ranjan | Jang, Byoung Kuk | Jani, Alkesh | Janji, Bassam | Jannig, Paulo Roberto | Jansson, Patric J | Jean, Steve | Jendrach, Marina | Jeon, Ju-Hong | Jessen, Niels | Jeung, Eui-Bae | Jia, Kailiang | Jia, Lijun | Jiang, Hong | Jiang, Hongchi | Jiang, Liwen | Jiang, Teng | Jiang, Xiaoyan | Jiang, Xuejun | Jiang, Xuejun | Jiang, Ying | Jiang, Yongjun | Jiménez, Alberto | Jin, Cheng | Jin, Hongchuan | Jin, Lei | Jin, Meiyan | Jin, Shengkan | Jinwal, Umesh Kumar | Jo, Eun-Kyeong | Johansen, Terje | Johnson, Daniel E | Johnson, Gail VW | Johnson, James D | Jonasch, Eric | Jones, Chris | Joosten, Leo AB | Jordan, Joaquin | Joseph, Anna-Maria | Joseph, Bertrand | Joubert, Annie M | Ju, Dianwen | Ju, Jingfang | Juan, Hsueh-Fen | Juenemann, Katrin | Juhász, Gábor | Jung, Hye Seung | Jung, Jae U | Jung, Yong-Keun | Jungbluth, Heinz | Justice, Matthew J | Jutten, Barry | Kaakoush, Nadeem O | Kaarniranta, Kai | Kaasik, Allen | Kabuta, Tomohiro | Kaeffer, Bertrand | Kågedal, Katarina | Kahana, Alon | Kajimura, Shingo | Kakhlon, Or | Kalia, Manjula | Kalvakolanu, Dhan V | Kamada, Yoshiaki | Kambas, Konstantinos | Kaminskyy, Vitaliy O | Kampinga, Harm H | Kandouz, Mustapha | Kang, Chanhee | Kang, Rui | Kang, Tae-Cheon | Kanki, Tomotake | Kanneganti, Thirumala-Devi | Kanno, Haruo | Kanthasamy, Anumantha G | Kantorow, Marc | Kaparakis-Liaskos, Maria | Kapuy, Orsolya | Karantza, Vassiliki | Karim, Md Razaul | Karmakar, Parimal | Kaser, Arthur | Kaushik, Susmita | Kawula, Thomas | Kaynar, A Murat | Ke, Po-Yuan | Ke, Zun-Ji | Kehrl, John H | Keller, Kate E | Kemper, Jongsook Kim
Autophagy  2016;12(1):1-222.
doi:10.1080/15548627.2015.1100356
PMCID: PMC4835977  PMID: 26799652
autolysosome; autophagosome; chaperone-mediated autophagy; flux; LC3; lysosome; macroautophagy; phagophore; stress; vacuole
3.  Acute effects of ethanol on GABAA and glycine currents in the lateral habenula neurons of young rats 
Compelling evidence has shown a pivotal role of dopaminergic function in drug addiction. Recently, the lateral habenula (LHb) has attracted a great deal of attention as another target for abused drugs in the brain because its role in regulating dopaminergic system, among others. GABA and glycine are major inhibitory neurotransmitters. Their corresponding receptors are key targets of ethanol. The properties of these receptors in LHb neurons and their responses to ethanol in particular however, remain unknown. Using the patch clamp techniques, we examined the effects of ethanol on the chloride currents elicited by GABA and glycine in LHb neurons acutely dissociated from 10-20 day-old Sprague–Dawley rats. We show that GABA concentration-dependently elicited a bicuculline sensitive inward current in 96% (130/140) of the neurons tested. Ethanol (43.2 mM) suppressed current elicited by a wide range of concentrations (1-300 μM) of GABA in 74% (35/47) cells tested. Ethanol suppression is dependent on its concentrations but not on membrane potentials of the neurons. Moreover, glycine concentration-dependently elicited an inward current in 94% (112/120) of the neurons tested. Both strychnine and picrotoxin concentration dependently suppressed glycine current with IC50 of 220 nM and 813 μM, respectively. Ethanol (43.2 mM) potentiated current elicited by unsaturated but not saturated concentrations of glycine. Thus, the LHb neurons of young rats contain both functional GABAA and glycine receptors which are sensitive to ethanol at pharmacologically relevant concentrations. These effects of ethanol might be important in the control of the activity and output of LHb neurons.
doi:10.13055/ojns_3_1_5.130821
PMCID: PMC5218823  PMID: 28066680
4.  Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy 
Nature medicine  2016;22(8):851-860.
Single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that acts as a barrier to T-cell infiltration. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 significantly limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This delay in tumor progression was associated with dramatically reduced tumor fibrosis, and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.
doi:10.1038/nm.4123
PMCID: PMC4935930  PMID: 27376576
FAK; PDAC; pancreatic cancer; PD-1; fibrosis; CXCL12; immunotherapy; tumor microenvironment; VS-4718
5.  Therapeutic Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Acute Lung Injury Mice 
Scientific Reports  2017;7:39889.
The incidence and mortality of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are still very high, but stem cells show some promise for its treatment. Here we found that intratracheal administration of human umbilical cord-mesenchymal stem cells (UC-MSCs) significantly improved survival and attenuated the lung inflammation in lipopolysaccharide (LPS)-induced ALI mice. We also used the proteins-chip and bioinformatics to analyze interactions between UC-MSCs treatment and immune-response alternations of ALI mice. Then we demonstrated that UC-MSCs could inhibit the inflammatory response of mouse macrophage in ALI mice, as well as enhance its IL-10 expression. We provide data to support the concept that the therapeutic capacity of UC-MSCs for ALI was primarily through paracrine secretion, particularly of prostaglandin-E2 (PGE2). Furthermore, we showed that UC-MSCs might secrete a panel of factors including GM-CSF, IL-6 and IL-13 to ameliorate ALI. Our study suggested that UC-MSCs could protect LPS-induced ALI model by immune regulation and paracrine factors, indicating that UC-MSCs should be a promising strategy for ALI/ARDS.
doi:10.1038/srep39889
PMCID: PMC5209685  PMID: 28051154
6.  Identifying the functional contribution of the defatty-acylase activity of SIRT6 
Nature chemical biology  2016;12(8):614-620.
Mammalian sirtuin 6 (SIRT6) exhibits many pivotal functions and multiple enzymatic activities, but the contribution of each activity to the various functions is unclear. We identified a SIRT6 G60A mutant that possesses efficient defatty-acylase activity, but has significantly decreased deacetylase activity in vitro and no detectable deacetylase activity in cells. The G60A mutant has decreased ability to bind NAD+, but the presence of fatty-acyl lysine peptides restores NAD+ binding, explaining the retention of the defatty-acylase activity. Using this mutant, we found that SIRT6’s defatty-acylase activity regulates the secretion of numerous proteins. Interestingly, many ribosomal proteins were secreted via exosomes from Sirt6 KO mouse embryonic fibroblasts, and these exosomes increased NIH 3T3 cell proliferation compared with control exosomes. Our data supports that distinct activities of SIRT6 regulate different pathways, and that the G60A mutant is a useful tool to study the contribution of the defatty-acylase activity to SIRT6’s various functions.
doi:10.1038/nchembio.2106
PMCID: PMC4955683  PMID: 27322069
7.  Salivary and serum inflammatory mediators among pre-conception women with periodontal disease 
BMC Oral Health  2016;16:131.
Background
There have been inconsistent conclusions regarding the levels of inflammatory mediators in saliva and serum among people with or without periodontal disease. Although pre-conception has been put forward as the optimal time for the periodontal treatment in order to improving pregnancy outcomes, few studies have been conducted to examine inflammatory mediators in saliva and serum among pre-conception women.
Methods
Pre-conception women were recruited between January 2012 and December 2014. Women were provided with an oral health examination to detect periodontal disease. Salivary and serum samples were collected at the same of examination. Inflammatory mediators includinginterleukin-1 beta (IL-1β), IL-6, tumor necrosis factor alpha (TNF-α) and beta-glucuronidase (β–glucuronidase) were tested and analyzed among women with overall periodontal disease (n = 442) or moderate/severe periodontal disease (n = 247). Results were compared to that in women with a healthy periodontium (n = 91).
Results
Significantly increased concentrations of inflammatory mediators of IL-1β, IL-6, TNF-α and β-glucuronidase in saliva and IL-1β, β-glucuronidase and TNF-α in serum were found among pre-conception women with moderate/severe periodontal disease, compared with women without periodontal disease. Significantly increased levels were also found in all the above saliva inflammatory mediators and in serum IL-1β and TNF-α among women with overall periodontal disease. The levels of all inflammatory mediators in saliva and almost all inflammatory mediators except IL-6 in serum significantly increased with severity of periodontal disease.
Conclusion
Periodontal disease is highly associated with the elevated levels of inflammatory mediators in saliva and some mediators in serum among pre-conception women.
doi:10.1186/s12903-016-0306-9
PMCID: PMC5159988  PMID: 27978823
Periodontal disease; Inflammatory mediators; Saliva; Serum; Pre-conception women
8.  Simulated effects of nitrogen saturation on the global carbon budget using the IBIS model 
Scientific Reports  2016;6:39173.
Over the past 100 years, human activity has greatly changed the rate of atmospheric N (nitrogen) deposition in terrestrial ecosystems, resulting in N saturation in some regions of the world. The contribution of N saturation to the global carbon budget remains uncertain due to the complicated nature of C-N (carbon-nitrogen) interactions and diverse geography. Although N deposition is included in most terrestrial ecosystem models, the effect of N saturation is frequently overlooked. In this study, the IBIS (Integrated BIosphere Simulator) was used to simulate the global-scale effects of N saturation during the period 1961–2009. The results of this model indicate that N saturation reduced global NPP (Net Primary Productivity) and NEP (Net Ecosystem Productivity) by 0.26 and 0.03 Pg C yr−1, respectively. The negative effects of N saturation on carbon sequestration occurred primarily in temperate forests and grasslands. In response to elevated CO2 levels, global N turnover slowed due to increased biomass growth, resulting in a decline in soil mineral N. These changes in N cycling reduced the impact of N saturation on the global carbon budget. However, elevated N deposition in certain regions may further alter N saturation and C-N coupling.
doi:10.1038/srep39173
PMCID: PMC5155240  PMID: 27966643
9.  Sulfiredoxin Promotes Colorectal Cancer Cell Invasion and Metastasis through a Novel Mechanism of Enhancing EGFR Signaling# 
Molecular cancer research : MCR  2015;13(12):1554-1566.
Sulfiredoxin (SRXN1/Srx) is a multifunction enzyme with a primary antioxidant role of reducing the overoxidized inactive form of peroxiredoxins (Prxs). The function and mechanisms of Srx in cancer development are not well understood. Here, Srx is preferentially expressed in human colorectal cancer (CRC) cells but not in normal colon epithelial cells. Loss-of-function studies demonstrate that knockdown of Srx in poorly differentiated CRC cells not only leads to the inhibition of colony formation and cell invasion in vitro, but also reduces tumor xenograft growth and represses metastasis to distal organs in a mouse orthotopic implantation model. Notably, exactly opposite effects were observed in gain-of-function experiments when Srx was ectopically expressed in well-differentiated CRC cells. Mechanistically, expression of Srx enhances the activation of mitogen activated protein kinase (MAPK) signaling through increasing the C-terminal tyrosine phosphorylation levels of epidermal growth factor receptor (EGFR). This function of Srx is mediated through its inhibition of EGFR acetylation at K1037, a novel post-translational modification of EGFR in human CRC cells identified by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) proteomic analysis. Furthermore, abolishment of K1037 acetylation in human CRC cells by site-specific mutagenesis leads to sustained activation of EGFR-MAPK signaling. Combined, these data reveal that Srx promotes CRC cell invasion and metastasis through a novel mechanism of enhancing EGFR signaling.
Implications
Sulfiredoxin is a critical oncogenic protein that can be used as a molecular target to develop therapeutics for patients with metastatic colorectal cancer.
doi:10.1158/1541-7786.MCR-15-0240
PMCID: PMC4684963  PMID: 26290602
Sulfiredoxin; Antioxidant; Tumor Invasion and Metastasis; Cell Signaling; Molecular Therapeutics
10.  Prevalence and risk factors of periodontal disease among pre-conception Chinese women 
Reproductive Health  2016;13:141.
Background
Periodontal disease is one of the most common chronic infectious diseases. It has been reported that periodontal disease is associated with various adverse pregnancy outcomes including preterm birth, low birth weight, and gestational diabetes mellitus. Given the fact that the treatment for periodontal disease during pregnancy was ineffective in improving pregnancy outcomes by most of studies, the pre-conception period has been put forward as a more optimal time. However, very few studies have reported the prevalence of periodontal disease among pre-conception women. This study aimed to examine the prevalence and risk factors of periodontal disease among Chinese pre-conception women.
Methods
A survey was conducted among pre-conception women at the Maternal and Child Health Hospital, Changzhou, China between January 2012 and December 2014. A total of 987 pre-conception women were recruited for a full-mouth dental examination after providing informed consent. A dental examination was carried out by probing six sites per tooth using a manual UNC-15 probe and a recording form.
Results
The overall rate of periodontal disease among participants was 73.9% (729/987) (95% confidence interval (CI): 71.0–76.6%). Among women with periodontal disease, 48.0% of cases were mild, 50.9% were moderate and 1.1% were severe. Self-reported bleeding during tooth brushing was the only significant predictive factor for overall periodontal disease (adjusted odds ratio (aOR): 3.71, 95% CI: 2.24, 6.15, P < 0.001) and moderate/severe periodontal disease (aOR: 5.17, 95% CI: 3.05, 8.79, P < 0.001).
Conclusion
A high prevalence of periodontal disease was found in pre-conception Chinese women. Women who have bleeding during tooth brushing could be at increased risk of periodontal disease, and might require further oral health care.
doi:10.1186/s12978-016-0256-3
PMCID: PMC5131524  PMID: 27903295
Periodontal disease; Prevalence; Risk factors; Pre-conception women
11.  Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid 
Background: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS. Results: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice. Conclusion: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS.
doi:10.3390/ijms17122129
PMCID: PMC5187929  PMID: 27999308
Homer1b/c; amyotrophic lateral sclerosis; SOD1 G93A; lithium; valproic acid (VPA)
12.  Association among Complement Factor H Autoantibodies, Deletions of CFHR, and the Risk of Atypical Hemolytic Uremic Syndrome 
To evaluate the association among complement factor H-related (CFHRs) gene deficiency, complement factor H (CFH) autoantibodies, and atypical hemolytic uremic syndrome (aHUS) susceptibility. EMBASE, PubMed, and the ISI Web of Science databases were searched for all eligible studies on the relationship among CFHRs deficiency, anti-FH autoantibodies, and aHUS risk. Eight case-control studies with 927 cases and 1182 controls were included in this study. CFHR1 deficiency was significantly associated with an increased risk of aHUS (odds ratio (OR) = 3.61, 95% confidence interval (95% CI), 1.96, 6.63, p < 0.001), while no association was demonstrated in individuals with only CFHR1/R3 deficiency (OR = 1.32, 95% CI, 0.50, 3.50, p = 0.56). Moreover, a more significant correlation was observed in people with both FH-anti autoantibodies and CFHR1 deficiency (OR = 11.75, 95% CI, 4.53, 30.44, p < 0.001) in contrast to those with only CFHR1 deficiency. In addition, the results were essentially consistent among subgroups stratified by study quality, ethnicity, and gene detection methods. The present meta-analysis indicated that CFHR1 deletion was significantly associated with the risk of aHUS, particularly when combined with anti-FH autoantibodies, indicating that potential interactions among CFHR1 deficiency and anti-FH autoantibodies might impact the risk of aHUS.
doi:10.3390/ijerph13121209
PMCID: PMC5201350  PMID: 27929404
complement factor H-related genes; complement factor H; atypical hemolytic uremic syndrome; meta-analysis
13.  The measurement repeatability using different partition methods of intraretinal tomographic thickness maps in healthy human subjects 
Purpose
To determine the repeatability and profiles with different partition methods in intraretinal thickness layers in healthy human subjects, using optical coherence tomography (OCT).
Methods
A custom-built ultrahigh-resolution OCT was used to acquire three-dimensional volume of the macula in 20 healthy subjects. The dataset was acquired twice using the macular cube 512×128 protocol in an area of 6×6 mm2 centered on the fovea. Commercially available segmentation software (Orion™) was used to segment the dataset into thickness maps of six intraretinal layers. The coefficient of repeatability and intraclass coefficient of correlation (ICC) were analyzed using hemispheric zoning and sectors defined by the Early Treatment Diabetic Retinopathy Study (ETDRS).
Results
All datasets were successfully segmented to create six thickness maps of individual intraretinal layers. Coefficients of repeatabilities of these layers in hemispheric zones ranged from 0.9 to 6.6 µm, with an average of 3.6 µm (standard deviation [SD] 1.4), which was not significantly different compared to ETDRS sectors (P>0.05). ICCs of these layers in hemispheric zones ranged from 0.68 to 0.99, with an average of 0.91 (SD 0.07). There were no significant differences in ICCs between two zoning methods (P>0.05). Significant variations of tomographic intraretinal thicknesses were found between the inner and outer annuli and among the quadrantal sectors within the inner and outer annuli (P<0.05). Significant variations of the quadrantal sectors including both inner and outer annuli were evident in intraretinal layers (P<0.05) except for the outer plexiform layer.
Conclusion
The measurement repeatabilities of tomographic thicknesses of intraretinal layers are comparable using both hemispheric and ETDRS partitions in volumetric data combined with the commercially available segmentation software. In keeping with known, normal anatomical variation, significant differences in tomographic thickness in various intraretinal layers were apparent in both hemispheric and ETDRS sectors.
doi:10.2147/OPTH.S117494
PMCID: PMC5136365  PMID: 27942202
intraretinal layer; thickness variation; tomography; healthy subject
14.  Climate-driven increase of natural wetland methane emissions offset by human-induced wetland reduction in China over the past three decades 
Scientific Reports  2016;6:38020.
Both anthropogenic activities and climate change can affect the biogeochemical processes of natural wetland methanogenesis. Quantifying possible impacts of changing climate and wetland area on wetland methane (CH4) emissions in China is important for improving our knowledge on CH4 budgets locally and globally. However, their respective and combined effects are uncertain. We incorporated changes in wetland area derived from remote sensing into a dynamic CH4 model to quantify the human and climate change induced contributions to natural wetland CH4 emissions in China over the past three decades. Here we found that human-induced wetland loss contributed 34.3% to the CH4 emissions reduction (0.92 TgCH4), and climate change contributed 20.4% to the CH4 emissions increase (0.31 TgCH4), suggesting that decreasing CH4 emissions due to human-induced wetland reductions has offset the increasing climate-driven CH4 emissions. With climate change only, temperature was a dominant controlling factor for wetland CH4 emissions in the northeast (high latitude) and Qinghai-Tibet Plateau (high altitude) regions, whereas precipitation had a considerable influence in relative arid north China. The inevitable uncertainties caused by the asynchronous for different regions or periods due to inter-annual or seasonal variations among remote sensing images should be considered in the wetland CH4 emissions estimation.
doi:10.1038/srep38020
PMCID: PMC5125101  PMID: 27892535
15.  Autologous platelet lysates local injections for treatment of tibia non-union with breakage of the nickelclad: a case report 
SpringerPlus  2016;5(1):2013.
Background
Nonunions of the tibia represent challenging orthopedic problems, which require the surgeon to analyze numerous factors and choose an appropriate treatment. This article presents a case report of tibia and fibula fracture patient who failed the internal fixation surgery and successfully recovered after one course of percutaneous autologous platelet lysates injection.
Case description
The patient received an internal nickelclad breakage at 9 months post-surgery but reluctant to accept a second surgery, then autologous platelet lysates (APL) injection which is a less invasive method was recommended. The injections were carried once a week for three times. Radiologic evaluation was conducted every month until recovery.
Discussion and evaluation
To the best of our knowledge, this is the first reported case of tibia delayed union with breakage of the plate resolved with APL injection. Improved clinical evidence was observed at 4 and 6 months after injection. The patient got good bony union at 8 months post-injection. The patient didn’t feel any discomfort postinjection, no complications such as infection, refracture etc. were observed.
Conclusions
APL percutaneous injection could be a new therapeutic option for the treatment of nonunion or delayed healing fractures.
doi:10.1186/s40064-016-3683-2
PMCID: PMC5122524  PMID: 27933268
Tibia and fibula fracture; Non-union; Autologous platelet lysates; Percutaneous injections
16.  Slit-lamp photography and videography with high magnifications 
Eye & contact lens  2015;41(6):391-397.
Purpose
To demonstrate the use of the slit-lamp photography and videography with extremely high magnifications for visualizing structures of the anterior segment of the eye.
Methods
A Canon 60D digital camera with Movie Crop Function was adapted into a Nikon FS-2 slit-lamp to capture still images and video clips of the structures of the anterior segment of the eye. Images obtained using the slit-lamp were tested for spatial resolution. The cornea of human eyes was imaged with the slit-lamp and the structures were compared with the pictures captured using the ultra-high resolution optical coherence tomography (UHR-OCT). The central thickness of the corneal epithelium and total cornea was obtained using the slit-lamp and the results were compared with the thickness obtained using UHR-OCT.
Results
High-quality ocular images and higher spatial resolutions were obtained by using the slit-lamp with extremely high magnifications and Movie Crop Function, rather than the traditional slit-lamp. The structures and characteristics of the cornea, such as the normal epithelium, abnormal epithelium of corneal intraepithelial neoplasia, LASIK interface, and contact lenses, were clearly visualized using this device. These features were confirmed by comparing the obtained images with those acquired using UHR-OCT. Moreover, the tear film debris on the ocular surface and the corneal nerve in the anterior corneal stroma were also visualized. The thicknesses of the corneal epithelium and total cornea were similar to that measured using UHR-OCT (P < 0.05).
Conclusions
We demonstrated that the slit-lamp photography and videography with extremely high magnifications allows better visualization of the anterior segment structures of the eye, especially of the epithelium, when compared with the traditional slit-lamp.
doi:10.1097/ICL.0000000000000148
PMCID: PMC4630077  PMID: 26020484
slit lamp biomicroscopy; videography; high magnification; ultra high optical coherence topography; corneal epithelium thickness
18.  Clinical, molecular and immune analysis of dabrafenib and trametinib in metastatic melanoma patients that progressed on BRAF inhibitor monotherapy: a phase II clinical trial 
JAMA oncology  2016;2(8):1056-1064.
Importance
Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only ~15% of BRAF inhibitor (BRAFi)-refractory metastatic melanoma patients, in contrast to the high activity observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development.
Objective
To determine correlates of benefit from CombiDT therapy in BRAFi-refractory metastatic melanoma patients.
Design
Single-center, single-arm prospective phase II study of CombiDT in patients with BRAFV600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014.
Setting
University of Texas MD Anderson Cancer Center.
Participants
28 patients were screened and 23 enrolled. Key eligibility criteria included: BRAFV600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and accessible tumor for biopsy.
Intervention
Patients were treated with dabrafenib (150 mg twice daily) and trametinib (2 mg daily) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsies were performed on-treatment and at progression. Whole-exome sequencing, RT-PCR for BRAF splicing, RNAseq and IHC were performed on tumor samples, and blood was analyzed for levels of circulating BRAFV600.
Main outcome measures
Primary endpoint was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical endpoints.
Results
Among evaluable patients, the confirmed ORR was 10%, disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi >6 months (DCR 73% vs. 11% for ≤6 months, p=0.02) and decrease in circulating BRAFV600 at day 8 of cycle 1 (DCR 75% vs. 18% for no decrease, p=0.015), but not by pre-treatment MAPK pathway mutations or activation. On-treatment biopsies demonstrated that CombiDT failed to achieve significant MAPK pathway inhibition or immune infiltration in most patients.
Conclusions and relevance
The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT in BRAFi-refractory metastatic melanoma patients. Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of CombiDT in this setting. Circulating BRAF V600 is a promising early biomarker of clinical response.
doi:10.1001/jamaoncol.2016.0509
PMCID: PMC4982774  PMID: 27124486
19.  Neuronal Nav1.8 Channels as a Novel Therapeutic Target of Acute Atrial Fibrillation Prevention 
Background
Ganglionated plexus have been developed as additional ablation targets to improve the outcome of atrial fibrillation (AF) besides pulmonary vein isolation. Recent studies implicated an intimate relationship between neuronal sodium channel Nav1.8 (encoded by SCN10A) and AF. The underlying mechanism between Nav1.8 and AF remains unclear. This study aimed to determine the role of Nav1.8 in cardiac electrophysiology in an acute AF model and explore possible therapeutic targets.
Methods and Results
Immunohistochemical study was used on canine cardiac ganglionated plexus. Both Nav1.5 and Nav1.8 were expressed in ganglionated plexus with canonical neuronal markers. Sixteen canines were randomly administered either saline or the Nav1.8 blocker A‐803467. Electrophysiological study was compared between the 2 groups before and after 6‐hour rapid atrial pacing. Compared with the control group, administration of A‐803467 decreased the incidence of AF (87.5% versus 25.0%, P<0.05), shortened AF duration, and prolonged AF cycle length. A‐803467 also significantly suppressed the decrease in the effective refractory period and the increase in effective refractory period dispersion and cumulative window of vulnerability caused by rapid atrial pacing in all recording sites. Patch clamp study was performed under 100 nmol/L A‐803467 in TSA201 cells cotransfected with SCN10A‐WT,SCN5A‐WT, and SCN3B‐WT. IN a,P was reduced by 45.34% at −35 mV, and IN a,L by 68.57% at −20 mV. Evident fast inactivation, slow recovery, and use‐dependent block were also discovered after applying the drug.
Conclusions
Our study demonstrates that Nav1.8 could exert its effect on electrophysiological characteristics through cardiac ganglionated plexus. It indicates that Nav1.8 is a novel target in understanding cardiac electrophysiology and SCN10A‐related arrhythmias.
doi:10.1161/JAHA.116.004050
PMCID: PMC5210368  PMID: 27806967
atrial fibrillation; electrophysiology; ganglionated plexus; Nav1.8; SCN10A; Atrial Fibrillation; Electrophysiology; Autonomic Nervous System; Ion Channels/Membrane Transport; Gene Expression & Regulation
20.  Diagnostic Utility of ANG in Coronary Heart Disease Complicating Chronic Heart Failure: A Cross-Sectional Study 
Disease Markers  2016;2016:2740826.
Angiogenin (ANG) has been shown to be elevated in several cardiovascular diseases. To detect its levels and diagnostic capacity in coronary heart disease (CHD) patients complicating chronic heart failure (CHF), we performed this cross-sectional study and enrolled 616 CHD patients and 53 healthy controls. According to complicating CHF or not, the patients were divided into CHF group (n = 203) and CHD disease controls (n = 413), in which the CHF group was subdivided as heart failure with reduced ejection fraction (HFrEF) group or heart failure with preserved ejection fraction (HFpEF) group on the basis of left ventricular ejection fraction (LVEF), or as different NYHA class group. Their plasma ANG levels were detected using enzyme-linked immunosorbent assay (ELISA). Plasma ANG was 342.8 (IQR [273.9,432.9]), 304.5 (IQR [254.0,370.5]), and 279.7 (IQR [214.4,344.0]) ng/mL in the CHF group, CHD disease controls, and healthy controls, respectively, significantly higher in the CHF group compared with the others. Furthermore, among CHF group, ANG is dramatically higher in the HFrEF patients compared with the HFpEF patients. As for the diagnostic capacity of ANG, the area under the receiver operating characteristic curve was 0.71 (95% CI 0.63–0.78). We concluded that plasma ANG is elevated in CHD complicating CHF patients and may be a moderate discriminator of CHF from CHD or the healthy.
doi:10.1155/2016/2740826
PMCID: PMC5107839  PMID: 27872509
22.  Production of inflammatory cytokines, cortisol, and Aβ1-40 in elderly oral cancer patients with postoperative delirium 
Aim
Pathophysiological disorders after surgery might be related to postoperative delirium (POD). This study was designed to elucidate the pathogenesis of POD in elderly oral cancer patients by determining the perioperative kinetics of inflammatory cytokines, cortisol, and amyloid β1-40 (Aβ1-40).
Methods
A total of 257 elderly oral cancer patients who underwent tumor resection surgery were selected. Venous blood was collected prior to surgery (T0), at the end of surgery (T1), and at 12 hours after surgery (T2). During the first three postoperative days, patients were examined using the confusion assessment method twice a day (8 am and 8 pm). Mini-Mental State Examination scores were recorded at T0 and on postoperative days 1, 3, and 7. Ultimately, 56 patients suffering from POD made up the POD group, and 56 patients randomly selected from a cohort of patients without POD were allocated to the no POD (NPOD) group. Subsequently, interleukin-6, C-reactive protein, procalcitonin, cortisol, and Aβ1-40 in plasma from the two groups were measured.
Results
The two groups displayed comparable basic characteristics. There were no differences in all tested biomarkers between the two groups at T0. However, after surgery, the biomarker levels displayed distinct patterns between the two groups. The peak levels of all biomarkers were higher in the POD group than in the NPOD group. Conversely, the Mini-Mental State Examination scores after surgery were lower in the POD group than in the no POD group.
Conclusion
The boost of inflammatory cytokines, cortisol, and Aβ1-40 after surgery might be involved in POD onset among elderly oral cancer patients. POD was accompanied by progressive cognitive deficiency.
doi:10.2147/NDT.S113077
PMCID: PMC5089834  PMID: 27822051
elderly; postoperative delirium; inflammatory cytokines; cortisol; β-amyloid protein
23.  The Effects of High-fat-diet Combined with Chronic Unpredictable Mild Stress on Depression-like Behavior and Leptin/LepRb in Male Rats 
Scientific Reports  2016;6:35239.
Leptin plays a key role in the pathogenesis of obesity and depression via the long form of leptin receptor (LepRb). An animal model of comorbid obesity and depression induced by high-fat diet (HFD) combined with chronic unpredictable mild stress (CUMS) was developed to study the relationship between depression/anxiety-like behavior, levels of plasma leptin and LepRb in the brains between four groups of rats, the combined obesity and CUMS (Co) group, the obese (Ob) group, the CUMS group and controls. Our results revealed that the Co group exhibited most severe depression-like behavior in the open field test (OFT), anxiety-like behavior in elevated plus maze test (EMT) and cognitive impairment in the Morris water maze (MWM). The Ob group had the highest weight and plasma leptin levels while the Co group had the lowest levels of protein of LepRb in the hypothalamus and hippocampus. Furthermore, depressive and anxiety-like behaviors as well as cognitive impairment were positively correlated with levels of LepRb protein and mRNA in the hippocampus and hypothalamus. The down-regulation of leptin/LepRb signaling might be associated with depressive-like behavior and cognitive impairment in obese rats facing chronic mild stress.
doi:10.1038/srep35239
PMCID: PMC5064321  PMID: 27739518
24.  An Animal Model of Modic Changes by Embedding Autogenous Nucleus Pulposus inside Subchondral Bone of Lumbar Vertebrae 
Scientific Reports  2016;6:35102.
The establishment of Modic changes (MCs) in animal model was vital for research of MCs. Fifty-four rabbits were divided into a sham group, a muscle embedment group (ME group) and nucleus pulposus (NP) embedment group (NPE group). In the NPE group, the discs were exposed by the lumbar anterolateral surgical approach. A needle was used to puncture the L5 vertebral body close to the endplate. NP was extracted by a syringe from L1/2 intervertebral discs and then injected into the drilled hole of subchondral bone. The muscle embedment group and sham group had the same procedure and drill method as the NP embedment group. Some pieces of muscle were put into the hole in the ME group, but nothing was put into the hole in the sham group. After the operation, MRI scan and molecular biology tests were applied. The signal changes were found in the NPE group; while the sham group and the ME group showed no significant signal change. Histological observation confirmed that there was abnormal tissue proliferation in imbed site. High expression of IL-4, IL-17 and IFN-γ were detected in the NPE group. The embedment of NP into subchondral bone can create an animal model of MCs.
doi:10.1038/srep35102
PMCID: PMC5054372  PMID: 27713567
25.  Combination with intravenous iron supplementation or doubling erythropoietin dose for patients with chemotherapy-induced anaemia inadequately responsive to initial erythropoietin treatment alone: study protocol for a randomised controlled trial 
BMJ Open  2016;6(10):e012231.
Introduction
Erythropoietin (EPO) is a commonly used option in the treatment of chemotherapy-induced anaemia (CIA). However, ∼30–50% of patients fail to achieve an adequate response after initial treatment. Prior studies have demonstrated that intravenous iron might synergistically improve therapeutic response to EPO treatment in this patient population.
Methods and analysis
We will perform this multicentre, randomised, open-label, parallel-group, active controlled non-inferiority study to compare the two combination therapies of EPO plus intravenous iron regimen versus doubling the dose of EPO in patients with CIA who have an inadequate response to initial EPO treatment at a routine dose. A total of 603 patients with an increase in haemoglobin (Hb) <1 g/dL will be enrolled and randomised to one of the three study treatment groups at a 1:1:1 ratio Group 1: EPO treatment at the original dose plus intravenous iron dextran 200 mg every 3 weeks (Q3W) for 15 weeks; Group 2: EPO treatment at the original dose plus intravenous iron dextran 100 mg, twice a week for 5 weeks; Group 3: the control group, doubling the EPO dose without preplanned iron supplementation. The primary outcome measure to compare is the Hb response rate at week 15 and the secondary end points involve therapeutic blood transfusions. Time-to-progression, adverse events and quality of life will also be evaluated.
Ethics and dissemination
All participants will provide informed consent; the study protocol has been approved by the independent ethics committee of Shanghai East Hospital. This study would clearly demonstrate the potential benefit of combining epoetin treatment with intravenous iron supplementation. Findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of CIA in China.
Trial registration number
NCT02731378.
doi:10.1136/bmjopen-2016-012231
PMCID: PMC5073518  PMID: 27855097
erythropoietin; iron supplementation; inadequately responsive; chemotherapy-induced anaemia; randomized controlled trial

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