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PubMed Central Canada to be taken offline in February 2018

On February 23, 2018, PubMed Central Canada (PMC Canada) will be taken offline permanently. No author manuscripts will be deleted, and the approximately 2,900 manuscripts authored by Canadian Institutes of Health Research (CIHR)-funded researchers currently in the archive will be copied to the National Research Council’s (NRC) Digital Repository over the coming months. These manuscripts along with all other content will also remain publicly searchable on PubMed Central (US) and Europe PubMed Central, meaning such manuscripts will continue to be compliant with the Tri-Agency Open Access Policy on Publications.

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1.  Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis 
Nature Communications  2018;9:256.
Cellular homoeostatic pathways such as macroautophagy (hereinafter autophagy) are regulated by basic mechanisms that are conserved throughout the eukaryotic kingdom. However, it remains poorly understood how these mechanisms further evolved in higher organisms. Here we describe a modification in the autophagy pathway in vertebrates, which promotes its activity in response to oxidative stress. We have identified two oxidation-sensitive cysteine residues in a prototypic autophagy receptor SQSTM1/p62, which allow activation of pro-survival autophagy in stress conditions. The Drosophila p62 homologue, Ref(2)P, lacks these oxidation-sensitive cysteine residues and their introduction into the protein increases protein turnover and stress resistance of flies, whereas perturbation of p62 oxidation in humans may result in age-related pathology. We propose that the redox-sensitivity of p62 may have evolved in vertebrates as a mechanism that allows activation of autophagy in response to oxidative stress to maintain cellular homoeostasis and increase cell survival.
The cellular mechanisms underlying autophagy are conserved; however it is unclear how they evolved in higher organisms. Here the authors identify two oxidation-sensitive cysteine residues in the autophagy receptor SQSTM1/p62 in vertebrates which allow activation of pro-survival autophagy in stress conditions.
doi:10.1038/s41467-017-02746-z
PMCID: PMC5772351  PMID: 29343728
2.  Dysregulation of mTORC1/autophagy axis in senescence 
Aging (Albany NY)  2017;9(8):1851-1852.
doi:10.18632/aging.101277
PMCID: PMC5611974  PMID: 28783710
senescence; mTORC1; autophagy
3.  Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing 
The Journal of Cell Biology  2017;216(7):1949-1957.
It is unclear how mTORC1 signaling differs in senescent and young cells. Carroll et al. show that senescence leads to constitutive mTORC1 activation and resistance to serum and amino acid starvation. This is associated with elevated autophagy, depolarization of cell plasma membrane, and primary cilia defects.
Mammalian target of rapamycin complex 1 (mTORC1) and cell senescence are intimately linked to each other and to organismal aging. Inhibition of mTORC1 is the best-known intervention to extend lifespan, and recent evidence suggests that clearance of senescent cells can also improve health and lifespan. Enhanced mTORC1 activity drives characteristic phenotypes of senescence, although the underlying mechanisms responsible for increased activity are not well understood. We have identified that in human fibroblasts rendered senescent by stress, replicative exhaustion, or oncogene activation, mTORC1 is constitutively active and resistant to serum and amino acid starvation. This is driven in part by depolarization of senescent cell plasma membrane, which leads to primary cilia defects and a resultant failure to inhibit growth factor signaling. Further, increased autophagy and high levels of intracellular amino acids may act to support mTORC1 activity in starvation conditions. Interventions to correct these phenotypes restore sensitivity to the mTORC1 signaling pathway and cause death, indicating that persistent signaling supports senescent cell survival.
doi:10.1083/jcb.201610113
PMCID: PMC5496614  PMID: 28566325
4.  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
5.  Mitochondria are required for pro‐ageing features of the senescent phenotype 
The EMBO Journal  2016;35(7):724-742.
Abstract
Cell senescence is an important tumour suppressor mechanism and driver of ageing. Both functions are dependent on the development of the senescent phenotype, which involves an overproduction of pro‐inflammatory and pro‐oxidant signals. However, the exact mechanisms regulating these phenotypes remain poorly understood. Here, we show the critical role of mitochondria in cellular senescence. In multiple models of senescence, absence of mitochondria reduced a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis. Global transcriptomic analysis by RNA sequencing revealed that a vast number of senescent‐associated changes are dependent on mitochondria, particularly the pro‐inflammatory phenotype. Mechanistically, we show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC‐1β‐dependent mitochondrial biogenesis, contributing to a ROS‐mediated activation of the DDR and cell cycle arrest. Finally, we demonstrate that the reduction in mitochondrial content in vivo, by either mTORC1 inhibition or PGC‐1β deletion, prevents senescence in the ageing mouse liver. Our results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues.
doi:10.15252/embj.201592862
PMCID: PMC4818766  PMID: 26848154
ageing; inflammation; mitochondria; mTOR; senescence; Ageing; Cell Cycle; Metabolism
7.  SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair 
Autophagy  2016;12(10):1917-1930.
ABSTRACT
SQSTM1/p62 (sequestosome 1) selectively targets polyubiquitinated proteins for degradation via macroautophagy and the proteasome. Additionally, SQSTM1 shuttles between the cytoplasmic and nuclear compartments, although its role in the nucleus is relatively unknown. Here, we report that SQSTM1 dynamically associates with DNA damage foci (DDF) and regulates DNA repair. Upon induction of DNA damage SQSTM1 interacts with FLNA (filamin A), which has previously been shown to recruit DNA repair protein RAD51 (RAD51 recombinase) to double-strand breaks and facilitate homologous recombination (HR). SQSTM1 promotes proteasomal degradation of FLNA and RAD51 within the nucleus, resulting in reduced levels of nuclear RAD51 and slower DNA repair. SQSTM1 regulates the ratio between HR and nonhomologous end joining (NHEJ) by promoting the latter at the expense of the former. This SQSTM1-dependent mechanism mediates the effect of macroautophagy on DNA repair. Moreover, nuclear localization of SQSTM1 and its association with DDF increase with aging and are prevented by life-span-extending dietary restriction, suggesting that an imbalance in the mechanism identified here may contribute to aging and age-related diseases.
doi:10.1080/15548627.2016.1210368
PMCID: PMC5391493  PMID: 27391408
aging; autophagy; DNA damage; homologous recombination; nonhomologous end joining; SQSTM1
8.  Mitochondria are required for pro‐ageing features of the senescent phenotype 
The EMBO Journal  2016;35(7):724-742.
Abstract
Cell senescence is an important tumour suppressor mechanism and driver of ageing. Both functions are dependent on the development of the senescent phenotype, which involves an overproduction of pro‐inflammatory and pro‐oxidant signals. However, the exact mechanisms regulating these phenotypes remain poorly understood. Here, we show the critical role of mitochondria in cellular senescence. In multiple models of senescence, absence of mitochondria reduced a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis. Global transcriptomic analysis by RNA sequencing revealed that a vast number of senescent‐associated changes are dependent on mitochondria, particularly the pro‐inflammatory phenotype. Mechanistically, we show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC‐1β‐dependent mitochondrial biogenesis, contributing to a ROS‐mediated activation of the DDR and cell cycle arrest. Finally, we demonstrate that the reduction in mitochondrial content in vivo, by either mTORC1 inhibition or PGC‐1β deletion, prevents senescence in the ageing mouse liver. Our results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues.
doi:10.15252/embj.201592862
PMCID: PMC4818766  PMID: 26848154
ageing; inflammation; mitochondria; mTOR; senescence; Ageing; Cell Cycle; Metabolism
9.  Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity 
eLife  null;5:e11058.
The mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that regulates cellular protein homeostasis, growth, and proliferation in health and disease. As a prerequisite for activation of mTORC1 by hormones and mitogens, there first has to be an available pool of intracellular amino acids. Arginine, an amino acid essential during mammalian embryogenesis and early development is one of the key activators of mTORC1. Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine cooperates with growth factor signaling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling. Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling.
DOI: http://dx.doi.org/10.7554/eLife.11058.001
eLife digest
Cells need to be able to sense and respond to signals from their environment. A group (or complex) of conserved proteins called mTORC1 acts a key signaling hub that regulates cell growth and many other processes. This complex can be activated by many different signals from outside the cell. However, mTORC1 can only be activated by these signals if there is also a good supply of amino acids – which are needed to make new proteins – within the cell.
The amino acids are thought to be presented to mTORC1 on the outer surface of cellular compartments known as lysosomes. A protein called Rheb on the surface of the lysosomes activates mTORC1, while a protein complex called TSC inhibits the activity of Rheb to regulate mTORC1 activity. Previous studies have shown that some amino acids influence whether mTORC1 can be activated by affecting whether it is localized to the lysosomes or not.
Here, Carroll et al. explored how an amino acid called arginine regulates mTORC1. The experiments show that arginine is the major amino acid that influences whether mTORC1 can be activated in several different types of human cell. When cells were deprived of arginine, the activity of the complex was strongly suppressed. However, microscopy showed that arginine had no effect on whether mTORC1 was found at the lysosomes or not, which suggests that arginine might be acting in a different way to other amino acids.
Further experiments found that a lack of arginine led to an increase in the number of TSC complexes at the lysosomes. This led to the inhibition of Rheb and therefore prevented mTORC1 from being activated. Together, Carroll et al.’s findings provide evidence that the different signals that regulate mTORC1 signaling cooperate to a greater extent than previously thought. A future challenge will be to understand the molecular details of how the arginine is detected.
DOI: http://dx.doi.org/10.7554/eLife.11058.002
doi:10.7554/eLife.11058
PMCID: PMC4764560  PMID: 26742086
mTOR; amino acids; autophagy; signal transduction; Human
10.  Dual Proteolytic Pathways Govern Glycolysis and Immune Competence 
Cell  2014;159(7):1578-1590.
SUMMARY
Proteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cells is to maintain amino acid levels, and that TPPII-deficient cells compensate by increasing lysosome number and proteolytic activity. However, the overabundant lysosomes derange cellular metabolism by consuming the key glycolytic enzyme hexokinase-2 through chaperone-mediated autophagy. This reduces glycolysis and impairs the production of effector cytokines including IFN-γ and IL-1β. Thus, TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, which is vital for adaptive and innate immunity and neurodevelopmental health.
doi:10.1016/j.cell.2014.12.001
PMCID: PMC4297473  PMID: 25525876
11.  Impaired autophagy in the lipid storage disorder Niemann–Pick type C1 disease 
Cell reports  2013;5(5):1302-1315.
SUMMARY
Autophagy dysfunction has been implicated in misfolded protein accumulation and cellular toxicity in several diseases. Whether alterations in autophagy also contribute to the pathology of lipid storage disorders is not clear. Here we show defective autophagy in Niemann-Pick type C1 (NPC1) disease associated with cholesterol accumulation, where maturation of autophagosomes is impaired due to defective amphisome formation caused by failure in SNARE machinery, whilst the lysosomal proteolytic function remains unaffected. Expression of functional NPC1 protein rescues this defect. Inhibition of autophagy also causes cholesterol accumulation. Compromised autophagy was seen in disease-affected organs of Npc1 mutant mice. Of potential therapeutic relevance is that HP-β-cyclodextrin, which is used for cholesterol depletion treatment, impedes autophagy, whereas stimulating autophagy restores its function independent of amphisome formation. Our data suggest that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may provide a rational treatment strategy for NPC1 disease.
doi:10.1016/j.celrep.2013.10.042
PMCID: PMC3957429  PMID: 24290752
Autophagy; Niemann-Pick type C1 disease; Cholesterol; Autophagy enhancer; Lipid storage disorder; Lysosomal storage disorder; Neurodegeneration
12.  The TBC/RabGAP Armus Coordinates Rac1 and Rab7 Functions during Autophagy 
Developmental Cell  2013;25(1):15-28.
Summary
Autophagy is an evolutionarily conserved process that enables catabolic and degradative pathways. These pathways commonly depend on vesicular transport controlled by Rabs, small GTPases inactivated by TBC/RabGAPs. The Rac1 effector TBC/RabGAP Armus (TBC1D2A) is known to inhibit Rab7, a key regulator of lysosomal function. However, the precise coordination of signaling and intracellular trafficking that regulates autophagy is poorly understood. We find that overexpression of Armus induces the accumulation of enlarged autophagosomes, while Armus depletion significantly delays autophagic flux. Upon starvation-induced autophagy, Rab7 is transiently activated. This spatiotemporal regulation of Rab7 guanosine triphosphate/guanosine diphosphate cycling occurs by Armus recruitment to autophagosomes via interaction with LC3, a core autophagy regulator. Interestingly, autophagy potently inactivates Rac1. Active Rac1 competes with LC3 for interaction with Armus and thus prevents its appropriate recruitment to autophagosomes. The precise coordination between Rac1 and Rab7 activities during starvation suggests that Armus integrates autophagy with signaling and endocytic trafficking.
Graphical Abstract
Highlights
► Autophagy strongly inactivates Rac1 GTPase and recruits the TBC/RabGAP Armus ► Appropriate Armus localization at autophagosomes requires binding to LC3 ► Armus inhibition delays autophagic flux and increases levels of Rab7·GTP ► Rac1, Armus, and Rab7 coordinate efficient lysosome fusion with autophagosomes
The Rac1 effector Armus is a GTPase-activating protein that regulates Rab7 function and thus endosomal trafficking to lysosomes. Carroll et al. find that Armus binds directly to the core autophagy factor LC3, facilitates fusion of autophagosomes with lysosomes, and integrates local Rac1 activity into the control of autophagy.
doi:10.1016/j.devcel.2013.03.005
PMCID: PMC3898768  PMID: 23562278
13.  Progressive 3q Amplification Consistently Targets SOX2 in Preinvasive Squamous Lung Cancer 
Rationale: Amplification of distal 3q is the most common genomic aberration in squamous lung cancer (SQC). SQC develops in a multistage progression from normal bronchial epithelium through dysplasia to invasive disease. Identifying the key driver events in the early pathogenesis of SQC will facilitate the search for predictive molecular biomarkers and the identification of novel molecular targets for chemoprevention and therapeutic strategies. For technical reasons, previous attempts to analyze 3q amplification in preinvasive lesions have focused on small numbers of predetermined candidate loci rather than an unbiased survey of copy-number variation.
Objectives: To perform a detailed analysis of the 3q amplicon in bronchial dysplasia of different histological grades.
Methods: We use molecular copy-number counting (MCC) to analyze the structure of chromosome 3 in 19 preinvasive bronchial biopsy specimens from 15 patients and sequential biopsy specimens from 3 individuals.
Measurements and Main Results: We demonstrate that no low-grade lesions, but all high-grade lesions, have 3q amplification. None of seven low-grade lesions progressed clinically, whereas 8 of 10 patients with high-grade disease progressed to cancer. We identify a minimum commonly amplified region on chromosome 3 consisting of 17 genes, including 2 known oncogenes, SOX2 and PIK3CA. We confirm that both genes are amplified in all high-grade dysplastic lesions tested. We further demonstrate, in three individuals, that the clinical progression of high-grade preinvasive disease is associated with incremental amplification of SOX2, suggesting this promotes malignant progression.
Conclusions: These findings demonstrate progressive 3q amplification in the evolution of preinvasive SQC and implicate SOX2 as a key target of this dynamic process.
doi:10.1164/rccm.201001-0005OC
PMCID: PMC2902760  PMID: 20299530
bronchial dysplasia; squamous lung cancer; gene amplification; molecular copy-number counting; SOX2
14.  The incidence of malaria in travellers to South-East Asia: is local malaria transmission a useful risk indicator? 
Malaria Journal  2010;9:266.
Background
The presence of ongoing local malaria transmission, identified though local surveillance and reported to regional WHO offices, by S-E Asian countries, forms the basis of national and international chemoprophylaxis recommendations in western countries. The study was designed to examine whether the strategy of using malaria transmission in a local population was an accurate estimate of the malaria threat faced by travellers and a correlate of malaria in returning travellers.
Methods
Malaria endemicity was described from distribution and intensity in the local populations of ten S-E Asian destination countries over the period 2003-2008 from regionally reported cases to WHO offices. Travel acquired malaria was collated from malaria surveillance reports from the USA and 12 European countries over the same period. The numbers of travellers visiting the destination countries was based on immigration and tourism statistics collected on entry of tourists to the destination countries.
Results
In the destination countries, mean malaria rates in endemic countries ranged between 0.01 in Korea to 4:1000 population per year in Lao PDR, with higher regional rates in a number of countries. Malaria cases imported into the 13 countries declined by 47% from 140 cases in 2003 to 66 in 2008. A total of 608 cases (27.3% Plasmodium falciparum (Pf)) were reported over the six years, the largest number acquired in Indonesia, Thailand and Korea. Four countries had an incidence > 1 case per 100,000 traveller visits; Burma (Myanmar), Indonesia, Cambodia and Laos (range 1 to 11.8-case per 100,000 visits). The remaining six countries rates were < 1 case per 100,000 visits. The number of visitors arriving from source countries increased by 60% from 8.5 Million to 13.6 million over the 6 years.
Conclusion
The intensity of malaria transmission particularly sub-national activity did not correlate with the risk of travellers acquiring malaria in the large numbers of arriving visitors. It is proposed to use a threshold incidence of > 1 case per 100,000 visits to consider targeted malaria prophylaxis recommendations to minimize use of chemoprophylaxis for low risk exposure during visits to S-E Asia. Policy needs to be adjusted regularly to reflect the changing risk.
doi:10.1186/1475-2875-9-266
PMCID: PMC2959067  PMID: 20920352
15.  Declining incidence of malaria imported into the UK from West Africa 
Malaria Journal  2008;7:235.
Background
Two thirds of all falciparum malaria cases reported in the United Kingdom (UK) are acquired in West Africa (WA). To ensure recommendations and guidelines for malaria prophylaxis in travellers to West Africa correlate to the risk of infection, a study was undertaken to examine recent trends and predict future patterns of imported malaria acquired by UK residents visiting West Africa and West African visitors to the UK between 1993 and 2006.
Methods and Results
Using passenger numbers and malaria surveillance reports, the data revealed a 2.3-fold increase in travel to West Africa with a five-fold increase in travelers visiting friends and relatives (VFR). Malaria incidence fell through the study period, the greatest decline noted in VFR with a fall from 196 cases/1,000 person-years to 52 cases/1,000 person-years, 9.8% per year p < 0.0001. The risk for travellers from the UK visiting for other reasons declined 2.7 fold, at an annual decrease of 7.0%, with the incidence in West African visitors to the UK falling by 2.3 fold, a rate of 7.9% annually.
Discussion
The reduction in incidence among all three groups of travellers may be explained by several factors; changing chemoprophylaxis usage and/or increased travel in urban areas where malaria risk has declined over the past decade, or widespread reduction in malaria transmission in West Africa.
Conclusion
With the reduction in malaria incidence seen in both visitors to and from West Africa, the most rational explanation for these findings is a fall in malaria transmission in West Africa, which may require a change in chemoprophylaxis policy for UK travelers over the next 5–10 years.
doi:10.1186/1475-2875-7-235
PMCID: PMC2613412  PMID: 19000299
16.  The low and declining risk of malaria in travellers to Latin America: is there still an indication for chemoprophylaxis? 
Malaria Journal  2007;6:114.
A comparison was made between local malaria transmission and malaria imported by travellers to identify the utility of national and regional annual parasite index (API) in predicting malaria risk and its value in generating recommendations on malaria prophylaxis for travellers.
Regional malaria transmission data was correlated with malaria acquired in Latin America and imported into the USA and nine European countries. Between 2000 and 2004, most countries reported declining malaria transmission. Highest API's in 2003/4 were in Surinam (287.4) Guyana (209.2) and French Guiana (147.4). The major source of travel associated malaria was Honduras, French Guiana, Guatemala, Mexico and Ecuador. During 2004 there were 6.3 million visits from the ten study countries and in 2005, 209 cases of malaria of which 22 (11%) were Plasmodium falciparum. The risk of adverse events are high and the benefit of avoided benign vivax malaria is very low under current policy, which may be causing more harm than benefit.
doi:10.1186/1475-2875-6-114
PMCID: PMC2020466  PMID: 17716367
17.  Cell migration leads to spatially distinct but clonally related airway cancer precursors 
Thorax  2014;69(6):548-557.
Background
Squamous cell carcinoma of the lung is a common cancer with 95% mortality at 5 years. These cancers arise from preinvasive lesions, which have a natural history of development progressing through increasing severity of dysplasia to carcinoma in situ (CIS), and in some cases, ending in transformation to invasive carcinoma. Synchronous preinvasive lesions identified at autopsy have been previously shown to be clonally related.
Methods
Using autofluorescence bronchoscopy that allows visual observation of preinvasive lesions within the upper airways, together with molecular profiling of biopsies using gene sequencing and loss-of-heterozygosity analysis from both preinvasive lesions and from intervening normal tissue, we have monitored individual lesions longitudinally and documented their visual, histological and molecular relationship.
Results
We demonstrate that rather than forming a contiguous field of abnormal tissue, clonal CIS lesions can develop at multiple anatomically discrete sites over time. Further, we demonstrate that patients with CIS in the trachea have invariably had previous lesions that have migrated proximally, and in one case, into the other lung over a period of 12 years.
Conclusions
Molecular information from these unique biopsies provides for the first time evidence that field cancerisation of the upper airways can occur through cell migration rather than via local contiguous cellular expansion as previously thought. Our findings urge a clinical strategy of ablating high-grade premalignant airway lesions with subsequent attentive surveillance for recurrence in the bronchial tree.
doi:10.1136/thoraxjnl-2013-204198
PMCID: PMC4033139  PMID: 24550057
Lung Cancer; Airway Epithelium
18.  LRIG1 regulates cadherin-dependent contact inhibition directing epithelial homeostasis and pre-invasive squamous cell carcinoma development 
The Journal of Pathology  2013;229(4):608-620.
Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine-rich immunoglobulin repeats-1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re-expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E-cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition.
doi:10.1002/path.4148
PMCID: PMC3806036  PMID: 23208928
EGFR; LRIG1; squamous cell carcinoma; lung cancer; pre-invasive; E-cadherin; cell-cell contact

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