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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.  Differences of protein expression profiles, KRAS and BRAF mutation, and prognosis in right-sided colon, left-sided colon and rectal cancer 
Scientific Reports  2017;7:7882.
To compare protein expression levels, gene mutation and survival among Right-Sided Colon Cancer (RSCC), Left-Sided Colon Cancer (LSCC) and rectal cancer patients, 57 cases of RSCC, 87 LSCC and 145 rectal cancer patients were included retrospectively. Our results demonstrated significant differences existed among RSCC, LSCC and rectal cancer regarding tumor diameter, differentiation, invasion depth and TNM stage. No significant difference was identified in expression levels of MLH1, MSH2, MSH6, PMS2, β-Tubulin III, P53, Ki67 and TOPIIα, and gene mutation of KRAS and BRAF among three groups. Progression Free Survival (PFS) of RSCC was significantly lower than that of LRCC and rectal cancer. In univariate analyses, RSCC, preoperative chemoradiotherapy, poor differentiation, advanced TNM stage, elevated serum CEA and CA19-9 level, tumor deposit, perineural and vascular invasion were found to be predictive factors of shorter PFS. In multivariate analyses, only differentiation and TNM stages were found to be independent predictors of PFS. In conclusion, compared with LSCC and rectal cancer, RSCC has larger tumor size, poor differentiation, advanced TNM stage and shorter survival. The shorter survival in RSCC might be attributed to the advanced tumor stage caused by its inherent position feature of proximal colon rather than genetic difference.
doi:10.1038/s41598-017-08413-z
PMCID: PMC5554205  PMID: 28801584
2.  World Congress Integrative Medicine & Health 2017: Part one 
Brinkhaus, Benno | Falkenberg, Torkel | Haramati, Aviad | Willich, Stefan N. | Briggs, Josephine P. | Willcox, Merlin | Linde, Klaus | Theorell, Töres | Wong, Lisa M. | Dusek, Jeffrey | Wu, Darong | Eisenberg, David | Haramati, Aviad | Berger, Bettina | Kemper, Kathi | Stock-Schröer, Beate | Sützl-Klein, Hedda | Ferreri, Rosaria | Kaplan, Gary | Matthes, Harald | Rotter, Gabriele | Schiff, Elad | Arnon, Zahi | Hahn, Eckhard | Luberto, Christina M. | Martin, David | Schwarz, Silke | Tauschel, Diethard | Flower, Andrew | Gramminger, Harsha | Gupta, Hedwig H. | Gupta, S. N. | Kerckhoff, Annette | Kessler, Christian S. | Michalsen, Andreas | Kessler, Christian S. | Kim, Eun S. | Jang, Eun H. | Kim, Rana | Jan, Sae B. | Mittwede, Martin | Mohme, Wiebke | Ben-Arye, Eran | Bonucci, Massimo | Saad, Bashar | Breitkreuz, Thomas | Rossi, Elio | Kebudi, Rejin | Daher, Michel | Razaq, Samaher | Gafer, Nahla | Nimri, Omar | Hablas, Mohamed | Kienle, Gunver Sophia | Samuels, Noah | Silbermann, Michael | Bandelin, Lena | Lang, Anna-Lena | Wartner, Eva | Holtermann, Christoph | Binstock, Maxwell | Riebau, Robert | Mujkanovic, Edin | Cramer, Holger | Lauche, Romy | Michalsen, Andres | Ward, Lesley | Cramer, Holger | Irnich, Dominik | Stör, Wolfram | Burnstock, Geoffrey | Schaible, Hans-Georg | Ots, Thomas | Langhorst, Jost | Lauche, Romy | Sundberg, Tobias | Falkenberg, Torkel | Amarell, Catherina | Amarell, Catherina | Anheyer, Melanie | Eckert, Marion | Eckert, Marion | Ogal, Mercedes | Eckert, Marion | Amarell, Catherina | Schönauer, Annette | Reisenberger, Birgit | Brand, Bernhard | Anheyer, Dennis | Dobos, Gustav | Kroez, Matthias | Martin, David | Matthes, Harald | Ammendola, Aldo | Mao, Jun J. | Witt, Claudia | Yang, Yufei | Dobos, Gustav | Oritz, Miriam | Horneber, Markus | Voiß, Petra | Reisenberger, Birgit | von Rosenstiel, Alexandra | Eckert, Marion | Ogal, Mercedes | Amarell, Catharina | Anheyer, Melanie | Schad, Friedemann | Schläppi, Marc | Kröz, Matthias | Büssing, Arndt | Bar-Sela, Gil | Matthes, Harald | Schiff, Elad | Ben-Arye, Eran | Arnon, Zahi | Avshalomov, David | Attias, Samuel | Schönauer, Annette | Haramati, Aviad | Witt, Claudia | Brinkhaus, Benno | Cotton, Sian | Jong, Miek | Jong, Mats | Scheffer, Christian | Haramati, Aviad | Tauschel, Diethard | Edelhäuser, Friedrich | AlBedah, Abdullah | Lee, Myeong Soo | Khalil, Mohamed | Ogawa, Keiko | Motoo, Yoshiharu | Arimitsu, Junsuke | Ogawa, Masao | Shimizu, Genki | Stange, Rainer | Kraft, Karin | Kuchta, Kenny | Watanabe, Kenji | Bonin, D | Büssing, Arndt | Gruber, Harald | Koch, Sabine | Gruber, Harald | Pohlmann, Urs | Caldwell, Christine | Krantz, Barbara | Kortum, Ria | Martin, Lily | Wieland, Lisa S. | Kligler, Ben | Gould-Fogerite, Susan | Zhang, Yuqing | Wieland, Lisa S. | Riva, John J. | Lumpkin, Michael | Ratner, Emily | Ping, Liu | Jian, Pei | Hamme, Gesa-Meyer | Mao, Xiaosong | Chouping, Han | Schröder, Sven | Hummelsberger, Josef | Wullinger, Michael | Brodzky, Marc | Zalpour, Christoff | Langley, Julia | Weber, Wendy | Mudd, Lanay M. | Wayne, Peter | Witt, Clauda | Weidenhammer, Wolfgang | Fønnebø, Vinjar | Boon, Heather | Steel, Amie | Bugarcic, Andrea | Rangitakatu, Melisa | Steel, Amie | Adams, Jon | Sibbritt, David | Wardle, Jon | Leach, Matthew | Schloss, Janet | Dieze, Helene | Boon, Heather | Ijaz, Nadine | Willcox, Merlin | Heinrich, Michael | Lewith, George | Flower, Andrew | Graz, Bertrand | Adam, Daniela | Grabenhenrich, Linus | Ortiz, Miriam | Binting, Sylvia | Reinhold, Thomas | Brinkhaus, Benno | Andermo, Susanne | Sundberg, Tobias | Falkenberg, Torkel | Nordberg, Johanna Hök | Arman, Maria | Bhasin, Manoj | Fan, Xueyi | Libermann, Towia | Fricchione, Gregory | Denninger, John | Benson, Herbert | Berger, Bettina | Stange, Rainer | Michalsen, Andreas | Martin, David D. | Boers, Inge | Vlieger, Arine | Jong, Miek | Brinkhaus, Benno | Teut, Michael | Ullmann, Alexander | Ortiz, Miriam | Rotter, Gabriele | Binting, Sylvia | Lotz, Fabian | Roll, Stephanie | Canella, Claudia | Mikolasek, Michael | Rostock, Matthias | Beyer, Jörg | Guckenberger, Matthias | Jenewein, Josef | Linka, Esther | Six, Claudia | Stoll, Sarah | Stupp, Roger | Witt, Claudia M. | Chuang, Elisabeth | Kligler, Ben | McKee, Melissa D. | Cramer, Holger | Lauche, Romy | Klose, Petra | Lange, Silke | Langhorst, Jost | Dobos, Gustav | Chung, Vincent C. H. | Wong, Hoi L. C. | Wu, Xin Y. | Wen, Grace Y. G. | Ho, Robin S. T. | Ching, Jessica Y. L. | Wu, Justin C. Y. | Coakley, Amanda | Flanagan, Jane | Annese, Christine | Empoliti, Joanne | Gao, Zishan | Liu, Xugang | Yu, Shuguang | Yan, Xianzhong | Liang, Fanrong | Hohmann, Christoph D. | Steckhan, Nico | Ostermann, Thomas | Paetow, Arion | Hoff, Evelyn | Michalsen, Andreas | Hu, Xiao-Yang | Wu, Ruo-Han | Logue, Martin | Blonde, Clara | Lai, Lily Y. | Stuart, Beth | Flower, Andrew | Fei, Yu-Tong | Moore, Michael | Liu, Jian-Ping | Lewith, George | Hu, Xiao-Yang | Wu, Ruo-Han | Logue, Martin | Blonde, Clara | Lai, Lily Y. | Stuart, Beth | Flower, Andrew | Fei, Yu-Tong | Moore, Michael | Liu, Jian-Ping | Lewith, George | Jeitler, Michael | Zillgen, Hannah | Högl, Manuel | Steckhan, Nico | Stöckigt, Barbara | Seifert, Georg | Michalsen, Andreas | Kessler, Christian | Khadivzadeh, Talat | Bashtian, Maryam Hassanzadeh | Aval, Shapour Badiee | Esmaily, Habibollah | Kim, Jihye | Kim, Keun H. | Klocke, Carina | Joos, Stefanie | Koshak, Abdulrahman | Wie, Li | Koshak, Emad | Wali, Siraj | Alamoudi, Omer | Demerdash, Abdulrahman | Qutub, Majdy | Pushparaj, Peter | Heinrich, Michael | Kruse, Sigrid | Fischer, Isabell | Tremel, Nadine | Rosenecker, Joseph | Leung, Brenda | Takeda, Wendy | Liang, Ning | Feng, Xue | Liu, Jian-ping | Cao, Hui-juan | Luberto, Christina M. | Shinday, Nina | Philpotts, Lisa | Park, Elyse | Fricchione, Gregory L. | Yeh, Gloria | Munk, Niki | Zakeresfahani, Arash | Foote, Trevor R. | Ralston, Rick | Boulanger, Karen | Özbe, Dominik | Gräßel, Elmar | Luttenberger, Katharina | Pendergrass, Anna | Pach, Daniel | Bellmann-Strobl, Judit | Chang, Yinhui | Pasura, Laura | Liu, Bin | Jäger, Sven F. | Loerch, Ronny | Jin, Li | Brinkhaus, Benno | Ortiz, Miriam | Reinhold, Thomas | Roll, Stephanie | Binting, Sylvia | Icke, Katja | Shi, Xuemin | Paul, Friedemann | Witt, Claudia M. | Rütz, Michaela | Lynen, Andreas | Schömitz, Meike | Vahle, Maik | Salomon, Nir | Lang, Alon | Lahat, Adi | Kopylov, Uri | Ben-Horin, Shomron | Har-Noi, Ofir | Avidan, Benjamin | Elyakim, Rami | Gamus, Dorit | NG, Siew | Chang, Jessica | Wu, Justin | Kaimiklotis, John | Schumann, Dania | Buttó, Ludovica | Langhorst, Jost | Dobos, Gustav | Haller, Dirk | Cramer, Holger | Smith, Caroline | de Lacey, Sheryl | Chapman, Michael | Ratcliffe, Julie | Johnson, Neil | Lyttleton, Jane | Boothroyd, Clare | Fahey, Paul | Tjaden, Bram | van Vliet, Marja | van Wietmarschen, Herman | Jong, Miek | Tröger, Wilfried | Vuolanto, Pia | Aarva, Paulina | Sorsa, Minna | Helin, Kaija | Wenzel, Claudia | Zoderer, Iris | Pammer, Patricia | Simon, Patrick | Tucek, Gerhard | Wode, Kathrin | Henriksson, Roger | Sharp, Lena | Stoltenberg, Anna | Nordberg, Johanna Hök | Xiao-ying, Yang | Wang, Li-qiong | Li, Jin-gen | Liang, Ning | Wang, Ying | Liu, Jian-ping | Balneaves, Lynda | Capler, Rielle | Bocci, Chiara | Guffi, Marta | Paolini, Marina | Meaglia, Ilaria | Porcu, Patrizia | Ivaldi, Giovanni B. | Dragan, Simona | Bucuras, Petru | Pah, Ana M. | Badalica-Petrescu, Marius | Buleu, Florina | Hogea-Stoichescu, Gheorghe | Christodorescu, Ruxandra | Kao, Lan | Cho, Yumin | Klafke, Nadja | Mahler, Cornelia | von Hagens, Cornelia | Uhlmann, Lorenz | Bentner, Martina | Schneeweiss, Andreas | Mueller, Andreas | Szecsenyi, Joachim | Joos, Stefanie | Neri, Isabella | Ortiz, Miriam | Schnabel, Katharina | Teut, Michael | Rotter, Gabriele | Binting, Sylvia | Cree, Margit | Lotz, Fabian | Suhr, Ralf | Brinkhaus, Benno | Rossi, Elio | Baccetti, Sonia | Firenzuoli, Fabio | Monechi, Maria V. | Di Stefano, Mariella | Amunni, Gianni | Wong, Wendy | Chen, Bingzhong | Wu, Justin | Amri, Hakima | Haramati, Aviad | Kotlyanskaya, Lucy | Anderson, Belinda | Evans, Roni | Kligler, Ben | Marantz, Paul | Bradley, Ryan | Booth-LaForce, Cathryn | Zwickey, Heather | Kligler, Benjamin | Brooks, Audrey | Kreitzer, Mary J. | Lebensohn, Patricia | Goldblatt, Elisabeth | Esmel-Esmel, Neus | Jiménez-Herrera, Maria | Ijaz, Nadine | Boon, Heather | Jocham, Alexandra | Stock-Schröer, Beate | Berberat, Pascal O. | Schneider, Antonius | Linde, Klaus | Masetti, Morgana | Murakozy, Henriette | Van Vliet, Marja | Jong, Mats | Jong, Miek | Agdal, Rita | Atarzadeh, Fatemeh | Jaladat, Amir M. | Hoseini, Leila | Amini, Fatemeh | Bai, Chen | Liu, Tiegang | Zheng, Zian | Wan, Yuxiang | Xu, Jingnan | Wang, Xuan | Yu, He | Gu, Xiaohong | Daneshfard, Babak | Nimrouzi, Majid | Tafazoli, Vahid | Alorizi, Seyed M. Emami | Saghebi, Seyed A. | Fattahi, Mohammad R. | Salehi, Alireza | Rezaeizadeh, Hossein | Zarshenas, Mohammad M. | Nimrouzi, Majid | Fox, Kealoha | Hughes, John | Kostanjsek, Nenad | Espinosa, Stéphane | Lewith, George | Fisher, Peter | Latif, Abdul | Lefeber, Donald | Paske, William | Öztürk, Ali Ö. | Öztürk, Gizemnur | Boers, Inge | Tissing, Wim | Naafs, Marianne | Busch, Martine | Jong, Miek | Daneshfard, Babak | Sanaye, Mohammad R. | Dräger, Kilian | Fisher, Peter | Kreitzer, Mary J. | Evans, Roni | Leininger, Brent | Shafto, Kate | Breen, Jenny | Sanaye, Mohammad R. | Daneshfard, Babak | Simões-Wüst, Ana P. | Moltó-Puigmartí, Carolina | van Dongen, Martien | Dagnelie, Pieter | Thijs, Carel | White, Shelley | Wiesener, Solveig | Salamonsen, Anita | Stub, Trine | Fønnebø, Vinjar | Abanades, Sergio | Blanco, Mar | Masllorens, Laia | Sala, Roser | Al-Ahnoumy, Shafekah | Han, Dongwoon | He, Luzhu | Kim, Ha Yun | In Choi, Da | Alræk, Terje | Stub, Trine | Kristoffersen, Agnete | von Sceidt, Christel | Michalsen, Andreas | Bruset, Stig | Musial, Frauke | Anheyer, Dennis | Cramer, Holger | Lauche, Romy | Saha, Felix J. | Dobos, Gustav | Anheyer, Dennis | Haller, Heidemarie | Lauche, Romy | Dobos, Gustav | Cramer, Holger | Azizi, Hoda | Khadem, Nayereh | Hassanzadeh, Malihe | Estiri, Nazanin | Azizi, Hamideh | Tavassoli, Fatemeh | Lotfalizadeh, Marzieh | Zabihi, Reza | Esmaily, Habibollah | Azizi, Hoda | Shabestari, Mahmoud Mohammadzadeh | Paeizi, Reza | Azari, Masoumeh Alvandi | Bahrami-Taghanaki, Hamidreza | Zabihi, Reza | Azizi, Hamideh | Esmaily, Habibollah | Baars, Erik | De Bruin, Anja | Ponstein, Anne | Baccetti, Sonia | Di Stefano, Mariella | Rossi, Elio | Firenzuoli, Fabio | Segantini, Sergio | Monechi, Maria Valeria | Voller, Fabio | Barth, Jürgen | Kern, Alexandra | Lüthi, Sebastian | Witt, Claudia | Barth, Jürgen | Zieger, Anja | Otto, Fabius | Witt, Claudia | Beccia, Ariel | Dunlap, Corina | Courneene, Brendan | Bedregal, Paula | Passi, Alvaro | Rodríguez, Alfredo | Chang, Mayling | Gutiérrez, Soledad | Beissner, Florian | Beissner, Florian | Preibisch, Christine | Schweizer-Arau, Annemarie | Popovici, Roxana | Meissner, Karin | Beljanski, Sylvie | Belland, Laura | Rivera-Reyes, Laura | Hwang, Ula | Berger, Bettina | Sethe, Dominik | Hilgard, Dörte | Heusser, Peter | Bishop, Felicity | Al-Abbadey, Miznah | Bradbury, Katherine | Carnes, Dawn | Dimitrov, Borislav | Fawkes, Carol | Foster, Jo | MacPherson, Hugh | Roberts, Lisa | Yardley, Lucy | Lewith, George | Bishop, Felicity | Al-Abbadey, Miznah | Bradbury, Katherine | Carnes, Dawn | Dimitrov, Borislav | Fawkes, Carol | Foster, Jo | MacPherson, Hugh | Roberts, Lisa | Yardley, Lucy | Lewith, George | Bishop, Felicity | Holmes, Michelle | Lewith, George | Yardley, Lucy | Little, Paul | Cooper, Cyrus | Bogani, Patrizia | Maggini, Valentina | Gallo, Eugenia | Miceli, Elisangela | Biffi, Sauro | Mengoni, Alessio | Fani, Renato | Firenzuoli, Fabio | Brands-Guendling, Nadine | Guendling, Peter W. | Bronfort, Gert | Evans, Roni | Haas, Mitch | Leininger, Brent | Schulz, Craig | Bu, Xiangwei | Wang, J. | Fang, T. | Shen, Z. | He, Y. | Zhang, X. | Zhang, Zhengju | Wang, Dali | Meng, Fengxian | Büssing, Arndt | Baumann, Klaus | Frick, Eckhard | Jacobs, Christoph | Büssing, Arndt | Grünther, Ralph-Achim | Lötzke, Désirée | Büssing, Arndt | Jung, Sonny | Lötzke, Désirée | Recchia, Daniela R. | Robens, Sibylle | Ostermann, Thomas | Berger, Bettina | Stankewitz, Josephin | Kröz, Matthias | Jeitler, Mika | Kessler, Christian | Michalsen, Andreas | Cheon, Chunhoo | Jang, Bo H. | Ko, Seong G. | Huang, Ching W. | Sasaki, Yui | Ko, Youme | Cheshire, Anna | Ridge, Damien | Hughes, John | Peters, David | Panagioti, Maria | Simon, Chantal | Lewith, George | Cho, Hyun J. | Han, Dongwoon | Choi, Soo J. | Jung, Young S. | Im, Hyea B | Cooley, Kieran | Tummon-Simmons, Laura | Cotton, Sian | Luberto, Christina M. | Wasson, Rachel | Kraemer, Kristen | Sears, Richard | Hueber, Carly | Derk, Gwendolyn | Lill, JR | An, Ruopeng | Steinberg, Lois | Rodriguez, Lourdes Diaz | la Fuente, Francisca García-de | De la Vega, Miguel | Vargas-Román, Keyla | Fernández-Ruiz, Jonatan | Cantarero-Villanueva, Irene | Rodriguez, Lourdes Diaz | García-De la Fuente, Francisca | Jiménez-Guerrero, Fanny | Vargas-Román, Keyla | Fernández-Ruiz, Jonatan | Galiano-Castillo, Noelia | Diaz-Saez, Gualberto | Torres-Jimenez, José I. | Garcia-Gomez, Olga | Hortal-Muñoz, Luis | Diaz-Diez, Camino | Dicen, Demijon | Diezel, Helene | Adams, Jon | Steel, Amie | Wardle, Jon | Diezel, Helene | Steel, Amie | Frawley, Jane | Wardle, Jon | Broom, Alex | Adams, Jon | Dong, Fei | Yu, He | Liu, Tiegang | Ma, Xueyan | Yan, Liyi | Wan, Yuxiang | Zheng, Zian | Gu, Xiaohong | Dong, Fei | Yu, He | Wu, Liqun | Liu, Tiegang | Ma, Xueyan | Ma, Jiaju | Yan, Liyi | Wan, Yuxiang | Zheng, Zian | Zhen, Jianhua | Gu, Xiaohong | Dubois, Julie | Rodondi, Pierre-Yves | Edelhäuser, Friedrich | Schwartze, Sophia | Trapp, Barbara | Cysarz, Dirk
doi:10.1186/s12906-017-1782-4
PMCID: PMC5498855
3.  World Congress Integrative Medicine & Health 2017: part three 
Ortiz, Miriam | Schnabel, Katharina | Teut, Michael | Rotter, Gabriele | Binting, Sylvia | Cree, Margit | Lotz, Fabian | Suhr, Ralf | Brinkhaus, Benno | Parvizi, Mohammad M. | Handjani, Farhad | Zarshenas, Mohammad M. | Moein, Mahmood R. | Nimrouzi, Majid | Hatam, Gholamreza | Hasanzadeh, Jafar | Hamidizadeh, Nasrin | Parvizi, Mohammad M. | Heydari, Mojtaba | Namazi, Mohammad R. | Parvizi, Zahra | Pasalar, Mehdi | Mosaffa-Jahromi, Maryam | Bagheri-Lankarani, Kamran | Afsharypuor, Suleiman | Tamaddon, Ali M. | Ostovar, Mohadeseh | Peloni, Giuseppe | Bolliger, Ingo | Faria, Rui M. Da Cunha | Quadri, Pierluigi | Sanzeni, Wilma | Zemp, Damiano | Risvoll, Hilde | Giverhaug, Trude | Halvorsen, Kjell H. | Waaseth, Marit | Musial, Frauke | Rossi, Elio | Baccetti, Sonia | Picchi, Marco | Conti, Tommaso | Firenzuoli, Fabio | Guido, Carmelo | Bosco, Filippo | Guido, Carmelo | Rossi, Elio | Panozzo, Marialessandra | Picchi, Marco | Cervino, Chiara | Nurra, Linda | Rossi, Elio | Picchi, Marco | Firenzuoli, Fabio | Traversi, Antonella | Vuono, Katia | Sabatini, Federica | Bellandi, Tommaso | Rutert, Britta | Eggert, Angelika | Seifert, Georg | Stritter, Wiebke | Holmberg, Christine | Längler, Alfred | Salamonsen, Anita | Wiesener, Solveig | Schad, Friedemann | Steele, Megan | Kröz, Matthias | Matthes, Harald | Herbstreit, Cornelia | Thronicke, Anja | Schlingensiepen, Irene | von Schoen-Angerer, Tido | Schneider, Romy | Waeber, Livia | Vagedes, Jan | Kaczala, Gregor | Pharisa, Cosette | Wildhaber, Johannes | Huber, Benedikt | Sidorov, Pavel | Sovershaeva, Evgeniya | Simões-Wüst, Ana P. | Nietlispach, Anna | Mennet, Mónica | Schnelle, Martin | von Mandach, Ursula | Wang, Xia | Woo, Hye L. | Lee, Jin M. | Wu, Yuhao | Cho, Yumin | Yun, Younghee | Kim, Hyunho | Jung, Wonmo | Jang, Bo-Hyung | Ziea, Eric | Hui, Henny | Li, Mia | Tsui, Dora | Lam, Christine | Hsieh, Joyce | Chan, Edith | Balneaves, Lynda | Burnside, Sandra | Doyle, Ethel | Dorazio, Shelley | Chan, Pak K. | Bhagra, Anjali | Chen, Po-Hsu | Chung, Vincent C. H. | Wu, Justin C. Y. | Lin, Zhi X. | Wong, Wendy | Wu, Xin Y. | Ho, Robin S. T. | Wong, Charlene H. L. | Chan, Lily | Ziea, Eric T. C. | Elder, William | Cardarelli, Roberto | Kaspar, Cornelia | Kempenich, Robert | Kopferschmitt, Jacques | Marinko, Zulj | Damir, Sebo | Vcev, Aleksandar | Monezi, Ricardo | Ruggerini, Eny Márcia | Fuchigami, Ivna M. | Mazini, Ana C. Moreno | Monezi, Ricardo | Oliveira, Maria Waldenez | Papuga, Petar | Schloss, Janet | Steel, Amie | Jacobsen, Márcia da Silva | Monezi, Ricardo | Jacobsen, Miranda Rodrigo | Mangini, Maria T. | Trapani, Gianfranco | Di Giampietro, Tiziana | Zanino, Luisella | Ciullo, Luigi | Lanaro, Diego | Cerritelli, Francesco | Macrì, Francesco | Tsai, Andre | Lin, Chin | Wu, Tu-Hsing | D’Alessandro, Eduardo | Watts, Sam | Zhang, Ying | Wu, Xufang | Li, Xun | Fei, Yutong | Liu, Jianping | Zhao, Nanqi | Jia, Liyan | Yan, Xiaoyi | Zhen, Fei | Liu, Zhaolan | Liu, Jianping | Ahn, Jinhyang | Yun, Younghee | AlEidi, Sulaiman | Mohamed, Ashry Gad | Al-Beda, Abdullah M. | Abutalib, Raid A. | Khalil, Mohemmed K. M. | Amri, Hakima | Badekila, Sathyanarayana | Behmanesh, Elham | Mozaffarpour, Seyyedali | Behmanesh, Elham | Mozaffarpour, Seyyedali | Behmanesh, Elham | Shirooye, Pantea | Meybodi, Razie N. | Mokaberinejad, Roshanak | Tansaz, Mojgan | Mozaffarpour, Seyyedali | Chung, Vincent C. H. | Wu, Xin Y. | Wu, Justin C. Y. | Daneshfard, Babak | Hosseinkhani, Ayda | Tafazoli, Vahid | Jaladat, Amir M. | Jaladat, Amir M. | Sadeghi, Hasan | Jia, Liyan | Zhao, Nanqi | Yan, Xiaoyi | Zhou, Li | Zhao, Meng | Li, Weiwei | Liu, Jianping | Liu, Zhaolan | Jia, Liyan | Zhao, Nanqi | Yan, Xiaoyi | Zhou, Li | Zhao, Meng | Li, Weiwei | Liu, Jianping | Liu, Zhaolan | Larsen, Anette L. | Salamonsen, Anita | Kristoffersen, Agnete E. | Hamran, Torunn | Evjen, Bjørg | Stub, Trine | Li, Meiling | Cai, Jianxiong | Lu, Taoying | Yin, Lingjia | Wu, Darong | Wang, Lixin | Liew, Siaw M. | Liu, Tiegang | Bai, Chen | Zheng, Zian | Wan, Yuxiang | Xu, Jingnan | Wang, Xuan | Yu, He | Gu, Xiaohong | Liu, Zhaolan | Yan, Xiaoyi | Jia, Liyan | Zhao, Nanqi | Yang, Guoyan | Liu, Jianping | Mozaffarpour, Seyyedali | Behmanesh, Elham | Nimrouzi, Majid | Tafazoli, Vahid | Daneshfard, Babak | Ostrowski, Deja | Fox, Kealoha | Pasalar, Mehdi | Tabatabei, Fatemeh | Amini, Fatemeh | Sathasivampillai, Saravanan | Rajamanoharan, Pholtan | Munday, Michael | Heinrich, Michael | Scherrer, Yvonne M. | Heinrich, Michael | Szuter, Carolyn | Amini, Fatemeh | Tabatabaei, Fatemeh | Tavakoli, Ali | Tavakoli, Fatemeh | Pasalar, Mehdi | rostami, Mahsa | Torri, Maria C. | Szuter, Carolyn | Walach, Harald | Warner, Faith | Majumdar, Anne | Serasingh, Palitha | Yan, Xiaoyi | Jia, Liyan | Zhao, Nanqi | Liu, Zhaolan | Liu, Jianping | Zhao, Nanqi | Zhen, Fei | Jia, Liyan | Yan, Xiaoyi | Liu, Zhaolan | Liu, Jianping | Abbing, Annemarie | Ponstein, Anne | Baars, Erik | Croke, Sarah | Hanser, Suzanne | Heckel, Viola | Krüerke, Daniel | Simões-Wüst, Ana P. | Weiss, Sebastian | Metzner, Susanne | Lee, Jang W. | Hyun, Min K. | Masetti, Morgana | Oepen, Renate | Gruber, Harald | Heusser, Peter | Pelz, Holger | Perlitz, Volker | Ponstein, Anne | Abbing, Annemarie | Baars, Erik | Robinson, Nicola | Ronan, Patricia | Mian, Awais | Madge, Su | Lorenc, Ava | Agent, Penny | Carr, Siobhan | Ronan, Patricia | Robinson, Nicola | Carr, Siobhan | Mian, Awais | Lorenc, Ava | Agent, Penny | Madge, Su | Winnubst, Monica E. | Monezi, Ricardo | Abolghasemi, Jafar | Heydari, Mojtaba | Baccetti, Sonia | Rossi, Elio | Fedi, Paolo | Di Stefano, Mariella | Belvedere, Katia | Baccetti, Sonia | Rossi, Elio | Firenzuoli, Fabio | Di Stefano, Mariella | Belvedere, Katia | Beaven, Katherine | Rose, Anita | Florschutz, Gerhard | Phil, Nicola Brough | Parsons, Helen | Stewart-Brown, Sarah | Burke, Katherine | Busch, Martine | Heyning, Fenna | Smit, Jan | Jeekel, Hans | de Goeij, Hans | Guido, Paulo Caceres | Barraza, Norma | Balbarrey, Ziomara | Ribas, Alejandra | Jimenez, Beatriz | Iachino, Claudia | Quattrone, Fabiana | Gaioli, Marisa | Dell’Orso, Marta | Villanueva, Silvia | Rocha, Carmen | Macchi, Adriana | Cai, Jianxiong | Chen, Lina | Wu, Darong | Wang, Sicheng | Choi, Eunji | Go, Namgyeong | Lee, Yongho | Dahal, Gokarna | Frauenknecht, Xaver | Gerhardt, Heike | Galanti, Mónica | Cerda, Carmen J. | Galanti, Mónica | Galanti, Mónica | Heckersdorf, Daniela Navarrete | Jorquera, Héctor | Saldivia, María L. Alcázar | Jakubonienė, Daiva | McEwen, Bradley | Melo, Francislete | Fontana, Fernanda Mulinari | Valle, Ana C. Viana | Neres, Maria T. Borges | Mohagheghzadeh, Abolali | Zohalinezhad, Mohammad E. | Njaradi, Olja | Dunjic, Momir | Njaradi, Olja | Dunjic, Momir | Ostrowski, Deja | Fox, Kealoha | Pokladnikova, Jitka | Selke-Krulichova, Iva | Seo, Jinsoon | Jang, Hyunchul | Simões-Wüst, Ana P. | Moltó-Puigmartí, Carolina | van Dongen, Martien | Dagnelie, Pieter | Thijs, Carel | Tihanyi, Eva | Hegyi, Gabriella | Zhang, Ying | Li, Xun | Fei, Yutong | Liu, Jianping | Zhang, Ying | Liu, Jianping | Tong, Xiaolin
doi:10.1186/s12906-017-1784-2
PMCID: PMC5499100
4.  Chemistry with semi-classical electrons: reaction trajectories auto-generated by sub-atomistic force fields 
Chemical Science  2017;8(6):4203-4210.
Suitable force fields animate “Lewis-dots” with sufficient accuracy to efficiently predict reaction pathways without prior knowledge of products.
For a century now, “Lewis dots” have been a mainstay of chemical thinking, teaching and communication. However, chemists have assumed that this semi-classical picture of electrons needs to be abandoned for quantitative work, and the recourse in computational simulations has been to the extremes of first principles treatments of electrons on the one hand and force fields that avoid explicit electrons on the other hand. Given both the successes and limitations of these highly divergent approaches, it seems worth considering whether the Lewis dot picture might be made quantitative after all. Here we review progress to that end, including variations that have been implemented and examples of applications, specifically the acid–base behavior of water, several organic reactions, and electron dynamics in silicon fracture. In each case, the semi-classical approach is highly efficient and generates reasonable and readily interpreted reaction trajectories in turnkey fashion (i.e., without any input about products). Avenues for further progress are also discussed.
doi:10.1039/c7sc01181d
PMCID: PMC5468998
5.  Seizure syndrome as a first manifestation of solitary tumor-like mass lesion of PACNS 
Medicine  2017;96(9):e6018.
Abstract
Rationale:
Primary angiitis of the central nervous system (PACNS) is an inflammatory disease involving cerebrovascular and parenchymal, and solitary tumor-like mass lesion of PACNS (TLML-PACNS) is frequently misdiagnosed as neoplastic or other inflammatory diseases. However, seizure syndrome as a first manifestation of TLML-PACNS has rarely reported before.
Patient concerns:
Here, we report 2 cases of seizure syndrome, which was the first sign that presented prior to the diagnosis of TLML-PACNS by brain biopsy.
Diagnoses:
A mass lesion in the white and gray matters was detected by magnetic resonance imaging. The pathology for leptomeningeal lesion biopsy observed a transmural inflammation of the artery, with T lymphocyte infiltration. Patients were diagnosed with PACNS and epileptic seizure by biopsy and electroencephalogram.
Interventions:
Patients were treated with glucocorticoid pulse therapy for 3 days, and subsequently oral prednisone was continued, in combination with immunosuppressant.
Outcomes:
Luckily, both two patients were improved after treatment, and only mild cognitive impairment remained without adverse event.
Lessons:
Patient with mass lesion in CNS, which is similar to tumor, presented with seizure, headache, or cerebrovascular events without any other risk factors for stroke or tumor, should be considered the feasible with the disease of TLML-PACNS.
doi:10.1097/MD.0000000000006018
PMCID: PMC5340432  PMID: 28248859
case report; central nervous system; primary angiitis; seizure; tumor-like lesion
6.  Dishevelled2 promotes apoptosis and inhibits inflammatory cytokine secretion in rheumatoid arthritis fibroblast-like synoviocytes through crosstalk with the NF-κB pathway 
Oncotarget  2017;8(8):12649-12663.
Dishevelled (Dvl) not only links the canonical Wnt and non-canonical Wnt pathways but can also crosstalk with other pathways. As there is no systematic study to date on Dvl in rheumatoid arthritis (RA), we explored the impact of Dvl2 on proliferation and inflammatory cytokine secretion in RA fibroblast-like synoviocytes (FLSs). Expression of Dvl2 in RA synovial tissue and RA-FLSs was measured. Dvl2 was overexpressed in collagen-induced arthritis rats and human RA-FLSs,. the apoptosis and secretion of inflammatory cytokines were observed. Genetic changes and corresponding mechanisms caused by overexpressing Dvl2 in RA-FLSs were assessed. Dvl2 was found to be overexpressed in RA synovial tissue and RA-FLSs. Overexpression of Dvl2 increased apoptosis and inhibited inflammatory cytokine secretion by RA-FLSs in vivo and in vitro, and Dvl2 inhibited expression of anti-apoptotic and inflammatory genes. One possible mechanism is that Dvl2 decreases the nuclear translocation of P65 and inhibits its ability to bind to the promoters of NF-κB target genes. Our findings reveal an underappreciated role of Dvl2 in regulating inflammation and RA-FLS apoptosis and provide insight into crosstalk between the Wnt and nuclear factor-κB (NF-κB) pathways.
doi:10.18632/oncotarget.15172
PMCID: PMC5355042  PMID: 28187436
rheumatoid arthritis; synovial fibroblast; apoptosis; inflammation; dishevelled2; Immunology and Microbiology Section; Immune response; Immunity
7.  The anti-inflammatory effects of asiatic acid in lipopolysaccharide-stimulated human corneal epithelial cells 
AIM
To investigate the anti-inflammatory effects of asiatic acid (AA) on lipopolysaccharide (LPS)-induced inflammatory response in human corneal epithelial cells (HCECs).
METHODS
Cell viability was measured using a cell counting kit-8 (CCK-8) assay. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the mRNA expression of interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-β (TGF-β) in HCECs. Intracellular reactive oxygen species (ROS) was measured using the ROS assay kit. Glutathione (GSH) concentration was measured using the total GSH assay kit. Akt1 and Akt phosphorylation (p-Akt1) levels were measured by Western blotting and immunofluorescence.
RESULTS
AA induced toxicity at high concentrations and significantly stimulated the proliferation of HCECs at concentrations of 20 µmol/L for 1h. LPS at concentrations of 300 ng/mL for 1h significantly stimulated the mRNA expression of IL-8, IL-6, IL-1β, TNF-α, and TGF-β in HCECs, while the stimulation effects were significantly inhibited by AA (20 µmol/L). In addition, AA was found to decrease the content of ROS, increase GSH generation, and also inhibit LPS-induced p-Akt in HCECs.
CONCLUSION
AA decreases the generation of inflammatory factors IL-8, IL-6, IL-1β, TNF-α, and TGF-β in LPS-stimulated HCECs. AA significantly inhibites the intracellular concentrations of ROS and increases GSH generation. AA also inhibites LPS-induced p-Akt in HCECs. These findings reveal that AA has anti-inflammation effects in LPS-stimulated HCECs.
doi:10.18240/ijo.2017.02.01
PMCID: PMC5313538
asiatic acid; lipopolysaccharide; inflammatory factors; reactive oxygen species; glutathione; Akt phosphorylation
8.  Microscale screening of antibody libraries as maytansinoid antibody-drug conjugates 
mAbs  2016;8(3):513-523.
ABSTRACT
Antibody-drug conjugates (ADCs) are of great interest as targeted cancer therapeutics. Preparation of ADCs for early stage screening is constrained by purification and biochemical analysis techniques that necessitate burdensome quantities of antibody. Here we describe a method, developed for the maytansinoid class of ADCs, enabling parallel conjugation of antibodies in 96-well format. The method utilizes ∼100 µg of antibody per well and requires <5 µg of ADC for characterization. We demonstrate the capabilities of this system using model antibodies. We also provide multiple examples applying this method to early-stage screening of maytansinoid ADCs. The method can greatly increase the throughput with which candidate ADCs can be screened in cell-based assays, and may be more generally applicable to high-throughput preparation and screening of different types of protein conjugates.
doi:10.1080/19420862.2015.1134408
PMCID: PMC4966849  PMID: 26752675
Antibody; antibody-drug conjugate; conjugation; high-throughput; maytansinoid; protein chemistry
9.  Histone Acetylation Modifications Affect Tissue-Dependent Expression of Poplar Homologs of C4 Photosynthetic Enzyme Genes 
Histone modifications play important roles in regulating the expression of C4 photosynthetic genes. Given that all enzymes required for the C4 photosynthesis pathway are present in C3 plants, it has been hypothesized that this expression regulatory mechanism has been conserved. However, the relationship between histone modification and the expression of homologs of C4 photosynthetic enzyme genes has not been well determined in C3 plants. In the present study, we cloned nine hybrid poplar (Populus simonii × Populus nigra) homologs of maize (Zea mays) C4 photosynthetic enzyme genes, carbonic anhydrase (CA), pyruvate orthophosphate dikinase (PPDK), phosphoenolpyruvate carboxykinase (PCK), and phosphoenolpyruvate carboxylase (PEPC), and investigated the correlation between the expression levels of these genes and the levels of promoter histone acetylation modifications in four vegetative tissues. We found that poplar homologs of C4 homologous genes had tissue-dependent expression patterns that were mostly well-correlated with the level of histone acetylation modification (H3K9ac and H4K5ac) determined by chromatin immunoprecipitation assays. Treatment with the histone deacetylase inhibitor trichostatin A further confirmed the role of histone acetylation in the regulation of the nine target genes. Collectively, these results suggest that both H3K9ac and H4K5ac positively regulate the tissue-dependent expression pattern of the PsnCAs, PsnPPDKs, PsnPCKs, and PsnPEPCs genes and that this regulatory mechanism seems to be conserved among the C3 and C4 species. Our findings provide new insight that will aid efforts to modify the expression pattern of these homologs of C4 genes to engineer C4 plants from C3 plants.
doi:10.3389/fpls.2017.00950
PMCID: PMC5462996
poplar; C4 genes; homologs; transcriptional regulation; histone acetylation modification
10.  Variants of the yeast MAPK Mpk1 are fully functional independently of activation loop phosphorylation 
Molecular Biology of the Cell  2016;27(17):2771-2783.
MAPKs are catalytically and biologically active only when dually phosphorylated on a TEY motif. Mutations in the yeast MAPK Mpk1 are described that render it fully functional when mutated in its TEY motif and even when it carries a kinase-dead mutation.
MAP kinases of the ERK family are conserved from yeast to humans. Their catalytic activity is dependent on dual phosphorylation of their activation loop’s TEY motif, catalyzed by MAPK kinases (MEKs). Here we studied variants of Mpk1, a yeast orthologue of Erk, which is essential for cell wall integrity. Cells lacking MPK1, or the genes encoding the relevant MEKs, MKK1 and MKK2, do not proliferate under cell wall stress, imposed, for example, by caffeine. Mutants of Mpk1, Mpk1(Y268C) and Mpk1(Y268A), function independently of Mkk1 and Mkk2. We show that these variants are phosphorylated at their activation loop in mkk1∆mkk2∆ and mkk1∆mkk2∆pbs2∆ste7∆ cells, suggesting that they autophosphorylate. However, strikingly, when Y268C/A mutations were combined with the kinase-dead mutation, K54R, or mutations at the TEY motif, T190A+Y192F, the resulting proteins still allowed mkk1∆mkk2∆ cells to proliferate under caffeine stress. Mutating the equivalent residue, Tyr-280/Tyr-261, in Erk1/Erk2 significantly impaired Erk1/2’s catalytic activity. This study describes the first case in which a MAPK, Erk/Mpk1, imposes a phenotype via a mechanism that is independent of TEY phosphorylation and an unusual case in which an equivalent mutation in a highly conserved domain of yeast and mammalian Erks causes an opposite effect.
doi:10.1091/mbc.E16-03-0167
PMCID: PMC5007096  PMID: 27413009
11.  PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function* 
The Journal of Biological Chemistry  2015;290(33):20580-20589.
Background: Prolyl hydroxylases (PHDs) are linked to inflammatory bowel diseases (IBD); however, the exact role of PHD3, a member of PHD family, in IBD is unknown.
Results: Deletion of Phd3 in mice intestinal epithelial cells causes spontaneous colitis.
Conclusion: PHD3 protects the intestinal epithelial barrier function.
Significance: The results are helpful for the development of therapeutic strategies for IBD.
Prolyl hydroxylase domain proteins (PHDs) control cellular adaptation to hypoxia. PHDs are found involved in inflammatory bowel disease (IBD); however, the exact role of PHD3, a member of the PHD family, in IBD remains unknown. We show here that PHD3 plays a critical role in maintaining intestinal epithelial barrier function. We found that genetic ablation of Phd3 in intestinal epithelial cells led to spontaneous colitis in mice. Deletion of PHD3 decreases the level of tight junction protein occludin, leading to a failure of intestinal epithelial barrier function. Further studies indicate that PHD3 stabilizes occludin by preventing the interaction between the E3 ligase Itch and occludin, in a hydroxylase-independent manner. Examination of biopsy of human ulcerative colitis patients indicates that PHD3 is decreased with disease severity, indicating that PHD3 down-regulation is associated with progression of this disease. We show that PHD3 protects intestinal epithelial barrier function and reveal a hydroxylase-independent function of PHD3 in stabilizing occludin. These findings may help open avenues for developing a therapeutic strategy for IBD.
doi:10.1074/jbc.M115.653584
PMCID: PMC4536461  PMID: 26124271
cell biology; colitis; inflammatory bowel disease (IBD); intestinal epithelium; tight junction; occludin; prolyl hydroxylase
12.  The Endoplasmic Reticulum Stress Sensor IRE1α in Intestinal Epithelial Cells Is Essential for Protecting against Colitis* 
The Journal of Biological Chemistry  2015;290(24):15327-15336.
Background: Endoplasmic reticulum (ER) stress is implicated in inflammatory bowel disease (IBD) and IRE1α plays a critical role in ER stress.
Results: Genetic ablation of Ire1α in intestinal epithelial cells leads to colitis in mice.
Conclusion: IRE1α acts as an important defense molecule against IBD.
Significance: The finding provides insight into the regulation of intestinal epithelium homeostasis by IRE1α.
Intestinal epithelial cells (IECs) have critical roles in maintaining homeostasis of intestinal epithelium. Endoplasmic reticulum (ER) stress is implicated in intestinal epithelium homeostasis and inflammatory bowel disease; however, it remains elusive whether IRE1α, a major sensor of ER stress, is directly involved in these processes. We demonstrate here that genetic ablation of Ire1α in IECs leads to spontaneous colitis in mice. Deletion of IRE1α in IECs results in loss of goblet cells and failure of intestinal epithelial barrier function. IRE1α deficiency induces cell apoptosis through induction of CHOP, the pro-apoptotic protein, and sensitizes cells to lipopolysaccharide, an endotoxin from bacteria. IRE1α deficiency confers upon mice higher susceptibility to chemical-induced colitis. These results suggest that IRE1α functions to maintain the intestinal epithelial homeostasis and plays an important role in defending against inflammation bowel diseases.
doi:10.1074/jbc.M114.633560
PMCID: PMC4463471  PMID: 25925952
colitis; endoplasmic reticulum stress (ER stress); inflammation; inflammatory bowel disease (IBD); intestinal epithelium
13.  Surface Propensities of the Self-Ions of Water 
ACS Central Science  2016;2(4):225-231.
The surface charge of water, which is important in a wide range of chemical, biological, material, and environmental contexts, has been a subject of lengthy and heated debate. Recently, it has been shown that the highly efficient LEWIS force field, in which semiclassical, independently mobile valence electron pairs capture the amphiproticity, polarizability and H-bonding of water, provides an excellent description of the solvation and dynamics of hydroxide and hydronium in bulk water. Here we turn our attention to slabs, cylinders, and droplets. In extended simulations with 1000 molecules, we find that hydroxide consistently prefers the surface, hydronium consistently avoids the surface, and the two together form an electrical double layer until neutralization occurs. The behavior of hydroxide can largely be accounted for by the observation that hydroxide moving to the surface loses fewer hydrogen bonds than are gained by the water molecule that it displaces from the surface. At the same time, since the orientation of the hydroxide increases the ratio of dangling hydrogens to dangling lone pairs, the proton activity of the exposed surface may be increased, rather than decreased. Hydroxide also moves more rapidly in the surface than in the bulk, likely because the proton donating propensity of neighboring water molecules is focused on the one hydrogen that is not dangling from the surface.
LEWIS, a force field that captures the amphiproticity, polarizability, and H-bonding of water, predicts that hydroxide consistently prefers the water−air interface and hydronium consistently avoids it.
doi:10.1021/acscentsci.6b00013
PMCID: PMC4850511  PMID: 27163053
14.  The yeast Hot1 transcription factor is critical for activating a single target gene, STL1 
Molecular Biology of the Cell  2015;26(12):2357-2374.
An active variant of the MAPK Hog1 is used to identify its target genes. The promoter of one target, STL1, possesses a Hog1-responsive element (HoRE) that binds the transcription factor Hot1. HoRE is not found in other promoters, and the STL1 mRNA is the only one abolished in hot1Δ cells. Hot1 may be essential for transcription of one gene.
Transcription factors are commonly activated by signal transduction cascades and induce expression of many genes. They therefore play critical roles in determining the cell's fate. The yeast Hog1 MAP kinase pathway is believed to control the transcription of hundreds of genes via several transcription factors. To identify the bona fide target genes of Hog1, we inducibly expressed the spontaneously active variant Hog1D170A+F318L in cells lacking the Hog1 activator Pbs2. This system allowed monitoring the effects of Hog1 by itself. Expression of Hog1D170A+F318L in pbs2∆ cells imposed induction of just 105 and suppression of only 26 transcripts by at least twofold. We looked for the Hog1-responsive element within the promoter of the most highly induced gene, STL1 (88-fold). A novel Hog1 responsive element (HoRE) was identified and shown to be the direct target of the transcription factor Hot1. Unexpectedly, we could not find this HoRE in any other yeast promoter. In addition, the only gene whose expression was abolished in hot1∆ cells was STL1. Thus Hot1 is essential for transcription of just one gene, STL1. Hot1 may represent a class of transcription factors that are essential for transcription of a very few genes or even just one.
doi:10.1091/mbc.E14-12-1626
PMCID: PMC4462951  PMID: 25904326
15.  14-3-3ε Boosts Bleomycin-induced DNA Damage Response by Inhibiting the Drug-Resistant Activity of MVP 
Journal of proteome research  2013;12(6):2511-2524.
Major vault protein (MVP) is the predominant constituent of the vault particle, the largest known ribonuclear protein complex. Although emerging evidences have been establishing the links between MVP (vault) and multidrug resistance (MDR), little is known regarding exactly how the MDR activity of MVP is modulated during cellular response to drug-induced DNA damage (DDR). Bleomycin (BLM), an anti-cancer drug, induces DNA double-stranded breaks (DSBs) and consequently triggers the cellular DDR. Due to its physiological implications in hepatocellular carcinoma (HCC) and cell fate decision, 14-3-3ε was chosen as the pathway-specific bait protein to identify the critical target(s) responsible for HCC MDR. By using LC-MS/MS-based proteomic approach, MVP was first identified in the BLM-induced 14-3-3ε interactome formed in HCC cells. Biological characterization revealed that MVP possesses specific activity to promote the resistance to the BLM-induced DDR. On the other hand, 14-3-3ε enhances BLM-induced DDR by interacting with MVP. Mechanistic investigation further revealed that 14-3-3ε, in a phosphorylation-dependent manner, binds to the phosphorylated sites at both Thr52 and Ser864 of the monomer of MVP. Consequently, the phosphorylation-dependent binding between 14-3-3ε and MVP inhibits the drug-resistant activity of MVP for an enhanced DDR to BLM treatment. Our findings provide an insight into the mechanism underlying how the BLM-induced interaction between 14-3-3ε and MVP modulates MDR, implicating novel strategy to overcome the chemotherapeutic resistance through interfering specific protein-protein interactions.
doi:10.1021/pr301085c
PMCID: PMC4077179  PMID: 23590642
14-3-3ε; bleomycin (BLM); major vault protein (MVP); vault; drug resistance; DNA damage response (DDR); LC-MS/MS
16.  Differential proteomic analysis of grapevine leaves by iTRAQ reveals responses to heat stress and subsequent recovery 
BMC Plant Biology  2014;14:110.
Background
High temperature is a major environmental factor limiting grape yield and affecting berry quality. Thermotolerance includes the direct response to heat stress and the ability to recover from heat stress. To better understand the mechanism of the thermotolerance of Vitis, we combined a physiological analysis with iTRAQ-based proteomics of Vitis vinifera cv Cabernet Sauvignon, subjected to 43°C for 6 h, and then followed by recovery at 25/18°C.
Results
High temperature increased the concentrations of TBARS and inhibited electronic transport in photosynthesis apparatus, indicating that grape leaves were damaged by heat stress. However, these physiological changes rapidly returned to control levels during the subsequent recovery phase from heat stress. One hundred and seventy-four proteins were differentially expressed under heat stress and/or during the recovery phase, in comparison to unstressed controls, respectively. Stress and recovery conditions shared 42 proteins, while 113 and 103 proteins were respectively identified under heat stress and recovery conditions alone. Based on MapMan ontology, functional categories for these dysregulated proteins included mainly photosynthesis (about 20%), proteins (13%), and stress (8%). The subcellular localization using TargetP showed most proteins were located in the chloroplasts (34%), secretory pathways (8%) and mitochondrion (3%).
Conclusion
On the basis of these findings, we proposed that some proteins related to electron transport chain of photosynthesis, antioxidant enzymes, HSPs and other stress response proteins, and glycolysis may play key roles in enhancing grapevine adaptation to and recovery capacity from heat stress. These results provide a better understanding of the proteins involved in, and mechanisms of thermotolerance in grapevines.
doi:10.1186/1471-2229-14-110
PMCID: PMC4108046  PMID: 24774513
Cabernet sauvignon; Heat stress; iTRAQ; Photosynthesis; Proteomics; Recovery
17.  Identification and Analysis of the Acetylated Status of Poplar Proteins Reveals Analogous N-Terminal Protein Processing Mechanisms with Other Eukaryotes 
PLoS ONE  2013;8(3):e58681.
Background
The N-terminal protein processing mechanism (NPM) including N-terminal Met excision (NME) and N-terminal acetylation (Nα-acetylation) represents a common protein co-translational process of some eukaryotes. However, this NPM occurred in woody plants yet remains unknown.
Methodology/Principal Findings
To reveal the NPM in poplar, we investigated the Nα-acetylation status of poplar proteins during dormancy by combining tandem mass spectrometry with TiO2 enrichment of acetylated peptides. We identified 58 N-terminally acetylated (Nα-acetylated) proteins. Most proteins (47, >81%) are subjected to Nα-acetylation following the N-terminal removal of Met, indicating that Nα-acetylation and NME represent a common NPM of poplar proteins. Furthermore, we confirm that poplar shares the analogous NME and Nα-acetylation (NPM) to other eukaryotes according to analysis of N-terminal features of these acetylated proteins combined with genome-wide identification of the involving methionine aminopeptidases (MAPs) and N-terminal acetyltransferase (Nat) enzymes in poplar. The Nα-acetylated reactions and the involving enzymes of these poplar proteins are also identified based on those of yeast and human, as well as the subcellular location information of these poplar proteins.
Conclusions/Significance
This study represents the first extensive investigation of Nα-acetylation events in woody plants, the results of which will provide useful resources for future unraveling the regulatory mechanisms of Nα-acetylation of proteins in poplar.
doi:10.1371/journal.pone.0058681
PMCID: PMC3594182  PMID: 23536812
18.  Expression of stem cell factor in gastrointestinal stromal tumors: Implications for proliferation and imatinib resistance 
Oncology Letters  2012;5(2):552-558.
KIT autophosphorylation caused by mutation of KIT is considered to be a critical mechanism for the oncogenesis of gastrointestinal stromal tumors (GISTs). However, little is known regarding whether stem cell factor (SCF), the KIT ligand, is able to induce the proliferation of GIST cells by activating the wild-type KIT receptor in GISTs. Imatinib, a tyrosine kinase inhibitor, has been demonstrated to be effective as treatment for the majority of GISTs. However, primary resistance to imatinib in GISTs with wild-type KIT and acquired resistance in GISTs with mutant KIT are becoming increasingly significant problems. The aims of this study were to detect the expression and function of SCF in 68 GIST samples, and to explore the relationship between SCF activity and imatinib resistance using immunohistochemical staining and western blot analysis. Results showed abundant expression of SCF in GISTs and demonstrated that SCF is capable of enhancing GIST cell proliferation. Similar to its ineffectiveness in wild-type GISTs, imatinib also failed to inhibit SCF-induced KIT activation in GISTs with mutant KIT. We also found increased SCF expression in GIST cells treated with imatinib. Overall, our results indicated that SCF-induced KIT activation is a novel essential pathway for the proliferation of GISTs. Imatinib was not able to inhibit the activity of SCF, while it promoted the expression of SCF, which may have contributed to acquired imatinib resistance.
doi:10.3892/ol.2012.1019
PMCID: PMC3572958  PMID: 23420128
stem cell factor; gastrointestinal stromal tumor; KIT; imatinib resistance
19.  Stem cell factor-mediated wild-type KIT receptor activation is critical for gastrointestinal stromal tumor cell growth 
AIM: To clarify the biological role of stem cell factor (SCF)-mediated wild-type KIT receptor activation in gastrointestinal stromal tumor (GIST) growth.
METHODS: The co-expression of wild-type KIT receptor and SCF was evaluated in 51 GIST samples using mutation analysis and immunohistochemistry, and the results were correlated with clinicopathological parameters, including the mitotic count, proliferative index (Ki-67 immunohistochemical staining), mitotic index (phospho-histone H3 immunohistochemical staining) and apoptotic index (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling). Using primary cultured GIST cells, the effect of SCF-mediated wild-type KIT receptor activation was determined by western blotting, methyl thiazolyl tetrazolium (MTT), and apoptosis assays.
RESULTS: We found that wild-type KIT receptor and SCF protein were expressed in 100% and 76.5% of the 51 GIST samples, respectively, and the co-expression of wild-type KIT receptor and SCF was associated with known indicators of poor prognosis, including larger tumor size (P = 0.0118), higher mitotic count (P = 0.0058), higher proliferative index (P = 0.0012), higher mitotic index (P = 0.0282), lower apoptosis index (P = 0.0484), and increased National Institutes of Health risk level (P = 0.0012). We also found that the introduction of exogenous SCF potently increased KIT kinase activity, stimulated cell proliferation (P < 0.01) and inhibited apoptosis (P < 0.01) induced by serum starvation, while a KIT immunoblocking antibody suppressed proliferation (P = 0.01) and promoted apoptosis (P < 0.01) in cultured GIST cells.
CONCLUSION: SCF-mediated wild-type KIT receptor activation plays an important role in GIST cell growth. The inhibition of SCF-mediated wild-type KIT receptor activation may prove to be particularly important for GIST therapy.
doi:10.3748/wjg.v18.i23.2929
PMCID: PMC3380320  PMID: 22736916
Gastrointestinal stromal tumor; Stem cell factor; Wild-type KIT receptor; Cell growth; In vitro
20.  Genome-Wide Identification and in Silico Analysis of Poplar Peptide Deformylases 
Peptide deformylases (PDF) behave as monomeric metal cation hydrolases for the removal of the N-formyl group (Fo). This is an essential step in the N-terminal Met excision (NME) that occurs in these proteins from eukaryotic mitochondria or chloroplasts. Although PDFs have been identified and their structure and function have been characterized in several herbaceous species, it remains as yet unexplored in poplar. Here, we report on the first identification of two genes (PtrPDF1A and PtrPDF1B) respectively encoding two putative PDF polypeptides in Populus trichocarpa by genome-wide investigation. One of them (XP_002300047.1) encoded by PtrPDF1B (XM_002300011.1) was truncated, and then revised into a complete sequence based on its ESTs support with high confidence. We document that the two PDF1s of Populus are evolutionarily divergent, likely as a result of independent duplicated events. Furthermore, in silico simulations demonstrated that PtrPDF1A and PtrPDF1B should act as similar PDF catalytic activities to their corresponding PDF orthologs in Arabidopsis. This result would be value of for further assessment of their biological activities in poplar, and further experiments are now required to confirm them.
doi:10.3390/ijms13045112
PMCID: PMC3344269  PMID: 22606033
peptide deformylase; N-terminal Met excision; in silico simulation; genome-wide investigation; phylogenetic analysis; gene duplication; ghromosome location; gene structure display
21.  Iridium-Catalyzed Kinetic Asymmetric Transformations of Racemic Allylic Benzoates 
Versatile methods for iridium-catalyzed, kinetic asymmetric substitution of racemic, branched allylic esters are reported. These reactions occur with a variety of aliphatic, aryl, and heteroaryl allylic benzoates to form the corresponding allylic substitution products in high yields (74–96%) with good to excellent enantioselectivity (84–98% ee) with a scope that encompasses a range of anionic carbon and heteroatom nucleophiles. These kinetic asymmetric processes occur with distinct stereochemical courses for racemic aliphatic and aromatic allylic benzoates, and the high reactivity of branched allylic benzoates enables enantioselective allylic substitutions that are slow or poorly selective with linear allylic electrophiles.
doi:10.1021/ja103779e
PMCID: PMC2909832  PMID: 20552969
22.  Label-free Quantitative Proteomics Analysis of Etiolated Maize Seedling Leaves during Greening* 
To better understand light regulation of C4 plant maize development, we investigated dynamic proteomic differences between green seedlings (control), etiolated seedlings, and etiolated seedlings illuminated for 6 or 12 h using a label-free quantitative proteomics approach based on nanoscale ultraperformance liquid chromatography-ESI-MSE. Among more than 400 proteins identified, 73 were significantly altered during etiolated maize seedling greening. Of these 73 proteins, 25 were identified as membrane proteins that seldom had been identified with two-dimensional electrophoresis methods, indicating the power of our label-free method for membrane protein identification; 31 were related to light reactions of chlorophyll biosynthesis, photosynthesis, and photosynthetic carbon assimilation. The expression of photosystem II subunits was highly sensitive to light; most of them were not identified in etiolated maize seedlings but drastically increased upon light exposure, indicating that the complex process of biogenesis of the photosynthetic apparatus correlates with the transition from a dark-grown to a light-grown morphology. However, transcriptional analysis indicated that most transcripts encoding these proteins were not regulated by light. In contrast, the levels of mRNAs and proteins for enzymes involved in carbon assimilation were tightly regulated by light. Additionally phosphoenolpyruvate carboxykinase, the key enzyme of the phosphoenolpyruvate carboxykinase C4 pathway, was more tightly regulated by light than the key enzymes of the NADP-malic enzyme C4 pathway. Furthermore phosphoenolpyruvate carboxylase 1C, which was originally reported to be specifically expressed in roots, was also identified in this study; expression of this enzyme was more sensitive to light than its isoforms. Taken together, these results represent a comprehensive dynamic protein profile and light-regulated network of C4 plants for etiolated seedling greening and provide a basis for further study of the mechanism of gene function and regulation in light-induced development of C4 plants.
doi:10.1074/mcp.M900187-MCP200
PMCID: PMC2773713  PMID: 19666873
23.  Self-renewal and chemotherapy resistance of p75NTR positive cells in esophageal squamous cell carcinomas 
BMC Cancer  2009;9:9.
Background
p75NTR has been used to isolate esophageal and corneal epithelial stem cells. In the present study, we investigated the expression of p75NTR in esophageal squamous cell carcinoma (ESCC) and explored the biological properties of p75NTR+ cells.
Methods
p75NTR expression in ESCC was assessed by immunohistochemistry. p75NTR+ and p75NTR- cells of 4 ESCC cell lines were separated by fluorescence-activated cell sorting. Differentially expressed genes between p75NTR+ and p75NTR- cells were determined by real-time quantitative reverse transcription-PCR. Sphere formation assay, DDP sensitivity assay, 64copper accumulation assay and tumorigenicity analysis were performed to determine the capacity of self-renewal, chemotherapy resistance and tumorigenicity of p75NTR+ cells.
Results
In ESCC specimens, p75NTR was found mainly confined to immature cells and absent in cells undergoing terminal differentiation. The percentage of p75NTR+ cells was 1.6%–3.7% in Eca109 and 3 newly established ESCC cell lines. The expression of Bmi-1, which is associated with self-renewal of stem cells, was significantly higher in p75NTR+ cells. p63, a marker identified in keratinocyte stem cells, was confined mainly to p75NTR+ cells. The expression of CTR1, which is associated with cisplatin (DDP)-resistance, was significantly decreased in p75NTR+ cells. Expression levels of differentiation markers, such as involucrin, cytokeratin 13, β1-integrin and β4-integrin, were lower in p75NTR+ cells. In addition, p75NTR+ cells generated both p75NTR+ and p75NTR- cells, and formed nonadherent spherical clusters in serum-free medium supplemented with growth factors. Furthermore, p75NTR+ cells were found to be more resistant to DDP and exhibited lower 64copper accumulation than p75NTR- cells.
Conclusion
Our results demonstrated that p75NTR+ cells possess some characteristics of CSCs, namely, self-renewal and chemotherapy resistance. Chemotherapy resistance of p75NTR+ cells may probably be attributable to decreased expression of CTR1.
doi:10.1186/1471-2407-9-9
PMCID: PMC2637890  PMID: 19134212
24.  Proteomic analysis of differential proteins in pancreatic carcinomas: Effects of MBD1 knock-down by stable RNA interference 
BMC Cancer  2008;8:121.
Background
Methyl-CpG binding domain protein 1 (MBD1), a suppressor of gene transcription, may be involved in inactivation of tumor suppressor genes during tumorigenesis. Over-expression of MBD1 has been reported in human pancreatic carcinomas.
Methods
In this study, we established a MBD1-knock-down pancreatic cancer cell line (BxPC-3) using stable RNA interference, to compare the proteomic changes between control and MBD1-knock-down cells using two-dimensional gel electrophoresis and mass spectrometry.
Results
We identified five proteins that were up-regulated and nine proteins that were down-regulated. Most of the identified proteins are involved in tumorigenesis, some are prognostic biomarkers for human malignant tumors.
Conclusion
Our data suggest that these differential proteins may be associated with the function of MBD1, and provide some insight into the functional mechanism of MBD1 in the development of pancreatic cancer.
doi:10.1186/1471-2407-8-121
PMCID: PMC2386481  PMID: 18445260
25.  Angiopoietin-1 targeted RNA interference suppresses angiogenesis and tumor growth of esophageal cancer 
AIM: To determine the inhibitory effect of the adenovirus-based angiopoietin-1 (Ang-1) targeted small interfering RNA expression system (Ad/Ang-1si) on the expression of the Ang-1 gene, cell growth and apoptosis in human esophageal cancer cell line Eca109.
METHODS: siRNA-expressing adenovirus targeting Ang-1 gene was constructed using the Ad Easy System. Cultured Eca109 cells were transfected with Ad/Ang-1si (Eca109/Ang-1si), and Ad/si was used to infect Eca109 cells as control (Eca109/si). Ang-1 gene expression and concentration was determined with RT-PCR and ELISA, respectively. Human umbilical vein endothelial cell (HUVEC) migration and proliferation were analyzed. After s.c. injection into athymic nu/nu mice, the tumor growth, vessel density and apoptosis of each group was also determined.
RESULTS: HUVEC migration induced by conditioned medium from Ang-1si-transfected Eca109 cells was significantly less than that induced by conditioned medium from Eca109 cells and control adenovirus-transfected Eca109 cells. Furthermore, after s.c. injection into athymic nu/nu mice, the tumor growth and cell apoptosis of Ad/Ang-1si -expressing Eca109 cells was significantly lower than that of parental or control adenovirus-transfected cells. Vessel density assessed by CD31 immunohistochemical analysis and Ang-1 expression by RT-PCR were also decreased.
CONCLUSION: The targeting Ang-1 may provide a therapeutic option for esophageal cancer.
doi:10.3748/wjg.14.1575
PMCID: PMC2693755  PMID: 18330951
Angiopoietin-1; Angiogenesis; Esophageal cancer; RNA Interference; Cancer

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