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1.  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
2.  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
3.  Patient-centered boundary mechanisms to foster intercultural partnerships in health care: a case study in Guatemala 
Background
Up to one half of the population in Africa, Asia and Latin America has little access to high-quality biomedical services and relies on traditional health systems. Medical pluralism is thus in many developing countries the rule rather than the exception, which is why the World Health Organization is calling for intercultural partnerships to improve health care in these regions. They are, however, challenging due to disparate knowledge systems and lack of trust that hamper understanding and collaboration. We developed a collaborative, patient-centered boundary mechanism to overcome these challenges and to foster intercultural partnerships in health care. To assess its impact on the quality of intercultural patient care in a medically pluralistic developing country, we conducted and evaluated a case study.
Methods
The case study took place in Guatemala, since previous efforts to initiate intercultural medical partnerships in this country were hampered by intense historical and societal conflicts. It was designed by a team from ETH Zurich’s Transdisciplinarity Lab, the National Cancer Institute of Guatemala, two traditional Councils of Elders and 25 Mayan healers from the Kaqchikel and Q’eqchi’ linguistic groups. It was implemented from January 2014 to July 2015. Scientists and traditional political authorities collaborated to facilitate workshops, comparative diagnoses and patient referrals, which were conducted jointly by biomedical and traditional practitioners. The traditional medical practices were thoroughly documented, as were the health-seeking pathways of patients, and the overall impact was evaluated.
Results
The boundary mechanism was successful in discerning barriers of access for indigenous patients in the biomedical health system, and in building trust between doctors and healers. Learning outcomes included a reduction of stereotypical attitudes towards traditional healers, improved biomedical procedures due to enhanced self-reflection of doctors, and improved traditional health care due to refined diagnoses and adapted treatment strategies. In individual cases, the beneficial effects of traditional treatments were remarkable, and the doctors continued to collaborate with healers after the study was completed. Comparison of the two linguistic groups illustrated that the outcomes are highly context-dependent.
Conclusions
If well adapted to local context, patient-centered boundary mechanisms can enable intercultural partnerships by creating access, building trust and fostering mutual learning, even in circumstances as complex as those in Guatemala. Creating multilateral patient-centered boundary mechanisms is thus a promising approach to improve health care in medically pluralistic developing countries.
doi:10.1186/s13002-017-0170-y
PMCID: PMC5549296  PMID: 28789670
Boundary management; Partnerships; Intercultural health; Integrative medicine; Traditional medicine; Mayan medicine; Central America; Guatemala
4.  Medicinally Used Asarum Species: High-Resolution LC-MS Analysis of Aristolochic Acid Analogs and In vitro Toxicity Screening in HK-2 Cells 
Species of Asarum are used in traditional Chinese medicine and, similar to members of the genus Aristolochia, they contain aristolochic acid analogs (AAAs). These compounds are known for their nephrotoxic and carcinogenic effects. So far, the phytochemistry and nephrotoxicity of species of Asarum is not well studied. A high-resolution LC-MS-based metabolomic approach was used to study the phytochemical variation in medicinally used Asarum species. The cytotoxicity of the samples was assessed using human kidney (HK-2) cells. The majority of samples contained potentially nephrotoxic AAAs, including 9-methoxy aristolactam (AL) IV, AL I, and AL IV. These compounds were present in methanol as well as water extracts. AAAs were detected in all parts of the plant. The majority of the extracts were not cytotoxic to HK-2 cells at the doses tested. However, other mechanisms relating to aristolochic acid nephropathy and cancer development, such as DNA adduct formation may occur. The results of this study provide a model for assessing lesser-known plant species for toxicity.
doi:10.3389/fphar.2017.00215
PMCID: PMC5439001
metabolomics; LC-MS; nephrotoxicity; Asarum; aristolactam
5.  MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation 
Nature Communications  2017;8:14674.
KIT, PDGFRA, NF1 and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumours (GISTs), and additional genetic alterations are required for progression to malignancy. The most frequent secondary alteration, demonstrated in ∼70% of GISTs, is chromosome 14q deletion. Here we report hemizygous or homozygous inactivating mutations of the chromosome 14q MAX gene in 16 of 76 GISTs (21%). We find MAX mutations in 17% and 50% of sporadic and NF1-syndromic GISTs, respectively, and we find loss of MAX protein expression in 48% and 90% of sporadic and NF1-syndromic GISTs, respectively, and in three of eight micro-GISTs, which are early GISTs. MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion and MAX induction restores p16 expression and inhibits GIST proliferation. Hence, MAX inactivation is a common event in GIST progression, fostering cell cycle activity in early GISTs.
In gastrointestinal stromal tumours early mutations in known genes are frequently followed by chromosome 14q deletion. Here the authors find mutations resulting in loss of MAX protein expression conserved between primary tumours and metastases in the same patients, suggesting that MAX mutation is an early event.
doi:10.1038/ncomms14674
PMCID: PMC5344969  PMID: 28270683
6.  FGFR1 and NTRK3 actionable alterations in “Wild-Type” gastrointestinal stromal tumors 
Background
About 10–15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.
Methods
We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.
Results
We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1–HOOK3, FGFR1–TACC1) and one harbored an ETV6–NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1–TACC1 and ETV6–NTRK3 fusions.
Conclusions
Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST.
Trial registration NCT 02576431. Registered October 12, 2015
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-016-1075-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-016-1075-6
PMCID: PMC5157084  PMID: 27974047
Gene sequencing; Mutation; GIST; FGFR1; ETV6–NTRK3
7.  Combination Therapy for KIT-Mutant Mast Cells: Targeting Constitutive NFAT and KIT Activity 
Molecular cancer therapeutics  2014;13(12):2840-2851.
Resistant KIT mutations have hindered the development of KIT kinase inhibitors for treatment of patients with systemic mastocytosis. The goal of this research was to characterize the synergistic effects of a novel combination therapy involving inhibition of KIT and calcineurin phosphatase, a nuclear factor of activated T cells (NFAT) regulator, using a panel of KIT-mutant mast cell lines. The effects of monotherapy or combination therapy on the cellular viability/survival of KIT-mutant mast cells were evaluated. In addition, NFAT-dependent transcriptional activity was monitored in a representative cell line to evaluate the mechanisms responsible for the efficacy of combination therapy. Finally, shRNA was used to stably knockdown calcineurin expression to confirm the role of calcineurin in the observed synergy. The combination of a KIT inhibitor and a calcineurin phosphatase inhibitor (CNPI) synergized to reduce cell viability and induce apoptosis in six distinct KIT-mutant mast cell lines. Both KIT inhibitors and CNPIs were found to decrease NFAT-dependent transcriptional activity. NFAT-specific inhibitors induced similar synergistic apoptosis induction as CNPIs when combined with a KIT inhibitor. Notably, NFAT was constitutively active in each KIT-mutant cell line tested. Knockdown of calcineurin subunit PPP3R1 sensitized cells to KIT inhibition and increased NFAT phosphorylation and cytoplasmic localization. Constitutive activation of NFAT appears to represent a novel and targetable characteristic of KIT-mutant mast cell disease. Our studies suggest that combining KIT inhibition with NFAT inhibition might represent a new treatment strategy for mast cell disease.
doi:10.1158/1535-7163.MCT-13-0830
PMCID: PMC5026483  PMID: 25253785
8.  Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition 
Purpose
Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases is unknown.
Experimental Design
We conducted a phase II study of nilotinib 400 mg BID in two cohorts of patients with melanomas harboring KIT mutations or amplification: A) those refractory or intolerant to a prior KIT inhibitor; and B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression and overall survival. A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in Cohorts A and B, respectively.
Results
Twenty patients were enrolled and 19 treated (11-Cohort A; 8-Cohort B). Three patients on Cohort A (27%; 95% CI, 8% – 56%) and 1 on Cohort B (12.5%; 90% CI, 0.6% – 47%) achieved the primary endpoint. Two partial responses were observed in Cohort A (18.2%, 90% CI, 3% – 47%); none were observed in Cohort B. The median time-to-progression and overall survival was 3·3 (90% CI, 2.1 – 3.9 months) and 9.1 months (90% CI, 4.3 – 14.2 months), respectively, in all treated patients.
Conclusion
Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT altered melanoma with brain metastasis is limited.
doi:10.1158/1078-0432.CCR-14-1630
PMCID: PMC5013827  PMID: 25695690
Melanoma; KIT; Mucosal; Acral
9.  From Traditional Resource to Global Commodities:—A Comparison of Rhodiola Species Using NMR Spectroscopy—Metabolomics and HPTLC 
The fast developing international trade of products based on traditional knowledge and their value chains has become an important aspect of the ethnopharmacological debate. The structure and diversity of value chains and their impact on the phytochemical composition of herbal medicinal products, as well as the underlying government policies and regulations, have been overlooked in the debate about quality problems in transnational trade. Rhodiola species, including Rhodiola rosea L. and Rhodiola crenulata (Hook. f. & Thomson) H. Ohba, are used as traditional herbal medicines. Faced with resource depletion and environment destruction, R. rosea and R. crenulata are becoming endangered, making them more economically valuable to collectors and middlemen, and also increasing the risk of adulteration and low quality. Rhodiola products have been subject to adulteration and we recently assessed 39 commercial products for their composition and quality. However, the range of Rhodiola species potentially implicated has not been assessed. Also, the ability of selected analytical techniques in differentiating these species is not known yet. Using a strategy previously developed by our group, we compare the phytochemical differences among Rhodiola raw materials available on the market to provide a practical method for the identification of different Rhodiola species from Europe and Asia and the detection of potential adulterants. Nuclear magnetic resonance spectroscopy coupled with multivariate analysis software and high performance thin layer chromatography techniques were used to analyse the samples. Rosavin and rosarin were mainly present in R. rosea but also in Rosea sachalinensis Borris. 30% of the Rhodiola samples purchased from the Chinese market were adulterated by other Rhodiola spp. The utilization of a combined platform based on 1H-NMR and HPTLC methods resulted in an integrated analysis of different Rhodiola species. We identified adulteration at the earliest stage of the value chains, i.e., during collection as a key problem involving several species. This project also highlights the need to further study the links between producers and consumers in national and trans-national trade.
doi:10.3389/fphar.2016.00254
PMCID: PMC5002433  PMID: 27621703
Rhodiola; metabolomics; herb quality; adulteration; HPTLC; NMR
10.  Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib 
Oncotarget  2016;7(27):41390-41403.
Gastrointestinal stromal tumors (GIST) exhibit a strong oncogenic dependency on KIT and KIT inhibitors confer long lasting disease stabilization in the majority of patients. Nonetheless, KIT inhibition alone does not cure GIST as a subset of GIST cells evade apoptosis and eventually develop resistance. Inhibitors of Apoptosis Proteins (IAPs) may confer resistance to drug-induced apoptosis. We observed that the mRNA and protein of IAPs XIAP (BIRC4) and survivin (BIRC5) were highly expressed in primary GIST tumors and cell line models. Amplification of the respective gene loci (BIRC2, BIRC3, BIRC4, BIRC5) was detected in 47% of GIST studied by SNP arrays. Whole exome analyses revealed a mutation of SMAC(DIABLO) in a heavily pretreated patient. Both, survivin (rank 62-92/11.194 tested proteins) and XIAP (rank 106-557/11.194) were found to be essential proteins for survival in a synthetic lethality screen. Expression of XIAP and survivin decreased upon KIT inhibition and may play a role in KIT-regulated pro-survival signaling. SMAC-mimetic treatment with LCL161 and TL32711 reduced cIAP1 and XIAP expression. Survivin inhibitor YM155 lead to transcriptional repression of BIRC5/survivin (YM155) and induced apoptosis. Combinational treatment with KIT inhibitors (imatinib, regorafenib) enhanced the proapoptotic effect. These findings support the combination of KIT inhibition with IAP antagonists in GIST.
doi:10.18632/oncotarget.9159
PMCID: PMC5173067  PMID: 27167336
GIST; inhibitors of apoptosis proteins; LCL161; TL32711; YM155
11.  Quality and safety of herbal medical products: regulation and the need for quality assurance along the value chains 
Herbal medicines and products derived from them are a diverse group of products for which different (and often limited) levels of evidence are available. As importantly, such products generally vary in their composition and are at the end of an often poorly understood value chain, which often links producers in biodiversity rich countries with the large markets in the North. This paper discusses the current regulatory framework of such herbal medical products (with a focus on the UK) and using examples from our own metabolomic research on Curcumal longa L. (turmeric, Zingiberaceae) how value chains impact on the composition and quality (and thus the safety) of such products.
Overall, our recent research demonstrates the need for studying the links between producers and consumers of commodities produced in provider countries and that plant metabolomics offer a novel way of assessing the chemical variability along a value chain.
doi:10.1111/bcp.12586
PMCID: PMC4500325  PMID: 25581270
herbal medicines; HPTLC; metabolomics; quality assurance; traditional herbal regulation
12.  Crosstalk between KIT and FGFR3 Promotes Gastrointestinal Stromal Tumor Cell Growth and Drug Resistance 
Cancer research  2014;75(5):880-891.
Kinase inhibitors such as imatinib have dramatically improved outcomes for GIST patients, but many patients develop resistance to these treatments. While in some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients development resistance without KIT mutations. In this study, we address this patient subset in reporting a functional dependence of GIST on the FGF receptor FGFR3 and its crosstalk with KIT in GIST cells. Addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment, allowing sensitive cells to proliferate in the presence of the drug. FGF2 expression was increased in imatinib-resistant GIST cells, the growth of which was blocked by RNAi-mediated silencing of FGFR3. Moreover, combining KIT and FGFR3 inhibitors synergized to block the growth of imatinib-resistant cells. Signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. Clinically, an immunohistochemical analysis of tumor specimens from imatinib-resistant GIST patients revealed a relative increase in FGF2 levels, with a trend towards increased expression in imatinib-naïve samples consistent with possible involvement in drug resistance. Our findings provide a mechanistic rationale to evaluate existing FGFR inhibitors and multi-kinase inhibitors that target FGFR3 as promising strategies to improve treatment of GIST patients with de novo or acquired resistance to imatinib.
doi:10.1158/0008-5472.CAN-14-0573
PMCID: PMC4348216  PMID: 25432174
13.  Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial 
BMC Cancer  2016;16:22.
Background
Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-α (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population.
Methods
This is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre-imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson χ2 test) in the same molecular subgroups.
Results
Of the 1124 sunitinib-treated patients in the treatment-use study, 230 (20 %) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39–0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy of sunitinib treatment.
Conclusions
This large retrospective analysis confirms the prognostic significance of KIT mutation status in patients with GIST. This analysis also confirms the effectiveness of sunitinib as a post-imatinib therapy, regardless of mutational status.
Trial registration
NCT01459757.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2051-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-2051-5
PMCID: PMC4714485  PMID: 26772734
Sunitinib; Imatinib; GIST; KIT; KIT mutation; Imatinib-resistant GIST; Overall survival; Progression-free survival
14.  Medicinal and local food plants in the south of Alava (Basque Country, Spain) 
Journal of Ethnopharmacology  2015;176:207-224.
Ethnobotanical relevance
Medicinal and food plants in the Basque Country are an integral part of a fast changing culture. With a distinct tradition and language, this region of Europe provides an important example demonstrating the changing role of local and traditional knowledge in industrial countries. As other Mediterranean regions it preserves a rich heritage of using plants as medicine and food, offering a unique opportunity for studying the medicine food interface in an ethnopharmacological context. Therefore, the key goal of this study has been to contribute to an understanding of local and traditional plant usage, to evaluate their uses as food and medicine as well as to critically assess the role of these plants in the south of the Basque Country contributing to an understanding of how foods and medicines are used.
Methods
A mixed methods approach, including participant observation; open and semi structured interviews was used. Ethnobotanical field work included 183 people, ages ranged from 24 to 98 years old with a majority being between 70 and 80 years old (mean age 71) from 31 towns of three different regions. The basic interview was a one-to-one meeting, which often included field walking and collection of samples as directed by the informants. 700 voucher specimens (most of them with duplicates) were collected for the data obtained.
Using SPSS version 20 the gathered information was processed and the replies of the different informants were subsequently organised in variables like medicine and food plants, part of the plants used, forms of preparations, zones preferred for collecting these plants. The data were analysed based on the frequency of records. This type of approach allows us to understand the way the informant’s categorize the species, and how these categories are distributed along the sample. In order to analyse the data three main categories of use were distinguished: Medicine (M), Food (F) and an intermediate Health-Food (H-F). The three categories were divided in 27 subcategories (common uses).
Results and discussion
The informants recognise and use a total of 184 species from 49 families. During interviews, 5658 individual use-reports were collected relating to three use-categories – as medicines, food and health-food. The two main groups with almost the same number of species each are health-food (75 species) and (locally gathered) food only (73), with medicinal uses only (36) being the smallest group. This highlights the important overlap between food and medicines.
Overall, three core families were identified (based on the number of use reports and in the number of species): Asteraceae (25 species), Lamiaceae and Rosaceae (24 each). The most frequently reported species are Jasonia glutinosa, Chamaemelum nobile, Prunus spinosa and Quercus ilex subsp. ballota.
The most important general use-subcategories are as raw vegetables (27.43% of the use-reports and including 81 species), infusions (14.74%/42) and gastrointestinal (12.53%/42). Conceptually foods and medicines are clearly distinguished but the intermediate group of health foods is more ambiguous.
Conclusion
Food and medicinal uses of plants are culturally closely linked. A wide range of plants are known and many still used. The analysis shows that the Basques use a wide range of species which are typical for Western European cultures. In comparison to other studies in the Mediterranean countries there are many similarities in the uses of different families, species of plants and their use and preparations. Some of these plants are key Mediterranean species, often used for a multitude of uses as food and medicine.
Graphical abstract
fx1
doi:10.1016/j.jep.2015.10.022
PMCID: PMC4675496  PMID: 26481607
F, food; H-F, Health food; I, Izki; M, medicinal; V, Valderejo; VA, Valle de Arana; VIVA area, the combined area of Izki, Valderejo and Valle de Arana.; Spanish Basque Country; Food plants; Food-medicines; Traditional knowledge; Ethnopharmacology; Ethnobotany
15.  S0502: A SWOG Phase III Randomized Study of Imatinib, With or Without Bevacizumab, in Patients With Untreated Metastatic or Unresectable Gastrointestinal Stromal Tumors 
The Oncologist  2015;20(12):1353-1354.
Lessons Learned
Despite having significant rationale, S0502 failed to accrue for a number of reasons.
Vetting a trial first, with scientific experts and funding agencies, does not guarantee success, especially when dealing with a rare tumor and/or one with an existing highly effective therapy.
In the present case, adding an intravenous drug to an oral medication as part of a regimen expected to be continued for many years likely decreased patient (and physician) convenience and, thus, interest in the study.
Background.
Imatinib mesylate, a potent inhibitor of the KIT and PDGFR tyrosine kinases, is highly effective in the treatment of advanced gastrointestinal stromal tumors (GISTs). However, most imatinib-treated tumors eventually become resistant, accounting for a median progression-free survival of 19–23 months. Expression of vascular endothelial growth factor (VEGF) correlates with poor prognosis in GIST; bevacizumab, a monoclonal antibody against VEGF, is effective in a variety of solid tumors. We postulated combination therapy with imatinib plus bevacizumab would benefit patients with advanced GIST, particularly those reliant on VEGFA-dependent angiogenesis.
Methods.
Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial, S0502. At registration, patients were randomly assigned to either imatinib 400 mg (standard) or 800 mg (patients with exon 9 KIT mutations), or imatinib plus bevacizumab, 7.5 mg/kg i.v. every 3 weeks. Patients were treated to progression, symptomatic deterioration, unacceptable toxicity, treatment delay greater than 4 weeks, or patient choice to withdraw from the study. The primary objective was to determine whether the addition of bevacizumab to imatinib would improve progression-free survival (PFS) in first-line treatment of incurable GIST.
Results.
S0502 opened on April 15, 2008. As of fall 2009, only 12 patients from at least 178 eligible SWOG centers plus those participating through Cancer Trials Support Unit had been entered in the study. Despite an aggressive promotion scheme involving the other cooperative groups and a major GIST patient advocacy group, accrual remained slow. The trial was closed on October 1, 2009, having accrued only 2% of the 572 patients planned. No scientific conclusions were forthcoming because of the small number of patients entered in the study. Two patients of the 6 in the combination arm reported grade 3 toxicities, 1 with proteinuria and 1 with fatigue, upper gastrointestinal hemorrhage, and anemia.
Conclusion.
No conclusions may be drawn from this trial and, thus, the combination of imatinib plus bevacizumab cannot be recommended for use.
doi:10.1634/theoncologist.2015-0295
PMCID: PMC4679092  PMID: 26576593
16.  Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients 
Purpose
KIT is the major oncogenic driver of gastrointestinal stromal tumors (GISTs). Imatinib, sunitinib and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here we explored the KIT inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in GIST patients.
Experimental Design
The cellular and in vivo activities of ponatinib, imatinib, sunitinib and regorafenib against mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib-KIT co-structure was also determined. The clinical activity of ponatinib was examined in three GIST patients previously treated with all 3 FDA-approved agents.
Results
In engineered and GIST-derived cell lines, ponatinib potently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinib also induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nM ponatinib was sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nM. This inhibitory profile could be rationalized based on structural analyses. Ponatinib (30 mg daily) displayed encouraging clinical activity in two of three GIST patients.
Conclusion
Ponatinib possesses potent activity against most major clinically-relevant KIT mutants, and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinib in GIST patients.
doi:10.1158/1078-0432.CCR-14-1397
PMCID: PMC4233175  PMID: 25239608
KIT; GIST; ponatinib; tyrosine kinase inhibitor; resistance
18.  Natural products and drug discovery: a survey of stakeholders in industry and academia 
Context: In recent decades, natural products have undisputedly played a leading role in the development of novel medicines. Yet, trends in the pharmaceutical industry at the level of research investments indicate that natural product research is neither prioritized nor perceived as fruitful in drug discovery programmes as compared with incremental structural modifications and large volume HTS screening of synthetics.
Aim: We seek to understand this phenomenon through insights from highly experienced natural product experts in industry and academia.
Method: We conducted a survey including a series of qualitative and quantitative questions related to current insights and prospective developments in natural product drug development. The survey was completed by a cross-section of 52 respondents in industry and academia.
Results: One recurrent theme is the dissonance between the perceived high potential of NP as drug leads among individuals and the survey participants' assessment of the overall industry and/or company level strategies and their success. The study's industry and academic respondents did not perceive current discovery efforts as more effective as compared with previous decades, yet industry contacts perceived higher hit rates in HTS efforts as compared with academic respondents. Surprisingly, many industry contacts were highly critical to prevalent company and industry-wide drug discovery strategies indicating a high level of dissatisfaction within the industry.
Conclusions: These findings support the notion that there is an increasing gap in perception between the effectiveness of well established, commercially widespread drug discovery strategies between those working in industry and academic experts. This research seeks to shed light on this gap and aid in furthering natural product discovery endeavors through an analysis of current bottlenecks in industry drug discovery programmes.
doi:10.3389/fphar.2015.00237
PMCID: PMC4620409  PMID: 26578954
natural products; drug discovery; academia-industry links; Big Pharma; HTS; strategy
19.  SDHC methylation in gastrointestinal stromal tumors (GIST): a case report 
BMC Medical Genetics  2015;16:87.
Background
Gastrointestinal stromal tumors (GIST) recently have been recognized as a genetically and biologically heterogeneous disease. In addition to KIT or PDGFRA mutated GIST, mutational inactivation of succinate dehydrogenase (SDH) subunits has been detected in the KIT/PDGFRA wild-type subgroup, referred to as SDH deficient (dSDH). Even though most dSDH GIST harbor mutations in SDHx subunit genes, some are SDHx wild type.
Epigenetic regulation by DNA methylation of CpG islands recently has been found to be an alternative mechanism underlying the lack of SDH complex in GIST.
Case presentation
We report a particular case of dSDH GIST, previously analyzed with microarrays and next-generation sequencing, for which no molecular pathogenetic events have been identified. Gene expression analysis showed remarkable down-modulation of SDHC mRNA with respect to all other GIST samples, both SDHA-mutant and KIT/PDGFRA-mutant GIST. By a bisulfite methylation assay targeted to 2 SDHC CpG islands, we detected hypermethylation of the SDHC promoter.
Conclusion
Herein we report an additional case of dSDH GIST without SDHx mutation but harboring hypermethylation in the SDHC promoter, thus confirming the complexity of the molecular background of this subtype of GIST.
Electronic supplementary material
The online version of this article (doi:10.1186/s12881-015-0233-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12881-015-0233-7
PMCID: PMC4587653  PMID: 26415883
SDHC; Methylation; Hypermethylation; GIST; dSDH GIST
20.  Oncogenic mutations in melanomas and benign melanocytic nevi of the female genital tract 
Background
The genetic heterogeneity of melanomas and melanocytic nevi of the female genital tract is poorly understood.
Objective
We aim to characterize the frequency of mutations of the following genes: BRAF, NRAS, KIT, GNA11, and GNAQ in female genital tract melanomas. We also characterize the frequency of BRAF mutations in female genital tract melanomas compared with melanocytic nevi.
Methods
Mutational screening was performed on the following female genital tract melanocytic neoplasms: 25 melanomas, 7 benign melanocytic nevi, and 4 atypical melanocytic nevi.
Results
Of the 25 female genital tract melanoma specimens queried, KIT mutations were detected in 4 (16.0%), NRAS mutations in 4 (16.0%), and BRAF mutations in 2 (8.0%) samples. Two of the tumors with KIT mutations harbored double mutations in the same exon. No GNAQ or GNA11 mutations were identified among 11 melanomas screened. BRAF V600E mutations were detected in 7 of 7 benign melanocytic genital nevi (100%) and 3 of 4 atypical genital nevi (75%).
Limitations
Our study is limited by the small sample size of this rare subset of melanomas.
Conclusion
KIT, NRAS, and BRAF mutations are found in a subset of female genital tract melanomas. Screening for oncogenic mutations is important for developing and applying clinical therapies for melanomas of the female genital tract.
doi:10.1016/j.jaad.2014.03.033
PMCID: PMC4450888  PMID: 24842760
BRAF; female genital melanomas; female genital nevi; KIT; NRAS; oncogenic mutations
21.  Pathologic and Molecular Features Correlate With Long-Term Outcome After Adjuvant Therapy of Resected Primary GI Stromal Tumor: The ACOSOG Z9001 Trial 
Journal of Clinical Oncology  2014;32(15):1563-1570.
Purpose
The ACOSOG (American College of Surgeons Oncology Group) Z9001 (Alliance) study, a randomized, placebo-controlled trial, demonstrated that 1 year of adjuvant imatinib prolonged recurrence-free survival (RFS) after resection of primary GI stromal tumor (GIST). We sought to determine the pathologic and molecular factors associated with patient outcome.
Patients and Methods
There were 328 patients assigned to the placebo arm and 317 to the imatinib arm. Median patient follow-up was 74 months. There were 645 tumor specimens available for mitotic rate or mutation analysis.
Results
RFS remained superior in the imatinib arm (hazard ratio, 0.6; 95% CI, 0.43 to 0.75; Cox model–adjusted P < .001). On multivariable analysis of patients in the placebo arm, large tumor size, small bowel location, and high mitotic rate were associated with lower RFS, whereas tumor genotype was not significantly associated with RFS. Multivariable analysis of patients in the imatinib arm yielded similar findings. When comparing the two arms, imatinib therapy was associated with higher RFS in patients with a KIT exon 11 deletion of any type, but not a KIT exon 11 insertion or point mutation, KIT exon 9 mutation, PDGFRA mutation, or wild-type tumor, although some of these patient groups were small. Adjuvant imatinib did not seem to alter overall survival.
Conclusion
Our findings show that tumor size, location, and mitotic rate, but not tumor genotype, are associated with the natural history of GIST. Patients with KIT exon 11 deletions assigned to 1 year of adjuvant imatinib had a longer RFS.
doi:10.1200/JCO.2013.51.2046
PMCID: PMC4026579  PMID: 24638003
22.  Genetic Profiling to Determine Risk of Relapse Free Survival in High-risk Localized Prostate Cancer 
Purpose
The characterization of actionable mutations in human tumors is a prerequisite for the development of individualized, targeted therapy. We examined the prevalence of potentially therapeutically actionable mutations in patients with high risk clinically localized prostate cancer.
Experimental Design
48 samples of formalin fixed paraffin embedded prostatectomy tissue from a neoadjuvant chemotherapy trial were analyzed. DNA extracted from microdissected tumor was analyzed for 643 common solid tumor mutations in 53 genes using mass spectroscopy based sequencing. In addition, PTEN loss and ERG translocations were examined using immunohistochemistry in associated tissue microarrays. Association with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations.
Results
Of the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 47 tumors evaluable for IHC, 36% had PTEN loss and 40% had ERG rearrangement. Individual mutations were not frequent enough to determine associations with relapse. Using Kaplan-Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median relapse free survival, 19 vs. 106 months (p = .01).
Conclusions
This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. While point mutations alone did not have a statistically significant association with relapse, PTEN loss was associated with an increased relapse in high risk prostate cancer treated with chemotherapy followed by surgery.
doi:10.1158/1078-0432.CCR-13-1775
PMCID: PMC3947466  PMID: 24352642
23.  Quadruple wild-type (WT) GIST: defining the subset of GIST that lacks abnormalities of KIT, PDGFRA, SDH, or RAS signaling pathways 
Cancer Medicine  2014;4(1):101-103.
A subset of GISTs lack mutations in the KIT/PDGFRA or RAS pathways and yet retain an intact succinate dehydrogensase (SDH) complex. We propose that these KIT/PDGFRA/SDH/RAS-P WT GIST tumors be designated as quadruple wild-type (WT) GIST. Further molecular and clinicophatological characterization of quadruple WT GIST will help to determine their prognosis as well as assist in the optimization of medical management, including clinical test of novel therapies.
doi:10.1002/cam4.325
PMCID: PMC4312123  PMID: 25165019
BRAF; gastrointestinal stromal tumors; GIST; NF-1; quadruple negative; quadruple WT; RAS; SDH deficiency; SDHA; SDHB; wild type
24.  Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST) 
BMC Cancer  2014;14:685.
Background
About 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations (J Clin Oncol 22:3813–3825, 2004; Hematol Oncol Clin North Am 23:15–34, 2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild-type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate dehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (RAS-pathway or RAS-P).
In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild-type GIST (quadrupleWT or KITWT/PDGFRAWT/SDHWT/RAS-PWT) remains undefined. The aim of this study is to investigate the genomic profile of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, by using a massively parallel sequencing and microarray approach, and compare it with the genomic profile of other GIST subtypes.
Methods
We performed a whole genome analysis using a massively parallel sequencing approach on a total of 16 GIST cases (2 KITWT/PDGFRAWT/SDHWT and SDHBIHC+/SDHAIHC+, 2 KITWT/PDGFRAWT/SDHAmut and SDHBIHC-/SDHAIHC- and 12 cases of KITmut or PDGFRAmut GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KITWT/PDGFRAWTSDHAmut GIST and 19 KITmut or PDGFRAmut GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis.
Results
We found that both cases of quadrupleWT GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadrupleWT GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG).
Conclusion
We report for the first time an integrated genomic picture of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, using massively parallel sequencing and gene expression analyses, and found that quadrupleWT GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadrupleWT GIST represent another unique group within the family of gastrointestintal stromal tumors.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-685) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-685
PMCID: PMC4181714  PMID: 25239601
Gastrointestinal stromal tumors (GIST); Wild-type; KIT; PDGFRA; Succinate dehydrogenase; SDHA; RAS; QuadrupleWT
25.  Food, home and health: the meanings of food amongst Bengali Women in London 
Background
This paper explores the nature of food and plants and their meanings in a British Bengali urban context. It focuses on the nature of plants and food in terms of their role in home making, transnational connections, generational change and concepts of health.
Methods
An ethnographic approach to the research was taken, specific methods included participant observation, focus group discussions and semi-structured interviews. Thirty women of Bengali origin were mostly composed of “mother” and “daughter” pairs. The mothers were over 45 years old and had migrated from Bangladesh as adults and their grown-up daughters grew up in the UK.
Results
Food and plants play an important role in the construction of home “here” (London) while continuing to connect people to home “there” (Sylhet). This role, however, changes and is re-defined across generations. Looking at perceptions of “healthy” and “unhealthy” food, particularly in the context of Bengali food, multiple views of what constitutes “healthy” food exist. However, there appeared to be little two-way dialogue about this concept between the research participants and health professionals. This seems to be based on “cultural” and power differences that need to be addressed for a meaningful dialogue to occur.
Conclusion
In summary, this paper argues that while food is critical to the familial spaces of home (both locally and globally), it is defined by a complex interplay of actors and wider meanings as illustrated by concepts of health and what constitutes Bengali food. Therefore, we call for greater dialogue between health professionals and those they interact with, to allow for an enhanced appreciation of the dynamic nature of food and plants and the diverse perceptions of the role that they play in promoting health.
doi:10.1186/1746-4269-10-44
PMCID: PMC4035805  PMID: 24886061
Food; Home; Garden vegetables; Food perceptions; Health promotion; Bengalis in London; Ethnography

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