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1.  31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one 
Lundqvist, Andreas | van Hoef, Vincent | Zhang, Xiaonan | Wennerberg, Erik | Lorent, Julie | Witt, Kristina | Sanz, Laia Masvidal | Liang, Shuo | Murray, Shannon | Larsson, Ola | Kiessling, Rolf | Mao, Yumeng | Sidhom, John-William | Bessell, Catherine A. | Havel, Jonathan | Schneck, Jonathan | Chan, Timothy A. | Sachsenmeier, Eliot | Woods, David | Berglund, Anders | Ramakrishnan, Rupal | Sodre, Andressa | Weber, Jeffrey | Zappasodi, Roberta | Li, Yanyun | Qi, Jingjing | Wong, Philip | Sirard, Cynthia | Postow, Michael | Newman, Walter | Koon, Henry | Velcheti, Vamsidhar | Callahan, Margaret K. | Wolchok, Jedd D. | Merghoub, Taha | Lum, Lawrence G. | Choi, Minsig | Thakur, Archana | Deol, Abhinav | Dyson, Gregory | Shields, Anthony | Haymaker, Cara | Uemura, Marc | Murthy, Ravi | James, Marihella | Wang, Daqing | Brevard, Julie | Monaghan, Catherine | Swann, Suzanne | Geib, James | Cornfeld, Mark | Chunduru, Srinivas | Agrawal, Sudhir | Yee, Cassian | Wargo, Jennifer | Patel, Sapna P. | Amaria, Rodabe | Tawbi, Hussein | Glitza, Isabella | Woodman, Scott | Hwu, Wen-Jen | Davies, Michael A. | Hwu, Patrick | Overwijk, Willem W. | Bernatchez, Chantale | Diab, Adi | Massarelli, Erminia | Segal, Neil H. | Ribrag, Vincent | Melero, Ignacio | Gangadhar, Tara C. | Urba, Walter | Schadendorf, Dirk | Ferris, Robert L. | Houot, Roch | Morschhauser, Franck | Logan, Theodore | Luke, Jason J. | Sharfman, William | Barlesi, Fabrice | Ott, Patrick A. | Mansi, Laura | Kummar, Shivaani | Salles, Gilles | Carpio, Cecilia | Meier, Roland | Krishnan, Suba | McDonald, Dan | Maurer, Matthew | Gu, Xuemin | Neely, Jaclyn | Suryawanshi, Satyendra | Levy, Ronald | Khushalani, Nikhil | Wu, Jennifer | Zhang, Jinyu | Basher, Fahmin | Rubinstein, Mark | Bucsek, Mark | Qiao, Guanxi | MacDonald, Cameron | Hylander, Bonnie | Repasky, Elizabeth | Chatterjee, Shilpak | Daenthanasanmak, Anusara | Chakraborty, Paramita | Toth, Kyle | Meek, Megan | Garrett-Mayer, Elizabeth | Nishimura, Michael | Paulos, Chrystal | Beeson, Craig | Yu, Xuezhong | Mehrotra, Shikhar | Zhao, Fei | Evans, Kathy | Xiao, Christine | Holtzhausen, Alisha | Hanks, Brent A. | Scharping, Nicole | Menk, Ashley V. | Moreci, Rebecca | Whetstone, Ryan | Dadey, Rebekah | Watkins, Simon | Ferris, Robert | Delgoffe, Greg M. | Peled, Jonathan | Devlin, Sean | Staffas, Anna | Lumish, Melissa | Rodriguez, Kori Porosnicu | Ahr, Katya | Perales, Miguel | Giralt, Sergio | Taur, Ying | Pamer, Eric | van den Brink, Marcel R. M. | Jenq, Robert | Annels, Nicola | Pandha, Hardev | Simpson, Guy | Mostafid, Hugh | Harrington, Kevin | Melcher, Alan | Grose, Mark | Davies, Bronwyn | Au, Gough | Karpathy, Roberta | Shafren, Darren | Ricca, Jacob | Merghoub, Taha | Wolchok, Jedd D. | Zamarin, Dmitriy | Batista, Luciana | Marliot, Florence | Vasaturo, Angela | Carpentier, Sabrina | Poggionovo, Cécile | Frayssinet, Véronique | Fieschi, Jacques | Van den Eynde, Marc | Pagès, Franck | Galon, Jérôme | Hermitte, Fabienne | Smith, Sean G. | Nguyen, Khue | Ravindranathan, Sruthi | Koppolu, Bhanu | Zaharoff, David | Schvartsman, Gustavo | Bassett, Roland | McQuade, Jennifer L. | Haydu, Lauren E. | Davies, Michael A. | Tawbi, Hussein | Glitza, Isabella | Kline, Douglas | Chen, Xiufen | Fosco, Dominick | Kline, Justin | Overacre, Abigail | Chikina, Maria | Brunazzi, Erin | Shayan, Gulidanna | Horne, William | Kolls, Jay | Ferris, Robert L. | Delgoffe, Greg M. | Bruno, Tullia C. | Workman, Creg | Vignali, Dario | Adusumilli, Prasad S. | Ansa-Addo, Ephraim A | Li, Zihai | Gerry, Andrew | Sanderson, Joseph P. | Howe, Karen | Docta, Roslin | Gao, Qian | Bagg, Eleanor A. L. | Tribble, Nicholas | Maroto, Miguel | Betts, Gareth | Bath, Natalie | Melchiori, Luca | Lowther, Daniel E. | Ramachandran, Indu | Kari, Gabor | Basu, Samik | Binder-Scholl, Gwendolyn | Chagin, Karen | Pandite, Lini | Holdich, Tom | Amado, Rafael | Zhang, Hua | Glod, John | Bernstein, Donna | Jakobsen, Bent | Mackall, Crystal | Wong, Ryan | Silk, Jonathan D. | Adams, Katherine | Hamilton, Garth | Bennett, Alan D. | Brett, Sara | Jing, Junping | Quattrini, Adriano | Saini, Manoj | Wiedermann, Guy | Gerry, Andrew | Jakobsen, Bent | Binder-Scholl, Gwendolyn | Brewer, Joanna | Duong, MyLinh | Lu, An | Chang, Peter | Mahendravada, Aruna | Shinners, Nicholas | Slawin, Kevin | Spencer, David M. | Foster, Aaron E. | Bayle, J. Henri | Bergamaschi, Cristina | Ng, Sinnie Sin Man | Nagy, Bethany | Jensen, Shawn | Hu, Xintao | Alicea, Candido | Fox, Bernard | Felber, Barbara | Pavlakis, George | Chacon, Jessica | Yamamoto, Tori | Garrabrant, Thomas | Cortina, Luis | Powell, Daniel J. | Donia, Marco | Kjeldsen, Julie Westerlin | Andersen, Rikke | Westergaard, Marie Christine Wulff | Bianchi, Valentina | Legut, Mateusz | Attaf, Meriem | Dolton, Garry | Szomolay, Barbara | Ott, Sascha | Lyngaa, Rikke | Hadrup, Sine Reker | Sewell, Andrew Kelvin | Svane, Inge Marie | Fan, Aaron | Kumai, Takumi | Celis, Esteban | Frank, Ian | Stramer, Amanda | Blaskovich, Michelle A. | Wardell, Seth | Fardis, Maria | Bender, James | Lotze, Michael T. | Goff, Stephanie L. | Zacharakis, Nikolaos | Assadipour, Yasmine | Prickett, Todd D. | Gartner, Jared J. | Somerville, Robert | Black, Mary | Xu, Hui | Chinnasamy, Harshini | Kriley, Isaac | Lu, Lily | Wunderlich, John | Robbins, Paul F. | Rosenberg, Steven | Feldman, Steven A. | Trebska-McGowan, Kasia | Kriley, Isaac | Malekzadeh, Parisa | Payabyab, Eden | Sherry, Richard | Rosenberg, Steven | Goff, Stephanie L. | Gokuldass, Aishwarya | Blaskovich, Michelle A. | Kopits, Charlene | Rabinovich, Brian | Lotze, Michael T. | Green, Daniel S. | Kamenyeva, Olena | Zoon, Kathryn C. | Annunziata, Christina M. | Hammill, Joanne | Helsen, Christopher | Aarts, Craig | Bramson, Jonathan | Harada, Yui | Yonemitsu, Yoshikazu | Helsen, Christopher | Hammill, Joanne | Mwawasi, Kenneth | Denisova, Galina | Bramson, Jonathan | Giri, Rajanish | Jin, Benjamin | Campbell, Tracy | Draper, Lindsey M. | Stevanovic, Sanja | Yu, Zhiya | Weissbrich, Bianca | Restifo, Nicholas P. | Trimble, Cornelia L. | Rosenberg, Steven | Hinrichs, Christian S. | Tsang, Kwong | Fantini, Massimo | Hodge, James W. | Fujii, Rika | Fernando, Ingrid | Jochems, Caroline | Heery, Christopher | Gulley, James | Soon-Shiong, Patrick | Schlom, Jeffrey | Jing, Weiqing | Gershan, Jill | Blitzer, Grace | Weber, James | McOlash, Laura | Johnson, Bryon D. | Kiany, Simin | Gangxiong, Huang | Kleinerman, Eugenie S. | Klichinsky, Michael | Ruella, Marco | Shestova, Olga | Kenderian, Saad | Kim, Miriam | Scholler, John | June, Carl H. | Gill, Saar | Moogk, Duane | Zhong, Shi | Yu, Zhiya | Liadi, Ivan | Rittase, William | Fang, Victoria | Dougherty, Janna | Perez-Garcia, Arianne | Osman, Iman | Zhu, Cheng | Varadarajan, Navin | Restifo, Nicholas P. | Frey, Alan | Krogsgaard, Michelle | Landi, Daniel | Fousek, Kristen | Mukherjee, Malini | Shree, Ankita | Joseph, Sujith | Bielamowicz, Kevin | Byrd, Tiara | Ahmed, Nabil | Hegde, Meenakshi | Lee, Sylvia | Byrd, David | Thompson, John | Bhatia, Shailender | Tykodi, Scott | Delismon, Judy | Chu, Liz | Abdul-Alim, Siddiq | Ohanian, Arpy | DeVito, Anna Marie | Riddell, Stanley | Margolin, Kim | Magalhaes, Isabelle | Mattsson, Jonas | Uhlin, Michael | Nemoto, Satoshi | Villarroel, Patricio Pérez | Nakagawa, Ryosuke | Mule, James J. | Mailloux, Adam W. | Mata, Melinda | Nguyen, Phuong | Gerken, Claudia | DeRenzo, Christopher | Spencer, David M. | Gottschalk, Stephen | Mathieu, Mélissa | Pelletier, Sandy | Stagg, John | Turcotte, Simon | Minutolo, Nicholas | Sharma, Prannda | Tsourkas, Andrew | Powell, Daniel J. | Mockel-Tenbrinck, Nadine | Mauer, Daniela | Drechsel, Katharina | Barth, Carola | Freese, Katharina | Kolrep, Ulrike | Schult, Silke | Assenmacher, Mario | Kaiser, Andrew | Mullinax, John | Hall, MacLean | Le, Julie | Kodumudi, Krithika | Royster, Erica | Richards, Allison | Gonzalez, Ricardo | Sarnaik, Amod | Pilon-Thomas, Shari | Nielsen, Morten | Krarup-Hansen, Anders | Hovgaard, Dorrit | Petersen, Michael Mørk | Loya, Anand Chainsukh | Junker, Niels | Svane, Inge Marie | Rivas, Charlotte | Parihar, Robin | Gottschalk, Stephen | Rooney, Cliona M. | Qin, Haiying | Nguyen, Sang | Su, Paul | Burk, Chad | Duncan, Brynn | Kim, Bong-Hyun | Kohler, M. Eric | Fry, Terry | Rao, Arjun A. | Teyssier, Noam | Pfeil, Jacob | Sgourakis, Nikolaos | Salama, Sofie | Haussler, David | Richman, Sarah A. | Nunez-Cruz, Selene | Gershenson, Zack | Mourelatos, Zissimos | Barrett, David | Grupp, Stephan | Milone, Michael | Rodriguez-Garcia, Alba | Robinson, Matthew K. | Adams, Gregory P. | Powell, Daniel J. | Santos, João | Havunen, Riikka | Siurala, Mikko | Cervera-Carrascón, Víctor | Parviainen, Suvi | Antilla, Marjukka | Hemminki, Akseli | Sethuraman, Jyothi | Santiago, Laurelis | Chen, Jie Qing | Dai, Zhimin | Wardell, Seth | Bender, James | Lotze, Michael T. | Sha, Huizi | Su, Shu | Ding, Naiqing | Liu, Baorui | Stevanovic, Sanja | Pasetto, Anna | Helman, Sarah R. | Gartner, Jared J. | Prickett, Todd D. | Robbins, Paul F. | Rosenberg, Steven A. | Hinrichs, Christian S. | Bhatia, Shailender | Burgess, Melissa | Zhang, Hui | Lee, Tien | Klingemann, Hans | Soon-Shiong, Patrick | Nghiem, Paul | Kirkwood, John M. | Rossi, John M. | Sherman, Marika | Xue, Allen | Shen, Yueh-wei | Navale, Lynn | Rosenberg, Steven A. | Kochenderfer, James N. | Bot, Adrian | Veerapathran, Anandaraman | Gokuldass, Aishwarya | Stramer, Amanda | Sethuraman, Jyothi | Blaskovich, Michelle A. | Wiener, Doris | Frank, Ian | Santiago, Laurelis | Rabinovich, Brian | Fardis, Maria | Bender, James | Lotze, Michael T. | Waller, Edmund K. | Li, Jian-Ming | Petersen, Christopher | Blazar, Bruce R. | Li, Jingxia | Giver, Cynthia R. | Wang, Ziming | Grossenbacher, Steven K. | Sturgill, Ian | Canter, Robert J. | Murphy, William J. | Zhang, Congcong | Burger, Michael C. | Jennewein, Lukas | Waldmann, Anja | Mittelbronn, Michel | Tonn, Torsten | Steinbach, Joachim P. | Wels, Winfried S. | Williams, Jason B. | Zha, Yuanyuan | Gajewski, Thomas F. | Williams, LaTerrica C. | Krenciute, Giedre | Kalra, Mamta | Louis, Chrystal | Gottschalk, Stephen | Xin, Gang | Schauder, David | Jiang, Aimin | Joshi, Nikhil | Cui, Weiguo | Zeng, Xue | Menk, Ashley V. | Scharping, Nicole | Delgoffe, Greg M. | Zhao, Zeguo | Hamieh, Mohamad | Eyquem, Justin | Gunset, Gertrude | Bander, Neil | Sadelain, Michel | Askmyr, David | Abolhalaj, Milad | Lundberg, Kristina | Greiff, Lennart | Lindstedt, Malin | Angell, Helen K. | Kim, Kyoung-Mee | Kim, Seung-Tae | Kim, Sung | Sharpe, Alan D. | Ogden, Julia | Davenport, Anna | Hodgson, Darren R. | Barrett, Carl | Lee, Jeeyun | Kilgour, Elaine | Hanson, Jodi | Caspell, Richard | Karulin, Alexey | Lehmann, Paul | Ansari, Tameem | Schiller, Annemarie | Sundararaman, Srividya | Lehmann, Paul | Hanson, Jodi | Roen, Diana | Karulin, Alexey | Lehmann, Paul | Ayers, Mark | Levitan, Diane | Arreaza, Gladys | Liu, Fang | Mogg, Robin | Bang, Yung-Jue | O’Neil, Bert | Cristescu, Razvan | Friedlander, Philip | Wassman, Karl | Kyi, Chrisann | Oh, William | Bhardwaj, Nina | Bornschlegl, Svetlana | Gustafson, Michael P. | Gastineau, Dennis A. | Parney, Ian F. | Dietz, Allan B. | Carvajal-Hausdorf, Daniel | Mani, Nikita | Velcheti, Vamsidhar | Schalper, Kurt | Rimm, David | Chang, Serena | Levy, Ronald | Kurland, John | Krishnan, Suba | Ahlers, Christoph Matthias | Jure-Kunkel, Maria | Cohen, Lewis | Maecker, Holden | Kohrt, Holbrook | Chen, Shuming | Crabill, George | Pritchard, Theresa | McMiller, Tracee | Pardoll, Drew | Pan, Fan | Topalian, Suzanne | Danaher, Patrick | Warren, Sarah | Dennis, Lucas | White, Andrew M. | D’Amico, Leonard | Geller, Melissa | Disis, Mary L. | Beechem, Joseph | Odunsi, Kunle | Fling, Steven | Derakhshandeh, Roshanak | Webb, Tonya J. | Dubois, Sigrid | Conlon, Kevin | Bryant, Bonita | Hsu, Jennifer | Beltran, Nancy | Müller, Jürgen | Waldmann, Thomas | Duhen, Rebekka | Duhen, Thomas | Thompson, Lucas | Montler, Ryan | Weinberg, Andrew | Kates, Max | Early, Brandon | Yusko, Erik | Schreiber, Taylor H. | Bivalacqua, Trinity J. | Ayers, Mark | Lunceford, Jared | Nebozhyn, Michael | Murphy, Erin | Loboda, Andrey | Kaufman, David R. | Albright, Andrew | Cheng, Jonathan | Kang, S. Peter | Shankaran, Veena | Piha-Paul, Sarina A. | Yearley, Jennifer | Seiwert, Tanguy | Ribas, Antoni | McClanahan, Terrill K. | Cristescu, Razvan | Mogg, Robin | Ayers, Mark | Albright, Andrew | Murphy, Erin | Yearley, Jennifer | Sher, Xinwei | Liu, Xiao Qiao | Nebozhyn, Michael | Lunceford, Jared | Joe, Andrew | Cheng, Jonathan | Plimack, Elizabeth | Ott, Patrick A. | McClanahan, Terrill K. | Loboda, Andrey | Kaufman, David R. | Forrest-Hay, Alex | Guyre, Cheryl A. | Narumiya, Kohei | Delcommenne, Marc | Hirsch, Heather A. | Deshpande, Amit | Reeves, Jason | Shu, Jenny | Zi, Tong | Michaelson, Jennifer | Law, Debbie | Trehu, Elizabeth | Sathyanaryanan, Sriram | Hodkinson, Brendan P. | Hutnick, Natalie A. | Schaffer, Michael E. | Gormley, Michael | Hulett, Tyler | Jensen, Shawn | Ballesteros-Merino, Carmen | Dubay, Christopher | Afentoulis, Michael | Reddy, Ashok | David, Larry | Fox, Bernard | Jayant, Kumar | Agrawal, Swati | Agrawal, Rajendra | Jeyakumar, Ghayathri | Kim, Seongho | Kim, Heejin | Silski, Cynthia | Suisham, Stacey | Heath, Elisabeth | Vaishampayan, Ulka | Vandeven, Natalie | Viller, Natasja Nielsen | O’Connor, Alison | Chen, Hui | Bossen, Bolette | Sievers, Eric | Uger, Robert | Nghiem, Paul | Johnson, Lisa | Kao, Hsiang-Fong | Hsiao, Chin-Fu | Lai, Shu-Chuan | Wang, Chun-Wei | Ko, Jenq-Yuh | Lou, Pei-Jen | Lee, Tsai-Jan | Liu, Tsang-Wu | Hong, Ruey-Long | Kearney, Staci J. | Black, Joshua C. | Landis, Benjamin J. | Koegler, Sally | Hirsch, Brooke | Gianani, Roberto | Kim, Jeffrey | He, Ming-Xiao | Zhang, Bingqing | Su, Nan | Luo, Yuling | Ma, Xiao-Jun | Park, Emily | Kim, Dae Won | Copploa, Domenico | Kothari, Nishi | doo Chang, Young | Kim, Richard | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Knaus, Hanna A. | Berglund, Sofia | Hackl, Hubert | Karp, Judith E. | Gojo, Ivana | Luznik, Leo | Hong, Henoch S. | Koch, Sven D. | Scheel, Birgit | Gnad-Vogt, Ulrike | Kallen, Karl-Josef | Wiegand, Volker | Backert, Linus | Kohlbacher, Oliver | Hoerr, Ingmar | Fotin-Mleczek, Mariola | Billingsley, James M. | Koguchi, Yoshinobu | Conrad, Valerie | Miller, William | Gonzalez, Iliana | Poplonski, Tomasz | Meeuwsen, Tanisha | Howells-Ferreira, Ana | Rattray, Rogan | Campbell, Mary | Bifulco, Carlo | Dubay, Christopher | Bahjat, Keith | Curti, Brendan | Urba, Walter | Vetsika, E-K | Kallergi, G. | Aggouraki, Despoina | Lyristi, Z. | Katsarlinos, P. | Koinis, Filippos | Georgoulias, V. | Kotsakis, Athanasios | Martin, Nathan T. | Aeffner, Famke | Kearney, Staci J. | Black, Joshua C. | Cerkovnik, Logan | Pratte, Luke | Kim, Rebecca | Hirsch, Brooke | Krueger, Joseph | Gianani, Roberto | Martínez-Usatorre, Amaia | Jandus, Camilla | Donda, Alena | Carretero-Iglesia, Laura | Speiser, Daniel E. | Zehn, Dietmar | Rufer, Nathalie | Romero, Pedro | Panda, Anshuman | Mehnert, Janice | Hirshfield, Kim M. | Riedlinger, Greg | Damare, Sherri | Saunders, Tracie | Sokol, Levi | Stein, Mark | Poplin, Elizabeth | Rodriguez-Rodriguez, Lorna | Silk, Ann | Chan, Nancy | Frankel, Melissa | Kane, Michael | Malhotra, Jyoti | Aisner, Joseph | Kaufman, Howard L. | Ali, Siraj | Ross, Jeffrey | White, Eileen | Bhanot, Gyan | Ganesan, Shridar | Monette, Anne | Bergeron, Derek | Amor, Amira Ben | Meunier, Liliane | Caron, Christine | Morou, Antigoni | Kaufmann, Daniel | Liberman, Moishe | Jurisica, Igor | Mes-Masson, Anne-Marie | Hamzaoui, Kamel | Lapointe, Rejean | Mongan, Ann | Ku, Yuan-Chieh | Tom, Warren | Sun, Yongming | Pankov, Alex | Looney, Tim | Au-Young, Janice | Hyland, Fiona | Conroy, Jeff | Morrison, Carl | Glenn, Sean | Burgher, Blake | Ji, He | Gardner, Mark | Mongan, Ann | Omilian, Angela R. | Conroy, Jeff | Bshara, Wiam | Angela, Omilian | Burgher, Blake | Ji, He | Glenn, Sean | Morrison, Carl | Mongan, Ann | Obeid, Joseph M. | Erdag, Gulsun | Smolkin, Mark E. | Deacon, Donna H. | Patterson, James W. | Chen, Lieping | Bullock, Timothy N. | Slingluff, Craig L. | Obeid, Joseph M. | Erdag, Gulsun | Deacon, Donna H. | Slingluff, Craig L. | Bullock, Timothy N. | Loffredo, John T. | Vuyyuru, Raja | Beyer, Sophie | Spires, Vanessa M. | Fox, Maxine | Ehrmann, Jon M. | Taylor, Katrina A. | Korman, Alan J. | Graziano, Robert F. | Page, David | Sanchez, Katherine | Ballesteros-Merino, Carmen | Martel, Maritza | Bifulco, Carlo | Urba, Walter | Fox, Bernard | Patel, Sapna P. | De Macedo, Mariana Petaccia | Qin, Yong | Reuben, Alex | Spencer, Christine | Guindani, Michele | Bassett, Roland | Wargo, Jennifer | Racolta, Adriana | Kelly, Brian | Jones, Tobin | Polaske, Nathan | Theiss, Noah | Robida, Mark | Meridew, Jeffrey | Habensus, Iva | Zhang, Liping | Pestic-Dragovich, Lidija | Tang, Lei | Sullivan, Ryan J. | Logan, Theodore | Khushalani, Nikhil | Margolin, Kim | Koon, Henry | Olencki, Thomas | Hutson, Thomas | Curti, Brendan | Roder, Joanna | Blackmon, Shauna | Roder, Heinrich | Stewart, John | Amin, Asim | Ernstoff, Marc S. | Clark, Joseph I. | Atkins, Michael B. | Kaufman, Howard L. | Sosman, Jeffrey | Weber, Jeffrey | McDermott, David F. | Weber, Jeffrey | Kluger, Harriet | Halaban, Ruth | Snzol, Mario | Roder, Heinrich | Roder, Joanna | Asmellash, Senait | Steingrimsson, Arni | Blackmon, Shauna | Sullivan, Ryan J. | Wang, Chichung | Roman, Kristin | Clement, Amanda | Downing, Sean | Hoyt, Clifford | Harder, Nathalie | Schmidt, Guenter | Schoenmeyer, Ralf | Brieu, Nicolas | Yigitsoy, Mehmet | Madonna, Gabriele | Botti, Gerardo | Grimaldi, Antonio | Ascierto, Paolo A. | Huss, Ralf | Athelogou, Maria | Hessel, Harald | Harder, Nathalie | Buchner, Alexander | Schmidt, Guenter | Stief, Christian | Huss, Ralf | Binnig, Gerd | Kirchner, Thomas | Sellappan, Shankar | Thyparambil, Sheeno | Schwartz, Sarit | Cecchi, Fabiola | Nguyen, Andrew | Vaske, Charles | Hembrough, Todd
Journal for Immunotherapy of Cancer  2016;4(Suppl 1):1-106.
doi:10.1186/s40425-016-0172-7
PMCID: PMC5123387
2.  BubR1 Insufficiency Results in Decreased Macrophage Proliferation and Attenuated Atherogenesis in Apolipoprotein E‐Deficient Mice 
Background
Budding uninhibited by benzimidazole‐related 1 (BubR1), a cell cycle–related protein, is an essential component of the spindle checkpoint that regulates cell division. BubR1 insufficiency causes early aging‐associated vascular phenotypes. We generated low‐BubR1‐expressing mutant (BubR1 L/L) and apolipoprotein E‐deficient (ApoE −/−) mice (BubR1 L/L ‐ApoE −/− mice) to investigate the effects of BubR1 on atherosclerosis.
Methods and Results
Eight‐week‐old male BubR1 L/L ‐ApoE −/− mice and age‐matched ApoE −/− mice were used in this study. Atherosclerotic lesion development after being fed a high‐cholesterol diet for 12 weeks was inhibited in BubR1 L/L ‐ApoE −/− mice compared with ApoE −/− mice, and was accompanied by decreased accumulation of macrophages. To address the relative contribution of BubR1 on bone marrow–derived cells compared with non‐bone marrow–derived cells, we performed bone marrow transplantation in ApoE −/− and BubR1 L/L ‐ApoE −/− mice. Decreased BubR1 in bone marrow cells and non‐bone marrow–derived cells decreased the atherosclerotic burden. In vitro assays indicated that decreased BubR1 expression impaired proliferation, but not migration, of bone marrow–derived macrophages.
Conclusions
BubR1 may represent a promising new target for regulating atherosclerosis.
doi:10.1161/JAHA.116.004081
PMCID: PMC5079050  PMID: 27664806
atherosclerosis; cell cycle; macrophage; proliferation; Atherosclerosis; Vascular Disease; Genetically Altered and Transgenic Models
3.  Improved quality of life in patients with no-option critical limb ischemia undergoing gene therapy with DVC1-0101 
Scientific Reports  2016;6:30035.
Critical limb ischemia (CLI) has a poor prognosis and adversely affects patients’ quality of life (QOL). Therapeutic angiogenesis may improve mobility, mortality, and QOL in CLI patients. However, the effectiveness of gene therapy on such patients’ QOL is unknown. DVC1-0101, a non-transmissible recombinant Sendai virus vector expressing human fibroblast growth factor-2 gene, demonstrated safety and efficacy in a phase I/II study of CLI patients. We investigated the effects of DVC1-0101 on QOL in this cohort. QOL was assessed using the Short Form-36 health survey version 2 (SF-36) in 12 patients at pre-administration, 28 days, and 3, 6, and 12 months post-treatment. We examined differences between pre and post-administration QOL scores and correlations between QOL scores and vascular parameters. Patients demonstrated low baselines scores on every SF-36 dimension. Post-treatment scores showed significant improvements in physical functioning at 3 and 6 months (P < 0.05), role-physical at 3, 6, and 12 months (P < 0.05), bodily pain at 1, 3, 6, and 12 months (P < 0.05), vitality at 1, 6, and 12 months (P < 0.05), and physical component summary at 6 and 12 months (P < 0.05). DVC1-0101-based gene therapy may improve QOL in CLI patients over a 6-month period.
doi:10.1038/srep30035
PMCID: PMC4945920  PMID: 27418463
4.  Dendritic cell-based vaccine for pancreatic cancer in Japan 
“Vaccell” is a dendritic cell (DC)-based cancer vaccine which has been established in Japan. The DCs play central roles in deciding the direction of host immune reactions as well as antigen presentation. We have demonstrated that DCs treated with a streptococcal immune adjuvant OK-432, produce interleukin-12, induce Th1-dominant state, and elicit anti-tumor effects, more powerful than those treated with the known DC-maturating factors. We therefore decided to mature DCs by the OK-432 for making an effective DC vaccine, Vaccell. The 255 patients with inoperable pancreatic cancer who received standard chemotherapy combined with DC vaccines, were analyzed retrospectively. Survival time of the patients with positive delayed type hypersensitivity (DTH) skin reaction was significantly prolonged as compared with that of the patients with negative DTH. The findings strongly suggest that there may be “Responders” for the DC vaccine in advanced pancreatic cancer patients. We next conducted a small-scale prospective clinical study. In this trial, we pulsed HLA class II-restricted WT1 peptide (WT1-II) in addition to HLA class I-restricted peptide (WT1-I) into the DCs. Survival of the patients received WT1-I and -II pulsed DC vaccine was significantly extended as compared to that of the patients received DCs pulsed with WT1-I or WT1-II alone. Furthermore, WT1-specific DTH positive patients showed significantly improved the overall survival as well as progression-free survival as compared to the DTH negative patients. The activation of antigen-specific immune responses by DC vaccine in combination with standard chemotherapy may be associated with a good clinical outcome in advanced pancreatic cancer. We are now planning a pivotal study of the Vaccell in appropriate protocols in Japan.
doi:10.4292/wjgpt.v7.i1.133
PMCID: PMC4734946  PMID: 26855819
Dendritic cell; Cancer vaccine; Pancreatic cancer; Cancer immunotherapy; Anti-cancer immunity
5.  Effective recovery of highly purified CD326+ tumor cells from lavage fluid of patients treated with a novel cell-free and concentrated ascites reinfusion therapy (KM-CART) 
SpringerPlus  2015;4:780.
For the production of tumor-specific vaccines, including dendritic cell (DC) vaccines, the tumor cells themselves are an ideal source. Floating tumor cells in the ascites fluid from patients with malignant ascites are a good candidate source, but it is not easy to obtain pure tumor cells from ascites because of various types of cell contamination as well as protein aggregates. We here report an effective method to recover pure tumor cells from malignant ascites. We used lavage fluid from 13 patients with malignant ascites who were treated with modified cell-free and concentrated ascites reinfusion therapy (KM-CART). Cellular components were separated from the lavage fluid by centrifugation, enzymatic digestion and hemolysis. Tumor cells were purified by depleting CD45+ leukocytes with antibody-conjugated magnetic beads. The tumor cell lysate was extracted by freeze-and-thaw cycles. The mean obtained total cell number was 7.50 × 107 cells (range 4.40 × 106–2.48 × 108 cells). From this fraction, 6.39 × 106 (range 3.23 × 105–2.53 × 107) CD45− cells were collected, and the tumor cell purity was over 80 % defined as CD45−CD326+. A sufficient amount of tumor lysate, average  = 2416 μg (range 25–8743 μg), was extracted from CD45−CD326+ tumor cells. We here established an effective method to produce highly purified tumor cells from KM-CART lavage fluid. The clinical feasibility of this simple preparation method for generating tumor lysate should be examined in clinical studies of DC vaccines.
doi:10.1186/s40064-015-1508-3
PMCID: PMC4683161  PMID: 26702369
CART; Tumor lysate; Ascites
8.  Therapeutic effect of intratumoral injections of dendritic cells for locally recurrent gastric cancer: a case report 
An 80-year-old man with a history of gastric cancer and pulmonary emphysema underwent a distal gastrectomy for gastric cancer in 1997. In 2010, an endoscopic examination revealed a depressed-type lesion at the oral side of the anastomosis, which was diagnosed as signet-ring adenocarcinoma. Surgical management was considered, but was rejected because of obstructive and restrictive respiratory events. Chemotherapy was terminated because of adverse events. Endoscopy was used to administer intratumoral injections of dendritic cells (DCs) targeting synthesized peptides of Wilms tumor 1 (WT1) and mucin 1, cell-surface associated (MUC1). An immunohistochemical analysis of the tumor samples indicated positivity for WT1 and MUC1. One month after seven cycles of DC had been administered (between November 2010 and April 2011), no suspicious lesions were evident, and his biopsy results were normal. The patient has been in remission for 30 months. Intratumoral injections of DCs showed therapeutic effects in this patient, who could not undergo endoscopic submucosal dissection or surgery.
doi:10.1186/1477-7819-12-390
PMCID: PMC4320508  PMID: 25526950
Dendritic cell; WT1; MUC1; Immunotherapy and recurrent gastric cancer
9.  Ex Vivo Generation of Highly Purified and Activated Natural Killer Cells from Human Peripheral Blood 
Human Gene Therapy Methods  2013;24(4):241-252.
Abstract
Adoptive immunotherapy using natural killer (NK) cells has been a promising treatment for intractable malignancies; however, there remain a number of difficulties with respect to the shortage and limited anticancer potency of the effector cells. We here established a simple feeder-free method to generate purified (>90%) and highly activated NK cells from human peripheral blood-derived mononuclear cells (PBMCs). Among the several parameters, we found that CD3 depletion, high-dose interleukin (IL)-2, and use of a specific culture medium were sufficient to obtain highly purified, expanded (∼200-fold) and activated CD3−/CD56+ NK cells from PBMCs, which we designated zenithal-NK (Z-NK) cells. Almost all Z-NK cells expressed the lymphocyte-activated marker CD69 and showed dramatically high expression of activation receptors (i.e., NKG2D), interferon-γ, perforin, and granzyme B. Importantly, only 2 hours of reaction at an effector/target ratio of 1:1 was sufficient to kill almost all K562 cells, and the antitumor activity was also replicated in tumor-bearing mice in vivo. Cytolysis was specific for various tumor cells, but not for normal cells, irrespective of MHC class I expression. These findings strongly indicate that Z-NK cells are purified, expanded, and near-fully activated human NK cells and warrant further investigation in a clinical setting.
Saito and colleagues report on a simple feeder-free method for the generation of purified (>90%) and highly activated natural killer (NK) cells from human peripheral blood-derived mononuclear cells (PBMCs). Almost all of the NK cells derived by this method express lymphocyte activation markers and are capable of lysing cells in tumor-bearing mice in vivo.
doi:10.1089/hgtb.2012.183
PMCID: PMC3753730  PMID: 23885718
10.  The feasibility and clinical effects of dendritic cell-based immunotherapy targeting synthesized peptides for recurrent ovarian cancer 
Background
Despite the increased rate of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Dendritic cell (DC)-based immunotherapy has been developed as a novel strategy for generating antitumor immunity as part of cancer treatments. The present study aimed to assess the feasibility and clinical effects of DC therapy for recurrent ovarian cancer (ROC).
Methods
This retrospective study included 56 ROC patients who initially received standard chemotherapy followed by DC-based immunotherapy targeting synthesized peptides at 2 institutions between March 2007 and August 2013. The adverse events (AEs) and clinical responses were examined.
Results
No serious treatment-related AEs were observed. Seventy one percent of the enrolled patients developed an immunologic response. The median survival time (MST) from ROC diagnosis was 30.4 months, and that from the first vaccination was 14.5 months. Albumin levels of ≥4.0 g/dL and lactate dehydrogenase levels of <200 IU/L before vaccination were identified as significant independent factors by multivariate Cox proportional hazard analysis. The MST from the first vaccination in patients with albumin levels of ≥4.0 and <4.0 g/dL were 19.9 and 11.6 months, respectively. The corresponding disease control rates were 36% and 15%, respectively.
Conclusions
Our results demonstrated the feasibility and potential clinical effectiveness of DC-based immunotherapy for ROC patients. Additionally, a good nutritional status might be an important factor for further clinical effects.
doi:10.1186/1757-2215-7-48
PMCID: PMC4108140  PMID: 25298213
Dendritic cell; WT1; MUC1; CA125; Immunotherapy and recurrent ovarian cancer
11.  Endogenous Cardiac Troponin T Modulates Ca2+-Mediated Smooth Muscle Contraction 
Scientific Reports  2012;2:979.
Mechanisms linked to actin filaments have long been thought to cooperate in smooth muscle contraction, although key molecules were unclear. We show evidence that cardiac troponin T (cTnT) substantially contributes to Ca2+-mediated contraction in a physiological range of cytosolic Ca2+ concentration ([Ca2+]i). cTnT was detected in various smooth muscles of the aorta, trachea, gut and urinary bladder, including in humans. Also, cTnT was distributed along with tropomyosin in smooth muscle cells, suggesting that these proteins are ready to cause smooth muscle contraction. In chemically permeabilised smooth muscle of cTnT+/− mice in which cTnT reduced to ~50%, the Ca2+-force relationship was shifted toward greater [Ca2+]i, indicating a sizeable contribution of cTnT to smooth muscle contraction at [Ca2+]i < 1 μM. Furthermore, addition of supplemental TnI and TnC reconstructed a troponin system to enhance contraction. The results indicated that a Tn/Tn-like system on actin-filaments cooperates together with the thick-filament pathway.
doi:10.1038/srep00979
PMCID: PMC3522072  PMID: 23248744
12.  Cytokine-based high log-scale expansion of functional human dendritic cells from cord-blood CD34-positive cells 
Scientific Reports  2011;1:174.
Dendritic cells (DCs) play a crucial role in maintaining the immune system. Though DC-based cancer immunotherapy has been suggested as a potential treatment for various kinds of malignancies, its clinical efficacies are still insufficient in many human trials. Issues that limit the clinical efficacy of DC-based immunotherapy, as well as the difficulty of the industrial production of DCs, are largely due to the limited number of autologous DCs available from each patient. We here established a possible breakthrough, a simple cytokine-based culture method to expand the log-scale order of functional human DCs. Floating cultivation of cord-blood CD34+ cells under an optimized cytokine cocktail led these progenitor cells to stable log-scale proliferation and to DC differentiation. The expanded DCs had typical features of conventional myeloid DCs in vitro. Therefore, the concept of DC expansion should contribute significantly to the progress of DC immunotherapy.
doi:10.1038/srep00174
PMCID: PMC3240956  PMID: 22355689
13.  RIG-I Helicase-Independent Pathway in Sendai Virus-Activated Dendritic Cells Is Critical for Preventing Lung Metastasis of AT6.3 Prostate Cancer123 
Neoplasia (New York, N.Y.)  2010;12(11):906-914.
We recently demonstrated highly efficient antitumor immunity against dermal tumors of B16F10 murine melanoma with the use of dendritic cells (DCs) activated by replication-competent, as well as nontransmissible-type, recombinant Sendai viruses (rSeV), and proposed a new concept, “immunostimulatory virotherapy,” for cancer immunotherapy. However, there has been little information on the efficacies of thismethod: 1) inmore clinically relevant situations including metastatic diseases, 2) on other tumor types and other animal species, and 3) on the related molecular/cellular mechanisms. In this study, therefore, we investigated the efficacy of vaccinating DCs activated by fusion gene-deleted nontransmissible rSeV on a rat model of lung metastasis using a highly malignant subline of Dunning R-3327 prostate cancer, AT6.3. rSeV/dF-green fluorescent protein (GFP)-activated bone marrow-derived DCs (rSeV/dF-GFP-DC), consistent with results previously observed in murine DCs. Vaccination of rSeV/dF-GFP-DC was highly effective at preventing lung metastasis after intravenous loading of R-3327 tumor cells, compared with the effects observed with immature DCs or lipopolysaccharide-activated DCs. Interestingly, neither CTL activity nor DC trafficking showed any apparent difference among groups. Notably, rSeV/dF-DCs expressing a dominant-negative mutant of retinoic acid-inducible gene I (RIG-I) (rSeV/dF-RIGIC-DC), an RNA helicase that recognizes the rSeV genome for inducing type I interferons, largely lost the expression of proinflammatory cytokines without any impairment of antitumor activity. These results indicate the essential role of RIG-I-independent signaling on antimetastatic effect induced by rSeV-activated DCs and may provide important insights to DC-based immunotherapy for advanced malignancies.
PMCID: PMC2978913  PMID: 21076616
14.  Podoplanin in cancer cells is experimentally able to attenuate prolymphangiogenic and lymphogenous metastatic potentials of lung squamoid cancer cells 
Molecular Cancer  2010;9:287.
Background
Podoplanin, a mucin-like transmembrane glycoprotein, is reportedly expressed in a variety of malignant cells and is generally regarded as a factor for promoting tumor progression in conventional studies. By contrast, a clinicopathologically conflicting role for podoplanin, namely as a favorable prognostic factor for patients with lung/cervical squamous cell carcinoma (SCC), has recently been reported. Here, we investigated the role of podoplanin expressed in lung squamoid cancer cells (LSCCs) in experimental tumor progression.
Results
Using EBC-1 cells, a lung SCC cell line without podoplanin expression and with lymphogenous metastatic potential, stable transformants with or without an exogenous human podoplanin gene were established and applied to a mouse tumor implantation model. In vivo examinations revealed that exogenous podoplanin had no influence on tumor growth, whereas it significantly restrained axillary lymph node metastasis associated with the suppression of lymphangiogenesis but not angiogenesis and with the downregulation of EBC-1-derived VEGF-C but not other lymphangiogenesis-related factor mRNAs in implanted tumor tissue. In vitro examinations to clarify the mechanisms underlying the in vivo phenomena revealed that exogenous podoplanin significantly suppressed the expression of VEGF-C mRNA and of the protein, and also increased the level of phosphorylated c-jun N terminal kinase (JNK) in EBC-1 cells. The former effect of exogenous podoplanin was impaired by treatment with either JNK inhibitor sp600125 or podoplanin-siRNA, and the latter effect was impaired by treatment with podoplanin-siRNA, suggesting that podoplanin was able to activate JNK, thereby downregulating VEGF-C gene expression in LSCCs (podoplanin-JNK-VEGF-C axis). Furthermore, supporting evidence in regard to the axis present in LSCCs was obtained from similar experiments using H157 cells, another lung SCC cell line expressing endogenous podoplanin.
Conclusions
Our findings suggested that LSCC-associated podoplanin was functional and could attenuate the potential for lymph node metastasis, possibly based on the suppression of tumor lymphangiogenesis; thus, podoplanin in cancer cells may become a useful biomarker to measure the malignancy of lung SCC.
doi:10.1186/1476-4598-9-287
PMCID: PMC2987985  PMID: 21034514
15.  Cytokine-Based Log-Scale Expansion of Functional Murine Dendritic Cells 
PLoS ONE  2009;4(8):e6674.
Background
Limitations of the clinical efficacy of dendritic cell (DC)-based immunotherapy, as well as difficulties in their industrial production, are largely related to the limited number of autologous DCs from each patient. We here established a possible breakthrough, a simple and cytokine-based culture method to realize a log-scale order of functional murine DCs (>1,000-fold), which cells were used as a model before moving to human studies.
Methodology/Principal Findings
Floating cultivation of lineage-negative hematopoietic progenitors from bone marrow in an optimized cytokine cocktail (FLT3-L, IL-3, IL-6, and SCF) led to a stable log-scale proliferation of these cells, and a subsequent differentiation study using IL-4/GM-CSF revealed that 3-weeks of expansion was optimal to produce CD11b+/CD11c+ DC-like cells. The expanded DCs had typical features of conventional myeloid DCs in vitro and in vivo, including identical efficacy as tumor vaccines.
Conclusions/Significance
The concept of DC expansion should make a significant contribution to the progress of DC-based immunotherapy.
doi:10.1371/journal.pone.0006674
PMCID: PMC2723913  PMID: 19688095
16.  Suppression of Sproutys Has a Therapeutic Effect for a Mouse Model of Ischemia by Enhancing Angiogenesis 
PLoS ONE  2009;4(5):e5467.
Sprouty proteins (Sproutys) inhibit receptor tyrosine kinase signaling and control various aspects of branching morphogenesis. In this study, we examined the physiological function of Sproutys in angiogenesis, using gene targeting and short-hairpin RNA (shRNA) knockdown strategies. Sprouty2 and Sprouty4 double knockout (KO) (DKO) mice were embryonic-lethal around E12.5 due to cardiovascular defects. The number of peripheral blood vessels, but not that of lymphatic vessels, was increased in Sprouty4 KO mice compared with wild-type (WT) mice. Sprouty4 KO mice were more resistant to hind limb ischemia and soft tissue ischemia than WT mice were, because Sprouty4 deficiency causes accelerated neovascularization. Moreover, suppression of Sprouty2 and Sprouty4 expression in vivo by shRNA targeting accelerated angiogenesis and has a therapeutic effect in a mouse model of hind limb ischemia. These data suggest that Sproutys are physiologically important negative regulators of angiogenesis in vivo and novel therapeutic targets for treating peripheral ischemic diseases.
doi:10.1371/journal.pone.0005467
PMCID: PMC2674940  PMID: 19424491
17.  Spreds Are Essential for Embryonic Lymphangiogenesis by Regulating Vascular Endothelial Growth Factor Receptor 3 Signaling▿  
Molecular and Cellular Biology  2007;27(12):4541-4550.
Spred/Sprouty family proteins negatively regulate growth factor-induced ERK activation. Although the individual physiological roles of Spred-1 and Spred-2 have been investigated using gene-disrupted mice, the overlapping functions of Spred-1 and Spred-2 have not been clarified. Here, we demonstrate that the deletion of both Spred-1 and Spred-2 resulted in embryonic lethality at embryonic days 12.5 to 15.5 with marked subcutaneous hemorrhage, edema, and dilated lymphatic vessels filled with erythrocytes. This phenotype resembled that of Syk−/− and SLP-76−/− mice with defects in the separation of lymphatic vessels from blood vessels. The number of LYVE-1-positive lymphatic vessels and lymphatic endothelial cells increased markedly in Spred-1/2-deficient embryos compared with WT embryos, while the number of blood vessels was not different. Ex vivo colony assay revealed that Spred-1/2 suppressed lymphatic endothelial cell proliferation and/or differentiation. In cultured cells, the overexpression of Spred-1 or Spred-2 strongly suppressed vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3-mediated ERK activation, while Spred-1/2-deficient cells were extremely sensitive to VEGFR-3 signaling. These data suggest that Spreds play an important role in lymphatic vessel development by negatively regulating VEGF-C/VEGFR-3 signaling.
doi:10.1128/MCB.01600-06
PMCID: PMC1900061  PMID: 17438136
18.  The effects of flavoxate hydrochloride on voltage-dependent L-type Ca2+ currents in human urinary bladder 
British Journal of Pharmacology  2005;146(1):25-32.
The effects of flavoxate hydrochloride (Bladderon®, piperidinoethyl-3-methylflavone-8-carboxylate; hereafter referred as flavoxate) on voltage-dependent nifedipine-sensitive inward Ba2+ currents in human detrusor myocytes were investigated using a conventional whole-cell patch-clamp. Tension measurement was also performed to study the effects of flavoxate on K+-induced contraction in human urinary bladder.Flavoxate caused a concentration-dependent reduction of the K+-induced contraction of human urinary bladder.In human detrusor myocytes, flavoxate inhibited the peak amplitude of voltage-dependent nifedipine-sensitive inward Ba2+ currents in a voltage- and concentration-dependent manner (Ki=10 μM), and shifted the steady-state inactivation curve of Ba2+ currents to the left at a holding potential of −90 mV.Immunohistochemical studies indicated the presence of the α1C subunit protein, which is a constituent of human L-type Ca2+ channels (CaV1.2), in the bundles of human detrusor smooth muscle.These results suggest that flavoxate caused muscle relaxation through the inhibition of L-type Ca2+ channels in human detrusor.
doi:10.1038/sj.bjp.0706284
PMCID: PMC1576239  PMID: 15965499
Flavoxate; frequency of micturition; human detrusor myocytes; L-type Ca2+ channels; overactive bladder; spasmolytic agent
19.  Dual action of ZD6169, a novel K+ channel opener, on ATP-sensitive K+ channels in pig urethral myocytes 
British Journal of Pharmacology  2001;133(1):154-164.
The effects of ZD6169, a novel K+ channel opener, on both membrane and unitary currents in pig urethra were investigated using patch-clamp techniques. Its effect was also examined on currents in inside-out patches of COS7 cells expressing carboxy terminus truncated inwardly rectifying K+ channel (Kir6.2) subunits (Kir6.2ΔC36) which form ATP-sensitive K+ channels (KATP channels).In current-clamp mode, ZD6169 (⩽10 μM) induced a concentration-dependent membrane hyperpolarization. Higher concentrations (⩾30 μM) caused a transient membrane hyperpolarization, followed by a gradual membrane depolarization. On removal of ZD6169, an after hyperpolarization was observed.In conventional voltage-clamp configuration, at −50 mV in symmetrical 140 mM K+ conditions, ZD6169 (100 μM) caused a transient inward current which gradually decayed. Removal of ZD6169 evoked a much larger amplitude K+ current with a similar time course.ZD6169 produced an inward glibenclamide-sensitive K+ current, demonstrating a bell-shaped concentration-response relationship.In cell-attached configuration in symmetrical 140 mM K+ conditions, ZD6169 (⩽30 μM) activated an KATP channel which was reversibly suppressed by application of glibenclamide. In contrast, ZD6169 (100 μM) inhibited the activity of the levcromakalim-induced KATP channels.ZD6169 (100 μM) had no significant effect on the channel activity of Kir6.2ΔC36 in inside-out configuration, although cibenzoline greatly suppressed the channel activity.These results demonstrate that ZD6169 possesses a dual effect on the activity of the KATP channel; activating at low concentration and inhibiting at higher concentration.
doi:10.1038/sj.bjp.0704042
PMCID: PMC1572759  PMID: 11325805
Carboxy terminus truncated Kir6.2; dual action; K+ channel opener; unstable urinary bladder; urinary bladder-selectivity; ZD6169
20.  The effects of caffeine on ATP-sensitive K+ channels in smooth muscle cells from pig urethra 
British Journal of Pharmacology  2000;131(3):505-513.
The effects of caffeine on both levcromakalim-induced macroscopic and unitary currents in pig proximal urethra were investigated by the use of patch-clamp techniques (conventional whole-cell configuration and cell-attached configuration). The effects of caffeine were also examined on currents in inside-out patches of COS7 cells expressing carboxy terminus truncated inwardly rectifying K+ channel (Kir6.2) subunits (i.e. Kir6.2ΔC36) which form ATP-sensitive K+ channels (KATP channels).In conventional whole-cell configuration, the levcromakalim (100 μM)-induced inward current (symmetrical 140 mM K+ conditions) was inhibited by caffeine (⩾1 mM) at a holding potential of −50 mV. In contrast, ryanodine (10 μM) caused no significant inhibitory effect on the gradual decay of the levcromakalim-induced current at −50 mV.The amplitude of the 30 μM levcromakalim-induced current was enhanced by 3-isobutyl-1-methylxanthine (IBMX, 100 μM).In cell-attached configuration, the levcromakalim-induced K+ channel openings were inhibited by subsequent application of 10 mM caffeine, decreasing the channel open probability at −50 mV.Reverse transcriptase-polymerase chain reaction (RT–PCR) analysis revealed the presence of Kir6.2 transcript in pig urethra.Caffeine (⩾3 mM) inhibited the channel activity of Kir6.2ΔC36 expressed in COS7 cells (3 mM caffeine, 65±6%, n=4; 10 mM caffeine, 29±2%, n=4).These results suggest that caffeine can inhibit the activity of KATP channels through a direct blocking effect on the pore-forming Kir subunit.
doi:10.1038/sj.bjp.0703586
PMCID: PMC1572345  PMID: 11015301
ATP-sensitive K+ channel; caffeine; carboxy terminus truncated Kir6.2; glibenclamide; levcromakalim; phosphodiesterase inhibitor

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