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1.  37th International Symposium on Intensive Care and Emergency Medicine (part 1 of 3) 
Karavana, V. | Smith, I. | Kanellis, G. | Sigala, I. | Kinsella, T. | Zakynthinos, S. | Liu, L. | Chen, J. | Zhang, X. | Liu, A. | Guo, F. | Liu, S. | Yang, Y. | Qiu, H. | Grimaldi, D. G. | Kaya, E. | Acicbe, O. | Kayaalp, I. | Asar, S. | Dogan, M. | Eren, G. | Hergunsel, O. | Pavelescu, D. | Grintescu, I. | Mirea, L. | Guanziroli, M. | Gotti, M. | Marino, A. | Cressoni, M. | Vergani, G. | Chiurazzi, C. | Chiumello, D. | Gattinoni, L. | Guanziroli, M. | Gotti, M. | Vergani, G. | Cressoni, M. | Chiurazzi, C. | Marino, A. | Spano, S. | Chiumello, D. | Gattinoni, L. | Guanziroli, M. | Gotti, M. | Vergani, G. | Marino, A. | Cressoni, M. | Chiurazzi, C. | Chiumello, D. | Gattinoni, L. | Massaro, F. | Moustakas, A. | Johansson, S. | Larsson, A. | Perchiazzi, G. | Zhang, X. W. | Guo, F. M. | Chen, J. X. | Xue, M. | Yang, Y. | Qiu, H. B. | Chen, J. X. | Liu, L. | Yang, L. | Zhang, X. W. | Guo, F. M. | Yang, Y. | Qiu, H. B. | Fister, M. | Knafelj, R. | Suzer, M. A. | Kavlak, M. E. | Atalan, H. K. | Gucyetmez, B. | Cakar, N. | Weller, D. | Grootendorst, A. F. | Dijkstra, A. | Kuijper, T. M. | Cleffken, B. I. | Regli, A. | De Keulenaer, B. | Van Heerden, P. | Hadfield, D. | Hopkins, P. A. | Penhaligon, B. | Reid, F. | Hart, N. | Rafferty, G. F. | Grasselli, G. | Mauri, T. | Lazzeri, M. | Carlesso, E. | Cambiaghi, B. | Eronia, N. | Maffezzini, E. | Bronco, A. | Abbruzzese, C. | Rossi, N. | Foti, G. | Bellani, G. | Pesenti, A. | Bassi, G. Li | Panigada, M. | Ranzani, O. | Kolobow, T. | Zanella, A. | Cressoni, M. | Berra, L. | Parrini, V. | Kandil, H. | Salati, G. | Livigni, S. | Livigni, S. | Amatu, A. | Girardis, M. | Barbagallo, M. | Moise, G. | Mercurio, G. | Costa, A. | Vezzani, A. | Lindau, S. | Babel, J. | Cavana, M. | Torres, A. | Panigada, M. | Bassi, G. Li | Ranzani, O. T. | Kolobow, T. | Zanella, A. | Cressoni, M. | Berra, L. | Parrini, V. | Kandil, H. | Salati, G. | Livigni, S. | Amatu, A. | Girardis, M. | Barbagallo, M. | Moise, G. | Mercurio, G. | Costa, A. | Vezzani, A. | Lindau, S. | Babel, J. | Cavana, M. | Torres, A. | Umbrello, M. | Taverna, M. | Formenti, P. | Mistraletti, G. | Vetrone, F. | Marino, A. | Vergani, G. | Baisi, A. | Chiumello, D. | Garnero, A. G. | Novotni, D. N. | Arnal, J. A. | Urner, M. | Fan, E. | Dres, M. | Vorona, S. | Brochard, L. | Ferguson, N. D. | Goligher, E. C. | Leung, C. | Joynt, G. | Wong, W. | Lee, A. | Gomersall, C. | Poels, S. | Casaer, M. | Schetz, M. | Van den Berghe, G. | Meyfroidt, G. | Holzgraefe, B. | Von Kobyletzki, L. B. | Larsson, A. | Cianchi, G. | Becherucci, F. | Batacchi, S. | Cozzolino, M. | Franchi, F. | Di Valvasone, S. | Ferraro, M. C. | Peris, A. | Phiphitthanaban, H. | Wacharasint, P. | Wongsrichanalai, V. | Lertamornpong, A. | Pengpinij, O. | Wattanathum, A. | Oer-areemitr, N. | Boddi, M. | Cianchi, G. | Cappellini, E. | Ciapetti, M. | Batacchi, S. | Di Lascio, G. | Bonizzoli, M. | Cozzolino, M. | Peris, A. | Lazzeri, C. | Cianchi, G. | Bonizzoli, M. | Di Lascio, G. | Cozzolino, M. | Peris, A. | Katsin, M. L. | Hurava, M. Y. | Dzyadzko, A. M. | Hermann, A. | Schellongowski, P. | Bojic, A. | Riss, K. | Robak, O. | Lamm, W. | Sperr, W. | Staudinger, T. | Buoninsegni, L. Tadini | Bonizzoli, M. | Cozzolino, M. | Parodo, J. | Ottaviano, A. | Cecci, L. | Corsi, E. | Ricca, V. | Peris, A. | de Garibay, A. Perez Ruiz | Ende-Schneider, B. | Schreiber, C. | Kreymann, B. | Turani, F. | Resta, M. | Niro, D. | Castaldi, P. | Boscolo, G. | Gonsales, G. | Martini, S. | Belli, A. | Zamidei, L. | Falco, M. | Lamas, T. | Mendes, J. | Galazzi, A. | Mauri, T. | Benco, B. | Binda, F. | Masciopinto, L. | Lazzeri, M. | Carlesso, E. | Lissoni, A. | Grasselli, G. | Adamini, I. | Pesenti, A. | Thamjamrassri, T. | Watcharotayangul, J. | Numthavaj, P. | Kongsareepong, S. | Higuera, J. | Cabestrero, D. | Rey, L. | Narváez, G. | Blandino, A. | Aroca, M. | Saéz, S. | De Pablo, R. | Mohamed, A. | Sklar, M. | Munshi, L. | Mauri, T. | Lazzeri, M. | Alban, L. | Turrini, C. | Panigada, M. | Taccone, P. | Carlesso, E. | Marenghi, C. | Spadaro, S. | Grasselli, G. | Volta, C. | Pesenti, A. | Higuera, J. | Alonso, D. Cabestrero | Blandino, A. | Narváez, G. | González, L. Rey | Aroca, M. | Saéz, S. | De Pablo, R. | Franci, A. | Stocchi, G. | Cappuccini, G. | Socci, F. | Cozzolino, M. | Guetti, C. | Rastrelli, P. | Peris, A. | Nestorowicz, A. | Glapinski, J. | Fijalkowska-Nestorowicz, A. | Wosko, J. | Fijalkowska-Nestorowicz, A. | Glapinski, J. | Wosko, J. | Duprez, F. | Bonus, T. | Cuvelier, G. | Mashayekhi, S. | Ollieuz, S. | Reychler, G. | Bonus, T. | Duprez, F. | Cuvelier, G. | Mashayekhi, S. | Ollieuz, S. | Reychler, G. | Kuchyn, I. | Bielka, K. | Sergienko, A. | Jones, H. | Day, C. | Park, S. C. | Yeom, S. R. | Myatra, S. N. | Gupta, S. | Rajnala, V. | Divatia, J. | Silva, J. Villalobos | Olvera, O. Aguilera | Schulte, R. Cavazos | Bermudez, M. Castañeda | Zorrilla, L. Pariente | Ferretis, H. Lopez | García, K. Trejo | Balciuniene, N. | Ramsaite, J. | Kriukelyte, O. | Krikscionaitiene, A. | Tamosuitis, T. | Terragni, P. | Brazzi, L. | Falco, D. | Pistidda, L. | Magni, G. | Bartoletti, L. | Mascia, L. | Filippini, C. | Ranieri, V. | Kyriakoudi, A. | Rovina, N. | Koltsida, O. | Konstantellou, E. | Kardara, M. | Kostakou, E. | Gavriilidis, G. | Vasileiadis, I. | Koulouris, N. | Koutsoukou, A. | Van Snippenburg, W. | Kröner, A. | Flim, M. | Buise, M. | Hemler, R. | Spronk, P. | Regli, A. | Noffsinger, B. | De Keulenaer, B. | Singh, B. | Hockings, L. | Van Heerden, P. | Spina, C. | Bronco, A. | Magni, F. | Di Giambattista, C. | Vargiolu, A. | Bellani, G. | Foti, G. | Citerio, G. | Scaramuzzo, G. | Spadaro, S. | Waldmann, A. D. | Böhm, S. H. | Ragazzi, R. | Volta, C. A. | Heines, S. J. | Strauch, U. | Van de Poll, M. C. | Roekaerts, P. M. | Bergmans, D. C. | Sosio, S. | Gatti, S. | Maffezzini, E. | Punzi, V. | Asta, A. | Foti, G. | Bellani, G. | Glapinski, J. | Mroczka, J. | Nestorowicz, A. | Fijalkowska-Nestorowicz, A. | Yaroshetskiy, A. I | Rezepov, N. A. | Mandel, I. A. | Gelfand, B. R. | Ozen, E. | Karakoc, E. | Ayyildiz, A. | Kara, S. | Ekemen, S. | Yelken, B. Buyukkidan | Saasouh, W. | Freeman, J. | Turan, A. | Hajjej, Z. | Sellami, W. | Bousselmi, M. | Samoud, W. | Gharsallah, H. | Labbene, I. | Ferjani, M. | Vetrugno, L. | Barbariol, F. | Forfori, F. | Regeni, I. | Della Rocca, G. | Jansen, D. | Jonkman, A. | Doorduin, J. | Roesthuis, L. | Van der Hoeven, J. | Heunks, L. | Marocco, S. Arrigoni | Bottiroli, M. | Pinciroli, R. | Galanti, V. | Calini, A. | Gagliardone, M. | Bellani, G. | Fumagalli, R. | Gatti, S. | Abbruzzese, C. | Ippolito, D. | Sala, V. L. | Meroni, V. | Bronco, A. | Foti, G. | Bellani, G. | Elbanna, M. | Nassar, Y. | Abdelmohsen, A. | Yahia, M. | Mongodi, S. | Mojoli, F. | Via, G. | Tavazzi, G. | Fava, F. | Pozzi, M. | Iotti, G. A. | Bouhemad, B. | Ruiz-Ferron, F. | Simón, J. Serrano | Gordillo-Resina, M. | Chica-Saez, V. | Garcia, M. Ruiz | Vela-Colmenero, R. | Redondo-Orts, M. | Gontijo-Coutinho, C. | Ozahata, T. | Nocera, P. | Franci, D. | Santos, T. | Carvalho-Filho, M. | Fochi, O. | Gatti, S. | Nacoti, M. | Signori, D. | Bronco, A. | Bonacina, D. | Bellani, G. | Bonanomi, E. | Mongodi, S. | Bonvecchio, E. | Stella, A. | Roldi, E. | Orlando, A. | Luperto, M. | Bouhemad, B. | Iotti, G. A. | Mojoli, F. | Trunfio, D. | Licitra, G. | Martinelli, R. | Vannini, D. | Giuliano, G. | Vetrugno, L. | Forfori, F. | Näslund, E. | Lindberg, L. G. | Lund, I. | Larsson, A. | Frithiof, R. | Nichols, A. | Freeman, J. | Pentakota, S. | Kodali, B. | Pranskunas, A. | Kiudulaite, I. | Simkiene, J. | Damanskyte, D. | Pranskuniene, Z. | Arstikyte, J. | Vaitkaitis, D. | Pilvinis, V. | Brazaitis, M. | Pool, R. | Haugaa, H. | Botero, A. | Escobar, D. | Maberry, D. | Tønnessen, T. | Zuckerbraun, B. | Pinsky, M. | Gomez, H. | Lyons, H. | Trimmings, A. | Domizi, R. | Scorcella, C. | Damiani, E. | Pierantozzi, S. | Tondi, S. | Monaldi, V. | Carletti, A. | Zuccari, S. | Adrario, E. | Pelaia, P. | Donati, A. | Kazune, S. | Grabovskis, A. | Volceka, K. | Rubins, U. | Bol, M. | Suverein, M. | Delnoij, T. | Driessen, R. | Heines, S. | Delhaas, T. | Vd Poll, M. | Sels, J. | Jozwiak, M. | Chambaz, M. | Sentenac, P. | Richard, C. | Monnet, X. | Teboul, J. L. | Bitar, Z. | Maadarani, O. | Al Hamdan, R. | Huber, W. | Malbrain, M. | Chew, M. | Mallat, J. | Tagami, T. | Hundeshagen, S. | Wolf, S. | Huber, W. | Mair, S. | Schmid, R. | Aron, J. | Adlam, M. | Dua, G. | Mu, L. | Chen, L. | Yoon, J. | Clermont, G. | Dubrawski, A. | Duhailib, Z. | Al Assas, K. | Shafquat, A. | Salahuddin, N. | Donaghy, J. | Morgan, P. | Valeanu, L. | Stefan, M. | Provenchere, S. | Longrois, D. | Shaw, A. | Mythen, M. G. | Shook, D. | Hayashida, D. | Zhang, X. | Munson, S. H. | Sawyer, A. | Mariyaselvam, M. | Blunt, M. | Young, P. | Nakwan, N. | Khwannimit, B. | Checharoen, P. | Berger, D. | Moller, P. | Bloechlinger, S. | Bloch, A. | Jakob, S. | Takala, J. | Van den Brule, J. M. | Stolk, R. | Vinke, E. | Van Loon, L. M. | Pickkers, P. | Van der Hoeven, J. G. | Kox, M. | Hoedemaekers, C. W. | Werner-Moller, P. | Jakob, S. | Takala, J. | Berger, D. | Bertini, P. | Guarracino, F. | Colosimo, D. | Gonnella, S. | Brizzi, G. | Mancino, G. | Baldassarri, R. | Pinsky, M. R. | Bertini, P. | Gonnella, S. | Brizzi, G. | Mancino, G. | Amitrano, D. | Guarracino, F. | Goslar, T. | Stajer, D. | Radsel, P. | De Vos, R. | Dijk, N. Bussink-van | Stringari, G. | Cogo, G. | Devigili, A. | Graziadei, M. Ceola | Bresadola, E. | Lubli, P. | Amella, S. | Marani, F. | Polati, E. | Gottin, L. | Colinas, L. | Hernández, G. | Vicho, R. | Serna, M. | Canabal, A. | Cuena, R. | Jozwiak, M. | Gimenez, J. | Teboul, J. L. | Mercado, P. | Depret, F. | Richard, C. | Monnet, X. | Hajjej, Z. | Sellami, W. | Sassi, K. | Gharsallah, H. | Labbene, I. | Ferjani, M. | Herner, A. | Schmid, R. | Huber, W. | Abded, N. | Nassar, Y. | Elghonemi, M. | Monir, A. | Nikhilesh, J. | Apurv, T. | Uber, A. U. | Grossestreuer, A. | Moskowitz, A. | Patel, P. | Holmberg, M. J. | Donnino, M. W. | Graham, C. A. | Hung, K. | Lo, R. | Leung, L. Y. | Lee, K. H. | Yeung, C. Y. | Chan, S. Y. | Trembach, N. | Zabolotskikh, I. | Caldas, J. | Panerai, R. | Camara, L. | Ferreira, G. | Almeida, J. | de Oliveira, G. Queiroz | Jardim, J. | Bor-Seng-Shu, E. | Lima, M. | Nogueira, R. | Jatene, F. | Zeferino, S. | Galas, F. | Robinson, T. | Hajjar, L. A. | Caldas, J. | Panerai, R. | Ferreira, G. | Camara, L. | Zeferino, S. | Jardim, J. | Bor-Seng-Shu, E. | Oliveira, M. | Norgueira, R. | Groehs, R. | Ferreira-Santos, L. | Galas, F. | Oliveira, G. | Almeida, J. | Robinson, T. | Jatene, F. | Hajjar, L. | Ferreira, G. | Ribeiro, J. | Galas, F. | Gaiotto, F. | Lisboa, L. | Fukushima, J. | Rizk, S. | Almeida, J. | Jatene, F. | Osawa, E. | Franco, R. | Kalil, R. | Hajjar, L. | Chlabicz, M. | Sobkowicz, B. | Kaminski, K. | Kazimierczyk, R. | Musial, W. | Tycińska, A. | Siranovic, M. | Gopcevic, A. | Gavranovic, Z. G. | Horvat, A. H. | Krolo, H. | Rode, B. | Videc, L. | Trifi, A. | Abdellatif, S. | Ismail, K. Ben | Bouattour, A. | Daly, F. | Nasri, R. | Lakhal, S. Ben | Beurton, A. | Teboul, J. L. | Girotto, V. | Galarza, L. | Richard, C. | Monnet, X. | Beurton, A. | Teboul, J. L. | Girotto, V. | Galarza, L. | Richard, C. | Monnet, X. | Girotto, V. | Teboul, J. L. | Beurton, A. | Galarza, L. | Guedj, T. | Monnet, X. | Galarza, L. | Mercado, P. | Teboul, J. L. | Girotto, V. | Beurton, A. | Richard, C. | Monnet, X. | Iliæ, M. Karaman | Sakic, L. | NN, V. | Stojcic, L. | Jozwiak, M. | Depret, F. | Teboul, J. L. | Alphonsine, J. | Lai, C. | Richard, C. | Monnet, X. | Tapanwong, N. | Chuntupama, P. | Wacharasint, P. | Huber, W. | Hoellthaler, J. | Lahmer, T. | Schmid, R. | Latham, H. | Bengtson, C. D. | Satterwhite, L. | Stites, M. | Simpson, S. Q. | Latham, H. | Bengtson, C. D. | Satterwhite, L. | Stites, M. | Simpson, S. Q. | Skladzien, T. | Cicio, M. | Garlicki, J. | Serednicki, W. | Wordliczek, J. | Vargas, P. | Salazar, A. | Mercado, P. | Espinoza, M. | Graf, J. | Kongpolprom, N. | Sanguanwong, N. | Jonnada, S. | Gerrard, C. | Jones, N. | Morley, T. | Thorburn, P. T. | Trimmings, A. | Musaeva, T. | Zabolotskikh, I. | Salazar, A. | Vargas, P. | Mercado, P. | Espinoza, M. | Graf, J. | Horst, S. | Lipcsey, M. | Kawati, R. | Pikwer, A. | Rasmusson, J. | Castegren, M. | Shilova, A. | Yafarova, A. | Gilyarov, M. | Shilova, A. | Yafarova, A. | Gilyarov, M. | Stojiljkovic, D. L. Loncar | Ulici, A. | Reidt, S. | Lam, T. | Jancik, J. | Ragab, D. | Taema, K. | Farouk, W. | Saad, M. | Liu, X. | Holmberg, M. J. | Uber, A. | Montissol, S. | Donnino, M. | Andersen, L. W. | Perlikos, F. | Lagiou, M. | Papalois, A. | Kroupis, C. | Toumpoulis, I. | Osawa, E. | Carter, D. | Sardo, S. | Almeida, J. | Galas, F. | Rizk, S. | Franco, R. | Hajjar, L. | Landoni, G. | Kongsayreepong, S. | Sungsiri, R. | Wongsripunetit, P. | Marchio, P. | Guerra-Ojeda, S. | Gimeno-Raga, M. | Mauricio, M. D. | Valles, S. L. | Aldasoro, C. | Jorda, A. | Aldasoro, M. | Vila, J. M. | Borg, U. B. | Neitenbach, A. M. | García, M. | González, P. Guijo | Romero, M. Gracia | Orduña, P. Saludes | Cano, A. Gil | Rhodes, A. | Grounds, R. M. | Cecconi, M. | Lee, C. | Hatib, F. | Jian, Z. | Rinehart, J. | De Los Santos, J. | Canales, C. | Cannesson, M. | García, M. I. Monge | Hatib, F. | Jian, Z. | Scheeren, T. | Jian, Z. | Hatib, F. | Pinsky, M. | Chantziara, V. | Vassi, A. | Michaloudis, G. | Sanidas, E. | Golemati, S. | Bateman, R. M. | Mokhtar, A. | Omar, W. | Aziz, K. Abdel | El Azizy, H. | Nielsen, D. L. Lykke | Holler, J. G. | Lassen, A. | Eriksson, M. | Strandberg, G. | Lipcsey, M. | Larsson, A. | Capoletto, C. | Almeida, J. | Ferreira, G. | Fukushima, J. | Nakamura, R. | Risk, S. | Osawa, E. | Park, C. | Oliveira, G. | Galas, F. | Franco, R. | Hajjar, L. | Dias, F. | D’Arrigo, N. | Fortuna, F. | Redaelli, S. | Zerman, L. | Becker, L. | Serrano, T. | Cotes, L. | Ramos, F. | Fadel, L. | Coelho, F. | Mendes, C. | Real, J. | Pedron, B. | Kuroki, M. | Costa, E. | Azevedo, L.
Critical Care  2017;21(Suppl 1):57.
doi:10.1186/s13054-017-1628-y
PMCID: PMC5374603
2.  TRPM2 channel deficiency prevents delayed cytosolic Zn2+ accumulation and CA1 pyramidal neuronal death after transient global ischemia 
Cell Death & Disease  2014;5(11):e1541-.
Transient ischemia is a leading cause of cognitive dysfunction. Postischemic ROS generation and an increase in the cytosolic Zn2+ level ([Zn2+]c) are critical in delayed CA1 pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2 (transient receptor potential melastatin-related 2) channel. Using in vivo and in vitro models of ischemia–reperfusion, we showed that genetic knockout of TRPM2 strongly prohibited the delayed increase in the [Zn2+]c, ROS generation, CA1 pyramidal neuronal death and postischemic memory impairment. Time-lapse imaging revealed that TRPM2 deficiency had no effect on the ischemia-induced increase in the [Zn2+]c but abolished the cytosolic Zn2+ accumulation during reperfusion as well as ROS-elicited increases in the [Zn2+]c. These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn2+]c and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury.
doi:10.1038/cddis.2014.494
PMCID: PMC4260752  PMID: 25429618
3.  TRAF1 is a key mediator for hepatic ischemia/reperfusion injury 
Cell Death & Disease  2014;5(10):e1467-.
Tumor necrosis factor receptor-associated factor 1 (TRAF1), an adapter in signal transduction, is involved in immunity and in apoptotic processes in various cell types. However, little is known about its function and the molecular mechanism of its activation during liver injury. This study tested the hypothesis that TRAF1 is a mediator of cell injury after hepatic ischemia/reperfusion injury (I/R). In a mouse hepatic I/R injury model, we found that TRAF1 expression was highly induced. TRAF1 deficiency was liver protective, whereas sustained TRAF1 overexpression aggravated liver injury in response to hepatic I/R injury. Mechanistic studies demonstrated that a deficiency of TRAF1 in cultured hepatocytes led to the inhibition of NF-κB-mediated inflammatory responses, suppression of the ASK/JNK pro-death pathway and promotion of cellular regeneration capacity. In contrast, the converse occurred in hepatocyte-specific TRAF1 transgenic mice. TRAF1 activated the ASK1/JNK pathway and promoted hepatic injury. Our study demonstrates that TRAF1 is a crucial early mediator of hepatic I/R injury and suggests that TRAF1 may be a potential gene therapy target for the treatment of liver injury.
doi:10.1038/cddis.2014.411
PMCID: PMC4649517  PMID: 25321474
4.  Accelerated partial-breast irradiation using intensity-modulated proton radiotherapy: do uncertainties outweigh potential benefits? 
The British Journal of Radiology  2013;86(1029):20130176.
Objective:
Passive scattering proton beam (PSPB) radiotherapy for accelerated partial-breast irradiation (APBI) provides superior dosimetry for APBI three-dimensional conformal photon radiotherapy (3DCRT). Here we examine the potential incremental benefit of intensity-modulated proton radiotherapy (IMPT) for APBI and compare its dosimetry with PSPB and 3DCRT.
Methods:
Two theoretical IMPT plans, TANGENT_PAIR and TANGENT_ENFACE, were created for 11 patients previously treated with 3DCRT APBI and were compared with PSPB and 3DCRT plans for the same CT data sets. The impact of range, motion and set-up uncertainties as well as scanned spot mismatching between fields of IMPT plans was evaluated.
Results:
IMPT plans for APBI were significantly better regarding breast skin sparing (p<0.005) and other normal tissue sparing than 3DCRT plans (p<0.01) with comparable target coverage (p=ns). IMPT plans were statistically better than PSPB plans regarding breast skin (p<0.002) and non-target breast (p<0.007) in higher dose regions but worse or comparable in lower dose regions. IMPT plans using TANGENT_ENFACE were superior to that using TANGENT_PAIR in terms of target coverage (p<0.003) and normal tissue sparing (p<0.05) in low-dose regions. IMPT uncertainties were demonstrated for multiple causes. Qualitative comparison of dose–volume histogram confidence intervals for IMPT suggests that numeric gains may be offset by IMPT uncertainties.
Conclusion:
Using current clinical dosimetry, PSPB provides excellent dosimetry compared with 3DCRT with fewer uncertainties compared with IMPT.
Advances in knowledge:
As currently delivered in the clinic, PSPB planning for APBI provides as good or better dosimetry than IMPT with less uncertainty.
doi:10.1259/bjr.20130176
PMCID: PMC3755395  PMID: 23728947
5.  Peroxisome proliferator-activated receptor α activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway 
Jiao, M | Ren, F | Zhou, L | Zhang, X | Zhang, L | Wen, T | Wei, L | Wang, X | Shi, H | Bai, L | Zhang, X | Zheng, S | Zhang, J | Chen, Y | Han, Y | Zhao, C | Duan, Z
Cell Death & Disease  2014;5(8):e1397-.
Peroxisome proliferator-activated receptor α (PPARα) has been reported to induce a potent anti-inflammatory response. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of the present study was to test the hypothesis that PPARα activation mediates autophagy to inhibit liver inflammation and protect against acute liver failure (ALF). PPARα expression during ALF and the impact of PPARα activation by Wy-14 643 on the hepatic immune response were studied in a D-galactosamine/lipopolysaccharide-induced mouse model. Autophagy was inhibited by 3-methyladenine or small interfering RNA (siRNA) against Atg7. In both the mouse model and human ALF subjects, PPARα was significantly downregulated in the injured liver. PPARα activation by pretreatment with Wy-14 643 protected against liver injury in mice. The protective effect of PPARα activation relied on the suppression of inflammatory mechanisms through the induction of autophagy. This hypothesis is supported by the following evidence: first, PPARα activation suppressed proinflammatory responses and inhibited phosphorylated NF-κBp65, phosphorylated JNK and phosphorylated ERK pathways in vivo. Second, protection by PPARα activation was due to the induction of autophagy because inhibition of autophagy by 3-methyladenine or Atg7 siRNA reversed liver protection and inflammation. Third, PPARα activation directly induced autophagy in primary macrophages in vitro, which protected cells from a lipopolysaccharide-induced proinflammatory response. Here, for the first time, we have demonstrated that PPARα-mediated induction of autophagy ameliorated liver injury in cases of ALF by attenuating inflammatory responses, indicating a potential therapeutic application for ALF treatment.
doi:10.1038/cddis.2014.361
PMCID: PMC4454331  PMID: 25165883
6.  Continuous Cyclic Mechanical Tension Increases Ank Expression in Endplate Chondrocytes Through the TGF-β1 and p38 Pathway 
The normal ANK protein has a strong influence on anti-calcification. It is known that TGF-β1 is also able to induce extracellular inorganic pyrophosphate (ePPi) elaboration via the TGF-β1-induced ank gene expression and the mitogen-activated protein kinase (MAPK) signaling acts as a downstream effector of TGF-β1. We hypothesized that the expression of the ank gene is regulated by mechanics through TGF-β1-p38 pathway. In this study, we investigated the mechanism of short-time mechanical tension-induced ank gene expression. We found that the continuous cyclic mechanical tension (CCMT) increased the ank gene expression in the endplate chondrocytes, and there was an increase in the TGF-β1 expression after CCMT stimulation. The ank gene expression significantly increased when treated by TGF-β1 in a dose-dependent manner and decreased when treated by SB431542 (ALK inhibitor) in a dose-dependent manner. Our study results indicate that CCMT-induced ank gene expressions may be regulated by TGF-β1 and p38 MAPK pathway.
doi:10.4081/ejh.2013.e28
PMCID: PMC3794359  PMID: 24085277
Continuous cyclic mechanical tension (CCMT); Endplate chondrocytes; ank; TGF-β1; p38
7.  Genetic Differentiation of Chinese Indigenous Meat Goats Ascertained Using Microsatellite Information 
To investigate the genetic diversity of seven Chinese indigenous meat goat breeds (Tibet goat, Guizhou white goat, Shannan white goat, Yichang white goat, Matou goat, Changjiangsanjiaozhou white goat and Anhui white goat), explain their genetic relationship and assess their integrity and degree of admixture, 302 individuals from these breeds and 42 Boer goats introduced from Africa as reference samples were genotyped for 11 microsatellite markers. Results indicated that the genetic diversity of Chinese indigenous meat goats was rich. The mean heterozygosity and the mean allelic richness (AR) for the 8 goat breeds varied from 0.697 to 0.738 and 6.21 to 7.35, respectively. Structure analysis showed that Tibet goat breed was genetically distinct and was the first to separate and the other Chinese goats were then divided into two sub-clusters: Shannan white goat and Yichang white goat in one cluster; and Guizhou white goat, Matou goat, Changjiangsanjiaozhou white goat and Anhui white goat in the other cluster. This grouping pattern was further supported by clustering analysis and Principal component analysis. These results may provide a scientific basis for the characteristization, conservation and utilization of Chinese meat goats.
doi:10.5713/ajas.2011.11308
PMCID: PMC4093133  PMID: 25049548
Meat Goat; Genetic Diversity; Genetic Differentiation; Microsatellite
8.  Pre-45s rRNA promotes colon cancer and is associated with poor survival of CRC patients 
Oncogene  2017;36(44):6109-6118.
One characteristic of cancer cells is the abnormally high rate of cell metabolism to sustain their enhanced proliferation. However, the behind mechanism of this phenomenon is still elusive. Here we find that enhanced precursor 45s ribosomal RNA (pre-45s rRNA) is one of the core mechanisms in promoting the pathogenesis of colorectal cancer (CRC). Pre-45s rRNA expression is significantly higher in primary CRC tumor tissues samples and cancer cell lines compared with the non-tumorous colon tissues, and is associated with tumor sizes. Knockdown of pre-45s rRNA inhibits G1/S cell-cycle transition by stabilizing p53 through inducing murine double minute 2 (MDM2) and ribosomal protein L11 (RpL11) interaction. In addition, we revealed that high rate of cancer cell metabolism triggers the passive release of calcium ion from endoplasmic reticulum to the cytoplasm. The elevated calcium ion in the cytoplasm activates the signaling cascade of calcium/calmodulin-dependent protein kinase II, ribosomal S6 kinase (S6K) and ribosomal S6K (CaMKII-S6K-UBF). The activated UBF promotes the transcription of rDNA, which therefore increases pre-45s rRNA. Disruption of CaMKII-S6K-UBF axis by either RNAi or pharmaceutical approaches leads to reduction of pre-45s rRNA expression, which subsequently suppresses cell proliferation in colon cancer cells by causing cell-cycle arrest. Knockdown of APC activates CaMKII-S6K-UBF cascade and thus enhances pre-45s rRNA expression. Moreover, the high expression level of pre-45s rRNA is associated with poor survival of CRC patients in two independent cohorts. Our study identifies a novel mechanism in CRC pathogenesis mediated by pre-45s rRNA and a prognostic factor of pre-45s rRNA in CRC patients.
doi:10.1038/onc.2017.86
PMCID: PMC5671943  PMID: 28692053
9.  Direction-specific interaction forces underlying zinc oxide crystal growth by oriented attachment 
Nature Communications  2017;8:835.
Crystallization by particle attachment is impacting our understanding of natural mineralization processes and holds promise for novel materials design. When particles assemble in crystallographic alignment, expulsion of the intervening solvent and particle coalescence are enabled by near-perfect co-alignment via interparticle forces that remain poorly quantified. Here we report measurement and simulation of these nanoscale aligning forces for the ZnO(0001)-ZnO(000\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\bar 1$$\end{document}1¯) system in aqueous solution. Dynamic force spectroscopy using nanoengineered single crystal probes reveals an attractive force with 60o rotational periodicity. Calculated distance and orientation-dependent potentials of mean force show several attractive free energy wells distinguished by numbers of intervening water layers, which reach a minimum when aligned. The calculated activation energy to separate the attractively bound solvated interfaces perfectly reproduces the measured 60o periodicity, revealing the key role of intervening water structuring as a basis to generate the interparticle torque that completes alignment and enables coalescence.
Crystal growth is a fundamental process, important in a wide range of fields, but the interparticle forces responsible for molecule alignment are not well understood. Here, the authors measure the alignment forces in ZnO using dynamic force spectroscopy, highlighting the role of intervening water molecules.
doi:10.1038/s41467-017-00844-6
PMCID: PMC5635138  PMID: 29018200
10.  The role of routine screening in blood-borne pathogens in Chinese patients undergoing joint arthroplasty 
Bone & Joint Research  2017;6(9):566-571.
Objectives
Surgeons face a substantial risk of infection because of the occupational exposure to blood-borne pathogens (BBPs) from patients undergoing high-risk orthopaedic procedures. This study aimed to determine the seroprevalence of four BBPs among patients undergoing joint arthroplasty in Shanghai, China. In addition, we evaluated the significance of pre-operative screening by calculating a cost-to-benefit ratio.
Methods
A retrospective observational study of pre-operative screening for BBPs, including hepatitis B and C viruses (HBV and HCV), human immunodeficiency virus (HIV) and Treponema pallidum (TP), was conducted for sequential patients in the orthopaedic department of a large urban teaching hospital between 01 January 2009 and 30 May 2016. Medical records were analysed to verify the seroprevalence of these BBPs among the patients stratified by age, gender, local origin, type of surgery, history of previous transfusion and marital status.
Results
Of the subjects who underwent arthroplasty surgery in our institution, pre-operative screening tests were available for 96.1% (11 609 patients). The seroprevalence of HBV, HCV, HIV and TP was 5.47%, 0.45%, 0.08% and 3.6%, respectively. A total of 761 seropositive cases (68.4%) were previously undiagnosed. Pre-operative screening for HIV resulted in a low cost to benefit ratio, followed by HCV and HBV.
Conclusion
Routine HCV and HIV screening prior to joint arthroplasty is not a cost-effective strategy. Considering the high rate of undiagnosed patients and the shortage of protective options, targeted pre-operative screening for HBV and syphilis should be considered for the protection of healthcare workers in China who have not been vaccinated.
Cite this article: Bone Joint Res 2017;6:566–571.
doi:10.1302/2046-3758.69.BJR-2017-0066.R2
PMCID: PMC5630999  PMID: 28963103
Blood-borne pathogens; Pre-operative screening; Joint arthroplasty
11.  Combination curcumin and (−)-epigallocatechin-3-gallate inhibits colorectal carcinoma microenvironment-induced angiogenesis by JAK/STAT3/IL-8 pathway 
Jin, G | Yang, Y | Liu, K | Zhao, J | Chen, X | Liu, H | Bai, R | Li, X | Jiang, Y | Zhang, X | Lu, J | Dong, Z
Oncogenesis  2017;6(10):e384-.
Tumor microenvironment has a crucial role in cancer development and progression, whereas the mechanism of how it regulates angiogenesis is unclear. In this study, we simulated the colorectal carcinoma microenvironment by conditioned medium (CM) of colorectal carcinoma cell lines (SW620, HT-29, HCT116) supernatant or colorectal carcinoma tissue homogenate supernatant to induce normal endothelial cells (NECs). We found that colorectal carcinoma CM promoted tumor angiogenesis by coercing NECs toward tumor endothelial cells (TECs) with the activation of the JAK/STAT3 signaling pathway. Antibody array analysis showed HT-29 supernatant contained numerous angiogenesis-related proteins, especially IL-8. Interestingly, the production of IL-8 in NECs induced by HT-29 CM was also increased. We also verified the crucial role of IL-8 in promoting the CM-induced angiogenesis, as IL-8 repression by neutralizing antibody abolished the transition of NECs toward TECs. Curcumin and (−)-epigallocatechin-3-gallate (EGCG) are broadly investigated in cancer chemoprevention. However, poor bioavailability hurdles their application alone, and the mechanism of their anti-angiogenesis still need to be illuminated. Here, we found that curcumin combination with EGCG attenuated the tumor CM-induced transition of NECs toward TECs by inhibiting JAK/STAT3 signaling pathway. Furthermore, the combination of curcumin and EGCG markedly reduced tumor growth and angiogenesis in the colorectal carcinoma PDX mouse model, and the combined anti-angiogenic effect was better than that of curcumin or EGCG alone. Taken together, our findings provide a new mechanism of tumor angiogenesis, and the combination of curcumin and EGCG represents a potential anti-angiogenic therapeutic method for colorectal carcinoma.
doi:10.1038/oncsis.2017.84
PMCID: PMC5668882  PMID: 28967875
12.  Diabetes mitigates the role of memory complaint in predicting dementia risk: Results from the Prevention of Alzheimer’s Disease with Vitamin E and Selenium Study 
Background
Subjective memory complaints (SMCs) are associated with increased risk of dementia in older adults, but the role of comorbidities in modifying this risk is unknown.
Objectives
To assess whether comorbidities modify estimated dementia risk based on SMCs.
Design
The Prevention of Alzheimer’s Disease with Vitamin E and Selenium Study (PREADVISE) was designed as an ancillary study to the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized, multi-center prostate cancer prevention trial with sites in the Unites States, Puerto Rico, and Canada. In 2009, PREADVISE and SELECT were changed into cohort studies.
Setting
Secondary analysis of PREADVISE data.
Participants
PREADVISE recruited 7,540 non-demented male volunteers from participating SELECT sites from 2002 to 2009. SMCs, demographics, and comorbidities including hypertension, diabetes, coronary artery bypass graft (CABG), stroke, sleep apnea, and head injury were ascertained by participant interview.
Measurements
Cox models were used to investigate whether baseline comorbidities modified hazard ratios (HR) for SMC-associated dementia risk using two methods: (1) we included one interaction term between SMC and a comorbidity in the model at a time, and (2) we included all two-way interactions between SMC and covariates of interest and reduced the model by “backward” selection. SMC was operationalized as any complaint vs. no complaint.
Results
Baseline SMCs were common (23.6%). In the first analyses, with the exception of stroke, presence of self-reported comorbidities was associated with lower estimated HR for dementia based on SMC status (complaint vs. no complaint), but this difference was only significant for diabetes. In the second analysis, the two-way interactions between SMC and race as well as SMC and diabetes were significant. Here, black men without diabetes who reported SMC had the highest estimated dementia risk (HR=5.05, 95% CI 2.55–10.00), while non-black men with diabetes who reported SMC had the lowest estimated risk (HR=0.71, 95% CI 0.35–1.41).
Conclusions
SMCs were more common among men with comorbidities, but these complaints appeared to be less predictive of dementia risk than those originating from men without comorbidities, suggesting that medical conditions such as diabetes may explain SMCs that are unrelated to an underlying neurodegenerative process.
doi:10.14283/jpad.2017.7
PMCID: PMC5607951  PMID: 28944218
Subjective memory complaints (SMCs); Alzheimer’s disease; dementia; comorbidities; effect measure modification
13.  Intramolecular Radical Aziridination of Allylic Sulfamoyl Azides via Co(II)-Based Metalloradical Catalysis: Effective Construction of Strained Heterobicyclic Structures 
Co(II)-based metalloradical catalysis (MRC) has been successfully applied for effective construction of the highly strained 2-sulfonyl-1,3-diazabicyclo[3.1.0]-hexane structures in high yields through intramolecular radical aziridination of allylic sulfamoyl azides. The resulting [3.1.0]-bicyclic aziridines prove to be versatile synthons for preparation of a diverse range of 1,2- and 1,3-diamine derivatives by selective ring-opening reactions in exo- and endo-fashion, respectively. As a demonstration of its application for target synthesis, the metalloradical intramolecular aziridination reaction has been incorporated as a key step for efficient synthesis of a potent neurokinin 1 (NK1) antagonist in 60% overall yield.
doi:10.1002/anie.201605238
PMCID: PMC5014589  PMID: 27511474
intramolecular aziridination; aziridine ring-opening; neurokinin 1 (NK1) receptor; metalloradical catalysis; cobalt porphyrin
14.  Negative Differential Conductance & Hot-Carrier Avalanching in Monolayer WS2 FETs 
Scientific Reports  2017;7:11256.
The high field phenomena of inter-valley transfer and avalanching breakdown have long been exploited in devices based on conventional semiconductors. In this Article, we demonstrate the manifestation of these effects in atomically-thin WS2 field-effect transistors. The negative differential conductance exhibits all of the features familiar from discussions of this phenomenon in bulk semiconductors, including hysteresis in the transistor characteristics and increased noise that is indicative of travelling high-field domains. It is also found to be sensitive to thermal annealing, a result that we attribute to the influence of strain on the energy separation of the different valleys involved in hot-electron transfer. This idea is supported by the results of ensemble Monte Carlo simulations, which highlight the sensitivity of the negative differential conductance to the equilibrium populations of the different valleys. At high drain currents (>10 μA/μm) avalanching breakdown is also observed, and is attributed to trap-assisted inverse Auger scattering. This mechanism is not normally relevant in conventional semiconductors, but is possible in WS2 due to the narrow width of its energy bands. The various results presented here suggest that WS2 exhibits strong potential for use in hot-electron devices, including compact high-frequency sources and photonic detectors.
doi:10.1038/s41598-017-11647-6
PMCID: PMC5595880  PMID: 28900169
15.  Molecular analogue of the perovskite repeating unit and evidence for direct MnIII-CeIV-MnIII exchange coupling pathway 
Nature Communications  2017;8:500.
The perovskite manganites AMnO3 and their doped analogues A1–xBxMnO3 (A and B = main group and lanthanide metals) are a fascinating family of magnetic oxides exhibiting a rich variety of properties. They are thus under intense investigation along multiple fronts, one of which is how their structural and physical properties are modified at the nanoscale. Here we show that the molecular compound [Ce3Mn8O8(O2CPh)18(HO2CPh)2] (CeIII 2CeIVMnIII 8; hereafter Ce3Mn8) bears a striking structural resemblance to the repeating unit seen in the perovskite manganites. Further, magnetic studies have established that Ce3Mn8 exhibits both the combination of pairwise MnIII 2 ferromagnetic and antiferromagnetic exchange interactions, and the resultant spin vector alignments that are found within the 3-D C-type antiferromagnetic perovskites. First-principles theoretical calculations reveal not only the expected nearest-neighbor MnIII 2 exchange couplings via superexchange pathways through bridging ligands but also an unusual, direct MnIII–CeIV–MnIII metal-to-metal channel involving the CeIV f orbitals.
Perovskite manganites exhibit intriguing but poorly understood properties, including multiferroicity. Here, the authors synthesize a Ce3Mn8 cluster that structurally resembles a perovskite repeat unit, and use this molecular analogue to elucidate mechanisms driving bulk perovskite properties.
doi:10.1038/s41467-017-00642-0
PMCID: PMC5593820  PMID: 28894086
16.  PRAS40 promotes NF-κB transcriptional activity through association with p65 
Zhu, G | Qi, Q | Havel, J J | Li, Z | Du, Y | Zhang, X | Fu, H
Oncogenesis  2017;6(9):e381-.
PRAS40 has been shown to have a crucial role in the repression of mammalian target of rapamycin (mTOR). Nonetheless, PRAS40 appears to have an oncogenic function in cancer cells. Whether PRAS40 mediates signaling independent of mTOR inhibition in cancer cells remains elusive. Here PRAS40 overexpression in lung adenocarcinoma and cutaneous melanoma was significantly correlated to worse prognosis. And we identified an unexpected role for PRAS40 in the regulation of nuclear factor (NF)-κB signaling. P65, a subunit of the NF-κB transcription factor complex, was confirmed to associate with PRAS40 by glutathione S-transferase co-precipitation. Importantly, we found that PRAS40 can enhance NF-κB transcriptional activity in a manner dependent upon PRAS40–P65 association. Furthermore, we found that a small p65-derived peptide can disrupt the PRAS40–P65 association and significantly decrease NF-κB transcriptional activity. These findings may help elucidate the pleiotropic functions of PRAS40 in cells and suggest a novel therapeutic strategy in cancer patients with high expression of PRAS40 and NF-κB.
doi:10.1038/oncsis.2017.80
PMCID: PMC5623906  PMID: 28945219
17.  Epitaxial thin films of pyrochlore iridate Bi2+xIr2-yO7-δ: structure, defects and transport properties 
Scientific Reports  2017;7:7740.
While pyrochlore iridate thin films are theoretically predicted to possess a variety of emergent topological properties, experimental verification of these predictions can be obstructed by the challenge in thin film growth. Here we report on the pulsed laser deposition and characterization of thin films of a representative pyrochlore compound Bi2Ir2O7. The films were epitaxially grown on yttria-stabilized zirconia substrates and have lattice constants that are a few percent larger than that of the bulk single crystals. The film composition shows a strong dependence on the oxygen partial pressure. Density-functional-theory calculations indicate the existence of BiIr antisite defects, qualitatively consistent with the high Bi: Ir ratio found in the films. Both Ir and Bi have oxidation states that are lower than their nominal values, suggesting the existence of oxygen deficiency. The iridate thin films show a variety of intriguing transport characteristics, including multiple charge carriers, logarithmic dependence of resistance on temperature, antilocalization corrections to conductance due to spin-orbit interactions, and linear positive magnetoresistance.
doi:10.1038/s41598-017-06785-w
PMCID: PMC5552750  PMID: 28798487
18.  Evolution and functional significance of derived sternal ossification patterns in ornithothoracine birds 
Journal of evolutionary biology  2015;28(8):1550-1567.
The midline pattern of sternal ossification characteristic of the Cretaceous enantiornithine birds is unique among the Ornithodira, the group containing birds, nonavian dinosaurs and pterosaurs. This has been suggested to indicate that Enantiornithes is not the sister group of Ornithuromorpha, the clade that includes living birds and their close relatives, which would imply rampant convergence in many nonsternal features between enantiornithines and ornithuromorphs. However, detailed comparisons reveal greater similarity between neornithine (i.e. crown group bird) and enantiornithine modes of sternal ossification than previously recognized. Furthermore, a new subadult enantiornithine specimen demonstrates that sternal ossification followed a more typically ornithodiran pattern in basal members of the clade. This new specimen, referable to the Pengornithidae, indicates that the unique ossification pattern observed in other juvenile enantiornithines is derived within Enantiornithes. A similar but clearly distinct pattern appears to have evolved in parallel in the ornithuromorph lineage. The atypical mode of sternal ossification in some derived enantiornithines should be regarded as an autapomorphic condition rather than an indication that enantiornithines are not close relatives of ornithuromorphs. Based on what is known about molecular mechanisms for morphogenesis and the possible selective advantages, the parallel shifts to midline ossification that took place in derived enantiornithines and living neognathous birds appear to have been related to the development of a large ventral keel, which is only present in ornithuromorphs and enantiornithines. Midline ossification can serve to medially reinforce the sternum at a relatively early ontogenetic stage, which would have been especially beneficial during the protracted development of the superprecocial Cretaceous enantiornithines.
doi:10.1111/jeb.12675
PMCID: PMC5548695  PMID: 26079847
Aves; development; Enantiornithes; keel; Neornithes; Ornithothoraces; ossification; sternum
19.  Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: Report of an FDA Public Workshop 
On May 19, 2016, the US Food and Drug Administration (FDA) hosted a public workshop, entitled “Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation.”1 The topic of mechanistic oral absorption modeling, which is one of the major applications of physiologically based pharmacokinetic (PBPK) modeling and simulation, focuses on predicting oral absorption by mechanistically integrating gastrointestinal transit, dissolution, and permeation processes, incorporating systems, active pharmaceutical ingredient (API), and the drug product information, into a systemic mathematical whole‐body framework.2
doi:10.1002/psp4.12204
PMCID: PMC5572334  PMID: 28571121
20.  Integrating In Vitro, Modeling, and In Vivo Approaches to Investigate Warfarin Bioequivalence 
We demonstrate the use of modeling and simulation to investigate bioequivalence (BE) concerns raised about generic warfarin products. To test the hypothesis that the loss of isopropyl alcohol and slow dissolution in acidic pH has significant impact on the pharmacokinetics of warfarin sodium tablets, we conducted physiologically based pharmacokinetic absorption modeling and simulation using formulation factors or in vitro dissolution profiles as input parameters. Sensitivity analyses indicated that warfarin pharmacokinetics was not sensitive to solubility, particle size, density, or dissolution rate in pH 4.5, but was affected by dissolution rate in pH 6.8 and potency. Virtual BE studies suggested that stressed warfarin sodium tablets with slow dissolution rate in pH 4.5 but having similar dissolution rate in pH 6.8 would be bioequivalent to the unstressed warfarin sodium tablets. A four‐way, crossover, single‐dose BE study in healthy subjects was conducted to test the same hypothesis and confirmed the simulation conclusion.
doi:10.1002/psp4.12198
PMCID: PMC5572358  PMID: 28379643
21.  Intramolecular 1,5-C(sp3)–H Radical Amination via Co(II)-Based Metalloradical Catalysis for Five-Membered Cyclic Sulfamides 
Chemical science  2016;7(12):6934-6939.
Co(II)-based metalloradical catalysis (MRC) proves effective for intramolecular 1,5-C–H amination of sulfamoyl azides under neutral and nonoxidative conditions, providing a straightforward approach to access strained 5-membered cyclic sulfamides with nitrogen gas as the only byproduct. The metalloradical amination system is applicable to different types of C(sp3)–H bonds and has a high degree of functional group tolerance. Additional features of the Co(II)-catalyzed 1,5-C–H amination include excellent chemoselectivity toward allylic and propargylic C–H bonds. The unique reactivity and selectivity profile of the Co(II)-catalyzed 1,5-C–H amination is attributed to the underlying radical mechanism of MRC.
Graphical Abstract
doi:10.1039/C6SC02231F
PMCID: PMC5271564  PMID: 28138382
22.  Prediction of size-resolved number concentration of cloud condensation nuclei and long-term measurements of their activation characteristics 
Scientific Reports  2017;7:5819.
Atmospheric aerosol particles acting as cloud condensation nuclei (CCN) are key elements in the hydrological cycle and climate. To improve our understanding of the activation characteristics of CCN and to obtain accurate predictions of their concentrations, a long-term field campaign was carried out in the Yangtze River Delta, China. The results indicated that the CCN were easier to activate in this relatively polluted rural station than in clean (e.g., the Amazon region) or dusty (e.g., Kanpur-spring) locations, but were harder to activate than in more polluted urban areas (e.g., Beijing). An improved method, using two additional parameters—the maximum activation fraction and the degree of heterogeneity, is proposed to predict the accurate, size-resolved concentration of CCN. The value ranges and prediction uncertainties of these parameters were evaluated. The CCN predicted using this improved method with size-resolved chemical compositions under an assumption that all particles were internally mixed showed the best agreement with the long-term field measurements.
doi:10.1038/s41598-017-05998-3
PMCID: PMC5517613
23.  Tangeretin has anti-asthmatic effects via regulating PI3K and Notch signaling and modulating Th1/Th2/Th17 cytokine balance in neonatal asthmatic mice 
Asthma is a chronic allergic disease characterized by airway inflammation, airway hyper-responsiveness (AHR), and mucus hypersecretion. T-lymphocytes are involved in the pathogenesis of asthma, mediating airway inflammatory reactions by secreting cytokines. The phosphoinositide 3-kinase (PI3K) and Notch signaling pathways are associated with T cell signaling, proliferation, and differentiation, and are important in the progression of asthma. Thus, compounds that can modulate T cell proliferation and function may be of clinical value. Here, we assessed the effects of tangeretin, a plant-derived flavonoid, in experimental asthma. BALB/c mice at postnatal day (P) 12 were challenged with ovalbumin (OVA). Separate groups of mice (n=18/group) were administered tangeretin at 25 or 50 mg/kg body weight by oral gavage. Dexamethasone was used as a positive control. Tangeretin treatment reduced inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) and also restored the normal histology of lung tissues. OVA-specific IgE levels in serum and BALF were reduced. AHR, as determined by airway resistance and lung compliance, was normalized. Flow cytometry analyses revealed a reduced Th17 cell population. Tangeretin reduced the levels of Th2 and Th17 cytokines and raised IFN-γ levels. PI3K signaling was inhibited. The expressions of the Notch 1 receptor and its ligands Jagged 1 and 2 were downregulated by tangeretin. Our findings support the possible use of tangeretin for treating allergic asthma.
doi:10.1590/1414-431X20175991
PMCID: PMC5520220  PMID: 28746467
Asthma; Inflammation; Notch signaling; PI3K; Tangeretin; T-helper cells
24.  Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test 
Genes, brain, and behavior  2016;15(6):604-615.
Mechanical sensitivity is commonly affected in chronic pain and other neurological disorders. To discover mechanisms of individual differences in punctate mechanosensation, we performed quantitative trait locus (QTL) mapping of the response to von Frey monofilament stimulation in BXD recombinant inbred (BXD) mice. Significant loci were detected on mouse chromosome (Chr) 5 and 15, indicating the location of underlying polymorphisms that cause heritable variation in von Frey response. Convergent evidence from public gene expression data implicates candidate genes within the loci: von Frey thresholds were strongly correlated with baseline expression of Cacna2d1, Ift27 and Csnk1e in multiple brain regions of BXD strains. Systemic gabapentin and PF-670462, which target the protein products of Cacna2d1 and Csnk1e, respectively, significantly increased von Frey thresholds in a genotype-dependent manner in progenitors and BXD strains. Real-time polymerase chain reaction confirmed differential expression of Cacna2d1 and Csnk1e in multiple brain regions in progenitors and showed differential expression of Cacna2d1 and Csnk1e in the dorsal root ganglia of the progenitors and BXD strains grouped by QTL genotype. Thus, linkage mapping, transcript covariance and pharmacological testing suggest that genetic variation affecting Cacna2d1 and Csnk1e may contribute to individual differences in von Frey filament response. This study implicates Cacna2d1 and Ift27 in basal mechanosensation in line with their previously suspected role in mechanical hypersensitivity. Csnk1e is implicated for von Frey response for the first time. Further investigation is warranted to identify the specific polymorphisms involved and assess the relevance of these findings to clinical conditions of disturbed mechanosensation.
doi:10.1111/gbb.12302
PMCID: PMC4955286  PMID: 27231153
Casein kinase 1; linkage mapping; microarray; quantitative trait locus; transcript abundance; voltage-gated calcium channels; von Frey
25.  Arginine vasopressin ameliorates spatial learning impairments in chronic cerebral hypoperfusion via V1a receptor and autophagy signaling partially 
Translational Psychiatry  2017;7(7):e1174-.
Chronic cerebral hypoperfusion (CCH) is a major factor contributing to neurological disorders and cognitive decline. Autophagy activation is believed to provide both beneficial and detrimental roles during hypoxic/ischemic cellular injury. Although arginine vasopressin (AVP) has been strongly involved in many behaviors, especially in learning and memory, the effects of AVP on CCH and their molecular mechanisms remain unclear. Here, to investigate whether there was neuroprotective effects of AVP on CCH through V1a receptor (an AVP receptor) signaling, permanent bilateral carotid arteries occlusion (two vessel occlusion, 2VO) was used to establish a rat model of CCH, and hypertonic saline (5.3%) was injected intraperitoneally to induce the secretion of AVP. Results showed that hypertonic saline effectively alleviated spatial learning and memory deficit, enhanced synaptic plasticity of CA3-CA1 hippocampal synapses, upregulated N-methyl-d-aspartate receptor subunit 2B (NR2B) and postsynaptic density protein 95 (PSD-95) surface expressions, reduced oxidative stress and increased Nissl bodies in 2VO model rats. These phenomena were significantly decreased by V1a receptor antagonist SR49059. Interestingly, hypertonic saline also upregulated autophagy in the hippocampus of 2VO rats partly through V1a receptor. These findings imply that AVP has a beneficial role for the treatment of cognitive impairments partly through V1a receptor signaling in CCH, which is possibly related to improving synaptic plasticity by promoting NR2B and PSD-95 externalization and by enhancing autophagy.
doi:10.1038/tp.2017.121
PMCID: PMC5538111

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