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1.  Albumin Binding Function: The Potential Earliest Indicator for Liver Function Damage 
Background. Currently there is no indicator that can evaluate actual liver lesion for early stages of viral hepatitis, nonalcoholic fatty liver disease (NAFLD), and cirrhosis. Aim of this study was to investigate if albumin binding function could better reflect liver function in these liver diseases. Methods. An observational study was performed on 193 patients with early NAFLD, viral hepatitis, and cirrhosis. Cirrhosis patients were separated according to Child-Pugh score into A, B, and C subgroup. Albumin metal ion binding capacity (Ischemia-modified albumin transformed, IMAT) and fatty acid binding capacity (total binding sites, TBS) were detected. Results. Both IMAT and TBS were significantly decreased in patients with NAFLD and early hepatitis. In hepatitis group, they declined prior to changes of liver enzymes. IMAT was significantly higher in cirrhosis Child-Pugh class A group than hepatitis patients and decreased in Child-Pugh class B and class C patients. Both IMAT/albumin and TBS/albumin decreased significantly in hepatitis and NAFLD group patients. Conclusions. This is the first study to discover changes of albumin metal ion and fatty acid binding capacities prior to conventional biomarkers for liver damage in early stage of liver diseases. They may become potential earliest sensitive indicators for liver function evaluation.
doi:10.1155/2016/5120760
PMCID: PMC5212348
2.  Comprehensive investigation of tobacco leaves during natural early senescence via multi-platform metabolomics analyses 
Scientific Reports  2016;6:37976.
Senescence is the final stage of leaf growth and development. Many different physiological activities occur during this process. A comprehensive metabolomics analysis of tobacco middle leaves at 5 different developmental stages was implemented through multi-platform methods based on liquid chromatography, capillary electrophoresis and gas chromatography coupled with mass spectrometry. In total, 412 metabolites were identified, including pigments, sterols, lipids, amino acids, polyamines, sugars and secondary metabolites. Dramatic metabolic changes were observed. Firstly, membrane degradation and chlorophyll down-regulation occurred after the 50% flower bud stage. Levels of major membrane lipids decreased, including those of the glycolipids in chloroplast thylakoids and phospholipids in membrane envelopes. Clear decreases in free sterols and acylated sterol glucosides were detected along with the accumulation of sterol esters. The accumulation of alkaloids was found. The amino acid levels were significantly decreased, particularly those of N-rich amino acids (glutamine and asparagine), thus reflecting N translocation. Subsequently, the antioxidant system was activated. Sugar alcohols and polyphenols accumulated when the lower leaves turned yellow. These results comprehensively revealed the metabolic changes that occur during tobacco leaf development and senescence under natural conditions.
doi:10.1038/srep37976
PMCID: PMC5126694  PMID: 27897248
3.  5th International Symposium on Focused Ultrasound 
Zaaroor, Menashe | Sinai, Alon | Goldsher, Dorit | Eran, Ayelet | Nassar, Maria | Schlesinger, Ilana | Parker, Jonathon | Ravikumar, Vinod | Ghanouni, Pejman | Stein, Sherman | Halpern, Casey | Krishna, Vibhor | Hargrove, Amelia | Agrawal, Punit | Changizi, Barbara | Bourekas, Eric | Knopp, Michael | Rezai, Ali | Mead, Brian | Kim, Namho | Mastorakos, Panagiotis | Suk, Jung Soo | Miller, Wilson | Klibanov, Alexander | Hanes, Justin | Price, Richard | Wang, Shutao | Olumolade, Oluyemi | Kugelman, Tara | Jackson-Lewis, Vernice | Karakatsani, Maria Eleni (Marilena) | Han, Yang | Przedborski, Serge | Konofagou, Elisa | Hynynen, Kullervo | Aubert, Isabelle | Leinenga, Gerhard | Nisbet, Rebecca | Hatch, Robert | Van der Jeugd, Anneke | Evans, Harrison | Götz, Jürgen | Götz, Jürgen | Nisbet, Rebecca | Van der Jeugd, Ann | Evans, Harrison | Leinenga, Gerhard | Fishman, Paul | Yarowsky, Paul | Frenkel, Victor | Wei-Bin, Shen | Nguyen, Ben | Sanchez, Carlos Sierra | Acosta, Camilo | Chen, Cherry | Wu, Shih-Ying | Karakatsani, Maria Eleni (Marilena) | Konofagou, Elisa | Aryal, Muna | Papademetriou, Iason T. | Zhang, Yong-Zhi | Power, Chanikarn | McDannold, Nathan | Porter, Tyrone | Kovacs, Zsofia | Kim, Saejeong | Jikaria, Neekita | Qureshi, Farhan | Bresler, Michele | Frank, Joseph | Odéen, Henrik | Chiou, George | Snell, John | Todd, Nick | Madore, Bruno | Parker, Dennis | Pauly, Kim Butts | Marx, Mike | Ghanouni, Pejman | Jonathan, Sumeeth | Grissom, William | Arvanitis, Costas | McDannold, Nathan | Clement, Gregory | Parker, Dennis | de Bever, Joshua | Odéen, Henrik | Payne, Allison | Christensen, Douglas | Maimbourg, Guillaume | Santin, Mathieu David | Houdouin, Alexandre | Lehericy, Stéphane | Tanter, Mickael | Aubry, Jean Francois | Pauly, Kim Butts | Federau, Christian | Werner, Beat | Halpern, Casey | Ghanouni, Pejman | Paeng, Dong-Guk | Xu, Zhiyuan | Snell, John | Quigg, Anders | Eames, Matt | Jin, Changzhu | Everstine, Ashli | Sheehan, Jason | Lopes, M. Beatriz | Kassell, Neal | Snell, John | Quigg, Anders | Drake, James | Price, Karl | Lustgarten, Lior | Sin, Vivian | Mougenot, Charles | Donner, Elizabeth | Tam, Emily | Hodaie, Mojgan | Waspe, Adam | Looi, Thomas | Pichardo, Samuel | Lee, Wonhye | Chung, Yong An | Jung, Yujin | Song, In-Uk | Yoo, Seung-Schik | Lee, Wonhye | Kim, Hyun-Chul | Jung, Yujin | Chung, Yong An | Song, In-Uk | Lee, Jong-Hwan | Yoo, Seung-Schik | Caskey, Charles | Zinke, Wolf | Cosman, Josh | Shuman, Jillian | Schall, Jeffrey | Aurup, Christian | Wang, Shutao | Chen, Hong | Acosta, Camilo | Konofagou, Elisa | Kamimura, Hermes | Carneiro, Antonio | Todd, Nick | Sun, Tao | Zhang, Yong-Zhi | Power, Chanikarn | Nazai, Navid | Patz, Sam | Livingstone, Margaret | McDannold, Nathan | Mainprize, Todd | Huang, Yuexi | Alkins, Ryan | Chapman, Martin | Perry, James | Lipsman, Nir | Bethune, Allison | Sahgal, Arjun | Trudeau, Maureen | Hynynen, Kullervo | Liu, Hao-Li | Hsu, Po-Hung | Wei, Kuo-Chen | Sun, Tao | Power, Chanikarn | Zhang, Yong-Zhi | Sutton, Jonathan | Alexander, Phillip | Aryal, Muna | Miller, Eric | McDannold, Nathan | Kobus, Thiele | Zhang, Yong-Zhi | McDannold, Nathan | Carpentier, Alexandre | Canney, Michael | Vignot, Alexandre | Beccaria, Kevin | Leclercq, Delphine | Lafon, Cyril | Chapelon, Jean Yves | Hoang-Xuan, Khe | Delattre, Jean-Yves | Idbaih, Ahmed | Xu, Zhiyuan | Moore, David | Xu, Alexis | Schmitt, Paul | Snell, John | Foley, Jessica | Eames, Matt | Sheehan, Jason | Kassell, Neal | Sukovich, Jonathan | Cain, Charles | Xu, Zhiyuan | Pandey, Aditya | Snell, John | Chaudhary, Neeraj | Camelo-Piragua, Sandra | Allen, Steven | Paeng, Dong-Guk | Cannata, Jon | Teofilovic, Dejan | Bertolina, Jim | Kassell, Neal | Hall, Timothy | Xu, Zhen | Wu, Shih-Ying | Karakatsani, Maria Eleni (Marilena) | Grondin, Julien | Sanchez, Carlos Sierra | Ferrera, Vincent | Konofagou, Elisa | ter Haar, Gail | Mouratidis, Petros | Repasky, Elizabeth | Timbie, Kelsie | Badr, Lena | Campbell, Benjamin | McMichael, John | Buckner, Andrew | Prince, Jessica | Stevens, Aaron | Bullock, Timothy | Price, Richard | Skalina, Karin | Guha, Chandan | Orsi, Franco | Bonomo, Guido | Vigna, Paolo Della | Mauri, Giovanni | Varano, Gianluca | Schade, George | Wang, Yak-Nam | Pillarisetty, Venu | Hwang, Joo Ha | Khokhlova, Vera | Bailey, Michael | Khokhlova, Tatiana | Khokhlova, Vera | Sinilshchikov, Ilya | Yuldashev, Petr | Andriyakhina, Yulia | Kreider, Wayne | Maxwell, Adam | Khokhlova, Tatiana | Sapozhnikov, Oleg | Partanen, Ari | Lundt, Jonathan | Allen, Steven | Sukovich, Jonathan | Hall, Timothy | Cain, Charles | Xu, Zhen | Preusser, Tobias | Haase, Sabrina | Bezzi, Mario | Jenne, Jürgen | Langø, Thomas | Midiri, Massimo | Mueller, Michael | Sat, Giora | Tanner, Christine | Zangos, Stephan | Guenther, Matthias | Melzer, Andreas | Menciassi, Arianna | Tognarelli, Selene | Cafarelli, Andrea | Diodato, Alessandro | Ciuti, Gastone | Rothluebbers, Sven | Schwaab, Julia | Strehlow, Jan | Mihcin, Senay | Tanner, Christine | Tretbar, Steffen | Preusser, Tobias | Guenther, Matthias | Jenne, Jürgen | Payen, Thomas | Palermo, Carmine | Sastra, Steve | Chen, Hong | Han, Yang | Olive, Kenneth | Konofagou, Elisa | Adams, Matthew | Salgaonkar, Vasant | Scott, Serena | Sommer, Graham | Diederich, Chris | Vidal-Jove, Joan | Perich, Eloi | Ruiz, Antonio | Velat, Manuela | Melodelima, David | Dupre, Aurelien | Vincenot, Jeremy | Yao, Chen | Perol, David | Rivoire, Michel | Tucci, Samantha | Mahakian, Lisa | Fite, Brett | Ingham, Elizabeth | Tam, Sarah | Hwang, Chang-il | Tuveson, David | Ferrara, Katherine | Scionti, Stephen | Chen, Lili | Cvetkovic, Dusica | Chen, Xiaoming | Gupta, Roohi | Wang, Bin | Ma, Charlie | Bader, Kenneth | Haworth, Kevin | Maxwell, Adam | Holland, Christy | Sanghvi, Narendra | Carlson, Roy | Chen, Wohsing | Chaussy, Christian | Thueroff, Stefan | Cesana, Claudio | Bellorofonte, Carlo | Wang, Qingguo | Wang, Han | Wang, Shengping | Zhang, Junhai | Bazzocchi, Alberto | Napoli, Alessandro | Staruch, Robert | Bing, Chenchen | Shaikh, Sumbul | Nofiele, Joris | Szczepanski, Debra | Staruch, Michelle Wodzak | Williams, Noelle | Laetsch, Theodore | Chopra, Rajiv | Ghanouni, Pejman | Rosenberg, Jarrett | Bitton, Rachelle | Napoli, Alessandro | LeBlang, Suzanne | Meyer, Joshua | Hurwitz, Mark | Pauly, Kim Butts | Partanen, Ari | Yarmolenko, Pavel | Partanen, Ari | Celik, Haydar | Eranki, Avinash | Beskin, Viktoriya | Santos, Domiciano | Patel, Janish | Oetgen, Matthew | Kim, AeRang | Kim, Peter | Sharma, Karun | Chisholm, Alexander | Drake, James | Aleman, Dionne | Waspe, Adam | Looi, Thomas | Pichardo, Samuel | Napoli, Alessandro | Bazzocchi, Alberto | Scipione, Roberto | Temple, Michael | Waspe, Adam | Amaral, Joao Guilherme | Huang, Yuexi | Endre, Ruby | Lamberti-Pasculli, Maria | de Ruiter, Joost | Campbell, Fiona | Stimec, Jennifer | Gupta, Samit | Singh, Manoj | Mougenot, Charles | Hopyan, Sevan | Hynynen, Kullervo | Czarnota, Gregory | Drake, James | Brenin, David | Rochman, Carrie | Kovatcheva, Roussanka | Vlahov, Jordan | Zaletel, Katja | Stoinov, Julian | Han, Yang | Wang, Shutao | Konofagou, Elisa | Bucknor, Matthew | Rieke, Viola | Shim, Jenny | Staruch, Robert | Koral, Korgun | Chopra, Rajiv | Laetsch, Theodore | Lang, Brian | Wong, Carlos | Lam, Heather | Kovatcheva, Roussanka | Vlahov, Jordan | Zaletel, Katja | Stoinov, Julian | Shinkov, Alexander | Hu, Jim | Sharma, Karun | Zhang, Xi | Macoskey, Jonathan | Ives, Kimberly | Owens, Gabe | Gurm, Hitinder | Shi, Jiaqi | Pizzuto, Matthew | Cain, Charles | Xu, Zhen | Payne, Allison | Dillon, Christopher | Christofferson, Ivy | Hilas, Elaine | Shea, Jill | Greillier, Paul | Ankou, Bénédicte | Bessière, Francis | Zorgani, Ali | Pioche, Mathieu | Kwiecinski, Wojciech | Magat, Julie | Melot-Dusseau, Sandrine | Lacoste, Romain | Quesson, Bruno | Pernot, Mathieu | Catheline, Stefan | Chevalier, Philippe | Lafon, Cyril | Marquet, Fabrice | Bour, Pierre | Vaillant, Fanny | Amraoui, Sana | Dubois, Rémi | Ritter, Philippe | Haïssaguerre, Michel | Hocini, Mélèze | Bernus, Olivier | Quesson, Bruno | Tebebi, Pamela | Burks, Scott | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Gertner, Michael | Zhang, Jimin | Wong, Andrew | Fite, Brett | Liu, Yu | Kheirolomoom, Azadeh | Seo, Jai | Watson, Katherine | Mahakian, Lisa | Tam, Sarah | Zhang, Hua | Foiret, Josquin | Borowsky, Alexander | Ferrara, Katherine | Xu, Doudou | Melzer, Andreas | Thanou, Maya | Centelles, Miguell | Wright, Mike | Amrahli, Maral | So, Po-Wah | Gedroyc, Wladyslaw | Centelles, Miguell | Wright, Mike | Gedroyc, Wladyslaw | Thanou, Maya | Kneepkens, Esther | Heijman, Edwin | Keupp, Jochen | Weiss, Steffen | Nicolay, Klaas | Grüll, Holger | Fite, Brett | Wong, Andrew | Liu, Yu | Kheirolomoom, Azadeh | Mahakian, Lisa | Tam, Sarah | Foiret, Josquin | Ferrara, Katherine | Burks, Scott | Nagle, Matthew | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Sapozhnikov, Oleg | Nikolaeva, Anastasia V. | Terzi, Marina E. | Tsysar, Sergey A. | Maxwell, Adam | Cunitz, Bryan | Bailey, Michael | Mourad, Pierre | Downs, Matthew | Yang, Georgiana | Wang, Qi | Konofagou, Elisa | Burks, Scott | Nagle, Matthew | Nguyen, Ben | Bresler, Michele | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Burks, Scott | Nagle, Matthew | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Chen, Johnny | Farry, Justin | Dixon, Adam | Du, Zhongmin | Dhanaliwala, Ali | Hossack, John | Klibanov, Alexander | Ranjan, Ashish | Maples, Danny | Chopra, Rajiv | Bing, Chenchen | Staruch, Robert | Wardlow, Rachel | Staruch, Michelle Wodzak | Malayer, Jerry | Ramachandran, Akhilesh | Nofiele, Joris | Namba, Hirofumi | Kawasaki, Motohiro | Izumi, Masashi | Kiyasu, Katsuhito | Takemasa, Ryuichi | Ikeuchi, Masahiko | Ushida, Takahiro | Crake, Calum | Papademetriou, Iason T. | Zhang, Yong-Zhi | Porter, Tyrone | McDannold, Nathan | Kothapalli, Satya V. V. N. | Leighton, Wan | Wang, Zhaorui | Partanen, Ari | Gach, H. Michael | Straube, William | Altman, Michael | Chen, Hong | Kim, Young-sun | Lim, Hyo Keun | Rhim, Hyunchul | Kim, Young-sun | Lim, Hyo Keun | Rhim, Hyunchul | van Breugel, Johanna | Braat, Manon | Moonen, Chrit | van den Bosch, Maurice | Ries, Mario | Marrocchio, Cristina | Dababou, Susan | Bitton, Rachelle | Pauly, Kim Butts | Ghanouni, Pejman | Lee, Jae Young | Lee, Jae Young | Chung, Hyun Hoon | Kang, Soo Yeon | Kang, Kook Jin | Son, Keon Ho | Zhang, Dandan | Adams, Matthew | Salgaonkar, Vasant | Plata, Juan | Jones, Peter | Pascal-Tenorio, Aurea | Bouley, Donna | Sommer, Graham | Pauly, Kim Butts | Diederich, Chris | Bond, Aaron | Dallapiazza, Robert | Huss, Diane | Warren, Amy | Sperling, Scott | Gwinn, Ryder | Shah, Binit | Elias, W. Jeff | Curley, Colleen | Zhang, Ying | Negron, Karina | Miller, Wilson | Klibanov, Alexander | Abounader, Roger | Suk, Jung Soo | Hanes, Justin | Price, Richard | Karakatsani, Maria Eleni (Marilena) | Samiotaki, Gesthimani | Wang, Shutao | Kugelman, Tara | Acosta, Camilo | Konofagou, Elisa | Kovacs, Zsofia | Tu, Tsang-Wei | Papadakis, Georgios | Hammoud, Dima | Frank, Joseph | Silvestrini, Matthew | Wolfram, Frank | Güllmar, Daniel | Reichenbach, Juergen | Hofmann, Denis | Böttcher, Joachim | Schubert, Harald | Lesser, Thomas G. | Almquist, Scott | Parker, Dennis | Christensen, Douglas | Camarena, Francisco | Jiménez-Gambín, Sergio | Jiménez, Noé | Konofagou, Elisa | Chang, Jin Woo | Chaplin, Vandiver | Griesenauer, Rebekah | Miga, Michael | Caskey, Charles | Ellens, Nicholas | Airan, Raag | Quinones-Hinojosa, Alfredo | Farahani, Keyvan | Partanen, Ari | Feng, Xue | Fielden, Samuel | Zhao, Li | Miller, Wilson | Wintermark, Max | Pauly, Kim Butts | Meyer, Craig | Guo, Sijia | Lu, Xin | Zhuo, Jiachen | Xu, Su | Gullapalli, Rao | Gandhi, Dheeraj | Jin, Changzhu | Brokman, Omer | Eames, Matt | Snell, John | Paeng, Dong-Guk | Baek, Hongchae | Kim, Hyungmin | Leung, Steven | Webb, Taylor | Pauly, Kim Butts | McDannold, Nathan | Zhang, Yong-Zhi | Vykhodtseva, Natalia | Nguyen, Thai-Son | Sukovich, Jonathan | Hall, Timothy | Xu, Zhen | Cain, Charles | Park, Chang Kyu | Park, Sang Man | Jung, Na Young | Kim, Min Soo | Chang, Won Seok | Jung, Hyun Ho | Chang, Jin Woo | Pichardo, Samuel | Hynynen, Kullervo | Plaksin, Michael | Weissler, Yoni | Shoham, Shy | Kimmel, Eitan | Quigg, Anders | Snell, John | Paeng, Dong-Guk | Eames, Matt | Sapozhnikov, Oleg | Rosnitskiy, Pavel B. | Khokhlova, Vera | Shoham, Shy | Krupa, Steve | Hazan, Eilon | Naor, Omer | Levy, Yoav | Maimon, Noam | Brosh, Inbar | Kimmel, Eitan | Kahn, Itamar | Sukovich, Jonathan | Xu, Zhen | Hall, Timothy | Allen, Steven | Cain, Charles | Cahill, Jessica | Sun, Tao | Zhang, Yong-Zhi | Power, Chanikarn | Livingstone, Margaret | McDannold, Nathan | Todd, Nick | Colas, Elodie Constanciel | Wydra, Adrian | Waspe, Adam | Looi, Thomas | Maev, Roman | Pichardo, Samuel | Drake, James | Aly, Amirah | Sun, Tao | Zhang, Yong-Zhi | Sesenoglu-Laird, Ozge | Padegimas, Linas | Cooper, Mark | McDannold, Nathan | Waszczak, Barbara | Tehrani, Seruz | Miller, Wilson | Slingluff, Craig | Larner, James | Andarawewa, Kumari | Bucknor, Matthew | Ozhinsky, Eugene | Shah, Rutwik | Krug, Roland | Rieke, Viola | Deckers, Roel | Linn, Sabine | Suelmann, Britt | Braat, Manon | Witkamp, Arjen | Vaessen, Paul | van Diest, Paul | Bartels, Lambertus W. | Bos, Clemens | van den Bosch, Maurice | Borys, Nicolas | Storm, Gert | Van der Wall, Elsken | Moonen, Chrit | Farr, Navid | Alnazeer, Moez | Yarmolenko, Pavel | Katti, Prateek | Partanen, Ari | Eranki, Avinash | Kim, Peter | Wood, Bradford | Farrer, Alexis | Almquist, Scott | Dillon, Christopher | Parker, Dennis | Christensen, Douglas | Payne, Allison | Ferrer, Cyril | Bartels, Lambertus W. | de Senneville, Baudouin Denis | van Stralen, Marijn | Moonen, Chrit | Bos, Clemens | Liu, Yu | Liu, Jingfei | Fite, Brett | Foiret, Josquin | Leach, J. Kent | Ferrara, Katherine | Gupta, Roohi | Cvetkovic, Dusica | Ma, Charlie | Chen, Lili | Haase, Sabrina | Zidowitz, Stephan | Melzer, Andreas | Preusser, Tobias | Lee, Hsin-Lun | Hsu, Fang-Chi | Kuo, Chia-Chun | Jeng, Shiu-Chen | Chen, Tung-Ho | Yang, Nai-Yi | Chiou, Jeng-Fong | Jeng, Shiu-Chen | Kao, Yi-tzu | Pan, Chia-Hsin | Wu, Jing-Fu | Chen, Tung-Ho | Hsu, Fang-Chi | Lee, Hsin-Lun | Chiou, Jeng-Fong | Hsu, Fang-Chi | Tsai, Yi-Chieh | Lee, Hsin-Lun | Chiou, Jeng-Fong | Johnson, Sara | Parker, Dennis | Payne, Allison | Li, Dawei | He, Ye | Mihcin, Senay | Karakitsios, Ioannis | Strehlow, Jan | Schwenke, Michael | Haase, Sabrina | Demedts, Daniel | Levy, Yoav | Preusser, Tobias | Melzer, Andreas | Mihcin, Senay | Rothluebbers, Sven | Karakitsios, Ioannis | Xiao, Xu | Strehlow, Jan | Demedts, Daniel | Cavin, Ian | Sat, Giora | Preusser, Tobias | Melzer, Andreas | Minalga, Emilee | Payne, Allison | Merrill, Robb | Parker, Dennis | Hadley, Rock | Ramaekers, Pascal | Ries, Mario | Moonen, Chrit | de Greef, Martijn | Shahriari, Kian | Parvizi, Mohammad Hossein | Asadnia, Kiana | Chamanara, Marzieh | Kamrava, Seyed Kamran | Chabok, Hamid Reza | Schwenke, Michael | Strehlow, Jan | Demedts, Daniel | Tanner, Christine | Rothluebbers, Sven | Preusser, Tobias | Strehlow, Jan | Stein, Ruben | Demedts, Daniel | Schwenke, Michael | Rothluebbers, Sven | Preusser, Tobias | Demedts, Daniel | Haase, Sabrina | Muller, Sébastien | Strehlow, Jan | Langø, Thomas | Preusser, Tobias | Tan, Jeremy | Zachiu, Cornel | Ramaekers, Pascal | Moonen, Chrit | Ries, Mario | Wolfram, Frank | Güllmar, Daniel | Schubert, Harald | Lesser, Thomas G. | Erasmus, Hans-Peter | Colas, Elodie Constanciel | Waspe, Adam | Mougenot, Charles | Looi, Thomas | Van Arsdell, Glen | Benson, Lee | Drake, James | Jang, Kee W. | Tu, Tsang-Wei | Jikaria, Neekita | Nagle, Matthew | Angstadt, Mary | Lewis, Bobbi | Qureshi, Farhan | Burks, Scott | Frank, Joseph | McLean, Hailey | Payne, Allison | Hoogenboom, Martijn | Eikelenboom, Dylan | den Brok, Martijn | Wesseling, Pieter | Heerschap, Arend | Fütterer, Jurgen | Adema, Gosse | Wang, Kevin | Zhang, Ying | Zhong, Pei | Xiao, Xu | Joy, Joyce | McLeod, Helen | Melzer, Andreas | Bing, Chenchen | Staruch, Robert | Nofiele, Joris | Szczepanski, Debra | Staruch, Michelle Wodzak | Laetsch, Theodore | Chopra, Rajiv | Bing, Chenchen | Staruch, Robert | Yarmolenko, Pavel | Celik, Haydar | Nofiele, Joris | Szczepanski, Debra | Kim, Peter | Kim, Harry | Lewis, Matthew | Chopra, Rajiv | Shah, Rutwik | Ozhinsky, Eugene | Rieke, Viola | Bucknor, Matthew | Diederich, Chris | Salgaonkar, Vasant | Jones, Peter | Adams, Matthew | Ozilgen, Arda | Zahos, Peter | Coughlin, Dezba | Tang, Xinyan | Lotz, Jeff | Jedruszczuk, Kathleen | Gulati, Amitabh | Solomon, Stephen | Kaye, Elena | Fielden, Samuel | Mugler, John | Miller, Wilson | Pauly, Kim Butts | Meyer, Craig | Barbato, Gaetano | Scoarughi, Gian Luca | Corso, Cristiano | Gorgone, Alessandro | Migliore, Ilaria Giuseppina | Larrabee, Zachary | Hananel, Arik | Eames, Matt | Aubry, Jean-Francois | Eranki, Avinash | Farr, Navid | Partanen, Ari | Sharma, Karun | Yarmolenko, Pavel | Wood, Bradford | Kim, Peter | Farr, Navid | Kothapalli, Satya V. V. N. | Eranki, Avinash | Negussie, Ayele | Wilson, Emmanuel | Seifabadi, Reza | Kim, Peter | Chen, Hong | Wood, Bradford | Partanen, Ari | Moon, Hyungwon | Kang, Jeeun | Sim, Changbeom | Chang, Jin Ho | Kim, Hyuncheol | Lee, Hak Jong | Sasaki, Noboru | Takiguchi, Mitsuyoshi | Sebeke, Lukas | Luo, Xi | de Jager, Bram | Heemels, Maurice | Heijman, Edwin | Grüll, Holger | Strehlow, Jan | Schwenke, Michael | Demedts, Daniel | Preusser, Tobias
Journal of Therapeutic Ultrasound  2016;4(Suppl 1):1-113.
doi:10.1186/s40349-016-0076-5
PMCID: PMC5123388
4.  What Drives Variation in Episode-of-care Payments for Primary TKA? An Analysis of Medicare Administrative Data 
Background
Episode-of-care payments are defined as a single lump-sum payment for all services associated with a single medical event or surgery and are designed to incentivize efficiency and integration among providers and healthcare systems. A TKA is considered an exemplar for an episode-of-care payment model by many policymakers, but data describing variation payments between hospitals for TKA are extremely limited.
Questions/purposes
We asked: (1) How much variation is there between hospitals in episode-of-care payments for primary TKA? (2) Is variation in payment explained by differences in hospital structural characteristics such as teaching status or geographic location, patient factors (age, sex, ethnicity, comorbidities), and discharge disposition during the postoperative period (home versus skilled nursing facility)? (3) After accounting for those factors, what proportion of the observed variation remains unexplained?
Methods
We used Medicare administrative data to identify fee-for-service beneficiaries who underwent a primary elective TKA in 2009. After excluding low-volume hospitals, we created longitudinal records for all patients undergoing TKAs in eligible hospitals encompassing virtually all payments by Medicare for a 120-day window around the TKA (30 days before to 90 days after). We examined payments for the preoperative, perioperative, and postdischarge periods based on the hospital where the TKA was performed. Confounding variables were controlled for using multivariate analyses to determine whether differences in hospital payments could be explained by differences in patient demographics, comorbidity, or hospital structural factors.
Results
There was considerable variation in payments across hospitals. Median (interquartile range) hospital preoperative, perioperative, postdischarge, and 120-day payments for patients who did not experience a complication were USD 623 (USD 516-768), USD 13,119 (USD 12,165-14,668), USD 8020 (USD 6403-9933), and USD 21,870 (USD 19,736-25,041), respectively. Variation cannot be explained by differences in hospital structure. Median (interquartile range) episode payments were greater for hospitals in the Northeast (USD 26,291 [22,377-30,323]) compared with the Midwest, South, and West (USD 20,614, [USD 18,592-22.968]; USD 21,584, [USD 19,663-23,941]; USD 22,421, [USD 20,317-25,860]; p < 0.001) and for teaching compared with nonteaching hospitals (USD 23,152 [USD 20,426-27,127] versus USD 21,336 [USD 19,352-23,846]; p < 0.001). Patient characteristics explained approximately 15% of the variance in hospital payments, hospital characteristics (teaching status, geographic region) explained 30% of variance, and approximately 55% of variance was not explained by either factor.
Conclusions
There is much unexplained variation in episode-of-care payments at the hospital-level, suggesting opportunities for enhanced efficiency. Further research is needed to ensure an appropriate balance between such efficiencies and access to care.
Level of Evidence
Level II, economic analysis.
Electronic supplementary material
The online version of this article (doi:10.1007/s11999-015-4445-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s11999-015-4445-0
PMCID: PMC4586190  PMID: 26239239
5.  Patient Preferences for Test Result Notification 
Journal of General Internal Medicine  2015;30(11):1651-1656.
Importance
Patients are increasingly being given access to their test results, but little is known about how preferences vary with the test under consideration or the results of the test (normal or abnormal).
Objective
This study was conducted to examine preferences for test result communication.
Design, Setting, and Participants
We surveyed adults to explore their preferences for test result notification for three common diagnostic tests of varying “emotional impact” (dual-energy x-ray absorptiometry [DXA], genital herpes, and cancer biopsy) when test results were 1) normal and 2) abnormal. We conducted our survey between June and August 2012 on the campus of an academic medical center. For each scenario, subjects were asked to rank seven methods that might be used to communicate test results (letter, unsecured email, secured email, text message, telephone call, secure Web portal, office visit) in order of acceptability.
Main Outcome Measures
The main measures were the percentage of respondents who ranked a particular test result notification method favorably and the percentage who ranked it as unacceptable.
Results
When test results were normal, subjects’ notification preferences were generally similar for DXA, herpes and cancer biopsy, with telephone and letter ranked most favorably for all three tests. Conversely, text message and unsecured email were viewed as unacceptable notification methods for normal results by 45.0–55.0 % of subjects across all three tests. When test results were abnormal, office visits became more popular. A higher proportion of subjects ranked office visits as their most preferred notification method for our test with high “emotional impact” (cancer biopsy) (38.4 %) as compared to DXA (28.2 %) and herpes (27.9 %) (P = 0.02). For most test scenarios, younger subjects appeared to rank electronic communication modalities (secure email or Web portal) higher than older subjects, though this difference did not reach statistical significance (P = 0.29).
Conclusions
Preferences for test result notification can differ substantially depending upon the test under consideration and results of the test. Providers and health care systems should consider these factors when deciding how to communicate results to patients.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-015-3344-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-015-3344-0
PMCID: PMC4617924  PMID: 25944020
test results notification; patient preferences
8.  Hepatocellular carcinoma: an entity needed to be differentiated 
doi:10.21037/hbsn.2016.09.06
PMCID: PMC5075825  PMID: 27826564
9.  Analysis of heterogeneous dengue transmission in Guangdong in 2014 with multivariate time series model 
Scientific Reports  2016;6:33755.
Guangdong experienced the largest dengue epidemic in recent history. In 2014, the number of dengue cases was the highest in the previous 10 years and comprised more than 90% of all cases. In order to analyze heterogeneous transmission of dengue, a multivariate time series model decomposing dengue risk additively into endemic, autoregressive and spatiotemporal components was used to model dengue transmission. Moreover, random effects were introduced in the model to deal with heterogeneous dengue transmission and incidence levels and power law approach was embedded into the model to account for spatial interaction. There was little spatial variation in the autoregressive component. In contrast, for the endemic component, there was a pronounced heterogeneity between the Pearl River Delta area and the remaining districts. For the spatiotemporal component, there was considerable heterogeneity across districts with highest values in some western and eastern department. The results showed that the patterns driving dengue transmission were found by using clustering analysis. And endemic component contribution seems to be important in the Pearl River Delta area, where the incidence is high (95 per 100,000), while areas with relatively low incidence (4 per 100,000) are highly dependent on spatiotemporal spread and local autoregression.
doi:10.1038/srep33755
PMCID: PMC5036033  PMID: 27666657
10.  Bactericidal effect of plasma jet with helium flowing through 3% hydrogen peroxide against Enterococcus faecalis 
The aim of the present study was to assess the antimicrobial activity of plasma jet with helium (He) flowing through 3% hydrogen peroxide in root canals infected with Enterococcus faecalis. A total of 42 single-rooted anterior teeth were prepared, sterilized, inoculated with an E. faecalis suspension and incubated for 7 days. Next, the teeth were randomly divided into six experimental groups (including groups treated by plasma jet with or without He for different time durations) and one control group treated without plasma. The number of surviving bacteria in each canal was determined by counting the colony forming units (CFU)/ml on nutrient agar plates. The results indicated that statistically significant reduction in CFU/ml (P<0.005) existed for all treatment groups relative to the control group. The greatest reductions in CFU/ml were observed for Group 3 (7.027 log unit reduction) and Group 2 (6.237 log unit reduction), which were treated by plasma jet sterilization with He flowing through 3% hydrogen peroxide for 4 min or for 2 min, respectively. In addition, the reduction in Group 3 was significantly greater compared with that in Group 2 or in the groups treated by plasma jet sterilization without He flowing through 3% hydrogen peroxide for 1, 2 or 4 min. In conclusion, plasma jet with or without He flowing through 3% hydrogen peroxide can effectively sterilized root canals infected with E. faecalis and should be considered as an alternative method for root canal disinfection in endodontic treatments.
doi:10.3892/etm.2016.3726
PMCID: PMC5103749  PMID: 27882119
antimicrobial efficacy; plasma jet; hydrogen peroxide; Enterococcus faecalis
11.  Mice produced by mitotic reprogramming of sperm injected into haploid parthenogenotes 
Nature Communications  2016;7:12676.
Sperm are highly differentiated and the activities that reprogram them for embryonic development during fertilization have historically been considered unique to the oocyte. We here challenge this view and demonstrate that mouse embryos in the mitotic cell cycle can also directly reprogram sperm for full-term development. Developmentally incompetent haploid embryos (parthenogenotes) injected with sperm developed to produce healthy offspring at up to 24% of control rates, depending when in the embryonic cell cycle injection took place. This implies that most of the first embryonic cell cycle can be bypassed in sperm genome reprogramming for full development. Remodelling of histones and genomic 5′-methylcytosine and 5′-hydroxymethylcytosine following embryo injection were distinct from remodelling in fertilization and the resulting 2-cell embryos consistently possessed abnormal transcriptomes. These studies demonstrate plasticity in the reprogramming of terminally differentiated sperm nuclei and suggest that different epigenetic pathways or kinetics can establish totipotency.
It is unclear what regulates gamete reprogramming competence. Here, the authors inject sperm into parthenogenetic embryos, generating viable offspring and show that mouse embryos in the mitotic cell cycle can reprogram sperm for full term development.
doi:10.1038/ncomms12676
PMCID: PMC5027272  PMID: 27623537
12.  Transcriptomic profiling of long non-coding RNAs in dermatomyositis by microarray analysis 
Scientific Reports  2016;6:32818.
Long non-coding RNAs (lncRNAs) are prevalently transcribed in the genome and have been found to be of functional importance. However, the potential roles of lncRNAs in dermatomyositis (DM) remain unknown. In this study, a lncRNA + mRNA microarray analysis was performed to profile lncRNAs and mRNAs from 15 treatment-naive DM patients and 5 healthy controls. We revealed a total of 1198 lncRNAs (322 up-regulated and 876 down-regulated) and 1213 mRNAs (665 up-regulated and 548 down-regulated) were significantly differentially expressed in DM patients compared with the healthy controls (fold change>2, P < 0.05). Subgrouping DM patients according to the presence of interstitial lung disease and anti-Jo-1 antibody revealed different expression patterns of the lncRNAs. Pathway and gene ontology analysis for the differentially expressed mRNAs confirmed that type 1 interferon signaling was the most significantly dysregulated pathway in all DM subgroups. In addition, distinct pathways that uniquely associated with DM subgroup were also identified. Bioinformatics prediction suggested that linc-DGCR6-1 may be a lncRNA that regulates type 1 interferon-inducible gene USP18, which was found highly expressed in the perifascicular areas of the muscle fibers of DM patients. Our findings provide an overview of aberrantly expressed lncRNAs in DM muscle and further broaden the understanding of DM pathogenesis.
doi:10.1038/srep32818
PMCID: PMC5015085  PMID: 27605457
13.  LECT2 drives haematopoietic stem cell expansion and mobilization via regulating the macrophages and osteolineage cells 
Nature Communications  2016;7:12719.
Haematopoietic stem cells (HSCs) can differentiate into cells of all lineages in the blood. However, the mechanisms by which cytokines in the blood affect HSC homeostasis remain largely unknown. Here we show that leukocyte cell-derived chemotaxin 2 (LECT2), a multifunctional cytokine, induces HSC expansion and mobilization. Recombinant LECT2 administration results in HSC expansion in the bone marrow and mobilization to the blood via CD209a. The effect of LECT2 on HSCs is reduced after specific depletion of macrophages or reduction of osteolineage cells. LECT2 treatment reduces the tumour necrosis factor (TNF) expression in macrophages and osteolineage cells. In TNF knockout mice, the effect of LECT2 on HSCs is reduced. Moreover, LECT2 induces HSC mobilization in irradiated mice, while granulocyte colony-stimulating factor does not. Our results illustrate that LECT2 is an extramedullar cytokine that contributes to HSC homeostasis and may be useful to induce HSC mobilization.
How extramedullar cytokines regulate hematopoietic stem cell (HSC) homeostasis is unclear. Here, the authors show that the cytokine leukocyte cell-derived chemotaxin 2 regulates HSC expansion and mobilisation via tumour necrosis factor and interaction with CD209a in macrophages.
doi:10.1038/ncomms12719
PMCID: PMC5025878  PMID: 27596364
14.  Identification of late-onset hypogonadism in middle-aged and elderly men from a community of China 
Asian Journal of Andrology  2015;18(5):747-753.
In this study, we investigated the essential criteria for late-onset hypogonadism (LOH) syndrome based on the presence of symptoms associated with low testosterone levels in Han Chinese men. Blood tests for total testosterone (TT) and sex hormone–binding globulin (SHBG) were performed, and the aging male symptoms (AMS) questionnaire was conducted in a randomly selected cohort composed of 944 Chinese men aged 40 to 79 years from nine urban communities. Three sexual symptoms (decreased ability/frequency of sexual activity, decreased number of morning erections, and decreased libido) were confirmed to be related to the total and free testosterone levels. The thresholds for TT were approximately 12.55 nmol l−1 for a decreased ability/frequency to perform sex, 12.55 nmol l−1 for decreased frequency of morning erections, and 14.35 nmol l−1 for decreased sexual desire. The calculated free testosterone (CFT) thresholds for these three sexual symptoms were 281.14, 264.90, and 287.21 pmol l−1, respectively. TT <13.21 nmol l−1 (OR = 1.4, 95%CI: 1.0–1.9, P = 0.037) or CFT <268.89 pmol l−1 (OR = 1.5, 95%CI: 1.1–20, P = 0.020) was associated with an increase in the aforementioned three sexual symptoms. The prevalence of LOH was 9.1% under the criteria, including all three sexual symptoms with TT levels <13.21 nmol l−1 and CFT levels <268.89 pmol l−1. Our results may improve the diagnostic accuracy of LOH in older men.
doi:10.4103/1008-682X.160883
PMCID: PMC5000798  PMID: 26354142
diagnosis; hypogonadism; middle-aged and elderly male; reference values; sexual dysfunction; testosterone
15.  Health in a fragile state: a five-year review of mortality patterns and trends at Somalia’s Banadir Hospital 
Background
The recurrent civil conflict in Somalia has impeded progress toward improving health and health care, with lack of data and poor performance of health indicators. This study aimed at making inference about Banadir region by exploring morbidity and mortality trends at Banadir Hospital. This is one of the few functional hospitals during war.
Methods
A retrospective analysis was conducted with data collected at Banadir Hospital for the period of January 2008–December 2012. The data were aggregated from patient records and summarized on a morbidity and mortality surveillance form with respect to age groups and stratified by sex. The main outcome was the number of patients that died in the hospital. Chi-square tests were used to evaluate the association between sex and hospital mortality.
Results
Conditions of infectious origin were the major presentations at the hospital. The year 2011 recorded the highest number of cases of diarrhea and mortality due to diarrhea. The stillbirth rate declined during the study period from 272 to 48 stillbirths per 1,000 live births by 2012. The sum of total cases that were attended to at the hospital by the end of 2012 was four times the number at the baseline year of the study in 2008; however, the overall mortality rate among those admitted declined between 2008 and 2012.
Conclusion
There was reduction in patient mortality at the hospital over the study period. Data from Banadir Hospital are consistent with findings from Banadir region and could give credible public health reflections for the region given the lack of data on a population level.
doi:10.2147/IJGM.S109024
PMCID: PMC5012843  PMID: 27621664
Banadir Hospital; Somalia; hospital mortality; sex; health indicators
16.  CCCCC pentadentate chelates with planar Möbius aromaticity and unique properties 
Science Advances  2016;2(8):e1601031.
Planar Möbius aromatic metallacycles show NIR absorption spectrum and the highest carbon coordination number for a metal atom.
The coordinating atoms in polydentate chelates are primarily heteroatoms. We present the first examples of pentadentate chelates with all binding atoms of the chelating agent being carbon atoms, denoted as CCCCC chelates. Having up to five metal-carbon bonds in the equatorial plane has not been previously observed in transition metal chemistry. Density functional theory calculations showed that the planar metallacycle has extended Craig-Möbius aromaticity arising from 12-center–12-electron dπ-pπ π-conjugation. These planar chelates have broad absorption in the ultraviolet-visible–near-infrared region and, thus, notable photothermal performance upon irradiation by an 808-nm laser, indicating that these chelates have potential applications in photothermal therapy. The combination of facile synthesis, high stability, and broad absorption of these complexes could make the polydentate carbon chain a novel building block in coordination chemistry.
doi:10.1126/sciadv.1601031
PMCID: PMC5001811  PMID: 27574707
Metallacycles; Möbius Aromaticity; Carbon Chain; Pentadentate Chelate
17.  Combined hepatocellular and cholangiocarcinoma originating from the same clone: a pathomolecular evidence-based study 
Chinese Journal of Cancer  2016;35(1):82.
Background
Combined hepatocellular and cholangiocarcinoma (CHC) is a unique subtype of liver cancer comprising both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC); however, its cellular origin remains unclear. The purpose of this study was to investigate the clinicopathologic features and the clonal relationship between HCC and ICC in 34 patients with CHC.
Methods
The clinicopathologic features and prognosis of the 34 CHC patients were compared with those of 29 patients with separated HCC and ICC (SHC). Loss of heterozygosity (LOH) at 10 highly polymorphic microsatellite markers was detected in 16 CHC and 10 SHC tissues for determination of the clonal origin of CHC. Expression of hepatocyte markers [hepatocyte paraffin 1 (Hep Par 1) and glypican 3 (GPC3)] and cholangiocyte markers [cytokeratin (CK)7 and 19] in tumor tissues was examined by immuno histochemical analysis.
Results
In the 16 CHC specimens, the difference in LOH patterns between HCC and ICC was less than 30%, suggesting the same clonal origin of HCC and ICC. Consistent with this finding, immunohistochemical analysis revealed that hepatocyte markers (Hep Par 1 and GPC3) and cholangiocyte markers (CK7 and CK19) were simultaneously expressed in both the HCC and ICC components in 52.9% of CHC specimens, suggesting that the two components shared a similar phenotype with hepatic progenitor cells (HPCs). On the contrary, in all 10 SHC cases, the difference in LOH patterns between the HCC and ICC components was greater than 30%, suggesting different clonal origins of HCC and ICC. Overall survival and disease-free survival were shorter for patients with CHC than for patients with SHC (P < 0.05).
Conclusions
Our results suggest that the HCC and ICC components of CHC may originate from the same clone, having the potential for dual-directional differentiation similar to HPCs. CHC tended to exhibit the biological behaviors of both HCC and ICC, which may enhance the infiltrative capacity of tumor cells, leading to poor clinical outcomes for patients with CHC.
doi:10.1186/s40880-016-0146-7
PMCID: PMC4995671  PMID: 27552844
Combined hepatocellular and cholangiocarcinoma; Hepatocellular carcinoma; Intrahepatic cholangiocellular carcinoma; Loss of heterozygosity; Clonal origin; Prognosis
18.  Assembled molecular face-rotating polyhedra to transfer chirality from two to three dimensions 
Nature Communications  2016;7:12469.
In nature, protein subunits on the capsids of many icosahedral viruses form rotational patterns, and mathematicians also incorporate asymmetric patterns into faces of polyhedra. Chemists have constructed molecular polyhedra with vacant or highly symmetric faces, but very little is known about constructing polyhedra with asymmetric faces. Here we report a strategy to embellish a C3h truxene unit with rotational patterns into the faces of an octahedron, forming chiral octahedra that exhibit the largest molar ellipticity ever reported, to the best of our knowledge. The directionalities of the facial rotations can be controlled by vertices to achieve identical rotational directionality on each face, resembling the homo-directionality of virus capsids. Investigations of the kinetics and mechanism reveal that non-covalent interaction among the faces is essential to the facial homo-directionality.
Protein subunits on the capsids of icosahedral viruses can form patterns with rotational symmetry, which are difficult to recreate in the laboratory. Here the authors report a strategy to construct 3D chiral polyhedra with rotational faces from 2D chiral truxene-based units through dynamic covalent chemistry.
doi:10.1038/ncomms12469
PMCID: PMC4999497  PMID: 27555330
19.  HMGB1 May Be a Biomarker for Predicting the Outcome in Patients with Polymyositis /Dermatomyositis with Interstitial Lung Disease 
PLoS ONE  2016;11(8):e0161436.
Objective
To investigate the significance of high mobility group box 1 (HMGB1) levels in polymyositis (PM) and dermatomyositis (DM) patients with interstitial lung disease and whether HMGB1 levels could predict disease outcome.
Methods
HMGB1 levels were measured in sera from 34 patients with PM/DM and from 34 healthy controls by ELISA.
Results
Significantly higher serum levels of HMGB1 were found in patients with PM [12.75 ng/ml (4.34–25.07 ng/ml), p < 0.001] and DM [20.75 ng/ml (3.80–124.88 ng/ml), p < 0.001] than in healthy controls [5.64 ng/ml (2.71–8.71 ng/ml)]. Importantly, the average HMGB1 level in PM/DM patients with interstitial lung disease (ILD) was 25.84 ng/ml, which is significantly higher than that in PM/DM patients without ILD [12.68 ng/ml] (p < 0.05). A receiver operating characteristic (ROC) curve analysis revealed that the serum HMGB1 cutoff value that best discriminated PM/DM patients with ILD from those without ILD was 14.5ng/ml. The area under the curve was 0.87±0.05, and the 95% Confidence interval (CI) was 0.77–0.98. The diagnostic sensitivity and specificity of this serum HMGB1 cutoff level was 84.6% and 89% respectively. Patients with higher levels of HMGB1 expression had lower overall survival rates and disease-free survival rates, whereas patients with lower levels of HMGB1 expression had higher survival rates.
Conclusion
Multivariate analysis showed that HMGB1 expression is a prognostic indicator for patient survival. These data support the notion that HMGB1 overexpression is involved in PM/DM progression for patients with ILD and is relative to its poor clinical outcomes.
doi:10.1371/journal.pone.0161436
PMCID: PMC4990180  PMID: 27537498
20.  Long noncoding RNA C17orf91 is a potential prognostic marker and functions as an oncogene in ovarian cancer 
Background
This study was aimed to explore the role of long noncoding RNA C17orf91 and its potential mechanisms in ovarian cancer development.
Results
To assess its role in ovarian cancer, microarray datasets (GSE14407, GSE30587, and GSE17260) in Gene Expression Omnibus (GEO) were utilized to assess the expression and clinical significance of C17orf91 in ovarian cancer. Next, loss-of-function studies were performed to establish the role of C17orf91 and the underlying mechanisms in ovarian cancer development. It was found that elevated expression of C17orf91 was observed in omental metastases when compared with matched primary ovarian tumors(GSE30587, P = 0.016). Moreover, Log Rank analysis revealed that increased expression of C17orf91 was associated with shorter progression free survival(PFS)(HR = 1.90(1.19-3.03), P = 0.008). Overall survival(OS) also showed a similar trend, but did not reach statistical significance(HR = 1.75(0.97-3.13), P = 0.061). Loss-of-function studies further demonstrated that C17orf91 repression impaired migration, invasion and viability of ovarian cancer cells, and downregulated the pro-metastatic gene, MYC, at both mRNA and protein level.
Conclusion
Collectively, our findings revealed that C17orf91 was a potential prognostic marker and functioned as an oncogene in ovarian cancer. It remains to be seen whether modulation of C17orf91 expression will cause phenotypic changes in vivo.
Electronic supplementary material
The online version of this article (doi:10.1186/s13048-016-0258-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13048-016-0258-3
PMCID: PMC4989523  PMID: 27535740
Ovarian cancer; Long noncoding RNA; C17orf91; MYC
21.  CDH1 rs9929218 variant at 16q22.1 contributes to colorectal cancer susceptibility 
Oncotarget  2016;7(30):47278-47286.
Colorectal cancer (CRC) is the third most common cancer. Large-scale genome-wide association studies (GWAS) have been performed and reported some novel CRC susceptibility variants in European ancestry including the CDH1 rs9929218. Following GWAS and candidate studies evaluated the association between the CDH1 rs9929218 polymorphism and CRC in European, Asian and American populations. However, these studies reported inconsistent associations. Evidence shows that rs9929218 may regulate different gene expressions in different human tissues. Here, we reevaluated this association using large-scale samples from 16 studies (n=131768) using a meta-analysis method. In heterogeneity test, we did not identify significant heterogeneity among these studies. Meta-analysis using fixed effect model showed significant association between rs9929218 and CRC (P=6.16E-21, odds ratio (OR) =0.92, 95% confidence interval (CI) 0.91-0.94). In order to validate the effect of rs9929218 variant on CDH1 expression, we further performed a functional analysis using two large-scale expression datasets. We identified significant regulation relation between rs9929218 variant and the expression of CDH1, ZFP90, RP11-354M1.2 and MCOLN2 by both cis-effect and trans-effect. In summary, our analysis highlights significant association between rs9929218 polymorphism and CRC susceptibility.
doi:10.18632/oncotarget.9758
PMCID: PMC5216941  PMID: 27259261
genome-wide association study; colorectal cancer; rs9929218; meta-analysis; eQTL
22.  Targeting YAP-dependent MDSC infiltration impairs tumor progression 
Cancer discovery  2015;6(1):80-95.
The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSCs) as the major infiltrating immune cell type and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified Cxcl5 as a cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving Cxcl5 upregulation in cancer cells through YAP-TEAD complex and promoting MDSCs recruitment. Clinico-pathological studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC relevant genes. Together, YAP-driven MDSC recruitment via heterotypic Cxcl5-Cxcr2 signaling reveals effective therapeutic strategy for advanced prostate cancer.
Significance
We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell non-autonomous function of Hippo-YAP pathway in regulation of Cxcl5, a ligand for Cxcr2 expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CxCl5-Cxcr2 signaling circuit elicits robust anti-tumor responses and prolongs survival.
doi:10.1158/2159-8290.CD-15-0224
PMCID: PMC4707102  PMID: 26701088
Cancer; prostate; genetics Yap1; MDSCs; Cxcr2; Pten; Smad4
23.  Race- and sex-related differences in care for patients newly diagnosed with atrial fibrillation 
BACKGROUND
Atrial fibrillation (AF) is associated with an increased risk of stroke and death. Uniform utilization of appropriate therapies for AF may help reduce those risks.
OBJECTIVE
We sought to determine whether significant race and sex differences exist in the treatment of newly diagnosed AF in Medicare beneficiaries.
METHODS
We used administrative encounter data for Medicare beneficiaries to identify patients with newly diagnosed AF during 2010–2011. Services received after initial AF diagnosis were cataloged, including visits with a cardiologist or electrophysiolo-gist, catheter ablation procedures, and use of oral anticoagulants, rate control agents, and antiarrhythmic drugs.
RESULTS
Overall, 517,941 patients met study criteria, of whom 452,986 (87%) were white, 36,425 (7%) black, and 28,530 (6%) Hispanic. Male patients comprised 209,788 (41%) of the cohort. In multivariate analysis, there were statistically significant differences in the use of AF-related services by both race and sex, with white patients and male patients receiving the most care. The most notable disparities were for catheter ablation (Hispanic vs white: adjusted hazard ratio [AHR] 0.70; 95% confidence interval [CI] 0.63–0.79; P < .001; female vs male: AHR 0.65; 95% CI 0.63–0.68; P < .001) and receipt of oral anticoagulation (black vs white: AHR 0.94; 95% CI 0.92–0.95; P < .001; Hispanic vs white: AHR 0.94; 95% CI 0.93–0.97; P < .001; female vs male: AHR 0.93; 95% CI 0.93–0.94; P < .001).
CONCLUSION
Race and sex appear to have a significant effect on the health care provided to this cohort of Medicare beneficiaries diagnosed with AF. Possible explanations include racial differences in access, patient preferences, treatment bias, and unmeasured clinical characteristics.
doi:10.1016/j.hrthm.2015.03.031
PMCID: PMC4787261  PMID: 25814418
Outcomes; Disparities; Atrial fibrillation
24.  Environmental tobacco smoke increases autophagic effects but decreases longevity associated with Sirt-1 protein expression in young C57BL mice hearts 
Oncotarget  2016;7(26):39017-39025.
Recently, a survey by the Centers for Disease Control and Prevention (CDC) reported that nearly 90% of U.S. adult smokers began smoking at the age of 18. This demonstrates that the exposure to environmental tobacco smoke (ETS) of youngsters today is changing from passive smoking to active smoking (direct inhalation of tobacco). In the current study, an investigation of ETS exposure in young C57BL mice was conducted. After 6 weeks of ETS exposure, the Sirt-1 protein level was decreased and cardiac autophagy was increased in C57BL mice. Furthermore, the IGF2R cardiac hypertrophy signaling pathway was also triggered, although cardiac apoptosis and hypertrophy were not induced. Youngsters' desire to look more mature is one of the psychological factors that impacts smoking amongst young people. Our results suggest that though ETS exposure might cause cardiac autophagy amongst youngsters, the loss of the longevity Sirt-1 protein and the increase in IGF2R cardiac hypertrophy signaling could still promote heart diseases that are age-specific.
doi:10.18632/oncotarget.9176
PMCID: PMC5129910  PMID: 27167200
environmental tobacco smoke (ETS); Sirt-1; autophagy; Gerotarget
25.  Noninvasive detection of tumor-associated mutations from circulating cell-free DNA in hepatocellular carcinoma patients by targeted deep sequencing 
Oncotarget  2016;7(26):40481-40490.
Background
Detection of circulating cell-free DNA (cfDNA) has potential clinical value for assessing tumor biology in patients with hepatocellular carcinoma (HCC), yet many traditional assays lack robustness. This study was the first to apply a high-throughput sequencing platform to detect tumor-associated mutations in HCC from circulating tumor-derived DNA (ctDNA) and to evaluate the utility and feasibility of this approach.
Methods
Using the MiSeq™ system, plasma and matched tumor DNA samples were analyzed for hotspot mutations in the TERT, CTNNB1, and TP53 genes that had been verified as the most prevalent mutations in HCC. We compared tumor and plasma data and prospectively investigated the association between significant mutations detected in ctDNA and the patients' clinical outcomes.
Results
In 41 patients, we detected tumor-associated mutations for HCC in 8 (19.5%) plasma samples. Among them, one showed a tumor-associated mutation in ctDNA but not in the tumor tissue which we used to detect. We also found that ctDNA with mutations could be detected more easily in patients who suffered vascular invasion (P=0.041) and predicted a shorter recurrence-free survival time (P<0.001). There was no relationship between detectable mutations and concentration of cfDNA (P=0.818).
Conclusions
The results of our study suggest that tumor-associated mutations detected in plasma are associated with vascular invasion and might be used to predict a shorter recurrence-free survival time for HCC patients. This kind of biomarker can overcome the limitations of tumor heterogeneity. Moreover, the diagnostic performance is improved if multiple mutations in different genes are combined.
doi:10.18632/oncotarget.9629
PMCID: PMC5130021  PMID: 27248174
circulating cell-free DNA; circulating tumor DNA; hepatocellular carcinoma; tumor-associated mutation; MiSeq sequencing

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