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1.  Accurate genetic detection of hepatitis C virus transmissions in outbreak settings 
The Journal of infectious diseases  2015;213(6):957-965.
Hepatitis C is a major public health problem in the United States and worldwide. Outbreaks of hepatitis C virus (HCV) infections are associated with unsafe injection practices, drug diversion, and other exposures to blood, being difficult to detect and investigate. Here, we developed and validated a simple approach for molecular detection of HCV transmissions in outbreak settings. We obtained sequences from the HCV hypervariable region 1 (HVR1) using End-Point Limiting-Dilution (EPLD) from 127 cases involved in 32 epidemiologically defined HCV outbreaks and 193 individuals with unrelated HCV strains. We compared several types of genetic distances and calculated a threshold using minimal Hamming distances that identifies transmission clusters in all tested outbreaks with 100% accuracy. The approach was also validated on sequences from 239 individuals obtained using next-generation sequencing, showing the same accuracy as EPLD. In average, nucleotide diversity of the intra-host population was 6.2-times greater in the source than in any incident case, allowing the correct detection of transmission direction in 8 outbreaks for which source cases were known. A simple and accurate distance-based approach for detecting HCV transmissions developed here streamlines molecular investigation of outbreaks, thus improving the public health capacity for rapid and effective control of hepatitis C.
PMCID: PMC5119477  PMID: 26582955
HCV; Outbreak; Threshold; NGS; Nucleotide diversity; Phylogenetic analysis; Hamming distance; Transmission networks
3.  Gene-gene Interaction Analyses for Atrial Fibrillation 
Scientific Reports  2016;6:35371.
Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27–1.65, P = 4.3 × 10–8). Eight additional gene-gene interactions were also marginally significant (P < 5 × 10–7). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF.
PMCID: PMC5099695  PMID: 27824142
4.  Human cytomegalovirus and Epstein–Barr virus inhibit oral bacteria-induced macrophage activation and phagocytosis 
Oral microbiology and immunology  2009;24(3):243-248.
Periodontal disease is an inflammatory condition caused by periodontal microorganisms. Viruses such as human cytomegalovirus (HCMV) and Epstein–Barr virus (EBV) are associated with certain types of periodontal disease, but their roles in promoting the disease are unclear. Because both viruses infect human macrophages, cells which play key roles in the clearance of pathogenic bacteria, it is likely that the viruses alter the functional capacity of macrophages by inhibiting their defense mechanisms against invading pathogens.
Macrophages preinfected with HCMV or EBV were evaluated following stimulation by selected oral bacteria. Bacteria-induced macrophage activation was assayed by measuring the levels of tumor necrosis factor-α (TNF-α) produced in the media, and phagocytic activity was analysed by a phagocytosis assay with fluorescein isothiocyanate-labeled bacteria. The virus-infected macrophages were also subjected to semi-quantitative polymerase chain reaction to measure the expression of toll-like receptor 9, which is involved in the activation of phagocytosis-related pathways.
Both HCMV and EBV significantly diminished the TNF-α production typically induced by oral bacteria, inhibited the phagocytic activity of macrophages, and downregulated the expression of toll-like receptor 9.
Infection by HCMV or EBV inhibits the functional ability of macrophages to respond to bacterial challenge, thereby suggesting their pathogenic role in the development of periodontal disease.
PMCID: PMC5081175  PMID: 19416455
cytomegalovirus; Epstein-Barr virus; macrophages; phagocytosis
5.  ESICM LIVES 2016: part one 
Bos, L. | Schouten, L. | van Vught, L. | Wiewel, M. | Ong, D. | Cremer, O. | Artigas, A. | Martin-Loeches, I. | Hoogendijk, A. | van der Poll, T. | Horn, J. | Juffermans, N. | Schultz, M. | de Prost, N. | Pham, T. | Carteaux, G. | Dessap, A. Mekontso | Brun-Buisson, C. | Fan, E. | Bellani, G. | Laffey, J. | Mercat, A. | Brochard, L. | Maitre, B. | Howells, P. A. | Thickett, D. R. | Knox, C. | Park, D. P. | Gao, F. | Tucker, O. | Whitehouse, T. | McAuley, D. F. | Perkins, G. D. | Pham, T. | Laffey, J. | Bellani, G. | Fan, E. | Pisani, L. | Roozeman, J. P. | Simonis, F. D. | Giangregorio, A. | Schouten, L. R. | Van der Hoeven, S. M. | Horn, J. | Neto, A. Serpa | Festic, E. | Dondorp, A. M. | Grasso, S. | Bos, L. D. | Schultz, M. J. | Koster-Brouwer, M. | Verboom, D. | Scicluna, B. | van de Groep, K. | Frencken, J. | Schultz, M. | van der Poll, T. | Bonten, M. | Cremer, O. | Ko, J. I. | Kim, K. S. | Suh, G. J. | Kwon, W. Y. | Kim, K. | Shin, J. H. | Ranzani, O. T. | Prina, E. | Menendez, R. | Ceccato, A. | Mendez, R. | Cilloniz, C. | Gabarrus, A. | Ferrer, M. | Torres, A. | Urbano, A. | Zhang, L. A. | Swigon, D. | Pike, F. | Parker, R. S. | Clermont, G. | Scheer, C. | Kuhn, S. O. | Modler, A. | Vollmer, M. | Fuchs, C. | Hahnenkamp, K. | Rehberg, S. | Gründling, M. | Taggu, A. | Darang, N. | Öveges, N. | László, I. | Tánczos, K. | Németh, M. | Lebák, G. | Tudor, B. | Érces, D. | Kaszaki, J. | Huber, W. | Trásy, D. | Molnár, Z. | Ferrara, G. | Edul, V. S. Kanoore | Canales, H. S. | Martins, E. | Canullán, C. | Murias, G. | Pozo, M. O. | Eguillor, J. F. Caminos | Buscetti, M. G. | Ince, C. | Dubin, A. | Aya, H. D. | Rhodes, A. | Fletcher, N. | Grounds, R. M. | Cecconi, M. | Jacquet-Lagrèze, M. | Riche, M. | Schweizer, R. | Portran, P. | Fornier, W. | Lilot, M. | Neidecker, J. | Fellahi, J. L. | Escoresca-Ortega, A. | Gutiérrez-Pizarraya, A. | Charris-Castro, L. | Corcia-Palomo, Y. | Fernandez-Delgado, E. | Garnacho-Montero, J. | Roger, C. | Muller, L. | Elotmani, L. | Lipman, J. | Lefrant, J. Y. | Roberts, J. A. | Muñoz-Bermúdez, R. | Samper, M. | Climent, C. | Vasco, F. | Sara, V. | Luque, S. | Campillo, N. | Cerrato, S. Grau | Masclans, J. R. | Alvarez-Lerma, F. | Brugger, S. Carvalho | Jimenez, G. Jimenez | Torner, M. Miralbés | Cabello, J. Trujillano | Garrido, B. Balsera | Casals, X. Nuvials | Gaite, F. Barcenilla | Vidal, M. Vallverdú | Martínez, M. Palomar | Gusarov, V. | Shilkin, D. | Dementienko, M. | Nesterova, E. | Lashenkova, N. | Kuzovlev, A. | Zamyatin, M. | Demoule, A. | Carreira, S. | Lavault, S. | Palancca, O. | Morawiec, E. | Mayaux, J. | Arnulf, I. | Similowski, T. | Rasmussen, B. S. | Maltesen, R. G. | Hanifa, M. | Pedersen, S. | Kristensen, S. R. | Wimmer, R. | 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. | Andreotti, A. | Tagliaferri, F. | Moise, G. | Mercurio, G. | Costa, A. | Vezzani, A. | Lindau, S. | Babel, J. | Cavana, M. | Consonni, D. | Pesenti, A. | Gattinoni, L. | Torres, A. | Mansouri, P. | Zand, F. | Zahed, L. | Dehghanrad, F. | Bahrani, M. | Ghorbani, M. | Cambiaghi, B. | Moerer, O. | Mauri, T. | Kunze-Szikszay, N. | Ritter, C. | Pesenti, A. | Quintel, M. | Vilander, L. M. | Kaunisto, M. A. | Vaara, S. T. | Pettilä, V. | Mulier, J. L. G. Haitsma | Rozemeijer, S. | Spoelstra-de Man, A. M. E. | Elbers, P. E. | Tuinman, P. R. | de Waard, M. C. | Oudemans-van Straaten, H. M. | Liberatore, A. M. A. | Souza, R. B. | Martins, A. M. C. R. P. F. | Vieira, J. C. F. | Koh, I. H. J. | Martínez, M. Galindo | Sánchez, R. Jiménez | Gascón, L. Martínez | Mulero, M. D. Rodríguez | Freire, A. Ortín | Muñoz, A. Ojados | Acebes, S. Rebollo | Martínez, Á. Fernández | Aliaga, S. Moreno | Para, L. Herrera | Payá, J. Murcia | Mulero, F. Rodríguez | Guerci, P. | Ince, Y. | Heeman, P. | Ergin, B. | Ince, C. | Uz, Z. | Massey, M. | Ince, Y. | Papatella, R. | Bulent, E. | Guerci, P. | Toraman, F. | Ince, C. | Longbottom, E. R. | Torrance, H. D. | Owen, H. C. | Hinds, C. J. | Pearse, R. M. | O’Dywer, M. J. | Trogrlic, Z. | van der Jagt, M. | Lingsma, H. | Ponssen, H. H. | Schoonderbeek, J. F. | Schreiner, F. | Verbrugge, S. J. | Duran, S. | van Achterberg, T. | Bakker, J. | Gommers, D. A. M. P. J. | Ista, E. | Krajčová, A. | Waldauf, P. | Duška, F. | Shah, A. | Roy, N. | McKechnie, S. | Doree, C. | Fisher, S. | Stanworth, S. J. | Jensen, J. F. | Overgaard, D. | Bestle, M. H. | Christensen, D. F. | Egerod, I. | Pivkina, A. | Gusarov, V. | Zhivotneva, I. | Pasko, N. | Zamyatin, M. | Jensen, J. F. | Egerod, I. | Bestle, M. H. | Christensen, D. F. | Alklit, A. | Hansen, R. L. | Knudsen, H. | Grode, L. B. | Overgaard, D. | Hravnak, M. | Chen, L. | Dubrawski, A. | Clermont, G. | Pinsky, M. R. | Parry, S. M. | Knight, L. D. | Connolly, B. C. | Baldwin, C. E. | Puthucheary, Z. A. | Denehy, L. | Hart, N. | Morris, P. E. | Mortimore, J. | Granger, C. L. | Jensen, H. I. | Piers, R. | Van den Bulcke, B. | Malmgren, J. | Metaxa, V. | Reyners, A. K. | Darmon, M. | Rusinova, K. | Talmor, D. | Meert, A. P. | Cancelliere, L. | Zubek, L. | Maia, P. | Michalsen, A. | Decruyenaere, J. | Kompanje, E. | Vanheule, S. | Azoulay, E. | Vansteelandt, S. | Benoit, D. | Van den Bulcke, B. | Piers, R. | Jensen, H. I. | Malmgren, J. | Metaxa, V. | Reyners, A. K. | Darmon, M. | Rusinova, K. | Talmor, D. | Meert, A. P. | Cancelliere, L. | Zubek, L. | Maia, P. | Michalsen, A. | Decruyenaere, J. | Kompanje, E. | Vanheule, S. | Azoulay, E. | Vansteelandt, S. | Benoit, D. | Ryan, C. | Dawson, D. | Ball, J. | Noone, K. | Aisling, B. | Prudden, S. | Ntantana, A. | Matamis, D. | Savvidou, S. | Giannakou, M. | Gouva, M. | Nakos, G. | Koulouras, V. | Aron, J. | Lumley, G. | Milliken, D. | Dhadwal, K. | McGrath, B. A. | Lynch, S. J. | Bovento, B. | Sharpe, G. | Grainger, E. | Pieri-Davies, S. | Wallace, S. | McGrath, B. | Lynch, S. J. | Bovento, B. | Grainger, E. | Pieri-Davies, S. | Sharpe, G. | Wallace, S. | Jung, M. | Cho, J. | Park, H. | Suh, G. | Kousha, O. | Paddle, J. | Gripenberg, L. Gamrin | Rehal, M. Sundström | Wernerman, J. | Rooyackers, O. | de Grooth, H. J. | Choo, W. P. | Spoelstra-de Man, A. M. | Swart, E. L. | Oudemans-van Straaten, H. M. | Talan, L. | Güven, G. | Altıntas, N. D. | Padar, M. | Uusvel, G. | Starkopf, L. | Starkopf, J. | Blaser, A. Reintam | Kalaiselvan, M. S. | Arunkumar, A. S. | Renuka, M. K. | Shivkumar, R. L. | Volbeda, M. | ten Kate, D. | Hoekstra, M. | van der Maaten, J. M. | Nijsten, M. W. | Komaromi, A. | Rooyackers, O. | Wernerman, J. | Norberg, Å. | Smedberg, M. | Mori, M. | Pettersson, L. | Norberg, Å. | Rooyackers, O. | Wernerman, J. | Theodorakopoulou, M. | Christodoulopoulou, T. | Diamantakis, A. | Frantzeskaki, F. | Kontogiorgi, M. | Chrysanthopoulou, E. | Lygnos, M. | Diakaki, C. | Armaganidis, A. | Gundogan, K. | Dogan, E. | Coskun, R. | Muhtaroglu, S. | Sungur, M. | Ziegler, T. | Guven, M. | Kleyman, A. | Khaliq, W. | Andreas, D. | Singer, M. | Meierhans, R. | Schuepbach, R. | De Brito-Ashurst, I. | Zand, F. | Sabetian, G. | Nikandish, R. | Hagar, F. | Masjedi, M. | Maghsudi, B. | Vazin, A. | Ghorbani, M. | Asadpour, E. | Kao, K. C. | Chiu, L. C. | Hung, C. Y. | Chang, C. H. | Li, S. H. | Hu, H. C. | El Maraghi, S. | Ali, M. | Rageb, D. | Helmy, M. | Marin-Corral, J. | Vilà, C. | Masclans, J. R. | Vàzquez, A. | Martín-Loeches, I. | Díaz, E. | Yébenes, J. C. | Rodriguez, A. | Álvarez-Lerma, F. | Varga, N. | Cortina-Gutiérrez, A. | Dono, L. | Martínez-Martínez, M. | Maldonado, C. | Papiol, E. | Pérez-Carrasco, M. | Ferrer, R. | Nweze, K. | Morton, B. | Welters, I. | Houard, M. | Voisin, B. | Ledoux, G. | Six, S. | Jaillette, E. | Nseir, S. | Romdhani, S. | Bouneb, R. | Loghmari, D. | Aicha, N. Ben | Ayachi, J. | Meddeb, K. | Chouchène, I. | Khedher, A. | Boussarsar, M. | Chan, K. S. | Yu, W. L. | Marin-Corral, J. | Vilà, C. | Masclans, J. R. | Nolla, J. | Vidaur, L. | Bonastre, J. | Suberbiola, B. | Guerrero, J. E. | Rodriguez, A. | Coll, N. Ramon | Jiménez, G. Jiménez | Brugger, S. Carvalho | Calero, J. Codina | Garrido, B. Balsera | García, M. | Martínez, M. Palomar | Vidal, M. Vallverdú | de la Torre, M. C. | Vendrell, E. | Palomera, E. | Güell, E. | Yébenes, J. C. | Serra-Prat, M. | Bermejo-Martín, J. F. | Almirall, J. | Tomas, E. | Escoval, A. | Froe, F. | Pereira, M. H. Vitoria | Velez, N. | Viegas, E. | Filipe, E. | Groves, C. | Reay, M. | Chiu, L. C. | Hu, H. C. | Hung, C. Y. | Chang, C. H. | Li, S. H. | Kao, K. C. | Ballin, A. | Facchin, F. | Sartori, G. | Zarantonello, F. | Campello, E. | Radu, C. M. | Rossi, S. | Ori, C. | Simioni, P. | Umei, N. | Shingo, I. | Santos, A. C. | Candeias, C. | Moniz, I. | Marçal, R. | e Silva, Z. Costa | Ribeiro, J. M. | Georger, J. F. | Ponthus, J. P. | Tchir, M. | Amilien, V. | Ayoub, M. | Barsam, E. | Martucci, G. | Panarello, G. | Tuzzolino, F. | Capitanio, G. | Ferrazza, V. | Carollo, T. | Giovanni, L. | Arcadipane, A. | Sánchez, M. López | González-Gay, M. A. | Díaz, F. J. Llorca | López, M. I. Rubio | Zogheib, E. | Villeret, L. | Nader, J. | Bernasinski, M. | Besserve, P. | Caus, T. | Dupont, H. | Morimont, P. | Habran, S. | Hubert, R. | Desaive, T. | Blaffart, F. | Janssen, N. | Guiot, J. | Pironet, A. | Dauby, P. | Lambermont, B. | Zarantonello, F. | Ballin, A. | Facchin, F. | Sartori, G. | Campello, E. | Pettenuzzo, T. | Citton, G. | Rossi, S. | Simioni, P. | Ori, C. | Kirakli, C. | Ediboglu, O. | Ataman, S. | Yarici, M. | Tuksavul, F. | Keating, S. | Gibson, A. | Gilles, M. | Dunn, M. | Price, G. | Young, N. | Remeta, P. | Bishop, P. | Zamora, M. D. Fernández | Muñoz-Bono, J. | Curiel-Balsera, E. | Aguilar-Alonso, E. | Hinojosa, R. | Gordillo-Brenes, A. | Arboleda-Sánchez, J. A. | Skorniakov, I. | Vikulova, D. | Whiteley, C. | Shaikh, O. | Jones, A. | Ostermann, M. | Forni, L. | Scott, M. | Sahatjian, J. | Linde-Zwirble, W. | Hansell, D. | Laoveeravat, P. | Srisawat, N. | Kongwibulwut, M. | Peerapornrattana, S. | Suwachittanont, N. | Wirotwan, T. O. | Chatkaew, P. | Saeyub, P. | Latthaprecha, K. | Tiranathanagul, K. | Eiam-ong, S. | Kellum, J. A. | Berthelsen, R. E. | Perner, A. | Jensen, A. E. K. | Jensen, J. U. | Bestle, M. H. | Gebhard, D. J. | Price, J. | Kennedy, C. E. | Akcan-Arikan, A. | Liberatore, A. M. A. | Souza, R. B. | Martins, A. M. C. R. P. F. | Vieira, J. C. F. | Kang, Y. R. | Nakamae, M. N. | Koh, I. H. J. | Hamed, K. | Khaled, M. M. | Soliman, R. Aly | Mokhtar, M. Sherif | Seller-Pérez, G. | Arias-Verdú, D. | Llopar-Valdor, E. | De-Diós-Chacón, I. | Quesada-García, G. | Herrera-Gutierrez, M. E. | Hafes, R. | Carroll, G. | Doherty, P. | Wright, C. | Vera, I. G. Guerra | Ralston, M. | Gemmell, M. L. | MacKay, A. | Black, E. | Wright, C. | Docking, R. I. | Appleton, R. | Ralston, M. R. | Gemmell, L. | Appleton, R. | Wright, C. | Docking, R. I. | Black, E. | Mackay, A. | Rozemeijer, S. | Mulier, J. L. G. Haitsma | Röttgering, J. G. | Elbers, P. W. G. | Spoelstra-de Man, A. M. E. | Tuinman, P. R. | de Waard, M. C. | Oudemans-van Straaten, H. M. | Mejeni, N. | Nsiala, J. | Kilembe, A. | Akilimali, P. | Thomas, G. | Egerod, I. | Andersson, A. E. | Fagerdahl, A. M. | Knudsen, V. | Meddeb, K. | Cheikh, A. Ben | Hamdaoui, Y. | Ayachi, J. | Guiga, A. | Fraj, N. | Romdhani, S. | Sma, N. | Bouneb, R. | Chouchene, I. | Khedher, A. | Bouafia, N. | Boussarsar, M. | Amirian, A. | Ziaian, B. | Masjedi, M. | Fleischmann, C. | Thomas-Rueddel, D. O. | Schettler, A. | Schwarzkopf, D. | Stacke, A. | Reinhart, K. | Filipe, E. | Escoval, A. | Martins, A. | Sousa, P. | Velez, N. | Viegas, E. | Tomas, E. | Snell, G. | Matsa, R. | Paary, T. T. S. | Kalaiselvan, M. S. | Cavalheiro, A. M. | Rocha, L. L. | Vallone, C. S. | Tonilo, A. | Lobato, M. D. S. | Malheiro, D. T. | Sussumo, G. | Lucino, N. M. | Zand, F. | Rosenthal, V. D. | Masjedi, M. | Sabetian, G. | Maghsudi, B. | Ghorbani, M. | Dashti, A. Sanaei | Yousefipour, A. | Goodall, J. R. | Williamson, M. | Tant, E. | Thomas, N. | Balci, C. | Gonen, C. | Haftacı, E. | Gurarda, H. | Karaca, E. | Paldusová, B. | Zýková, I. | Šímová, D. | Houston, S. | D’Antona, L. | Lloyd, J. | Garnelo-Rey, V. | Sosic, M. | Sotosek-Tokmazic, V. | Kuharic, J. | Antoncic, I. | Dunatov, S. | Sustic, A. | Chong, C. T. | Sim, M. | Lyovarin, T. | Díaz, F. M. Acosta | Galdó, S. Narbona | Garach, M. Muñoz | Romero, O. Moreno | Bailón, A. M. Pérez | Pinel, A. Carranza | Colmenero, M. | Gritsan, A. | Gazenkampf, A. | Korchagin, E. | Dovbish, N. | Lee, R. M. | Lim, M. P. P. | Chong, C. T. | Lim, B. C. L. | See, J. J. | Assis, R. | Filipe, F. | Lopes, N. | Pessoa, L. | Pereira, T. | Catorze, N. | Aydogan, M. S. | Aldasoro, C. | Marchio, P. | Jorda, A. | Mauricio, M. D. | Guerra-Ojeda, S. | Gimeno-Raga, M. | Colque-Cano, M. | Bertomeu-Artecero, A. | Aldasoro, M. | Valles, S. L. | Tonon, D. | Triglia, T. | Martin, J. C. | Alessi, M. C. | Bruder, N. | Garrigue, P. | Velly, L. | Spina, S. | Scaravilli, V. | Marzorati, C. | Colombo, E. | Savo, D. | Vargiolu, A. | Cavenaghi, G. | Citerio, G. | Andrade, A. H. V. | Bulgarelli, P. | Araujo, J. A. P. | Gonzalez, V. | Souza, V. A. | Costa, A. | Massant, C. | Filho, C. A. C. Abreu | Morbeck, R. A. | Burgo, L. E. | van Groenendael, R. | van Eijk, L. T. | Leijte, G. P. | Koeneman, B. | Kox, M. | Pickkers, P. | García-de la Torre, A. | de la Torre-Prados, M. | Fernández-Porcel, A. | Rueda-Molina, C. | Nuevo-Ortega, P. | Tsvetanova-Spasova, T. | Cámara-Sola, E. | García-Alcántara, A. | Salido-Díaz, L. | Liao, X. | Feng, T. | Zhang, J. | Cao, X. | Wu, Q. | Xie, Z. | Li, H. | Kang, Y. | Winkler, M. S. | Nierhaus, A. | Mudersbach, E. | Bauer, A. | Robbe, L. | Zahrte, C. | Schwedhelm, E. | Kluge, S. | Zöllner, C. | Morton, B. | Mitsi, E. | Pennington, S. H. | Reine, J. | Wright, A. D. | Parker, R. | Welters, I. D. | Blakey, J. D. | Rajam, G. | Ades, E. W. | Ferreira, D. M. | Wang, D. | Kadioglu, A. | Gordon, S. B. | Koch, R. | Kox, M. | Rahamat-Langedoen, J. | Schloesser, J. | de Jonge, M. | Pickkers, P. | Bringue, J. | Guillamat-Prats, R. | Torrents, E. | Martinez, M. L. | Camprubí-Rimblas, M. | Artigas, A. | Blanch, L. | Park, S. Y. | Park, Y. B. | Song, D. K. | Shrestha, S. | Park, S. H. | Koh, Y. | Park, M. J. | Hong, C. W. | Lesur, O. | Coquerel, D. | Sainsily, X. | Cote, J. | Söllradl, T. | Murza, A. | Dumont, L. | Dumaine, R. | Grandbois, M. | Sarret, P. | Marsault, E. | Salvail, D. | Auger-Messier, M. | Chagnon, F. | Lauretta, M. P. | Greco, E. | Dyson, A. | Singer, M. | Preau, S. | Ambler, M. | Sigurta, A. | Saeed, S. | Singer, M. | Sarıca, L. Topcu | Zibandeh, N. | Genc, D. | Gul, F. | Akkoc, T. | Kombak, E. | Cinel, L. | Akkoc, T. | Cinel, I. | Pollen, S. J. | Arulkumaran, N. | Singer, M. | Torrance, H. D. | Longbottom, E. R. | Warnes, G. | Hinds, C. J. | Pennington, D. J. | Brohi, K. | O’Dwyer, M. J. | Kim, H. Y. | Na, S. | Kim, J. | Chang, Y. F. | Chao, A. | Shih, P. Y. | Lee, C. T. | Yeh, Y. C. | Chen, L. W. | Adriaanse, M. | Trogrlic, Z. | Ista, E. | Lingsma, H. | Rietdijk, W. | Ponssen, H. H. | Schoonderbeek, J. F. | Schreiner, F. | Verbrugge, S. J. | Duran, S. | Gommers, D. A. M. P. J. | van der Jagt, M. | Funcke, S. | Sauerlaender, S. | Saugel, B. | Pinnschmidt, H. | Reuter, D. A. | Nitzschke, R. | Perbet, S. | Biboulet, C. | Lenoire, A. | Bourdeaux, D. | Pereira, B. | Plaud, B. | Bazin, J. E. | Sautou, V. | Mebazaa, A. | Constantin, J. M. | Legrand, M. | Boyko, Y. | Jennum, P. | Nikolic, M. | Oerding, H. | Holst, R.
PMCID: PMC5042924
6.  Anatomy of a negative feedback loop: the case of IκBα 
Journal of the Royal Society Interface  2015;12(110):20150262.
The magnitude, duration and oscillation of cellular signalling pathway responses are often limited by negative feedback loops, defined as an ‘activator-induced inhibitor’ regulatory motif. Within the NFκB signalling pathway, a key negative feedback regulator is IκBα. We show here that, contrary to current understanding, NFκB-inducible expression is not sufficient for providing effective negative feedback. We then employ computational simulations of NFκB signalling to identify IκBα molecular properties that are critical for proper negative feedback control and test the resulting predictions in biochemical and single-cell live-imaging studies. We identified nuclear import and nuclear export of IκBα and the IκBα–NFκB complex, as well as the free IκBα half-life, as key determinants of post-induction repression of NFκB and the potential for subsequent reactivation. Our work emphasizes that negative feedback is an emergent systems property determined by multiple molecular and biophysical properties in addition to the required ‘activator-induced inhibitor’ relationship.
PMCID: PMC4614452  PMID: 26311312
negative feedback; gene regulation; NFκB; IκBα; oscillation
7.  Distribution of Omega-6 and Omega-3 Polyunsaturated Fatty Acids in the Whole Rat Body and 25 Compartments 
The steady state compositions of omega-6 and omega-3 polyunsaturated fatty acids (PUFA) throughout the various viscera and tissues within the whole body of rats have not previously been described in a comprehensive manner. Dams consumed diets containing 10 wt% fat (15% linoleate and 3% α-linolenate). Male offspring (n=9) at 7-wks of age were euthanized and dissected into 25 compartments. Total lipid fatty acids for each compartment were quantified by GC/FID and summed for the rat whole body; total n-6 PUFA was 12 wt% and total n-3 PUFA was 2.1% of total fatty acids. 18:2n-6 accounted for 84% of the total n-6 PUFA, 20:4n-6 was 12%, 18:3n-3 was 59% of the total n-3 PUFA, 20:5n-3 was 2.1%, and 22:6n-3 was 32%. The white adipose tissue contained the greatest amounts of 18:2n-6 (1.5 g) and 18:3n-3 (0.2 g). 20:4n-6 was highest in muscle (60 mg) and liver (57 mg), while 22:6n-3 was greatest in muscle (46 mg), followed by liver (27 mg) and carcass (20 mg). In terms of fatty acid composition expressed as a percentage, 18:2n-6 was the highest in the heart (13 wt%), while 18:3n-3 was about 1.3 wt% for skin, white adipose tissue and fur. 20:4n-6 was highest (21–25 wt%) in the circulation, kidney, and spleen, while 22:6n-3 was highest in the brain (12 wt%), followed by the heart (7.9 wt%), liver (5.9 wt%), and spinal cord (5.1 wt%). Selectivity was greatest when comparing 22:6n-3 in brain (12%) to white adipose (0.08%) (68-fold) and 22:5n-6 in testes (15.6%) compared to white adipose (0.02%), 780-fold.
PMCID: PMC4555191  PMID: 26120061
alpha-linolenic acid; linoleic acid; docosahaexenoic acid; arachidonic acid; n-3; n-6
8.  Did FIDELIS projects contribute to the detection of new smear-positive pulmonary tuberculosis cases in China? 
Public Health Action  2016;6(3):176-180.
Setting: The first phase of the Fund for Innovative DOTS Expansion through Local Initiatives to Stop TB (FIDELIS) projects in China started in 2003.
Objective: To determine whether the FIDELIS projects contributed to the increased case detection rate for new smear-positive pulmonary tuberculosis (PTB) in China.
Methods: We compared the case notification rates (CNRs) in the intervention year with those of the previous year in the FIDELIS areas, then compared the difference between the CNRs of the intervention year and the previous year in the FIDELIS areas with those in the non-FI-DELIS areas within the province.
Results: There was an increase in the CNR in the intervention year compared with the previous year for all the project sites. The differences between the CNR in the intervention year and the previous year ranged from 6.4 to 31.1 per 100 000 population in the FIDELIS areas and from 2.9 to 20.4/100 000 in the non-FIDELIS areas. Differences-in-differences analysis shows that the differences in the CNRs in the FIDELIS areas were not statistically significantly different from those in the non-FIDELIS areas (P = 0.393).
Conclusion: The FIDELIS projects may have contributed to the increase in case detection of new smear-positive PTB in China, but the level of evidence is low.
PMCID: PMC5034783  PMID: 27695680
tuberculosis; case detection; FIDELIS; China
9.  Low Heart Rate Variability in a 2-Minute Electrocardiogram Recording Is Associated with an Increased Risk of Sudden Cardiac Death in the General Population: The Atherosclerosis Risk in Communities Study 
PLoS ONE  2016;11(8):e0161648.
Low heart rate variability (HRV) has been linked to increased total mortality in the general population; however, the relationship between low HRV and sudden cardiac death (SCD) is less well-characterized. The goal of this study was to evaluate the relationship between low HRV and SCD in a community-based cohort. Our cohort consisted of 12,543 participants from the Atherosclerosis Risk in Communities (ARIC) study. HRV measures were derived from 2-minute electrocardiogram recordings obtained during the baseline exam (1987–89). Time domain measurements included the standard deviation of all normal RR intervals (SDNN) and the root mean squared successive difference (r-MSSD). Frequency domain measurements included low frequency power (LF) and high frequency (HF) power. During a median follow-up of 13 years, 215 SCDs were identified from physician adjudication of all coronary heart disease deaths through 2001. In multivariable adjusted Cox proportional hazards models, each standard deviation decrement in SDNN, LF, and HF were associated with 24%, 27% and 16% increase in SCD risk, respectively. Low HRV is independently associated with increased risk of SCD in the general population.
PMCID: PMC4995012  PMID: 27551828
10.  Rainfall-enhanced blooming in typhoon wakes 
Scientific Reports  2016;6:31310.
Strong phytoplankton blooming in tropical-cyclone (TC) wakes over the oligotrophic oceans potentially contributes to long-term changes in global biogeochemical cycles. Yet blooming has traditionally been discussed using anecdotal events and its biophysical mechanics remain poorly understood. Here we identify dominant blooming patterns using 16 years of ocean-color data in the wakes of 141 typhoons in western North Pacific. We observe right-side asymmetric blooming shortly after the storms, attributed previously to sub-mesoscale re-stratification, but thereafter a left-side asymmetry which coincides with the left-side preference in rainfall due to the large-scale wind shear. Biophysical model experiments and observations demonstrate that heavier rainfall freshens the near-surface water, leading to stronger stratification, decreased turbulence and enhanced blooming. Our results suggest that rainfall plays a previously unrecognized, critical role in TC-induced blooming, with potentially important implications for global biogeochemical cycles especially in view of the recent and projected increases in TC-intensity that harbingers stronger mixing and heavier rain under the storm.
PMCID: PMC4992858  PMID: 27545899
11.  Pregabalin and pain after total knee arthroplasty: a double-blind, randomized, placebo-controlled, multidose trial† 
BJA: British Journal of Anaesthesia  2015;115(2):285-293.
Pregabalin may reduce postoperative pain and opioid use. Higher doses may be more effective, but may cause sedation and confusion. This prospective, randomized, blinded, placebo-controlled study tested the hypothesis that pregabalin reduces pain at 2 weeks after total knee arthroplasty, but increases drowsiness and confusion.
Patients (30 per group) received capsules containing pregabalin (0, 50, 100, or 150 mg); two capsules before surgery, one capsule twice a day until postoperative day (POD) 14, one on POD15, and one on POD16. Multimodal analgesia included femoral nerve block, epidural analgesia, oxycodone–paracetamol, and meloxicam. The primary outcome was pain with flexion (POD14).
Pregabalin did not reduce pain at rest, with ambulation, or with flexion at 2 weeks (P=0.69, 0.23, and 0.90, respectively). Pregabalin increased POD1 drowsiness (34.5, 37.9, 55.2, and 58.6% in the 0, 50, 100, and 150 mg arms, respectively; P=0.030), but did not increase confusion (0, 3.5, 0, and 3.5%, respectively; P=0.75). Pregabalin had no effect on acute or chronic pain, opioid consumption, or analgesic side-effects. Pregabalin reduced POD14 patient satisfaction [1–10 scale, median (first quartile, third quartile): 9 (8, 10), 8 (7, 10), 8 (5, 9), and 8 (6, 9.3), respectively; P=0.023). Protocol compliance was 63% by POD14 (50.0, 70.0, 76.7, and 56.7% compliance, respectively), with no effect of dose on compliance. Per-protocol analysis of compliant patients showed no effect of pregabalin on pain scores.
Pregabalin had no beneficial effects, but increased sedation and decreased patient satisfaction. This study does not support routine perioperative pregabalin for total knee arthroplasty patients.
Clinical trial registration.
PMCID: PMC4500762  PMID: 26170351
analgesia; anticonvulsants; arthroplasty; knee; pain management; perioperative care; replacement
12.  Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome 
Blood Cancer Journal  2016;6(7):e442-.
Clinical outcome and mutations of 96 core-binding factor acute myeloid leukemia (AML) patients 18–60 years old were examined. Complete remission (CR) after induction was 94.6%. There was no significant difference in CR, leukemia-free-survival (LFS) and overall survival (OS) between t(8;21) (N=67) and inv(16) patients (N=29). Univariate analysis showed hematopoietic stem cell transplantation at CR1 as the only clinical parameter associated with superior LFS. Next-generation sequencing based on a myeloid gene panel was performed in 72 patients. Mutations in genes involved in cell signaling were associated with inferior LFS and OS, whereas those in genes involved in DNA methylation were associated with inferior LFS. KIT activation loop (AL) mutations occurred in 25 patients, and were associated with inferior LFS (P=0.003) and OS (P=0.001). TET2 mutations occurred in 8 patients, and were associated with significantly shorter LFS (P=0.015) but not OS. Patients negative for KIT-AL and TET2 mutations (N=41) had significantly better LFS (P<0.001) and OS (P=0.012) than those positive for both or either mutation. Multivariate analysis showed that KIT-AL and TET2 mutations were associated with inferior LFS, whereas age ⩾40 years and marrow blast ⩾70% were associated with inferior OS. These observations provide new insights that may guide better treatment for this AML subtype.
PMCID: PMC5030377  PMID: 27391574
13.  Evolving changes in disease biomarkers and risk of early progression in smoldering multiple myeloma 
Blood Cancer Journal  2016;6(7):e454-.
We studied 190 patients with smoldering multiple myeloma (SMM) at our institution between 1973 and 2014. Evolving change in monoclonal protein level (eMP) was defined as ⩾10% increase in serum monoclonal protein (M) and/or immunoglobulin (Ig) (M/Ig) within the first 6 months of diagnosis (only if M-protein ⩾3 g/dl) and/or ⩾25% increase in M/Ig within the first 12 months, with a minimum required increase of 0.5 g/dl in M-protein and/or 500 mg/dl in Ig. Evolving change in hemoglobin (eHb) was defined as ⩾0.5 g/dl decrease within 12 months of diagnosis. A total of 134 patients (70.5%) progressed to MM over a median follow-up of 10.4 years. On multivariable analysis adjusting for factors known to predict for progression to MM, bone marrow plasma cells ⩾20% (odds ratio (OR)=3.37 (1.30–8.77), P=0.013), eMP (OR=8.20 (3.19–21.05), P<0.001) and eHb (OR=5.86 (2.12–16.21), P=0.001) were independent predictors of progression within 2 years of SMM diagnosis. A risk model comprising these variables was constructed, with median time to progression of 12.3, 5.1, 2.0 and 1.0 years among patients with 0–3 risk factors respectively. The 2-year progression risk was 81.5% in individuals who demonstrated both eMP and eHb, and 90.5% in those with all three risk factors.
PMCID: PMC5030386  PMID: 27471870
14.  Effect of Monochromic Light-emitting Diode Light with Different Color on the Growth and Reproductive Performances of Breeder Geese 
The purpose of this study was to investigate the effect of monochromic light-emitting diode (LED) light with different color on the growth and reproductive performances of white Roman breeder geese. A randomized complete batch design was utilized for the trial, and the replicate was regarded as one batch. Twenty ganders and fifty-five dames were used in batch 1 (started on 2011/6/17 and ended on 2012/1/31), thirty ganders and eighty-four dames were used in batch 2 (started on 2012/3/23 and ended on 2012/10/26), and thirty ganders and seventy-two dames were used in batch 3 (started on 2013/3/12 and ended on 2013/12/20). Two hundred and ninety-one geese were randomly assigned to 6 rooms in an environmentally controlled house. They were randomly allotted into one of three monochromatic light treatments: Blue, red, or white. The results showed that there was no significant difference in body weight among the three lighting groups at any point throughout the experimental period. However, compared to the blue light group, significantly more eggs were produced by the red and white light groups (p<0.05). Furthermore, the laying period of the red light group was significantly longer than that of other two groups (p<0.05). In conclusion, our results suggested that red LED-light has the best effect on reproductive performance (i.e. longer laying period and higher total eggs number) at 30 lux light intensity, and is therefore a better choice for the management of breeding geese than blue or white LED-light.
PMCID: PMC4852250  PMID: 26954165
Monochromatic Light; Reproductive Performance; Breeder Geese
15.  Factors Affecting the Incidence of Angel Wing in White Roman Geese: Stocking Density and Genetic Selection 
The present study investigated stocking density and genetic lines, factors that may alter the severity and incidence of angel wing (AW), in White Roman geese. Geese (n = 384) from two genetically selected lines (normal- winged line, NL, and angel-winged line, AL, respectively) and one commercial line (CL) were raised in four pens. Following common commercial practice, low-stocking-density (LD), medium-stocking-density, and high-stocking-density treatments were respectively administered to 24, 32, and 40 geese per pen at 0 to 3 weeks (1.92 m2/pen) and 4 to 6 weeks (13.2 m2/pen) of age and to 24, 30, and 36 geese at 7 to 14 weeks (20.0 m2/pen) of age. The results revealed that stocking density mainly affected body weight gain in geese younger than 4 weeks, and that geese subjected to LD had a high body weight at 2 weeks of age. However, the effect of stocking density on the severity score of AW (SSAW) and incidence of AW (IAW) did not differ significantly among the treatments. Differences were observed among the genetic stocks; that is, SSAW and IAW were significantly higher in AL than in NL and CL. Genetic selection generally aggravates AW, complicating its elimination. To effectively reduce IAW, stocking density, a suspected causal factor, should be lower than that presently applied commercially.
PMCID: PMC4852259  PMID: 26954185
Angel Wing; Stocking Density; Genetics; White Roman Geese
16.  Cdk12 is essential for embryonic development and the maintenance of genomic stability 
Cell Death and Differentiation  2015;23(6):1038-1048.
The maintenance of genomic integrity during early embryonic development is important in order to ensure the proper development of the embryo. Studies from cultured cells have demonstrated that cyclin-dependent kinase 12 (Cdk12) is a multifunctional protein that maintains genomic stability and the pluripotency of embryonic stem cells. Perturbation of its functions is also known to be associated with pathogenesis and drug resistance in human cancers. However, the biological significance of Cdk12 in vivo is unclear. Here we bred mice that are deficient in Cdk12 and demonstrated that Cdk12 depletion leads to embryonic lethality shortly after implantation. We also used an in vitro culture system of blastocysts to examine the molecular mechanisms associated with the embryonic lethality of Cdk12-deficient embryos. Cdk12−/− blastocysts fail to undergo outgrowth of the inner cell mass because of an increase in the apoptosis of these cells. Spontaneous DNA damage was revealed by an increase in 53BP1 foci among cells cultured from Cdk12−/− embryos. Furthermore, the expression levels of various DNA damage response genes, namely Atr, Brca1, Fanci and Fancd2, are reduced in Cdk12−/− embryos. These findings indicate that Cdk12 is important for the correct expression of some DNA damage response genes and indirectly has an influence on the efficiency of DNA repair. Our report also highlights that DNA breaks occurring during DNA replication are frequent in mouse embryonic cells and repair of such damage is critical to the successful development of mouse embryos.
PMCID: PMC4987723  PMID: 26658019
17.  Atrial Fibrillation and Risk of ST-Segment Elevation versus Non-ST Segment Elevation Myocardial Infarction: The Atherosclerosis Risk in Communities (ARIC) Study 
Circulation  2015;131(21):1843-1850.
It has recently been reported that atrial fibrillation [AF] is associated with an increased risk of myocardial infarction [MI]. However, the mechanism underlying this association is currently unknown. Further study of the relationship of AF with type of MI [ST elevation MI (STEMI) vs. non-ST elevation MI [NSTEMI] might shed light on the potential mechanisms.
Methods and Results
We examined the association between AF and incident MI in 14,462 participants [mean age 54 years, 56% women, 26% African Americans] from the Atherosclerosis Risk in Communities study who were free of coronary heart disease at baseline [1987–1989] with follow-up through December 31, 2010. AF cases were identified from study visits electrocardiogram and by review of hospital discharge records. Incident MI and its types were ascertained by an independent adjudication committee. Over a median follow up of 21.6 years, 1374 MI events occurred [829 NSTEMI, 249 STEMI, 296 unclassifiable]. In a multivariable adjusted model, AF [n=1545] as a time-varying variable was associated with a 63% increased risk of MI [HR (95% CI):1.63(1.32–2.02)]. However, AF was associated with NSTEMI [HR (95% CI): 1.80(1.39–2.31)] but not STEMI [HR (95% CI): 0.49(0.18–1.34)]; p-value for hazard ratios comparison=0.004. Combining the unclassifiable MI group with either STEMI or NSTEMI did not change this conclusion. The association between AF and MI, total and NSTEMI, was stronger in women than in men [interaction p-value<0.01 for both].
AF is associated with an increased risk of incident MI, especially in women. However, this association is limited to NSTEMI.
PMCID: PMC4447576  PMID: 25918127
Atrial Fibrillation; Myocardial Infarction; STEMI; NSTEMI
18.  Characterizing the malignancy and drug resistance of cancer cells from their membrane resealing response 
Scientific Reports  2016;6:26692.
In this report, we showed that two tumor cell characteristics, namely the malignancy and drug-resistance status can be evaluated by their membrane resealing response. Specifically, membrane pores in a number of pairs of cancer and normal cell lines originated from nasopharynx, lung and intestine were introduced by nano-mechanical puncturing. Interestingly, such nanometer-sized holes in tumor cells can reseal ~2–3 times faster than those in the corresponding normal cells. Furthermore, the membrane resealing time in cancer cell lines exhibiting resistance to several leading chemotherapeutic drugs was also found to be substantially shorter than that in their drug-sensitive counterparts, demonstrating the potential of using this quantity as a novel marker for future cancer diagnosis and drug resistance detection. Finally, a simple model was proposed to explain the observed resealing dynamics of cells which suggested that the distinct response exhibited by normal, tumor and drug resistant cells is likely due to the different tension levels in their lipid membranes, a conclusion that is also supported by direct cortical tension measurement.
PMCID: PMC4880901  PMID: 27225309
19.  Histidine-tryptophan-ketoglutarate solution decreases mortality and morbidity in high-risk patients with severe pulmonary arterial hypertension associated with complex congenital heart disease: an 11-year experience from a single institution 
Cardioplegic reperfusion during a long term ischemic period interrupts cardiac surgery and also increases cellular edema due to repeated solution administration. We reviewed the clinical experiences on myocardial protection of a single perfusion with histidine-tryptophan-ketoglutarate (HTK) for high-risk patients with severe pulmonary arterial hypertension associated with complex congenital heart disease. This retrospective study included 101 high-risk patients undergoing arterial switch operation between March 2001 and July 2012. We divided the cohort into two groups: HTK group, myocardial protection was carried out with one single perfusion with HTK solution; and St group, myocardial protection with conventional St. Thomas' crystalloid cardioplegic solution. The duration of cardiopulmonary bypass did not differ between the two groups. The mortality, morbidity, ICU stay, post-operative hospitalization time, and number of transfusions in HTK group were lower than those in St group (P<0.05). Univariate and multivariate analysis showed that HTK is a statistically significant independent predictor of decreased early mortality and morbidity (P<0.05). In conclusion, HTK solution seems to be an effective and safe alternative to St. Thomas' solution for cardioplegic reperfusion in high-risk patients with complex congenital heart disease.
PMCID: PMC4869826  PMID: 27191607
Histidine-tryptophan-ketoglutarate; Myocardial protection; Cardiac surgery
20.  Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome 
EBioMedicine  2016;9:257-277.
Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT). Using oligonucleotide-based compounds (AntagoNATs) targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology.
•Expression of the Dravet syndrome gene SCN1A can be increased using oligonucleotide-based compounds (AntagoNATs) targeting a regulatory ncRNA•AntagoNAT treatment in vivo in monkeys and Dravet mice led to SCN1A upregulation and significant improvements in disease phenotype•These results outline a possible new approach for the treatment of Dravet syndrome and other disorders with similar etiology
PMCID: PMC4972487  PMID: 27333023
Dravet syndrome; SCN1A; Long non-coding RNA; Natural antisense transcript; AntagoNAT; Oligonucleotide-based compound
21.  NKX6.1 functions as a metastatic suppressor through epigenetic regulation of the epithelial–mesenchymal transition 
Oncogene  2015;35(17):2266-2278.
The transcription factor NKX6.1 (NK6 homeobox 1) is important in the development of pancreatic β-cells and neurons. Although recent publications show that NKX6.1 is hypermethylated and downregulated during tumorigenesis, the function of NKX6.1 in carcinogenesis remains elusive. Here, we address the metastasis suppressor function of human NKX6.1 using cell, animal and clinical analyses. Our data show that NKX6.1 represses tumor formation and metastatic ability both in vitro and in vivo. Mechanistically, NKX6.1 suppresses cell invasion by inhibiting the epithelial-to-mesenchymal transition (EMT). NKX6.1 directly enhances the mRNA level of E-cadherin by recruiting BAF155 coactivator and represses that of vimentin and N-cadherin by recruiting RBBP7 (retinoblastoma binding protein 7) corepressor. Clinical cancer tumors with metastasis show low NKX6.1 protein expression coinciding with low E-cadherin and high vimentin expression. Our results demonstrate that NKX6.1 functions as an EMT suppressor by interacting with different epigenetic modifiers, making it a potential novel therapeutic option.
PMCID: PMC4855079  PMID: 26257059
22.  Carotid Intima‐Media Thickness and Arterial Stiffness and the Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study, Multi‐Ethnic Study of Atherosclerosis (MESA), and the Rotterdam Study 
We evaluated the association of carotid intima‐media thickness (cIMT), carotid plaque, carotid distensibility coefficient (DC), and aortic pulse wave velocity (PWV) with incident atrial fibrillation (AF) and their role in improving AF risk prediction beyond the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)‐AF risk score.
Methods and Results
We analyzed data from 3 population‐based cohort studies: Atherosclerosis Risk in Communities (ARIC) Study (n=13 907); Multi‐Ethnic Study of Atherosclerosis (MESA; n=6640), and the Rotterdam Study (RS; n=5220). We evaluated the association of arterial indices with incident AF and computed the C‐statistic, category‐based net reclassification improvement (NRI), and relative integrated discrimination improvement (IDI) of incorporating arterial indices into the CHARGE‐AF risk score (age, race, height weight, systolic and diastolic blood pressure, antihypertensive medication use, smoking, diabetes, previous myocardial infarction, and previous heart failure). Higher cIMT (meta‐analyzed hazard ratio [95% CI] per 1‐SD increment, 1.12 [1.08–1.16]) and presence of carotid plaque (1.30 [1.19–1.42]) were associated with higher AF incidence after adjustment for CHARGE‐AF risk‐score variables. Lower DC and higher PWV were associated with higher AF incidence only after adjustment for the CHARGE‐AF risk‐score variables excepting height, weight, and systolic and diastolic blood pressure. Addition of cIMT or carotid plaque marginally improved CHARGE‐AF score prediction as assessed by the relative IDI (estimates, 0.025–0.051), but not when assessed with the C‐statistic and NRI.
Higher cIMT, presence of carotid plaque, and greater arterial stiffness are associated with higher AF incidence, indicating that atherosclerosis and arterial stiffness play a role in AF etiopathogenesis. However, arterial indices only modestly improve AF risk prediction.
PMCID: PMC4889172  PMID: 27207996
arterial stiffness; atherosclerosis; atrial fibrillation; carotid intima‐media thickness; Atrial Fibrillation; Epidemiology
23.  Eicosapentaenoic acid attenuates dexamethasome-induced apoptosis by inducing adaptive autophagy via GPR120 in murine bone marrow-derived mesenchymal stem cells 
Gao, B | Han, Y-H | Wang, L | Lin, Y-J | Sun, Z | Lu, W-G | Hu, Y-Q | Li, J-Q | Lin, X-S | Liu, B-H | Jie, Q | Yang, L | Luo, Z-J
Cell Death & Disease  2016;7(5):e2235-.
Long-term use of glucocorticoids is a widespread clinical problem, which currently has no effective solution other than discontinuing the use. Eicosapentaenoic acid (EPA), an omega-3 long chain polyunsaturated fatty acid (n-3 PUFA), which is largely contained in fish or fish oil, has been reported to promote cell viability and improve bone metabolism. However, little is known about the effects of EPA on dexamethasome (Dex)-induced cell apoptosis. In this study, we showed that EPA-induced autophagy of murine bone marrow-derived mesenchymal stem cells (mBMMSCs). Meanwhile, EPA, but not arachidonic acid (AA), markedly inhibited Dex-induced apoptosis and promoted the viability of mBMMSCs. We also observed that EPA-induced autophagy was modulated by GPR120, but not GPR40. Further experiments showed that the mechanism of EPA-induced autophagy associated with GPR120 modulation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of RAPA. The protective effect of EPA on Dex-induced apoptosis via GPR120-meditated induction of adaptive autophagy was supported by in vivo experiments. In summary, our findings may have important implications in developing future strategies to use EPA in the prevention and therapy of the side effects induced by long-term Dex-abuse.
PMCID: PMC4917672  PMID: 27228350
24.  Serum microRNA-210 as a potential noninvasive biomarker for the diagnosis and prognosis of glioma 
British Journal of Cancer  2015;112(7):1241-1246.
MicroRNA-210 (miR-210) is an oncogenic miRNA previously associated with prognosis in human gliomas, an incurable tumour type of the central nervous system. Here miR-210 was investigated as a potential serum biomarker in the diagnosis and prognosis of glioma.
Serum was immediately prepared from blood samples collected from patients with glioma grades I–IV at primary diagnosis (n=136) and healthy controls (n=50) from February 2007 to March 2014 in the Department of Neurosurgery of the First Affiliated Hospital of Wannan Medical College (Wuhu, China). Total RNA was isolated from serum. cDNA was synthesised with primers specific for miR-210 and miR-16-1 (internal control), and quantitative real-time RT-PCR was performed. Results were statistically analysed to determine the role of miR-210 in the diagnosis and prognosis of human glioma patients.
An approximately seven-fold increase in miR-210 expression was detected in serum samples from glioblastoma patients relative to healthy controls. A threshold expression value (2.259) was chosen from receiver operator characteristic curves (ROC), and the low and high miR-210 expression groups were analysed by multivariate Cox proportional hazard regression and Kaplan–Meier analyses. Results revealed an association of high serum miR-210 expression with tumour grade and poor patient outcome (P-values <0.001).
Serum miR-210 is a promising diagnostic and prognostic biomarker that can be detected in the peripheral blood of patients with glioma.
PMCID: PMC4385967  PMID: 25756397
glioma; microRNA-210; diagnosis; prognosis; biomarker
25.  A genomic case study of mixed fibrolamellar hepatocellular carcinoma 
Annals of Oncology  2016;27(6):1148-1154.
We report the first comprehensive genomic analysis of a case of mixed conventional and fibrolamellar HCC (mFL-HCC). This study confirms the expression of DNAJB1:PRKACA, a fusion previously associated with pure FL-HCC but not conventional HCC, in mFL-HCC. These results indicate the DNAJB1:PRKACA fusion has diagnostic utility for both pure and mixed FL-HCC.
Mixed fibrolamellar hepatocellular carcinoma (mFL-HCC) is a rare liver tumor defined by the presence of both pure FL-HCC and conventional HCC components, represents up to 25% of cases of FL-HCC, and has been associated with worse prognosis. Recent genomic characterization of pure FL-HCC identified a highly recurrent transcript fusion (DNAJB1:PRKACA) not found in conventional HCC.
Patients and Methods
We performed exome and transcriptome sequencing of a case of mFL-HCC. A novel BAC-capture approach was developed to identify a 400 kb deletion as the underlying genomic mechanism for a DNAJB1:PRKACA fusion in this case. A sensitive Nanostring Elements assay was used to screen for this transcript fusion in a second case of mFL-HCC, 112 additional HCC samples and 44 adjacent non-tumor liver samples.
We report the first comprehensive genomic analysis of a case of mFL-HCC. No common HCC-associated mutations were identified. The very low mutation rate of this case, large number of mostly single-copy, long-range copy number variants, and high expression of ERBB2 were more consistent with previous reports of pure FL-HCC than conventional HCC. In particular, the DNAJB1:PRKACA fusion transcript specifically associated with pure FL-HCC was detected at very high expression levels. Subsequent analysis revealed the presence of this fusion in all primary and metastatic samples, including those with mixed or conventional HCC pathology. A second case of mFL-HCC confirmed our finding that the fusion was detectable in conventional components. An expanded screen identified a third case of fusion-positive HCC, which upon review, also had both conventional and fibrolamellar features. This screen confirmed the absence of the fusion in all conventional HCC and adjacent non-tumor liver samples.
These results indicate that mFL-HCC is similar to pure FL-HCC at the genomic level and the DNAJB1:PRKACA fusion can be used as a diagnostic tool for both pure and mFL-HCC.
PMCID: PMC4880064  PMID: 27029710
mixed fibrolamellar hepatocellular carcinoma; genome analysis; fusion transcript; DNAJB1:PRKACA

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