122 results on '"Goodyear CS"'
Search Results
2. S50 Oxidative stress driven inflammatory responses in lung epithelial cells
- Author
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Tarhini, F, primary, Crilly, A, additional, Brzeszczynska, J, additional, McGarvey, L, additional, Thornbury, K, additional, Goodyear, CS, additional, Lockhart, JC, additional, and Litherland, GJ, additional
- Published
- 2021
- Full Text
- View/download PDF
3. Immunoglobulin A antibodies to oxidized collagen type II as a potential biomarker for the stratification of spondyloarthritis from rheumatoid arthritis
- Author
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Vinci, C, primary, Infantino, M, additional, Raturi, S, additional, Tindell, A, additional, Topping, LM, additional, Strollo, R, additional, Amital, H, additional, Shoenfeld, Y, additional, Gertel, S, additional, Grossi, V, additional, Manfredi, M, additional, Rutigliano, IM, additional, Bandinelli, F, additional, Li Gobbi, F, additional, Damiani, A, additional, Pozzilli, P, additional, Mcinnes, IB, additional, Goodyear, CS, additional, Benucci, M, additional, and Nissim, A, additional
- Published
- 2020
- Full Text
- View/download PDF
4. Large expert-curated database for benchmarking document similarity detection in biomedical literature search
- Author
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Brown, P, Zhou, Y, Tan, AC, El-Esawi, MA, Liehr, T, Blanck, O, Gladue, DP, Almeida, GMF, Cernava, T, Sorzano, CO, Yeung, AWK, Engel, MS, Chandrasekaran, AR, Muth, T, Staege, MS, Daulatabad, SV, Widera, D, Zhang, J, Meule, A, Honjo, K, Pourret, O, Yin, CC, Zhang, Z, Cascella, M, Flegel, WA, Goodyear, CS, van Raaij, MJ, Bukowy-Bieryllo, Z, Campana, LG, Kurniawan, NA, Lalaouna, D, Hüttner, FJ, Ammerman, BA, Ehret, F, Cobine, PA, Tan, EC, Han, H, Xia, W, McCrum, C, Dings, RPM, Marinello, F, Nilsson, H, Nixon, B, Voskarides, K, Yang, L, Costa, VD, Bengtsson-Palme, J, Bradshaw, W, Grimm, DG, Kumar, N, Martis, E, Prieto, D, Sabnis, SC, Amer, SEDR, Liew, AWC, Perco, P, Rahimi, F, Riva, G, Zhang, C, Devkota, HP, Ogami, K, Basharat, Z, Fierz, W, Siebers, R, Tan, KH, Boehme, KA, Brenneisen, P, Brown, JAL, Dalrymple, BP, Harvey, DJ, Ng, G, Werten, S, Bleackley, M, Dai, Z, Dhariwal, R, Gelfer, Y, Hartmann, MD, Miotla, P, Tamaian, R, Govender, P, Gurney-Champion, OJ, Kauppila, JH, Zhang, X, Echeverría, N, Subhash, S, Sallmon, H, Tofani, M, Bae, T, Bosch, O, Cuív, PO, Danchin, A, Diouf, B, Eerola, T, Evangelou, E, Filipp, F, Klump, H, Kurgan, L, Smith, SS, Terrier, O, Tuttle, N, Brown, P, Zhou, Y, Tan, AC, El-Esawi, MA, Liehr, T, Blanck, O, Gladue, DP, Almeida, GMF, Cernava, T, Sorzano, CO, Yeung, AWK, Engel, MS, Chandrasekaran, AR, Muth, T, Staege, MS, Daulatabad, SV, Widera, D, Zhang, J, Meule, A, Honjo, K, Pourret, O, Yin, CC, Zhang, Z, Cascella, M, Flegel, WA, Goodyear, CS, van Raaij, MJ, Bukowy-Bieryllo, Z, Campana, LG, Kurniawan, NA, Lalaouna, D, Hüttner, FJ, Ammerman, BA, Ehret, F, Cobine, PA, Tan, EC, Han, H, Xia, W, McCrum, C, Dings, RPM, Marinello, F, Nilsson, H, Nixon, B, Voskarides, K, Yang, L, Costa, VD, Bengtsson-Palme, J, Bradshaw, W, Grimm, DG, Kumar, N, Martis, E, Prieto, D, Sabnis, SC, Amer, SEDR, Liew, AWC, Perco, P, Rahimi, F, Riva, G, Zhang, C, Devkota, HP, Ogami, K, Basharat, Z, Fierz, W, Siebers, R, Tan, KH, Boehme, KA, Brenneisen, P, Brown, JAL, Dalrymple, BP, Harvey, DJ, Ng, G, Werten, S, Bleackley, M, Dai, Z, Dhariwal, R, Gelfer, Y, Hartmann, MD, Miotla, P, Tamaian, R, Govender, P, Gurney-Champion, OJ, Kauppila, JH, Zhang, X, Echeverría, N, Subhash, S, Sallmon, H, Tofani, M, Bae, T, Bosch, O, Cuív, PO, Danchin, A, Diouf, B, Eerola, T, Evangelou, E, Filipp, F, Klump, H, Kurgan, L, Smith, SS, Terrier, O, and Tuttle, N
- Abstract
Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical science.
- Published
- 2019
5. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
- Author
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Cossarizza, A, Chang, H-D, Radbruch, A, Acs, A, Adam, D, Adam-Klages, S, Agace, WW, Aghaeepour, N, Akdis, M, Allez, M, Almeida, LN, Alvisi, G, Anderson, G, Andrae, I, Annunziato, F, Anselmo, A, Bacher, P, Baldari, CT, Bari, S, Barnaba, V, Barros-Martins, J, Battistini, L, Bauer, W, Baumgart, S, Baumgarth, N, Baumjohann, D, Baying, B, Bebawy, M, Becher, B, Beisker, W, Benes, V, Beyaert, R, Blanco, A, Boardman, DA, Bogdan, C, Borger, JG, Borsellino, G, Boulais, PE, Bradford, JA, Brenner, D, Brinkman, RR, Brooks, AES, Busch, DH, Buescher, M, Bushnell, TP, Calzetti, F, Cameron, G, Cammarata, I, Cao, X, Cardell, SL, Casola, S, Cassatella, MA, Cavani, A, Celada, A, Chatenoud, L, Chattopadhyay, PK, Chow, S, Christakou, E, Cicin-Sain, L, Clerici, M, Colombo, FS, Cook, L, Cooke, A, Cooper, AM, Corbett, AJ, Cosma, A, Cosmi, L, Coulie, PG, Cumano, A, Cvetkovic, L, Dang, VD, Dang-Heine, C, Davey, MS, Davies, D, De Biasi, S, Del Zotto, G, Dela Cruz, GV, Delacher, M, Della Bella, S, Dellabona, P, Deniz, G, Dessing, M, Di Santo, JP, Diefenbach, A, Dieli, F, Dolf, A, Doerner, T, Dress, RJ, Dudziak, D, Dustin, M, Dutertre, C-A, Ebner, F, Eckle, SBG, Edinger, M, Eede, P, Ehrhardt, GRA, Eich, M, Engel, P, Engelhardt, B, Erdei, A, Esser, C, Everts, B, Evrard, M, Falk, CS, Fehniger, TA, Felipo-Benavent, M, Ferry, H, Feuerer, M, Filby, A, Filkor, K, Fillatreau, S, Follo, M, Foerster, I, Foster, J, Foulds, GA, Frehse, B, Frenette, PS, Frischbutter, S, Fritzsche, W, Galbraith, DW, Gangaev, A, Garbi, N, Gaudilliere, B, Gazzinelli, RT, Geginat, J, Gerner, W, Gherardin, NA, Ghoreschi, K, Gibellini, L, Ginhoux, F, Goda, K, Godfrey, DI, Goettlinger, C, Gonzalez-Navajas, JM, Goodyear, CS, Gori, A, Grogan, JL, Grummitt, D, Gruetzkau, A, Haftmann, C, Hahn, J, Hammad, H, Haemmerling, G, Hansmann, L, Hansson, G, Harpur, CM, Hartmann, S, Hauser, A, Hauser, AE, Haviland, DL, Hedley, D, Hernandez, DC, Herrera, G, Herrmann, M, Hess, C, Hoefer, T, Hoffmann, P, Hogquist, K, Holland, T, Hollt, T, Holmdahl, R, Hombrink, P, Houston, JP, Hoyer, BF, Huang, B, Huang, F-P, Huber, JE, Huehn, J, Hundemer, M, Hunter, CA, Hwang, WYK, Iannone, A, Ingelfinger, F, Ivison, SM, Jaeck, H-M, Jani, PK, Javega, B, Jonjic, S, Kaiser, T, Kalina, T, Kamradt, T, Kaufmann, SHE, Keller, B, Ketelaars, SLC, Khalilnezhad, A, Khan, S, Kisielow, J, Klenerman, P, Knopf, J, Koay, H-F, Kobow, K, Kolls, JK, Kong, WT, Kopf, M, Korn, T, Kriegsmann, K, Kristyanto, H, Kroneis, T, Krueger, A, Kuehne, J, Kukat, C, Kunkel, D, Kunze-Schumacher, H, Kurosaki, T, Kurts, C, Kvistborg, P, Kwok, I, Landry, J, Lantz, O, Lanuti, P, LaRosa, F, Lehuen, A, LeibundGut-Landmann, S, Leipold, MD, Leung, LYT, Levings, MK, Lino, AC, Liotta, F, Litwin, V, Liu, Y, Ljunggren, H-G, Lohoff, M, Lombardi, G, Lopez, L, Lopez-Botet, M, Lovett-Racke, AE, Lubberts, E, Luche, H, Ludewig, B, Lugli, E, Lunemann, S, Maecker, HT, Maggi, L, Maguire, O, Mair, F, Mair, KH, Mantovani, A, Manz, RA, Marshall, AJ, Martinez-Romero, A, Martrus, G, Marventano, I, Maslinski, W, Matarese, G, Mattioli, AV, Maueroder, C, Mazzoni, A, McCluskey, J, McGrath, M, McGuire, HM, McInnes, IB, Mei, HE, Melchers, F, Melzer, S, Mielenz, D, Miller, SD, Mills, KHG, Minderman, H, Mjosberg, J, Moore, J, Moran, B, Moretta, L, Mosmann, TR, Mueller, S, Multhoff, G, Munoz, LE, Munz, C, Nakayama, T, Nasi, M, Neumann, K, Ng, LG, Niedobitek, A, Nourshargh, S, Nunez, G, O'Connor, J-E, Ochel, A, Oja, A, Ordonez, D, Orfao, A, Orlowski-Oliver, E, Ouyang, W, Oxenius, A, Palankar, R, Panse, I, Pattanapanyasat, K, Paulsen, M, Pavlinic, D, Penter, L, Peterson, P, Peth, C, Petriz, J, Piancone, F, Pickl, WF, Piconese, S, Pinti, M, Pockley, AG, Podolska, MJ, Poon, Z, Pracht, K, Prinz, I, Pucillo, CEM, Quataert, SA, Quatrini, L, Quinn, KM, Radbruch, H, Radstake, TRDJ, Rahmig, S, Rahn, H-P, Rajwa, B, Ravichandran, G, Raz, Y, Rebhahn, JA, Recktenwald, D, Reimer, D, Reis e Sousa, C, Remmerswaal, EBM, Richter, L, Rico, LG, Riddell, A, Rieger, AM, Robinson, JP, Romagnani, C, Rubartelli, A, Ruland, J, Saalmueller, A, Saeys, Y, Saito, T, Sakaguchi, S, Sala-de-Oyanguren, F, Samstag, Y, Sanderson, S, Sandrock, I, Santoni, A, Sanz, RB, Saresella, M, Sautes-Fridman, C, Sawitzki, B, Schadt, L, Scheffold, A, Scherer, HU, Schiemann, M, Schildberg, FA, Schimisky, E, Schlitzer, A, Schlosser, J, Schmid, S, Schmitt, S, Schober, K, Schraivogel, D, Schuh, W, Schueler, T, Schulte, R, Schulz, AR, Schulz, SR, Scotta, C, Scott-Algara, D, Sester, DP, Shankey, TV, Silva-Santos, B, Simon, AK, Sitnik, KM, Sozzani, S, Speiser, DE, Spidlen, J, Stahlberg, A, Stall, AM, Stanley, N, Stark, R, Stehle, C, Steinmetz, T, Stockinger, H, Takahama, Y, Takeda, K, Tan, L, Tarnok, A, Tiegs, G, Toldi, G, Tornack, J, Traggiai, E, Trebak, M, Tree, TIM, Trotter, J, Trowsdale, J, Tsoumakidou, M, Ulrich, H, Urbanczyk, S, van de Veen, W, van den Broek, M, van der Pol, E, Van Gassen, S, Van Isterdael, G, van Lier, RAW, Veldhoen, M, Vento-Asturias, S, Vieira, P, Voehringer, D, Volk, H-D, von Borstel, A, von Volkmann, K, Waisman, A, Walker, RV, Wallace, PK, Wang, SA, Wang, XM, Ward, MD, Ward-Hartstonge, KA, Warnatz, K, Warnes, G, Warth, S, Waskow, C, Watson, JV, Watzl, C, Wegener, L, Weisenburger, T, Wiedemann, A, Wienands, J, Wilharm, A, Wilkinson, RJ, Willimsky, G, Wing, JB, Winkelmann, R, Winkler, TH, Wirz, OF, Wong, A, Wurst, P, Yang, JHM, Yang, J, Yazdanbakhsh, M, Yu, L, Yue, A, Zhang, H, Zhao, Y, Ziegler, SM, Zielinski, C, Zimmermann, J, Zychlinsky, A, Cossarizza, A, Chang, H-D, Radbruch, A, Acs, A, Adam, D, Adam-Klages, S, Agace, WW, Aghaeepour, N, Akdis, M, Allez, M, Almeida, LN, Alvisi, G, Anderson, G, Andrae, I, Annunziato, F, Anselmo, A, Bacher, P, Baldari, CT, Bari, S, Barnaba, V, Barros-Martins, J, Battistini, L, Bauer, W, Baumgart, S, Baumgarth, N, Baumjohann, D, Baying, B, Bebawy, M, Becher, B, Beisker, W, Benes, V, Beyaert, R, Blanco, A, Boardman, DA, Bogdan, C, Borger, JG, Borsellino, G, Boulais, PE, Bradford, JA, Brenner, D, Brinkman, RR, Brooks, AES, Busch, DH, Buescher, M, Bushnell, TP, Calzetti, F, Cameron, G, Cammarata, I, Cao, X, Cardell, SL, Casola, S, Cassatella, MA, Cavani, A, Celada, A, Chatenoud, L, Chattopadhyay, PK, Chow, S, Christakou, E, Cicin-Sain, L, Clerici, M, Colombo, FS, Cook, L, Cooke, A, Cooper, AM, Corbett, AJ, Cosma, A, Cosmi, L, Coulie, PG, Cumano, A, Cvetkovic, L, Dang, VD, Dang-Heine, C, Davey, MS, Davies, D, De Biasi, S, Del Zotto, G, Dela Cruz, GV, Delacher, M, Della Bella, S, Dellabona, P, Deniz, G, Dessing, M, Di Santo, JP, Diefenbach, A, Dieli, F, Dolf, A, Doerner, T, Dress, RJ, Dudziak, D, Dustin, M, Dutertre, C-A, Ebner, F, Eckle, SBG, Edinger, M, Eede, P, Ehrhardt, GRA, Eich, M, Engel, P, Engelhardt, B, Erdei, A, Esser, C, Everts, B, Evrard, M, Falk, CS, Fehniger, TA, Felipo-Benavent, M, Ferry, H, Feuerer, M, Filby, A, Filkor, K, Fillatreau, S, Follo, M, Foerster, I, Foster, J, Foulds, GA, Frehse, B, Frenette, PS, Frischbutter, S, Fritzsche, W, Galbraith, DW, Gangaev, A, Garbi, N, Gaudilliere, B, Gazzinelli, RT, Geginat, J, Gerner, W, Gherardin, NA, Ghoreschi, K, Gibellini, L, Ginhoux, F, Goda, K, Godfrey, DI, Goettlinger, C, Gonzalez-Navajas, JM, Goodyear, CS, Gori, A, Grogan, JL, Grummitt, D, Gruetzkau, A, Haftmann, C, Hahn, J, Hammad, H, Haemmerling, G, Hansmann, L, Hansson, G, Harpur, CM, Hartmann, S, Hauser, A, Hauser, AE, Haviland, DL, Hedley, D, Hernandez, DC, Herrera, G, Herrmann, M, Hess, C, Hoefer, T, Hoffmann, P, Hogquist, K, Holland, T, Hollt, T, Holmdahl, R, Hombrink, P, Houston, JP, Hoyer, BF, Huang, B, Huang, F-P, Huber, JE, Huehn, J, Hundemer, M, Hunter, CA, Hwang, WYK, Iannone, A, Ingelfinger, F, Ivison, SM, Jaeck, H-M, Jani, PK, Javega, B, Jonjic, S, Kaiser, T, Kalina, T, Kamradt, T, Kaufmann, SHE, Keller, B, Ketelaars, SLC, Khalilnezhad, A, Khan, S, Kisielow, J, Klenerman, P, Knopf, J, Koay, H-F, Kobow, K, Kolls, JK, Kong, WT, Kopf, M, Korn, T, Kriegsmann, K, Kristyanto, H, Kroneis, T, Krueger, A, Kuehne, J, Kukat, C, Kunkel, D, Kunze-Schumacher, H, Kurosaki, T, Kurts, C, Kvistborg, P, Kwok, I, Landry, J, Lantz, O, Lanuti, P, LaRosa, F, Lehuen, A, LeibundGut-Landmann, S, Leipold, MD, Leung, LYT, Levings, MK, Lino, AC, Liotta, F, Litwin, V, Liu, Y, Ljunggren, H-G, Lohoff, M, Lombardi, G, Lopez, L, Lopez-Botet, M, Lovett-Racke, AE, Lubberts, E, Luche, H, Ludewig, B, Lugli, E, Lunemann, S, Maecker, HT, Maggi, L, Maguire, O, Mair, F, Mair, KH, Mantovani, A, Manz, RA, Marshall, AJ, Martinez-Romero, A, Martrus, G, Marventano, I, Maslinski, W, Matarese, G, Mattioli, AV, Maueroder, C, Mazzoni, A, McCluskey, J, McGrath, M, McGuire, HM, McInnes, IB, Mei, HE, Melchers, F, Melzer, S, Mielenz, D, Miller, SD, Mills, KHG, Minderman, H, Mjosberg, J, Moore, J, Moran, B, Moretta, L, Mosmann, TR, Mueller, S, Multhoff, G, Munoz, LE, Munz, C, Nakayama, T, Nasi, M, Neumann, K, Ng, LG, Niedobitek, A, Nourshargh, S, Nunez, G, O'Connor, J-E, Ochel, A, Oja, A, Ordonez, D, Orfao, A, Orlowski-Oliver, E, Ouyang, W, Oxenius, A, Palankar, R, Panse, I, Pattanapanyasat, K, Paulsen, M, Pavlinic, D, Penter, L, Peterson, P, Peth, C, Petriz, J, Piancone, F, Pickl, WF, Piconese, S, Pinti, M, Pockley, AG, Podolska, MJ, Poon, Z, Pracht, K, Prinz, I, Pucillo, CEM, Quataert, SA, Quatrini, L, Quinn, KM, Radbruch, H, Radstake, TRDJ, Rahmig, S, Rahn, H-P, Rajwa, B, Ravichandran, G, Raz, Y, Rebhahn, JA, Recktenwald, D, Reimer, D, Reis e Sousa, C, Remmerswaal, EBM, Richter, L, Rico, LG, Riddell, A, Rieger, AM, Robinson, JP, Romagnani, C, Rubartelli, A, Ruland, J, Saalmueller, A, Saeys, Y, Saito, T, Sakaguchi, S, Sala-de-Oyanguren, F, Samstag, Y, Sanderson, S, Sandrock, I, Santoni, A, Sanz, RB, Saresella, M, Sautes-Fridman, C, Sawitzki, B, Schadt, L, Scheffold, A, Scherer, HU, Schiemann, M, Schildberg, FA, Schimisky, E, Schlitzer, A, Schlosser, J, Schmid, S, Schmitt, S, Schober, K, Schraivogel, D, Schuh, W, Schueler, T, Schulte, R, Schulz, AR, Schulz, SR, Scotta, C, Scott-Algara, D, Sester, DP, Shankey, TV, Silva-Santos, B, Simon, AK, Sitnik, KM, Sozzani, S, Speiser, DE, Spidlen, J, Stahlberg, A, Stall, AM, Stanley, N, Stark, R, Stehle, C, Steinmetz, T, Stockinger, H, Takahama, Y, Takeda, K, Tan, L, Tarnok, A, Tiegs, G, Toldi, G, Tornack, J, Traggiai, E, Trebak, M, Tree, TIM, Trotter, J, Trowsdale, J, Tsoumakidou, M, Ulrich, H, Urbanczyk, S, van de Veen, W, van den Broek, M, van der Pol, E, Van Gassen, S, Van Isterdael, G, van Lier, RAW, Veldhoen, M, Vento-Asturias, S, Vieira, P, Voehringer, D, Volk, H-D, von Borstel, A, von Volkmann, K, Waisman, A, Walker, RV, Wallace, PK, Wang, SA, Wang, XM, Ward, MD, Ward-Hartstonge, KA, Warnatz, K, Warnes, G, Warth, S, Waskow, C, Watson, JV, Watzl, C, Wegener, L, Weisenburger, T, Wiedemann, A, Wienands, J, Wilharm, A, Wilkinson, RJ, Willimsky, G, Wing, JB, Winkelmann, R, Winkler, TH, Wirz, OF, Wong, A, Wurst, P, Yang, JHM, Yang, J, Yazdanbakhsh, M, Yu, L, Yue, A, Zhang, H, Zhao, Y, Ziegler, SM, Zielinski, C, Zimmermann, J, and Zychlinsky, A
- Abstract
These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
- Published
- 2019
6. Novel methodology to discern predictors of remission and patterns of disease activity over time using rheumatoid arthritis clinical trials data
- Author
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Tom, BDM, Symmons, D, Brockbank, S, Carini, C, Cope, AP, Ehrenstein, MR, Fisher, BA, Goodyear, CS, Gozzard, N, Harris, R, Hicks, K, Hollis, S, Hughes-Morley, A, Isaacs, J, Kola, B, McInnes, IB, Mela, CM, Parker, G, Pedersen, AW, Ponchel, F, Sabin, T, Scott, DL, Scott, IC, Sleeman, MA, Taylor, PC, Tsuji, W, Zhong, Y, Hilkens, C, Anderson, A, Stocks, P, Lendrem, D, Tarn, J, Smith, G, Allen, B, Casement, J, Diboll, J, Harry, R, Simpson, G, Toward, R, Noble, H, Parke, A, Wu, W, Clarke, F, Galloway, J, Lempp, H, Ibrahim, F, Schwank, S, Molyneux, G, Lazarov, T, Geissmann, F, Donnelly, I, Gilmour, A, Virlan, AT, Porter, D, Emery, P, El-Jawhari, J, Parmar, R, McDermot, MF, Buch, M, Buckley, C, Young, SP, Jones, P, Raza, K, Filer, A, Pitzalis, C, Barnes, MR, Watson, DS, Tzanis, E, Thorborn, G, Fossati-Jimack, L, Kelly, S, Humby, F, Bombardieri, M, Rana, S, Jia, Z, Goldmann, K, Lewis, M, Altobelli, G, John, C, Martins, S, Nguyen, D, Ali, H, Ciurtin, C, Worthington, J, Bruce, IN, Sergeant, JC, Verstappen, SMM, Stirling, F, Farewell, V, Keidel, S, Cuff, C, Levesque, M, Long, A, Liu, Z, Lipsky, S, Harvey, B, Macoritto, M, Hong, F, Kaymakcalan, S, Ward, N, Talbot, S, Padhji, D, Sleeman, M, Finch, D, Herath, A, Lindholm, C, Jenkins, M, Ho, M, Marshall, C, Page, M, Edwards, H, Cuza, A, Rowe, A, Capdevila, FB, Loza, M, Curran, M, Verbeeck, D, Baker, D, Vranic, I, Mela, CT, Wright, S, Rowell, L, Vernon, E, Joseph, N, Payne, N, Rao, R, Binks, M, Belson, A, Ludbrook, V, Tipney, H, Ellis, J, Hasan, S, Didierlaurent, A, Burny, W, Haynes, A, Larminie, C, Dastros-Pitel, D, Jelinsky, S, Hodge, M, Maciejewski, M, Ziemek, D, Schulz-Knappe, P, Zucht, H-D, Budde, P, Coles, MC, Butler, JA, Read, S, and Consortium, RA-MAP
- Subjects
musculoskeletal diseases ,immune system diseases ,skin and connective tissue diseases - Abstract
Objectives: To identify predictors of remission and disease activity patterns in patients with rheumatoid arthritis (RA) using individual participant data (IPD) from clinical trials. Methods: Phase II and III clinical trials completed between 2002 and 2012 were identified by systematic literature review and contact with UK market authorisation holders. Anonymised baseline and follow-up IPD from non-biological arms were amalgamated. Multiple imputation was used to handle missing outcome and covariate information. Random effects logistic regression was used to identify predictors of remission, measured by the Disease Activity Score 28 (DAS28) at 6 months. Novel latent class mixed models characterised DAS28 over time. Results: IPD of 3290 participants from 18 trials were included. Of these participants, 92% received methotrexate (MTX). Remission rates were estimated at 8.4%(95%CI 7.4%to9.5%) overall, 17%(95%CI 14.8%to19.4%) for MTX-naïve patients with early RA and 3.2% (95% CI 2.4% to 4.3%) for those with prior MTX exposure at entry. In prior MTX-exposed patients, lower baseline DAS28 and MTX reinitiation were associated with remission. In MTX-naïve patients, being young, white, male, with better functional and mental health, lower baseline DAS28 and receiving concomitant glucocorticoids were associated with remission. Three DAS28 trajectory subpopulations were identified in MTX-naïve and MTX-exposed patients. A number of variables were associated with subpopulation membership and DAS28 levels within subpopulations. Conclusions: Predictors of remission differed between MTX-naïve and prior MTX-exposed patients at entry. Latent class mixed models supported differential non-biological therapy response, with three distinct trajectories observed in both MTX-naïve and MTX-exposed patients. Findings should be useful when designing future RA trials and interpreting results of biomarker studies.
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- 2018
7. The RA-MAP Consortium: a working model for academia-industry collaboration
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Cope, AP, Barnes, MR, Belson, A, Binks, M, Brockbank, S, Bonachela-Capdevila, F, Carini, C, Fisher, BA, Goodyear, CS, Emery, P, Ehrenstein, MR, Gozzard, N, Harris, R, Hollis, S, Keidel, S, Levesque, M, Lindholm, C, McDermott, MF, McInnes, IB, Mela, CM, Parker, G, Read, S, Pedersen, AW, Ponchel, F, Porter, D, Rao, R, Rowe, A, Schulz-Knappe, P, Sleeman, MA, Symmons, D, Taylor, PC, Tom, B, Tsuji, W, Verbeeck, D, Isaacs, JD, Consortium, Ra-Map, Tom, Brian [0000-0002-3335-9322], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Biomedical Research ,Big data ,MEDLINE ,Globe ,History, 21st Century ,Article ,Arthritis, Rheumatoid ,03 medical and health sciences ,Rheumatology ,medicine ,Genomic medicine ,Humans ,Industry ,Cooperative Behavior ,business.industry ,Research ,Genomics ,Public relations ,United Kingdom ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,Cooperative behavior ,business ,Biomarkers - Abstract
Collaboration can be challenging; nevertheless, the emerging successes of large, multi-partner, multi-national cooperatives and research networks in the biomedical sector have sustained the appetite of academics and industry partners for developing and fostering new research consortia. This model has percolated down to national funding agencies across the globe, leading to funding for projects that aim to realise the true potential of genomic medicine in the 21st century and to reap the rewards of ‘big data’. In this Perspectives article, the experiences of the RA-MAP consortium, a group of more than 140 individuals affiliated with 21 academic and industry organizations that are focused on making genomic medicine in rheumatoid arthritis a reality are described. The challenges of multi-partner collaboration in the UK are highlighted and wide-ranging solutions are offered that might benefit large research consortia around the world.
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- 2018
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8. S100 Reduction of inflammatory cytokine production in chronic obstructive pulmonary disease (COPD) epithelial cells by protease activated receptor 2 (PAR2) antagonism
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Bailo, M, primary, Dunning, L, additional, Brzeszczynska, J, additional, McIntosh, K, additional, Plevin, R, additional, Martin, SL, additional, Sergeant, GP, additional, Goodyear, CS, additional, Litherland, GJ, additional, Lockhart, JC, additional, and Crilly, A, additional
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- 2019
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9. P074 The alarmin S100A9 hampers osteoclast differentiation from circulating precursors by reducing the expression of rank
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van den Bosch, MH, primary, Di Ceglie, I, additional, Blom, AB, additional, Logie, C, additional, Martens, JH, additional, Roth, J, additional, Vogl, T, additional, Goodyear, CS, additional, van der Kraan, PM, additional, and van Lent, PL, additional
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- 2019
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10. P108/O28 Fatty acid oxidation can drive human monocyte derived CCL20 in the RA synovial environment
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Rodgers, LC, primary, Cole, J, additional, Rattigan, K, additional, Barrett, MP, additional, Kurian, N, additional, McInnes, IB, additional, and Goodyear, CS, additional
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- 2019
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11. P018 Protease activated receptor 2 (PAR2) expression in the myeloid compartment impacts osteoclastogenesis
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McGrath, S, primary, Hultin, L, additional, Lockhart, JC, additional, and Goodyear, CS, additional
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- 2018
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12. Antibodies to heteromeric glycolipid complexes in Guillain-Barre syndrome
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Rinaldi, S, Brennan, KM, Kalna, G, Walgaard, C, Van Doorn, P, Jacobs, BC, Yu, RK, Mansson, JE, Goodyear, CS, Willison, HJ, and Neurology
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lcsh:R ,lcsh:Medicine ,lcsh:Q ,lcsh:Science - Abstract
Autoantibodies are infrequently detected in the sera of patients with the demyelinating form of Guillain-Barré syndrome most commonly encountered in the Western world, despite abundant circumstantial evidence suggesting their existence. We hypothesised that antibody specificities reliant on the cis interactions of neighbouring membrane glycolipids could explain this discrepancy, and would not have been detected by traditional serological assays using highly purified preparations of single gangliosides. To assess the frequency of glycolipid complex antibodies in a Western European cohort of patients GBS we used a newly developed combinatorial glycoarray methodology to screen against large range of antigens (11 gangliosides, 8 other single glycolipids and 162 heterodimeric glycolipid complexes). Serum samples of 181 patients from a geographically defined, Western European cohort of GBS cases were analysed, along with 161 control sera. Serum IgG binding to single gangliosides was observed in 80.0% of axonal GBS cases, but in only 11.8% of cases with demyelinating electrophysiology. The inclusion of glycolipid complexes increased the positivity rate in demyelinating disease to 62.4%. There were 40 antigens with statistically significantly increased binding intensities in GBS as compared to healthy control sera. Of these, 7 complex antigens and 1 single ganglioside also produced statistically significantly increased binding intensities in GBS versus neurological disease controls. The detection of antibodies against specific complexes was associated with particular clinical features including disease severity, requirement for mechanical ventilation, and axonal electrophysiology. This study demonstrates that while antibodies against single gangliosides are often found in cases with axonal-type electrophysiology, antibodies against glycolipid complexes predominate in cases with demyelinating electrophysiology, providing a more robust serum biomarker than has ever been previously available for such cases. This work confirms the activation of the humoral immune system in the dysimmune disease process in GBS, and correlates patterns of antigen recognition with different clinical features.
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- 2016
13. A1.10 The GM-CSF/CCL17 axis in the rheumatoid synovial environment
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Kidger, SV, primary, Ellson, CD, additional, McInnes, IB, additional, Sleeman, MA, additional, Robinson, MJ, additional, and Goodyear, CS, additional
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- 2016
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14. A10.07 The kinetic cytokine/chemokine secretory profile in surgical models of osteoarthritis
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Ortiz, AC, primary, Dunning, L, additional, Huesa, C, additional, Ferrell, WR, additional, McInnes, IB, additional, Lockhart, JC, additional, Goodyear, CS, additional, and Crilly, A, additional
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- 2016
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15. Antibodies to Heteromeric Glycolipid Complexes in Guillain-Barre Syndrome
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Rinaldi, S, Brennan, KM, Kalna, G, Walgaard, Christa, van Doorn, Pieter, Jacobs, B.C., Yu, RK, Mansson, JE, Goodyear, CS, Willison, HJ, Rinaldi, S, Brennan, KM, Kalna, G, Walgaard, Christa, van Doorn, Pieter, Jacobs, B.C., Yu, RK, Mansson, JE, Goodyear, CS, and Willison, HJ
- Abstract
Autoantibodies are infrequently detected in the sera of patients with the demyelinating form of Guillain-Barre syndrome most commonly encountered in the Western world, despite abundant circumstantial evidence suggesting their existence. We hypothesised that antibody specificities reliant on the cis interactions of neighbouring membrane glycolipids could explain this discrepancy, and would not have been detected by traditional serological assays using highly purified preparations of single gangliosides. To assess the frequency of glycolipid complex antibodies in a Western European cohort of patients GBS we used a newly developed combinatorial glycoarray methodology to screen against large range of antigens (11 gangliosides, 8 other single glycolipids and 162 heterodimeric glycolipid complexes). Serum samples of 181 patients from a geographically defined, Western European cohort of GBS cases were analysed, along with 161 control sera. Serum IgG binding to single gangliosides was observed in 80.0% of axonal GBS cases, but in only 11.8% of cases with demyelinating electrophysiology. The inclusion of glycolipid complexes increased the positivity rate in demyelinating disease to 62.4%. There were 40 antigens with statistically significantly increased binding intensities in GBS as compared to healthy control sera. Of these, 7 complex antigens and 1 single ganglioside also produced statistically significantly increased binding intensities in GBS versus neurological disease controls. The detection of antibodies against specific complexes was associated with particular clinical features including disease severity, requirement for mechanical ventilation, and axonal electrophysiology. This study demonstrates that while antibodies against single gangliosides are often found in cases with axonal-type electrophysiology, antibodies against glycolipid complexes predominate in cases with demyelinating electrophysiology, providing a more robust serum biomarker than has ever been previ
- Published
- 2013
16. Sialylation of Campylobacter jejuni Lipo-Oligosaccharides: Impact on Phagocytosis and Cytokine Production in Mice
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Huizinga, Ruth, Easton, AS, Donachie, AM, Guthrie, J, Rijs, Wouter, Heikema, Astrid, Boon, L (Louis), Samsom, Janneke, Jacobs, B.C., Willison, HJ, Goodyear, CS, Huizinga, Ruth, Easton, AS, Donachie, AM, Guthrie, J, Rijs, Wouter, Heikema, Astrid, Boon, L (Louis), Samsom, Janneke, Jacobs, B.C., Willison, HJ, and Goodyear, CS
- Abstract
Background: Guillain-Barre syndrome (GBS) is a post-infectious polyradiculoneuropathy, frequently associated with antecedent Campylobacter jejuni (C. jejuni) infection. The presence of sialic acid on C. jejuni lipo-oligosaccharide (LOS) is considered a risk factor for development of GBS as it crucially determines the structural homology between LOS and gangliosides, explaining the induction of cross-reactive neurotoxic antibodies. Sialylated C. jejuni are recognised by TLR4 and sialoadhesin; however, the functional implications of these interactions in vivo are unknown. Methodology/Principal Findings: In this study we investigated the effects of bacterial sialylation on phagocytosis and cytokine secretion by mouse myeloid cells in vitro and in vivo. Using fluorescently labelled GM1a/GD1a ganglioside-mimicking C. jejuni strains and corresponding (Cst-II-mutant) control strains lacking sialic acid, we show that sialylated C. jejuni was more efficiently phagocytosed in vitro by BM-M Phi, but not by BM-DC. In addition, LOS sialylation increased the production of IL Conclusions/Significance: These results identify novel immune stimulatory effects of C. jejuni sialylation, which may be important in inducing cross-reactive humoral responses that cause GBS.
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- 2012
17. Novel B-lymphocyte-deleting agents for the treatment of autoimmune diseases: induction of the mitochondrial pathway of apoptosis
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Silverman, G and Goodyear, CS
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Poster Presentation - Published
- 2003
18. Large expert-curated database for benchmarking document similarity detection in biomedical literature search
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Zeineb, Zian, Brown, Peter, Tan, Aik-Choon, El-Esawi, Mohamed A., Liehr, Thomas, Blanck, Oliver, Gladue, Douglas P., Almeida, Gabriel M. F., Cernava, Tomislav, Sorzano, Carlos O., Yeung, Andy W. K., Engel, Michael S., Chandrasekaran, Arun Richard, Muth, Thilo, Staege, Martin S., Daulatabad, Swapna V., Widera, Darius, Zhang, Junpeng, Meule, Adrian, Honjo, Ken, Pourret, Olivier, Yin, Cong-Cong, Zhang, Zhongheng, Cascella, Marco, Flegel, Willy A., Goodyear, Carl S., Raaij, Mark J. van, Bukowy-Bieryllo, Zuzanna, Campana, Luca G., Kurniawan, Nicholas A., Lalaouna, David, Hüttner, Felix J., Ammerman, Brooke A., Ehret, Felix, Cobine, Paul A., Tan, Ene-Choo, Han, Hyemin, Xia, Wenfeng, McCrum, Christopher, Dings, Ruud P. M., Marinello, Francesco, Nilsson, Henrik, Nixon, Brett, Voskarides, Konstantinos, Yang, Long, Costa, Vincent D., Bengtsson-Palme, Johan, Bradshaw, William, Grimm, Dominik G., Kumar, Nitin, Martis, Elvis, Prieto, Daniel, Sabnis, Sandeep C., Amer, Said E. D. R., Liew, Alan W. C., Perco, Paul, Rahimi, Farid, Riva, Giuseppe, Zhang, Chongxing, Devkota, Hari P., Ogami, Koichi, Basharat, Zarrin, Fierz, Walter, Siebers, Robert, Tan, Kok-Hian, Boehme, Karen A., Brenneisen, Peter, Brown, James A. L., Dalrymple, Brian P., Harvey, David J., Ng, Grace, Werten, Sebastiaan, Bleackley, Mark, Dai, Zhanwu, Dhariwal, Raman, Gelfer, Yael, Hartmann, Marcus D., Miotla, Pawel, Tamaian, Radu, Govender, Pragashnie, Gurney-Champion, Oliver J., Kauppila, Joonas H., Zhang, Xiaolei, Echeverría, Natalia, Subhash, Santhilal, Sallmon, Hannes, Tofani, Marco, Bae, Taeok, Bosch, Oliver, Cuív, Páraic O., Danchin, Antoine, Diouf, Barthelemy, Eerola, Tuomas, Evangelou, Evangelos, Filipp, Fabian V., Klump, Hannes, Kurgan, Lukasz, Smith, Simon S., Terrier, Olivier, Tuttle, Neil, Ascher, David B., Janga, Sarath C., Schulte, Leon N., Becker, Daniel, Browngardt, Christopher, Bush, Stephen J., Gaullier, Guillaume, Ide, Kazuki, Meseko, Clement, Werner, Gijsbert D. A., Zaucha, Jan, Al-Farha, Abd A., Greenwald, Noah F., Popoola, Segun I., Rahman, Md Shaifur, Xu, Jialin, Yang, Sunny Y., Hiroi, Noboru, Alper, Ozgul M., Baker, Chris I., Bitzer, Michael, Chacko, George, Debrabant, Birgit, Dixon, Ray, Forano, Evelyne, Gilliham, Matthew, Kelly, Sarah, Klempnauer, Karl-Heinz, Lidbury, Brett A., Lin, Michael Z., Lynch, Iseult, Ma, Wujun, Maibach, Edward W., Mather, Diane E., Nandakumar, Kutty S., Ohgami, Robert S., Parchi, Piero, Tressoldi, Patrizio, Xue, Yu, Armitage, Charles, Barraud, Pierre, Chatzitheochari, Stella, Coelho, Luis P., Diao, Jiajie, Doxey, Andrew C., Hu, Pingzhao, Kaiser, Stefan, Mitchell, Kate M., Salama, Mohamed F., Shabalin, Ivan G., Song, Haijun, Stevanovic, Dejan, Yadollahpour, Ali, Zeng, Erliang, Zinke, Katharina, Alimba, C. G., Beyene, Tariku J., Cao, Zehong, Chan, Sherwin S., Gatchell, Michael, Kleppe, Andreas, Piotrowski, Marcin, Torga, Gonzalo, Woldesemayat, Adugna A., Cosacak, Mehmet I., Haston, Scott, Ross, Stephanie A., Williams, Richard, Wong, Alvin, Abramowitz, Matthew K., Effiong, Andem, Lee, Senhong, Abid, Muhammad Bilal, Agarabi, Cyrus, Alaux, Cedric, Albrecht, Dirk R., Atkins, Gerald J., Beck, Charles R., Bonvin, A. M. J. J., Bourke, Emer, Brand, Thomas, Braun, Ralf J., Bull, James A., Cardoso, Pedro, Carter, Dee, Delahay, Robin M., Ducommun, Bernard, Duijf, Pascal H. G., Epp, Trevor, Eskelinen, Eeva-Liisa, Fallah, Mazyar, Farber, Debora B., Fernandez-Triana, Jose, Feyerabend, Frank, Florio, Tullio, Friebe, Michael, Furuta, Saori, Gabrielsen, Mads, Gruber, Jens, Grybos, Malgorzata, Han, Qian, Heinrich, Michael, Helanterä, Heikki, Huber, Michael, Jeltsch, Albert, Jiang, Fan, Josse, Claire, Jurman, Giuseppe, Kamiya, Haruyuki, Keersmaecker, Kim de, Kristiansson, Erik, Leeuw, Frank-Erik de, Li, Jiuyong, Liang, Shide, Lopez-Escamez, Jose A., Lopez-Ruiz, Francisco J., Marchbank, Kevin J., Marschalek, Rolf, Martín, Carmen S., Miele, Adriana E., Montagutelli, Xavier, Morcillo, Esteban, Nicoletti, Rosario, Niehof, Monika, O’Toole, Ronan, Ohtomo, Toshihiko, Oster, Henrik, Palma, Jose-Alberto, Paterson, Russell, Peifer, Mark, Portilla, Maribel, Portillo, M. C., Pritchard, Antonia L., Pusch, Stefan, Raghava, Gajendra P. S., Roberts, Nicola J., Ross, Kehinde, Schuele, Birgitt, Sergeant, Kjell, Shen, Jun, Stella, Alessandro, Sukocheva, Olga, Uversky, Vladimir N., Vanneste, Sven, Villet, Martin H., Viveiros, Miguel, Vorholt, Julia A., Weinstock, Christof, Yamato, Masayuki, Zabetakis, Ioannis, Zhao, Xin, Ziegler, Andreas, Aizat, Wan M., Atlas, Lauren, Bridges, Kristina M., Chakraborty, Sayan, Deschodt, Mieke, Domingues, Helena S., Esfahlani, Shabnam S., Falk, Sebastian, Guisado, J. L., Kane, Nolan C., Kueberuwa, Gray, Lau, Colleen L., Liang, Dai, Liu, Enwu, Luu, Andreas M., Ma, Chuang, Ma, Lisong, Moyer, Robert, Norris, Adam D., Panthee, Suresh, Parsons, Jerod R., Peng, Yousong, Pinto, Inês Mendes, Reschke, Cristina R., Sillanpää, Elina, Stewart, Christopher J., Uhle, Florian, Yang, Hui, Zhou, Kai, Zhu, Shu, Ashry, Mohamed, Bergsland, Niels, Berthold, Maximilian, Chen, Chang-Er, Colella, Vito, Cuypers, Maarten, Eskew, Evan A., Fan, Xiao, Gajda, Maksymilian, Gonzálezlez-Prendes, Rayner, Goodin, Amie, Graham, Emily B., Groen, Ewout J. N., Gutiérrez-Sacristán, Alba, Habes, Mohamad, Heffler, Enrico, Higginbottom, Daniel B., Janzen, Thijs, Jayaraman, Jayakumar, Jibb, Lindsay A., Jongen, Stefan, Kinyanjui, Timothy, Koleva-Kolarova, Rositsa G., Li, Zhixiu, Liu, Yu-Peng, Lund, Bjarte A., Lussier, Alexandre A., Ma, Liping, Mier, Pablo, Moore, Matthew D., Nagler, Katja, Orme, Mark W., Pearson, James A., Prajapati, Anilkumar S., Saito, Yu, Tröder, Simon E., Uchendu, Florence, Verloh, Niklas, Voutchkova, Denitza D., Abu-Zaid, Ahmed, Bakkach, Joaira, Baumert, Philipp, Dono, Marcos, Hanson, Jack, Herbelet, Sandrine, Hobbs, Emma, Kulkarni, Ameya, Kumar, Narendra, Liu, Siqi, Loft, Nikolai D., Reddan, Tristan, Senghore, Thomas, Vindin, Howard, Xu, Haotian, Bannon, Ross, Chen, Branson, Cheung, Johnny T. K., Cooper, Jeffrey, Esnakula, Ashwini K., Feghali, Karine A., Ghelardi, Emilia, Gnasso, Agostino, Horbar, Jeffrey, Lai, Hei M., Li, Jian, Ma, Lan, Ma, Ruiyan, Pan, Zihang, Peres, Marco A., Pranata, Raymond, Seow, Esmond, Sydes, Matthew, Testoni, Ines, Westermair, Anna L., Yang, Yongliang, Afnan, Masoud, Albiol, Joan, Albuquerque, Lucia G., Amiya, Eisuke, Amorim, Rogerio M., An, Qianli, Andersen, Stig U., Aplin, John D., Argyropoulos, Christos, Asmann, Yan W., Assaeed, Abdulaziz M., Atanasov, Atanas G., Atchison, David A., Avery, Simon V., Avillach, Paul, Baade, Peter D., Backman, Lars, Badie, Christophe, Baldi, Alfonso, Ball, Elizabeth, Bardot, Olivier, Barnett, Adrian G., Basner, Mathias, Batra, Jyotsna, Bazanova, O. M., Beale, Andrew, Beddoe, Travis, Bell, Melanie L., Berezikov, Eugene, Berners-Price, Sue, Bernhardt, Peter, Berry, Edward, Bessa, Theolis B., Billington, Craig, Birch, John, Blakely, Randy D., Blaskovich, Mark A. T., Blum, Robert, Boelaert, Marleen, Bogdanos, Dimitrios, Bosch, Carles, Bourgoin, Thierry, Bouvard, Daniel, Boykin, Laura M., Bradley, Graeme, Braun, Daniel, Brownlie, Jeremy, Brühl, Albert, Burt, Austin, Butler, Lisa M., Byrareddy, Siddappa N., Byrne, Hugh J., Cabantous, Stephanie, Calatayud, Sara, Candal, Eva, Carlson, Kimberly, Casillas, Sònia, Castelvetro, Valter, Caswell, Patrick T., Cavalli, Giacomo, Cerovsky, Vaclav, Chagoyen, Monica, Chen, Chang-Shi, Chen, Dong F., Chen, Hao, Chen, Hui, Chen, Jui-Tung, Chen, Yinglong, Cheng, Changxiu, Cheng, Jianlin, Chinapaw, Mai, Chinopoulos, Christos, Cho, William C. S., Chong, Lillian, Chowdhury, Debashish, Chwalibog, Andre, Ciresi, A., Cockcroft, Shamshad, Conesa, Ana, Cook, Penny A., Cooper, David N., Coqueret, Olivier, Corea, Enoka M., Costa, Elisio, Coupland, Carol, Crawford, Stephanie Y., Cruz, Aparecido D., Cui, Huijuan, Cui, Qiang, Culver, David C., D’Angiulli, Amedeo, Dahms, Tanya E. S., Daigle, France, Dalgleish, Raymond, Danielsen, Håvard E., Darras, Sébastien, Davidson, Sean M., Day, David A., Degirmenci, Volkan, Demaison, Luc, Devriendt, Koenraad, Ding, Jiandong, Dogan, Yunus, Dong, X. C., Donner, Claudio F., Dressick, Walter, Drevon, Christian A., Duan, Huiling, Ducho, Christian, Dumaz, Nicolas, Dwarakanath, Bilikere S., Ebell, Mark H., Eisenhardt, Steffen, Elkum, Naser, Engel, Nadja, Erickson, Timothy B., Fairhead, Michael, Faville, Marty J., Fejzo, Marlena S., Festa, Fernanda, Feteira, Antonio, Flood-Page, Patrick, Forsayeth, John, Fox, Simon A., Franks, Steven J., Frentiu, Francesca D., Frilander, Mikko J., Fu, Xinmiao, Fujita, Satoshi, Galea, Ian, Galluzzi, Luca, Gani, Federica, Ganpule, Arvind P., García-Alix, Antonio, Gedye, Kristene, Giordano, Maurizio, Giunta, Cecilia, Gleeson, Paul A., Goarant, Cyrille, Gong, Haipeng, Gora, Diop, Gough, Michael J., Goyal, Ravinder, Graham, Kathryn E., Grande-Pérez, Ana, Graves, Patricia M., Greidanus, Harm, Grice, Darren, Grunau, Christoph, Gumulya, Yosephine, Guo, Yabin, Gurevich, Vsevolod V., Gusev, Oleg, Hacker, Elke, Hage, Steffen R., Hagen, Guy, Hahn, Steven, Haller, Dagmar M., Hammerschmidt, Sven, Han, Jianwei, Han, Renzhi, Handfield, Martin, Hapuarachchi, Hapuarachchige C., Harder, Timm, Hardingham, Jennifer E., Heck, Michelle, Heers, Marcel, Hew, Khe F., Higuchi, Yohei, Hilaire, Cynthia St, Hilton, Rachel, Hodzic, Enisa, Hone, Andrew, Hongoh, Yuichi, Hu, Guoku, Huber, Heinz P., Hueso, Luis E., Huirne, Judith, Hurt, Lisa, Idborg, Helena, Ikeo, Kazuho, Ingley, Evan, Jakeman, Philip M., Jensen, Arne, Jia, Hong, Jia, Husen, Jia, Shuqin, Jiang, Jianping, Jiang, Xingyu, Jin, Yi, Jo, Daehyun, Johnson, Andrew M., Johnston, Marie, Jonscher, Karen R., Jorens, Philippe G., Jorgensen, Jens O. L., Joubert, Johan W., Jung, Sin-Ho, Junior, Antonio M., Kahan, Thomas, Kamboj, Sunjeev K., Kang, Yong-Kook, Karamanos, Yannis, Karp, Natasha A., Kelly, Ryan, Kenna, Ralph, Kennedy, Jonathan, Kersten, Birgit, Khalaf, Roy A., Khalid, Javaria M., Khatlani, T., Khider, Tarig, Kijanka, Gregor S., King, Sarah R. B., Kluz, Tomasz, Knox, Paul, Kobayashi, Tatsuya, Koch, Karl-Wilhelm, Kohonen-Corish, Maija R. J., Kong, Xiangpeng, Konkle-Parker, Deborah, Korpela, Kalevi M., Kostrikis, Leondios G., Kraiczy, Peter, Kratz, Harald, Krause, Günter, Krebsbach, Paul H., Kristensen, Søren R., Kumari, Prerna, Kunimatsu, Akira, Kurdak, Hatice, Kwon, Young D., Lachat, Carl, Lagisz, Malgorzata, Laky, Brenda, Lammerding, Jan, Lange, Matthias, Larrosa, Mar, Laslett, Andrew L., LeClair, Elizabeth E., Lee, Kyung-Woo, Lee, Ming-Yih, Lee, Moon-Soo, Li, Genyuan, Li, Jiansheng, Lieb, Klaus, Lim, Yau Y., Lindsey, Merry L., Line, Paul-Dag, Liu, Dengcai, Liu, Fengbin, Liu, Haiyan, Liu, Hongde, Lloyd, Vett K., Lo, Te-Wen, Locci, Emanuela, Loidl, Josef, Lorenzen, Johan, Lorkowski, Stefan, Lovell, Nigel H., Lu, Hua, Lu, Wei, Lu, Zhiyong, Luengo, Gustavo S., Lundh, Lars-Gunnar, Lysy, Philippe A., Mabb, Angela, Mack, Heather G., Mackey, David A., Mahdavi, S. R., Maher, Pamela, Maher, Toby, Maity, Sankar N., Malgrange, Brigitte, Mamoulakis, Charalampos, Mangoni, Arduino A., Manke, Thomas, Manstead, Antony S. R., Mantalaris, Athanasios, Marsal, Jan, Marschall, Hanns-Ulrich, Martin, Francis L., Martinez-Raga, Jose, Martinez-Salas, Encarnacion, Mathieu, Daniel, Matsui, Yoichi, Maza, Elie, McCutcheon, James E., McKay, Gareth J., McMillan, Brian, McMillan, Nigel, Meads, Catherine, Medina, Loreta, Merrick, B. Alex, Metzger, Dennis W., Meunier, Frederic A., Michaelis, Martin, Micheau, Olivier, Mihara, Hisaaki, Mintz, Eric M., Mizukami, Takuo, Moalic, Yann, Mohapatra, D. P., Monteiro, Antonia, Montes, Matthieu, Moran, John V., Morozov, Sergey Y., Mort, Matthew, Murai, Noriyuki, Murphy, Denis J., Murphy, Susan K., Murray, Shauna A., Naganawa, Shinji, Nammi, Srinivas, Nasios, Grigorios, Natoli, Roman M., Nguyen, Frederique, Nicol, Christine, Nieuwerburgh, Filip van, Nilsen, Erlend B., Nobile, Clarissa J., O’Mahony, Margaret, Ohlsson, Sophie, Olatunbosun, Oluremi, Olofsson, Per, Ortiz, Alberto, Ostrikov, Kostya, Otto, Siegmar, Outeiro, Tiago F., Ouyang, Songying, Paganoni, Sabrina, Page, Andrew, Palm, Christoph, Paradies, Yin, Parsons, Michael H., Parsons, Nick, Pascal, Pigny, Paul, Elisabeth, Peckham, Michelle, Pedemonte, Nicoletta, Pellizzon, Michael A., Petrelli, M., Pichugin, Alexander, Pinto, Carlos J. 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A., Williams, Brendan A., Workman, Alan D., Xiang, Tingxiu, Xie, Li-Xin, Xu, Jun, Xu, Taosheng, Yang, Chongjun, Yoon, Jihoon G., Yuan, Christina M., Zaritsky, Arno, Zhang, Yao, Zhao, Haochen, Zuckerman, Hannah, Lyu, Ran, Pullan, Wayne, Zhou, Yaoqi, Gobet, Angélique, Sadoine, Margaux L., Ontwikkelingspsychologie (Psychologie, FMG), British Lung Foundation, Brown, P, Zhou, Y, Tan, A, El-Esawi, M, Liehr, T, Blanck, O, Gladue, D, Almeida, G, Cernava, T, Sorzano, C, Yeung, A, Engel, M, Chandrasekaran, A, Muth, T, Staege, M, Daulatabad, S, Widera, D, Zhang, J, Meule, A, Honjo, K, Pourret, O, Yin, C, Zhang, Z, Cascella, M, Flegel, W, Goodyear, C, van Raaij, M, Bukowy-Bieryllo, Z, Campana, L, Kurniawan, N, Lalaouna, D, Huttner, F, Ammerman, B, Ehret, F, Cobine, P, Tan, E, Han, H, Xia, W, Mccrum, C, Dings, R, Marinello, F, Nilsson, H, Nixon, B, Voskarides, K, Yang, L, Costa, V, Bengtsson-Palme, J, Bradshaw, W, Grimm, D, Kumar, N, Martis, E, Prieto, D, Sabnis, S, Amer, S, Liew, A, Perco, P, 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Mechanisms, Pediatric surgery, APH - Methodology, ACS - Atherosclerosis & ischemic syndromes, RELISH Consortium [Member of the MPIB: Lucas Molleman], Kostrikis, Leondios G. [0000-0002-5340-7109], Tan, AC, El-Esawi, MA, Gladue, DP, Almeida, GMF, Sorzano, CO, Yeung, AWK, Engel, MS, Chandrasekaran, AR, Staege, MS, Daulatabad, SV, Yin, CC, Flegel, WA, Goodyear, CS, van Raaij, MJ, Campana, LG, Kurniawan, NA, Huttner, FJ, Ammerman, BA, Cobine, PA, Tan, EC, Han, HM, Xia, WF, McCrum, C, Dings, RPM, Costa, VD, Grimm, DG, Sabnis, SC, Amer, SEDR, Liew, AWC, Zhang, CX, Devkota, HP, Tan, KH, Boehme, KA, Brown, JAL, Dalrymple, BP, Harvey, DJ, Dai, ZW, Hartmann, MD, Gurney-Champion, OJ, Kauppila, JH, Zhang, XL, Cuiv, PO, Filipp, FV, Smith, SS, Ascher, DB, Janga, SC, Schulte, LN, Bush, SJ, Werner, GDA, Al-Farha, AA, Greenwald, NF, Popoola, SI, Rahman, MS, Xu, JL, Yang, SY, Alper, OM, Baker, CI, Klempnauer, KH, Lidbury, BA, Lin, MZ, Ma, WJ, Maibach, EW, Mather, DE, Nandakumar, KS, Ohgami, RS, Coelho, LP, Doxey, AC, Hu, PZ, Mitchell, KM, Salama, MF, Shabalin, IG, Song, HJ, Zeng, EL, Alimba, CG, Beyene, TJ, Cao, ZH, Chan, SS, Woldesemayat, AA, Cosacak, MI, Ross, SA, Abramowitz, MK, Lee, SH, Abid, MB, Albrecht, DR, Atkins, GJ, Beck, CR, Bonvin, AMJJ, Braun, RJ, Bull, JA, Delahay, RM, Duijf, PHG, Eskelinen, EL, Farber, DB, Leeuw, FE, Lopez-Escamez, JA, Lopez-Ruiz, FJ, Marchbank, KJ, Martin, CS, Miele, AE, Palma, JA, Portillo, MC, Pritchard, AL, Raghava, GPS, Roberts, NJ, Uversky, VN, Villet, MH, Vorholt, JA, Aizat, WM, Bridges, KM, Domingues, HS, Esfahlani, SS, Guisado, JL, Kane, NC, Lau, CL, Luu, AM, Ma, LS, Norris, AD, Parsons, JR, Pinto, IM, Reschke, CR, Stewart, CJ, Chen, CE, Eskew, EA, Graham, EB, Groen, EJN, Higginbottom, DB, Jibb, LA, Koleva-Kolarova, RG, Liu, YP, Lund, BA, Lussier, AA, Moore, MD, Orme, MW, Pearson, JA, Prajapati, AS, Troder, SE, Voutchkova, DD, Liu, SQ, Loft, ND, Xu, HT, Cheung, JTK, Esnakula, AK, Feghali, KA, Lai, HM, Ma, RY, Pan, ZH, Peres, MA, Westermair, AL, Albuquerque, LG, Amorim, RM, Andersen, SU, Aplin, JD, Asmann, YW, Assaeed, AM, Atanasov, AG, Atchison, DA, Avery, SV, Baade, PD, Barnett, AG, Bazanova, OM, Bell, ML, Bessa, TB, Blakely, RD, Blaskovich, MAT, Boykin, LM, Butler, LM, Byrareddy, SN, Byrne, HJ, Caswell, PT, Chen, CS, Chen, DF, Chen, JT, Chen, YL, Cheng, CX, Cheng, JL, Cho, WCS, Cook, PA, Cooper, DN, Corea, EM, Crawford, SY, Cruz, AD, Cui, HJ, Culver, DC, Dahms, TES, Danielsen, HE, Davidson, SM, Day, DA, Dong, XC, Donner, CF, Drevon, CA, Duan, HL, Dwarakanath, BS, Ebell, MH, Erickson, TB, Faville, MJ, Fejzo, MS, Fox, SA, Franks, SJ, Frentiu, FD, Frilander, MJ, Fu, XM, Ganpule, AP, Gleeson, PA, Gong, HP, Gough, MJ, Graham, KE, Graves, PM, Guo, YB, Gurevich, VV, Hage, SR, Haller, DM, Han, JW, Hapuarachchi, HC, Hardingham, JE, Hew, KF, St Hilaire, C, Hu, GK, Huber, HP, Hueso, LE, Jakeman, PM, Jia, HS, Jia, SQ, Jiang, JP, Jiang, XY, Johnson, AM, Jonscher, KR, Jorens, PG, Jorgensen, JOL, Joubert, JW, Jung, SH, Junior, AM, Kamboj, SK, Kang, YK, Karp, NA, Khalaf, RA, Khalid, JM, Kijanka, GS, King, SRB, Koch, KW, Kohonen-Corish, MRJ, Korpela, KM, Kostrikis, LG, Krebsbach, PH, Kristensen, SR, Kwon, YD, Laslett, AL, LeClair, EE, Lee, KW, Lee, MY, Lee, MS, Li, GY, Li, JS, Lim, YY, Lindsey, ML, Line, PD, Liu, DC, Liu, FB, Liu, HY, Liu, HD, Lloyd, VK, Lo, TW, Lovell, NH, Lu, ZY, Luengo, GS, Lundh, LG, Lysy, PA, Mack, HG, Mackey, DA, Mahdavi, SR, Maity, SN, Mangoni, AA, Manstead, ASR, Marschall, HU, Martin, FL, McCutcheon, JE, Mckay, GJ, McMillan, B, McMillan, N, Merrick, BA, Metzger, DW, Meunier, FA, Mintz, EM, Mohapatra, DP, Moran, JV, Morozov, SY, Murphy, DJ, Murphy, SK, Murray, SA, Natoli, RM, Nilsen, EB, Nobile, CJ, Outeiro, TF, Parsons, MH, Pellizzon, MA, Pinto, CJC, Plevris, JN, Quinn, GP, Quinn, TJ, Reiling, JH, Riddick, EW, Roach, NW, Roberts, DD, Roobol, MJ, Rowe, JA, Sack, GH, Seib, KL, Shi, HP, Shin, JS, Smeets, PAM, So, PW, Sonenshine, DE, Song, JN, Speakman, JR, Srinivasan, MV, Stabile, LP, Steadman, KJ, Stephens, AW, Stewart, DI, Stoynova, NV, Suarez, OM, Sumant, AV, Summers, MJ, Tang, HX, Tebbe, CC, Telfer, EE, Teodorczyk-Injeyan, JA, Thrift, AG, Tjahjono, DH, del Tredici, AL, Udo, EE, Vandenbroucke, RE, Veiga, FH, Vesk, PA, Victor, VM, Vohl, MC, Voolstra, CR, Walsh, LJ, Wang, AY, Wen, JC, White, EP, Wojan, TR, Wong, BM, Wu, TW, Xiao, XS, Xu, JW, Xu, JP, Yang, EC, Yang, SQ, Ye, YZ, Ye, ZQ, Yuan, GC, Yuh, CH, Zhang, YK, Zhang, YS, Zhang, ZY, Aanei, CM, Atack, JM, Biedermann, PHW, den Bos, W, Boudreau, SA, Bramoweth, AD, Cao, ZX, Cheng, SQ, Chung, HJ, Chavez-Fumagalli, MA, Costa, BM, Dean, LT, Denzel, MS, Dlamini, SV, Dudley, KJ, Emmrich, JV, Eustace, AJ, Falter-Wagner, CM, Gao, JZ, Gill, MR, Grundle, DS, Ikonomopoulou, MP, Johnson, DM, Kaye, LK, Khan, MM, Kim, YM, Kish, JK, Kugler, JM, Lauschke, VM, Li, BL, Lim, CJ, Liu, XD, Lu, JJ, McGarrigle, CA, Mondal, SR, Van de Mortel, T, Moss, WN, Moultos, OA, Neumann, PA, Nie, JY, Nie, YJ, Oldenmenger, WH, Ou, JH, Pearce, SP, Pelleri, MC, Pereira, JL, Pinto, KA, Podolsky, IM, Qi, DC, Qi, XS, Raikou, VD, Rotge, JY, Rowe, AD, Schuon, RA, Smout, MJ, Song, CJ, Srivastava, RK, Tai, CNP, Tao, WY, Tian, CF, 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Univ Calif Irvine, Univ Hosp Leuven, Chongqing Med Univ, Childrens Hosp Kings Daughters, China Three Gorges Univ, and Xiangtan Univ
- Subjects
Technology and Engineering ,SCIENTIFIC SEARCH ,Expert-curated database ,Biokemia, solu- ja molekyylibiologia - Biochemistry, cell and molecular biology ,Databases ,RElevant LIterature SearcH consortium ,Medicine and Health Sciences ,Biomedical research ,benchmarking ,Biology ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Settore MED/42 - IGIENE GENERALE E APPLICATA ,database ,Computer. Automation ,Science & Technology ,0804 Data Format ,relisch ,Scientific research in health sciences ,Mathematics and Statistics ,litearture search ,relisch , database ,biomedical research ,Biomedical literature ,Original Article ,RELISH ,Mathematical & Computational Biology ,RECOMMENDER-SYSTEMS ,Life Sciences & Biomedicine ,Mathematics ,0807 Library and Information Studies - Abstract
Made available in DSpace on 2020-12-11T01:57:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-10-29 Griffith University Gowonda HPC Cluster Queensland Cyber Infrastructure Foundation Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research. 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London, England La Trobe Univ, Anim Plant & Soil Sci, Melbourne, Vic, Australia Univ Arizona, Epidemiol & Biostat, Tucson, AZ USA Univ Groningen, Univ Med Ctr Groningen, ERIBA, Groningen, Netherlands Univ Gothenburg, Inst Clin Sci, Dept Radiat Phys, Gothenburg, Sweden SUNY Upstate Med Univ, Biochem & Mol Biol, Syracuse, NY 13210 USA Fundacao Oswaldo Cruz, Ctr Pesquisas Goncalo Moniz, Salvador, Bahia, Brazil Inst Environm Sci & Res ESR, Food Water & Environm Microbiol, Christchurch, New Zealand Univ Otago, Food Sci, Dunedin, New Zealand Florida Atlantic Univ, Biomed Sci, Boca Raton, FL 33431 USA Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia Univ Hosp Wurzburg, Inst Clin Neurobiol, Wurzburg, Germany Inst Trop Med, Publ Hlth, Antwerp, Belgium Univ Thessaly, Sch Hlth Sci, Fac Med, Dept Rheumatol & Clin Immunol, Larisa, Greece Univ Basel, UZB Univ Ctr Dent Med, Dept Orthodont & Pediat Dent, Basel, Switzerland Sorbonne Univ, Museum Natl Hist Nat, Inst Systemat Evolut 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Montpellier, CNRS, Inst Human Genet, Montpellier, France Czech Acad Sci, Inst Organ Chem & Biochem, Prague, Czech Republic CSIC, Natl Ctr Biotechnol CNB, Computat Syst Biol Grp, Madrid, Spain Natl Cheng Kung Univ, Dept Biochem & Mol Biol, Tainan, Taiwan Harvard Med Sch, Schepens Eye Res Inst, Ophthalmol, Boston, MA 02115 USA Lanzhou Univ, Hosp 2, Dept Gen Surg, Lanzhou, Gansu, Peoples R China Univ Technol Sydney, Sch Life Sci, Sydney, NSW, Australia JT Chen Clin, Gynecol, Tokyo, Japan Univ Western Australia, Sch Agr & Environm, Perth, WA, Australia Beijing Normal Univ, Fac Geog Sci, Beijing, Peoples R China Univ Missouri, Elect Engn & Comp Sci, Columbia, MO USA Vrije Univ Amsterdam Med Ctr, Amsterdam Publ Hlth Res Inst, Dept Publ & Occupat Hlth, Amsterdam, Netherlands Semmelweis Univ, Med Biochem, Budapest, Hungary Queen Elizabeth Hosp, Dept Clin Oncol, Hong Kong, Peoples R China Univ Pittsburgh, Chem, Pittsburgh, PA USA GB Pant Inst Post Grad Med Educ & Res, Neurol, New Delhi, India Univ Copenhagen, Vet & Anim Sci, Copenhagen, Denmark Univ Palermo, Biomed Dept Internal & Specialist Med DIBIMIS, Sect Endocrinol, Palermo, Italy UCL, NPP, London, England Univ Florida, Microbiol & Cell Sci, Gainesville, FL USA Univ Salford, Sch Hlth Sci, Manchester, Lancs, England Cardiff Univ, Inst Med Genet, Cardiff, S Glam, Wales INSERM, ICO Canc Ctr, Angers, France Univ Colombo, Fac Med, Microbiol, Colombo, Sri Lanka Beijing Univ Chinese Med, Sch Chinese Mat Med, Beijing, Peoples R China Univ Porto, Fac Pharm, Porto, Portugal Univ Nottingham, Div Primary Care, Nottingham, England Univ Illinois, Pharm Syst Outcomes & Policy, Chicago, IL USA Pontificia Univ Catolica Goias, Escola Ciencias Agr & Biol, Goiania, Go, Brazil China Japan Friendship Hosp, Dept Oncol, Beijing, Peoples R China Boston Univ, Chem, Boston, MA 02215 USA Amer Univ, Environm Sci, Washington, DC 20016 USA Carleton Univ, Neurosci, Ottawa, ON, Canada Univ Regina, Chem & Biochem, Regina, SK, Canada Univ Montreal, Microbiolgy, Montreal, PQ, Canada Univ Leicester, Dept Genet & Genome Biol, Leicester, Leics, England Univ Queensland, Sch Agr & Food Sci, Gatton, Qld, Australia CNRS, BIOM, Paris, France UCL, Hatter Cardiovasc Inst, London, England Flinders Univ S Australia, Sci & Engn, Adelaide, SA, Australia Univ Warwick, Engn, Coventry, W Midlands, England Katholieke Univ Leuven, Ctr Human Genet, Leuven, Belgium Fudan Univ, Dept Macromol Sci, Shanghai, Peoples R China Dokuz Eylul Univ, Biol Educ, Izmir, Turkey Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA Mondo Med, Pulm Dis, Borgomanero, Italy US Naval, Res Lab, Ctr Bio Mol Sci & Engn, Washington, DC USA Univ Oslo, Inst Basic Med Sci, Dept Nutr, Oslo, Norway Peking Univ, Dept Mech & Engn Sci, Beijing, Peoples R China Saarland Univ, Dept Pharm Pharmaceut & Med Chem, Saarbrucken, Germany INSERM, Natl Inst Hlth & Med Res, Skin Res Inst, Paris, France Shanghai Proton & Heavy Ion Ctr, Res & Dev, Shanghai, Peoples R China Univ Georgia, Epidemiol, Athens, GA 30602 USA Univ Freiburg, Med Ctr, Dept Plast & Hand Surg, Freiburg, Germany Sidra Med, Res, Doha, Qatar Rostock Univ, Med Ctr, Dept Oral Maxillofacial & Plast Surg, Rostock, Germany Harvard Med Sch, Brigham & Womens Hosp, Emergency Med, Boston, MA 02115 USA AgResearch, Forage Sci, Palmerston North, New Zealand Univ Calif Los Angeles, Med, Los Angeles, CA USA Arizona State Univ, Biodesign Inst, Virginia G Piper Ctr Personalized Diagnost, Tempe, AZ USA Sheffield Hallam Univ, Res Inst, Mat & Engn, Sheffield, S Yorkshire, England Aneurin Bevan Univ Healthboard, Resp Med, Newport, Shrops, England Univ Calif San Francisco, Neurol Surg, San Francisco, CA 94143 USA Univ Western Australia, UWA Dent Sch, Perth, WA, Australia Fordham Univ, Biol Sci, Bronx, NY 10458 USA Univ Helsinki, Inst Biotechnol, Helsinki, Finland Fujian Normal Univ, Coll Life Sci, Fuzhou, Fujian, Peoples R China Univ Fukui, Dept Frontier Fiber Technol & Sci, Fukui, Japan Univ Southampton, Fac Med, Clin & Expt Sci, Southampton, Hants, England Univ Urbino, Dept Biomol Sci, Urbino, Italy Osped San Luigi, Allergol Unit, Turin, Italy Muljibhai Patel Urol Hosp, Dept Urol, Nadiad, Gujarat, India Univ Granada, Stratig & Paleontol, Granada, Spain Massey Univ, Sch Vet Sci, Auckland, New Zealand CNR, High Performance Comp & Networking Inst, Naples, Italy Univ Childrens Hosp Zurich, Div Metab, Zurich, Switzerland Univ Childrens Hosp Zurich, Childrens Res Ctr, Zurich, Switzerland Univ Melbourne, Biochem & Mol Biol, Parkville, Vic, Australia Inst Pasteur, Leptospirosis Res & Expertise Unit, Noumea, New Caledonia Tsinghua Univ, Sch Life Sci, Beijing, Peoples R China Cheikh Anta Diop Univ UCAD, Sci Fac, Biol Anim Dept, Dakar, Senegal Providence Portland Med Ctr, Earle A Chiles Res Inst, Portland, OR USA Agr & Agri Food Canada, Lacombe Res & Dev Ctr, Lacombe, AB, Canada Alberta Innovates, Performance Management & Evaluat, Edmonton, AB, Canada Univ Malaga, CSIC, Inst Hortofruticultura Subtrop Mediterranea La Ma, IHSM,UMA, Malaga, Spain James Cook Univ, Coll Publ Hlth Med & Vet Sci, Cairns, Qld, Australia European Commiss, Joint Res Ctr, Ispra, Italy Univ Montpellier, Montpellier, France CSIRO, Floreat, WA, Australia Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Guangzhou, Guangdong, Peoples R China Vanderbilt Univ, Pharmacol, 221 Kirkland Hall, Nashville, TN 37235 USA RIKEN, KFU RIKEN Translat Genom Unit, Yokohama, Kanagawa, Japan Univ Tubingen, Neurobiol Vocal Commun, Tubingen, Germany Univ Colorado, UCCS Ctr Biofrontiers Inst, Colorado Springs, CO 80907 USA Fred Hutchinson Canc Ctr, Div Basic Sci, Seattle, WA USA Univ Geneva, Fac Med, Primary Care Unit, Geneva, Switzerland Ernst Moritz Arndt Univ Greifswald, Dept Mol Genet & Infect Biol, Greifswald, Germany East China Univ Sci & Technol, Dept Fine Chem, Shanghai, Peoples R China Ohio State Univ, Surg, Columbus, OH 43210 USA Oragenics, R&D, Tampa, FL USA Natl Environm Agcy, Environm Hlth Inst, Singapore, Singapore Friedrich Loeffler Inst, Inst Diagnost Virol, Greifswald, Germany Queen Elizabeth Hosp, Oncol, Woodville, SA, Australia USDA, Emerging Pests & Pathogens Res Unit, Ithaca, NY USA Univ Freiburg, Med Ctr, Dept Neurosurg, Epilepsy Ctr, Freiburg, Germany Univ Hong Kong, Fac Educ, Informat & Technol Studies, Hong Kong, Peoples R China Univ Tokyo, Grad Sch Agr & life Sci, Agr & Environm Biol, Tokyo, Japan Univ Pittsburgh, Dept Med, Pittsburgh Heart Lung & Blood Vasc Med Inst, Pittsburgh, PA USA Guys & St Thomas NHS Fdn Trust, Directorate Transplant Renal & Urol, London, England Univ Sarajevo, Clin Ctr, Clin Heart Blood Vessel & Rheumat Dis, Sarajevo, Bosnia & Herceg Univ Kent, Sch Math Stat & Actuarial Sci, Canterbury, Kent, England Tokyo Inst Technol, Dept Life Sci & Technol, Tokyo, Japan Univ Appl Sci Munich, Laser Ctr Dept Appl Sci & Mechatron, Munich, Germany CIC NanoGUNE, Nanodevices, San Sebastian, Spain Vrije Univ Amsterdam Med Ctr, Gynaecol, Amsterdam, Netherlands Cardiff Univ, Med Sch, Div Populat Med, Cardiff, S Glam, Wales Karolinska Inst, Dept Med, Solna, Sweden Natl Inst Genet, Ctr Informat Biol, Mishima, Shizuoka, Japan Murdoch Univ, Harry Perkins Inst Med Res, Perth, WA, Australia Univ Limerick, Phys Educ & Sport Sci, Limerick, Ireland Ruhr Univ Bochum, Campus Clin Gynecol, Univ Str, Bochum, Germany Southwest Med Univ, Sch Publ Hlth, Epidemiol & Biostat, Luzhou, Sichuan, Peoples R China Beijing Canc Hosp, Minist Educ Beijing, Key Lab Carcinogenesis & Translat Res, Ctr Mol Diagnost, Beijing, Peoples R China Chinese Acad Sci, Chengdu Inst Biol, Herpetol Dept, Chengdu, Sichuan, Peoples R China Key Lab Nano Biol Effects & Safety, Beijing, Peoples R China NIBR, PK Sci, Basel, Switzerland Daejeon St Marys Hosp, Pain Ctr, Daejeon, South Korea Univ Western Ontario, Sch Hlth Studies, London, ON, Canada Univ Aberdeen, Hlth Psychol Grp, Aberdeen, Scotland Univ Colorado, Anesthesiol, Anschutz Med Campus, Boulder, CO 80309 USA Univ Antwerp, UZA Antwerp Univ Hosp, Crit 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Res Ctr, Stem Cell & Regenerat Med, Riyadh, Saudi Arabia Univ Bahri, Ind Pulp & Paper, Khartoum, Sudan Univ Queensland, Mater Med Res Inst, Mater Res Inst, Brisbane, Qld, Australia Colorado State Univ, NREL, Ft Collins, CO 80523 USA Rzeszow Univ Hosp, Ob Gyn Dept, Rzeszow, Poland Univ Leeds, Fac Biol Sci, Leeds, W Yorkshire, England Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA Carl von Ossietzky Univ Oldenburg, Neurosci, Oldenburg, Germany UNSW, St George & Sutherland Clin Sch, Microbiome Res Ctr, Sydney, NSW, Australia NYU, Sch Med, Dept Biochem, New York, NY 10016 USA NYU, Sch Med, Dept Mol Pharmacol, New York, NY USA Univ Mississippi, Med Ctr, Med Infect Dis, Jackson, MS 39216 USA Tampere Univ, Fac Social Sci Psychol, Tampere, Finland Univ Cyprus, Dept Biol Sci, Nicosia, Cyprus Goethe Univ, Inst Med Microbiol & Infect Control, Frankfurt, Germany Charite Med Univ Berlin, Inst Radiol, Berlin, Germany Univ Cologne, Univ Hosp Cologne, Internal Med 1, Cologne, Germany Univ Calif Los Angeles, Sch Dent, Sect Periodont, Los Angeles, CA 90024 USA Aalborg Univ Hosp, Dept Clin Biochem, Aalborg, Denmark Manipal Acad Higher Educ, Pharm Practice, Manipal, Karnataka, India Univ Tokyo, Inst Med Sci, Dept Radiol, Tokyo, Japan Cukurova Univ, Family Med, Fac Med, Adana, Turkey Catholic Univ Korea, Coll Med, Dept Humanities & Social Med, Seoul, South Korea Univ Ghent, Food Technol Safety & Hlth, Ghent, Belgium UNSW Sydney, Sch Biol Earth & Environm Sci BEES, Sydney, NSW, Australia St Vincent Shoulder & Sports Clin, Res Unit, Vienna, Austria Cornell Univ, Biomed Engn, Ithaca, NY USA Leibniz Inst Plant Genet & Crop Plant Res IPK, Res Grp Bioinformat & Informat Technol, Gatersleben, Germany Univ Europea Madrid, Sch Doctoral Studies, Madrid, Spain CSIRO Mfg, Biomed Mfg, Melbourne, Vic, Australia Depaul Univ, Biol Sci, Chicago, IL 60604 USA Konkuk Univ, Dept Anim Sci & Technol, Seoul, South Korea Chang Gung Univ, Grad Inst Med Mechatron, Taoyuan, Taiwan Korea Univ, Coll Med, Psychiat, Seoul, South Korea Princeton Univ, Chem, Princeton, NJ 08544 USA Henan Univ Chinese Med, Henan Key Lab Chinese Med Resp Dis, Zhengzhou, Henan, Peoples R China Univ Med Ctr Mainz, Dept Psychiat & Psychotherapy, Mainz, Germany Monash Univ Malaysia, Sch Sci, Selangor, Malaysia Univ Mississippi, Med Ctr, Physiol & Biophys, Jackson, MS 39216 USA Univ Oslo, Dept Transplantat Med, Oslo, Norway Sichuan Agr Univ, Triticeae Res Inst, Yaan, Sichuan, Peoples R China Guangzhou Univ Chinese Med, Gastroenterol, Guangzhou, Guangdong, Peoples R China Southeast Univ, Sch Biol Sci & Med Engn, Suzhou, Jiangsu, Peoples R China Mt Allison Univ, Biol, Sackville, NB, Canada Ithaca Coll, Biol, Ithaca, NY 14850 USA Univ Cagliari, Dept Med Sci & Publ Hlth, Monserrato, Italy Univ Vienna, Chromosome Biol, Vienna, Austria Univ Zurich, Nephrol, Zurich, Switzerland Friedrich Schiller Univ, Inst Nutr Sci, Jena, Germany UNSW Sydney, Grad Sch Biomed Engn, Sydney, NSW, Australia Tulane Univ, Sch Med, Biochem & Mol Biol, 1430 Tulane Ave, New Orleans, LA 70112 USA NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA NIH, NCBI, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA LOreal Res & Innovat, Aulnay Sous Bois, France Lund Univ, Dept Psychol, Malmo, Sweden Catholic Univ Louvain, Inst Rech Expt & Clin, Brussels, Belgium Georgia State Univ, Neurosci Inst, Atlanta, GA 30303 USA Univ Melbourne, Ophthalmol, Surg, Parkville, Vic, Australia Univ Western Australia, Ctr Ophthalmol & Visual Sci, Perth, WA, Australia Iran Univ Med Sci, Med Phys, Fac Med, Tehran, Iran Salk Inst Biol Studies, Cellular Neurobiol, La Jolla, CA USA Imperial Coll London, Fibrosis Res Grp, London, England Univ Texas MD Anderson Canc Ctr, Genitourinary Med Oncol, Houston, TX 77030 USA Univ Liege, GIGA Neurosci, Liege, Belgium Univ Crete, Sch Med, Urol, Iraklion, Greece Flinders Univ S Australia, Flinders Med Ctr, Dept Clin Pharmacol, Adelaide, SA, Australia Max Planck Inst Immunobiol & Epigenet, Bioinformat, Breisgau, Germany Cardiff Univ, Sch Psychol, Cardiff, S Glam, Wales Imperial Coll London, Chem Engn, London, England Lund Univ, Skane Univ Hosp, Clin Sci, Malmo, Sweden Sahlgrens Acad, Inst Clin Sci, Dept Mol & Clin Med, Gothenburg, Sweden Univ Cent Lancashire, Sch Pharm & Biomed Sci, Preston, Lancs, England Hosp Univ Doctor Peset, Psychiat & Clin Psychol, Valencia, Spain Ctr Biol Mol Severo Ochoa, Genome Dynam & Funct, Madrid, Spain Unvivers Hosp Lille, Dept Intens Care, Lille, France Kansai Med Univ, Surg, Osaka, Japan Univ Toulouse, Inst Natl Polytech Toulouse, Ecole Natl Super Agron Toulouse, Lab Genom & Biotechnol Fruit, Toulouse, France UiT Arctic Univ Norway, Inst Psychol, Tromsto, Norway Queens Univ, Ctr Publ Hlth, Belfast, Antrim, North Ireland Univ Manchester, Ctr Primary Care & Hlth Serv Res, Manchester, Lancs, England Griffith Univ, Menzies Hlth Inst, Gold Coast, Qld, Australia Anglia Ruskin Univ, FHSCE, Cambridge, England Univ Lleida, Dept Expt Med, Lleida, Spain NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA Albany Med Coll, Immunol & Microbial Dis, Albany, NY 12208 USA Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia Univ Kent, Sch Biosci, Canterbury, Kent, England Univ Bourgogne Franche Comte, INSERM, LNC, UMR 1231, Besancon, France Ritsumeikan Univ, Coll Life Sci, Dept Biotechnol, Shiga, Japan Kent State Univ, Biol Sci, Kent, OH 44242 USA Natl Inst Infect Dis, Dept Safety Res Blood & Biol Prod, Tokyo, Japan European Inst Marine Studies, Lab Microbiol Extreme Environm, Plouzane, France Univ Iowa, Dept Pharmacol, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA Natl Univ Singapore, Biol Sci, Singapore, Singapore Conservatoire Natl Arts & Metiers, Lab GBA, EA4627, Paris, France Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA Lomonosov Moscow State Univ, Belozersky Inst Physicochem Biol, Moscow, Russia Jikei Univ, Sch Med, Dept Mol Biol, Tokyo, Japan Univ South Wales, Genom & Computat Biol, Treforest, Wales Duke Univ, Med Ctr, Obstet & Gynecol, Durham, NC USA Univ Technol Sydney, Climate Change Cluster, Sydney, NSW, Australia Nagoya Univ, Grad Sch Med, Dept Radiol, Nagoya, Aichi, Japan Western Sydney Univ, Sch Sci & Hlth, Sydney, NSW, Australia TEI Epirus, Dept Speech & Language Therapy, Ioannina, Greece Indiana Univ Purdue Univ, Orthopaed Surg, Indianapolis, IN 46202 USA Oniris, Vet Pathol, Nantes, France Royal Vet Coll, Pathobiol & Populat Sci, Hatfield, Herts, England Univ Ghent, Lab Pharmaceut Biotechnol, Ghent, Belgium Norwegian Inst Nat Res, Terr Ecol, Trondheim, Norway Univ Calif Merced, Mol & Cell Biol, Merced, CA USA Univ Dublin, Trinity Coll Dublin, Sch Engn, Ctr Transport Res, Dublin, Ireland Lund Univ, Inst Clin Sci, Nephrol, Malmo, Sweden Univ Birmingham, Mech Engn, Birmingham, W Midlands, England Lund Univ, Inst Clin Sci, OB GYN, Lund, Sweden Fdn Jimenez Diaz Hosp, Nephrol & Hypertens, Madrid, Spain Queensland Univ Technol, Sch Chem Phys & Mech Engn, Brisbane, Qld, Australia Otto von Guericke Univ, Psychol, Magdeburg, Germany Univ Med Ctr Gottingen, Dept Expt Neurodegenerat, Gottingen, Germany Harvard Med Sch, Spaulding Rehabil Hosp, Phys Med & Rehabil, Boston, MA 02115 USA Quadram Inst Biosci, Sci Operat, Norwich, Norfolk, England Ostbayer Tech Hsch Regensburg OTH Regensburg, Regensburg Med Image Comp ReMIC, Regensburg, Germany Deakin Univ, Fac Arts & Educ, Melbourne, Vic, Australia Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England INSERM, Natl Inst Hlth & Med Res, Biochem & Mol Biol, Paris, France Univ Liege, Tax Inst, Liege, Belgium Univ Leeds, Sch Mol & Cellular Biol, Leeds, W Yorkshire, England IRCCS Ist Giannina Gaslini, UOC Genet Med, Genoa, Italy Res Diets Inc, Sci, New Brunswick, NJ USA Univ Perugia, Dept Phys & Geol, Perugia, Italy Walter Reed Natl Mil Med Ctr, Cellular Immunol, Bethesda, MD USA Univ Fed Santa Catarina, Biol Sci Ctr, Microbiol Immunol & Parasitol Dept, Florianopolis, SC, Brazil Univ Edinburgh, Royal Infirm, Ctr Liver & Digest Disorders, Edinburgh, Midlothian, Scotland Orion Pharma, Crit Care Proprietary Prod Div, Espoo, Finland MIT, Dept Civil & Environm Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA Univ Turin, Dept Vet Sci, Turin, Italy Univ G dAnnunzio, Dept Psychol Hlth & Territorial Sci, Chieti, Italy NYU, Sch Med, OB GYN, New York, NY USA Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland Univ Turku, Dept Biol, Turku, Finland Tech Univ Berlin, Bioanalyt, Berlin, Germany Univ Goettingen, Inst Phys Biophys 3, Gottingen, Germany Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Translat Res Adv Therapeut & Innovat Oncol TRACTI, Houston, TX 77030 USA Univ Liege, Life Sci, Liege, Belgium Tarbiat Modares Univ, Fac Med Sci, Dept Toxicol, Tehran, Iran ARS, USDA, Stoneville, MS USA Univ Regensburg, RCI Regensburg Ctr Intervent Immunol, Regensburg, Germany Univ Nottingham, Sch Psychol, Nottingham, England NIH, Pathol Lab, Bethesda, MD 20892 USA Univ Carlos III Madrid, Elect Engn, Madrid, Spain Inst Med Mol, Chem Biol, Lisbon, Portugal Univ Costa Rica, CIET, San Jose, Costa Rica Univ Stavanger, Fac Hlth Sci, Stavanger, Norway Erasmus MC, Urol, Rotterdam, Netherlands Univ Edinburgh, Sch Biol Sci, Edinburgh, Midlothian, Scotland German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Bioinformat & Syst Biol IBIS, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany Leiden Univ, Huygens Kamerlingh Onnes Lab, Leiden, Netherlands Univ Vienna, Nutr Sci, Vienna, Austria Kolling Inst Med Res, Med, St Leonards, NSW, Australia Johns Hopkins Sch Med, Biol Chem, Baltimore, MD USA Univ Montreal, Med Nutr & Microbiome Lab, Montreal, PQ, Canada GlaxoSmithKline, Cell & Gene Therapy, Stevenage, Herts, England Univ Trieste, Life Sci, Trieste, Italy Rhein Westfal TH Aachen, Dept Radiol, Aachen, Germany Univ Duisburg Essen, Univ Hosp Essen, West German Canc Ctr, Dept Med Oncol, Essen, Germany Med Univ Vienna, Obstet & Gynecol, Vienna, Austria FHI 360, Social & Behav Hlth Sci Div, Washington, DC USA KU Leuven VIB, Switch Lab, Leuven, Belgium Bielefeld Univ, Fac Technol, Bielefeld, Germany Capital Med Univ, Beijing Shijitan Hosp, Dept Clin Nutr, Dept Gastrointestinal Surg, Beijing, Peoples R China Meiji Univ, Dept Agr Chem, Kawasaki, Japan Yonsei Univ, Coll Med, Microbiol, Seoul, South Korea Johnson & Johnson EAME, Maidenhead, Berks, England Penn State Coll Med, Pediat, Hershey, PA USA Univ N Carolina, Dept Social Med, Chapel Hill, NC 27515 USA Univ Western Australia, ARC CoE Plant Energy Biol, Perth, WA, Australia Wageningen Univ, Div Human Nutr & Hlth, Wageningen, Netherlands Kings Coll London, Dept Neuroimaging, London, England Univ Murcia, Biochem & Mol Biol, Murcia, Spain Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA Monash Univ, Biochem & Mol Biol, Melbourne, Vic, Australia Chinese Acad Sci, Inst Genet & Dev Biol, Beijing, Peoples R China Univ Pittsburgh, Pharmacol & Chem Biol, Pittsburgh, PA USA Univ Lausanne, Ctr Integrat Genom, Lausanne, Switzerland Univ Queensland, Sch Pharm, Brisbane, Qld, Australia Leibniz Inst Plant Genet & Crop Plant Res IPK Gat, Genebank, Gatersleben, Germany Piramal Imaging, Res & Dev, Berlin, Germany Univ Leeds, Civil Engn, Leeds, W Yorkshire, England Univ Missouri, Chem & Biochem, St Louis, MO 63121 USA US Geol Survey, Coastal & Marine Geol Program, Pacific Coastal & Marine Sci Ctr, Santa Cruz, CA USA Ajinomoto Genet Res Inst, Moscow, Russia Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Plant Biotechnol, Krakow, Poland Univ Puerto Rico, Engn Sci & Mat, Mayaguez, PR USA Univ Regina, Dept Chem & Biochem, Regina, SK, Canada Argonne Natl Lab, Ctr Nanoscale Mat, 9700 S Cass Ave, Argonne, IL 60439 USA Univ Sunshine Coast, Sunshine Coast Mind & Neurosci Thompson Inst, Sippy Downs, Qld, Australia Chinese Peoples Liberat Army Gen Hosp, Dept Gastroenterol & Hepatol, Beijing, Peoples R China Griffith Univ, Griffith Ctr Social & Cultural Res, Gold Coast, Qld, Australia Tohoku Univ, Inst Dev Aging Canc, Dept Mol Oncol, Sendai, Miyagi, Japan Indiana Univ, Comp Sci, Bloomington, IN USA Fukushima Med Univ, Sch Med, Dept Pulm Med, Fukushima, Japan MEDIVIR AB, Biol, Huddinge, Sweden Western Sydney Univ, Neuroimmunol, Sydney, NSW, Australia Univ Jordan, Nutr & Food Technol, Amman, Jordan Thunen Inst Forest Genet, Fed Res Ctr Rura Areas Forestry & Fisheries, Inst Biodivers, Grosshansdorf, Germany Univ Edinburgh, Inst Cell Biol, Edinburgh, Midlothian, Scotland Univ Edinburgh, Ctr Integrat Physiol, Edinburgh, Midlothian, Scotland Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada Canadian Mem Chiropract Coll, Grad Educ & Res, Toronto, ON, Canada Agilent Technol, R&D, Leuven, Belgium Univ British Columbia, Sch Nursing, Vancouver, BC, Canada Monash Univ, Monash Hlth, Sch Clin Sci, Stroke & Ageing Res,Dept Med, Melbourne, Vic, Australia French Natl Canc Inst, Innovat, Transfer, Biol, Boulogne, France Ludwig Maximilians Univ Munchen, Phys Chem, NanoBioSci, Munich, Germany Bandung Inst Technol, Sch Pharm, Med Chem, Bandung, Indonesia Univ Luxembourg, Life Sci Res Unit, Luxembourg, Luxembourg Lund Univ, Skane Univ Hosp, Dept Gastroenterol, Malmo, Sweden Millennium Hlth, Translat Genet, San Diego, CA USA Aristotle Univ Thessaloniki, Med Dept 2, Clin Res & Evidence Based Med Unit, Thessaloniki, Greece Jan Kochanowski Univ Humanities & Sci, Piotrkow Trybunalski Branch, Dept Psychol, Kielce, Poland McMaster Univ, Engn Phys, Hamilton, ON, Canada Marche Polytech Univ, Dept Agr Food & Environm Sci, Ancona, Italy Kuwait Univ, Fac Med, Microbiol, Kuwait, Kuwait Fujita Hlth Univ, Dept Breast Surg, Toyoake, Aich, Japan North West Reg Spinal Injuries Ctr, Spinal Injuries Ctr, Southport, Merseyside, England Luxembourg Inst Hlth, Competence Ctr Methodol & Stat, Luxembourg, Luxembourg Nestle Inst Hlth Sci SA, Metab Hlth, Ecublens, Vaud, Switzerland Ctr Inflammat Res VIB, Ghent, Belgium Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium Univ Lisbon, Inst Educ, Curriculo Formacao Prof & Tecnol, Lisbon, Portugal Univ Edinburgh, Ctr Inflammat Res, Edinburgh, Midlothian, Scotland Univ Melbourne, Sch BioSci, Parkville, Vic, Australia Northumbria Univ, Comp & Informat Sci, Newcastle Upon Tyne, Tyne & Wear, England Univ Valencia, Endocrinol, Valencia, Spain INRS, Inst Armand Frappier, Laval, PQ, Canada Univ Laval, INAF, Sch Nutr, Quebec City, PQ, Canada Univ Konstanz, Dept Biol, Constance, Germany Univ Cote dAzur, LAMHESS, Nice, France Scion, Syst Ecol, Christchurch, New Zealand CUNY, Grad Sch Publ Hlth & Hlth Policy, Epidemiol & Biostat, New York, NY 10021 USA Univ Queensland, Sch Dent, Brisbane, Qld, Australia George Inst Global Hlth, Renal & Metab Div, Sydney, NSW, Australia Wuhan Univ, Coll Chem & Mol Sci, Wuhan, Hubei, Peoples R China Griffith Univ, Sch Environm & Sci, Gold Coast, Qld, Australia Univ Minnesota, Radiat Oncol, Minneapolis, MN USA Goethe Univ, Fac Med, Frankfurt, Germany Natl Yunlin Univ Sci & Technol, Dept & Grad Sch Safety & Environm Engn, Touliu, Yunlin, Taiwan Massey Univ, Sch Sport Exercise & Nutr, Auckland, New Zealand Univ Florida, Wildlife Ecol & Conservat, Gainesville, FL USA Bournemouth Univ, Dept Psychol, Poole, Dorset, England Robert Koch Inst, Project Grp P2, Berlin, Germany Univ Edinburgh, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland Univ Basel, Biozentrum, Basel, Switzerland Univ Wollongong, Sch Med, Wollongong, NSW, Australia Univ Cologne, Inst Human Genet, Cologne, Germany Rural Econ Branch, Econ Res Serv, Washington, DC USA Uivers Bordeaux, CNRS, Inst Neurosci Cognit & Integrat Aquitaine, Bordeaux, France Univ Calif Riverside, Dept Chem & Environm Engn, Riverside, CA 92521 USA Univ Calif Riverside, Mat Sci & Engn Program, Riverside, CA 92521 USA Mackay Med Coll, Dept Med, New Taipei, Taiwan Univ Bern, Div Anim Welf, Bern, Switzerland Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Med Sci, Shanghai, Peoples R China McMaster Univ, Biol, Hamilton, ON, Canada Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL USA Hacettepe Univ, Inst Canc, Med Oncol, Ankara, Turkey City Univ Hong Kong, Dept Elect Engn, Hong Kong, Peoples R China Natl Taiwan Univ, Dept Entomol, Taipei, Taiwan Chinese Acad Agr Sci, Inst Environm & Sustainable Dev Agr, Ecol Secur, Beijing, Peoples R China Florida State Univ, Inst Mol Biophys, Chem & Biochem, Tallahassee, FL USA Peking Univ, Shenzhen Grad Sch, State Key Lab Chem Oncogen, Lab Computat Chem & Drug Design, Shenzhen, Peoples R China Univ Helsinki, Fac Pharm, Div Pharmaceut Chem & Technol, Drug Res Program, Helsinki, Finland Tohoku Univ, Microbial Biotechnol, Sendai, Miyagi, Japan Tianjin Med Univ, Sch Basical Med Sci, Dept Pharmacol, Tianjin, Peoples R China Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA Natl Hlth Res Inst, Inst Mol & Genom Med, Zhunan, Taiwan 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Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales Zurich Univ Appl Sci, Social Work, Zurich, Switzerland Jawaharlal Nehru Univ, Sch Life Sci, New Delhi, India Univ Burgundy Franche Comte, LE2I, Dijon, France Univ Roehampton, Life Sci, London, England Ghent Univ Hosp, Gen & HPB Surg, Ghent, Belgium Univ Wurzburg, Insect Fungus Symbiosis Lab, Wurzburg, Germany Radboud Univ Nijmegen, Behav Sci Inst, Nijmegen, Netherlands Fraunhofer WKI, Applicat Ctr HOFZET, Hannover, Germany UCL, Struct & Mol Biol, London, England Univ Amsterdam, Dev Psychol, Amsterdam, Netherlands Aalborg Univ, Hlth Sci & Technol, CNAP, SMI, Aalborg, Denmark VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA Cedars Sinai Med Ctr, Neurosurg, Los Angeles, CA 90048 USA Sun Yat Sen Univ, Sch Data & Comp Sci, Guangzhou, Guangdong, Peoples R China Dezhou Univ, Shandong Prov Key Lab Biophys, Guangzhou, Guangdong, Peoples R China Maison Teledetection, Inst Rech Dev, UMR Espace DEv, Montpellier, France Xiamen Univ, Sch Life Sci, Xiamen, Fujian, Peoples R China Nanjing Univ, Sch Med, Jinling Hosp, Natl Clin Res Ctr Kidney Dis,Dept Med Imaging, Nanjing, Jiangsu, Peoples R China Univ Kent, Sch Social Policy Sociol & Social Res, Canterbury, Kent, England Univ Fed Minas Gerais, Infect Dis & Trop Med, Belo Horizonte, MG, Brazil Univ Minho, Sch Med, Life & Hlth Sci Res Inst ICVS, Braga, Portugal Univ Montreal, Biochim & Med Mol, Montreal, PQ, Canada Johns Hopkins Bloomberg Sch Publ Hlth, Epidemiol, Baltimore, MD USA Max Planck Inst Biol Ageing, Metab & Genet Regulat Ageing, Cologne, Germany Univ Swaziland, Hlth Sci, Kwaluseni, Eswatini Queensland Univ Technol, Inst Future Environm, Brisbane, Qld, Australia Ctr Sci Monaco, Dept Biol Med, Monaco, Monaco HELIOS Hosp, Urol, Bad Saarow Pieskow, Germany Tech Univ Carolo Wilhelmina Braunschweig, Inst Microbiol, Braunschweig, Germany Univ Barcelona, Barcelona Ctr Maternal Fetal & Neonatal Med, Fetal i D Fetal Med Res Ctr, IDIBAPS BCNatal,Hosp Clin, Barcelona, Spain Univ Barcelona, Hosp St Joan de Deu, Barcelona, Spain Friedrich Loeffler Inst, Inst Bacterial Infect & Zoonoses, Jena, Germany Charite Med Univ Berlin, Neurol, Berlin, Germany Dublin City Univ, Natl Inst Cellular Biotechnol, Mol Therapeut Canc Ireland, Dublin, Ireland Schoen Clin Roseneck, Prien Am Chiemsee, Germany Univ Med Ctr Hamburg Eppendorf, Inst Sex Res & Forens Psychiat, Hamburg, Germany Nankai Univ, Sch Math Sci, Tianjin, Peoples R China Nankai Univ, LPMC, Tianjin, Peoples R China Univ Oxford, Oncol, Oxford, England Royal Holloway Univ London, Class, Egham, Surrey, England Cornell Univ, Clin Sci, Ithaca, NY USA Univ KwaZulu Natal, Pharmaceut Chem, Westville Campus, Durban, South Africa Royal Coll Surgeons Ireland, Med, Dublin, Ireland Univ Oslo, Dept Immunol, Oslo, Norway Bermuda Inst Ocean Sci, Marine Nitrogen Cycling Lab, St Georges, Bermuda Kanazawa Univ, Inst Liberal Arts & Sci, Kanazawa, Ishikawa, Japan World Hlth Org Reg Off Africa, Brazzaville, Rep Congo Univ Hosp BesanCon, Infect Control Dept, Besancon, France Galapagos NV, Clin Dev, Mechelen, Belgium Univ Tasmania, Integrated Marine Observing Syst, Hobart, Tas, Australia Georg August Univ Gottingen, Albrecht von Haller Inst Plant Sci, Dept Systemat Biodivers & Evolut Plants, Gottingen, Germany Univ Occupat & Environm Hlth, Dept Psychiat, Fukuoka, Fukuoka, Japan IMDEA Food, Program Precis Nutr & Aging, Madrid, Spain Radboud Univ Nijmegen, Med Sch, IQHealthcare, Nijmegen, Netherlands Maastricht Univ, Dept Cardiovasc Surg, Maastricht, Netherlands German Diabet Ctr, Inst Clin Biochem & Pathobiochem, Dusseldorf, Germany Juntendo Univ, Grad Sch Med, Dept Radiol, Tokyo, Japan Deakin Univ, Sch Informat Technol, Melbourne, Vic, Australia Max Planck Inst Eusenforschung, Dept Interface Chem & Surface Sci, Dusseldorf, Germany Edge Hill Univ, Dept Psychol, Ormskirk, England Aga Khan Univ, Psychiat, Karachi, Pakistan KRIBB, Korean Bioinformat Ctr, Seoul, South Korea Cardinal Hlth Specialty Solut, Hlth Econ & Outcomes Res, Dallas, TX USA Klinikum Univ Munchen, Div Clin Pharmacol, Munich, Germany Univ Pittsburgh, Neurol Surg, Pittsburgh, PA USA Rhein Westfal TH Aachen, Dept Child & Adolescent Psychiat Psychosomat & Ps, Aachen, Germany Univ Copenhagen, Inst Mol & Cellular Biol, Copenhagen, Denmark St Jude Childrens Res Hosp, Struct Biol, 332 N Lauderdale St, Memphis, TN 38105 USA Royal Shrewsbury Hosp, Colorectal Surg, Shrewsbury, Salop, England Univ Nottingham, Fac Med & Hlth Sci, Nottingham, England Karolinska Inst, Dept Physiol & Pharmacol, Solna, Sweden Chinese Acad Sci, Changchun Inst Appl Chem, State Key Lab Electroanalyt Chem, Jilin, Jilin, Peoples R China Univ British Columbia, Pediat, Vancouver, BC, Canada Chinese Acad Agr Sci, State Key Lab Cotton Biol, Res Base Anyang Inst Technol, Cotton Germplasm Resources,Inst Cotton Res, Beijing, Peoples R China Chinese Univ Hong Kong, Anaesthesia & Intens Care, Hong Kong, Peoples R China Univ Macau, ICMS, 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Cytotechnol Educ, Omaha, NE USA Shinko Mem Hosp, Dept Cardiovasc Med, Kobe, Hyogo, Japan Imperial Coll London, Mat, London, England Tech Univ Munich, Dept Surg, Munich, Germany Chinese Acad Agr Sci, Res Inst Pomol, Minist Agr, Lab Qual & Safety Risk Assessment Fruit Xingcheng, Shenyang, Liaoning, Peoples R China James Madison Univ, Commun Sci & Disorders, Harrisonburg, VA 22807 USA Univ Hosp Ulm, Inst Orthopaed Res & Biomech, Ulm, Germany Univ Essex, Sch Hlth & Social Care, Colchester, Essex, England Alpha Altis, Res Serv, Nottingham, England Erasmus MC, Med Oncol, Rotterdam, Netherlands Fed Univ Oye, Dept Ind Chem, Ekiti, Nigeria Duke Univ, Med Ctr, Cell Biol, Durham, NC USA Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England Univ Manchester, Canc Res UK Manchester Inst, Manchester, Lancs, England Helsinki Univ Hosp, Childrens Hosp, Helsinki, Finland Univ Aveiro, CESAM Ctr Environm & Marine Studies, Dept Biol, Aveiro, Portugal Univ Botswana, Psychol, Gaborone, Botswana Univ Fed Bahia, Nursing Sch, Salvador, BA, Brazil Queen Mary Univ London, Biol & Expt Psychol, London, England Natl Univ Pharm, Med Chem Dept, Kharkov, Ukraine Univ Bolton, Dept Educ & Psychol, Bolton, England La Trobe Univ, Dept Chem & Phys, Melbourne, Vic, Australia Gen Hosp Northern Theater Command, Dept Gastroenterol, Shenyang, Liaoning, Peoples R China Doctors Hosp, Dept Nephrol, Athens, Greece Univ Hosp Essen, Pediat 3, Essen, Germany Imperial Coll London, Infect Dis Epidemiol, London, England Sorbonne Univ, Dept Psychiat, Paris, France UNSW Sydney, Educ, Sydney, NSW, Australia Stanford Univ, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA Hannover Med Sch, Clin Laryngol Rhinol & Otol, Hannover, Germany Curtin Univ, Ctr Aboriginal Studies, Perth, WA, Australia Iran Univ Sci & Technol, Biomed Engn Dept, Tehran, Iran Univ Calif San Francisco, Anesthesiol, San Francisco, CA 94143 USA Khalifa Univ Sci & Technol, Mech Engn, Abu Dhabi, U Arab Emirates Univ Florida, Hort Sci, Gainesville, FL USA James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, Cairns, Qld, Australia Univ Porto, Fac Med, CINTESIS, Porto, Portugal Shaoxing Peoples Hosp, Med Res Ctr, Shaoxing, Zhejiang, Peoples R China NIH, Dept Transfus Med, Bethesda, MD 20892 USA AIIMS, Dept Biotechnol, New Delhi, India Univ Ottawa, Biochem Microbiol & Immunol, Ottawa, ON, Canada Univ Oslo, Inst Clin Med, Div Mental Hlth & Addict, Oslo, Norway Univ Groningen, Univ Med Ctr Groningen, Dept Radiol, Groningen, Netherlands Univ Hong Kong, Sch Nursing, Hong Kong, Peoples R China Tokyo Med Univ, Ibaraki Med Ctr, Urol, Tokyo, Japan Univ Hosp Zurich, Dept Radiat Oncol, Zurich, Switzerland Univ Maryland, Inst Human Virol, Div Immunotherapy, Baltimore, MD 21201 USA Univ Maryland, Dept Surg, Baltimore, MD 21201 USA Stellenbosch Univ, Fac Med & Hlth Sci, Div Mol Biol & Human Genet, Stellenbosch, South Africa China Agr Univ, Coll Biol Sci, Beijing, Peoples R China Osaka Univ, Grad Sch Pharmaceut Sci, Suita, Osaka, Japan Univ Washington, Biochem, Seattle, WA 98195 USA Natl Res Council Italy, Inst Biosci & BioResources, Naples, Italy Univ Lyon, Phys, Lyon, France Univ Basel, Fac Psychol, Ctr Social Psychol, Basel, Switzerland Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England EBI, EMBL, Samples Phenotypes & Ontol Team, Cambridge, England Charles Sturt Univ, Fac Arts & Educ, Bathurst, NSW, Australia Shandong Univ, Helmholtz Inst Biotechnol, Sch Life Sci, State Key Lab Microbial Technol, Jinan, Shandong, Peoples R China Shantou Univ, Dept Biol, Shantou, Guangdong, Peoples R China Shanxi Univ, Inst Biomed Sci, Taiyuan, Shanxi, Peoples R China St Jude Childrens Res Hosp, Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA Harbin Med Univ, Coll Bioinformat Sci & Technol, Harbin, Heilongjiang, Peoples R China NIH, Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA Georgia Inst Technol, Dept Biol Sci, Atlanta, GA 30332 USA XtalPi Inc, Cambridge, MA USA Consejo Nacl Invest Cient & Tecn, Partner Inst Max Planck Soc, Inst Invest Biomed Buenos Aires IBioBA, Bioinformat, Buenos Aires, DF, Argentina Univ Sydney, Save Sight Inst, Sydney, NSW, Australia Univ South Australia, Canc Res Inst, Australian Ctr Precis Hlth, Adelaide, SA, Australia Jinan Univ, Inst Life & Hlth Engn, Guangdong Higher Educ Inst, Key Lab Funct Prot Res, Guangzhou, Guangdong, Peoples R China Univ Texas Hlth Sci Ctr Houston, Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA Weill Cornell Med, Dept Microbiol & Immunol, New York, NY USA Guangdong Inst Appl Biol Resources, Biotechnol Lab, Guangzhou, Guangdong, Peoples R China Shandong Normal Univ, Coll Life Sci, Jinan, Shandong, Peoples R China Shandong Univ, Life Sci Dept, Jinan, Shandong, Peoples R China South China Agr Univ, Integrat Microbiol Res Ctr, Guangzhou, Guangdong, Peoples R China Liaoning Acad Agr Sci, Crop Mol Improving Lab, Shenyang, Liaoning, Peoples R China Lawson Hlth Res Inst, Med Biophys, London, ON, Canada Univ Melbourne, Infrastruct Engn, Parkville, Vic, Australia Univ Canberra, Fac Hlth, Canberra, ACT, Australia Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England Emory Univ, Biostat & Bioinformat, Atlanta, GA 30322 USA Johns Hopkins Sch Med, Anesthesiol & Crit Care Med, Baltimore, MD USA Nottingham Trent Univ, Sch Anim Rural & Environm Sci, Nottingham, England Univ Exeter, Biosci, Exeter, Devon, England Hillingdon Hosp NHS Fdn Trust, London, England Univ Glasgow, MRC CSO Social & Publ Hlth Sci Unit, Glasgow, Lanark, Scotland Natl & Kapodistrian Univ Athens, Evaggelismos Athens Hosp, ICU, Athens, Greece Univ Newcastle, Biol Sci, Callaghan, NSW, Australia Coventry Univ, Fac Hlth & Life Sci, Ctr Innovat Res Life Course, Coventry, W Midlands, England Lausanne Univ Hosp, Serv Endocrinol Diabet & Metab, Lausanne, Switzerland Charles Sturt Univ, Sch Community Hlth, Bathurst, NSW, Australia Queens Univ Belfast, Inst Global Food Secur, Belfast, Antrim, North Ireland Natl Univ Singapore, Inst Policy Studies, Singapore, Singapore Univ Penn, Intitute Med & Engn, Philadelphia, PA 19104 USA Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA Univ Michigan, EECS, Ann Arbor, MI 48109 USA Univ British Columbia, Ctr Blood Res, Vancouver, BC, Canada UiT Arctic Univ Norway, Dept Hlth & Care Sci, Fac Hlth Sci, Tromso, Norway Hosp Clin Porto Alegre, Physiotherapy, Porto Alegre, RS, Brazil Univ Paris 05, Med Sch, Paris, France Chinese Acad Agr Sci, Inst Crop Sci, Natl Key Facil Crop Gene Resources & Genet Improv, Beijing, Peoples R China Univ Ghent, Expt Clin & Hlth Psychol, Ghent, Belgium Indian Inst Adv Res, Bioinformat & Struct Biol, Gandhinagar, Gujart, India Bambino Ges Childrens Res Hosp, Lab Mol Med, Rome, Italy Heidelberg Univ, Ctr Infect Dis Parasitol, Heidelberg, Germany Stanford Univ, Elect Engn, Palo Alto, CA 94304 USA Univ Cadiz, Biol, Andalucia, Spain Mansoura Univ Hosp, Gen Surg, Mansoura, Egypt Inst Pasteur, Virol Pole, Dakar, Senegal Cardiff Univ, Div Canc & Genet, Cardiff, S Glam, Wales Ctr Expertise & Biol Diagnost Cameroon, Food Safety & Environm Microbiol, Yaounde, Cameroon Swiss Fed Labs Mat Sci & Technol, Lab Thin Films & Photovolta, Dubendorf, Switzerland Assiut Univ, Assiut Urol & Nephrol Hosp, Fac Med, Assiut, Egypt UCL, GEE, London, England UCL, IHA, London, England Univ Derby, Univ Derby Online Learning, Derby, England SUNY Stony Brook, Family Populat & Prevent Med, Stony Brook, NY 11794 USA Walter & Eliza Hall Inst Med Res, Mol Med Div, Melbourne, Vic, Australia Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne, Tyne & Wear, England German Ctr Neurodegenerat Dis, Clin Dementia Res, Bonn, Germany Sorbonne Univ, CNRS, UMR 7144, Stn Biol, Paris, France Univ Barcelona, Odontoestomatol, Barcelona, Spain Janelia Res Campus, Comp Sci, Ashburn, VA USA Univ Oxford, Ctr Trop Med & Global Hlth, Oxford, England Univ Bern, ARTORG Ctr Biomed Engn Res, Bern, Switzerland Australian Natl Univ, Eccles Inst Neurosci, John Curtain Sch Med Res, Canberra, ACT, Australia John Innes Ctr, Metab Biol, Norwich, Norfolk, England USDA ARS, Genom & Bioinformat Res Unit, Raleigh, NC 27695 USA Med Univ Graz, Inst Med Informat Stat & Documentat, Holzinger Grp, Graz, Austria Ajou Univ, Pharm, Suwon, South Korea City Univ Hong Kong, Sch Energy & Environm, Hong Kong, Peoples R China Univ British Columbia, Sch Kinseiol, Vancouver, BC, Canada Univ Copenhagen, Marine Biol Sect, Dept Biol, Copenhagen, Denmark Univ Vienna, Dept Commun, Vienna, Austria Univ Dundee, Sch Social Sci, Dundee, Scotland Tech Univ Dresden, Inst Bot, Dresden, Germany Univ Oxford, Div Struct Biol, Oxford, England Natl Univ Hlth Syst, Med, Singapore, Singapore Univ Canterbury, Sch Biol Sci, Christchurch, New Zealand Univ Hosp Southern Denmark, Focused Res Unit Mol Diagnost & Clin Res, Odense, Denmark Univ Oxford, Primary Care Hlth Sci, Oxford, England Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA Adnan Menderes Univ Aydin, Fac Nursing, Dept Publ Hlth Nursing, Aydin, Turkey Oasi Res Inst IRCCS, Dept Neurol IC, Troina, Italy Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA Kings Coll London, Kings Ctr Mil Hlth Res, London, England LSHTM, Dept Infect Dis Epidemiol, London, England Leibniz Univ Hannover, BMWZ Organ Chem, Hannover, Germany Xi An Jiao Tong Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Xian, Shaanxi, Peoples R China Univ South Australia, Sch Pharm & Med Sci, Adelaide, SA, Australia Univ Fed Santa Catarina, Dept Phys Educ, Florianopolis, SC, Brazil Southern Med Univ, Nanfang Hosp, Dept Oncol, Guangzhou, Guangdong, Peoples R China Stanford Univ, Hansen Expt Phys Lab, Palo Alto, CA 94304 USA Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Inst Translat Med, Shenzhen, Guangdong, Peoples R China Univ Hong Kong, Dept Stat & Actuarial Sci, Hong Kong, Peoples R China UCL, Dept Mech Engn, London, England ASTAR, Singapore Immunol Network, Lab Microbial Immun, Singapore, Singapore Cent South Univ, State Key Lab Powder Met, Changsha, Hunan, Peoples R China Univ Aberdeen, Inst Appl Hlth Sci, Aberdeen, Scotland Univ Bridgeport, Biomed Engn, Bridgeport, CT 06601 USA Texas Tech Univ, Hlth Sci Ctr, Pharmaceut Sci, Lubbock, TX 79430 USA Univ Montana, Ecosyst & Conservat Sci, Missoula, MT 59812 USA Univ Goettingen, Dept Syst Neurosci, Gottingen, Germany NHLBI, Lab Syst Genet, Bldg 10, Bethesda, MD 20892 USA Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Imaging, Las Vegas, NV USA Flinders Univ S Australia, Coll Nursing & Hlth Sci, Nutr & Dietet, Adelaide, SA, Australia Univ Padua, Dept Math, Padua, Italy Lund Univ, Fac Law, Lund, Sweden Univ Gothenburg, Dept Microbiol & Immunol, Gothenburg, Sweden NARO, Kachwekano Zardi, Entebbe, Uganda Natl Yunlin Univ Sci & Technol, Bachelor Program Interdisciplinary Studies, Touliu, Yunlin, Taiwan Aarhus Univ, Dept Biomed, Danish Res Inst Translat Neurosci DANDRITE, Aarhus, Denmark Eduardo Mondlane Univ, Math & Comp Sci, Maputo, Mozambique Univ Bern, Dept Old Age Psychiat & Psychotherapy, Bern, Switzerland RAS, Inst Cytol, Lab Cytol Unicellular Organisms, St Petersburg, Russia Beijing Inst Technol, Sch Chem & Chem Engn, Beijing, Peoples R China Univ Queensland, Queensland Alliance Agr & Food Innovat, Brisbane, Qld, Australia Fraunhofer Inst Toxicol & Expt Med ITEM, Inhalat Toxicol, Hannover, Germany Univ Hong Kong, Publ Hlth, Hong Kong, Peoples R China Univ Hlth Network, Anesthesia & Pain Med, Toronto, ON, Canada Univ Toronto, Toronto, ON, Canada Univ Bath, Dept Hlth, Bath, Avon, England Univ Copenhagen, Computat & RNA Biol, Copenhagen, Denmark Fisheries & Oceans Canada, Bedford Inst Oceanog, Dartmouth, NS, Canada Goethe Univ, CEF MC, BMLS, Phys Biol, Frankfurt, Germany Albert Einstein Coll Med, Anat & Struct Biol, New York, NY USA Queensland Govt, Dept Environm & Sci, Brisbane, Qld, Australia Uppsala Univ, Vasc Surg Sect, Dept Surg Sci, Uppsala, Sweden Childrens Canc Hosp, Res, Cairo, Egypt Leibniz Inst Nat Prod Res & Infect Biol, Bio Pilot Plant, Jena, Germany Duy Tan Univ, Inst Res & Dev, Da Nang, Vietnam Univ Helsinki, Helsinki Inst Life Sci HiLIFE, Helsinki, Finland Univ Queensland, Australian Inst Bioengn & Nanotechnol, Brisbane, Qld, Australia George Inst Global Hlth, Sydney, NSW, Australia Griffith Univ, Griffith Inst Drug Discovery, Brisbane, Qld, Australia Dezhou Univ, Coll Phys & Elect Informat, Shandong Prov Key Lab Biophys, Dezhou, Peoples R China Henan Agr Univ, Coll Life Sci, Zhengzhou, Henan, Peoples R China Univ Tokyo, Publ Hlth, Tokyo, Japan Sun Yat Sen Univ, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R China Univ Illinois, Dept Med, Chicago, IL USA Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing, Peoples R China Minist Hlth, Key Lab Neonatal Dis, Shanghai, Peoples R China Covenant Univ, Dept Phys, Ota, Nigeria Prince Sattam Bin Abdulaziz Univ, Dept Phys Therapy & Hlth Rehabil, Al Kharj, Saudi Arabia Lund Univ, Cognit Sci, Malmo, Sweden Natl Open Univ Nigeria, Dept Publ & Environm Hlth, Abuja, Nigeria Peking Univ, Sch Publ Hlth, Dept Lab Sci & Technol, Beijing, Peoples R China Univ Sydney, Sch Publ Hlth, Menzies Ctr Hlth Policy, Sydney, NSW, Australia Univ Auckland, Dept Elect & Comp Engn, Auckland, New Zealand Beijing Univ Chinese Med, Res Ctr TCM Informat Engn, Beijing, Peoples R China Osped Niguarda Ca Granda, Cardiac Surg, Milan, Italy Univ Vet Med, Clin Horses, Hannover, Germany Harbin Med Univ, Lab Med Genet, Harbin, Heilongjiang, Peoples R China Univ Saskatchewan, Dept Psychol, Saskatoon, SK, Canada Univ Coimbra, Ctr Studies Geog & Spatial Planning CEGOT, Coimbra, Portugal Univ Groningen, Univ Med Ctr Groningen, Epidemiol, Groningen, Netherlands South Cent High Specialty Hosp, Dept Neurol & Neurosurg, Pemex, Mexico Shandong Agr Univ, Coll Informat Sci & Engn, Tai An, Shandong, Peoples R China Curtin Univ, Natl Drug Res Inst, Perth, WA, Australia Wageningen Bioveterinary Res, Bacteriol & Epidemiol, Lelystad, Netherlands Guangdong Second Prov Gen Hosp, Dept Rheumatol & Immunol, Guangzhou, Guangdong, Peoples R China Erasmus MC, Biomed Rngineering, Rotterdam, Netherlands Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Hiroshima, Japan Univ Iceland, Sch Hlth Sci, Reykjavik, Iceland Ohio State Univ, Mat Sci & Engn, Columbus, OH 43210 USA Kathmandu Univ, Sch Med Sci, Dept Physiotherapy, Dhulikhel, Nepal Univ Queensland, Sch Biomed Sci, Brisbane, Qld, Australia Fraunhofer MEVIS, Image Guided Therapies, Bremen, Germany Natl Univ Hlth Syst, Haematol Oncol, Singapore, Singapore Sun Yat Sen Univ, Canc Ctr, Breast Oncol, Guangzhou, Guangdong, Peoples R China Med Coll Wisconsin, Pharmacol & Toxicol, Wauwatosa, WI USA Queensland Univ Technol, Sci & Engn Fac, Sch Chem Phys & Mech Engn, Brisbane, Qld, Australia Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy Univ Tehran Med Sci, Sch Rehabil, Physiotherapy Dept, Tehran, Iran Univ Helsinki, Dept Forest Sci, Helsinki, Finland Univ Messina, Human Pathol, Messina, Italy AO Papardo Hosp Messina, Messina, Italy Univ Ibadan, Coll Med, Inst Child Hlth, Ibadan, Nigeria King Faisal Univ, Coll Med, Fac Ophthalmol, Al Hasa, Saudi Arabia Univ Stirling, Inst Social Mkt, Stirling, Scotland Saveh Univ Med Sci, Social Determinants Hlth Res Ctr, Saveh, Iran Gakujutsu Shien Co Ltd, Tokyo, Japan Chinese Acad Sci, Inst Geochem, Guiyang, Guizhou, Peoples R China Univ Plymouth, Med Sch, Plymouth, Devon, England CHU Toulouse, Immunol, Toulouse, France Azorean Biodivers Grp, Ctr Ecol Evolut & Environm Changes, Azores, Portugal Univ Acores, Azores, Portugal RIKEN, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan Peking Univ, Sch Publ Hlth, Dept Global Hlth, Beijing, Peoples R China Chang Gung Univ, Chang Gung Mem Hosp, Dept Neurol, Linkou Med Ctr, Taoyuan, Taiwan Chang Gung Univ, Coll Med, Taoyuan, Taiwan Univ Malawi, Coll Med, Biomed Sci Dept, Blantyre, Malawi Univ Malawi, Coll Med, Pharm Dept, Blantyre, Malawi Bioself Commun, Biocurat, Marseille, France Peking Univ, Hosp 3, Dept Neurol, Beijing, Peoples R China Ahmadu Bello Univ, Fac Basic Clin Sci, Coll Hlth Sci, Dept Pathol, Zaria, Nigeria Dalhousie Univ, Dept Anesthesia Pain Management & Perioperat Med, Halifax, NS, Canada VisMederi Srl, Siena, Italy UCL, Canc Res UK, London, England UCL, UCL Canc Trials Ctr, London, England Univ Ottawa, Family Med, Ottawa, ON, Canada China Agr Univ, Coll Engn, Beijing, Peoples R China Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Leiden, Netherlands Sun Yat Sen Univ, Affiliated Hosp 1, Dept Intervent Radiol, Guangzhou, Guangdong, Peoples R China Amer Univ Beirut, Med Ctr, Infect Dis, Beirut, Lebanon Sheffield Hallam Univ, Dept Social Work Social Care & Community Studies, Sheffield, S Yorkshire, England Mechnikov Res Inst Vaccines & Sera, Viral Hepatitis, Moscow, Russia Univ Ottawa, Pediat, Ottawa, ON, Canada Vreden Russian Res Inst Traumatol & Orthopaed, Dept Wound Infect Treatment & Prevent, St Petersburg, Russia Hangzhou Ctr Dis Control & Prevent, Dept TB Control & Prevent, Hangzhou, Zhejiang, Peoples R China Kaohsiung Med Univ, Dept Biotechnol, Kaohsiung, Taiwan Zoetis, Diagnost, Kalamazoo, MI USA Aintree Univ Hosp NHS Fdn Trust, Head & Neck Oncol Res, Liverpool, Merseyside, England Wrightington Hosp, Trauma & Orthopaed, Manchester, Lancs, England Loyola Univ, Med Ctr, Dept Psychiat, 2160 S 1st Ave, Maywood, IL 60153 USA Atkins Vet Serv, Microbiol, Calgary, AB, Canada Univ Porto, FADEUP, CIAFEL, Porto, Portugal Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore Kangwon Natl Univ, Coll Biotechnol & Biosci, Dept Food Sci & Biotechnol, Chunchon, South Korea Kakatiya Med Coll, Internal Med, Warangal, Telangana, India Univ Antioquia, Vet Med Sch, CIBAV Res Grp, Medellin, Colombia IISER, Dept Phys, Soft & Act Matter Grp, Tirupati 517507, Andhra Pradesh, India Univ Rosario, Sch Med & Hlth, Ctr Studies Phys Activ Measurements, Bogota, Colombia Univ Hosp Essen, Cardiol & Vasc Med, Essen, Germany Univ Hosp Basel, Endocrinol, Basel, Switzerland Univ Tubingen, Inst Med Genet & Appl Genom, Tubingen, Germany Univ Hosp Munster, Div Gen Internal Med Nephrol & Rheumatolog, Dept Med D, Munster, Germany Univ Kentucky, Dept Nephrol, Lexington, KY USA Univ Freiburg, Dept Anaesthesiol & Crit Care, Med Ctr, Freiburg, Germany Univ Calif Irvine, Dept Med, Orange, CA 92668 USA Univ Hosp Leuven, Dept Urol, Leuven, Belgium Chinese Acad Sci, Coll Life Sci, Beijing, Peoples R China Univ Florida, Orthopaed & Rehabil, Gainesville, FL USA Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Mol Oncol & Epigenet, Chongqing, Peoples R China Tsinghua Univ, Dept Chem Engn, Beijing, Peoples R China Yonsei Univ, Coll Med, Dept Pharmacol, Seoul, South Korea Childrens Hosp Kings Daughters, Eastern Virginia Med Sch, Dept Pediat, Norfolk, VA USA China Three Gorges Univ, Coll Sci, Dept Math, Yichang, Peoples R China Xiangtan Univ, Coll Informat Engn, Xiangtan, Hunan, Peoples R China Univ Hlth Network, Mood Disorders & Psychopharmacol, Toronto, ON, Canada Sao Paulo State Univ UNESP, Dept Anim Sci, Sao Paulo, Brazil Sao Paulo State Univ, Vet Clin, Sao Paulo, Brazil
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19. Greater preservation of SARS-CoV-2 neutralising antibody responses following the ChAdOx1-S (AZD1222) vaccine compared with mRNA vaccines in haematopoietic cell transplant recipients.
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Colton H, Barratt N, Temperton N, Hornsby H, Angyal A, Grouneva I, Lindsey BB, Kearns P, Barnes E, Goodyear CS, Richter A, Thomas D, Cook G, McInnes IB, Willicombe M, Siebert S, Orchard K, Selby R, Bowden S, Collini PJ, Pope A, Kirkham A, Kronsteiner B, Dunachie SJ, Miller P, Clay J, Hurst E, Malladi R, Kesavan M, Kinsella F, Sanderson R, Yong KL, Rea D, Parry H, Lim SH, Snowden JA, and de Silva TI
- Abstract
Whilst SARS-CoV-2 mRNA vaccines generate high neutralising antibodies (nAb) in most individuals, haematopoietic stem cell transplant (HSCT) and chimeric antigen receptor T-cell (CAR-T) recipients respond poorly. HSCT/CAR-T treatment ablates existing immune memory, with recipients requiring revaccination analogous to being vaccine naive. An optimal revaccination strategy for this cohort has not been defined. Factors predicting immunogenicity following three ancestral SARS-CoV-2 vaccines were assessed in 198 HSCT/CAR-T recipients and 96 healthcare workers (HCWs) recruited to multicentre studies. Only 25% of HSCT/CAR-T recipients generated nAbs following one dose, with titres 167-fold and 7-fold lower than that in HCWs after the first and second doses, respectively. Lower post-second dose nAb titres were associated with older age, rituximab use, and previous HSCT. ChAdOx1-S recipients were more likely to generate nAbs compared with mRNA vaccines, with titres comparable to HCWs. In contrast, nAbs were significantly lower in HSCT/CAR-T recipients than HCWs after mRNA vaccination. The poor first-dose immunogenicity in HSCT/CAR-T recipients suggests a minimum licensed dosing interval could limit the period of vulnerability following HSCT/CAR-T. The relative preservation of nAbs with ChAdOx1-S vaccination highlights the importance of evaluating alternative platforms to mRNA vaccination within this highly vulnerable clinical cohort., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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20. Prevention is better than cure: immunocompromised people need COVID-19 prevention therapies now.
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Pagliuca A, Kaul S, Goodyear CS, and Lee L
- Abstract
Immunocompromised people are facing ongoing inequality in health outcomes because of COVID-19. Let's remain ambitious and improve availability and access to COVID-19 prevention therapies that protect patients and aid management. This article brings together opinions from four experts based in the United Kingdom who specialise in immunology, solid organ transplantation, respiratory medicine and critical care, oncology and haematology. In this article, they communicate the impact of SARS-CoV-2 infection on vulnerable patients with underlying conditions and the need for immediate policies to protect vulnerable people from COVID-19.
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- 2024
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21. Small extracellular vesicles derived from synovial fibroblasts contain distinct miRNA profiles and contribute to chondrocyte damage in osteoarthritis.
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Asghar S, Litherland GJ, Cole JJ, McInnes IB, Meek RMD, Lockhart JC, Goodyear CS, and Crilly A
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- Humans, Cells, Cultured, Aged, Male, Female, Middle Aged, Chondrocytes metabolism, Chondrocytes pathology, MicroRNAs genetics, MicroRNAs metabolism, Extracellular Vesicles metabolism, Extracellular Vesicles genetics, Synovial Membrane metabolism, Synovial Membrane pathology, Fibroblasts metabolism, Fibroblasts pathology, Osteoarthritis metabolism, Osteoarthritis genetics, Osteoarthritis pathology
- Abstract
Background: Small extracellular vesicles (sEV) derived from synovial fibroblasts (SF) represent a novel molecular mechanism regulating cartilage erosion in osteoarthritis (OA). However, a comprehensive evaluation using disease relevant cells has not been undertaken. The aim of this study was to isolate and characterise sEV from OA SF and to look at their ability to regulate OA chondrocyte effector responses relevant to disease. Profiling of micro (mi) RNA signatures in sEV and parental OA SF cells was performed., Methods: SF and chondrocytes were isolated from OA synovial membrane and cartilage respectively (n = 9). sEV were isolated from OA SF (± IL-1β) conditioned media by ultracentrifugation and characterised using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Particle size was confirmed by nanoparticle tracking analysis (NTA). sEV regulation of OA chondrocyte and cartilage effector response was evaluated using qPCR, ELISA and sulphated glycosaminoglycan assay (sGAG). RNA-sequencing was used to establish miRNA signatures in isolated sEV from OA SF., Results: OA SF derived sEV were readily taken up by OA chondrocytes, with increased expression of the catabolic gene MMP 13 (p < 0.01) and decreased expression of the anabolic genes aggrecan and COL2A1 (p < 0.01) observed. Treatment with sEV derived from IL-1β stimulated OA SF significantly decreased expression of aggrecan and COL2A1 (p < 0.001) and increased SOX 9 gene expression (p < 0.05). OA chondrocytes cultured with sEV from either non-stimulated or IL-1β treated OA SF, resulted in a significant increase in the secretion of IL-6, IL-8 and MMP-3 (p < 0.01). Cartilage explants cultured with sEV from SF (± IL-1β) had a significant increase in the release of sGAG (p < 0.01). miRNA signatures differed between parental SF cells and isolated sEV. The recently identified osteoclastogenic regulator miR182, along with miR4472-2, miR1302-3, miR6720, miR6087 and miR4532 were enriched in sEV compared to parental cells, p < 0.01. Signatures were similar in sEVs derived from non-stimulated or IL-1β stimulated SF., Conclusions: OA SF sEV regulate chondrocyte inflammatory and remodelling responses. OA SF sEV have unique signatures compared to parental cells which do not alter with IL-1β stimulation. This study provides insight into a novel regulatory mechanism within the OA joint which could inform future targeted therapy., (© 2024. The Author(s).)
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- 2024
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22. Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.
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Goodyear CS, Patel A, Barnes E, Willicombe M, Siebert S, de Silva TI, Snowden JA, Lim SH, Bowden SJ, Billingham L, Richter A, Carroll M, Carr EJ, Beale R, Rea D, Parry H, Pirrie S, Lim Z, Satsangi J, Dunachie SJ, Cook G, Miller P, Basu N, Gilmour A, Hodgkins AM, Evans L, Hughes A, Longet S, Meacham G, Yong KL, A'Hearne MJ, Koh MBC, Burns SO, Orchard K, Paterson C, McIlroy G, Murray SM, Thomson T, Dimitriadis S, Goulston L, Miller S, Keillor V, Prendecki M, Thomas D, Kirkham A, McInnes IB, and Kearns P
- Subjects
- Humans, Female, Male, Middle Aged, Aged, Antibodies, Viral blood, Prospective Studies, Immunization, Secondary, 2019-nCoV Vaccine mRNA-1273 immunology, Adult, T-Lymphocytes immunology, United Kingdom, ChAdOx1 nCoV-19 immunology, COVID-19 prevention & control, COVID-19 immunology, Immunocompromised Host immunology, SARS-CoV-2 immunology, COVID-19 Vaccines immunology, COVID-19 Vaccines administration & dosage, Immunogenicity, Vaccine, BNT162 Vaccine immunology, BNT162 Vaccine administration & dosage
- Abstract
Background: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies., Methods: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete., Findings: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related., Interpretation: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose., Funding: Medical Research Council, Blood Cancer UK., Competing Interests: Declaration of interests DR reports research funding from Roche, Biotheranostics, RNA diagnostics, and Celgene; and honoraria or consultancy fees from Novartis, Pfizer, Lily, Roche, and AstraZeneca–Diiachi Sankyo. EB reports research funding from Vaccitech; consultancy fees from Roche, Vaccitech, and AstraZeneca; and holds patents in ChAdOx1 hepatitis B virus and hepatitis C virus vaccines. HP reports honoraria from AstraZeneca. IBM reports research funding or consultancy fees from AbbVie, Amgen, Bristol-Myers Squibb (BMS), Causeway Therapeutics Cabaletta, Eli Lilly, Evelo Biosciences, Gilead, GSK, Janssen, Novartis, Pfizer, Sanofi Regeneron, and UCB; consultancy fees from AbbVie, Amgen, BMS, Causeway Therapeutics Cabaletta, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, and UCB; and is on the board of directors of Evelo Biosciences. KO reports royalties to his institution from Telix Pharmaceuticals for Radiolabelled anti-CD66 antibody; consulting fees from Sanofi and Takeda; and stocks in GSK. KLY reports honoraria from Sanofi Genzyme, Takeda, and Amgen; support for meeting attendance from Takeda; and participation on a trial steering committee for Sanofi and an advisory board for Janssen. MJA reports research funding from Pfizer. MW reports research funding from Oxford Immunotech. MBCK reports honoraria from Gilead. MC reports consultancy fees from VacciTech. PK reports research funding from Bayer; and consultancy fees from AstraZeneca, Merck, and BMS. SM reports stock options in TCB BioPharm. SHL reports honoraria from AstraZeneca. SS reports research funding from Amgen, Boehringer-Ingelheim, BMS, GSK, Janssen, and UCB; and consultancy fees or honoraria from AbbVie, Eli Lilly, GSK, Janssen, and UCB. SOB reports research funding from CSL Behring; and consultancy fees, honoraria, or support for attending meetings from GSK, Baxalta US, and Biotest. JAS reports honoraria from Novartis and Gilead; advisory board fees from the Kiadis clinical trial, Medac, and NHS England National Specialised Commissioning Clinical Reference Group for Blood and Marrow Transplantation; and unpaid roles as President of British Society of Blood and Marrow Transplantation and Cellular Therapy, secretary of the European Society for Blood and Marrow Transplantation and as a board member of the British Society of Haematology. SJD is a Scientific Advisor to the Scottish Parliament on COVID-19 for which she receives a fee. All other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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23. IĸB Protein BCL3 as a Controller of Osteogenesis and Bone Health.
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Jaffery H, Huesa C, Chilaka S, Cole J, Doonan J, Akbar M, Dunning L, Tanner KE, van 't Hof RJ, McInnes IB, Carmody RJ, and Goodyear CS
- Subjects
- Animals, Mice, Bone Density, Cell Differentiation, NF-kappa B metabolism, Osteoblasts metabolism, Osteoclasts metabolism, Bone and Bones metabolism, Osteogenesis, B-Cell Lymphoma 3 Protein genetics
- Abstract
Objective: IĸB protein B cell lymphoma 3-encoded protein (BCL3) is a regulator of the NF-κB family of transcription factors. NF-κB signaling fundamentally influences the fate of bone-forming osteoblasts and bone-resorbing osteoclasts, but the role of BCL3 in bone biology has not been investigated. The objective of this study was to evaluate BCL3 in skeletal development, maintenance, and osteoarthritic pathology., Methods: To assess the contribution of BCL3 to skeletal homeostasis, neonatal mice (n = 6-14) lacking BCL3 (Bcl3
-/- ) and wild-type (WT) controls were characterized for bone phenotype and density. To reveal the contribution to bone phenotype by the osteoblast compartment in Bcl3-/- mice, transcriptomic analysis of early osteogenic differentiation and cellular function (n = 3-7) were assessed. Osteoclast differentiation and function in Bcl3-/- mice (n = 3-5) was assessed. Adult 20-week Bcl3-/- and WT mice bone phenotype, strength, and turnover were assessed. A destabilization of the medial meniscus model of osteoarthritic osteophytogenesis was used to understand adult bone formation in Bcl3-/- mice (n = 11-13)., Results: Evaluation of Bcl3-/- mice revealed congenitally increased bone density, long bone dwarfism, increased bone biomechanical strength, and altered bone turnover. Molecular and cellular characterization of mesenchymal precursors showed that Bcl3-/- cells displayed an accelerated osteogenic transcriptional profile that led to enhanced differentiation into osteoblasts with increased functional activity, which could be reversed with a mimetic peptide. In a model of osteoarthritis-induced osteophytogenesis, Bcl3-/- mice exhibited decreased pathological osteophyte formation (P < 0.05)., Conclusion: Cumulatively, these findings demonstrate that BCL3 controls developmental mineralization to enable appropriate bone formation, whereas in a pathological setting, it contributes to skeletal pathology., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)- Published
- 2023
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24. Application of clinical and molecular profiling data to improve patient outcomes in psoriatic arthritis.
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FitzGerald O, Behrens F, Barton A, Bertheussen H, Boutouyrie-Dumont B, Coates L, Davies O, de Wit M, Fagni F, Goodyear CS, Gurke R, Hahnefeld L, Huppertz C, Ioannidis V, Ibberson M, Katz A, Klippstein M, Koehm M, Korish S, Mackay S, Martin DA, O'Sullivan D, Patel K, Rueping S, Schett G, Scholich K, Schwenk JM, Siebert S, Simon D, Vivekanantham A, and Pennington SR
- Abstract
Achieving a good outcome for a person with Psoriatic Arthritis (PsA) is made difficult by late diagnosis, heterogenous clinical disease expression and in many cases, failure to adequately suppress inflammatory disease features. Single-centre studies have certainly contributed to our understanding of disease pathogenesis, but to adequately address the major areas of unmet need, multi-partner, collaborative research programmes are now required. HIPPOCRATES is a 5-year, Innovative Medicines Initiative (IMI) programme which includes 17 European academic centres experienced in PsA research, 5 pharmaceutical industry partners, 3 small-/medium-sized industry partners and 2 patient-representative organizations. In this review, the ambitious programme of work to be undertaken by HIPPOCRATES is outlined and common approaches and challenges are identified. It is expected that, when completed, the results will ultimately allow for changes in the approaches to diagnosing, managing and treating PsA allowing for better short-term and long-term outcomes., Competing Interests: OF has received grants from AbbVie, Bristol Myers Squibb, Janssen, Eli-Lilly, Novartis, Pfizer and UCB. DS has received grants from AbbVie, Janssen, Eli-Lilly and Novartis. SK is an employee of and has stocks or stock options in Bristol Myers Squibb. LCC has received grants/research support from AbbVie, Amgen, Celgene, Eli-Lilly, Janssen, Novartis, Pfizer and UCB; worked as a paid consultant for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli-Lilly, Gilead, Galapagos, Janssen, Moonlake, Novartis, Pfizer and UCB and has been paid as a speaker for AbbVie, Amgen, Biogen, Celgene, Eli-Lilly, Galapagos, Gilead, GSK, Janssen, Medac, Novartis, Pfizer and UCB. FB and MK have received grants/research support from AbbVie, Amgen, Celgene, Eli-Lilly, Janssen, Novartis, Pfizer and UCB; worked as a paid consultant for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli-Lilly, Gilead, Galapagos, Janssen, Moonlake, Novartis, Pfizer and UCB and has been paid as a speaker for AbbVie, Amgen, Biogen, Celgene, Eli-Lilly, Galapagos, Gilead, GSK, Janssen, Medac, Novartis, Pfizer and UCB. AB has received grants/research support from Pfizer, Bristol Myers Squibb, Galapagos and Schiper Medicine and received speaker fees from Chugai-Roche. AV, MKl and JMS – no conflicts of interest to declare. CSG has received grants/research support from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim Pharmaceuticals, Eli-Lilly, Istesso, Janssen, MedAnnex, MiroBio, Pfizer, UCB; worked as a consultant for AstraZeneca, Bristol Myers Squibb, Janssen, MedAnnex, MiroBio; and has been paid as a speaker for AbbVie and UCB. BBD was an employee and then a consultant of Novartis Pharma AG. CH is an employee of Novartis Pharma AG. SS has received institutional research support from Amgen (previously Celgene), Boehringer Ingelheim, Bristol Myers Squibb, Eli-Lilly, GSK, Janssen and UCB; consultancy/speaker fees from AbbVie, Amgen, AstraZeneca, Eli-Lilly, GSK, Janssen and UCB. MdW: Over the last 3 years Stichting Tools has received fees for lectures or consultancy provided by Maarten de Wit from Celgene, Eli-Lilly, Pfizer and UCB., (© The Author(s), 2023.)
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- 2023
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25. Differential regulation of IL-17A and IL-17F via STAT5 contributes to psoriatic disease.
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Cole S, Manghera A, Burns L, Barrett J, Yager N, Rhys H, Skelton A, Cole J, Goodyear CS, Griffiths M, Baeten D, Bertolini M, Shaw S, Al-Mossawi H, and Maroof A
- Subjects
- Humans, Signal Transduction, Interleukin-17 metabolism, STAT5 Transcription Factor genetics, STAT5 Transcription Factor metabolism
- Abstract
Background: IL-17A plays a pivotal pathogenic role in several immune-mediated inflammatory diseases. Despite sharing 50% sequence homology with IL-17A, the role of IL-17F remains less clear. Clinical findings suggest that dual inhibition of IL-17A and IL-17F in psoriatic disease is more efficacious than IL-17A inhibition alone, positing a pathogenic role for IL-17F., Objective: We characterized the regulation of IL-17A and IL-17F in psoriatic disease., Methods: Using both in vitro systems and lesional skin tissue from patients, we interrogated the chromosomal, transcriptional, and protein expression landscape of IL-17A
+ and IL-17F+ TH 17 cells. Alongside established assays such as single-cell RNA sequencing, we developed a novel cytokine-capture technique that was combined with chromatin immunoprecipitation sequencing and RNA sequencing., Results: We confirm a preferential elevation of IL-17F over IL-17A in psoriatic disease and show that expression of each isoform predominantly occurs in distinct cell populations. The expression of both IL-17A and IL-17F exhibited a high degree of plasticity, with the balance between the 2 isoforms influenced by proinflammatory signaling and by anti-inflammatory drugs such as methylprednisolone. This plasticity was reflected in a broad H3K4me3 region at the IL17A-F locus, while opposing effects of STAT5/IL-2 signaling were observed for each of the 2 genes. Functionally, higher IL17F expression was linked to greater cell proliferation., Conclusion: There are key differences in the regulation of IL-17A and IL-17F in psoriatic disease, leading to distinct inflammatory cell populations. As such, we propose that both IL-17A and IL-17F neutralization may be required to maximally inhibit IL-17-driven pathology., (Copyright © 2023. Published by Elsevier Inc.)- Published
- 2023
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26. Double-negative-2 B cells are the major synovial plasma cell precursor in rheumatoid arthritis.
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Wing E, Sutherland C, Miles K, Gray D, Goodyear CS, Otto TD, Breusch S, Cowan G, and Gray M
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- Humans, Plasma Cells, B-Lymphocytes, Antibody-Producing Cells, Arthritis, Rheumatoid, B-Lymphocyte Subsets
- Abstract
B cells are key pathogenic drivers of chronic inflammation in rheumatoid arthritis (RA). There is limited understanding of the relationship between synovial B cell subsets and pathogenic antibody secreting cells (ASCs). This knowledge is crucial for the development of more targeted B-cell depleting therapies. While CD11c+ double-negative 2 (DN2) B cells have been suggested as an ASC precursor in lupus, to date there is no proven link between the two subsets in RA. We have used both single-cell gene expression and BCR sequencing to study synovial B cells from patients with established RA, in addition to flow cytometry of circulating B cells. To better understand the differentiation patterns within the diseased tissue, a combination of RNA-based trajectory inference and clonal lineage analysis of BCR relationships were used. Both forms of analysis indicated that DN2 B cells serve as a major precursors to synovial ASCs. This study advances our understanding of B cells in RA and reveals the origin of pathogenic ASCs in the RA synovium. Given the significant role of DN2 B cells as a progenitor to pathogenic B cells in RA, it is important to conduct additional research to investigate the origins of DN2 B cells in RA and explore their potential as therapeutic targets in place of the less specific pan-B cells depletion therapies currently in use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wing, Sutherland, Miles, Gray, Goodyear, Otto, Breusch, Cowan and Gray.)
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- 2023
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27. Low sulfated heparan sulfate mimetic differentially affects repair in immune-mediated and toxin-induced experimental models of demyelination.
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Lindsay SL, McCanney GA, Zhan J, Scheld M, Smith RS, Goodyear CS, Yates EA, Kipp M, Turnbull JE, and Barnett SC
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- Animals, Mice, Cuprizone toxicity, Sulfates adverse effects, Oligodendroglia pathology, Corpus Callosum pathology, Heparitin Sulfate therapeutic use, Mice, Inbred C57BL, Disease Models, Animal, Myelin Sheath pathology, Encephalomyelitis, Autoimmune, Experimental chemically induced, Encephalomyelitis, Autoimmune, Experimental drug therapy, Encephalomyelitis, Autoimmune, Experimental pathology, Central Nervous System Diseases pathology
- Abstract
There is an urgent need for therapies that target the multicellular pathology of central nervous system (CNS) disease. Modified, nonanticoagulant heparins mimic the heparan sulfate glycan family and are known regulators of multiple cellular processes. In vitro studies have demonstrated that low sulfated modified heparin mimetics (LS-mHeps) drive repair after CNS demyelination. Herein, we test LS-mHep7 (an in vitro lead compound) in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. In EAE, LS-mHep7 treatment resulted in faster recovery and rapidly reduced inflammation which was accompanied by restoration of animal weight. LS-mHep7 treatment had no effect on remyelination or on OLIG2 positive oligodendrocyte numbers within the corpus callosum in the cuprizone model. Further in vitro investigation confirmed that LS-mHep7 likely mediates its pro-repair effect in the EAE model by sequestering inflammatory cytokines, such as CCL5 which are upregulated during immune-mediated inflammatory attacks. These data support the future clinical translation of this next generation modified heparin as a treatment for CNS diseases with active immune system involvement., (© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)
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- 2023
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28. SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease.
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Barnes E, Goodyear CS, Willicombe M, Gaskell C, Siebert S, I de Silva T, Murray SM, Rea D, Snowden JA, Carroll M, Pirrie S, Bowden SJ, Dunachie SJ, Richter A, Lim Z, Satsangi J, Cook G, Pope A, Hughes A, Harrison M, Lim SH, Miller P, Klenerman P, Basu N, Gilmour A, Irwin S, Meacham G, Marjot T, Dimitriadis S, Kelleher P, Prendecki M, Clarke C, Mortimer P, McIntyre S, Selby R, Meardon N, Nguyen D, Tipton T, Longet S, Laidlaw S, Orchard K, Ireland G, Thomas D, Kearns P, Kirkham A, and McInnes IB
- Subjects
- Humans, COVID-19 Vaccines, BNT162 Vaccine, ChAdOx1 nCoV-19, Vaccination, Antibodies, Viral, SARS-CoV-2, COVID-19
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml
-1 ). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies., (© 2023. The Author(s).)- Published
- 2023
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29. Phenotypic heterogeneity in psoriatic arthritis: towards tissue pathology-based therapy.
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Najm A, Goodyear CS, McInnes IB, and Siebert S
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- Humans, Phenotype, Outcome Assessment, Health Care, Arthritis, Psoriatic drug therapy
- Abstract
Psoriatic arthritis (PsA) is a heterogeneous disease involving multiple potential tissue domains. Most outcome measures used so far in randomized clinical trials do not sufficiently reflect this domain heterogeneity. The concept that pathogenetic mechanisms might vary across tissues within a single disease, underpinning such phenotype diversity, could explain tissue-distinct levels of response to different therapies. In this Review, we discuss the tissue, cellular and molecular mechanisms that drive clinical heterogeneity in PsA phenotypes, and detail existing tissue-based research, including data generated using sophisticated interrogative technologies with single-cell precision. Finally, we discuss how these elements support the need for tissue-based therapy in PsA in the context of existing and new therapeutic modes of action, and the implications for future PsA trial outcomes and design., (© 2023. Springer Nature Limited.)
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- 2023
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30. C-terminal citrullinated peptide alters antigen-specific APC:T cell interactions leading to breach of immune tolerance.
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Malcolm J, Nyirenda MH, Brown JL, Adrados-Planell A, Campbell L, Butcher JP, Glass DG, Piela K, Goodyear CS, Wright AJ, McInnes IB, Millington OR, and Culshaw S
- Subjects
- Humans, Immune Tolerance, Peptides, Cell Communication, Citrulline, Arthritis, Rheumatoid
- Abstract
In rheumatoid arthritis, the emergence of anti-citrullinated autoimmunity is associated with HLA-antigen-T cell receptor complexes. The precise mechanisms underpinning this breach of tolerance are not well understood. Porphyromonas gingivalis expresses an enzyme capable of non-endogenous C-terminal citrullination with potential to generate citrullinated autoantigens. Here we document how C-terminal citrullination of ovalbumin peptide
323-339 alters the interaction between antigen-presenting cells and OTII T cells to induce functional changes in responding T cells. These data reveal that C-terminal citrullination is sufficient to breach T cell peripheral tolerance in vivo and reveal the potential of C-terminal citrullination to lower the threshold for T cell activation. Finally, we demonstrate a role for the IL-2/STAT5/CD25 signalling axis in breach of tolerance. Together, our data identify a tractable mechanism and targetable pathways underpinning breach of tolerance in rheumatoid arthritis and provide new conceptual insight into the origins of anti-citrullinated autoimmunity., Competing Interests: Declaration of competing interest IBM has received grants and honoraria from BMS, Pfizer, Lilly, Abbvie, Gilead and Galapagos., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)- Published
- 2023
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31. Differentiation of Functional Osteoclasts from Human Peripheral Blood CD14+ Monocytes.
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Riedlova P, Sood S, Goodyear CS, and Ansalone C
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- Humans, Actins, Cell Differentiation physiology, Cells, Cultured, Leukocytes, Mononuclear, Macrophage Colony-Stimulating Factor pharmacology, Monocytes, RANK Ligand, Bone Resorption, Osteoclasts
- Abstract
Osteoclasts (OCs) are bone-resorbing cells that play a pivotal role in skeletal development and adult bone remodeling. Several bone disorders are caused by increased differentiation and activation of OCs, so the inhibition of this pathobiology is a key therapeutic principle.Two key factors drive the differentiation of OCs from myeloid precursors: macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL). Human circulating CD14
+ monocytes have long been known to differentiate into OCs in vitro. However, the exposure time and the concentration of RANKL influence the differentiation efficiency. Indeed, protocols for the generation of human OCs in vitro have been described, but they often result in a poor and lengthy differentiation process. Herein, a robust and standardized protocol for generating functionally active mature human OCs in a timely manner is provided. CD14+ monocytes are enriched from human peripheral blood mononuclear cells (PBMCs) and primed with M-CSF to upregulate RANK. Subsequent exposure to RANKL generates OCs in a dose- and time-dependent manner. OCs are identified and quantified by staining with tartrate acid-resistant phosphatase (TRAP) and light microscopy analysis. Immunofluorescence staining of nuclei and F-actin is used to identify functionally active OCs. In addition, OSCAR+ CD14- mature OCs are further enriched via flow cytometry cell sorting, and OC functionality quantified by mineral (or dentine/bone) resorption assays and actin ring formation. Finally, a known OC inhibitor, rotenone, is used on mature OCs, demonstrating that adenosine triphosphate (ATP) production is essential for actin ring integrity and OC function. In conclusion, a robust assay for differentiating high numbers of OCs is established in this work, which in combination with actin ring staining and an ATP assay provides a useful in vitro model to evaluate OC function and to screen for novel therapeutic compounds that can modulate the differentiation process.- Published
- 2023
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32. JAK inhibitors disrupt T cell-induced proinflammatory macrophage activation.
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Nyirenda MH, Nijjar JS, Frleta-Gilchrist M, Gilchrist DS, Porter D, Siebert S, Goodyear CS, and McInnes IB
- Subjects
- Humans, Interleukin-10 pharmacology, Interleukin-10 therapeutic use, Synovial Membrane pathology, Interleukin-15 pharmacology, Interleukin-15 therapeutic use, Interleukin-6, Leukocytes, Mononuclear pathology, Macrophage Activation, Chemokine CXCL10 pharmacology, Chemokine CXCL10 therapeutic use, Macrophages, Cytokines, T-Lymphocytes, Janus Kinase Inhibitors pharmacology, Janus Kinase Inhibitors therapeutic use, Arthritis, Rheumatoid drug therapy
- Abstract
Objectives: Macrophage subsets, activated by T cells, are increasingly recognised to play a central role in rheumatoid arthritis (RA) pathogenesis. Janus kinase (JAK) inhibitors have proven beneficial clinical effects in RA. In this study, we investigated the effect of JAK inhibitors on the generation of cytokine-activated T (Tck) cells and the production of cytokines and chemokines induced by Tck cell/macrophage interactions., Methods: CD14
+ monocytes and CD4+ T cells were purified from peripheral blood mononuclear cells from buffy coats of healthy donors. As representative JAK inhibitors, tofacitinib or ruxolitinib were added during Tck cell differentiation. Previously validated protocols were used to generate macrophages and Tck cells from monocytes and CD4+ T cells, respectively. Cytokine and chemokine including TNF, IL-6, IL-15, IL-RA, IL-10, MIP1α, MIP1β and IP10 were measured by ELISA., Results: JAK inhibitors prevented cytokine-induced maturation of Tck cells and decreased the production of proinflammatory cytokines TNF, IL-6, IL-15, IL-1RA and the chemokines IL-10, MIP1α, MIP1β, IP10 by Tck cell-activated macrophages in vitro (p<0.05)., Conclusions: Our findings show that JAK inhibition disrupts T cell-induced macrophage activation and reduces downstream proinflammatory cytokine and chemokine responses, suggesting that suppressing the T cell-macrophage interaction contributes to the therapeutic effect of JAK inhibitors., Competing Interests: Competing interests: DP has received consultancy and sponsorship from Abbvie and Eli Lilly to attend scientific meetings. SS has received institutional research grants from Amgen (previously Celgene), Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline (GSK), Janssen, and UCB; and honoraria/speaker fees from AbbVie, Amgen, Eli Lilly, GSK, Janssen, and UCB. IBM has received consultancy and research support from Bristol Myers Squibb, Pfizer, Abbvie, Eli Lilly and Gilead, all of whom manufacture inhibitors of JAKs., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2023
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33. Moderate exercise protects against joint disease in a murine model of osteoarthritis.
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Huesa C, Dunning L, MacDougall K, Fegen M, Ortiz A, McCulloch K, McGrath S, Litherland GJ, Crilly A, Van 't Hof RJ, Ferrell WR, Goodyear CS, and Lockhart JC
- Abstract
Exercise is recommended as a non-pharmacological therapy for osteoarthritis (OA). Various exercise regimes, with differing intensities and duration, have been used in a range of OA rodent models. These studies show gentle or moderate exercise reduces the severity of OA parameters while high intensity load bearing exercise is detrimental. However, these studies were largely conducted in rats or in mouse models induced by severe injury, age or obesity, whilst destabilization of the medial meniscus (DMM) in mice has become a widely accepted model due to its lower variability, moderate progression and timescale. The present study was undertaken to provide insight into the effect of moderate exercise on early joint pathology in the DMM mouse model. Exercise was induced a week after induction by forced wheel walking for three or 7 weeks. Joints were analyzed by microcomputed tomography and histology. Assessment of skeletal parameters revealed that exercise offered protection against cartilage damage after 7 weeks of exercise, and a temporary protection against osteosclerosis was displayed after 3 weeks of exercise. Furthermore, exercise modified the metaphyseal trabecular microarchitecture of the osteoarthritic leg in both time points examined. Collectively, our findings corroborate previous studies showing that exercise has an important effect on bone in OA, which subsequently, at 8 weeks post-induction, translates into less cartilage damage. Thus, providing an exercise protocol in a surgical mouse model of OA, which can be used in the future to further dissect the mechanisms by which moderate exercise ameliorates OA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huesa, Dunning, MacDougall, Fegen, Ortiz, McCulloch, McGrath, Litherland, Crilly, Van ‘T Hof, Ferrell, Goodyear and Lockhart.)
- Published
- 2022
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34. A Specific Calprotectin Neo-epitope [CPa9-HNE] in Serum from Inflammatory Bowel Disease Patients Is Associated with Neutrophil Activity and Endoscopic Severity.
- Author
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Mortensen JH, Sinkeviciute D, Manon-Jensen T, Domislović V, McCall K, Thudium CS, Brinar M, Önnerfjord P, Goodyear CS, Krznarić Ž, Karsdal MA, and Bay-Jensen AC
- Subjects
- Biomarkers, Endoscopy, Gastrointestinal, Epitopes analysis, Feces chemistry, Humans, Leukocyte Elastase, Leukocyte L1 Antigen Complex analysis, Neutrophils chemistry, Severity of Illness Index, Colitis, Ulcerative diagnosis, Inflammatory Bowel Diseases diagnosis
- Abstract
Background and Aims: Endoscopy and the use of faecal calprotectin [faecal CP] are among the least-favoured methods for assessing disease activity by inflammatory bowel disease [IBD] patients; the handling/processing of faecal samples is also impractical. Therefore, we sought to develop a novel neo-epitope serum calprotectin enzyme-linked immunosorbent assay [ELISA], CPa9-HNE, with the aim of quantifying neutrophil activity and neutrophil extracellular trap [NET]-osis and proposing a non-invasive method for monitoring disease activity in IBD patients., Methods: In vitro cleavage was performed by mixing calprotectin [S100A9/S100A8] with human neutrophil elastase [HNE], and a novel HNE-derived calprotectin neo-epitope [CPa9-HNE] was identified by mass spectrometry for ELISA development. The CPa9-HNE ELISA was quantified in supernatants from ex vivo activated neutrophils and serum samples from patients with ulcerative colitis [UC, n = 43], Crohn's disease [CD, n = 93], and healthy subjects [HS, n = 23]. For comparison, faecal CP and MRP8/14 biomarkers were also measured., Results: CPa9-HNE was specific for activated neutrophils ex vivo. Serum CPa9-HNE levels were 4-fold higher in CD [p <0.0001] and UC [p <0.0001] patients than in HS. CPa9-HNE correlated well with the Simple Endoscopic Score [SES]-CD score [r = 0.61, p <0.0001], MES [r = 0.46, p = 0.0141], and the full Mayo score [r = 0.52, p = 0.0013]. CPa9-HNE was able to differentiate between CD and UC patients in endoscopic remission and moderate/severe disease activity (CD: area under the curve [AUC] = 0.82 [p = 0.0003], UC: AUC = 0.87 [p = 0.0004]). The performance of CPa9-HNE was equipotent or slightly better than that of faecal CP., Conclusions: Serum CPa9-HNE levels were highly associated with CD and UC patients. CPa9-HNE correlated with the SES-CD score and the full Mayo score, indicating a strong association with disease activity., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)
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- 2022
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35. Targeting 3D chromosomal architecture at the RANK loci to suppress myeloma-driven osteoclastogenesis.
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Thümmler K, Williams MT, Kitson S, Sood S, Akbar M, Cole JJ, Hunter E, Soutar R, and Goodyear CS
- Subjects
- Cell Differentiation genetics, Humans, Osteoclasts metabolism, Receptors, IgG genetics, Receptors, IgG metabolism, Tumor Microenvironment, Multiple Myeloma genetics, Multiple Myeloma metabolism, Osteogenesis genetics
- Abstract
Bone disease represents a major cause of morbidity and mortality in Multiple Myeloma (MM); primarily driven by osteoclasts whose differentiation is dependent on expression of RANKL by MM cells. Notably, costimulation by ITAM containing receptors (i.e., FcγR) can also play a crucial role in osteoclast differentiation. Modeling the pathology of the bone marrow microenvironment with an ex vivo culture system of primary human multiple myeloma cells, we herein demonstrate that FcγR-mediated signaling, via staphylococcal protein A (SpA) IgG immune-complexes, can act as a critical negative regulator of MM-driven osteoclast differentiation. Interrogation of the mode-of-action revealed that FcγR-mediated signaling causes epigenetic modulation of chromosomal 3D architecture at the RANK promoter; with altered spatial orientation of a proximal super enhancer. Combined this leads to substantial down-regulation of RANK at a transcript, protein, and functional level. These observations shed light on a novel mechanism regulating RANK expression and provide a rationale for targeting FcγR-signaling for the amelioration of osteolytic bone pathology in disease., Competing Interests: E.H is a full-time employee at Oxford Biodynamics Limited and has no other competing financial interests. The other authors declare no competing financial interests., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Published
- 2022
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36. Destabilization of the Medial Meniscus and Cartilage Scratch Murine Model of Accelerated Osteoarthritis.
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Dunning L, McCulloch K, Lockhart JC, Goodyear CS, and Huesa C
- Subjects
- Animals, Disease Models, Animal, Humans, Menisci, Tibial diagnostic imaging, Menisci, Tibial surgery, Mice, X-Ray Microtomography, Cartilage, Articular diagnostic imaging, Osteoarthritis diagnostic imaging, Osteoarthritis etiology, Osteoarthritis pathology
- Abstract
Osteoarthritis is the most prevalent musculoskeletal disease in people over 45, leading to an increasing economic and societal cost. Animal models are used to mimic many aspects of the disease. The present protocol describes the destabilization and cartilage scratch model (DCS) of post-traumatic osteoarthritis. Based on the widely used destabilization of the medial meniscus (DMM) model, DCS introduces three scratches on the cartilage surface. The current article highlights the steps to destabilize the knee by transecting the medial meniscotibial ligament followed by three intentional superficial scratches on the articular cartilage. The possible analysis methods by dynamic weight-bearing, microcomputed tomography, and histology are also demonstrated. While the DCS model is not recommended for studies that focus on the effect of osteoarthritis on the cartilage, it enables the study of osteoarthritis development in a shorter time window, with special focus on (1) osteophyte formation, (2) osteoarthritic and injury pain, and (3) the effect of cartilage damage in the whole joint.
- Published
- 2022
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37. Annexin-A1: The culprit or the solution?
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Kelly L, McGrath S, Rodgers L, McCall K, Tulunay Virlan A, Dempsey F, Crichton S, and Goodyear CS
- Subjects
- Adaptive Immunity, Animals, Anti-Inflammatory Agents, Humans, Inflammation, Mice, Receptors, Formyl Peptide metabolism, T-Lymphocytes metabolism, Annexin A1 metabolism
- Abstract
Annexin-A1 has a well-defined anti-inflammatory role in the innate immune system, but its function in adaptive immunity remains controversial. This glucocorticoid-induced protein has been implicated in a range of inflammatory conditions and cancers, as well as being found to be overexpressed on the T cells of patients with autoimmune disease. Moreover, the formyl peptide family of receptors, through which annexin-A1 primarily signals, has also been implicated in these diseases. In contrast, treatment with recombinant annexin-A1 peptides resulted in suppression of inflammatory processes in murine models of inflammation. This review will focus on what is currently known about annexin-A1 in health and disease and discuss the potential of this protein as a biomarker and therapeutic target., (© 2022 The Authors. Immunology published by John Wiley & Sons Ltd.)
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- 2022
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38. Human olfactory mesenchymal stromal cell transplantation ameliorates experimental autoimmune encephalomyelitis revealing an inhibitory role for IL16 on myelination.
- Author
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Lindsay SL, Molęda AM, MacLellan LM, Keh SM, McElroy DE, Linington C, Goodyear CS, and Barnett SC
- Subjects
- Animals, Encephalomyelitis, Autoimmune, Experimental metabolism, Humans, Mice, Neurogenesis physiology, Encephalomyelitis, Autoimmune, Experimental therapy, Interleukin-16 metabolism, Mesenchymal Stem Cell Transplantation methods, Myelin Sheath metabolism, Olfactory Mucosa cytology
- Abstract
One of the therapeutic approaches for the treatment of the autoimmune demyelinating disease, multiple sclerosis (MS) is bone marrow mesenchymal stromal cell (hBM-MSCs) transplantation. However, given their capacity to enhance myelination in vitro, we hypothesised that human olfactory mucosa-derived MSCs (hOM-MSCs) may possess additional properties suitable for CNS repair. Herein, we have examined the efficacy of hOM-MSCs versus hBM-MSCs using the experimental autoimmune encephalomyelitis (EAE) model. Both MSC types ameliorated disease, if delivered during the initial onset of symptomatic disease. Yet, only hOM-MSCs improved disease outcome if administered during established disease when animals had severe neurological deficits. Histological analysis of spinal cord lesions revealed hOM-MSC transplantation reduced blood-brain barrier disruption and inflammatory cell recruitment and enhanced axonal survival. At early time points post-hOM-MSC treatment, animals had reduced levels of circulating IL-16, which was reflected in both the ability of immune cells to secrete IL-16 and the level of IL-16 in spinal cord inflammatory lesions. Further in vitro investigation revealed an inhibitory role for IL-16 on oligodendrocyte differentiation and myelination. Moreover, the availability of bioactive IL-16 after demyelination was reduced in the presence of hOM-MSCs. Combined, our data suggests that human hOM-MSCs may have therapeutic benefit in the treatment of MS via an IL-16-mediated pathway, especially if administered during active demyelination and inflammation., (© 2022. The Author(s).)
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- 2022
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39. Large-vessel vasculitis.
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Pugh D, Karabayas M, Basu N, Cid MC, Goel R, Goodyear CS, Grayson PC, McAdoo SP, Mason JC, Owen C, Weyand CM, Youngstein T, and Dhaun N
- Subjects
- Adult, Aorta, Humans, Giant Cell Arteritis complications, Giant Cell Arteritis diagnosis, Giant Cell Arteritis epidemiology, Takayasu Arteritis complications, Takayasu Arteritis diagnosis, Takayasu Arteritis therapy
- Abstract
Large-vessel vasculitis (LVV) manifests as inflammation of the aorta and its major branches and is the most common primary vasculitis in adults. LVV comprises two distinct conditions, giant cell arteritis and Takayasu arteritis, although the phenotypic spectrum of primary LVV is complex. Non-specific symptoms often predominate and so patients with LVV present to a range of health-care providers and settings. Rapid diagnosis, specialist referral and early treatment are key to good patient outcomes. Unfortunately, disease relapse remains common and chronic vascular complications are a source of considerable morbidity. Although accurate monitoring of disease activity is challenging, progress in vascular imaging techniques and the measurement of laboratory biomarkers may facilitate better matching of treatment intensity with disease activity. Further, advances in our understanding of disease pathophysiology have paved the way for novel biologic treatments that target important mediators of disease in both giant cell arteritis and Takayasu arteritis. This work has highlighted the substantial heterogeneity present within LVV and the importance of an individualized therapeutic approach. Future work will focus on understanding the mechanisms of persisting vascular inflammation, which will inform the development of increasingly sophisticated imaging technologies. Together, these will enable better disease prognostication, limit treatment-associated adverse effects, and facilitate targeted development and use of novel therapies., (© 2022. Springer Nature Limited.)
- Published
- 2022
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40. Apremilast inhibits inflammatory osteoclastogenesis.
- Author
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Degboé Y, Sunzini F, Sood S, Bozec A, Sokolova MV, Zekovic A, McInnes IB, Schett G, and Goodyear CS
- Subjects
- Adult, Aged, Arthritis, Psoriatic drug therapy, Case-Control Studies, Cytokines metabolism, Drug Evaluation, Preclinical, Female, Humans, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, Male, Middle Aged, Phosphodiesterase 4 Inhibitors therapeutic use, Primary Cell Culture, Thalidomide pharmacology, Thalidomide therapeutic use, Osteogenesis drug effects, Phosphodiesterase 4 Inhibitors pharmacology, Thalidomide analogs & derivatives
- Abstract
Objectives: Psoriatic arthritis (PsA) is associated with bone erosion and inflammation-induced bone loss, which are mediated by osteoclasts (OC) and modulated by inflammatory cytokines. Apremilast (APR) (a selective phosphodiesterase 4 inhibitor) is efficacious in PsA and acts by inhibiting cytokine production. However, there are no direct data informing whether and how APR affects osteoclast formation in humans., Methods: Osteoclastogenic cytokine production by activated human peripheral blood mononuclear cells (PBMCs) was measured in the presence and absence of APR. Effects of APR on osteoclast differentiation were tested (i) in co-cultures of activated PBMCs and human CD14+ blood monocytes as well as (ii) in CD14+ blood monocytes stimulated with activated-PBMCs supernatant, TNF or IL-17A. Bone resorption was measured on OsteoAssay plates. Effects of APR on ex vivo osteoclast differentiation were compared in PsA, pre-PsA and psoriasis patients, as well as in healthy controls., Results: APR significantly impaired the expression of key osteoclastogenic cytokines in activated PBMCs. Furthermore, APR dose-dependently and significantly inhibited activated PBMC-driven osteoclast differentiation and ex vivo osteoclast differentiation of PBMCs derived from PsA and pre-PsA patients, but not from psoriasis patients or healthy controls. TNF and IL-17A-enhanced osteoclastogenesis and osteolytic activity of CD14+ blood monocytes from PsA patients was also significantly inhibited by APR. Finally, APR inhibited expression of the key osteoclast fusion protein dendritic cell-specific transmembrane protein., Conclusion: Phosphodiesterase 4 targeting by APR not only inhibits osteoclastogenic cytokine production, but also directly suppresses inflammation-driven osteoclastogenesis. These data provide initial evidence that APR has the potential to provide a direct bone protective effect in PsA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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41. Defining the structure of the NF-ĸB pathway in human immune cells using quantitative proteomic data.
- Author
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Kok FO, Wang H, Riedlova P, Goodyear CS, and Carmody RJ
- Subjects
- Animals, Humans, I-kappa B Kinase metabolism, Mice, Protein Serine-Threonine Kinases, Signal Transduction, NF-kappa B metabolism, Proteomics
- Abstract
The NF-ĸB transcription factor is a critical regulator of immune homeostasis and inflammatory responses and is a critical factor in the pathogenesis of inflammatory disease. The pathways to NF-ĸB activation are paradigms for signal-induced ubiquitination and proteasomal degradation, control of transcription factor function by subcellular localisation, and the control of gene transcription and physiological processes by signal transduction mechanisms. Despite the importance of NF-ĸB in disease, the NF-ĸB pathway remains unexploited for the treatment of inflammatory disease. Our understanding of NF-ĸB comes mostly from studies of transgenic mice and cell lines where components of the pathway have been deleted or over expressed. Recent advances in quantitative proteomics offer new opportunities to understand the NF-ĸB pathway using the absolute abundance of individual pathway components. We have analysed available quantitative proteomic datasets to establish the structure of the NF-ĸB pathway in human immune cells under both steady state and activated conditions. This reveals a conserved NF-κB pathway structure across different immune cell lineages and identifies important differences to the current model of the NF-ĸB pathway. These include the findings that the IKK complex in most cells is likely to consist predominantly of IKKβ homodimers, that the relative abundancies of IκB proteins show strong cell type variation, and that the components of the non-canonical NF-ĸB pathway are significantly increased in activated immune cells. These findings challenge aspects of our current view of the NF-κB pathway and identify outstanding questions important for defining the role of key components in regulating inflammation and immunity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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42. Nanovibrational stimulation inhibits osteoclastogenesis and enhances osteogenesis in co-cultures.
- Author
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Kennedy JW, Tsimbouri PM, Campsie P, Sood S, Childs PG, Reid S, Young PS, Meek DRM, Goodyear CS, and Dalby MJ
- Subjects
- Bone Marrow Cells metabolism, Humans, Nanotechnology, Osteoclasts metabolism, Osteoclasts pathology, Bone Marrow Cells cytology, Cell Differentiation, Coculture Techniques methods, Osteoclasts cytology, Osteogenesis, Vibration
- Abstract
Models of bone remodelling could be useful in drug discovery, particularly if the model is one that replicates bone regeneration with reduction in osteoclast activity. Here we use nanovibrational stimulation to achieve this in a 3D co-culture of primary human osteoprogenitor and osteoclast progenitor cells. We show that 1000 Hz frequency, 40 nm amplitude vibration reduces osteoclast formation and activity in human mononuclear CD14
+ blood cells. Additionally, this nanoscale vibration both enhances osteogenesis and reduces osteoclastogenesis in a co-culture of primary human bone marrow stromal cells and bone marrow hematopoietic cells. Further, we use metabolomics to identify Akt (protein kinase C) as a potential mediator. Akt is known to be involved in bone differentiation via transforming growth factor beta 1 (TGFβ1) and bone morphogenetic protein 2 (BMP2) and it has been implicated in reduced osteoclast activity via Guanine nucleotide-binding protein subunit α13 (Gα13). With further validation, our nanovibrational bioreactor could be used to help provide humanised 3D models for drug screening., (© 2021. The Author(s).)- Published
- 2021
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43. Searchlight: automated bulk RNA-seq exploration and visualisation using dynamically generated R scripts.
- Author
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Cole JJ, Faydaci BA, McGuinness D, Shaw R, Maciewicz RA, Robertson NA, and Goodyear CS
- Subjects
- RNA-Seq, Exome Sequencing, Workflow, Publications, Software
- Abstract
Background: Once bulk RNA-seq data has been processed, i.e. aligned and then expression and differential tables generated, there remains the essential process where the biology is explored, visualized and interpreted. Without the use of a visualisation and interpretation pipeline this step can be time consuming and laborious, and is often completed using R. Though commercial visualisation and interpretation pipelines are comprehensive, freely available pipelines are currently more limited., Results: Here we demonstrate Searchlight, a freely available bulk RNA-seq visualisation and interpretation pipeline. Searchlight provides: a comprehensive statistical and visual analysis, focusing on the global, pathway and single gene levels; compatibility with most differential experimental designs irrespective of organism or experimental complexity, via three workflows; reports; and support for downstream user modification of plots via user-friendly R-scripts and a Shiny app. We show that Searchlight offers greater automation than current best tools (VIPER and BioJupies). We demonstrate in a timed re-analysis study, that alongside a standard bulk RNA-seq processing pipeline, Searchlight can be used to complete bulk RNA-seq projects up to the point of manuscript quality figures, in under 3 h., Conclusions: Compared to a manual R based analysis or current best freely available pipelines (VIPER and BioJupies), Searchlight can reduce the time and effort needed to complete bulk RNA-seq projects to manuscript level. Searchlight is suitable for bioinformaticians, service providers and bench scientists. https://github.com/Searchlight2/Searchlight2 ., (© 2021. The Author(s).)
- Published
- 2021
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44. Losartan protects endothelium-dependent relaxation in vivo in a murine model of rheumatoid arthritis.
- Author
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Villaluz M, Dunning L, Goodyear CS, Ferrell WR, Lockhart JC, and MacKenzie A
- Subjects
- Acetylcholine pharmacology, Angiotensin II Type 1 Receptor Blockers administration & dosage, Animals, Arteries drug effects, Arthralgia chemically induced, Arthralgia drug therapy, Blood Circulation drug effects, Cytokines blood, Freund's Adjuvant toxicity, Injections, Intraperitoneal, Knee Joint drug effects, Losartan administration & dosage, Male, Mice, Inbred C57BL, Nitroprusside pharmacology, Weight-Bearing, Mice, Angiotensin II Type 1 Receptor Blockers pharmacology, Arthritis, Experimental drug therapy, Arthritis, Rheumatoid drug therapy, Losartan pharmacology
- Abstract
Angiotensin II-type 1 receptor stimulation is recognised to promote inflammation, a state central to the development and maintenance of rheumatoid arthritis. Herein we examined the use of losartan, an angiotensin II-type 1 receptor antagonist, on vascular reactivity, knee joint diameter and behavioural assessment of pain in a Freund's complete adjuvant (FCA) mouse model of joint inflammation. Monoarthritis was induced via FCA in the presence or absence of losartan with naive mice serving as controls. Knee joint swelling, joint pain (assessed by dynamic weight bearing of limb use), knee joint artery reactivity (assessed ex vivo) and blood perfusion of the knee joint (assessed in vivo) were determined. FCA mediated a significant increase in knee joint diameter and reduced weight-bearing (a surrogate for pain sensation) of the affected limb. Notably, these phenomena were substantially reduced when mice were prophylactically treated with losartan. Assessment of arterial relaxation and blood perfusion with acetylcholine stimulation revealed that FCA resulted in significant vascular dysfunction, which was resolved to naïve levels with losartan treatment. Through the actions of losartan, these findings indicate that the angiotensin II-type 1 receptor is a likely therapeutic target of importance in the development of the physical changes, pain sensation and vascular dysfunction found in inflammatory arthritis., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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45. BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study): protocol for a non-randomised longitudinal cohort study.
- Author
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Rayner F, Anderson AE, Baker KF, Buckley CD, Dyke B, Fenton S, Filer A, Goodyear CS, Hilkens CMU, Hiu S, Kerrigan S, Kurowska-Stolarska M, Matthews F, McInnes I, Ng WF, Pratt AG, Prichard J, Raza K, Siebert S, Stocken D, Teare MD, Young S, and Isaacs JD
- Abstract
Background: Our knowledge of immune-mediated inflammatory disease (IMID) aetiology and pathogenesis has improved greatly over recent years, however, very little is known of the factors that trigger disease relapses (flares), converting diseases from inactive to active states. Focussing on rheumatoid arthritis (RA), the challenge that we will address is why IMIDs remit and relapse. Extrapolating from pathogenetic factors involved in disease initiation, new episodes of inflammation could be triggered by recurrent systemic immune dysregulation or locally by factors within the joint, either of which could be endorsed by overarching epigenetic factors or changes in systemic or localised metabolism., Methods: The BIO-FLARE study is a non-randomised longitudinal cohort study that aims to enrol 150 patients with RA in remission on a stable dose of non-biologic disease-modifying anti-rheumatic drugs (DMARDs), who consent to discontinue treatment. Participants stop their DMARDs at time 0 and are offered an optional ultrasound-guided synovial biopsy. They are studied intensively, with blood sampling and clinical evaluation at weeks 0, 2, 5, 8, 12 and 24. It is anticipated that 50% of participants will have a disease flare, whilst 50% remain in drug-free remission for the study duration (24 weeks). Flaring participants undergo an ultrasound-guided synovial biopsy before reinstatement of previous treatment. Blood samples will be used to investigate immune cell subsets, their activation status and their cytokine profile, autoantibody profiles and epigenetic profiles. Synovial biopsies will be examined to profile cell lineages and subtypes present at flare. Blood, urine and synovium will be examined to determine metabolic profiles. Taking into account all generated data, multivariate statistical techniques will be employed to develop a model to predict impending flare in RA, highlighting therapeutic pathways and informative biomarkers. Despite initial recruitment to time and target, the SARS-CoV-2 pandemic has impacted significantly, and a decision was taken to close recruitment at 118 participants with complete data., Discussion: This study aims to investigate the pathogenesis of flare in rheumatoid arthritis, which is a significant knowledge gap in our understanding, addressing a major unmet patient need., Trial Registration: The study was retrospectively registered on 27/06/2019 in the ISRCTN registry 16371380 ., (© 2021. The Author(s).)
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- 2021
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46. TNF is a homoeostatic regulator of distinct epigenetically primed human osteoclast precursors.
- Author
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Ansalone C, Cole J, Chilaka S, Sunzini F, Sood S, Robertson J, Siebert S, McInnes IB, and Goodyear CS
- Subjects
- Cell Differentiation genetics, Homeostasis, Humans, Osteogenesis, RANK Ligand metabolism, Tumor Necrosis Factor-alpha, Arthritis, Rheumatoid pathology, Osteoclasts pathology
- Abstract
Objectives: Circulating myeloid precursors are responsible for post-natal osteoclast (OC) differentiation and skeletal health, although the exact human precursors have not been defined. Enhanced osteoclastogenesis contributes to joint destruction in rheumatoid arthritis (RA) and tumour necrosis factor (TNF) is a well-known pro-osteoclastogenic factor. Herein, we investigated the interplay between receptor activator of nuclear factor kappa-Β ligand (RANK-L), indispensable for fusion of myeloid precursors and the normal development of OCs, and TNF in directing the differentiation of diverse pre-OC populations derived from human peripheral blood., Methods: Flow cytometric cell sorting and analysis was used to assess the potential of myeloid populations to differentiate into OCs. Transcriptomic, epigenetic analysis, receptor expression and inhibitor experiments were used to unravel RANK-L and TNF signalling hierarchy., Results: TNF can act as a critical homoeostatic regulator of CD14
+ monocyte (MO) differentiation into OCs by inhibiting osteoclastogenesis to favour macrophage development. In contrast, a distinct previously unidentified CD14- CD16- CD11c+ myeloid pre-OC population was exempt from this negative regulation. In healthy CD14+ MOs, TNF drove epigenetic modification of the RANK promoter via a TNFR1-IKKβ-dependent pathway and halted osteoclastogenesis. In a subset of patients with RA, CD14+ MOs exhibited an altered epigenetic state that resulted in dysregulated TNF-mediated OC homoeostasis., Conclusions: These findings fundamentally re-define the relationship between RANK-L and TNF. Moreover, they have identified a novel pool of human circulating non-MO OC precursors that unlike MOs are epigenetically preconditioned to ignore TNF-mediated signalling. In RA, this epigenetic preconditioning occurs in the MO compartment providing a pathological consequence of failure of this pathway., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2021
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47. Analysis of Prostate Cancer Tumor Microenvironment Identifies Reduced Stromal CD4 Effector T-cell Infiltration in Tumors with Pelvic Nodal Metastasis.
- Author
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Ntala C, Salji M, Salmond J, Officer L, Teodosio AV, Blomme A, McGhee EJ, Powley I, Ahmad I, Kruithof-de Julio M, Thalmann G, Roberts E, Goodyear CS, Jamaspishvili T, Berman DM, Carlin LM, Le Quesne J, and Leung HY
- Abstract
Background: Pelvic nodal metastasis in prostate cancer impacts patient outcome negatively., Objective: To explore tumor-infiltrating immune cells as a potential predictive tool for regional lymph node (LN) metastasis., Design Setting and Participants: We applied multiplex immunofluorescence and targeted transcriptomic analysis on 94 radical prostatectomy specimens in patients with (LN+) or without (LN-) pelvic nodal metastases. Both intraepithelial and stromal infiltrations of immune cells and differentially expressed genes (mRNA and protein levels) were correlated with the nodal status., Outcome Measurements and Statistical Analysis: The identified CD4 effector cell signature of nodal metastasis was validated in a comparable independent patient cohort of 184 informative cases. Patient outcome analysis and decision curve analysis were performed with the CD4 effector cell density-based signature., Results and Limitations: In the discovery cohort, both tumor epithelium and stroma from patients with nodal metastasis had significantly lower infiltration of multiple immune cell types, with stromal CD4 effector cells highlighted as the top candidate marker. Targeted gene expression analysis and confirmatory protein analysis revealed key alteration of extracellular matrix components in tumors with nodal metastasis. Of note, stromal CD4 immune cell density was a significant independent predictor of LN metastasis (odds ratio [OR] = 0.15, p = 0.004), and was further validated as a significant predictor of nodal metastasis in the validation cohort (OR = 0.26, p < 0.001)., Conclusions: Decreased T-cell infiltrates in the primary tumor (particularly CD4 effector cells) are associated with a higher risk of LN metastasis. Future evaluation of CD4-based assays on prostate cancer diagnostic biopsy materials may improve selection of at-risk patients for the treatment of LN metastasis., Patient Summary: In this report, we found that cancer showing evidence of cancer metastasis to the lymph nodes tends to have less immune cells present within the tumor. We conclude that the extent of immune cells present within a prostate tumor can help doctors determine the most appropriate treatment plan for individual patients., (© 2021 Published by Elsevier B.V. on behalf of European Association of Urology.)
- Published
- 2021
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48. Clonal haematopoiesis of indeterminate potential: intersections between inflammation, vascular disease and heart failure.
- Author
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Mooney L, Goodyear CS, Chandra T, Kirschner K, Copland M, Petrie MC, and Lang NN
- Subjects
- Aging, Humans, Risk Factors, Stroke Volume, Cardiovascular Diseases, Clonal Hematopoiesis, Heart Failure, Inflammation
- Abstract
Ageing is a major risk factor for the development of cardiovascular disease (CVD) and cancer. Whilst the cumulative effect of exposure to conventional cardiovascular risk factors is important, recent evidence highlights clonal haematopoiesis of indeterminant potential (CHIP) as a further key risk factor. CHIP reflects the accumulation of somatic, potentially pro-leukaemic gene mutations within haematopoietic stem cells over time. The most common mutations associated with CHIP and CVD occur in genes that also play central roles in the regulation of inflammation. While CHIP carriers have a low risk of haematological malignant transformation (<1% per year), their relative risk of mortality is increased by 40% and this reflects an excess of cardiovascular events. Evidence linking CHIP, inflammation and atherosclerotic disease has recently become better defined. However, there is a paucity of information about the role of CHIP in the development and progression of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). While systemic inflammation plays a role in the pathophysiology of both heart failure with reduced and preserved ejection fraction (EF), it may be of greater relevance in the pathophysiology of HFpEF, which is also strongly associated with ageing. This review describes CHIP and its pathogenetic links with ageing, inflammation and CVD, while providing insight into its putative role in HFpEF., (© 2021 The Author(s).)
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- 2021
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49. MicroRNA-17-5p Reduces Inflammation and Bone Erosions in Mice With Collagen-Induced Arthritis and Directly Targets the JAK/STAT Pathway in Rheumatoid Arthritis Fibroblast-like Synoviocytes.
- Author
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Najm A, Masson FM, Preuss P, Georges S, Ory B, Quillard T, Sood S, Goodyear CS, Veale DJ, Fearon U, Le Goff B, and Blanchard F
- Subjects
- Animals, Arthritis, Experimental genetics, Arthritis, Experimental pathology, Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid pathology, Cell Proliferation physiology, Cytokines metabolism, Fibroblasts metabolism, Fibroblasts pathology, Humans, Inflammation genetics, Inflammation metabolism, Inflammation pathology, Janus Kinases metabolism, Mice, MicroRNAs genetics, STAT Transcription Factors metabolism, Synovial Membrane metabolism, Synovial Membrane pathology, Synoviocytes pathology, Arthritis, Experimental metabolism, Arthritis, Rheumatoid metabolism, MicroRNAs metabolism, Signal Transduction genetics, Synoviocytes metabolism
- Abstract
Objective: We undertook this study to examine microRNA (miRNA) expression across rheumatoid arthritis (RA) phenotypes, along with the effects and mechanisms of action of miRNA-17-5p (miR-17)., Methods: A miRNA array was performed in synovial tissue biopsied from patients with naive erosive RA (n = 3) and patients with nonerosive RA (n = 3). MicroRNA-17 lipoplex was delivered intraarticularly in the murine collagen-induced arthritis model. Clinical, histologic, and structural effects were studied over the course of arthritis. In-depth studies of the mechanisms of action of miR-17 were performed in primary RA fibroblast-like synoviocytes (FLS) isolated from synovial tissue., Results: Fifty-five miRNAs including miR-17 were reduced in erosive RA. The miR-17 transfection into arthritic paws reduced the clinical inflammation score between day 2 and day 7 (2.8 versus 1.9; P = 0.03). Synovial B cell, T cell, macrophage, and polynuclear neutrophil infiltration was significantly reduced. Structural damage was also decreased, as shown by a reduction in the number of osteoclasts detected using tartrate-resistant acid phosphatase staining (osteoclast surface/bone surface 32% versus 18%; P = 0.005) and erosion score by computed tomography analysis (2.9 versus 1.7; P = 0.023). Proinflammatory cytokines from the interleukin-6 (IL-6) family and IL-1β expression were also significantly reduced, but tumor necrosis factor was not. MicroRNA-17 directly targeted the 3'-untranslated regions of STAT3 and JAK1. STAT3 and JAK1 messenger RNA (mRNA) and protein expression were reduced in RA FLS following miR-17 transfection. STAT3 and JAK1 mRNA and activation of STAT3, as assessed by immunohistochemistry, were also reduced in injected paws (% stained area 93% versus 62%; P = 0.035)., Conclusion: We demonstrate an antiinflammatory and antierosive role of miR-17 in vivo. This effect involves the suppression of the IL-6 family autocrine-amplifying loop through the direct targeting of JAK1 and STAT3., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
- Published
- 2020
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50. β2 Integrins differentially regulate γδ T cell subset thymic development and peripheral maintenance.
- Author
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McIntyre CL, Monin L, Rop JC, Otto TD, Goodyear CS, Hayday AC, and Morrison VL
- Subjects
- Animals, Homeostasis immunology, Interleukin-17 genetics, Interleukin-17 immunology, Interleukin-17 metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, CD18 Antigens genetics, CD18 Antigens immunology, CD18 Antigens metabolism, Intraepithelial Lymphocytes immunology, Intraepithelial Lymphocytes metabolism, Intraepithelial Lymphocytes physiology, Thymus Gland growth & development, Thymus Gland immunology, Thymus Gland metabolism
- Abstract
The γδ T cells reside predominantly at barrier sites and play essential roles in immune protection against infection and cancer. Despite recent advances in the development of γδ T cell immunotherapy, our understanding of the basic biology of these cells, including how their numbers are regulated in vivo, remains poor. This is particularly true for tissue-resident γδ T cells. We have identified the β
2 family of integrins as regulators of γδ T cells. β2 -integrin-deficient mice displayed a striking increase in numbers of IL-17-producing Vγ6Vδ1+ γδ T cells in the lungs, uterus, and circulation. Thymic development of this population was normal. However, single-cell RNA sequencing revealed the enrichment of genes associated with T cell survival and proliferation specifically in β2 -integrin-deficient IL-17+ cells compared to their wild-type counterparts. Indeed, β2 -integrin-deficient Vγ6+ cells from the lungs showed reduced apoptosis ex vivo, suggesting that increased survival contributes to the accumulation of these cells in β2 -integrin-deficient tissues. Furthermore, our data revealed an unexpected role for β2 integrins in promoting the thymic development of the IFNγ-producing CD27+ Vγ4+ γδ T cell subset. Together, our data reveal that β2 integrins are important regulators of γδ T cell homeostasis, inhibiting the survival of IL-17-producing Vγ6Vδ1+ cells and promoting the thymic development of the IFNγ-producing Vγ4+ subset. Our study introduces unprecedented mechanisms of control for γδ T cell subsets., Competing Interests: The authors declare no competing interest.- Published
- 2020
- Full Text
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