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1. Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

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Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., S. M. E., Ng, Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., S. M., Ng, Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Munroe, P. B., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Ovington, N. R., Owen, M. J., Palin, K., Palotie, A., Parnell, K., Pearson, R., Pernet, D., Perry, J. R., Phillips, A., Plagnol, V., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Robson, S., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Sawcer, S. J., Schuilenburg, H., Scott, C. E., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stirrups, K., Stone, M. A., Strachan, D. P., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Tobin, M. D., Travers, M. E., Turnbull, C., Vukcevic, D., Wain, L. V., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Yau, C., Young, A. H., Zeggini, E., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Hurles, M. E., Duncanson, A., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., Kwiatkowski, D. P., Mccarthy, M. I., Craddock, N., Deloukas, P., Donnelly, P., Blackwell, J. M., Bramon, E., Casas, J. P., Corvin, A., Jankowski, J., Markus, H. S., Palmer, C. N., Plomin, R., Rautanen, A., Trembath, R. C., Viswanathan, A. C., Wood, N. W., Spencer, C. C. A., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Pirinen, M., Strange, A., Blackburn, H., Bumpstead, S. J., Dronov, S., Gillman, M., Jayakumar, A., Mccann, O. T., Liddle, J., Potter, S. C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., Ng, S. M. E., Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., Ng, S. M., Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Munroe, P. B., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Ovington, N. R., Owen, M. J., Palin, K., Palotie, A., Parnell, K., Pearson, R., Pernet, D., Perry, J. R., Phillips, A., Plagnol, V., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Robson, S., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Sawcer, S. J., Schuilenburg, H., Scott, C. E., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stirrups, K., Stone, M. A., Strachan, D. P., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Tobin, M. D., Travers, M. E., Turnbull, C., Vukcevic, D., Wain, L. V., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Yau, C., Young, A. H., Zeggini, E., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Hurles, M. E., Duncanson, A., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., Kwiatkowski, D. P., Mccarthy, M. I., Craddock, N., Deloukas, P., Donnelly, P., Blackwell, J. M., Bramon, E., Casas, J. P., Corvin, A., Jankowski, J., Markus, H. S., Palmer, C. N., Plomin, R., Rautanen, A., Trembath, R. C., Viswanathan, A. C., Wood, N. W., Spencer, C. C. A., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Pirinen, M., Strange, A., Blackburn, H., Bumpstead, S. J., Dronov, S., Gillman, M., Jayakumar, A., Mccann, O. T., Liddle, J., Potter, S. C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Daly, Mark J. [0000-0002-0949-8752], Apollo - University of Cambridge Repository, Hugot, Jean-Pierre [0000-0002-8446-6056], UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Romagnoni, A, Jegou, S, VAN STEEN, Kristel, Wainrib, G, Hugot, JP, Peyrin-Biroulet, L, Chamaillard, M, Colombel, JF, Cottone, M, D'Amato, M, D'Inca, R, Halfvarson, J, Henderson, P, Karban, A, Kennedy, NA, Khan, MA, Lemann, M, Levine, A, Massey, D, Milla, M, Ng, SME, Oikonomou, I, Peeters, H, Proctor, DD, Rahier, JF, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, KM, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, MH, Zhang, H, Zhang, W, Andrews, JM, Bampton, PA, Barclay, M, Florin, TH, Gearry, R, Krishnaprasad, K, Lawrance, IC, Mahy, G, Montgomery, GW, Radford-Smith, G, Roberts, RL, Simms, LA, Hanigan, K, Croft, A, Amininijad, L, Cleynen, I, Dewit, O, Franchimont, D, Georges, M, Laukens, D, Theatre, E, Vermeire, S, Aumais, G, Baidoo, L, Barrie, AM, Beck, K, Bernard, EJ, Binion, DG, Bitton, A, Brant, SR, Cho, JH, Cohen, A, Croitoru, K, Daly, MJ, Datta, LW, Deslandres, C, Duerr, RH, Dutridge, D, Ferguson, J, Fultz, J, Goyette, P, Greenberg, GR, Haritunians, T, Jobin, G, Katz, S, Lahaie, RG, McGovern, DP, Nelson, L, Ng, SM, Ning, K, Pare, P, Regueiro, MD, Rioux, JD, Ruggiero, E, Schumm, LP, Schwartz, M, Scott, R, Sharma, Y, Silverberg, MS, Spears, D, Steinhart, AH, Stempak, JM, Swoger, JM, Tsagarelis, C, Zhang, C, Zhao, HY, AERTS, Jan, Ahmad, T, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barnes, C, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Cardin, N, Clee, CM, Coffey, AJ, Mc Connell, J, Conrad, DF, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Frayling, TM, Freathy, RM, Giannoulatou, E, Gibbs, P, Gilbert, P, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Holmes, C, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Marchini, JL, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, McVean, G, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Munroe, PB, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Ovington, NR, Owen, MJ, Palin, K, Palotie, A, Parnell, K, Pearson, R, Pernet, D, Perry, JRB, Phillips, A, Plagnol, V, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Robson, S, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Sawcer, SJ, Schuilenburg, H, Scott, CE, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stirrups, K, Stone, MA, Strachan, DP, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Tobin, MD, Travers, ME, Turnbull, C, Vukcevic, D, Wain, LV, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Yau, C, Young, AH, Zeggini, E, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Hurles, ME, Duncanson, A, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, Kwiatkowski, DP, McCarthy, MI, Craddock, N, Deloukas, P, Donnelly, P, Blackwell, JM, Bramon, E, Casas, JP, Corvin, A, Jankowski, J, Markus, HS, Palmer, CNA, Plomin, R, Rautanen, A, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Pirinen, M, Strange, A, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, and Kwiatkowski, D

Subjects
Male, 692/4020/1503/257/1402, Genotype, Genotyping Techniques, LOCI, 45/43, lcsh:Medicine, Polymorphism, Single Nucleotide, Crohn's disease, genetics, genome wide association, Article, Deep Learning, Crohn Disease, INDEL Mutation, Genetics research, Humans, genetics, Genetic Predisposition to Disease, 129, lcsh:Science, Alleles, Science & Technology, genome wide association, RISK PREDICTION, 45, Models, Genetic, lcsh:R, Decision Trees, 692/308/2056, ASSOCIATION, Multidisciplinary Sciences, Crohn's disease, Logistic Models, Nonlinear Dynamics, ROC Curve, Area Under Curve, Science & Technology - Other Topics, lcsh:Q, Female, Neural Networks, Computer, INFLAMMATORY-BOWEL-DISEASE, Genome-Wide Association Study
Abstract

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers. Tis work was supported by Fondation pour la Recherche Médical (ref DEI20151234405) and Investissements d’Avenir programme ANR-11-IDEX-0005-02, Sorbonne Paris Cite, Laboratoire d’excellence INFLAMEX. Te authors thank the students that participated to the wisdom of the crowd exercise.

Published
2019

2. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

Author

Momozawa, Y, Dmitrieva, J, Theatre, E, Deffontaine, V, Rahmouni, S, Charloteaux, B, Crins, F, Docampo, E, Elansary, M, Gori, AS, Lecut, C, Mariman, R, Mni, M, Oury, C, Altukhov, I, Alexeev, D, Aulchenko, Y, Amininejad, L, Bouma, G, Hoentjen, F, Lowenberg, M, Oldenburg, B, Pierik, MJ, de Jong, AE, van der Woude, C.J., Visschedijk, MC, Lathrop, M, Hugot, JP, Weersma, RK, Vos, M, Franchimont, D, Vermeire, S, Kubo, M, Louis, E, Georges, M, Abraham, C, Achkar, JP, Ahmad, T, Ananthakrishnan, AN, Andersen, V, Anderson, CA, Andrews, JM, Annese, V, Aumais, G, Baidoo, L, Baldassano, RN, Bampton, PA, Barclay, M, Barrett, JC, Bayless, TM, Bethge, J, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, SR, Buning, C, Chew, A, Cho, JH, Cleynen, I, Cohain, A, Croft, A, Daly, MJ, D'Amato, M, Danese, S, Jong, D, Denapiene, G, Denson, LA, Devaney, KL, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, RH, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, LR, Festen, EA, Fleshner, P, Florin, T, Franke, A, Fransen, K, Gearry, R, Gieger, C, Glas, J, Goyette, P, Green, T, Griffiths, AM, Guthery, SL, Hakonarson, H, Halfvarson, J, Hanigan, K, Haritunians, T, de Hart, A, Hawkey, C, Hayward, NK, Hedl, M, Henderson, P, Hu, XH, Huang, HL, Hui, KY, Imielinski, M, Ippoliti, A, Jonaitis, L, Jostins, L, Karlsen, TH, Kennedy, NA, Khan, MA, Kiudelis, G, Krishnaprasad, K, Kugathasan, S, Kupcinskas, L, Latiano, A, Laukens, D, Lawrance, IC, Lee, JC, Lees, CW, Leja, M, van Limbergen, J, Lionetti, P, Liu, JZ, Mahy, G, Mansfield, J, Massey, D, Mathew, CG, McGovern, DPB, Milgrom, R, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Ng, A, Ng, SC, Ng, SME, Nikolaus, S, Ning, K, Nothen, M, Oikonomou, I, Palmieri, O, Parkes, M, Phillips, A, Ponsioen, CY, Potocnik, U, Prescott, NJ, Proctor, DD, Radford-Smith, G, Rahier, JF, Raychaudhuri, S, Regueiro, M, Rieder, F, Rioux, JD, Ripke, S, Roberts, R, Russell, RK, Sanderson, JD, Sans, M, Satsangi, J, Schadt, EE, Schreiber, S, Schulte, D, Schumm, LP, Scott, R, Seielstad, M, Sharma, Y, Silverberg, MS, Simms, LA, Skieceviciene, J, Spain, SL, Steinhart, AH, Stempak, JM, Stronati, L, Sventoraityte, J, Targan, SR, Taylor, KM, Velde, A, Torkvist, L, Tremelling, M, van Sommeren, S, Vasiliauskas, E, Verspaget, HW, Walters, T, Wang, K, Wang, MH, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, DC, Winkelmann, J, Xavier, RJ, Zhang, B, Zhang, CK, Zhang, H, Zhang, W, Zhao, HY, Zhao, ZZ, Momozawa, Y, Dmitrieva, J, Theatre, E, Deffontaine, V, Rahmouni, S, Charloteaux, B, Crins, F, Docampo, E, Elansary, M, Gori, A, Lecut, C, Mariman, R, Mni, M, Oury, C, Altukhov, I, Alexeev, D, Aulchenko, Y, Amininejad, L, Bouma, G, Hoentjen, F, Lowenberg, M, Oldenburg, B, Pierik, Mj, vander Meulen-de Jong, Ae, van der Woude, Cj, Visschedijk, Mc, Lathrop, M, Hugot, Jp, Weersma, Rk, De Vos, M, Franchimont, D, Vermeire, S, Kubo, M, Louis, E, Georges, M, Abraham, C, Achkar, Jp, Ahmad, T, Ananthakrishnan, An, Andersen, V, Anderson, Ca, Andrews, Jm, Annese, V, Aumais, G, Baidoo, L, Baldassano, Rn, Bampton, Pa, Barclay, M, Barrett, Jc, Bayless, Tm, Bethge, J, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, Sr, Buning, C, Chew, A, Cho, Jh, Cleynen, I, Cohain, A, Croft, A, Daly, Mj, D'Amato, M, Danese, S, De Jong, D, Denapiene, G, Denson, La, Devaney, Kl, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, Rh, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, Lr, Festen, Ea, Fleshner, P, Florin, T, Franke, A, Fransen, K, Gearry, R, Gieger, C, Glas, J, Goyette, P, Green, T, Griffiths, Am, Guthery, Sl, Hakonarson, H, Halfvarson, J, Hanigan, K, Haritunians, T, Hart, A, Hawkey, C, Hayward, Nk, Hedl, M, Henderson, P, Hu, Xh, Huang, Hl, Hui, Ky, Imielinski, M, Ippoliti, A, Jonaitis, L, Jostins, L, Karlsen, Th, Kennedy, Na, Khan, Ma, Kiudelis, G, Krishnaprasad, K, Kugathasan, S, Kupcinskas, L, Latiano, A, Laukens, D, Lawrance, Ic, Lee, Jc, Lees, Cw, Leja, M, Van Limbergen, J, Lionetti, P, Liu, Jz, Mahy, G, Mansfield, J, Massey, D, Mathew, Cg, Mcgovern, Dpb, Milgrom, R, Mitrovic, M, Montgomery, Gw, Mowat, C, Newman, W, Ng, A, Ng, Sc, Ng, Sme, Nikolaus, S, Ning, K, Nothen, M, Oikonomou, I, Palmieri, O, Parkes, M, Phillips, A, Ponsioen, Cy, Potocnik, U, Prescott, Nj, Proctor, Dd, Radford-Smith, G, Rahier, Jf, Raychaudhuri, S, Regueiro, M, Rieder, F, Rioux, Jd, Ripke, S, Roberts, R, Russell, Rk, Sanderson, Jd, Sans, M, Satsangi, J, Schadt, Ee, Schreiber, S, Schulte, D, Schumm, Lp, Scott, R, Seielstad, M, Sharma, Y, Silverberg, M, Simms, La, Skieceviciene, J, Spain, Sl, Steinhart, Ah, Stempak, Jm, Stronati, L, Sventoraityte, J, Targan, Sr, Taylor, Km, ter Velde, A, Torkvist, L, Tremelling, M, van Sommeren, S, Vasiliauskas, E, Verspaget, Hw, Walters, T, Wang, K, Wang, Mh, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, Dc, Winkelmann, J, Xavier, Rj, Zhang, B, Zhang, Ck, Zhang, H, Zhang, W, Zhao, Hy, Zhao, Zz, Gastroenterology & Hepatology, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, and UCL - (MGD) Service de gastro-entérologie

Subjects
Adult, Male, Multifactorial Inheritance, QUANTITATIVE TRAIT LOCUS, Genotype, SEQUENCING DATA, Quantitative Trait Loci, SUSCEPTIBILITY, Polymorphism, Single Nucleotide, Article, Cohort Studies, CODING VARIANTS, Crohn Disease, 80 and over, Journal Article, Medicine and Health Sciences, LOCUS, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Genetic Association Studies, Aged, Aged, 80 and over, Science & Technology, Female, Gene Expression Profiling, Inflammatory Bowel Diseases, Middle Aged, Sequence Analysis, DNA, COMPLEX TRAITS, Biology and Life Sciences, Single Nucleotide, DNA, CROHNS-DISEASE, Multidisciplinary Sciences, QUANTITATIVE TRAIT, RARE VARIANTS, Science & Technology - Other Topics, LOW-FREQUENCY, Sequence Analysis, INFLAMMATORY-BOWEL-DISEASE
Abstract

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach., Most of the more than 200 known genetic risk loci for inflammatory bowel disease (IBD) reside in regulatory regions. Here, the authors provide eQTL datasets for six circulating immune cell types and ileal, colonic and rectal biopsies to map regulatory modules and identify potential causative genes for IBD.

Published
2018

3. Low Dose of Dipotassium Glycyrrhizate Counteracts Atherosclerosis Progression in Apoe-/- Female Mice

Author

Palone, F., Pasquali, E., Giardullo, P., Stronati, L., Vitali, R., and Mancuso, M.

Subjects
Animal, Mice, Knockout, ApoE, Thoracic, Knockout, Aortic Diseases, Aorta, Thoracic, Atherosclerosis, Glycyrrhizic Acid, Lipids, Plaque, Atherosclerotic, Animals, Disease Models, Animal, Disease Progression, Female, HMGB1 Protein, Inflammation Mediators, Sex Factors, Mice, Disease Models, Aorta, ApoE, Plaque, Atherosclerotic
Published
2019

4. Dipotassium Glycyrrhizate Improves Intestinal Mucosal Healing by Modulating Extracellular Matrix Remodeling Genes and Restoring Epithelial Barrier Functions

Author

Salvatore Cucchiara, Laura Stronati, Anna Barbara Mancuso, Roberta Vitali, Eleonora Colantoni, Francesca Palone, Vincenzo Cesi, Sara Isoldi, Anna Negroni, Stronati, L., Palone, F., Negroni, A., Colantoni, E., Mancuso, A. B., Cucchiara, S., Cesi, V., Isoldi, S., and Vitali, R.

Subjects
0301 basic medicine, MMP9, Extracellular matrix, Mice, 0302 clinical medicine, Immunology and Allergy, HMGB1 Protein, Intestinal Mucosa, CCL12, DSS-induced colitis, Original Research, dipotassium glycyrrhizate, biology, Chemistry, Colitis, Extracellular Matrix, Cell biology, CXCL1, Cytokines, Female, medicine.symptom, HT29 Cells, DSS-induced coliti, lcsh:Immunologic diseases. Allergy, VTN, Immunology, Inflammation, HMGB1, Cell Line, mucosal healing, 03 medical and health sciences, plaur, Cell Line, Tumor, medicine, Animals, Humans, Wound Healing, Epithelial Cells, Glycyrrhizic Acid, medicine.disease, Dipotassium glycyrrhizate, Mucosal healing, Plaur, Mice, Inbred C57BL, 030104 developmental biology, biology.protein, Caco-2 Cells, lcsh:RC581-607, Wound healing, 030215 immunology
Abstract

Gut mucosal healing (MH) is considered a key therapeutic target and prognostic parameter in the management of inflammatory bowel disease (IBD). The dipotassium glycyrrhizate (DPG), a salt of the glycoconjugated triterpene glycyrrhizin, has been shown to inhibit the High Mobility Group Box 1 (HMGB1) protein, an allarmin strongly implicated in the pathogenesis of most inflammatory and auto-immune disorders. Here we discuss new insights on how DPG acts on MH comparing the acute phase and the recovery phase from experimental colitis in mice. We found that DPG strongly accelerates MH by differently regulating pro-inflammatory (CXCL1, CXCL3, CXCL5, PTGS2, IL-1β, IL-6, CCL12, CCL7) and wound healing (COL3A1, MMP9, VTN, PLAUR, SERPINE, CSF3, FGF2, FGF7, PLAT, TIMP1) genes as observed only during the recovery phase of colitis. Relevant issue is the identification of extracellular matrix (ECM) remodeling genes, VTN, and PLAUR, as crucial genes to achieve MH during DPG treatment. Furthermore, a noticeable recovery of intestinal epithelial barrier structural organization, wound repair ability, and functionality is observed in two human colorectal adenocarcinoma cell lines exposed to DPG during inflammation. Thus, our study identifies DPG as a potent tool for controlling intestinal inflammation and improving MH.

Published
2019

5. Functional analysis of gut microbiota and immunoinflammation in children with autism spectrum disorders

Author

Chiara Alfonsi, Vincenzo Cesi, Valerio Fulci, Sara Isoldi, Salvatore Cucchiara, Claudia Carissimi, Laura Stronati, Francesca Palone, Francesco Cardona, Ilaria Laudadio, Carissimi, C., Laudadio, I., Palone, F., Fulci, V., Cesi, V., Cardona, F., Alfonsi, C., Cucchiara, S., Isoldi, S., and Stronati, L.

Subjects
Male, Lipopolysaccharide, Gastrointestinal Diseases, autism spectrum disorders, Inflammation, gut microbiota, metagenomics, inflammation, hmgb1, Comorbidity, Gut flora, behavioral disciplines and activities, Feces, 03 medical and health sciences, chemistry.chemical_compound, Child Development, 0302 clinical medicine, Immune system, Autism spectrum disorders, Gut microbiota, HMGB1, Metagenomics, mental disorders, Escherichia coli, medicine, Humans, Autism spectrum disorder, Child, Phenylpropionates, Hepatology, biology, Catabolism, business.industry, Gastroenterology, biology.organism_classification, medicine.disease, Gastrointestinal Microbiome, chemistry, Case-Control Studies, Child, Preschool, 030220 oncology & carcinogenesis, Immunology, Cytokines, Biomarker (medicine), Autism, Female, 030211 gastroenterology & hepatology, Tumor necrosis factor alpha, medicine.symptom, business
Abstract

Background and Aims Recent evidence implicates gut microbiota (GM) and immune alterations in autism spectrum disorders (ASD). We assess GM profile and peripheral levels of immunological, neuronal and bacterial molecules in ASD children and controls. Alarmin HMGB1 was explored as a non-invasive biomarker to monitor gastrointestinal (GI) symptoms. Methods Thirty ASD children and 14 controls entered into the study. GM metagenomic analysis was performed for 16 ASD patients and 7 controls. GM functional profile was assessed by GO term analysis. Blood levels of IL-1β, TNFα, TGFβ, IL-10, INFγ, IL-8, lipopolysaccharide, Neurotensin, Sortilin1 and GSSG/GSH ratio were analyzed in all subjects by ELISA. Fecal HMGB1 was analyzed by Western blot. Results We observed a significant decrease in bacterial diversity. Furthermore, 82 GO terms underrepresented in ASD. Four of them pointed at 3,3 phenylpropionate catabolism and were imputable to Escherichia coli (E. coli) group. Serum levels of TNFα, TGFβ, NT, and SORT-1 increased in ASD patients. Fecal levels of HMGB1 correlated with GI sign severity in ASD children. Conclusions We suggest that a decrease of E. coli might affect the propionate catabolism in ASD. We report occurrence of peripheral inflammation in ASD children. We propose fecal HMGB1 as a non-invasive biomarker to detect GI symptoms.

Published
2019

6. LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease

Author

Chiara Rychlicki, Stefania Petrini, Gianluca Svegliati-Baroni, Cristiano De Stefanis, Sara Ceccarelli, Marco Mina, Nadia Panera, Daniela Gnani, Salvatore Cucchiara, Giovanni Musso, Valerio Nobili, Anna Alisi, Laura Agostinelli, Cesare Furlanello, Laura Stronati, Annalisa Crudele, Giovannella Bruscalupi, and Stronati, L.

Subjects
Lipopolysaccharides, Liver Cirrhosis, Male, Time Factors, Transcription, Genetic, Fibrosi, medicine.medical_treatment, Interleukin-1beta, LITAF, p38 Mitogen-Activated Protein Kinases, Mice, Non-alcoholic Fatty Liver Disease, Fibrosis, LPS, NAFLD, Pathology Section, fibrosis, inflammation, Promoter Regions, Genetic, Mice, Inbred BALB C, Fatty liver, Nuclear Proteins, Up-Regulation, Pathology section, DNA-Binding Proteins, Phenotype, Cytokine, Liver, Oncology, Cytokines, Female, RNA Interference, Tumor necrosis factor alpha, Inflammation Mediators, medicine.symptom, Inflammation, Signal Transduction, Transfection, Cell Line, Hepatic Stellate Cells, medicine, Animals, Humans, Gene silencing, Protein Kinase Inhibitors, Binding Sites, business.industry, medicine.disease, Research Paper: Pathology, Immunology, Hepatic stellate cell, Steatohepatitis, business, Transcription Factors
Abstract

Lipopolysaccharide (LPS) is currently considered one of the major players in non-alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-α factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH). We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1β, IL-6 and TNF-α in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-α was significantly reduced with the aid of p65NF-ĸB, while IL-1β transcription exclusively required LITAF expression/activity. Finally, IL-1β levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF-positive HSCs in children with NASH. In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1β levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro-inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH.

Published
2015

7. Macrophage Activation in Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) Correlates with Hepatic Progenitor Cell Response via Wnt3a Pathway

Author

Valerio Nobili, Gianfranco Alpini, Guido Carpino, Anna Alisi, Paolo Onori, Laura Stronati, Anastasia Renzi, Cristiano De Stefanis, Rita De Vito, Eugenio Gaudio, Antonio Franchitto, and Stronati, L.

Subjects
0301 basic medicine, Male, Pathology, Steatosis, Biopsy, Anti-Inflammatory Agents, lcsh:Medicine, Pathology and Laboratory Medicine, Pediatrics, Cytopathology, White Blood Cells, 0302 clinical medicine, Animal Cells, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, hepatic progenitor cell, Medicine and Health Sciences, Macrophage, Phosphorylation, lcsh:Science, Child, Immune Response, beta Catenin, Liver injury, Multidisciplinary, Liver Diseases, Stem Cells, Fatty liver, 3. Good health, medicine.anatomical_structure, Liver, Docosahexaenoic acid, Hepatocyte, Disease Progression, 030211 gastroenterology & hepatology, Female, Cellular Types, Anatomy, Research Article, Signal Transduction, medicine.medical_specialty, liver, non-alcoholic fatty liver disease, Adolescent, Docosahexaenoic Acids, Kupffer Cells, Immune Cells, Immunology, Macrophage polarization, Surgical and Invasive Medical Procedures, Gastroenterology and Hepatology, Biology, 03 medical and health sciences, Signs and Symptoms, Diagnostic Medicine, Wnt3A Protein, medicine, Humans, Progenitor cell, Inflammation, Blood Cells, Macrophages, lcsh:R, Biology and Life Sciences, Cell Biology, Macrophage Activation, medicine.disease, Fibrosis, Fatty Liver, 030104 developmental biology, Gene Expression Regulation, Anatomical Pathology, Hepatocytes, lcsh:Q, Developmental Biology
Abstract

Non-alcoholic fatty liver disease is one of the most important causes of liver-related morbidity in children. In non-alcoholic fatty liver disease, the activation of liver resident macrophage pool is a central event in the progression of liver injury. The aims of the present study were to evaluate the polarization of liver macrophages and the possible role of Wnt3a production by macrophages in hepatic progenitor cell response in the progression of pediatric nonalcoholic fatty liver disease. 32 children with biopsy-proven non-alcoholic fatty liver disease were included. 20 out of 32 patients were treated with docosahexaenoic acid for 18 months and biopsies at the baseline and after 18 months were included. Hepatic progenitor cell activation, macrophage subsets and Wnt/β-catenin pathway were evaluated by immunohistochemistry and immunofluorescence. Our results indicated that in pediatric non-alcoholic fatty liver disease, pro-inflammatory macrophages were the predominant subset. Macrophage polarization was correlated with Non-alcoholic fatty liver disease Activity Score, ductular reaction, and portal fibrosis; docosahexaenoic acid treatment determined a macrophage polarization towards an anti-inflammatory phenotype in correlation with the reduction of serum inflammatory cytokines, with increased macrophage apoptosis, and with the upregulation of macrophage Wnt3a expression; macrophage Wnt3a expression was correlated with β-catenin phosphorylation in hepatic progenitor cells and signs of commitment towards hepatocyte fate. In conclusion, macrophage polarization seems to have a key role in the progression of pediatric non-alcoholic fatty liver disease; the modulation of macrophage polarization could drive hepatic progenitor cell response by Wnt3a production. © 2016 Carpino et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Published
2016

8. NOD2 Is Regulated by MIR-320 in Physiological Conditions but this Control Is Altered in Inflamed Tissues of Patients with Inflammatory Bowel Disease

Author

Maria Pierdomenico, Manuela Costanzo, Enrica Prete, Salvatore Cucchiara, Roberta Vitali, Laura Stronati, Vincenzo Cesi, Salvatore Oliva, Marina Aloi, Stronati, L., Costanzo, M., Prete, E., Vitali, R., and Cesi, V.

Subjects
0301 basic medicine, Male, Nod2 Signaling Adaptor Protein, Fluorescent Antibody Technique, pediatric IBD, Inflammatory bowel disease, Immunoenzyme Techniques, Crohn Disease, NOD2, miRNAs, inflammation, innate immunity, Immunology and Allergy, Child, Cells, Cultured, Regulation of gene expression, Reverse Transcriptase Polymerase Chain Reaction, Gastroenterology, Transfection, Prognosis, Child, Preschool, Cytokines, Female, medicine.symptom, HT29 Cells, Adolescent, Blotting, Western, Inflammation, Biology, Real-Time Polymerase Chain Reaction, Proinflammatory cytokine, 03 medical and health sciences, microRNA, medicine, Humans, RNA, Messenger, miRNA, medicine.disease, digestive system diseases, Immunity, Innate, MicroRNAs, 030104 developmental biology, Gene Expression Regulation, Case-Control Studies, Immunology, Cancer research, Colitis, Ulcerative, Ex vivo, Follow-Up Studies
Abstract

Background: Large evidence supports the role of microRNAs as new important inflammatory mediators by regulating both the adaptive and innate immunity. In the present study, we speculated that miR-320 controls NOD2 (nucleotide-binding oligomerization domain) expression, because it contains multiple binding sites in the 3′-untranslated region of the gene. NOD2, the first gene associated to increased susceptibility to Crohn's disease, is a cytosolic receptor that senses wall peptides of bacteria and promotes their clearance through initiation of a proinflammatory transcriptional program. This study aims at demonstrating that NOD2 is a target of miR-320 as well as investigating the role of inflammation in modulating the miR-320 control on NOD2 expression and analyzing miR-320 expression in intestinal biopsies of children with inflammatory bowel disease. Methods: The colonic adenocarcinoma cell line HT29 was used to assess the miR-320-mediated regulation of NOD2 expression. MiR-320 and NOD2 expression were analyzed in mucosal samples of 40 children with inflammatory bowel disease. Results: During inflammation, NOD2 expression is inversely correlated with miR-320 expression in vitro and ex vivo. Exogenous miR-320 transfection in HT29 cells leads to a significant decrease of NOD2 expression, whereas the miR-320 inhibitor transfection leads to increase of NOD2 expression, nuclear translocation of nuclear factor B, and activation of downstream cytokines. Conclusions: We show for the first time that NOD2 expression is under the control of miR-320. We also show in vitro and ex vivo that inflammation induces a decrease of miR-320 and the latter correlates negatively with NOD2 expression. © 2016 Crohn's & Colitis Foundation of America, Inc.

Published
2016

9. Dipotassium glycyrrhizate via HMGB1 or AMPK signaling suppresses oxidative stress during intestinal inflammation

Author

Francesca Palone, Anna Negroni, Maria Pierdomenico, Salvatore Oliva, Marina Aloi, Laura Stronati, Roberta Vitali, Salvatore Cucchiara, Stronati, L., Negroni, A., Pierdomenico, M., Palone, F., and Vitali, R.

Subjects
Lipopolysaccharides, Nitric Oxide Synthase Type II, Inflammation, Oxidative phosphorylation, AMP-Activated Protein Kinases, Pharmacology, medicine.disease_cause, HMGB1, Biochemistry, Cell Line, Intestinal mucosa, AMP-activated protein kinase, medicine, Animals, HMGB1 Protein, Intestinal Mucosa, biology, Chemistry, Macrophages, AMPK, Colitis, Glycyrrhizic Acid, Mice, Inbred C57BL, Disease Models, Animal, Oxidative Stress, Mechanism of action, Cyclooxygenase 2, biology.protein, Chemical compound studied in this article Dipotassium glycyrrhizate (PubChem CID: 656852), Female, medicine.symptom, Oxidative stress, Signal Transduction
Abstract

Aims Oxidative stress and inflammation are always associated. Appropriate management of oxidative mediators may represent a therapeutic strategy to reduce inflammation, and use of antioxidant can be protective against inflammatory diseases. Glycyrrhizin (GL) plays an anti-inflammatory and antioxidant effect by inhibiting high mobility group box 1 (HMGB1) or 11-β-hydroxysteroid dehydrogenase type II (11βHSD2) enzyme. In this study, the potential role of dipotassium glycyrrhizate (DPG), a salt of GL, to reduce oxidative stress in intestinal inflammatory condition was investigated in vivo and the mechanism of action of DPG was studied in vitro. Results In a colitis mouse model DPG affected oxidative stress reducing iNOS and COX-2 expression, as well as NO and PGE2 levels. By means of LPS-stimulated macrophages we found that DPG inhibited the expression of pro-inflammatory cytokines and reduced iNOS and COX-2 expression in a time dependent manner, through two different ways of signal. DPG reduced, at a later time, both iNOS and COX-2, through a mechanism HMGB1-dependent, and at an earlier time only COX-2, through a mechanism AMP-activated kinase (AMPK)-phosphorylation-mediated. Conclusion DPG has a protective effect on colitis and inflammation through the inhibition of oxidative stress. This study clarifies the two-ways mechanism by which DPG inhibits iNOS and COX-2 during inflammation and demonstrates for the first time that AMPK is a target of DPG. Uncovering this mechanism is significant to clarify the relationship between energy homeostasis and anti-oxidative responses and suggests that DPG could play a relevant role in the development of new therapy against inflammatory diseases associated to oxidative stress. © 2015 Elsevier Inc. All rights reserved.

Published
2015

10. Micronuclei and chromosome aberrations in subjects occupationally exposed to antineoplastic drugs: a multicentric approach

Author

Milena Villarini, Silvano Monarca, Cristina Fatigoni, Laura Stronati, Laura Sabatini, Elisabetta Ceretti, Mariella Carrieri, Giuseppe Mastrangelo, Maria Giuseppa Grollino, Massimo Appolloni, Anna Barbieri, Sofia Pavanello, Giovanni Battista Bartolucci, Roberta Bonfiglioli, Francesca Mussi, Massimo Moretti, Luca Dominici, Stronati, L., Appolloni, M., Grollino, M. G., Moretti, Massimo, Grollino, Maria Giuseppa, Pavanello, Sofia, Bonfiglioli, Roberta, Villarini, Milena, Appolloni, Massimo, Carrieri, Mariella, Sabatini, Laura, Dominici, Luca, Stronati, Laura, Mastrangelo, Giuseppe, Barbieri, Anna, Fatigoni, Cristina, Bartolucci, Giovanni Battista, Ceretti, Elisabetta, Mussi, Francesca, and Monarca, Silvano

Subjects
Adult, medicine.medical_specialty, Cyclophosphamide, Antineoplastic drugs, Occupational exposure, Genotoxic hazard, Micronuclei, Chromosome aberrations, GSTM1 and GSTT1 polymorphisms, Antineoplastic Agents, Urine, Nursing Staff, Hospital, Pharmacology, Dermal exposure, Hospital, Internal medicine, Humans, Medicine, Antineoplastic drug, Lymphocytes, GSTM1 and GSTT1 polymorphism, Biomarkers, Chromosome Aberrations, DNA Damage, Environmental Monitoring, Female, Italy, Micronuclei, Chromosome-Defective, Occupational Exposure, Oncology Nursing, business.industry, Environmental and Occupational Health, Public Health, Environmental and Occupational Health, Metabolic detoxification, Micronucleus test, Antineoplastic Drugs, Biomarker (medicine), Nursing Staff, Public Health, Chromosome aberration, business, Chromosome-Defective, medicine.drug
Abstract

Objectives: Recently published works showed that occupational exposure to antineoplastic drugs (ANPD) is still frequent in hospital settings, despite significant safety policy improvements. The aim of this study was to assess the current level of occupational exposure to ANPD and any potentially associated cytogenetic damages in hospital nurses routinely handling ANPD. Methods: Occupationally ANPD-exposed (n = 71) and ANPD-unexposed (n = 77; control) nurses were recruited on a voluntary basis from five hospitals in Northern and Central Italy. Evaluation of surface contamination and dermal exposure to ANPD was assessed by determining cyclophosphamide (CP) on selected surfaces (wipes) and on exposed nurses’ clothes (pads). The concentration of unmetabolized CP—as a biomarker of internal dose—was measured in end-shift urine samples. Biomonitoring of genotoxic effects (i.e., biological effect monitoring) was conducted by analyzing micronuclei (MN) and chromosome aberrations (CA) in peripheral blood lymphocytes. Genetic polymorphisms for enzymes involved in metabolic detoxification (i.e., glutathione S-transferases) were analyzed as well. Results: We observed a significant increase in MN frequency (5.30 ± 2.99 and 3.29 ± 1.97; mean values ± standard deviation; p

Published
2015

11. Endoplasmic reticulum stress and unfolded protein response are involved in paediatric inflammatory bowel disease

Author

Fortunata Civitelli, Marina Aloi, Laura Stronati, Enrica Prete, Anna Negroni, Vincenzo Cesi, Roberta Vitali, Salvatore Cucchiara, Stronati, L., Vitali, R., Prete, E., and Negroni, A.

Subjects
Crohn's disease, Ulcerative colitis, Gene expression, Intestinal inflammation, Male, XBP1, Colon, Inflammation, Inflammatory bowel disease, Downregulation and upregulation, medicine, Humans, Prospective Studies, Intestinal Mucosa, Endoplasmic Reticulum Chaperone BiP, Colonoscopy, Female, Follow-Up Studies, Inflammatory Bowel Diseases, Middle Aged, Unfolded Protein Response, Endoplasmic Reticulum Stress, Gastroenterology, Hepatology, Medicine (all), Ulcerative coliti, business.industry, ATF6, Endoplasmic reticulum, medicine.disease, Immunology, Unfolded protein response, medicine.symptom, business
Abstract

Background: Endoplasmic reticulum stress and unfolded protein response have been recently associated with the development of inflammatory bowel diseases in adults. We aimed at assessing the involvement of these pathways also in paediatric inflammatory bowel disease by analysing the expression of the main genes involved in endoplasmic reticulum stress and correlating them with the degree of intestinal inflammation. Methods: Real-time PCR and Western blot analysis of the expression of the endoplasmic reticulum stress marker HSPA5 and of selected genes representing the three pathways of unfolded protein response (IRE-XBP1, PERK-ATF4, ATF6p90-p50) in inflamed and uninflamed biopsies from 28 inflammatory bowel disease paediatric patients and 10 controls. Results: HSPA5, PDIA4, as well as unspliced and spliced XBP1 mRNAs were significantly increased in patients' inflamed colonic mucosa compared to uninflamed mucosa and controls. HSPA5, PDIA4, ATF6, and phospho-IRE proteins were also upregulated, indicating the activation of the IRE-XBP1 and ATF6p90-p50 branches of unfolded protein response. A positive significant correlation between interleukin-8 levels, as a marker of inflammation, and upregulated genes was found in the inflamed colonic mucosa. Conclusion: A deregulation of the genes involved in the endoplasmic reticulum stress and unfolded protein response pathways may be a key component of the inflammatory response in paediatric patients with inflammatory bowel disease. © 2014 Editrice Gastroenterologica Italiana S.r.l.

Published
2014

12. Neuroimmune interactions at different intestinal sites are related to abdominal pain symptoms in children with IBS

Author

Sara Isoldi, Giovanni Barbara, Rosella Saulle, Salvatore Cucchiara, Lisa Zecchi, Lorenzo Drago, Cesare Cremon, Robert J. Shulman, Salvatore Oliva, Laura Stronati, G. Di Nardo, Maria Raffaella Barbaro, Di Nardo, G, Barbara, G, Cucchiara, S, Cremon, C, Shulman, R J, Isoldi, S, Zecchi, L, Drago, L, Oliva, S, Saulle, R, Barbaro, M R, and Stronati, L

Subjects
Male, medicine.medical_specialty, Abdominal pain, Adolescent, Physiology, Mast cell infiltration, Neuroimmunomodulation, Inflammation, Ileum, Gastroenterology, Nerve Fibers, fluids and secretions, children, Internal medicine, medicine, Humans, Mast Cell, Mast Cells, Child, Irritable bowel syndrome, Feces, irritable bowel syndrome, Endocrine and Autonomic Systems, business.industry, functional gastrointestinal disorder, medicine.disease, Rome iii, Abdominal Pain, Intestine, Intestines, medicine.anatomical_structure, Nerve Fiber, inflammation, Child, Preschool, Children, Functional gastrointestinal disorders, Female, medicine.symptom, Calprotectin, business, Leukocyte L1 Antigen Complex, Human
Abstract

Neuroimmune interactions and inflammation have been proposed as factors involved in sensory-motor dysfunction and symptom generation in adult irritable bowel syndrome (IBS) patients. In children with IBS and healthy controls, we measured ileocolonic mast cell infiltration and fecal calprotectin and evaluated the relationships between these parameters and abdominal pain symptoms and stooling pattern.Irritable bowel syndrome patients diagnosed according to Pediatric Rome III criteria and healthy controls kept a 2-week pain/stooling diary. Ileocolonic mucosal mast cells (MC) and MC in close proximity to nerve fibers (MC-NF) were identified immunohistochemically and quantified. Fecal calprotectin concentration was measured.21 IBS patients and 10 controls were enrolled. The MC-NF count was significantly higher in the ileum (p = 0.01), right colon (p = 0.04), and left colon (p0.001) of IBS patients compared with controls. No differences in fecal calprotectin concentration were noted. Abdominal pain intensity score correlated with ileal MC count (r(s) = 0.47, p = 0.030) and right colon MC-NF count (r(s) = 0.52, p = 0.015). In addition, children with IBS with3 abdominal pain episodes/week had greater ileal (p = 0.002) and right colonic (p = 0.01) MC counts and greater ileal (p = 0.05) and right colonic (p = 0.016) MC-NF counts than children with less frequent pain. No relationship was found between MC and MC-NF and fecal calprotectin or stooling pattern.Mast cells-nerve fibers counts are increased in the ileocolonic mucosa of children with IBS. Mast cells and MC-NF counts are related to the intensity and frequency of abdominal pain.

Published
2014

13. Plasma high mobility group box 1 protein reflects fibrosis in pediatric nonalcoholic fatty liver disease

Author

Salvatore Cucchiara, Nadia Panera, Roberta Vitali, Anna Alisi, Giorgio Bedogni, Sara Ceccarelli, Laura Stronati, Valerio Nobili, Rita De Vito, Cristiano De Stefanis, Clara Balsano, Stronati, L., and Vitali, R.

Subjects
Liver Cirrhosis, Male, Monocyte chemoattractant protein-1, Non-alcoholic fatty liver disease, Liver fibrosis, High mobility group box 1, TGF β, medicine.medical_specialty, Pathology, Biopsy, Case-Control Studies, Chemokine CCL2, Child, Child, Preschool, Cross-Sectional Studies, Female, HMGB1 Protein, Humans, Non-alcoholic Fatty Liver Disease, Transforming Growth Factor beta, Molecular Medicine, Molecular Biology, Genetics, 2734, Medicine (all), TGF ?, chemical and pharmacologic phenomena, Disease, HMGB1, Systemic inflammation, Gastroenterology, digestive system, Pathology and Forensic Medicine, Fibrosis, Internal medicine, Nonalcoholic fatty liver disease, medicine, biology, business.industry, Fatty liver, Liver fibrosi, nutritional and metabolic diseases, medicine.disease, digestive system diseases, High-mobility group, biology.protein, medicine.symptom, business, Pediatric population
Abstract

Non-alcoholic fatty liver disease (NAFLD) affects 3-12% of the general pediatric population. HMGB1 protein is presently considered a potent inflammatory mediator in several liver diseases, even if its role in NAFLD is still unknown in clinical studies. Here we investigated the relationships between circulating HMGB1, TGF-β and MCP-1 and liver damage in pediatric NAFLD. HMGB1, TGF-β and MCP-1 plasma levels were measured in 110 obese children with biopsy-proven NAFLD and 40 age-matched obese controls. HMGB1, TGF-β and MCP-1, ALT, AST and cholesterol plasma levels were significantly higher in NAFLD than in control children. A significant association between increased levels of HMGB1, TGF-β and MCP-1 and high degrees of fibrosis was found. In this study, we showed for the first time that circulating levels of HMGB1 were raised in children with NAFLD and strongly correlated with fibrosis and systemic inflammation. © 2014 Informa UK, Ltd.

Published
2014
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14. Role of HMGB1 as a suitable biomarker of subclinical intestinal inflammation and mucosal healing in patients with inflammatory bowel disease

Author

Federica Nuti, Maria Pierdomenico, Anna Negroni, Alessandro Armuzzi, Carla Felice, Marina Aloi, Roberta Vitali, Laura Stronati, Francesca Palone, Salvatore Cucchiara, Stronati, L., and Negroni, A.

Subjects
Male, Messenger, Ulcerative, Fecal biomarker, Inbred C57BL, Inflammatory bowel disease, Feces, Mice, Crohn Disease, Intestinal mucosa, Immunology and Allergy, Medicine, HMGB1 Protein, Intestinal Mucosa, Cells, Cultured, Gut inflammation, Human IBD, HMGB1, Mucosal healing, Subclinical infection, Cultured, biology, Blotting, Reverse Transcriptase Polymerase Chain Reaction, Medicine (all), Dextran Sulfate, Gastroenterology, Middle Aged, Colitis, Prognosis, Ulcerative colitis, Disease Progression, biomarker, Biological Markers, Female, medicine.symptom, Western, Adult, Aged, Animals, Blotting, Western, Case-Control Studies, Colitis, Ulcerative, Double-Blind Method, Enzyme-Linked Immunosorbent Assay, Follow-Up Studies, Humans, Inflammation, Mice, Inbred C57BL, Peroxidase, RNA, Messenger, Real-Time Polymerase Chain Reaction, Young Adult, Wound Healing, Cells, Settore MED/12 - GASTROENTEROLOGIA, chemical and pharmacologic phenomena, inflammatory bowel disease, business.industry, Surrogate endpoint, Settore MED/09 - MEDICINA INTERNA, medicine.disease, Immunology, biology.protein, RNA, business, Biomarkers
Abstract

Background: Noninvasive biomarkers of high- and low-grade intestinal inflammation and of mucosal healing (MH) in patients with inflammatory bowel disease are currently lacking. We have recently shown that fecal high mobility group box 1 (HMGB1) protein is a novel biomarker of gut inflammation. We aimed at investigating in a mouse model if HMGB1 was able to foresee both a clinically evident and a subclinical gut inflammation and if its normalization indicated MH. We also aimed at confirming the results in patients with Crohn's disease (CD) and ulcerative colitis. Methods: C57BL6/J mice were treated with increasing doses of dextran sodium sulphate to induce colitis of different severity degrees; 28 with CD, 23 with ulcerative colitis, and 17 controls were also enrolled. Fecal HMGB1 was analyzed by enzyme-linked immunosorbent assay and immunoblotting. Results: Fecal HMGB1 increased by 5-, 11-, 18-, and 24-folds with dextran sodium sulphate doses of 0.25%, 0.50%, 1%, and 4%, respectively, showing that the protein detected a high-grade and a subclinical inflammation. After a recovery time of 4-week posttreatment, HMGB1 returned to control levels, paralleling MH. In patients, fecal HMGB1 significantly correlated with endoscopic indexes (Simple Endoscopic Score for Crohn's Disease [SES-CD], endoscopic Mayo subscore), but not with the disease activity indexes (Crohn's disease Activity Index, partial Mayo score). Conclusions: Fecal HMGB1 is a robust noninvasive biomarker of clinically overt and subclinical gut inflammation; it can also be a surrogate marker of MH. We suggest the use of fecal HMGB1 to monitor the disease course and assess therapy outcomes in inflammatory bowel disease. Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.

Published
2014

15. Lactobacillus reuteri ATCC55730 in Cystic Fibrosis

Author

Laura Stronati, Giovanni Di Nardo, Francesca Patriarchi, Salvatore Cucchiara, Riccardo Pistelli, Alessandra Menichella, Riccardo Valerio De Biase, Salvatore Oliva, and Stronati, L.

Subjects
Limosilactobacillus reuteri, Adult, Lung Diseases, Male, medicine.medical_specialty, Adolescent, Cystic Fibrosis, Gastrointestinal Diseases, Lactobacillus reuteri, cystic fibrosis, probiotics, Child, DNA-Binding Proteins, Double-Blind Method, Female, Forced Expiratory Volume, Hospitalization, Humans, Interleukin-8, Leukocyte L1 Antigen Complex, Nuclear Proteins, Numbers Needed To Treat, Probiotics, Prospective Studies, Respiratory Tract Infections, Tumor Necrosis Factor-alpha, Young Adult, Lung, Gastroenterology, Pediatrics, Perinatology and Child Health, Placebo, Cystic fibrosis, Pediatrics, Internal medicine, medicine, Respiratory system, cystic fibrosi, Respiratory tract infections, business.industry, Respiratory infection, Odds ratio, Perinatology and Child Health, medicine.disease, Surgery, Number needed to treat, Calprotectin, business, Transcription Factors
Abstract

Objectives: The aim of this study was to evaluate in patients with cystic fibrosis (CF) the effect of Lactobacillus reuteri (LR) on the rate of respiratory exacerbations and of the infections of both upper respiratory and gastrointestinal tracts. METHODS: Prospective randomized, double-blind, placebo-controlled study enrolling 61 patients with CF with mild-to-moderate lung disease at the Regional Center for CF of the Department of Pediatrics, University of Rome "La Sapienza." All of the patients were not hospital inpatients at the time of the enrollment. Inclusion criteria were forced expiratory volume in the first second (FEV1) >70% predicted; no inhaled or systemic steroids, no anti-inflammatory drugs, antileukotrienes, and mast cell membrane stabilizers; and no serious organ involvement. Exclusion criteria were a history of pulmonary exacerbation or upper respiratory infection in the previous 2 months; changes in medications in the last 2 months; a history of hemoptysis in the last 2 months; and colonization with Burkholderia cepacia or mycobacteria. Patients were randomly assigned to receive LR (30 patients) in 5 drops per day (10 colony-forming units) or placebo (31 patients) for 6 months. Main outcomes were number of episodes of pulmonary exacerbations and hospital admissions for pulmonary exacerbations, number of gastrointestinal and upper respiratory tract infections. FEV1, fecal calprotectin, and cytokine profile in induced sputum and plasma were assessed at baseline and at the end of the trial. RESULTS: Pulmonary exacerbations were significantly reduced in the LR group compared with the placebo group (P

Published
2014

16. Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation

Author

Marina Aloi, Enrica Prete, Laura Stronati, Roberta Vitali, Maria Pierdomenico, Anna Negroni, John Bertin, Salvatore Cucchiara, Peter J. Gough, Prete, E., Vitali, R., Stronati, L., and Negroni, A.

Subjects
Male, medicine.medical_specialty, Adolescent, Cell Survival, Colon, Necroptosis, Blotting, Western, necroptosis, inflammatory bowel disease, children, Real-Time Polymerase Chain Reaction, Gastroenterology, Inflammatory bowel disease, Risk Assessment, Severity of Illness Index, Statistics, Nonparametric, Cohort Studies, Crohn Disease, Intestinal inflammation, Ileum, Internal medicine, medicine, Humans, Prospective Studies, Child, Caspase 8, Hepatology, Cell Death, business.industry, digestive, oral, and skin physiology, Biopsy, Needle, Age Factors, medicine.disease, Inflammatory Bowel Diseases, Immunohistochemistry, digestive system diseases, Gene Expression Regulation, Child, Preschool, Receptor-Interacting Protein Serine-Threonine Kinases, Immunology, Disease Progression, Colitis, Ulcerative, Female, business, Protein Kinases, Signal Transduction
Abstract

OBJECTIVES:A new caspase-independent mode of programmed cell death, termed necroptosis, has recently been identified. Altered expression of molecules involved in the necroptosis pathway has been shown to trigger intestinal inflammation. The initiation of necroptosis is principally mediated by the release of receptor interacting protein 3 (RIP3) from suppression by caspase-8. Furthermore, it has been suggested that the mixed lineage kinase domain-like (MLKL) factor is an interacting target of RIP3 in active necroptosis. This study aims at investigating the occurrence of necroptosis in children with inflammatory bowel disease (IBD) and its contribution to human intestinal inflammation.METHODS:Biopsy samples were collected from the ileum and colon of 33 children with Crohn's disease, 30 with ulcerative colitis, and 20 healthy controls. Ten children with allergic colitis (AC) were used as non-IBD comparators. RIP3, caspase-8, and MLKL protein expression levels were evaluated by western blotting. The adenocarcinoma cell line HT29 was used for in vitro experiments.RESULTS:RIP3 and MLKL increased (P

Published
2014

17. Associations between Genetic Polymorphisms in IL-33, IL1R1 and Risk for Inflammatory Bowel Disease

Author

Renata D'Incà, Theresa T. Pizarro, Bartolomeo Augello, Maurizio Vecchi, Maria Rosa Valvano, Giuseppe Merla, Luca Pastorelli, Giuseppe Corritore, Vito Annese, Alessia Settesoldi, Anna Latiano, Fabrizio Bossa, Orazio Palmieri, Tiziana Latiano, Laura Stronati, Angelo Andriulli, and Stronati, L.

Subjects
Genetics and Molecular Biology (all), Male, Gene Identification and Analysis, Gene Expression, Ulcerative, Inflammatory bowel disease, Biochemistry, Pediatrics, Cohort Studies, Crohn Disease, Receptors, 80 and over, Age of Onset, Child, Aged, 80 and over, Crohn's disease, Multidisciplinary, Medicine (all), Single Nucleotide, Middle Aged, Colitis, Ulcerative colitis, Phenotype, Child, Preschool, Cohort, Medicine, Pediatric Gastroenterology, Female, Cohort study, Research Article, Adult, Adolescent, Science, Immunology, Gastroenterology and Hepatology, Polymorphism, Single Nucleotide, Autoimmune Diseases, Molecular Genetics, Young Adult, medicine, Genetics, Genome-Wide Association Studies, Ulcerative Colitis, Humans, Genetic Predisposition to Disease, Genetic Testing, Polymorphism, Preschool, Biology, Genetic Association Studies, Aged, Interleukin-1 Type I, Clinical Genetics, Inflammation, Receptors, Interleukin-1 Type I, business.industry, Interleukins, Haplotype, Inflammatory Bowel Disease, Case-control study, Immunity, Infant, Human Genetics, medicine.disease, Interleukin-33, digestive system diseases, Agricultural and Biological Sciences (all), Gene Expression Regulation, Haplotypes, Case-Control Studies, Clinical Immunology, Colitis, Ulcerative, Age of onset, business, Biochemistry, Genetics and Molecular Biology (all)
Abstract

BackgroundRecent evidence suggests that the IL-33/IL1RL1 axis plays a critical role in several autoimmune and inflammatory disorders; however, its mechanistic role in inflammatory bowel disease (IBD) has not been clearly defined. We investigated the contribution of IL-33 and IL1RL1 polymorphisms to IBD risk, and possible correlations with phenotype in an Italian cohort of adult and pediatric patients.MethodsWe evaluated the association of six SNPs in IL-33 and IL1RL1 genes, in 805 Crohn's disease (CD), 816 ulcerative colitis (UC), and 752 controls, using Taqman. IL-33 and IL1RL1 mRNA expression was also analyzed.ResultsSignificant allele and genotype associations with IL-33 rs3939286 were found in CD (P = 0.004; P = 0.035) and UC patients (P = 0.002; P = 0.038). After stratifying the cohort for age at diagnosis, the differences remained significant only in the IBD adult-onset. Significant associations were also obtained in CD patients with two IL1RL1 polymorphisms (rs13015714 and rs2058660, PConclusionsCommon IL-33 and IL1RL1 polymorphisms contribute to the risk of IBD in an Italian cohort of adult and pediatric patients, with some influence on sub-phenotypes.

Published
2013

18. A study protocol for the evaluation of occupational mutagenic/carcinogenic risks in subjects exposed to antineoplastic drugs: a multicentric project

Author

Mariella Carrieri, Sofia Pavanello, Umberto Gelatti, Milena Villarini, Annamaria Buschini, Laura Stronati, Roberta Bonfiglioli, Paola Poli, Giovanni Battista Bartolucci, Donatella Feretti, Giuseppe Mastrangelo, Francesca Mussi, Maria Giuseppa Grollino, Silvano Monarca, Massimo Moretti, Luca Dominici, Laura Sabatini, Anna Barbieri, Massimo Appolloni, Elisabetta Ceretti, Moretti M, Bonfiglioli R, Feretti D, Pavanello S, Mussi F, Grollino MG, Villarini M, Barbieri A, Ceretti E, Carrieri M, Buschini A, Appolloni M, Dominici L, Sabatini L, Gelatti U, Bartolucci GB, Poli P, Stronati L, Mastrangelo G, and Monarca S

Subjects
Risk, medicine.medical_specialty, Pathology, Cyclophosphamide, Cross-sectional study, Population, Antineoplastic Agents, Nursing Staff, Hospital, HEALTH CARE WORKERS, Study Protocol, Occupational hygiene, Internal medicine, Neoplasms, Occupational Exposure, Epidemiology, medicine, Genetic predisposition, Humans, Antineoplasic drugs, education, Chromosome Aberrations, education.field_of_study, business.industry, lcsh:Public aspects of medicine, Oncology Nursing, Public Health, Environmental and Occupational Health, ANTINEOPLASTIC DRUGS, Deoxyguanosine, lcsh:RA1-1270, occupational exposure, biomonitoring, Occupational Diseases, Cross-Sectional Studies, Italy, 8-Hydroxy-2'-Deoxyguanosine, Micronucleus test, Biomarker (medicine), Female, Biomarkers, Environmental Monitoring, DNA Damage, OCCUPATIONAL, business, medicine.drug
Abstract

Background Some industrial hygiene studies have assessed occupational exposure to antineoplastic drugs; other epidemiological investigations have detected various toxicological effects in exposure groups labeled with the job title. In no research has the same population been studied both environmentally and epidemiologically. The protocol of the epidemiological study presented here uses an integrated environmental and biological monitoring approach. The aim is to assess in hospital nurses preparing and/or administering therapy to cancer patients the current level of occupational exposure to antineoplastic drugs, DNA and chromosome damage as cancer predictive effects, and the association between the two. Methods/Design About 80 healthy non-smoking female nurses, who job it is to prepare or handle antineoplastic drugs, and a reference group of about 80 healthy non-smoking female nurses not occupationally exposed to chemicals will be examined simultaneously in a cross-sectional study. All the workers will be recruited from five hospitals in northern and central Italy after their informed consent has been obtained. Evaluation of surface contamination and dermal exposure to antineoplastic drugs will be assessed by determining cyclophosphamide on selected surfaces (wipes) and on the exposed nurses' clothes (pads). The concentration of unmetabolized cyclophosphamide as a biomarker of internal dose will be measured in end-shift urine samples from exposed nurses. Biomarkers of effect and susceptibility will be assessed in exposed and unexposed nurses: urinary concentration of 8-hydroxy-2-deoxyguanosine; DNA damage detected using the single-cell microgel electrophoresis (comet) assay in peripheral white blood cells; micronuclei and chromosome aberrations in peripheral blood lymphocytes. Genetic polymorphisms for enzymes involved in metabolic detoxification (i.e. glutathione S-transferases) will also be analysed. Using standardized questionnaires, occupational exposure will be determined in exposed nurses only, whereas potential confounders (medicine consumption, lifestyle habits, diet and other non-occupational exposures) will be assessed in both groups of hospital workers. Statistical analysis will be performed to ascertain the association between occupational exposure to antineoplastic drugs and biomarkers of DNA and chromosome damage, after taking into account the effects of individual genetic susceptibility, and the presence of confounding exposures. Discussion The findings of the study will be useful in updating prevention procedures for handling antineoplastic drugs.

Published
2011

19. Chromosome aberrations and telomere length modulation in bone marrow and spleen cells of melphalan-treated p53+/- mice

Author

Serena Cinelli, Antonella Sgura, Andrea De Amicis, Laura Stronati, Francesca Pacchierotti, Caterina Tanzarella, Sgura, Antonella, DE AMICIS, A, Stronati, L, Cinelli, S, Pacchierotti, F, and Tanzarella, C.

Subjects
Genotype, Epidemiology, Health, Toxicology and Mutagenesis, p53+/-mice, Spleen, Bone Marrow Cells, In situ hybridization, Biology, Chromosome aberration, Chromosome Painting, Mice, medicine, Animals, Antineoplastic Agents, Alkylating, Melphalan, Genetics (clinical), Cells, Cultured, In Situ Hybridization, Fluorescence, Chromosome Aberrations, Mice, Knockout, telomere and chromosome aberration, Wild type, Chromosome, Cell cycle, Telomere, Molecular biology, melphalan, Mice, Inbred C57BL, medicine.anatomical_structure, Female, Bone marrow, Tumor Suppressor Protein p53
Abstract

The p53 gene regulates cell cycle and apoptotic pathways after induction of DNA damage. Telomeres, capping chromosome ends, are involved in maintaining chromosome stability; alterations of their length have been related to increased levels of chromosomal aberrations. To study a possible interaction between chromosome aberrations, telomere dysfunction, and p53, we investigated via painting analysis the induction and persistence of chromosome aberrations in bone marrow and spleen cells of p53+/− (and wild type) mice exposed for 4, 13, or 26 weeks to 2 mg/kg melphalan (MLP), a chemotherapeutic agent with carcinogenic potential. In addition, telomere length was evaluated in bone marrow cells by quantitative fluorescence in situ hybridization (Q-FISH). Chromosome aberrations were significantly increased in both tissues after MLP treatment. The p53 genotype did not influence the response of spleen cells, whereas a slight but significant increase of the aberration frequency was measured in the bone marrow of p53+/− mice exposed to MLP for 13 weeks with respect to the level detected in the matched wild-type group. The main finding of our still preliminary results on telomere length modulation was again a difference between the two genotypes. In bone marrow cells of wild-type mice, MLP treatment was associated with telomere shortening, while in p53+/− mice telomere elongation was the prevalent response to MLP exposure. In agreement with previous literature data, our in vivo study suggests that even the lack of a single functional copy of the p53 gene might have an impact on the quantity and quality of chromosome alterations induced in cycling cells by a clastogenic exposure. Environ. Mol. Mutagen., 2008. © 2008 Wiley-Liss, Inc.

Published
2008

20. Dipotassium Glycyrrhizate Inhibits HMGB1-Dependent Inflammation and Ameliorates Colitis in Mice

Author

Marina Aloi, Roberta Vitali, Leonardo Cavone, Anna Negroni, Laura Stronati, Anna Dilillo, Manuela Costanzo, Francesca Palone, Salvatore Cucchiara, Stronati, L., Costanzo, M., Negroni, A., Palone, F., and Vitali, R.

Subjects
Genetics and Molecular Biology (all), Mouse, lcsh:Medicine, Pharmacology, Bioinformatics, Biochemistry, Inflammatory bowel disease, Mice, Gene expression, Dipotassium Glycyrrhizate, HMGB1 Protein, lcsh:Science, Multidisciplinary, biology, Medicine (all), Animal Models, Colitis, Innate Immunity, Real-time polymerase chain reaction, Medicine, Cytokines, Female, Inflammation Mediators, medicine.symptom, Research Article, Colon, Immunology, chemical and pharmacologic phenomena, Inflammation, Gastroenterology and Hepatology, Real-Time Polymerase Chain Reaction, HMGB1, Microbiology, Cell Line, Model Organisms, Cell Line, Tumor, medicine, Animals, Humans, Agricultural and Biological Sciences (all), Biochemistry, Genetics and Molecular Biology (all), Biology, business.industry, lcsh:R, Immunity, Glycyrrhizic Acid, medicine.disease, Mice, Inbred C57BL, Cell culture, biology.protein, lcsh:Q, Clinical Immunology, business
Abstract

Background:High mobility group box-1 (HMGB1) is a DNA-binding protein that is released from injured cells during inflammation. Advances in targeting HMGB1 represent a major challenge to improve the treatment of acute/chronic inflammation.Aim:This study is aimed at verifying whether the inhibition of HMGB1 through dipotassium glycyrrhizate (DPG) is a good strategy to reduce intestinal inflammation.Methods:Human colon adenocarcinoma cell line, HT29, human epithelial colorectal adenocarcinoma, Caco2, and murine macrophage cell line, RAW 264.7, were cultured to investigate the effect of DPG on the secretion of HMGB1. Acute colitis was induced in C57BL/6 mice through administration of 3% dextran sodium sulphate (DSS); a combined treatment with DSS and 3 or 8 mg/kg/day DPG was used to investigate the effects of DPG on intestinal inflammation. Animals were euthanized at seventh day and colonic samples underwent molecular and histological analyses.Results:DPG significantly reduces in vitro the release of HMGB1 in the extracellular matrix as well as expression levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, by inhibiting HMGB1. Moreover, DPG significantly decreases the severity of DSS-induced colitis in mice. Murine colonic samples show decreased mRNA levels of pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, RAGE and TLR4. Finally, HMGB1, abundantly present in the feces of mice with DSS-induced colitis, is strongly reduced by DPG.Conclusions:HMGB1 is an early pro-inflammatory cytokine and an active protagonist of mucosal gut inflammation. DPG exerts inhibitory effects against HMGB1 activity, significantly reducing intestinal inflammation. Thus, we reason that DPG could represent an innovative tool for the management of human intestinal inflammation. © 2013 Vitali et al.

Published
2013

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