Author: "Strazzabosco, M." / Publisher: w.b. saunders - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Strazzabosco, M."' showing total 31 results

Start Over Author "Strazzabosco, M." Publisher w.b. saunders

31 results on '"Strazzabosco, M."'

1. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Author: Asselta, R., Paraboschi, E. M., Gerussi, A., Cordell, H. J., Mells, G. F., Sandford, R. N., Jones, D. E., Nakamura, M., Ueno, K., Hitomi, Y., Kawashima, M., Nishida, N., Tokunaga, K., Nagasaki, M., Tanaka, A., Tang, R., Li, Z., Shi, Y., Liu, X., Xiong, M., Hirschfield, G., Siminovitch, K. A., Walker, E., Xie, G., Mason, A., Myers, R., Peltekian, K., Ghent, C., Atkinson, E., Juran, B., Lazaridis, K., Lu, Y., Gu, X., Jing, K., Amos, C., Affronti, A., Brunetto, M., Coco, B., Spinzi, G., Elia, G., Ferrari, C., Lleo, A., Muratori, L., Muratori, P., Portincasa, P., Colli, A., Bruno, S., Colloredo, G., Azzaroli, F., Andreone, P., Bragazzi, M., Alvaro, D., Cardinale, V., Cazzagon, N., Rigamonti, C., Floreani, A., Rosina, F., Ciaccio, A., Cristoferi, L., D'Amato, D., Malinverno, F., Mancuso, C., Massironi, S., Milani, C., O'Donnell, S. E., Ronca, V., Barisani, D., Lampertico, P., Donato, Federica, Fagiuoli, Stefano, Almasio, P. L., Giannini, E., Cursaro, C., Colombo, M., Valenti, L., Miele, Luca, Andriulli, A., Niro, G. A., Grattagliano, I., Morini, L., Casella, G., Vinci, Maria Rosaria, Battezzati, P. M., Crosignani, A., Zuin, M., Mattalia, A., Calvaruso, V., Colombo, S., Benedetti, A., Marzioni, M., Galli, A., Marra, F., Tarocchi, M., Picciotto, A., Morisco, F., Fabris, L., Croce, L. S., Tiribelli, C., Toniutto, P., Strazzabosco, M., Ch'Ng, C. L., Rahman, M., Yapp, T., Sturgess, R., Healey, C., Czajkowski, M., Gunasekera, A., Gyawali, P., Premchand, P., Kapur, K., Marley, R., Foster, G., Watson, A., Dias, A., Subhani, J., Harvey, R., Mccorry, R., Ramanaden, D., Gasem, J., Evans, R., Mathialahan, T., Shorrock, C., Lipscomb, G., Southern, P., Tibble, J., Gorard, D., Palegwala, A., Jones, S., Dawwas, M., Alexander, G., Dolwani, S., Prince, M., Foxton, M., Elphick, D., Mitchison, H., Gooding, I., Karmo, M., Saksena, S., Mendall, M., Patel, M., Ede, R., Austin, A., Sayer, J., Hankey, L., Hovell, C., Fisher, N., Carter, M., Koss, K., Piotrowicz, A., Grimley, C., Neal, D., Lim, G., Levi, S., Ala, A., Broad, A., Saeed, A., Wood, G., Brown, J., Wilkinson, M., Gordon, H., Ramage, J., Ridpath, J., Ngatchu, T., Grover, B., Shaukat, S., Shidrawi, R., Abouda, G., Ali, F., Rees, I., Salam, I., Narain, M., Brown, A., Taylor-Robinson, S., Williams, S., Grellier, L., Banim, P., Das, D., Chilton, A., Heneghan, M., Curtis, H., Gess, M., Drake, I., Aldersley, M., Davies, M., Jones, R., Mcnair, A., Srirajaskanthan, R., Pitcher, M., Sen, S., Bird, G., Barnardo, A., Kitchen, P., Yoong, K., Chirag, O., Sivaramakrishnan, N., Macfaul, G., Jones, D., Shah, A., Evans, C., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Fraser, A., Mills, P., Shallcross, C., Campbell, S., Bathgate, A., Shepherd, A., Dillon, J., Rushbrook, S., Przemioslo, R., Macdonald, C., Metcalf, J., Shmueli, U., Davis, A., Naqvi, A., Lee, T., Ryder, S. D., Collier, J., Klass, H., Ninkovic, M., Cramp, M., Sharer, N., Aspinall, R., Goggin, P., Ghosh, D., Douds, A., Hoeroldt, B., Booth, J., Williams, E., Hussaini, H., Stableforth, W., Ayres, R., Thorburn, D., Marshall, E., Burroughs, A., Mann, S., Lombard, M., Richardson, P., Patanwala, I., Maltby, J., Brookes, M., Mathew, R., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Panter, S., Shearman, J., Bray, G., Butcher, G., Forton, D., Mclindon, J., Cowan, M., Whatley, G., Mandal, A., Gupta, H., Sanghi, P., Jain, S., Pereira, S., Prasad, G., Watts, G., Wright, M., Neuberger, J., Gordon, F., Unitt, E., Grant, A., Delahooke, T., Higham, A., Brind, A., Cox, M., Ramakrishnan, S., King, A., Collins, C., Whalley, S., Li, A., Fraser, J., Bell, A., Wong, V. S., Singhal, A., Gee, I., Ang, Y., Ransford, R., Gotto, J., Millson, C., Bowles, J., Thomas, C., Harrison, M., Galaska, R., Kendall, J., Whiteman, J., Lawlor, C., Gray, C., Elliott, K., Mulvaney-Jones, C., Hobson, L., Van Duyvenvoorde, G., Loftus, A., Seward, K., Penn, R., Maiden, J., Damant, R., Hails, J., Cloudsdale, R., Silvestre, V., Glenn, S., Dungca, E., Wheatley, N., Doyle, H., Kent, M., Hamilton, C., Braim, D., Wooldridge, H., Abrahams, R., Paton, A., Lancaster, N., Gibbins, A., Hogben, K., Desousa, P., Muscariu, F., Musselwhite, J., Mckay, A., Tan, L., Foale, C., Brighton, J., Flahive, K., Nambela, E., Townshend, P., Ford, C., Holder, S., Palmer, C., Featherstone, J., Nasseri, M., Sadeghian, J., Williams, B., Rolls, S. -A., Hynes, A., Duggan, C., Crossey, M., Stansfield, G., Macnicol, C., Wilkins, J., Wilhelmsen, E., Raymode, P., Lee, H. -J., Durant, E., Bishop, R., Ncube, N., Tripoli, S., Casey, R., Cowley, C., Miller, R., Houghton, K., Ducker, S., Wright, F., Bird, B., Baxter, G., Keggans, J., Hughes, M., Grieve, E., Young, K., Williams, D., Ocker, K., Hines, F., Martin, K., Innes, C., Valliani, T., Fairlamb, H., Thornthwaite, S., Eastick, A., Tanqueray, E., Morrison, J., Holbrook, B., Browning, J., Walker, K., Congreave, S., Verheyden, J., Slininger, S., Stafford, L., O'Donnell, D., Ainsworth, M., Lord, S., Kent, L., March, L., Dickson, C., Simpson, D., Longhurst, B., Hayes, M., Shpuza, E., White, N., Besley, S., Pearson, S., Wright, A., Jones, L., Gunter, E., Dewhurst, H., Fouracres, A., Farrington, L., Graves, L., Marriott, S., Leoni, M., Tyrer, D., Dali-kemmery, L., Lambourne, V., Green, M., Sirdefield, D., Amor, K., Colley, J., Shinder, B., Jones, J., Mills, M., Carnahan, M., Taylor, N., Boulton, K., Tregonning, J., Brown, C., Clifford, G., Archer, E., Hamilton, M., Curtis, J., Shewan, T., Walsh, S., Warner, K., Netherton, K., Mupudzi, M., Gunson, B., Gitahi, J., Gocher, D., Batham, S., Pateman, H., Desmennu, S., Conder, J., Clement, D., Gallagher, S., Orpe, J., Chan, P., Currie, L., O'Donohoe, L., Oblak, M., Morgan, L., Quinn, M., Amey, I., Baird, Y., Cotterill, D., Cumlat, L., Winter, L., Greer, S., Spurdle, K., Allison, J., Dyer, S., Sweeting, H., Kordula, J., Aiba, Y., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Kawai, Y., Kohn, S. -S., Gervais, O., Migita, K., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Higuchi, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Takikawa, H., Ohira, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Carbone, M., Cardamone, G., Duga, S., Gershwin, M. E., Seldin, M. F., Invernizzi, P., Donato F., Fagiuoli S., Miele L. (ORCID:0000-0003-3464-0068), Vinci M., Asselta, R., Paraboschi, E. M., Gerussi, A., Cordell, H. J., Mells, G. F., Sandford, R. N., Jones, D. E., Nakamura, M., Ueno, K., Hitomi, Y., Kawashima, M., Nishida, N., Tokunaga, K., Nagasaki, M., Tanaka, A., Tang, R., Li, Z., Shi, Y., Liu, X., Xiong, M., Hirschfield, G., Siminovitch, K. A., Walker, E., Xie, G., Mason, A., Myers, R., Peltekian, K., Ghent, C., Atkinson, E., Juran, B., Lazaridis, K., Lu, Y., Gu, X., Jing, K., Amos, C., Affronti, A., Brunetto, M., Coco, B., Spinzi, G., Elia, G., Ferrari, C., Lleo, A., Muratori, L., Muratori, P., Portincasa, P., Colli, A., Bruno, S., Colloredo, G., Azzaroli, F., Andreone, P., Bragazzi, M., Alvaro, D., Cardinale, V., Cazzagon, N., Rigamonti, C., Floreani, A., Rosina, F., Ciaccio, A., Cristoferi, L., D'Amato, D., Malinverno, F., Mancuso, C., Massironi, S., Milani, C., O'Donnell, S. E., Ronca, V., Barisani, D., Lampertico, P., Donato, Federica, Fagiuoli, Stefano, Almasio, P. L., Giannini, E., Cursaro, C., Colombo, M., Valenti, L., Miele, Luca, Andriulli, A., Niro, G. A., Grattagliano, I., Morini, L., Casella, G., Vinci, Maria Rosaria, Battezzati, P. M., Crosignani, A., Zuin, M., Mattalia, A., Calvaruso, V., Colombo, S., Benedetti, A., Marzioni, M., Galli, A., Marra, F., Tarocchi, M., Picciotto, A., Morisco, F., Fabris, L., Croce, L. S., Tiribelli, C., Toniutto, P., Strazzabosco, M., Ch'Ng, C. L., Rahman, M., Yapp, T., Sturgess, R., Healey, C., Czajkowski, M., Gunasekera, A., Gyawali, P., Premchand, P., Kapur, K., Marley, R., Foster, G., Watson, A., Dias, A., Subhani, J., Harvey, R., Mccorry, R., Ramanaden, D., Gasem, J., Evans, R., Mathialahan, T., Shorrock, C., Lipscomb, G., Southern, P., Tibble, J., Gorard, D., Palegwala, A., Jones, S., Dawwas, M., Alexander, G., Dolwani, S., Prince, M., Foxton, M., Elphick, D., Mitchison, H., Gooding, I., Karmo, M., Saksena, S., Mendall, M., Patel, M., Ede, R., Austin, A., Sayer, J., Hankey, L., Hovell, C., Fisher, N., Carter, M., Koss, K., Piotrowicz, A., Grimley, C., Neal, D., Lim, G., Levi, S., Ala, A., Broad, A., Saeed, A., Wood, G., Brown, J., Wilkinson, M., Gordon, H., Ramage, J., Ridpath, J., Ngatchu, T., Grover, B., Shaukat, S., Shidrawi, R., Abouda, G., Ali, F., Rees, I., Salam, I., Narain, M., Brown, A., Taylor-Robinson, S., Williams, S., Grellier, L., Banim, P., Das, D., Chilton, A., Heneghan, M., Curtis, H., Gess, M., Drake, I., Aldersley, M., Davies, M., Jones, R., Mcnair, A., Srirajaskanthan, R., Pitcher, M., Sen, S., Bird, G., Barnardo, A., Kitchen, P., Yoong, K., Chirag, O., Sivaramakrishnan, N., Macfaul, G., Jones, D., Shah, A., Evans, C., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Fraser, A., Mills, P., Shallcross, C., Campbell, S., Bathgate, A., Shepherd, A., Dillon, J., Rushbrook, S., Przemioslo, R., Macdonald, C., Metcalf, J., Shmueli, U., Davis, A., Naqvi, A., Lee, T., Ryder, S. D., Collier, J., Klass, H., Ninkovic, M., Cramp, M., Sharer, N., Aspinall, R., Goggin, P., Ghosh, D., Douds, A., Hoeroldt, B., Booth, J., Williams, E., Hussaini, H., Stableforth, W., Ayres, R., Thorburn, D., Marshall, E., Burroughs, A., Mann, S., Lombard, M., Richardson, P., Patanwala, I., Maltby, J., Brookes, M., Mathew, R., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Panter, S., Shearman, J., Bray, G., Butcher, G., Forton, D., Mclindon, J., Cowan, M., Whatley, G., Mandal, A., Gupta, H., Sanghi, P., Jain, S., Pereira, S., Prasad, G., Watts, G., Wright, M., Neuberger, J., Gordon, F., Unitt, E., Grant, A., Delahooke, T., Higham, A., Brind, A., Cox, M., Ramakrishnan, S., King, A., Collins, C., Whalley, S., Li, A., Fraser, J., Bell, A., Wong, V. S., Singhal, A., Gee, I., Ang, Y., Ransford, R., Gotto, J., Millson, C., Bowles, J., Thomas, C., Harrison, M., Galaska, R., Kendall, J., Whiteman, J., Lawlor, C., Gray, C., Elliott, K., Mulvaney-Jones, C., Hobson, L., Van Duyvenvoorde, G., Loftus, A., Seward, K., Penn, R., Maiden, J., Damant, R., Hails, J., Cloudsdale, R., Silvestre, V., Glenn, S., Dungca, E., Wheatley, N., Doyle, H., Kent, M., Hamilton, C., Braim, D., Wooldridge, H., Abrahams, R., Paton, A., Lancaster, N., Gibbins, A., Hogben, K., Desousa, P., Muscariu, F., Musselwhite, J., Mckay, A., Tan, L., Foale, C., Brighton, J., Flahive, K., Nambela, E., Townshend, P., Ford, C., Holder, S., Palmer, C., Featherstone, J., Nasseri, M., Sadeghian, J., Williams, B., Rolls, S. -A., Hynes, A., Duggan, C., Crossey, M., Stansfield, G., Macnicol, C., Wilkins, J., Wilhelmsen, E., Raymode, P., Lee, H. -J., Durant, E., Bishop, R., Ncube, N., Tripoli, S., Casey, R., Cowley, C., Miller, R., Houghton, K., Ducker, S., Wright, F., Bird, B., Baxter, G., Keggans, J., Hughes, M., Grieve, E., Young, K., Williams, D., Ocker, K., Hines, F., Martin, K., Innes, C., Valliani, T., Fairlamb, H., Thornthwaite, S., Eastick, A., Tanqueray, E., Morrison, J., Holbrook, B., Browning, J., Walker, K., Congreave, S., Verheyden, J., Slininger, S., Stafford, L., O'Donnell, D., Ainsworth, M., Lord, S., Kent, L., March, L., Dickson, C., Simpson, D., Longhurst, B., Hayes, M., Shpuza, E., White, N., Besley, S., Pearson, S., Wright, A., Jones, L., Gunter, E., Dewhurst, H., Fouracres, A., Farrington, L., Graves, L., Marriott, S., Leoni, M., Tyrer, D., Dali-kemmery, L., Lambourne, V., Green, M., Sirdefield, D., Amor, K., Colley, J., Shinder, B., Jones, J., Mills, M., Carnahan, M., Taylor, N., Boulton, K., Tregonning, J., Brown, C., Clifford, G., Archer, E., Hamilton, M., Curtis, J., Shewan, T., Walsh, S., Warner, K., Netherton, K., Mupudzi, M., Gunson, B., Gitahi, J., Gocher, D., Batham, S., Pateman, H., Desmennu, S., Conder, J., Clement, D., Gallagher, S., Orpe, J., Chan, P., Currie, L., O'Donohoe, L., Oblak, M., Morgan, L., Quinn, M., Amey, I., Baird, Y., Cotterill, D., Cumlat, L., Winter, L., Greer, S., Spurdle, K., Allison, J., Dyer, S., Sweeting, H., Kordula, J., Aiba, Y., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Kawai, Y., Kohn, S. -S., Gervais, O., Migita, K., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Higuchi, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Takikawa, H., Ohira, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Carbone, M., Cardamone, G., Duga, S., Gershwin, M. E., Seldin, M. F., Invernizzi, P., Donato F., Fagiuoli S., Miele L. (ORCID:0000-0003-3464-0068), and Vinci M.
Abstract: Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
Published: 2021

2. Outcome indicators in primary sclerosing cholangitis: Interim analysis of the value-based medicine in hepatology study

Author: Fabris, L, Ciaccio, A, Okolicsanyi, S, Rota, M, Cortesi, P, Buonocore, M, Gemma, M, Giani, P, Belli, L, Fagiuoli, S, Scalone, L, Valsecchi, M, Mantovani, L, Strazzabosco, M, Fabris, L, Ciaccio, A, Okolicsanyi, S, Rota, M, Cortesi, P, Buonocore, M, Gemma, M, Giani, P, Belli, L, Fagiuoli, S, Scalone, L, Valsecchi, M, Mantovani, L, and Strazzabosco, M
Subjects: outcome indicators, primary sclerosing cholangitis, value-based medicine, health care, Hepatology, MED/12 - GASTROENTEROLOGIA, MED/42 - IGIENE GENERALE E APPLICATA, outcome indicator, Gastroenterology, primary sclerosing cholangiti, MED/01 - STATISTICA MEDICA
Abstract: Introduction: Primary sclerosing cholangitis (PSC) is an enigmatic disease with scarce therapeutic options. The clinical management of PSC remains challenging and may benefit from Outcome Indicators (OI) to assess the quality of care. Aims: This study aims to: (A) identify OIs for PSC, and (B) validate OIs in a clinical context. Methods: (A) A panel of experts generated a list of OIs by Delphi method. (B) OIs with the highest RAND/UCLA score were tested in an ongoing multicentric, prospective study (Value-based Medicine in Hepatology, VBMH). Results: Five OIs were identified having the highest rating values and low disagreement indexes: annual rate of acute cholangitis episodes (OI#1); mortality rate for patients not yet listed for liver transplantation (OI#2); rate of quality of life improvement, measured by EQ-VAS and EQ-5D (OI#3); number of patients died for cholangiocarcinoma and colo-rectal carcinoma (OI#4); incidence and/or worsening of osteoporosis (OI#5). In the validation study, 63 consecutive patients with PSC enrolled in 3 tertiary centres in Northern Italy were evaluated for a median 24-months follow-up period. For each OI, the following values were reported: (OI#1) cumulative incidence of 5.2%, resulting in 0.029 cholangitis/patient; (OI#2, OI#4) no patients died without being listed for transplantation or because of cancer during study time; (OI#3) 38.9 and 19.4% of patients showed an improvement in EQ-VAS and EQ-5D parameters, respectively; (OI#5) 3% of patients developed or worsened osteoporosis. Conclusions: Five OIs for PSC were identified reporting high consensus. Albeit the study population is small (as in the case of rare diseases) and the follow-up time is short as compared to the long natural history of the disease, these OIs have proven to be easy to collect and to work appropriately. Therefore, they are suitable to be extended to specialized centres involved in PSC management to further validate their clinical usefulness.
Published: 2015

3. Characteristics of patients with Chronic Hepatitis C who have failed past treatment or who have never been treated: How much room left for Interferon?

Author: Ciaccio, A, Okolicsanyi, S, Rota, M, Cortesi, P, De Salvia, S, Gemma, M, Vinci, M, Mantovani, L, Belli, L, Strazzabosco, M, CIACCIO, ANTONIO, OKOLICSANYI, STEFANO, ROTA, MATTEO, CORTESI, PAOLO ANGELO, GEMMA, MARTA, MANTOVANI, LORENZO GIOVANNI, STRAZZABOSCO, MARIO, Ciaccio, A, Okolicsanyi, S, Rota, M, Cortesi, P, De Salvia, S, Gemma, M, Vinci, M, Mantovani, L, Belli, L, Strazzabosco, M, CIACCIO, ANTONIO, OKOLICSANYI, STEFANO, ROTA, MATTEO, CORTESI, PAOLO ANGELO, GEMMA, MARTA, MANTOVANI, LORENZO GIOVANNI, and STRAZZABOSCO, MARIO
Abstract: Background/aims: According to current guidelines on management of Chronic Hepatitis C (CHC), both interferon (IFN)-containing and IFN-free treatment combinations may be offered to patients, depending on viral genotype, previous treatment and contraindications to IFN. The past two decades of treatment have selected a large population of patients ineligible to IFN. Our aim is to characterize the current CHC population in order to best drive resource allocation. Patients and methods: we retrospectively retrieved the characteristics and outcomes of a cohort of 801 consecutive CHC outpatients followed-up at two tertiary Centers in Northern Italy. Baseline characteristics of never treated and treated CHC patients were compared by means of Chi-Square test for categorical and t-test for continuous variables. Results: fifty-three percent (426 out of 801) of patients had previously received treatment. Among them, 103 (24%) had achieved SVR; 323 (76%) had failed, of whom 74 (23%) did not complete and 249 (77%) did not respond to treatment. Adverse events were the main cause of treatment withdrawal (90%). Forty-seven percent (n = 375) of all participants had never received any treatment, mostly because of contraindications (27% overall, hematologic 11%, psychiatric 24%, cardiovascular 15%, autoimmune 7%, others 43%), advanced age (27%), personal choice (15%) or no fibrosis (10%). Never treated patients differed significantly (p < 0.01) from treated ones by age (61 vs 56 years) and gender (male 49 vs 65%). Six-hundred and ninety-eight patients (323 failed plus 375 never treated) are awaiting new antiviral therapy, of which 442 (63%) are candidate to all-oral combinations because of contraindications or past intolerance to IFN, while the remaining 256 (37%) may still receive an IFN-containing regimen. Conclusions: 37% of the CHC patients being followed in our clinics may receive IFN-containing protocols with newer DAAs, while about the two thirds of these patients are obligated c
Published: 2015

4. Value-based outcome indicators in the management of hepatocellular carcinoma: Clinical test in a large multicenter study (VBMH study)

Author: Okolicsanyi, S, Ciaccio, A, Rota, M, Gentiluomo, M, Gemma, M, Grisolia, A, Cortesi, P, Scalone, L, Mantovani, L, Pontisso, P, Burra, P, Fabris, L, Mondelli, M, Colledan, M, Fagiuoli, S, Valsecchi, M, Cesana, G, Belli, L, Mazzaferro, V, Strazzabosco, M, Okolicsanyi, S, Ciaccio, A, Rota, M, Gentiluomo, M, Gemma, M, Grisolia, A, Cortesi, P, Scalone, L, Mantovani, L, Pontisso, P, Burra, P, Fabris, L, Mondelli, M, Colledan, M, Fagiuoli, S, Valsecchi, M, Cesana, G, Belli, L, Mazzaferro, V, and Strazzabosco, M
Abstract: Introduction: The management of hepatocellular carcinoma (HCC) is a well-known public health problem, accounting for increasing mortality and high costs. Quality parameters able to measure clinical outcomes are still lacking. Aim of our study (Value Based Medicine in Hepatology, VBMH)was to identify and test outcome indicators (OIs) in HCC, in light of their potential use in policy decision models. Methods: A panel of experts identified a list of OIs using a modified Delphi method, according to experience and published evidence; four OIs with the highest RAND/UCLA score were tested in a prospective multicenter observational study. During 18 months, 711 HCC patients were enrolled and prospectively followed. 677 patients (95%) had at least one follow-up consultation. Median follow-up time was 14 months. Results: The first OI was 1–3–5 years survival stratified for BCLC stage or treatment (OI#1). One-year survival for BCLC stage 0/A–D was 93%, 86%, 50%, 26% respectively. One-year survival of 288 patients treated for the first time during the study was 88% for liver transplantation, 97% surgical resection, 100% ablation and 89% for TACE. The other three OIs evaluated the appropriateness of treatments: worsening of BCLC and/or CPT score after three months from a loco-regional therapy or surgical resection (OI#2), occurred in 16% of cases (76% after TACE). Recurrence of HCC within 6 months after curative treatments (OI#3) happened in 15% of patients treated, mainly after ablation (20%). Presence of severe morbidity three months after loco-regional procedure or resection, evaluated as grade≥3 according to Clavien-Dindo classification (OI#3), was found in 3% of patients treated. Conclusions: The outcome indicators identified in the VBMH study proved their feasibility in a large cohort of patients and could stand as a benchmark for healthcare providers to move towards a value-based approach in the management of HCC.
Published: 2014

5. Management of chronic hepatitis C (Chc) genotype 1 treatment-naïve patients in an era of rising opportunities and costs: A cost-effectiveness analysis

Author: Cortesi, P, Ciaccio, A, Rota, M, De Salvia, S, Okolicsanyi, S, Vinci, M, Belli, L, Lim, J, Mantovani, L, Strazzabosco, M, CORTESI, PAOLO ANGELO, CIACCIO, ANTONIO, ROTA, MATTEO, OKOLICSANYI, STEFANO, STRAZZABOSCO, MARIO, MANTOVANI, LORENZO GIOVANNI, Cortesi, P, Ciaccio, A, Rota, M, De Salvia, S, Okolicsanyi, S, Vinci, M, Belli, L, Lim, J, Mantovani, L, Strazzabosco, M, CORTESI, PAOLO ANGELO, CIACCIO, ANTONIO, ROTA, MATTEO, OKOLICSANYI, STEFANO, STRAZZABOSCO, MARIO, and MANTOVANI, LORENZO GIOVANNI
Abstract: Background and aims: To allocate treatment resources for chronic hepatitis C (CHC) genotype 1 naive patients, we performed a cost-effectiveness analysis of Boceprevir (BOC) and Telaprevir (TVR) based triple therapy according to different patient selection strategies. Methods: A semi-Markov model of CHC natural history and progression toward end stage liver diseases (decompensated cirrhosis, HCC and liver transplantation) was built. Model health states were defined by METAVIR fibrosis stages (F0–F4), and complications of cirrhosis. We considered 3 selection strategies based on fibrosis stage: (1) treat all patients with F1–F4 fibrosis, (2) only F2–F4 and (3) only F3–F4. For each strategy, TVR IL28B-guided and BOC RVRguided therapy was applied. The model assessed the costs and outcomes, including QALYs, Life Years and the number of End Stage Liver Diseases developed or Death (ESLD-D), using lifetime as time horizon and adopting the NHS perspective. An alternative simulation was performed using 5 year as time horizon, as coherent with upcoming main changes in standard of care (all-oral protocols). Results: The F3–F4 selection strategy proved the least expensive and the least effective. Adopting the lifetime horizon, F1–F4 strategy was cost-effective with an ICER of D 5132.13 for QALY, in TVR IL28B-guided, and D 7042.49 for QALY, in BOC RVR-guided therapy. In the 5 year scenario, only F3–F4 strategy showed costeffectiveness, while the F1–F4 strategy was not cost-effective, with an ICER of D 1,818,679 (TVR IL28B guided) and D 1866.437 (BOC RVR-guided) for each ESLD-D avoided. Conclusions: The present simulation study demonstrated that treating all CHC patients regardless of fibrosis stage is cost-effective in a lifetime horizon scenario. In a more realistic 5-year time horizon scenario, to treat patients with advanced fibrosis and cirrhosis was the only strategy to show cost-effectiveness.
Published: 2014

6. Outcome indicators in liver cirrhosis: Application of value-based medicine in a large multicenter study (VBMH study)

Author: Okolicsanyi, S, Ciaccio, A, Rota, M, Gentiluomo, M, Gemma, M, Grisolia, A, Cortesi, P, Scalone, L, Mantovani, L, Pontisso, P, Burra, P, Fabris, L, Mondelli, M, Colledan, M, Fagiuoli, S, Valsecchi, M, Cesana, G, Belli, L, Strazzabosco, M, OKOLICSANYI, STEFANO, CIACCIO, ANTONIO, ROTA, MATTEO, GENTILUOMO, MARIA, GEMMA, MARTA, CORTESI, PAOLO ANGELO, SCALONE, LUCIANA, MANTOVANI, LORENZO GIOVANNI, VALSECCHI, MARIA GRAZIA, CESANA, GIANCARLO, STRAZZABOSCO, MARIO, Okolicsanyi, S, Ciaccio, A, Rota, M, Gentiluomo, M, Gemma, M, Grisolia, A, Cortesi, P, Scalone, L, Mantovani, L, Pontisso, P, Burra, P, Fabris, L, Mondelli, M, Colledan, M, Fagiuoli, S, Valsecchi, M, Cesana, G, Belli, L, Strazzabosco, M, OKOLICSANYI, STEFANO, CIACCIO, ANTONIO, ROTA, MATTEO, GENTILUOMO, MARIA, GEMMA, MARTA, CORTESI, PAOLO ANGELO, SCALONE, LUCIANA, MANTOVANI, LORENZO GIOVANNI, VALSECCHI, MARIA GRAZIA, CESANA, GIANCARLO, and STRAZZABOSCO, MARIO
Abstract: Introduction: Liver Cirrhosis (LC) is responsible for high morbidity, mortality and costs, with increasing need to improve quality of care. Aim of our study (Value Based Medicine in Hepatology Study, VBMH) was to identify outcome indicators (OIs) able to measure quality in liver diseases, including compensated (CC) and decompensated (DC) LC. Methods: A panel of hepatologists identified a list of 7 OIs for LC according to experience and published evidence, using a modified Delphi method and a standard 9-pointRANDappropriateness scale. Then, these 7 OIs were tested in clinical practice in a prospective multicenter observational study involving three tertiary centers in Italy, using a web-based electronic medical record. 1751 LC patients were enrolled in 18 months: 1004 CC and 747 DC. 92% of patients had at least two consultations in 17 months median follow-up. Results: Annual rate of decompensation in CC was 12% (OI#1). Annual incidence of 1st variceal bleeding (VB) was 2% for low-risk and 3% for high-risk varices (OI#2) indicating a significant success of primary profilaxis. Annual incidence of HCC in CC was 4.3%, with 81% patients found at early stage (OI#3), underlining the accuracy of oncologic surveillance. One-year survival after the first decompensation episode (ascites in 74% of cases) was 96%, 81% and 59% stratified for CPT score A, B, C respectively (OI#4), and 94%, 56% stratified for MELD below or above 15 (OI#5). 4% of DC patients had an episode of VB with 90% survival after 6 weeks, and 33% recurrence (OI#6). Similarly, 3% ofDCpatients had spontaneous bacterial peritonitis with 6 weeks survival of 86% and 13% recurrence (OI#7). Conclusions: The value-based OIs generated in this study performed well in a large cohort of consecutive patients, and could represent a reference tool for healthcare providers to improve care in LC.
Published: 2014

7. Notch signaling in hepatocellular carcinoma: guilty in association!

Author: Strazzabosco, M, Fabris, L, STRAZZABOSCO, MARIO, Fabris, L., Strazzabosco, M, Fabris, L, STRAZZABOSCO, MARIO, and Fabris, L.
Published: 2012

8. Polycystic Liver Diseases: Congenital Disorders of Cholangiocyte Signaling

Author: Strazzabosco, M, Somlo, S, STRAZZABOSCO, MARIO, Somlo, S., Strazzabosco, M, Somlo, S, STRAZZABOSCO, MARIO, and Somlo, S.
Abstract: Polycystic liver diseases (PLD) are inherited disorders of the biliary epithelium, caused by genetic defects in proteins associated with intracellular organelles, mainly the endoplasmic reticulum and the cilium. PLD are characterized by the formation and progressive enlargement of multiple cysts scattered throughout the liver parenchyma, and include different entities, classified based on their pathology, inheritance pattern, involvement of the kidney and clinical features. PLD should be considered as congenital diseases of cholangiocyte signaling. Here, we will review the changes in signaling pathways involved in liver cyst formation and progression, and their impact on cholangiocyte physiology. Each pathway represents a potential target for therapies aimed at reducing disease progression.
Published: 2011

9. ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice

Author: Spirli, C, Okolicsanyi, S, Fiorotto, R, Fabris, L, Cadamuro, M, Lecchi, S, Tian, X, Somlo, S, Strazzabosco, M, CADAMURO, MASSIMILIANO, STRAZZABOSCO, MARIO, Spirli, C, Okolicsanyi, S, Fiorotto, R, Fabris, L, Cadamuro, M, Lecchi, S, Tian, X, Somlo, S, Strazzabosco, M, CADAMURO, MASSIMILIANO, and STRAZZABOSCO, MARIO
Abstract: BACKGROUND & AIMS: Severe polycystic liver disease can complicate adult dominant polycystic kidney disease, a genetic disease caused by defects in polycystin-1 (Pkd1) or polycystin-2 (Pkd2). Liver cyst epithelial cells (LCECs) express vascular endothelial growth factor (VEGF) and its receptor, VEGFR-2. We investigated the effects of VEGF on liver cyst growth and autocrine VEGF signaling in mice with Pkd1 and Pkd2 conditional knockouts. METHODS: We studied mice in which Pkd1 or Pkd2 were conditionally inactivated following exposure to tamoxifen; these mice were called Pkd1(flox/-):pCxCreER (Pkd1KO) and Pkd2(flox/-):pCxCreER (Pkd2KO). RESULTS: Pkd1KO and Pkd2KO mice developed liver defects; their LCECs expressed VEGF, VEGFR-2, hypoxia-inducible factor (HIF)-1alpha, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), and proliferating cell nuclear antigen (PCNA). In Pkd2KO but not Pkd1KO mice, exposure to the VEGFR-2 inhibitor SU5416 significantly reduced liver cyst development, liver/body weight ratio, and expression of pERK and PCNA. VEGF secretion and phosphorylation of ERK1/2 and VEGFR-2 were significantly increased in cultured LCECs from Pkd2KO compared with Pkd1KO mice. Inhibition of protein kinase A (PKA) reduced VEGF secretion and pERK1/2 expression. Addition of VEGF to LCECs from Pkd2KO mice increased phosphorylated VEGFR-2 and phosphorylated mitogen signal-regulated kinase (MEK) expression and induced phosphorylation of ERK1/2; this was inhibited by SU5416. Expression of HIF-1alpha increased in parallel with secretion of VEGF following LCEC stimulation. VEGF-induced cell proliferation was inhibited by the MEK inhibitor U1026 and by ERK1/2 small interfering RNA. CONCLUSIONS: The PKA-ERK1/2-VEGF signaling pathway promotes growth of liver cysts in mice. In Pkd2-defective LCECs, PKA-dependent ERK1/2 signaling controls HIF-1alpha-dependent VEGF secretion and VEGFR-2 signaling. Autocrine and paracrine VEGF signaling promotes the growth of liver cyst
Published: 2010

10. HCC persistence or recurrence after bridging therapy helps predict transplant list dropout and generate a more equitable exception policy

Author: De Giorgio, M, Vezzoli, S, Cohen, E, Armellini, E, Lucà, M, Verga, G, Pinelli, D, Nani, R, Valsecchi, M, Antolini, L, Colledan, M, Fagiuoli, S, Strazzabosco, M, Lucà, MG, Valsecchi, MG, De Giorgio, M, Vezzoli, S, Cohen, E, Armellini, E, Lucà, M, Verga, G, Pinelli, D, Nani, R, Valsecchi, M, Antolini, L, Colledan, M, Fagiuoli, S, Strazzabosco, M, Lucà, MG, and Valsecchi, MG
Abstract: Background and aim. Earlier diagnosis and more effective treatments are improving the survival of patients with HCC. Moreover, the natural history of HCC patients is different from that patients with non-neoplastic indications for liver transplantation. This issue becomes critical to provide an equitable allocation policy to patients listed for transplantation. UNOS adopted a MELD-based policy that assigns the native MELD for patients with stage I HCC and 22 points for patients stage II HCC listed for Liver Transplant (LT), with an additional three points added every 3 months of waiting time in list for the latter. Organs are then assigned on the basis of the MELD score, irrespective of the indication. In countries outside the UNOS area, allocation for HCC patients still misses uniformity. Aim. The aim of the study was to generate an updated prognostic model for HCC applicable to organ allocation. Material and methods. We analysed disease progression (death or progression of HCC beyond T2 stage) in a cohort of 177 consecutive patients that presented with HCC inside the Milan criteria. Patients were treated according to the BCLC algorithm and prospectively followed by imaging every 3 months; 76 patients (43%) were listed for transplantation according to AISF/CNT guidelines. Transplanted patients were censored at the time of transplantation. Results. Median follow-up was 16 months. HCC progressed beyond T2 stage in 75 cases; 8 patients died while in T2 stage and 68 were transplanted. To verify the ability of the UNOS policy to predict HCC progression rate (PR), we compared the expected PR according to the UNOS policy with the observed PR for the respective population at risk. The current policy resulted in a large overestimation of PR in T2 patients. Two sensitivity analyses were conducted to identify risk factor (RF) for progression using the log-rank method: in the first one, transplanted patients were considered as disease progression; in the second one, only non-t
Published: 2009

11. Glibenclamide stimulates fluid secretion in rodent cholangiocytes through a cystic fibrosis transmembrane conductance regulator-independent mechanism

Author: Spirlì, C, Fiorotto, R, Song, L, Santos Sacchi, J, Okolicsanyi, L, Masier, S, Rocchi, L, Vairetti, M, De Bernard, M, Melero, S, Pozzan, T, Strazzabosco, M, Vairetti, MP, STRAZZABOSCO, MARIO, Spirlì, C, Fiorotto, R, Song, L, Santos Sacchi, J, Okolicsanyi, L, Masier, S, Rocchi, L, Vairetti, M, De Bernard, M, Melero, S, Pozzan, T, Strazzabosco, M, Vairetti, MP, and STRAZZABOSCO, MARIO
Abstract: BACKGROUND & AIMS: Progressive liver disease is a severe complication of cystic fibrosis, a genetic disease characterized by impaired epithelial adenosine 3',5'-cyclic monophosphate-dependent secretion caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In the liver, CFTR is expressed in cholangiocytes and regulates the fluid and electrolyte content of the bile. Glibenclamide, a sulfonylurea and a known CFTR inhibitor, paradoxically stimulates cholangiocyte secretion. We studied the molecular mechanisms underlying this effect and whether glibenclamide could restore cholangiocyte secretion in cystic fibrosis. METHODS: NRC-1 cells, freshly isolated rat cholangiocytes, isolated rat biliary ducts, and isolated biliary ducts from CFTR-defective mice (Cftr tm1Unc ) were used to study fluid secretion (by video-optical planimetry), glibenclamide-induced secretion (by high-performance liquid chromatography in cell culture medium), intracellular pH and intracellular Ca 2+ concentration transients [2'7'-bis(2-carboxyethyl)-5,6,carboxyfluorescein-acetoxymethylester and Fura-2 f-AM (5-Oxazolecarboxylic acid, 2-(6-(bis(2-((acetyloxy)methoxy)-2-oxoethyl)amino)-5-(2-(2-(bis(2-((acetyloxy)methoxy)-2-oxoethyl)amino)-5-methylphenoxy)ethoxy)-2-benzofuranyl)-, (acetyloxy)methyl ester) microfluorometry], gene expression (by reverse-transcription polymerase chain reaction), and changes in membrane capacitance (by patch-clamp experiments). RESULTS: Stimulation of cholangiocyte secretion by glibenclamide and tolbutamide required Cl - and was mediated by the sulfonylurea receptor 2B. Glibenclamide-induced secretion was blocked by inhibitors of exocytosis (colchicine, wortmannin, LY294002, and N -ethylmaleimide) and by inhibitors of secretory granule acidification (vanadate, bafilomycin A1, and niflumic acid) but was Ca 2+ and depolarization independent; membrane capacitance measurements were consistent with stimulation of vesicular transport and fusion. Gli
Published: 2005

12. The cholangiopathies: disorders of biliary epithelia

Author: Lazaridis, K, Strazzabosco, M, Larusso, N, Lazaridis, KN, Larusso, N.F., STRAZZABOSCO, MARIO, Lazaridis, K, Strazzabosco, M, Larusso, N, Lazaridis, KN, Larusso, N.F., and STRAZZABOSCO, MARIO
Abstract: The intrahepatic bile ducts comprise a complex 3-dimensional network of conduits within the liver lined by specialized epithelial cells called cholangiocytes. A majorfunction of cholangiocytes is bile formation (Figure 1). Hepatocytes, the other epithelial cell type of the liver, produce primary or hepatic bile, which percolates through the intrahepatic bile ducts; during this journey, bile is modified by cholangiocytes via a series of secretory and absorptive processes that provide additional bile water (cholangiocytes secrete _40% of daily bile production in humans) and alkalinity (Figure 2).1,2 To perform this task, biliary epithelia express an array of “flux molecules” (i.e., proteins involved in transport, such as channels, exchangers, transporters) on their plasma membranes (see Strazzabosco et al.3–5 for reviews on structure, topography, and function of cholangiocyte flux molecules). Cholangiocytes also proliferate in response to endogenous or exogenous signals/stimuli and actively participate in inflammatory and reparative processes within the liver. Furthermore, cholangiocytes interact with the immune system and microorganisms and are involved in drug metabolism (Figure 1). To accomplish these multifaceted functions, cholangiocytes display morphologic and functional heterogeneity along the biliary tree. As shown on Figure 2, cholangiocytes lining large bile ducts (300–800 _m) participate in hormone-regulated bile secretion, whereas cholangiocytes lining small bile ducts (15–300 _m) possess proliferative capabilities and display considerable plasticity, being able to assume a “reactive phenotype” in disease conditions (see Marzioni et al.6 and Kanno et al.7 for recent reviews on cholangiocytes heterogeneity). Cholangiocytes represent the primary cell target of a diverse group of genetic and acquired biliary disorders, which we have called collectively “cholangiopathies” (Table 1). Many of the cholangiopathies are, at their early stages, site restricted along
Published: 2004

13. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes

Author: Spirlì, C, Fabris, L, Duner, E, Fiorotto, R, Ballardini, G, Roskams, T, Larusso, N, Sonzogni, A, Okolicsanyi, L, Strazzabosco, M, Larusso, NF, STRAZZABOSCO, MARIO, Spirlì, C, Fabris, L, Duner, E, Fiorotto, R, Ballardini, G, Roskams, T, Larusso, N, Sonzogni, A, Okolicsanyi, L, Strazzabosco, M, Larusso, NF, and STRAZZABOSCO, MARIO
Abstract: BACKGROUND & AIMS: The biliary epithelium is involved both in bile production and in the inflammatory/reparative response to liver damage. Recent data indicate that inflammatory aggression to intrahepatic bile ducts results in chronic progressive cholestasis. METHODS: To understand the effects of nitric oxide on cholangiocyte secretion and biliary tract pathophysiology we have investigated: (1) the effects of proinflammatory cytokines on NO production and expression of the inducible nitric oxide synthase (NOS2), (2) the effects of NO on cAMP-dependent secretory mechanisms, and (3) the immunohistochemical expression of NOS2 in a number of human chronic liver diseases. RESULTS: Our results show that: (1) tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma, synergically stimulate NO production in cultured cholangiocytes through an increase in NOS2 gene and protein expression; (2) micromolar concentrations of NO inhibit forskolin-stimulated cAMP production by adenylyl cyclase (AC), cyclic adenosine monophosphate (cAMP)-dependent fluid secretion, and cAMP-dependent Cl(-) and HCO(3)(-) transport mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and anion exchanger isoform 2, respectively; (3) cholestatic effects of NO and of proinflammatory cytokines are prevented by NOS-2 inhibitors and by agents (manganese(III)-tetrakis(4-benzoic acid)porphyrin [MnTBAP], urate, trolox) able to block the formation of reactive nitrogen oxide species (RNOS); (4) NOS2 expression is increased significantly in the biliary epithelium of patients with primary sclerosing cholangitis (PSC). CONCLUSIONS: Our findings show that proinflammatory cytokines stimulate the biliary epithelium to generate NO, via NOS2 induction, and that NO causes ductular cholestasis by a RNOS-mediated inhibition of AC and of cAMP-dependent HCO(3)(-) and Cl(-) secretory mechanisms. This pathogenetic sequence may contribute to ductal cholestasis in inflammatory cholangiopathies.
Published: 2003

14. Comparison between two high-dose methylprednisolone schedules in the treatment of acute hepatic cellular rejection in liver transplant recipients: A controlled clinical trial

Author: Volpin, R, Angeli, P, Galioto, A, Fasolato, S, Neri, D, Barbazza, F, Merenda, R, Del Piccolo, F, Strazzabosco, M, Casagrande, F, Feltracco, P, Sticca, A, Merkel, C, Gerunda, G, Gatta, A, Gatta, A., Volpin, R, Angeli, P, Galioto, A, Fasolato, S, Neri, D, Barbazza, F, Merenda, R, Del Piccolo, F, Strazzabosco, M, Casagrande, F, Feltracco, P, Sticca, A, Merkel, C, Gerunda, G, Gatta, A, and Gatta, A.
Abstract: Intravenous methylprednisolone is used in most liver transplant centers as first-line therapy of acute hepatic cellular rejection in patients who undergo liver transplant. However, no controlled study has been performed to date to define the optimal dose and duration of the steroid regimen. The schedules that actually are used in most transplant centers are drawn from those that were developed empirically for the treatment of acute renal graft rejection. Thus, the aim of the study was to compare two schedules of steroid treatment of acute hepatic cellular rejection among those most widely used. Thirty-eight eligible patients with grade II or III acute hepatic cellular rejection were randomized to receive two different high-dose methylprednisolone schedules. Eighteen patients were randomized in group A (intravenous dose of 1,000 mg of methylprednisolone followed by a 6-day taper from 200 to 20 mg/d). Twenty patients were randomized in group B (intravenous dose of 1,000 mg of methylprednisolone for three consecutive days). The response to treatment was evaluated by means of a second liver biopsy. The treatment of group A proved to be more effective than treatment of group B. The resolution of acute hepatic cellular rejection was observed in 83.3% of cases in group A and 50.0% of cases in group B (P <.05). The treatment of group A proved to be safer also than treatment of group B. Patients randomized in group B showed a higher prevalence of infections (90.0% of cases versus 55.5% of cases; P <.01) mainly because of bacterial (80.0% versus 50.0%; P <.05) and viral (50.0% versus 16.6%; P <.05) agents. In conclusion, the study shows that intravenous administration of 1,000 mg of methylprednisolone followed by a 6-day taper from 200 to 20 mg/d is more effective and safer than intravenous dose of 1,000 mg of methylprednisolone for three consecutive days in the treatment of acute cellular rejection in patients with liver transplantation
Published: 2002

15. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium

Author: Spirlì, C, Nathanson, M, Fiorotto, R, Duner, E, Denson, L, Sanz, J, Di Virgilio, F, Okolicsanyi, L, Casagrande, F, Strazzabosco, M, Nathanson, MH, Denson, LA, Sanz, JM, STRAZZABOSCO, MARIO, Spirlì, C, Nathanson, M, Fiorotto, R, Duner, E, Denson, L, Sanz, J, Di Virgilio, F, Okolicsanyi, L, Casagrande, F, Strazzabosco, M, Nathanson, MH, Denson, LA, Sanz, JM, and STRAZZABOSCO, MARIO
Abstract: BACKGROUND AND AIMS: Cholestatic disorders often are associated with portal inflammation, but whether or how inflammation contributes to cholestasis is unknown. Thus we studied the effects of proinflammatory cytokines on bile duct epithelia secretory mechanisms. METHODS: Isolated bile duct units (IBDUs) were cultured with interleukin (IL)-6, interferon gamma, tumor necrosis factor (TNF)-alpha, and IL-1 alone or in combination. Ductular secretion was measured using video-optical planimetry. Bicarbonate and Cl(-) transport were assessed microfluorimetric measuring pH(i) (BCECF) and [Cl(-)](i) transients (MEQ). Expression of Cl(-)/HCO(3)(-) exchanger (AE-2), cystic fibrosis transmembrane conductance regulator (CFTR), and the secretin receptor (SR) were assessed by ribonuclease protection assay. Cellular cyclic adenosine monophosphate (cAMP) levels were studied by enzymatic immunoassay. Paracellular permeability was assessed using fluorescein-labeled dextrans (FD) in cholangiocyte monolayers (NRC-1). RESULTS: Although not effective when given alone, each combination of IL-6, interferon gamma, IL-1, and TNF-alpha inhibited secretion in IBDU. Cytokines inhibited cAMP formation, AE-2 activity, and cyclic AMP-dependent Cl(-) efflux, but not that induced by purinergic agonists. AE-2 gene expression was unaffected by proinflammatory cytokines, whereas CFTR and SR expression was increased. In addition, paracellular transit of FD across NRC-1 monolayers was increased. CONCLUSIONS: Inflammatory cytokines inhibit cAMP-dependent fluid secretion in cholangiocytes and impair the barrier functions of biliary epithelia. These changes may represent the molecular mechanisms by which inflammation leads to ductular cholestasis in vivo.
Published: 2001

16. Value-based outcome indicators in the management of hepatocellular carcinoma: Clinical test in a large multicenter study (VBMH study)

Author: A. Ciaccio, Luciana Scalone, Patrizia Burra, Paolo Cortesi, Lorenzo G. Mantovani, Luca S. Belli, Mario Strazzabosco, M. Gentiluomo, Vincenzo Mazzaferro, Matteo Rota, Giancarlo Cesana, Maria Grazia Valsecchi, Patrizia Pontisso, S. Okolicsanyi, Luca Fabris, A. Grisolia, Stefano Fagiuoli, Marco Gemma, Mario U. Mondelli, Michele Colledan, Okolicsanyi, S, Ciaccio, A, Rota, M, Gentiluomo, M, Gemma, M, Grisolia, A, Cortesi, P, Scalone, L, Mantovani, L, Pontisso, P, Burra, P, Fabris, L, Mondelli, M, Colledan, M, Fagiuoli, S, Valsecchi, M, Cesana, G, Belli, L, Mazzaferro, V, and Strazzabosco, M
Subjects: Oncology, medicine.medical_specialty, Pathology, Hepatology, business.industry, MED/42 - IGIENE GENERALE E APPLICATA, Health care indicators, Hepatocellular carcinoma (HCC), Delphi method, Prospective study, Value-based Medicine in Hepatology, Gastroenterology, medicine.disease, Outcome (game theory), Test (assessment), Multicenter study, MED/12 - GASTROENTEROLOGIA, Internal medicine, Hepatocellular carcinoma, Medicine, business, Value (mathematics), Health care indicator, MED/01 - STATISTICA MEDICA
Abstract: Introduction: The management of hepatocellular carcinoma (HCC) is a well-known public health problem, accounting for increasing mortality and high costs. Quality parameters able to measure clinical outcomes are still lacking. Aim of our study (Value Based Medicine in Hepatology, VBMH)was to identify and test outcome indicators (OIs) in HCC, in light of their potential use in policy decision models. Methods: A panel of experts identified a list of OIs using a modified Delphi method, according to experience and published evidence; four OIs with the highest RAND/UCLA score were tested in a prospective multicenter observational study. During 18 months, 711 HCC patients were enrolled and prospectively followed. 677 patients (95%) had at least one follow-up consultation. Median follow-up time was 14 months. Results: The first OI was 1–3–5 years survival stratified for BCLC stage or treatment (OI#1). One-year survival for BCLC stage 0/A–D was 93%, 86%, 50%, 26% respectively. One-year survival of 288 patients treated for the first time during the study was 88% for liver transplantation, 97% surgical resection, 100% ablation and 89% for TACE. The other three OIs evaluated the appropriateness of treatments: worsening of BCLC and/or CPT score after three months from a loco-regional therapy or surgical resection (OI#2), occurred in 16% of cases (76% after TACE). Recurrence of HCC within 6 months after curative treatments (OI#3) happened in 15% of patients treated, mainly after ablation (20%). Presence of severe morbidity three months after loco-regional procedure or resection, evaluated as grade≥3 according to Clavien-Dindo classification (OI#3), was found in 3% of patients treated. Conclusions: The outcome indicators identified in the VBMH study proved their feasibility in a large cohort of patients and could stand as a benchmark for healthcare providers to move towards a value-based approach in the management of HCC.
Published: 2014

17. Outcome indicators in liver cirrhosis: Application of value-based medicine in a large multicenter study (VBMH study)

Author: Maria Grazia Valsecchi, Mario Strazzabosco, Giancarlo Cesana, Patrizia Pontisso, Paolo Cortesi, Matteo Rota, Lorenzo G. Mantovani, Patrizia Burra, M. Gentiluomo, Luciana Scalone, A. Grisolia, Michele Colledan, Mario U. Mondelli, Stefano Fagiuoli, Luca Fabris, Luca S. Belli, A. Ciaccio, Marco Gemma, S. Okolicsanyi, Okolicsanyi, S, Ciaccio, A, Rota, M, Gentiluomo, M, Gemma, M, Grisolia, A, Cortesi, P, Scalone, L, Mantovani, L, Pontisso, P, Burra, P, Fabris, L, Mondelli, M, Colledan, M, Fagiuoli, S, Valsecchi, M, Cesana, G, Belli, L, and Strazzabosco, M
Subjects: Pathology, medicine.medical_specialty, Health care indicators, Liver cirrhosis, Delphi method, Prospective study, Value-based Medicine in Hepatology, Cirrhosis, Hepatology, business.industry, MED/42 - IGIENE GENERALE E APPLICATA, Gastroenterology, medicine.disease, Outcome (game theory), Liver cirrhosi, Liver disease, Multicenter study, MED/12 - GASTROENTEROLOGIA, Internal medicine, medicine, business, Value (mathematics), Health care indicator, MED/01 - STATISTICA MEDICA
Abstract: Introduction: Liver Cirrhosis (LC) is responsible for high morbidity, mortality and costs, with increasing need to improve quality of care. Aim of our study (Value Based Medicine in Hepatology Study, VBMH) was to identify outcome indicators (OIs) able to measure quality in liver diseases, including compensated (CC) and decompensated (DC) LC. Methods: A panel of hepatologists identified a list of 7 OIs for LC according to experience and published evidence, using a modified Delphi method and a standard 9-pointRANDappropriateness scale. Then, these 7 OIs were tested in clinical practice in a prospective multicenter observational study involving three tertiary centers in Italy, using a web-based electronic medical record. 1751 LC patients were enrolled in 18 months: 1004 CC and 747 DC. 92% of patients had at least two consultations in 17 months median follow-up. Results: Annual rate of decompensation in CC was 12% (OI#1). Annual incidence of 1st variceal bleeding (VB) was 2% for low-risk and 3% for high-risk varices (OI#2) indicating a significant success of primary profilaxis. Annual incidence of HCC in CC was 4.3%, with 81% patients found at early stage (OI#3), underlining the accuracy of oncologic surveillance. One-year survival after the first decompensation episode (ascites in 74% of cases) was 96%, 81% and 59% stratified for CPT score A, B, C respectively (OI#4), and 94%, 56% stratified for MELD below or above 15 (OI#5). 4% of DC patients had an episode of VB with 90% survival after 6 weeks, and 33% recurrence (OI#6). Similarly, 3% ofDCpatients had spontaneous bacterial peritonitis with 6 weeks survival of 86% and 13% recurrence (OI#7). Conclusions: The value-based OIs generated in this study performed well in a large cohort of consecutive patients, and could represent a reference tool for healthcare providers to improve care in LC.
Published: 2014

18. Notch signaling in hepatocellular carcinoma: guilty in association!

Author: Mario Strazzabosco, Luca Fabris, Strazzabosco, M, and Fabris, L
Subjects: Carcinoma, Hepatocellular, Cellular differentiation, Notch signaling pathway, Cell fate determination, Biology, Article, Cell surface receptor, MED/12 - GASTROENTEROLOGIA, Animals, Humans, HEPATOCELLULAR CARCINOMA, Nuclear protein, Receptor, Notch 1, Hepatology, Receptors, Notch, Animal, Liver Neoplasms, Gastroenterology, notch, Cell biology, Gene Expression Regulation, Neoplastic, Notch proteins, Liver Neoplasm, Human, Signal Transduction
Abstract: Notch signaling is a complex, highly conserved mechanism, originally discovered as critical regulator of cell fate determination during development in several tissues and organs.1,2 Activation of Notch may stimulate cells either to undergo a phenotypic switch or to maintain the original cell phenotype by preventing further differentiation,3 Notch is also involved in establishing organ-specific stem cell niches necessary for epithelial tissue homeostasis.3,4 The Notch system encompasses 4 genes encoding for different membrane receptors (Notch 1, 2, 3, and 4), which are activated by their binding to 5 ligands (Jagged-1, Jagged-2, and Delta-like 1, 3, and 4).4 Cell-to-cell contact is a prerequisite for the activation of Notch signaling.3,4 Whereas Notch receptors are expressed by the “receiver” cell, ligands are expressed by the “transmitter” cell. This interaction leads to the proteolytic cleavage and subsequent nuclear translocation of the intracellular domain of Notch receptors (NICD). Once migrated into the nucleus, NICD associates with the nuclear protein of the RBP-Jκ family and transcriptionally activates several other transcriptional activators or repressors that act as critical regulators of cell differentiation, apoptosis, and proliferation4 (see drawing on the left side of Figure 1). NICD is then rapidly deactivated by phosphorylation and by proteosomal degradation. The signal is maintained through ligand-induced proteolytic supply of new NICD.
Published: 2012

19. ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice

Author: Romina Fiorotto, Mario Strazzabosco, S. Okolicsanyi, Silvia Lecchi, Massimiliano Cadamuro, Carlo Spirli, Stefan Somlo, Xin Tian, Luca Fabris, Spirli, C, Okolicsanyi, S, Fiorotto, R, Fabris, L, Cadamuro, M, Lecchi, S, Tian, X, Somlo, S, and Strazzabosco, M
Subjects: Vascular Endothelial Growth Factor A, MAPK/ERK pathway, Indoles, Mice, chemistry.chemical_compound, MED/12 - GASTROENTEROLOGIA, Vascular endothelial growth factor (VEGF), polycystic liver disease, Pkd2, VEGFR-2, Phosphorylation, Cells, Cultured, Mice, Knockout, Mitogen-Activated Protein Kinase 1, education.field_of_study, Mitogen-Activated Protein Kinase 3, Cysts, Liver Diseases, Polycystic liver disease, Gastroenterology, Vascular endothelial growth factor, polycystic liver disease, Vascular endothelial growth factor A, Phenotype, Polycystin 2, ERK pathway, medicine.medical_specialty, TRPP Cation Channels, MAP Kinase Signaling System, Biology, Article, Paracrine signalling, Proliferating Cell Nuclear Antigen, Internal medicine, medicine, Animals, Pyrroles, polycystins, education, Autocrine signalling, Protein Kinase Inhibitors, Hepatology, Tumor Suppressor Proteins, Kinase insert domain receptor, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, Cyclic AMP-Dependent Protein Kinases, Vascular Endothelial Growth Factor Receptor-2, Repressor Proteins, Endocrinology, chemistry, Cancer research
Abstract: Background & Aims Severe polycystic liver disease can complicate adult dominant polycystic kidney disease, a genetic disease caused by defects in polycystin-1 (Pkd1) or polycystin-2 (Pkd2). Liver cyst epithelial cells (LCECs) express vascular endothelial growth factor (VEGF) and its receptor, VEGFR-2. We investigated the effects of VEGF on liver cyst growth and autocrine VEGF signaling in mice with Pkd1 and Pkd2 conditional knockouts. Methods We studied mice in which Pkd1 or Pkd2 were conditionally inactivated following exposure to tamoxifen; these mice were called Pkd1 flox/− :pCxCreER (Pkd1KO) and Pkd2 flox/− :pCxCreER (Pkd2KO). Results Pkd1KO and Pkd2KO mice developed liver defects; their LCECs expressed VEGF, VEGFR-2, hypoxia-inducible factor (HIF)-1α, phosphorylated extracellular signal–regulated kinase 1/2 (pERK1/2), and proliferating cell nuclear antigen (PCNA). In Pkd2KO but not Pkd1KO mice, exposure to the VEGFR-2 inhibitor SU5416 significantly reduced liver cyst development, liver/body weight ratio, and expression of pERK and PCNA. VEGF secretion and phosphorylation of ERK1/2 and VEGFR-2 were significantly increased in cultured LCECs from Pkd2KO compared with Pkd1KO mice. Inhibition of protein kinase A (PKA) reduced VEGF secretion and pERK1/2 expression. Addition of VEGF to LCECs from Pkd2KO mice increased phosphorylated VEGFR-2 and phosphorylated mitogen signal-regulated kinase (MEK) expression and induced phosphorylation of ERK1/2; this was inhibited by SU5416. Expression of HIF-1α increased in parallel with secretion of VEGF following LCEC stimulation. VEGF-induced cell proliferation was inhibited by the MEK inhibitor U1026 and by ERK1/2 small interfering RNA. Conclusions The PKA–ERK1/2–VEGF signaling pathway promotes growth of liver cysts in mice. In Pkd2-defective LCECs, PKA-dependent ERK1/2 signaling controls HIF-1α–dependent VEGF secretion and VEGFR-2 signaling. Autocrine and paracrine VEGF signaling promotes the growth of liver cysts in Pkd2KO mice. VEGF inhibitors might be used to treat patients with polycystic liver disease.
Published: 2010

20. HCC persistence or recurrence after bridging therapy helps predict transplant list dropout and generate a more equitable exception policy

Author: M. De Giorgio, S. Vezzoli, E. Cohen, E. Armellini, M.G. Lucà, G. Verga, D. Pinelli, R. Nani, M.G. Valsecchi, L. Antolini, M. Colledan, S. Fagiuoli, M. Strazzabosco, De Giorgio, M, Vezzoli, S, Cohen, E, Armellini, E, Lucà, M, Verga, G, Pinelli, D, Nani, R, Valsecchi, M, Antolini, L, Colledan, M, Fagiuoli, S, and Strazzabosco, M
Subjects: Hepatology, none, Gastroenterology
Abstract: Background and aim. Earlier diagnosis and more effective treatments are improving the survival of patients with HCC. Moreover, the natural history of HCC patients is different from that patients with non-neoplastic indications for liver transplantation. This issue becomes critical to provide an equitable allocation policy to patients listed for transplantation. UNOS adopted a MELD-based policy that assigns the native MELD for patients with stage I HCC and 22 points for patients stage II HCC listed for Liver Transplant (LT), with an additional three points added every 3 months of waiting time in list for the latter. Organs are then assigned on the basis of the MELD score, irrespective of the indication. In countries outside the UNOS area, allocation for HCC patients still misses uniformity. Aim. The aim of the study was to generate an updated prognostic model for HCC applicable to organ allocation. Material and methods. We analysed disease progression (death or progression of HCC beyond T2 stage) in a cohort of 177 consecutive patients that presented with HCC inside the Milan criteria. Patients were treated according to the BCLC algorithm and prospectively followed by imaging every 3 months; 76 patients (43%) were listed for transplantation according to AISF/CNT guidelines. Transplanted patients were censored at the time of transplantation. Results. Median follow-up was 16 months. HCC progressed beyond T2 stage in 75 cases; 8 patients died while in T2 stage and 68 were transplanted. To verify the ability of the UNOS policy to predict HCC progression rate (PR), we compared the expected PR according to the UNOS policy with the observed PR for the respective population at risk. The current policy resulted in a large overestimation of PR in T2 patients. Two sensitivity analyses were conducted to identify risk factor (RF) for progression using the log-rank method: in the first one, transplanted patients were considered as disease progression; in the second one, only non-transplanted patients were analysed. RF significant in any analysis was considered for multivariable analysis. RF with the strongest relationship to progression included tumor persistence after local therapy or recurrence inside Milan criteria (HR 2.52–3.16; p < 0.0001). Using strongest RF for progression and the patient's natural MELD, an adjusted model applicable to organ allocation was generated, which decreased the discrepancy between expected and observed PR. Conclusions. Tumor persistence/recurrence inside Milan criteria after treatment strongly predicted the risk of tumor progression beyond Milan criteria. The current MELD exception largely overestimates progression in T2 patients treated according to BCLC. An adjusted model that begins with the patient's natural MELD, and stratifies progressive risk according to the response to local treatment, better captures the PR of T2 HCC
Published: 2009

21. Portal Fibrosis and the Ductular Reaction: Pathophysiological Role in the Progression of Liver Disease and Translational Opportunities.

Author: Gupta V, Sehrawat TS, Pinzani M, and Strazzabosco M
Abstract: A consistent feature of chronic liver diseases and the hallmark of pathologic repair is the so-called "ductular reaction." This is a histologic abnormality characterized by an expansion of dysmorphic cholangiocytes inside and around portal spaces infiltrated by inflammatory, mesenchymal, and vascular cells. The ductular reaction is a highly regulated response based on the reactivation of morphogenetic signaling mechanisms and a complex crosstalk among a multitude of cell types. The nature and mechanism of these exchanges determine the difference between healthy regenerative liver repair and pathologic repair. An orchestrated signaling among cell types directs mesenchymal cells to deposit a specific extracellular matrix with distinct physical and biochemical properties defined as portal fibrosis. Progression of fibrosis leads to vast architectural and vascular changes known as "liver cirrhosis." The signals regulating the ecology of this microenvironment are just beginning to be addressed. Contrary to the tumor microenvironment, immune modulation inside this "benign" microenvironment is scarcely known. One of the reasons for this is that both the ductular reaction and portal fibrosis have been primarily considered a manifestation of cholestatic liver disease, whereas this phenomenon is also present, albeit with distinctive features, in all chronic human liver diseases. Novel human-derived cellular models and progress in "omics" technologies are increasing our knowledge at a fast pace. Most importantly, this knowledge is on the edge of generating new diagnostic and therapeutic advances. Here, we will critically review the latest advances, in terms of mechanisms, pathophysiology, and treatment prospects. In addition, we will delineate future avenues of research, including innovative translational opportunities., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Published: 2024
Full Text: View/download PDF

22. Adjusting Barcelona Clinic Liver Cancer Staging System to the Evolving Landscape of Hepatocellular Carcinoma: A Look to the Future.

Author: Strazzabosco M, Cabibbo G, and Colombo M
Subjects: Hepatectomy, Humans, Neoplasm Staging, Prognosis, Carcinoma, Hepatocellular pathology, Liver Neoplasms pathology
Published: 2022
Full Text: View/download PDF

23. Notch signaling in hepatocellular carcinoma: guilty in association!

Author: Strazzabosco M and Fabris L
Subjects: Animals, Humans, Carcinoma, Hepatocellular physiopathology, Gene Expression Regulation, Neoplastic physiology, Liver Neoplasms physiopathology, Receptors, Notch physiology, Signal Transduction physiology
Published: 2012
Full Text: View/download PDF

24. Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-κB-mediated inflammatory response in mice.

Author: Fiorotto R, Scirpo R, Trauner M, Fabris L, Hoque R, Spirli C, and Strazzabosco M
Subjects: Animals, Anti-Bacterial Agents pharmacology, Bile Ducts drug effects, Bile Ducts metabolism, Bile Ducts microbiology, Cholagogues and Choleretics pharmacology, Cholangitis chemically induced, Cholangitis genetics, Cholangitis metabolism, Cholangitis microbiology, Cholangitis prevention & control, Colitis chemically induced, Colitis genetics, Colitis metabolism, Colitis microbiology, Cytokines metabolism, Dextran Sulfate, Disease Models, Animal, Epithelial Cells drug effects, Epithelial Cells metabolism, Epithelial Cells microbiology, HEK293 Cells, Humans, Keratin-19 metabolism, Leukocyte Common Antigens metabolism, Lipopolysaccharides pharmacology, Mice, Mice, Inbred C57BL, Mice, Inbred CFTR, Mice, Knockout, Neomycin pharmacology, Phosphorylation, Polymyxin B pharmacology, Time Factors, Toll-Like Receptor 4 genetics, Transfection, Ursodeoxycholic Acid analogs & derivatives, Ursodeoxycholic Acid pharmacology, src-Family Kinases, Bile Ducts immunology, Cholangitis immunology, Colitis immunology, Epithelial Cells immunology, Immunity, Innate drug effects, Inflammation Mediators metabolism, NF-kappa B metabolism, Toll-Like Receptor 4 metabolism
Abstract: Background & Aims: Loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) in the biliary epithelium reduces bile flow and alkalinization in patients with cystic fibrosis (CF). Liver damage is believed to result from ductal cholestasis, but only 30% of patients with CF develop liver defects, indicating that another factor is involved. We studied the effects of CFTR deficiency on Toll-like receptor 4 (TLR4)-mediated responses of the biliary epithelium to endotoxins., Methods: Dextran sodium sulfate (DSS) was used to induce colitis in C57BL/6J-Cftrtm1Unc (Cftr-KO) mice and their wild-type littermates. Ductular reaction and portal inflammation were quantified by keratin-19 and CD45 immunolabeling. Cholangiocytes isolated from wild-type and Cftr-KO mice were challenged with lipopolysaccharide (LPS); cytokine secretion was quantified. Activation of nuclear factor κB (NF-κB), phosphorylation of TLR4, and activity of Src were determined. HEK-293 that expressed the secreted alkaline phosphatase reporter and human TLR4 were transfected with CFTR complementary DNAs., Results: DSS-induced colitis caused biliary damage and portal inflammation only in Cftr-KO mice. Biliary damage and inflammation were not attenuated by restoring biliary secretion with 24-nor-ursodeoxycholic acid but were significantly reduced by oral neomycin and polymyxin B, indicating a pathogenetic role of gut-derived bacterial products. Cftr-KO cholangiocytes incubated with LPS secreted significantly higher levels of cytokines regulated by TLR4 and NF-κB. LPS-mediated activation of NF-κB was blocked by the TLR4 inhibitor TAK-242. TLR4 phosphorylation by Src was significantly increased in Cftr-KO cholangiocytes. Expression of wild-type CFTR in the HEK293 cells stimulated with LPS reduced activation of NF-κB., Conclusions: CFTR deficiency alters the innate immunity of the biliary epithelium and reduces its tolerance to endotoxin, resulting in an Src-dependent inflammatory response mediated by TLR4 and NF-κB. These findings might be used to develop therapies for CF-associated cholangiopathy., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Published: 2011
Full Text: View/download PDF

25. Polycystic liver diseases: congenital disorders of cholangiocyte signaling.

Author: Strazzabosco M and Somlo S
Subjects: Biliary Tract abnormalities, Cysts congenital, Cysts genetics, Cysts metabolism, Cysts therapy, Disease Progression, Epithelial Cells pathology, Genetic Predisposition to Disease, Humans, Liver Diseases congenital, Liver Diseases genetics, Liver Diseases metabolism, Liver Diseases therapy, Biliary Tract metabolism, Epithelial Cells metabolism, Signal Transduction genetics
Abstract: Polycystic liver diseases (PLD) are inherited disorders of the biliary epithelium, caused by genetic defects in proteins associated with intracellular organelles, mainly the endoplasmic reticulum and the cilium. PLD are characterized by the formation and progressive enlargement of multiple cysts scattered throughout the liver parenchyma, and include different entities, classified based on their pathology, inheritance pattern, involvement of the kidney and clinical features. PLD should be considered as congenital diseases of cholangiocyte signaling. Here, we will review the changes in signaling pathways involved in liver cyst formation and progression, and their impact on cholangiocyte physiology. Each pathway represents a potential target for therapies aimed at reducing disease progression., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Published: 2011
Full Text: View/download PDF

26. ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice.

Author: Spirli C, Okolicsanyi S, Fiorotto R, Fabris L, Cadamuro M, Lecchi S, Tian X, Somlo S, and Strazzabosco M
Subjects: Animals, Cells, Cultured, Cyclic AMP-Dependent Protein Kinases metabolism, Cysts pathology, Cysts physiopathology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Indoles pharmacology, Liver Diseases pathology, Liver Diseases physiopathology, Mice, Mice, Knockout, Phenotype, Phosphorylation physiology, Proliferating Cell Nuclear Antigen metabolism, Protein Kinase Inhibitors pharmacology, Pyrroles pharmacology, Repressor Proteins metabolism, Tumor Suppressor Proteins metabolism, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors, Vascular Endothelial Growth Factor Receptor-2 metabolism, Cysts metabolism, Liver Diseases metabolism, MAP Kinase Signaling System physiology, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, TRPP Cation Channels genetics
Abstract: Background & Aims: Severe polycystic liver disease can complicate adult dominant polycystic kidney disease, a genetic disease caused by defects in polycystin-1 (Pkd1) or polycystin-2 (Pkd2). Liver cyst epithelial cells (LCECs) express vascular endothelial growth factor (VEGF) and its receptor, VEGFR-2. We investigated the effects of VEGF on liver cyst growth and autocrine VEGF signaling in mice with Pkd1 and Pkd2 conditional knockouts., Methods: We studied mice in which Pkd1 or Pkd2 were conditionally inactivated following exposure to tamoxifen; these mice were called Pkd1(flox/-):pCxCreER (Pkd1KO) and Pkd2(flox/-):pCxCreER (Pkd2KO)., Results: Pkd1KO and Pkd2KO mice developed liver defects; their LCECs expressed VEGF, VEGFR-2, hypoxia-inducible factor (HIF)-1alpha, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), and proliferating cell nuclear antigen (PCNA). In Pkd2KO but not Pkd1KO mice, exposure to the VEGFR-2 inhibitor SU5416 significantly reduced liver cyst development, liver/body weight ratio, and expression of pERK and PCNA. VEGF secretion and phosphorylation of ERK1/2 and VEGFR-2 were significantly increased in cultured LCECs from Pkd2KO compared with Pkd1KO mice. Inhibition of protein kinase A (PKA) reduced VEGF secretion and pERK1/2 expression. Addition of VEGF to LCECs from Pkd2KO mice increased phosphorylated VEGFR-2 and phosphorylated mitogen signal-regulated kinase (MEK) expression and induced phosphorylation of ERK1/2; this was inhibited by SU5416. Expression of HIF-1alpha increased in parallel with secretion of VEGF following LCEC stimulation. VEGF-induced cell proliferation was inhibited by the MEK inhibitor U1026 and by ERK1/2 small interfering RNA., Conclusions: The PKA-ERK1/2-VEGF signaling pathway promotes growth of liver cysts in mice. In Pkd2-defective LCECs, PKA-dependent ERK1/2 signaling controls HIF-1alpha-dependent VEGF secretion and VEGFR-2 signaling. Autocrine and paracrine VEGF signaling promotes the growth of liver cysts in Pkd2KO mice. VEGF inhibitors might be used to treat patients with polycystic liver disease., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Published: 2010
Full Text: View/download PDF

27. Ursodeoxycholic acid stimulates cholangiocyte fluid secretion in mice via CFTR-dependent ATP secretion.

Author: Fiorotto R, Spirlì C, Fabris L, Cadamuro M, Okolicsanyi L, and Strazzabosco M
Subjects: Animals, Bile Ducts, Intrahepatic pathology, Calcium metabolism, Calcium Signaling physiology, Cyclic AMP metabolism, Cystic Fibrosis Transmembrane Conductance Regulator drug effects, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Mice, Mice, Knockout, Protein Kinase C metabolism, Wnt Proteins metabolism, Adenosine Triphosphate metabolism, Bile Ducts, Intrahepatic metabolism, Cholagogues and Choleretics pharmacology, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Ursodeoxycholic Acid pharmacology
Abstract: Background & Aims: Cholangiopathies are characterized by impaired cholangiocyte secretion. Ursodeoxycholic acid (UDCA) is widely used for cholangiopathy treatment, but its effects on cholangiocyte secretory functions remain unclear and are the subject of this study., Methods: Polarized mouse cholangiocytes in tubular (isolated bile-duct units [IBDU]) or monolayer configuration were obtained from wild-type (WT) and B6-129-Cftr(tm1Kth) and Cftr(tm1Unc) mice that are defective in CFTR, an adenosine 3',5'-cyclic monophosphate (cAMP)-stimulated Cl(-) channel expressed in cholangiocytes. Fluid secretion was assessed by video-optical planimetry, Cl(-) and Ca(2+) efflux by microfluorimetry (6-methoxy-N-ethylquinolinium chloride, fura-2, and fluo-4), adenosine triphosphate (ATP) secretion by luciferin-luciferase assay, and protein kinase C (PKC) by Western blot., Results: UDCA stimulated fluid secretion and Cl(-) efflux in WT-IBDU but not in CFTR-KO-IBDU or in WT-IBDU exposed to CFTR inhibitors. UDCA did not affect intracellular cAMP levels but increased [Ca(2+)]i in WT and not in CFTR-KO cholangiocytes. UDCA stimulated apical ATP secretion in WT but not in CFTR-KO cholangiocytes. UDCA-stimulated [Ca(2+)]i increase was inhibited by suramin, a purinergic 2Y-receptor inhibitor. UDCA stimulated the translocation of PKC-alpha and PKC-epsilon to the plasma membrane. UDCA-stimulated secretion was inhibited by 2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid and by phospholipase C and PKC inhibitors. UDCA increased ATP output in isolated perfused livers from WT but not from CFTR-KO mice., Conclusions: Our data indicate that UDCA stimulates a CFTR-dependent apical ATP release in cholangiocytes. Secreted ATP activates purinergic 2Y receptors, and, through [Ca(2+)]i increase and PKC activation stimulates Cl(-) efflux and fluid secretion. These data support the concept that CFTR plays a role in modulating purinergic signaling in secretory epithelia and suggest a novel mechanism explaining the choleretic effect of UDCA.
Published: 2007
Full Text: View/download PDF

28. Glibenclamide stimulates fluid secretion in rodent cholangiocytes through a cystic fibrosis transmembrane conductance regulator-independent mechanism.

Author: Spirlì C, Fiorotto R, Song L, Santos-Sacchi J, Okolicsanyi L, Masier S, Rocchi L, Vairetti MP, De Bernard M, Melero S, Pozzan T, and Strazzabosco M
Subjects: ATP-Binding Cassette Transporters metabolism, Animals, Bile Ducts cytology, Bile Ducts metabolism, Body Fluids metabolism, Calcium metabolism, Cell Line, Cystic Fibrosis metabolism, Cystic Fibrosis physiopathology, Electric Capacitance, Electric Conductivity, Liver drug effects, Liver physiology, Mice, Mice, Inbred CFTR, Patch-Clamp Techniques, Potassium Channels metabolism, Potassium Channels, Inwardly Rectifying metabolism, Rats, Receptors, Drug metabolism, Sulfonylurea Receptors, Bile Ducts drug effects, Cystic Fibrosis drug therapy, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Glyburide pharmacology, Hypoglycemic Agents pharmacology
Abstract: Background & Aims: Progressive liver disease is a severe complication of cystic fibrosis, a genetic disease characterized by impaired epithelial adenosine 3',5'-cyclic monophosphate-dependent secretion caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In the liver, CFTR is expressed in cholangiocytes and regulates the fluid and electrolyte content of the bile. Glibenclamide, a sulfonylurea and a known CFTR inhibitor, paradoxically stimulates cholangiocyte secretion. We studied the molecular mechanisms underlying this effect and whether glibenclamide could restore cholangiocyte secretion in cystic fibrosis., Methods: NRC-1 cells, freshly isolated rat cholangiocytes, isolated rat biliary ducts, and isolated biliary ducts from CFTR-defective mice (Cftr tm1Unc ) were used to study fluid secretion (by video-optical planimetry), glibenclamide-induced secretion (by high-performance liquid chromatography in cell culture medium), intracellular pH and intracellular Ca 2+ concentration transients [2'7'-bis(2-carboxyethyl)-5,6,carboxyfluorescein-acetoxymethylester and Fura-2 f-AM (5-Oxazolecarboxylic acid, 2-(6-(bis(2-((acetyloxy)methoxy)-2-oxoethyl)amino)-5-(2-(2-(bis(2-((acetyloxy)methoxy)-2-oxoethyl)amino)-5-methylphenoxy)ethoxy)-2-benzofuranyl)-, (acetyloxy)methyl ester) microfluorometry], gene expression (by reverse-transcription polymerase chain reaction), and changes in membrane capacitance (by patch-clamp experiments)., Results: Stimulation of cholangiocyte secretion by glibenclamide and tolbutamide required Cl - and was mediated by the sulfonylurea receptor 2B. Glibenclamide-induced secretion was blocked by inhibitors of exocytosis (colchicine, wortmannin, LY294002, and N -ethylmaleimide) and by inhibitors of secretory granule acidification (vanadate, bafilomycin A1, and niflumic acid) but was Ca 2+ and depolarization independent; membrane capacitance measurements were consistent with stimulation of vesicular transport and fusion. Glibenclamide, unlike secretin and forskolin, was able to stimulate secretion in Cftr tm1Unc mice, thus indicating that this secretory mechanism was preserved., Conclusions: The ability of glibenclamide to stimulate secretion in CFTR-defective mice makes sulfonylureas a model class of compounds to design drugs useful in the treatment of cystic fibrosis with liver impairment and possibly of other cholestatic diseases.
Published: 2005
Full Text: View/download PDF

29. The cholangiopathies: disorders of biliary epithelia.

Author: Lazaridis KN, Strazzabosco M, and Larusso NF
Subjects: Animals, Apoptosis, Bile Duct Diseases classification, Humans, Models, Biological, Bile Duct Diseases pathology, Bile Ducts, Intrahepatic, Epithelial Cells pathology
Published: 2004
Full Text: View/download PDF

30. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes.

Author: Spirlì C, Fabris L, Duner E, Fiorotto R, Ballardini G, Roskams T, Larusso NF, Sonzogni A, Okolicsanyi L, and Strazzabosco M
Subjects: Adenylyl Cyclases metabolism, Animals, Bile Ducts cytology, Bile Ducts, Intrahepatic cytology, Bile Ducts, Intrahepatic metabolism, Cell Line, Cyclic AMP metabolism, Drug Synergism, Gene Expression drug effects, Humans, Intracellular Fluid metabolism, Ion Transport drug effects, Liver Diseases enzymology, Nitrates metabolism, Nitric Oxide Donors pharmacology, Nitric Oxide Synthase genetics, Nitric Oxide Synthase Type II, Nitrites metabolism, Rats, Adenylyl Cyclase Inhibitors, Bile Ducts metabolism, Cyclic AMP physiology, Interferon-gamma pharmacology, Nitric Oxide biosynthesis, Tumor Necrosis Factor-alpha pharmacology
Abstract: Background & Aims: The biliary epithelium is involved both in bile production and in the inflammatory/reparative response to liver damage. Recent data indicate that inflammatory aggression to intrahepatic bile ducts results in chronic progressive cholestasis., Methods: To understand the effects of nitric oxide on cholangiocyte secretion and biliary tract pathophysiology we have investigated: (1) the effects of proinflammatory cytokines on NO production and expression of the inducible nitric oxide synthase (NOS2), (2) the effects of NO on cAMP-dependent secretory mechanisms, and (3) the immunohistochemical expression of NOS2 in a number of human chronic liver diseases., Results: Our results show that: (1) tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma, synergically stimulate NO production in cultured cholangiocytes through an increase in NOS2 gene and protein expression; (2) micromolar concentrations of NO inhibit forskolin-stimulated cAMP production by adenylyl cyclase (AC), cyclic adenosine monophosphate (cAMP)-dependent fluid secretion, and cAMP-dependent Cl(-) and HCO(3)(-) transport mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and anion exchanger isoform 2, respectively; (3) cholestatic effects of NO and of proinflammatory cytokines are prevented by NOS-2 inhibitors and by agents (manganese(III)-tetrakis(4-benzoic acid)porphyrin [MnTBAP], urate, trolox) able to block the formation of reactive nitrogen oxide species (RNOS); (4) NOS2 expression is increased significantly in the biliary epithelium of patients with primary sclerosing cholangitis (PSC)., Conclusions: Our findings show that proinflammatory cytokines stimulate the biliary epithelium to generate NO, via NOS2 induction, and that NO causes ductular cholestasis by a RNOS-mediated inhibition of AC and of cAMP-dependent HCO(3)(-) and Cl(-) secretory mechanisms. This pathogenetic sequence may contribute to ductal cholestasis in inflammatory cholangiopathies.
Published: 2003
Full Text: View/download PDF

31. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium.

Author: Spirlì C, Nathanson MH, Fiorotto R, Duner E, Denson LA, Sanz JM, Di Virgilio F, Okolicsanyi L, Casagrande F, and Strazzabosco M
Subjects: Animals, Colforsin pharmacology, Drug Interactions, Electrolytes metabolism, Hydrogen-Ion Concentration, Liver Cirrhosis, Biliary metabolism, Male, Rats, Rats, Sprague-Dawley, Bile Ducts drug effects, Bile Ducts metabolism, Cytokines pharmacology
Abstract: Background and Aims: Cholestatic disorders often are associated with portal inflammation, but whether or how inflammation contributes to cholestasis is unknown. Thus we studied the effects of proinflammatory cytokines on bile duct epithelia secretory mechanisms., Methods: Isolated bile duct units (IBDUs) were cultured with interleukin (IL)-6, interferon gamma, tumor necrosis factor (TNF)-alpha, and IL-1 alone or in combination. Ductular secretion was measured using video-optical planimetry. Bicarbonate and Cl(-) transport were assessed microfluorimetric measuring pH(i) (BCECF) and [Cl(-)](i) transients (MEQ). Expression of Cl(-)/HCO(3)(-) exchanger (AE-2), cystic fibrosis transmembrane conductance regulator (CFTR), and the secretin receptor (SR) were assessed by ribonuclease protection assay. Cellular cyclic adenosine monophosphate (cAMP) levels were studied by enzymatic immunoassay. Paracellular permeability was assessed using fluorescein-labeled dextrans (FD) in cholangiocyte monolayers (NRC-1)., Results: Although not effective when given alone, each combination of IL-6, interferon gamma, IL-1, and TNF-alpha inhibited secretion in IBDU. Cytokines inhibited cAMP formation, AE-2 activity, and cyclic AMP-dependent Cl(-) efflux, but not that induced by purinergic agonists. AE-2 gene expression was unaffected by proinflammatory cytokines, whereas CFTR and SR expression was increased. In addition, paracellular transit of FD across NRC-1 monolayers was increased., Conclusions: Inflammatory cytokines inhibit cAMP-dependent fluid secretion in cholangiocytes and impair the barrier functions of biliary epithelia. These changes may represent the molecular mechanisms by which inflammation leads to ductular cholestasis in vivo.
Published: 2001
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources

Refine your results

31 results on '"Strazzabosco, M."'

1. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

2. Outcome indicators in primary sclerosing cholangitis: Interim analysis of the value-based medicine in hepatology study

3. Characteristics of patients with Chronic Hepatitis C who have failed past treatment or who have never been treated: How much room left for Interferon?

4. Value-based outcome indicators in the management of hepatocellular carcinoma: Clinical test in a large multicenter study (VBMH study)

5. Management of chronic hepatitis C (Chc) genotype 1 treatment-naïve patients in an era of rising opportunities and costs: A cost-effectiveness analysis

6. Outcome indicators in liver cirrhosis: Application of value-based medicine in a large multicenter study (VBMH study)

7. Notch signaling in hepatocellular carcinoma: guilty in association!

8. Polycystic Liver Diseases: Congenital Disorders of Cholangiocyte Signaling

9. ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice

10. HCC persistence or recurrence after bridging therapy helps predict transplant list dropout and generate a more equitable exception policy

11. Glibenclamide stimulates fluid secretion in rodent cholangiocytes through a cystic fibrosis transmembrane conductance regulator-independent mechanism

12. The cholangiopathies: disorders of biliary epithelia

13. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes

14. Comparison between two high-dose methylprednisolone schedules in the treatment of acute hepatic cellular rejection in liver transplant recipients: A controlled clinical trial

15. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium

16. Value-based outcome indicators in the management of hepatocellular carcinoma: Clinical test in a large multicenter study (VBMH study)

17. Outcome indicators in liver cirrhosis: Application of value-based medicine in a large multicenter study (VBMH study)

18. Notch signaling in hepatocellular carcinoma: guilty in association!

19. ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice

20. HCC persistence or recurrence after bridging therapy helps predict transplant list dropout and generate a more equitable exception policy

21. Portal Fibrosis and the Ductular Reaction: Pathophysiological Role in the Progression of Liver Disease and Translational Opportunities.

22. Adjusting Barcelona Clinic Liver Cancer Staging System to the Evolving Landscape of Hepatocellular Carcinoma: A Look to the Future.

23. Notch signaling in hepatocellular carcinoma: guilty in association!

24. Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-κB-mediated inflammatory response in mice.

25. Polycystic liver diseases: congenital disorders of cholangiocyte signaling.

26. ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice.

27. Ursodeoxycholic acid stimulates cholangiocyte fluid secretion in mice via CFTR-dependent ATP secretion.

28. Glibenclamide stimulates fluid secretion in rodent cholangiocytes through a cystic fibrosis transmembrane conductance regulator-independent mechanism.

29. The cholangiopathies: disorders of biliary epithelia.

30. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes.

31. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium.

Catalog

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Database

Publisher

31 results on '"Strazzabosco, M."'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources