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Jeanbernard Otte - One of the best experts on this subject based on the ideXlab platform.

  • congenital intrahepatic bile duct dilatation is a potentially curable Disease long term results of a multi institutional study
    Annals of Surgery, 2007
    Co-Authors: Jean Yves Mabrut, Christian Partensky, Daniel Jaeck, Elie Oussoultzoglou, Jacques Baulieux, Olivier Boillot, Jan Lerut, Jean De Ville De Goyet, Catherine Hubert, Jeanbernard Otte
    Abstract:

    Objective: To report clinical presentation, perioperative outcome, and long-term results of surgical management of congenital intrahepatic bile duct (IHBD) dilatations (including Caroli Disease) in a multi-institutional setting. Summary Background Data: Congenital IHBD dilatations are a rare congenital disorder predisposing to intrahepatic stones, cholangitis, and cholangiocarcinoma. The management remains difficult and controversial for bilobar forms of the Disease or when concurrent congenital hepatic fibrosis is associated. Methods: From 1976 to 2004, 33 patients (range I I to 79 years) were retrospectively enrolled. Disease extent into the liver was unilobar in 26 patients and bilobar in 7 patients (21%). Cholangiocarcinoma, congenital hepatic fibrosis, and intrahepatic stones were present in 2, 10, and 20 patients, respectively. Transplantations or liver resections were performed in 5 and 27 patients, respectively, whereas I asymptomatic patient was managed conservatively. Results: Postoperative mortality was nil. Postoperative complications occurred in 16 of 32 operated patients (50%) and additional procedures for residual stones were required in 5 patients. During a median follow-up of 80 months (1 patient being lost for follow-up) no patient developed metachronous carcinoma. Six patients (30%) developed recur-rent intrahepatic stones but satisfactory late outcome was achieved in 27 patients (87%). Conclusions: Partial or total liver resection achieves satisfactory late outcome in congenital IHBD dilatations, when the affection is treated at an early stage and when the extent of liver resection is tailored to intrahepatic Disease extent and takes into consideration the presence and severity of underlying chronic liver and renal Diseases.

Jean Yves Mabrut - One of the best experts on this subject based on the ideXlab platform.

  • congenital intrahepatic bile duct dilatation is a potentially curable Disease long term results of a multi institutional study
    Annals of Surgery, 2007
    Co-Authors: Jean Yves Mabrut, Christian Partensky, Daniel Jaeck, Elie Oussoultzoglou, Jacques Baulieux, Olivier Boillot, Jan Lerut, Jean De Ville De Goyet, Catherine Hubert, Jeanbernard Otte
    Abstract:

    Objective: To report clinical presentation, perioperative outcome, and long-term results of surgical management of congenital intrahepatic bile duct (IHBD) dilatations (including Caroli Disease) in a multi-institutional setting. Summary Background Data: Congenital IHBD dilatations are a rare congenital disorder predisposing to intrahepatic stones, cholangitis, and cholangiocarcinoma. The management remains difficult and controversial for bilobar forms of the Disease or when concurrent congenital hepatic fibrosis is associated. Methods: From 1976 to 2004, 33 patients (range I I to 79 years) were retrospectively enrolled. Disease extent into the liver was unilobar in 26 patients and bilobar in 7 patients (21%). Cholangiocarcinoma, congenital hepatic fibrosis, and intrahepatic stones were present in 2, 10, and 20 patients, respectively. Transplantations or liver resections were performed in 5 and 27 patients, respectively, whereas I asymptomatic patient was managed conservatively. Results: Postoperative mortality was nil. Postoperative complications occurred in 16 of 32 operated patients (50%) and additional procedures for residual stones were required in 5 patients. During a median follow-up of 80 months (1 patient being lost for follow-up) no patient developed metachronous carcinoma. Six patients (30%) developed recur-rent intrahepatic stones but satisfactory late outcome was achieved in 27 patients (87%). Conclusions: Partial or total liver resection achieves satisfactory late outcome in congenital IHBD dilatations, when the affection is treated at an early stage and when the extent of liver resection is tailored to intrahepatic Disease extent and takes into consideration the presence and severity of underlying chronic liver and renal Diseases.

Strazzabosco M. - One of the best experts on this subject based on the ideXlab platform.

  • Pathobiology of inherited biliary Diseases: a roadmap to understand acquired liver Diseases
    'Springer Science and Business Media LLC', 2019
    Co-Authors: Fabris L., Spirli C, Fiorotto R, Cadamuro M, Perugorria M. J., Banales J. M., Strazzabosco M.
    Abstract:

    Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex Diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver Diseases, fibropolycystic liver Diseases (Caroli Disease and congenital hepatic fibrosis) and cystic fibrosis-related liver Disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver Diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver Disease, research has shown that loss of fibrocystin generates a signalling cascade that increases β-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1β and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver Disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies

  • PKA dependent p-Ser-675β-catenin, a novel signaling defect in a mouse model of Congenital Hepatic Fibrosis
    Whiley, 2013
    Co-Authors: Spirli C, Fabris Luca, Locatelli L, Cm Morell, Fiorotto R, Sd Moton, Cadamuro M, Strazzabosco M.
    Abstract:

    Background and Aims: Genetically-determined loss of fibrocystin function causes Congenital Hepatic Fibrosis (CHF), Caroli Disease (CD) and Autosomal Recessive Polycystic Kidney Disease (ARPKD). Cystic dysplasia of the intrahepatic bile ducts and progressive portal fibrosis characterize liver pathology in CHF/CD. At a cellular level, several functional morphological and signaling changes have been reported including increased levels of 3'-5'-cyclic adenosine monophosphate (cAMP). In this study, we have addressed the relationships between increased cAMP and \u3b2-catenin. Methods and Results: In cholangiocytes isolated ad cultured from Pkhd1del4/del4 mice, stimulation of cAMP/PKA signaling (forskolin 10 \u3bcM) stimulated Ser-675-phosphorylation of \u3b2-catenin, its nuclear localization and its transcriptional activity (Western blot and TOP Flash assay, respectively) along with a downregulation of E-cadherin expression (Immunocytochemistry and Western blot); these changes were inhibited by the PKA blocker, PKI (1 \u3bcM). The Rho-GTPase, Rac-1, was also significantly activated by cAMP in Pkhd1del4/del4 cholangiocytes. Rac-1 inhibition blocked cAMP-dependent nuclear translocation and transcriptional activity of pSer-675\u3b2-catenin. Cell migration (Boyden chambers) was significantly higher in cholangiocytes obtained from Pkhd1del4/del4 and was inhibited by: 1) PKI, 2) silencing \u3b2-catenin (siRNA) and 3) the Rac-1 inhibitor, NSC 23766. Conclusions: These data show that in fibrocystin-defective cholangiocytes, cAMP stimulates pSer-675phosphorylation of \u3b2-catenin and Rac-1 activity. In the presence of activated Rac-1, pSer-675-\u3b2-catenin is translocated to the nucleus, becomes transcriptionally active, and is responsible for increased motility of Pkhd1del4/del4 cholangiocytes. \u3b2-catenin dependent changes in cell motility may be central to the pathogenesis of the Disease and represent a potential therapeutic target

  • PKA dependent p-Ser-675\u3b2-catenin, a novel signaling defect in a mouse model of Congenital Hepatic Fibrosis
    Whiley, 2013
    Co-Authors: Spirli C, Fabris Luca, Locatelli L, Cm Morell, Fiorotto R, Sd Moton, Cadamuro M, Strazzabosco M.
    Abstract:

    Background and Aims: Genetically-determined loss of fibrocystin function causes Congenital Hepatic Fibrosis (CHF), Caroli Disease (CD) and Autosomal Recessive Polycystic Kidney Disease (ARPKD). Cystic dysplasia of the intrahepatic bile ducts and progressive portal fibrosis characterize liver pathology in CHF/CD. At a cellular level, several functional morphological and signaling changes have been reported including increased levels of 3'-5'-cyclic adenosine monophosphate (cAMP). In this study, we have addressed the relationships between increased cAMP and \u3b2-catenin. Methods and Results: In cholangiocytes isolated ad cultured from Pkhd1del4/del4 mice, stimulation of cAMP/PKA signaling (forskolin 10 \u3bcM) stimulated Ser-675-phosphorylation of \u3b2-catenin, its nuclear localization and its transcriptional activity (Western blot and TOP Flash assay, respectively) along with a downregulation of E-cadherin expression (Immunocytochemistry and Western blot); these changes were inhibited by the PKA blocker, PKI (1 \u3bcM). The Rho-GTPase, Rac-1, was also significantly activated by cAMP in Pkhd1del4/del4 cholangiocytes. Rac-1 inhibition blocked cAMP-dependent nuclear translocation and transcriptional activity of pSer-675\u3b2-catenin. Cell migration (Boyden chambers) was significantly higher in cholangiocytes obtained from Pkhd1del4/del4 and was inhibited by: 1) PKI, 2) silencing \u3b2-catenin (siRNA) and 3) the Rac-1 inhibitor, NSC 23766. Conclusions: These data show that in fibrocystin-defective cholangiocytes, cAMP stimulates pSer-675phosphorylation of \u3b2-catenin and Rac-1 activity. In the presence of activated Rac-1, pSer-675-\u3b2-catenin is translocated to the nucleus, becomes transcriptionally active, and is responsible for increased motility of Pkhd1del4/del4 cholangiocytes. \u3b2-catenin dependent changes in cell motility may be central to the pathogenesis of the Disease and represent a potential therapeutic target

Mario Strazzabosco - One of the best experts on this subject based on the ideXlab platform.

  • protein kinase a dependent pser 675 β catenin a novel signaling defect in a mouse model of congenital hepatic fibrosis
    Hepatology, 2013
    Co-Authors: Carlo Spirli, L Locatelli, Massimiliano Cadamuro, Romina Fiorotto, Cm Morell, Stuart Morton, Luca Fabris, Mario Strazzabosco
    Abstract:

    Genetically determined loss of fibrocystin function causes congenital hepatic fibrosis (CHF), Caroli Disease (CD), and autosomal recessive polycystic kidney Disease (ARPKD). Cystic dysplasia of the intrahepatic bile ducts and progressive portal fibrosis characterize liver pathology in CHF/CD. At a cellular level, several functional morphological and signaling changes have been reported including increased levels of 3′-5′-cyclic adenosine monophosphate (cAMP). In this study we addressed the relationships between increased cAMP and β-catenin. In cholangiocytes isolated and cultured from Pkhd1del4/del4 mice, stimulation of cAMP/PKA signaling (forskolin 10 μM) stimulated Ser675-phosphorylation of β-catenin, its nuclear localization, and its transcriptional activity (western blot and TOP flash assay, respectively) along with a down-regulation of E-cadherin expression (immunocytochemistry and western blot); these changes were inhibited by the PKA blocker, PKI (1 μM). The Rho-GTPase, Rac-1, was also significantly activated by cAMP in Pkhd1del4/del4 cholangiocytes. Rac-1 inhibition blocked cAMP-dependent nuclear translocation and transcriptional activity of pSer675-β-catenin. Cell migration (Boyden chambers) was significantly higher in cholangiocytes obtained from Pkhd1del4/del4 and was inhibited by: (1) PKI, (2) silencing β-catenin (siRNA), and (3) the Rac-1 inhibitor NSC 23766. Conclusion: These data show that in fibrocystin-defective cholangiocytes, cAMP/PKA signaling stimulates pSer675-phosphorylation of β-catenin and Rac-1 activity. In the presence of activated Rac-1, pSer675-β-catenin is translocated to the nucleus, becomes transcriptionally active, and is responsible for increased motility of Pkhd1del4/del4 cholangiocytes. β-Catenin-dependent changes in cell motility may be central to the pathogenesis of the Disease and represent a potential therapeutic target. (Hepatology 2013;58:1713–1723)

Cm Morell - One of the best experts on this subject based on the ideXlab platform.

  • protein kinase a dependent pser 675 β catenin a novel signaling defect in a mouse model of congenital hepatic fibrosis
    Hepatology, 2013
    Co-Authors: Carlo Spirli, L Locatelli, Massimiliano Cadamuro, Romina Fiorotto, Cm Morell, Stuart Morton, Luca Fabris, Mario Strazzabosco
    Abstract:

    Genetically determined loss of fibrocystin function causes congenital hepatic fibrosis (CHF), Caroli Disease (CD), and autosomal recessive polycystic kidney Disease (ARPKD). Cystic dysplasia of the intrahepatic bile ducts and progressive portal fibrosis characterize liver pathology in CHF/CD. At a cellular level, several functional morphological and signaling changes have been reported including increased levels of 3′-5′-cyclic adenosine monophosphate (cAMP). In this study we addressed the relationships between increased cAMP and β-catenin. In cholangiocytes isolated and cultured from Pkhd1del4/del4 mice, stimulation of cAMP/PKA signaling (forskolin 10 μM) stimulated Ser675-phosphorylation of β-catenin, its nuclear localization, and its transcriptional activity (western blot and TOP flash assay, respectively) along with a down-regulation of E-cadherin expression (immunocytochemistry and western blot); these changes were inhibited by the PKA blocker, PKI (1 μM). The Rho-GTPase, Rac-1, was also significantly activated by cAMP in Pkhd1del4/del4 cholangiocytes. Rac-1 inhibition blocked cAMP-dependent nuclear translocation and transcriptional activity of pSer675-β-catenin. Cell migration (Boyden chambers) was significantly higher in cholangiocytes obtained from Pkhd1del4/del4 and was inhibited by: (1) PKI, (2) silencing β-catenin (siRNA), and (3) the Rac-1 inhibitor NSC 23766. Conclusion: These data show that in fibrocystin-defective cholangiocytes, cAMP/PKA signaling stimulates pSer675-phosphorylation of β-catenin and Rac-1 activity. In the presence of activated Rac-1, pSer675-β-catenin is translocated to the nucleus, becomes transcriptionally active, and is responsible for increased motility of Pkhd1del4/del4 cholangiocytes. β-Catenin-dependent changes in cell motility may be central to the pathogenesis of the Disease and represent a potential therapeutic target. (Hepatology 2013;58:1713–1723)

  • PKA dependent p-Ser-675β-catenin, a novel signaling defect in a mouse model of Congenital Hepatic Fibrosis
    Whiley, 2013
    Co-Authors: Spirli C, Fabris Luca, Locatelli L, Cm Morell, Fiorotto R, Sd Moton, Cadamuro M, Strazzabosco M.
    Abstract:

    Background and Aims: Genetically-determined loss of fibrocystin function causes Congenital Hepatic Fibrosis (CHF), Caroli Disease (CD) and Autosomal Recessive Polycystic Kidney Disease (ARPKD). Cystic dysplasia of the intrahepatic bile ducts and progressive portal fibrosis characterize liver pathology in CHF/CD. At a cellular level, several functional morphological and signaling changes have been reported including increased levels of 3'-5'-cyclic adenosine monophosphate (cAMP). In this study, we have addressed the relationships between increased cAMP and \u3b2-catenin. Methods and Results: In cholangiocytes isolated ad cultured from Pkhd1del4/del4 mice, stimulation of cAMP/PKA signaling (forskolin 10 \u3bcM) stimulated Ser-675-phosphorylation of \u3b2-catenin, its nuclear localization and its transcriptional activity (Western blot and TOP Flash assay, respectively) along with a downregulation of E-cadherin expression (Immunocytochemistry and Western blot); these changes were inhibited by the PKA blocker, PKI (1 \u3bcM). The Rho-GTPase, Rac-1, was also significantly activated by cAMP in Pkhd1del4/del4 cholangiocytes. Rac-1 inhibition blocked cAMP-dependent nuclear translocation and transcriptional activity of pSer-675\u3b2-catenin. Cell migration (Boyden chambers) was significantly higher in cholangiocytes obtained from Pkhd1del4/del4 and was inhibited by: 1) PKI, 2) silencing \u3b2-catenin (siRNA) and 3) the Rac-1 inhibitor, NSC 23766. Conclusions: These data show that in fibrocystin-defective cholangiocytes, cAMP stimulates pSer-675phosphorylation of \u3b2-catenin and Rac-1 activity. In the presence of activated Rac-1, pSer-675-\u3b2-catenin is translocated to the nucleus, becomes transcriptionally active, and is responsible for increased motility of Pkhd1del4/del4 cholangiocytes. \u3b2-catenin dependent changes in cell motility may be central to the pathogenesis of the Disease and represent a potential therapeutic target

  • PKA dependent p-Ser-675\u3b2-catenin, a novel signaling defect in a mouse model of Congenital Hepatic Fibrosis
    Whiley, 2013
    Co-Authors: Spirli C, Fabris Luca, Locatelli L, Cm Morell, Fiorotto R, Sd Moton, Cadamuro M, Strazzabosco M.
    Abstract:

    Background and Aims: Genetically-determined loss of fibrocystin function causes Congenital Hepatic Fibrosis (CHF), Caroli Disease (CD) and Autosomal Recessive Polycystic Kidney Disease (ARPKD). Cystic dysplasia of the intrahepatic bile ducts and progressive portal fibrosis characterize liver pathology in CHF/CD. At a cellular level, several functional morphological and signaling changes have been reported including increased levels of 3'-5'-cyclic adenosine monophosphate (cAMP). In this study, we have addressed the relationships between increased cAMP and \u3b2-catenin. Methods and Results: In cholangiocytes isolated ad cultured from Pkhd1del4/del4 mice, stimulation of cAMP/PKA signaling (forskolin 10 \u3bcM) stimulated Ser-675-phosphorylation of \u3b2-catenin, its nuclear localization and its transcriptional activity (Western blot and TOP Flash assay, respectively) along with a downregulation of E-cadherin expression (Immunocytochemistry and Western blot); these changes were inhibited by the PKA blocker, PKI (1 \u3bcM). The Rho-GTPase, Rac-1, was also significantly activated by cAMP in Pkhd1del4/del4 cholangiocytes. Rac-1 inhibition blocked cAMP-dependent nuclear translocation and transcriptional activity of pSer-675\u3b2-catenin. Cell migration (Boyden chambers) was significantly higher in cholangiocytes obtained from Pkhd1del4/del4 and was inhibited by: 1) PKI, 2) silencing \u3b2-catenin (siRNA) and 3) the Rac-1 inhibitor, NSC 23766. Conclusions: These data show that in fibrocystin-defective cholangiocytes, cAMP stimulates pSer-675phosphorylation of \u3b2-catenin and Rac-1 activity. In the presence of activated Rac-1, pSer-675-\u3b2-catenin is translocated to the nucleus, becomes transcriptionally active, and is responsible for increased motility of Pkhd1del4/del4 cholangiocytes. \u3b2-catenin dependent changes in cell motility may be central to the pathogenesis of the Disease and represent a potential therapeutic target