Browsing by Author "Bosch, Jaime"

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    Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis
    (Wiley, 2022) Sanyal, Arun J.; Anstee, Quentin M.; Trauner, Michael; Lawitz, Eric J.; Abdelmalek, Manal F.; Ding, Dora; Han, Ling; Jia, Catherine; Huss, Ryan S.; Chung, Chuhan; Wong, Vincent Wai-Sun; Okanoue, Takeshi; Romero-Gomez, Manuel; Muir, Andrew J.; Afdhal, Nezam H.; Bosch, Jaime; Goodman, Zachary; Harrison, Stephen A.; Younossi, Zobair M.; Myers, Robert P.; Medicine, School of Medicine
    Background and aims: Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis. Approach and results: Patients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [FIB-4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events. Conclusions: In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis.
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    Donor Simvastatin Treatment Is Safe and Might Improve Outcomes After Liver Transplantation: A Randomized Clinical Trial
    (Wolters Kluwer, 2022) Pagano, Duilio; Bosch, Jaime; Tuzzolino, Fabio; Oliva, Elisabetta; Ekser, Burcin; Zito, Giovanni; Cintorino, Davide; di Francesco, Fabrizio; Petri, Sergio Li; Ricotta, Calogero; Bonsignore, Pasquale; Calamia, Sergio; Magro, Bianca; Trifirò, Gianluca; Alduino, Rossella; Barbara, Marco; Conaldi, Pier Giulio; Gallo, Alessia; Venuti, Francesca; Luca, Angelo; Gruttadauria, Salvatore; Surgery, School of Medicine
    Background: The current curative approaches for ischemia/reperfusion injury on liver transplantation are still under debate for their safety and efficacy in patients with end-stage liver disease. We present the SIMVA statin donor treatment before Liver Transplants study. Methods: SIMVA statin donor treatment before Liver Transplants is a monocentric, double-blind, randomized, prospective trial aiming to compare the safety and efficacy of preoperative brain-dead donors' treatment with the intragastric administration of 80 mg of simvastatin on liver transplant recipient outcomes in a real-life setting. Primary aim was incidence of patient and graft survival at 90 and 180 d posttransplant; secondary end-points were severe complications. Results: The trial enrolled 58 adult patients (18-65 y old). The minimum follow-up was 6 mo. No patient or graft was lost at 90 or 180 d in the experimental group (n = 28), whereas patient/graft survival were 93.1% ( P = 0.016) and 89.66% ( P = 0.080) at 90 d and 86.21% ( P = 0.041) and 86.2% ( P = 0.041) at 180 d in the control group (n = 29). The percentage of patients with severe complications (Clavien-Dindo ≥IIIb) was higher in the control group, 55.2% versus 25.0% in the experimental group ( P = 0.0307). The only significant difference in liver tests was a significantly higher gamma-glutamyl transferase and alkaline phosphatase at 15 d ( P = 0.017), ( P = 0.015) in the simvastatin group. Conclusions: Donor simvastatin treatment is safe, and may significantly improve early graft and patient survival after liver transplantation, although further research is mandatory.
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    Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension
    (Wiley, 2019-03) Abraldes, Juan G.; Trebicka, Jonel; Chalasani, Naga; D’Amico, Gennaro; Rockey, Don C.; Shah, Vijay H.; Bosch, Jaime; Garcia-Tsao, Guadalupe; Medicine, School of Medicine
    Portal hypertension (PH) is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. PH results initially from increased intrahepatic vascular resistance. Subsequently, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure (PP). Reducing PP in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve PP. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing PP. For over 35 years, the mainstay of such therapy has been the use of nonselective beta‐blockers (NSBBs) that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in preclinical and early clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2, and 3) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals, and industry partners.
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    Sex-related differences in aging rate are associated with sex chromosome system in amphibians
    (Wiley, 2022) Cayuela, Hugo; Lemaître, Jean-François; Léna, Jean-Paul; Ronget, Victor; Martínez-Solano, Iñigo; Muths, Erin; Pilliod, David S.; Schmidt, Benedikt R.; Sánchez-Montes, Gregorio; Gutiérrez-Rodríguez, Jorge; Pyke, Graham; Grossenbacher, Kurt; Lenzi, Omar; Bosch, Jaime; Beard, Karen H.; Woolbright, Lawrence L.; Lambert, Brad A.; Green, David M.; Jreidini, Nathalie; Garwood, Justin M.; Fisher, Robert N.; Matthews, Kathleen; Dudgeon, David; Lau, Anthony; Speybroeck, Jeroen; Homan, Rebecca; Jehle, Robert; Başkale, Eyup; Mori, Emiliano; Arntzen, Jan W.; Joly, Pierre; Stiles, Rochelle M.; Lannoo, Michael J.; Maerz, John C.; Lowe, Winsor H.; Valenzuela-Sánchez, Andrés; Christiansen, Ditte G.; Angelini, Claudio; Thirion, Jean-Marc; Merilä, Juha; Colli, Guarino R.; Vasconcellos, Mariana M.; Boas, Taissa C.V.; Arantes, Ísis da C.; Levionnois, Pauline; Reinke, Beth A.; Vieira, Cristina; Marais, Gabriel A.B.; Gaillard, Jean-Michel; Miller, David A.W.; Anatomy, Cell Biology and Physiology, School of Medicine
    Sex‐related differences in mortality are widespread in the animal kingdom. Although studies have shown that sex determination systems might drive lifespan evolution, sex chromosome influence on aging rates have not been investigated so far, likely due to an apparent lack of demographic data from clades including both XY (with heterogametic males) and ZW (heterogametic females) systems. Taking advantage of a unique collection of capture–recapture datasets in amphibians, a vertebrate group where XY and ZW systems have repeatedly evolved over the past 200 million years, we examined whether sex heterogamy can predict sex differences in aging rates and lifespans. We showed that the strength and direction of sex differences in aging rates (and not lifespan) differ between XY and ZW systems. Sex‐specific variation in aging rates was moderate within each system, but aging rates tended to be consistently higher in the heterogametic sex. This led to small but detectable effects of sex chromosome system on sex differences in aging rates in our models. Although preliminary, our results suggest that exposed recessive deleterious mutations on the X/Z chromosome (the “unguarded X/Z effect”) or repeat‐rich Y/W chromosome (the “toxic Y/W effect”) could accelerate aging in the heterogametic sex in some vertebrate clades.