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101. Mechanism of hard-nanomaterial clearance by the liver

Author

Tsoi, Kim M., primary, MacParland, Sonya A., additional, Ma, Xue-Zhong, additional, Spetzler, Vinzent N., additional, Echeverri, Juan, additional, Ouyang, Ben, additional, Fadel, Saleh M., additional, Sykes, Edward A., additional, Goldaracena, Nicolas, additional, Kaths, Johann M., additional, Conneely, John B., additional, Alman, Benjamin A., additional, Selzner, Markus, additional, Ostrowski, Mario A., additional, Adeyi, Oyedele A., additional, Zilman, Anton, additional, McGilvray, Ian D., additional, and Chan, Warren C. W., additional

Published
2016
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102. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: A prospective validation study

Author

Sapisochin, Gonzalo, primary, Goldaracena, Nicolas, additional, Laurence, Jerome M., additional, Dib, Martin, additional, Barbas, Andrew, additional, Ghanekar, Anand, additional, Cleary, Sean P., additional, Lilly, Les, additional, Cattral, Mark S., additional, Marquez, Max, additional, Selzner, Markus, additional, Renner, Eberhard, additional, Selzner, Nazia, additional, McGilvray, Ian D., additional, Greig, Paul D., additional, and Grant, David R., additional

Published
2016
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104. Live Donor Liver Transplantation With Older (≥50 Years) Versus Younger (<50 Years) Donors

Author

Goldaracena, Nicolas, primary, Sapisochin, Gonzalo, additional, Spetzler, Vinzent, additional, Echeverri, Juan, additional, Kaths, Moritz, additional, Cattral, Mark S., additional, Greig, Paul D., additional, Lilly, Les, additional, McGilvray, Ian D., additional, Levy, Gary A., additional, Ghanekar, Anand, additional, Renner, Eberhard L., additional, Grant, David R., additional, Selzner, Markus, additional, and Selzner, Nazia, additional

Published
2016
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107. Intensivpflichtigkeit mit Beatmung ist keine Kontraindikation zur Lebertransplantation bei Patienten mit chronischer Lebererkrankung

Author

Boehnert, Markus U., Selzner, Nazia, McCluskey, Stuart, Cattral, Mark S., Ghanekar, Anand, Levy, Gary A., Lilly, Les, Therapondos, George, Renner, Eberhard L., Greig, Paul D., McGilvray, Ian D., Grant, David R., and Selzner, Markus

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Einleitung: Aufgrund der Organknappheit wird die Verteilung von Organen an Patienten mit potentiell schlechtem postoperativem Überleben kontrovers diskutiert. Wir untersuchten den Einfluss von unmittelbar präoperativer Beatmungspflichtigkeit auf das Outcome der Lebertransplantation in einer[for full text, please go to the a.m. URL], 128. Kongress der Deutschen Gesellschaft für Chirurgie

Published
2011

108. Should We Exclude Live Donor Liver Transplantation for Liver Transplant Recipients Requiring Mechanical Ventilation and Intensive Care Unit Care?

Author

Goldaracena, Nicolas, primary, Spetzler, Vinzent N, additional, Sapisochin, Gonzalo, additional, J, Echeverri, additional, Moritz, Kaths, additional, Cattral, Mark S, additional, Greig, Paul D, additional, Lilly, Les, additional, McGilvray, Ian D, additional, Levy, Gary A, additional, Ghanekar, Anand, additional, Renner, Eberhard L, additional, Grant, David R, additional, Selzner, Markus, additional, and Selzner, Nazia, additional

Published
2015
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110. Replication and Oncolytic Activity of an Avian Orthoreovirus in Human Hepatocellular Carcinoma Cells.

Author

Kozak, Robert A., Hattin, Larissa, Biondi, Mia J., Corredor, Juan C., Walsh, Scott, Max Xue-Zhong, Manuel, Justin, McGilvray, Ian D., Morgenstern, Jason, Lusty, Evan, Cherepanov, Vera, McBey, Betty-Anne, Leishman, David, Feld, Jordan J., Bridle, Byram, and Nagy, Éva

Subjects
ORTHOREOVIRUSES, CANCER, VIRUSES, DISEASES, MICROORGANISMS
Abstract

Oncolytic viruses are cancer therapeutics with promising outcomes in pre-clinical and clinical settings. Animal viruses have the possibility to avoid pre-existing immunity in humans, while being safe and immunostimulatory. We isolated an avian orthoreovirus (ARV-PB1), and tested it against a panel of hepatocellular carcinoma cells.We found that ARV-PB1 replicated well and induced strong cytopathic effects. It was determined that one mechanism of cell death was through syncytia formation, resulting in apoptosis and induction of interferon stimulated genes (ISGs). As hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma worldwide, we investigated the effect of ARV-PB1 against cells already infected with this virus. Both HCV replicon-containing and infected cells supported ARV-PB1 replication and underwent cytolysis. Finally, we generated in silico models to compare the structures of human reovirus- and ARV-PB1-derived S1 proteins, which are the primary targets of neutralizing antibodies. Tertiary alignments confirmed that ARV-PB1 differs from its human homolog, suggesting that immunity to human reoviruses would not be a barrier to its use. Therefore, ARV-PB1 can potentially expand the repertoire of oncolytic viruses for treatment of human hepatocellular carcinoma and other malignancies. [ABSTRACT FROM AUTHOR]

Published
2017
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112. The Effect of Recipient Age on Outcome After Pancreas Transplantation

Author

Laurence, Jerome M., primary, Marquez, Max A., additional, Seal, John B., additional, Sapisochin, Gonzalo, additional, Bazerbachi, Fateh, additional, Selzner, Markus, additional, Norgate, Andrea, additional, Greig, Paul D., additional, McGilvray, Ian D., additional, Schiff, Jeffrey, additional, and Cattral, Mark S., additional

Published
2015
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113. Mesocaval Shunting

Author

Conneely, John B., primary, Smoot, Rory L., additional, Greig, Paul D., additional, and McGilvray, Ian D., additional

Published
2014
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116. Mo1002 In Non-Alcoholic Fatty Liver Disease, Differential Gene Expression for Phospholipid Metabolism Is Associated With Lower Hepatic Phosphatidylcholine to Phosphatidylethanolamine Ratio, but Not With Lower Choline Intake

Author

Arendt, Bianca M., primary, McGilvray, Ian D., additional, Comelli, Elena, additional, Ma, David W., additional, Fung, Scott, additional, Guzman, AnaLaura, additional, Fischer, Sandra E., additional, and Allard, Johane P., additional

Published
2013
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125. MurineHepatitis Virus Strain 1 Produces a Clinically Relevant Model of Severe Acute Respiratory Syndrome in A/J Mice

Author

De Albuquerque, Nadine, primary, Baig, Ehtesham, additional, Ma, Xuezhong, additional, Zhang, Jianhua, additional, He, William, additional, Rowe, Andrea, additional, Habal, Marlena, additional, Liu, Mingfeng, additional, Shalev, Itay, additional, Downey, Gregory P., additional, Gorczynski, Reginald, additional, Butany, Jagdish, additional, Leibowitz, Julian, additional, Weiss, Susan R., additional, McGilvray, Ian D., additional, Phillips, M. James, additional, Fish, Eleanor N., additional, and Levy, Gary A., additional

Published
2006
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137. Toronto Management of Initially Unresectable Liver Metastasis from Colorectal Cancer in a Living Donor Liver Transplant Program.

Author

Rajendran, Luckshi, Claasen, Marco PAW, McGilvray, Ian D., Cattral, Mark S., Ghanekar, Anand, Selzner, Nazia, Burkes, Ron, Winter, Erin, Gallinger, Steven, and Sapisochin, Gonzalo

Subjects
*LIVER tumors, *CONFIDENCE intervals, *CANCER chemotherapy, *METASTASIS, *MANN Whitney U Test, *RETROSPECTIVE studies, *ACQUISITION of data, *COLORECTAL cancer, *COMPARATIVE studies, *T-test (Statistics), *DESCRIPTIVE statistics, *CHI-squared test, *KAPLAN-Meier estimator, *MEDICAL records, *LIVER transplantation, *PROGRESSION-free survival, *DATA analysis software, *ORGAN donors, *OVERALL survival
Abstract

BACKGROUND: Living donor liver transplantation (LDLT) is an attractive option for patients with unresectable, bilobar colorectal liver metastases (CRLM). However, it is not available in most centers beyond study protocols. This study describes the interim experience with LDLT for CRLM at a large North American transplant and hepatobiliary center. f STUDY DESIGN: Adults with unresectable CRLM, receiving systemic chemotherapy, were recruited into a prospective clinical trial. Data on demographics, referral patterns, and clinical characteristics were extracted from October 2016 to February 2023. Patients were divided into 3 groups: transplanted, resected, and control (excluded with continuation of systemic chemotherapy). Overall survival and recurrence-free survival were compared. RESULTS: Eighty-one referred patients were assessed for LDLT: 7 received transplants, 22 underwent resection, and 48 were controls. All had similar preassessment baseline characteristics. Median time from initial assessment to transplantation was 15.4 months. The control population had significantly worse postassessment overall survival than the transplanted population (p = 0.002) and resected population (p < 0.001). The median postoperative follow-up duration was 21.4 months (resection) and 14.8 months (LDLT). There was no difference in overall survival between the transplanted and resected populations (1-year 100% vs 93.8%; 3-year 100% vs 43.3%, p = 0.17). However, recurrence-free survival was superior in the LDLT group (1-year 85.7% vs 11.4%; 3-year 68.6% vs 11.4%, p = 0.012). CONCLUSIONS: Most patients with unresectable CRLM referred for LDLT are deemed ineligible for trial inclusion. However, the excellent oncologic outcomes in patients who meet criteria for LDLT supports its role in highly selected populations. Future results after the trial's completion will inform long-term outcomes. [ABSTRACT FROM AUTHOR]

Published
2023
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138. Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid.

Author

Limin Chen, Borozan, Ivan, Milkiewicz, Piotr, Jing Sun, Xiangbin Meng, Coltescu, Catalina, Edwards, Aled M., Ostrowski, Mario A., Guindi, Maha, Heathcote, Elizabeth J., and McGilvray, Ian D.

Subjects
CIRRHOSIS of the liver, URSODEOXYCHOLIC acid, GENE expression, HEPATITIS B virus, BIOPSY
Abstract

Objectives: Primary biliary cirrhosis (PBC) is a poorly understood disease, both in terms of its pathogenesis and the mechanism of action of its most common treatment, ursodeoxycholic acid (UDCA). We used gene expression profiling to compare liver tissue from treatment-naïve and UDCA-treated patients in order to outline some of the molecular changes associated with PBC and its treatment. Patients and Experimental Design: Liver biopsy specimens from non-cirrhotic, treatment-naïve ( n=11) patients were compared with biopsies from UDCA-treated patients ( n=20) and with 10 normal, healthy female controls. Gene expression was determined using a 19K cDNA microarray. In order to determine whether the observed changes in gene expression levels were specific to PBC or generic to liver damage overall, PBC samples were also compared with chronically diseased [48 hepatitis C virus (HCV), 18 hepatitis B virus (HBV)] and acutely stressed liver tissue (25 liver biopsies taken after reperfusion of liver transplant grafts). Results: We found a gene signature specific to PBC ( P≤0.012), containing biologically plausible genes (221 genes with adjusted P≤0.05). Differences in the expression of selected genes were confirmed using real-time polymerase chain reaction. When gene expression from non-cirrhotic UDCA-treated ( n=20) and UDCA-naïve liver tissue was compared, we found a striking downregulation of a number of genes involved in protein biosynthetic pathways. Conclusions: These studies highlight the genes associated with both treatment-naïve and UDCA-treated PBC, and suggest that the effects of UDCA are mediated, at least in part, via a modulation of protein biosynthesic pathways. [ABSTRACT FROM AUTHOR]

Published
2008
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139. Contributors

Author

Abou-Alfa, Ghassan K., Adsay, N. Volkan, Akhurst, Timothy, Alemi, Farzad, Allegra, David, Allen, Peter J., Anderson, Christopher D., Aoki, Taku, Arulraj, Ramakrishnan, Auer, Rebecca Ann C., Aussilhou, B´atrice, Awad, Joseph, Ball, Chad G., Bamboat, Zubin M., Bassi, Claudio, Becker, Christoph D., Bedossa, Pierre, Belghiti, Jacques, Belletrutti, Paul, Bilchik, Anton J., Blumgart, Leslie H., Bornman, Philippus C., Boutros, Cherif, Brody, Jonathan R., Brody, Lynn A., Brouquet, Antoine, Brown, Karen T., Brugge, William R., Bruix, Jordi, Bruno, David A., Brunt, Elizabeth M., Büchler, Markus W., Burns, Justin M., Butturini, Giovanni, Callery, Mark P., Carr-Locke, David L., Cha, Charles, Chan, See Ching, Chapman, William C., Cherqui, Daniel, Cho, Clifford S., Chung, Jin Wook, Clary, Bryan, Cocieru, Andrei, Contreras, Carlos M., Conzen, Kendra D., Corvera, Carlos U., Covey, Anne M., Crippin, Jeffrey S., Dabbous, Hany, D’Angelica, Michael I., Darcy, Michael, Davenport, Mark, De Jonge, Jeroen, DeMatteo, Ronald P., Demetriou, Achilles A., Desai, Niraj M., De Santibañes, Eduardo, Desser, Terry S., Dhanireddy, Kiran K., Dokmak, Safi, Doyle, M.B. Majella, Earl, Truman M., Ebata, Tomoki, El-Gohary, Yousef, Epstein, Andrew S., Espat, N. Joseph, Fan, Sheung Tat, Farges, Olivier, Fernandez-Del Castillo, Carlos, Ferrone, Cristina R., Fischer, Mary, Fisher, James E., Fong, Yuman, Forner, Alejandro, Friedman, Scott L., Fritz, Stefan, Galloway, John R., Gerdes, Hans, Getrajdman, George, Ghaneh, Paula, Ghittoni, Giorgia, Gittes, George, Goodman, Karyn A., Gores, Gregory J., Gotuzzo, Eduardo, Gouma, Dirk J., Greig, Paul D., Halloran, Christopher M., Halpern, Neil A., Hann, Lucy E., Harrison, Ewen M., Hartwig, Werner, Heimbach, Julie K., Helton, William S., Hemming, Alan W., Henderson, J. Michael, Hessheimer, Amelia J., Hirshberg, Asher, Ho, Alice, House, Michael G., Hsieh, Chung-Bao, Hsu, Kuo-Feng, Iannitti, David A., Imamura, Hiroshi, Imrie, Clem W., Jarnagin, William R., Jenkins, Roger L., Kahl, Stefan, Kanagra, Ivan, Kelly, Kaitlyn, Kemeny, Nancy E., Kennedy, Eugene P., Kerlan Jr, Robert K., Khan, Adeel S., Khan, Saboor, Kingham, T. Peter, Kirk, Allan D., Kitagawa, Yuichi, Klimstra, David S., Kluger, Michael D., Knechtle, Stuart J., Kneuertz, Peter J., Koea, Jonathan, Koffron, Alan J., Kokudo, Norihiro, Kooby, David A., Korenblat, Kevin, Krasny, Robert M., Krige, Jake, Kurtz, Robert C., Landman, Matthew P., La Quaglia, Michael P., LaRusso, Nicholas F., Lau, Kwan N., Lazaridis, Konstantinos N., Lerch, Markus M., Lillegard, Joseph B., Lillemoe, Keith D., Linehan, David C., Logan, Susan, Loveday, Benjamin, Lowell, Jeffrey A., Madoff, David C., Maithel, Shishir K., Majeed, Ali W., Makuuchi, Masatoshi, Malfertheiner, Peter, Mamlouk, Mark, Marchegiani, Giovanni, Marcos, Luis A., Markmann, James F., Marsh, J. Wallis, Martin, Maureen, Martin, Robert C.G., II, Maru, Dipen M., Mattera, Francisco Juan, Mayerle, Julia V., Mazza, Oscar M., McGilvray, Ian D., McKay, Colin J., Melendez, Jose A., Mezhir, James J., Miller, George, Mönkemüller, Klaus, Moo-Young, Tricia A., Nadig, Satish N., Nagino, Masato, Nagle, Alexander, Nagorney, David M., Nakeeb, Atilla, Nazario, Hector E., Nedredal, Geir, Neoptolemos, John P., Neuberger, James, Nguyen, Douglas L., Nimura, Yuji, Nyberg, Scott L., O’Grady, John G., O’laoide, Risteard, Olthoff, Kim Marie, Orloff, Mark S., Orloff, Marshall J., Orloff, Susan L., Pai, Rish K., Papalezova, Katia, Paradis, Val´rie, Parks, Rowan W., Passik, Steven D., Pastores, Stephen M., Pessaux, Patrick, Petrov, Maxim S., Pillarisetty, Venu G., Pingpank Jr, James, Pinson, C. Wright, Pitka, Sofija, Pitt, Henry A., Pomposelli, James J., Pratt, Wande B., Prinz, Richard A., Puli, Srinivas R., Que, Florencia G., Ravetta, Valentina, Reig, Maria E., Riaz, Ahsun, Rich, Barrie S., Rittenhouse, David W., Roberts, John, Robson, Piera, Rocha, Flavio G., Roddenbery V, Seaborn A., Rodriguez de Lopes, Carlos, Roll, Garrett R., Rosemurgy, Alex S., II, Rosen, Charles B., Rossi, Sandro, Saldinger, Pierre F., Salem, Riad, Saltz, Leonard B., Sanchez, Norberto J., Sandroussi, Charbel, Sano, Tsuyoshi, Scatton, O., Schattner, Mark, Schecter, William P., Schiffman, Suzanne C., Schmidt, C. Max, Schoellnast, Helmut, Schwartz, Lawrence H., Shepherd, Ross W., Shimoda, Masafumi, Shokouh-Amiri, Hosein, Siddiqi, Nasir H., Solomon, Stephen B., Soper, Nathaniel J., Starzl, Thomas E., Steer, Michael, Stewart, Lygia, Strobel, Oliver, Teitcher, Jerrold, Terashima, Ang´lica, Terraz, Sylvain, Thomas, William E.G., Torzilli, Guido, Trotter, James F., Turmelle, Yumirle P., Van Cott, Christine, Vannucci, Andrea, vanSonnenberg, Eric, Vauthey, Jean-Nicolas, Vetter, Diana, Vilgrain, Valerie, Villamil, Alejandra, Voigt, Louis, Vollmer Jr, Charles M., Wands, Jack R., Wattacheril, Julia, Weber, Sharon, Weiss, Matthew, Weitz, Jürgen, Werner, Jens, Wheatley, Antony M., Windsor, John A., Winston, Corinne, Winter, Jordan, Witkiewicz, Agnieszka K., Wong, John, Yeo, Charles J., Yeo, Theresa P., Yoon, Chang Jin, Yopp, Adam, Zibari, Gazi, and Zuckerman, Randall

Published
2012
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140. Prognosis and results after resection of very large (>or=10 cm) hepatocellular carcinoma.

Author

Shah, Shimul A., Wei, Alice C., Cleary, Sean P., Yang, Ilun, McGilvray, Ian D., Gallinger, Steven, Grant, David R., and Greig, Paul D.

Subjects
LIVER cancer, PROGNOSIS, SURGICAL excision, LIVER transplantation, CANCER relapse, STERNUM surgery, INFERIOR vena cava surgery, DIAPHRAGM (Anatomy), BLOOD-vessel tumors, CANCER invasiveness, COMPARATIVE studies, HEPATECTOMY, HEPATOCELLULAR carcinoma, LIVER tumors, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, REOPERATION, RESEARCH, SURGICAL complications, SURVIVAL, EVALUATION research, TREATMENT effectiveness, RETROSPECTIVE studies, SURGERY
Abstract

Introduction: Few potentially curative treatment options exist besides resection for patients with very large (>or=10 cm) hepatocellular carcinoma (HCC). We sought to examine the outcomes and risk factors for recurrence after resection of >or=10 cm HCC.Methods: Perioperative and long-term outcomes were examined for 189 consecutive patients from 1993 to 2004 who underwent potentially curative resection of HCC >or=10 cm (n = 24; 13%) vs. those with HCC <10 cm (n = 165; 87%). Disease-free survival (DFS) and overall survival (OS) were determined by Kaplan-Meier analysis and patient, tumor, and treatment characteristics were compared using univariate and multivariate analysis.Results: Median follow-up was 34 months. Tumors >or=10 cm were more likely to be symptomatic, of poorer grade, and have vascular invasion (p < 0.05). Twelve patients (50%) underwent an extended resection of more than four hepatic segments or resection of adjacent organs for oncologic clearance (diaphragm-2, inferior vena cava (IVC)-2, median sternotomy-1). Postoperative complications were more common after resection of >10 cm HCC (12/24, 50% vs. 35/165, 21%; p = 0.04). Median DFS was significantly shorter in patients with large HCC (>or=10 cm) group compared to patients with smaller HCC (8.4 vs. 38 months; p = 0.001), but overall survival was not different between the two groups (5-year survival 54% vs. 53%; p = 0.43). Seventeen patients (71%) with very large HCC developed recurrences (12 intrahepatic, five systemic); eight of these patients (47%) underwent additional therapy (resection-4, TACE-3, RFA-1). Pathological positive margins and vascular invasion were significant determinants of DFS in tumors >or=10 cm (p < 0.05), but only vascular invasion was an independent risk factor for recurrence after multivariate analysis (HR 0.17; 95% CI: 0.04-0.8). Median OS after recurrence was 24 months.Conclusion: Surgical resection is the optimal therapy for very large (>or=10 cm) HCC. Although recurrences are common after resection of these tumors, overall survival was not significantly different from patients after resection of smaller HCC in this series. [ABSTRACT FROM AUTHOR]

Published
2007
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141. Antioxidant modulation of skin inflammation: Preventing inflammatory progression by inhibiting neutrophil influx.

Author

McGilvray, Ian D. and Rotstein, Ori D.

Subjects
*ANTIOXIDANTS, *INFLAMMATION prevention, *NEUTROPHILS
Abstract

Investigates whether antioxidants can prevent inflammatory progression by impairing neutrophil influx. Changes in vascular tissue permeability; Increase of vascular cell adhesion molecule-1; Protective effect of antioxidants; Mechanisms affecting inflammatory response.

Published
1999

142. NACETYL CYSTEINE ATTENUATES ACUTE LUNG INJURY IN THE RAT

Author

Davreux, Christopher J., Soric, Ivana, Nathens, Avery B., Watson, Ronald W.G., McGilvray, Ian D., Suntres, Zacharias E., Shek, Pang N., and Rotstein, Ori D.

Abstract

The development of the adult respiratory distress syndrome ARDS in the critically ill patient is associated with a significant morbidity and mortality. The pulmonary dysfunction in ARDS is largely secondary to neutrophilmediated oxidant injury. The purpose of these studies is to examine the effect of the antioxidant Nacetyl cysteine NAC on a rodent model of lung injury. We postulated that NAC might attenuate lung injury following intratracheal challenge with endotoxin lipopolysaccharide LPS. Male SpragueDawley rats were administered NAC systemically either before or after intratracheal administration of LPS. Lung injury was assessed by measuring the transpulmonary leakage of 125llabeled albumin, pulmonary myeloperoxidase content, bronchoalveolar lavage fluid cell counts, pulmonary lipid peroxidation and histology. NAC administration significantly attenuated the LPSinduced increases in lung permeability LPS .24 ± .08 vs. LPS NAC .12 ± .03, p< .05 and reduced the LPSdependent increase in lipid peroxidation. However, total and differential bronchoalveolar lavage cell counts and myeloperoxidase content were not affected by NAC pretreatment. Although neutrophil influx was unaffected, neutrophil activation as assessed by surface CD11b expression and chemiluminescence was significantly downregulated by NAC. Importantly, NAC administration up to 2 h after endotoxin challenge was still able to significantly ameliorate LPSinduced lung injury. Our data suggests that the attenuation of acute lung injury by NAC in our rodent model is related to free radical scavenging and inhibition of the neutrophil oxidative burst, rather than by an effect on inflammatory cell migration. These results suggest novel approaches for therapeutic interventions in acute lung injury.

Published
1997

143. NACETYL CYSTEINE ATTENUATES ACUTE LUNG INJURY IN THE RAT

Author

Davreux, Christopher J., Soric, Ivana, Nathens, Avery B., Watson, Ronald W.G., McGilvray, Ian D., Suntres, Zacharias E., Shek, Pang N., and Rotstein, Ori D.

Abstract

The development of the adult respiratory distress syndrome ARDS in the critically ill patient is associated with a significant morbidity and mortality. The pulmonary dysfunction in ARDS is largely secondary to neutrophilmediated oxidant injury. The purpose of these studies is to examine the effect of the antioxidant Nacetyl cysteine NAC on a rodent model of lung injury. We postulated that NAC might attenuate lung injury following intratracheal challenge with endotoxin lipopolysaccharide LPS. Male SpragueDawley rats were administered NAC systemically either before or after intratracheal administration of LPS. Lung injury was assessed by measuring the transpulmonary leakage of 125llabeled albumin, pulmonary myeloperoxidase content, bronchoalveolar lavage fluid cell counts, pulmonary lipid peroxidation and histology. NAC administration significantly attenuated the LPSinduced increases in lung permeability LPS .24 ± .08 vs. LPS NAC .12 ± .03, p< .05 and reduced the LPSdependent increase in lipid peroxidation. However, total and differential bronchoalveolar lavage cell counts and myeloperoxidase content were not affected by NAC pretreatment. Although neutrophil influx was unaffected, neutrophil activation as assessed by surface CD11b expression and chemiluminescence was significantly downregulated by NAC. Importantly, NAC administration up to 2 h after endotoxin challenge was still able to significantly ameliorate LPSinduced lung injury. Our data suggests that the attenuation of acute lung injury by NAC in our rodent model is related to free radical scavenging and inhibition of the neutrophil oxidative burst, rather than by an effect on inflammatory cell migration. These results suggest novel approaches for therapeutic interventions in acute lung injury.

Published
1995

144. Murine Hepatitis Virus Strain 3 Induces the Macrophage Prothrombinase fgl-2through p38 Mitogen-activated Protein Kinase Activation*

Author

McGilvray, Ian D., Lu, Ziu, Wei, Alice C., Dackiw, Alan P.B., Marshall, John C., Kapus, Andras, Levy, Gary, and Rotstein, Ori D.

Abstract

The clinical syndrome of acute liver failure produced by fulminant viral hepatitis can be reproduced in mice by infection with murine hepatitis virus strain 3 (MHV-3). Although it is clear that MHV-3-induced hepatitis depends upon macrophage activation and the expression of a specific prothrombinase,fgl-2, the signaling pathways involved in virally stimulated cell activation are unclear. Since we had previously found that MHV-3 induces the tyrosine phosphorylation of cellular proteins, we investigated the roles of the mitogen-activated protein kinase (MAPK) proteins. In a series of Western blots, immunoprecipitation and in vitrokinase assay studies, we found that both the extracellular signal-related kinase (ERK) and p38 MAPK proteins are tyrosine-phosphorylated and activated following exposure of murine peritoneal exudative macrophages (PEM) to MHV-3. Although p38 phosphorylation and activity are induced soon after MHV-3 exposure, peaking by 1–5 min, ERK phosphorylation and activity increase more gradually, peaking at 20–30 min and gradually fading thereafter. Interestingly, whereas selective p38 inhibition with SB203580 (1–20 μm) abolished the virally stimulated induction of fgl-2mRNA, protein, and functional activity, selective ERK inhibition with PD98059 (1–50 μm) limitedfgl-2functional activity but had little to no effect onfgl-2mRNA or protein levels. Moreover, whereas inhibition of ERK had no effect on p38 activity, p38 inhibition consistently increased MHV-3-induced ERK activity. To ensure that these pathways were relevant in vivo, MHV-3 was injected intraperitoneally, and peritoneal exudative macrophages were collected. Again, MHV-3 exposure led to increased p38 and ERK tyrosine phosphorylation. These data argue that MHV-3 induces tightly interconnected ERK and p38 MAPK cascades in the macrophage bothin vitroand in vivo. Although the ERK and p38 MAPK proteins have discordant effects at the level of fgl-2expression, both converge at the level of its activity, suggesting that targeted MAPK inhibition may ultimately be useful in the modulation of viral hepatitis.

Published
1998
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145. Evolving Trends in the Management of Duodenal Leaks After Pancreas Transplantation: A Single-Centre Experience.

Author

Ray, Samrat, Hobeika, Christian, Norgate, Andrea, Sawicka, Zaneta, Schiff, Jeffrey, Sapisochin, Gonzalo, McGilvray, Ian D., Selzner, Markus, Reichman, Trevor W., and Shwaartz, Chaya

Subjects
*PANCREAS transplantation, *GRAFT survival, *INTERVENTIONAL radiology, *PANCREATECTOMY, *MULTIVARIATE analysis
Abstract

Duodenal leaks (DL) contribute to most graft losses following pancreas transplantation. However, there is a paucity of literature comparing graft preservation approach versus upfront graft pancreatectomy in these patients. We reviewed all pancreas transplants performed in our institution between 2000 and 2020 and identified the recipients developing DL to compare based on their management: percutaneous drainage vs. operative graft preservation vs. upfront pancreatectomy. Of the 595 patients undergoing pancreas transplantation, 74 (12.4%) developed a duodenal leak with a median follow up of 108 months. Forty-five (61%) were managed by graft preservation strategies, with the rest being treated with upfront graft pancreatectomy. DL managed by graft preservation strategies had similar graft survival rates at 1 and 5-year compared to the matched cohort of population without DL (95% and 59% vs. 91% and 62%; p = 0.78). Multivariate analysis identified male recipient (OR: OR: 6.18; CI95%: 1.26–41.09; p = 0.04) to have higher odds of undergoing an upfront graft pancreatectomy. In appropriately selected recipients with DL, graft preservation strategies utilizing either interventional radiology guided percutaneous drainage or laparotomy with/without repair of leak can achieve comparable long-term graft survival rates compared to recipients without DL. [ABSTRACT FROM AUTHOR]

Published
2024
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147. Generation of Functional Liver Sinusoidal Endothelial Cells from Human Pluripotent Stem-Cell-Derived Venous Angioblasts

Author

Gage, Blair K., Liu, Jeff C., Innes, Brendan T., MacParland, Sonya A., McGilvray, Ian D., Bader, Gary D., and Keller, Gordon M.

Abstract

Liver sinusoidal endothelial cells (LSECs) form a highly specialized microvasculature that plays a critical role in liver function and disease. To better understand this role, we developed a strategy to generate LSECs from human pluripotent stem cells (hPSCs) by first optimizing the specification of arterial and venous angioblasts and derivative endothelial populations. Induction of a LSEC-like fate by hypoxia, cyclic AMP (cAMP) agonism, and transforming growth factor β (TGF-β) inhibition revealed that venous endothelial cells responded more rapidly and robustly than the arterial cells to upregulate LSEC markers and functions in vitro. Upon intrahepatic transplantation in neonates, venous angioblasts engrafted the liver and generated mature, fenestrated LSECs with scavenger functions and molecular profiles of primary human LSECs. When transplanted into the liver of adult mice, angioblasts efficiently gave rise to mature LSECs with robust factor VIII (FVIII) production. Humanization of the murine liver with hPSC-derived LSECs provides a tractable system for studying the biology of this key liver cell type.

Published
2020
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149. Characteristics of liver transplant candidates delisted following recompensation and predictors of such delisting in alcohol-related liver disease: a case-control study

Author

Aravinthan, Aloysious D., Barbas, Andrew S., Doyle, Adam C., Tazari, Mahmood, Sapisochin, Gonzalo, Cattral, Mark S., Ghanekar, Anand, McGilvray, Ian D., Selzner, Markus, Greig, Paul D., Bhat, Mamatha, Selzner, Nazia, Grant, David R., Lilly, Leslie B., Renner, Eberhard L., Aravinthan, Aloysious D., Barbas, Andrew S., Doyle, Adam C., Tazari, Mahmood, Sapisochin, Gonzalo, Cattral, Mark S., Ghanekar, Anand, McGilvray, Ian D., Selzner, Markus, Greig, Paul D., Bhat, Mamatha, Selzner, Nazia, Grant, David R., Lilly, Leslie B., and Renner, Eberhard L.

Abstract

Whether and when recovery beyond the need for transplant may occur in patients listed for decompensation remains unclear. This study aimed to investigate the characteristics of patients delisted following recompensation. Seventy-seven patients who were listed between 2005 and 2015 for decompensation, but later delisted following recompensation were included. Alcohol-related liver disease (ALD) was the underlying etiology in the majority (n=47, 61%). Listing characteristics of these patients were compared with those of decompensated ALD patients who either underwent deceased donor liver transplantation or died on the waiting list. The model for end-stage liver disease (MELD) score <20 and serum albumin ≥32g/l at listing were the only independent predictors of recompensation/delisting in ALD. The probability of recompensation was 70% when both factors were present at listing. Interestingly, about a tenth of decompensated ALD patients who died on the waiting list (median duration on waiting list 11 months) and a quarter of decompensated ALD patients who underwent living donor liver transplantation (median duration on waiting list 2 months) also had both factors at listing. In conclusion, ALD seems to be the most favorable etiology for recompensation beyond the need for transplantation. Both MELD and serum albumin at listing independently predict recompensation/delisting in ALD. It seems advisable to implement a period of observation for ALD patients with both favorable factors, before embarking on living donor liver transplantation.

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150. Liver transplantation is a preferable alternative to palliative therapy for selected patients with advanced hepatocellular carcinoma

Author

Aravinthan, Aloysious D., Bruni, Silvio G., Doyle, Adam C., Thein, Hla-Hla, Goldaracena, Nicolas, Issachar, Assaf, Lilly, Leslie B., Selzner, Nazia, Bhat, Mamatha, Sreeharsha, Boraiah, Selzner, Markus, Ghanekar, Anand, Cattral, Mark S., McGilvray, Ian D., Greig, Paul D., Renner, Eberhard L., Grant, David R., Sapisochin, Gonzalo, Aravinthan, Aloysious D., Bruni, Silvio G., Doyle, Adam C., Thein, Hla-Hla, Goldaracena, Nicolas, Issachar, Assaf, Lilly, Leslie B., Selzner, Nazia, Bhat, Mamatha, Sreeharsha, Boraiah, Selzner, Markus, Ghanekar, Anand, Cattral, Mark S., McGilvray, Ian D., Greig, Paul D., Renner, Eberhard L., Grant, David R., and Sapisochin, Gonzalo

Abstract

Background: Patients with hepatocellular carcinoma (HCC) beyond the traditional criteria (advanced HCC) are typically offered palliation, which is associated with a 3-year survival rate lower than 30%. This study aimed to describe the outcomes for a subset of patients with advanced HCC who satisfied the Extended Toronto Criteria (ETC) and were listed for liver transplantation (LT). Materials & Methods: All patients listed in the Toronto liver transplant program with HCC beyond both the Milan and University of California, San Francisco criteria were included in this study. Data were extracted from the prospectively collected electronic database. All radiological images were reviewed by two independent radiologists. The primary endpoint was patient survival. Results: Between January 1999 and August 2014, 96 patients with advanced HCC were listed for LT, and 62 (65%) of these patients received bridging therapy while on the waiting list. Bridging therapy led to a significant reduction in tumor progression (p=0.02) and tumor burden (p <0.001). The majority of those listed underwent LT (n=69, 72%). Both tumor progression on waiting list (HR 4.973 [1.599 – 15.464], p=0.006) and peak AFP ≥400ng/ml (HR 4.604 [1.660 – 12.768], p=0.003) were independently associated with waiting list dropout. Post-LT HCC recurrence occurred in 35% (n=24). Among those with HCC recurrence, survival was significantly better for those who received curative treatment (p=0.004). The overall actuarial survival rates from the listing were 76% at 1 year, 56% at 3 years, and 47% at 5 years, and the corresponding rates from LT were 93%, 71%, and 66%. Conclusion: LT provides significantly better survival rates than palliation for patients with selected advanced HCC.

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