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66. Transcriptional ontogeny of the developing liver

Author

Lee Janice S, Ward William O, Knapp Geremy, Ren Hongzu, Vallanat Beena, Abbott Barbara, Ho Karen, Karp Seth J, and Corton J

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background During embryogenesis the liver is derived from endodermal cells lining the digestive tract. These endodermal progenitor cells contribute to forming the parenchyma of a number of organs including the liver and pancreas. Early in organogenesis the fetal liver is populated by hematopoietic stem cells, the source for a number of blood cells including nucleated erythrocytes. A comprehensive analysis of the transcriptional changes that occur during the early stages of development to adulthood in the liver was carried out. Results We characterized gene expression changes in the developing mouse liver at gestational days (GD) 11.5, 12.5, 13.5, 14.5, 16.5, and 19 and in the neonate (postnatal day (PND) 7 and 32) compared to that in the adult liver (PND67) using full-genome microarrays. The fetal liver, and to a lesser extent the neonatal liver, exhibited dramatic differences in gene expression compared to adults. Canonical pathway analysis of the fetal liver signature demonstrated increases in functions important in cell replication and DNA fidelity whereas most metabolic pathways of intermediary metabolism were under expressed. Comparison of the dataset to a number of previously published microarray datasets revealed 1) a striking similarity between the fetal liver and that of the pancreas in both mice and humans, 2) a nucleated erythrocyte signature in the fetus and 3) under expression of most xenobiotic metabolism genes throughout development, with the exception of a number of transporters associated with either hematopoietic cells or cell proliferation in hepatocytes. Conclusions Overall, these findings reveal the complexity of gene expression changes during liver development and maturation, and provide a foundation to predict responses to chemical and drug exposure as a function of early life-stages.

Published
2012
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70. Reply

Author

Lynch, Raymond J., primary, Ye, Fei, additional, Sheng, Quanhu, additional, Zhao, Zhiguo, additional, and Karp, Seth J., additional

Published
2019
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71. FRI-388-Hepatitis C ilnfected liver grafts transplanted into non-infected recipients are safe in the era of highly effective direct-acting antiviral therapy

Author

O’dell, Heather, primary, Rafferty, Alison, additional, Schneider, Natasha, additional, Scanga, Andrew, additional, Wright, J. Kelly, additional, Geevarghese, Sunil, additional, Matsuoka, Lea, additional, Alexopoulos, Sophoclis, additional, Karp, Seth, additional, Perri, Roman, additional, Awad, Joseph, additional, and Gorden, Lee, additional

Published
2019
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75. Colaboradores

Author

Aberle, Corinne M., Abu-Freha, Naim, Adams, Andrew B., Adams, Reid B., Agrawal, Nikhil, Ahuja, Vanita, Alexopoulos, Sophoclis, Aliano, Kristen A., Alvarez, Ronald D., Aribindi, Vamsi, Arrington, Amanda K., Atassi, Omar, Badell, I. Raul, Bakaeen, Faisel G., Barreto, Juan Camilo, Beauchamp, R. Daniel, Becker, Yolanda, Blears, Elizabeth E., Bobanga, Iuliana, Bonds, Morgan, Borrelli, Mimi R., Boukovalas, Stefanos, Brooke, Benjamin S., Brown, Carlos V.R., Carbonell, Alfredo Maximiliano, Carmichael, Samuel P., II, Carson, Joshua S., Champion, Howard C., Chiang, Kevin J., Chung, Dai H., Coburn, Michael, Cole, Eric L., Contreras, Carlo M., Cooney, Robert N., Dawson, Jack, DeAnda, Abe, Jr., Dennis, Bradley M., Dhupar, Rajeev, Diaz, Jose J., Dissanaike, Sharmila, Dmochowski, Roger R., Dudeja, Vikas, Duh, Quan-Yang, Economou, James S., Egger, Michael E., Ellis, C. Tyler, Evers, B. Mark, Farmer, Diana L., Farroni, Jeffrey S., Ferrantella, Anthony, Fields, Ryan, Finlayson, Samuel R.G., Finnerty, Celeste C., II, Nicholas A. Fiore, Fishbein, Thomas, Fong, Yuman, Fraser, Chuck D., Jr., Fried, Gerald M., Galandiuk, Susan, Gan, Tong, Goedegebuure, S. Peter, Gunter, Oliver L., Gurney, Jennifer M., Halpern, Jennifer L., Hawksworth, Jason, Hawn, Mary, Hernandez, Antonio, Herndon, David N., Heslin, Marty J., Hirose, Shinjiro, Ho, Trung, Hodin, Richard, Hofstetter, Wayne L., Holt, Ginger E., Hu, Michael S., Hu, Yinnin, Hunt, Kelly K., Hyman, Neil, Izhar, Uzi, Jensen, Eric H., Jurkovich, Gregory J., Kalaria, Shana S., Karp, Seth J., Kesseli, Samuel J., Khaitan, Leena, Khoo, Kimberly H., Kim, Jae Y., Klimberg, V. Suzanne, Knight, Patrick H., Kramme, Katherine E., Krasnick, Bradley A., Laird, Amanda M., Landmann, Alessandra, Larsen, Christian P., Liao, Lillian, Libutti, Steven K., Livhits, Masha, Longaker, Michael T., Lorenz, H. Peter, Madani, Amin, Mahvi, David A., Mahvi, David M., Marston, William, Martin, Matthew J., Martin, R. Shayn, McHenry, Christopher R., McMasters, Kelly M., Mehra, Saral, Mell, Matthew, Meredith, J. Wayne, Miller, Richard S., Mills, Joseph L., Sr, Morpurgo, Emilio, Mowery, Nathan T., Mueller, Carmen L., Nassar, Aussama K., Nelson, Elaine E., Netscher, David, Netz, Uri, Norbury, William B., Norris, Robert L., Oelschlager, Brant K., Omer, Shuab, OnKendi, Edwin, Padilla, Pablo L., Pallister, Zachary S., Park, Julie E., Pascarella, Luigi, Patel, Samip, Patterson, Joel T., Phillips, Linda G., Pipinos, Iraklis I., Postier, Russell, Poulose, Benjamin K., Prescott, Lauren S., Privratsky, Anna M., Pruekprasert, Napat, Radkani, Pejman, Rajaram, Ravi, Riall, Taylor S., Richards, William O., Richmond, Bryan, Rose, J. Bart, Rosen, Michael J., Rosengart, Todd K., Rosenthal, Ronnie A., Ross, Evan, Russo, Rachel M., Rutkow, Ira, Ryan, Christopher, Saadai, Payam, Saillant, Noelle N., Sandberg, Warren, Santos, Ariel P., Sawyer, Robert G., Saydi, John P., Schreiber, Martin Allan, Schwartz, Herbert S., Sepesi, Boris, Sherwood, Edward R., Sheth, Mihir, Sise, Michael J., Smith, Michael C., Smith, Sawyer Gordon, Smith, Thomas G., III, Sommerhalder, Christian, Sosa, Julie Ann, Spicer, Jonathan D., Stewart, Ronald M., Sudan, Debra L., Sugarbaker, David J., Suh, Insoo, Sun, Daniel, Taylor, Jennifer M., Thompson, Jonathan R., Todd, S. Rob, Tomlinson, James S., Torquati, Alfonso, Tosato, Sara Maria, Turnage, Richard H., Tyler, Douglas S., Umanskiy, Konstantin, Vickers, Selwyn M., Wald, Ori, Well, Andrew, Winslade, William J., Wolf, Steven E., Woo, Yanghee, Worsham, Jennifer, Yang, James C., Yarbrough, Wendell G., Yates, Robert B., Yeh, Michael W., Yepuri, Natesh, Yunker, Amanda C., Zanation, Adam, Sirvent, Ramón Zapata, and Zaydfudim, Victor M.

Published
2022
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86. Interpreting Outcomes in DCDD Liver Transplantation

Author

Goldberg, David S., primary, Karp, Seth J., additional, McCauley, Maureen E., additional, Markmann, James F., additional, Croome, Kristopher P., additional, Taner, C. Burcin, additional, Heimbach, Julie K., additional, Leise, Michael D., additional, Fryer, Jonathan P., additional, Bohorquez, Humberto E., additional, Cohen, Ari J., additional, Gilroy, Richard K., additional, Kumer, Sean C., additional, Foley, David P., additional, Karim, Aos S., additional, Hernandez-Alejandro, Roberto, additional, Levstik, Mark A., additional, and Abt, Peter L., additional

Published
2017
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90. Quality Improvement in Transfusion Practice of Orthotopic Liver Transplantation Reduces Blood Utilization, Length of Hospital Stay, and Cost.

Author

Nedelcu, Elena, Wright, Martha Frances, Eichbaum, Quentin, Karp, Seth, Cook, Makenzie, and Barbu, Otilia

Subjects
LIVER, ABDOMEN, ENTEROHEPATIC circulation, BLOOD transfusion, LENGTH of stay in hospitals, LIVER transplantation, QUALITY assurance, RESEARCH funding, COST analysis, RETROSPECTIVE studies, ECONOMICS
Abstract

Objectives: Orthotopic liver transplantation (OLT) can require substantial usage of blood products. Higher rates of transfusion have been associated with increased length of hospital stay, higher rates of infection, graft failure, and mortality. This study was a retrospective analysis to assess the impact of quality improvement interventions in OLT.Methods: Data collection included demographics, preoperative and intraoperative data, blood utilization, and cost data. Statistical analysis was performed using R software.Results: Total blood product utilization was reduced by approximately 50%. Statistically significant decreases were noted in blood product usage in the intraoperative and first 48-hour postoperative utilization, the number of OLTs using fewer than five RBC units, length of hospital stay, and cost.Conclusions: This study showed successful implementation of quality improvement team interventions to reduce blood utilization during OLT. Reduced transfusion significantly correlated with decreased length of hospital stay and cost. [ABSTRACT FROM AUTHOR]

Published
2019
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92. Cytometry‐based single‐cell analysis of intact epithelial signaling reveals MAPK activation divergent from TNF ‐α‐induced apoptosis in vivo

Author

Simmons, Alan J, primary, Banerjee, Amrita, additional, McKinley, Eliot T, additional, Scurrah, Cherie’ R, additional, Herring, Charles A, additional, Gewin, Leslie S, additional, Masuzaki, Ryota, additional, Karp, Seth J, additional, Franklin, Jeffrey L, additional, Gerdes, Michael J, additional, Irish, Jonathan M, additional, Coffey, Robert J, additional, and Lau, Ken S, additional

Published
2016
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94. Public attitudes toward contemporary issues in liver allocation

Author

O'Dell, Heather W., McMichael, Benjamin J., Lee, Suzie, Karp, Jay L., VanHorn, R. Lawrence, and Karp, Seth J.

Abstract

Allocation of scarce livers for transplantation seeks to balance competing ethical principles of autonomy, utility, and justice. Given the history and ongoing dependence of transplantation on public support for funding and organs, understanding and incorporating public attitudes into allocation decisions seems appropriate. In the context of the current controversy around liver allocation, we sought to determine public preferences about issues relevant to the debate. We performed multiple surveys of attitudes around donation and evaluated these using conjoint analysis and clarifying follow‐up questions. We found little public support that allocation decisions should be based solely on risk of waiting‐list mortality. Strong public sentiment supported maximizing outcomes after transplantation, prioritizing UScitizens or residents, keeping organs local, and considering cost in allocation decisions. We then present a methodology for incorporating these preferences into the Model for End‐Stage Liver Disease (or MELD) priority score. Taken together, these findings suggest that current allocation schemes do not accurately reflect public preferences and suggest a framework to better align allocation with the values of the public. Surveys of attitudes around liver donation evaluated using conjoint analysis and clarifying follow‐up questions identify differences between allocation rules and public preferences with respect to incorporating outcomes after transplant, prioritizing US citizens or residents, keeping organs local, and including cost in allocation decisions.

Published
2019
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95. Novel Dynamic Organ Storage System Enhances Liver Graft Function in a Porcine Donation After Circulatory Death Model

Author

Shishido, Yutaka, Tracy, Kaitlyn M., Petrovic, Mark, Adesanya, TiOluwanimi, Fortier, Avery K., Raietparvar, Kimya, Glomp, Gabriella A., Simonds, Elizabeth, Harris, Timothy R., Simon, Victoria, Tucker, William D., Petree, Brandon, Cortelli, Michael, Cardwell, Nancy L., Crannell, Christian, Liang, Jiancong, Murphy, Alexandria C., Fields, Blanche L., McReynolds, Melanie, Demarest, Caitlin T., Ukita, Rei, Rizzari, Michael, Montenovo, Martin, Magliocca, Joseph F., Karp, Seth J., Rauf, M. Ameen, Shah, Ashish S., and Bacchetta, Matthew

Abstract

Donation after circulatory death (DCD) livers face increased risks of critical complications when preserved with static cold storage (SCS). Although machine perfusion (MP) may mitigate these risks, its cost and logistical complexity limit widespread application. We developed the Dynamic Organ Storage System (DOSS), which delivers oxygenated perfusate at 10°C with minimal electrical power requirement and allows real-time effluent sampling in a portable cooler. In a porcine DCD model, livers were preserved using DOSS or SCS for 10 hours and evaluated with 4 hours of normothermic MP, with n = 5 per group. After 4 hours of normothermic MP, the DOSS group demonstrated significantly lower perfusate lactate (p= 0.023), increased perfusate fibrinogen (p= 0.005), higher oxygen consumption (p= 0.018), greater bile production (p= 0.013), higher bile bicarbonate levels (p= 0.035) and bile/perfusate sodium ratio (p= 0.002), and lower hepatic arterial resistance after phenylephrine administration (p= 0.018). Histological analysis showed lower apoptotic markers in DOSS-preserved livers, with fewer cleaved caspase-3 (p= 0.039) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL; p= 0.009) positive cells. These findings suggest that DOSS can enhance DCD allograft function during transport, offering potential clinical benefits and contributing to the expansion of the donor pool.

Published
2024
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98. Dicer-dependent production of microRNA221 in hepatocytes inhibits p27 and is required for liver regeneration in mice.

Author

Yuki Oya, Ryota Masuzaki, Daisuke Tsugawa, Ray, Kevin C., Yongchao Dou, and Karp, Seth J.

Abstract

Dicer processes microRNAs (miRs) into active forms in a wide variety of tissues, including the liver. To determine the role of Dicer in liver regeneration, we performed a series of in vivo and in vitro studies in a murine 2/3 hepatectomy model. Dicer was downregulated after 2/3 hepatectomy, and loss of Dicer inhibited liver regeneration associated with decreased cyclin A2 and miR-221, as well as increased levels of the cell cycle inhibitor p27. In vitro, miR-221 inhibited p27 production in primary hepatocytes and increased hepatocyte proliferation. Specific reconstitution of miR-221 in hepatocyte-specific Dicer-null mice inhibited p27 and restored liver regeneration. In wild type mice, targeted inhibition of miR-221 using a cholesterol-conjugated miR-221 inhibited hepatocyte proliferation after 2/3 hepatectomy. These results identify Dicer production of miR-221 as an essential component of a miRNA-dependent mechanism for suppression of p27 that controls the rate of hepatocyte proliferation after partial hepatectomy. NEW & NOTEWORTHY Our findings demonstrate a direct role for microRNAs in controlling the rate of liver regeneration after injury. By deleting Dicer, an enzyme responsible for processing microRNAs into mature forms, we determined miR-221 is a critical microRNA in the physiological process of restoration of liver mass after injury. miR-221 suppresses p27, releasing its inhibitory effects on hepatocyte proliferation. Pharmaceuticals based on miR-221 may be useful to modulate hepatocyte proliferation in the setting of liver injury. [ABSTRACT FROM AUTHOR]

Published
2017
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99. Specific Activin Receptor–Like Kinase 3 Inhibitors Enhance Liver Regeneration

Author

Tsugawa, Daisuke, primary, Oya, Yuki, additional, Masuzaki, Ryota, additional, Ray, Kevin, additional, Engers, Darren W., additional, Dib, Martin, additional, Do, Nhue, additional, Kuramitsu, Kaori, additional, Ho, Karen, additional, Frist, Audrey, additional, Yu, Paul B., additional, Bloch, Kenneth D., additional, Lindsley, Craig W., additional, Hopkins, Corey R., additional, Hong, Charles C., additional, and Karp, Seth J., additional

Published
2014
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100. Combined In Silicoand In VitroApproach Predicts Low Wall Shear Stress Regions in a Hemofilter that Correlate with Thrombus Formation In Vivo

Author

Buck, Amanda K. W., Groszek, Joseph J., Colvin, Daniel C., Keller, Sara B., Kensinger, Clark, Forbes, Rachel, Karp, Seth, Williams, Phillip, Roy, Shuvo, and Fissell, William H.

Abstract

A major challenge in developing blood-contacting medical devices is mitigating thrombogenicity of an intravascular device. Thrombi may interfere with device function or embolize from the device to occlude distant vascular beds with catastrophic consequences. Chemical interactions between plasma proteins and bioengineered surface occur at the nanometer scale; however, continuum models of blood predict local shear stresses that lead to platelet activation or aggregation and thrombosis. Here, an iterative approach to blood flow path design incorporating in silico, in vitro, and in vivoexperiments predicted the occurrence and location of thrombi in an implantable hemofilter. Low wall shear stress (WSS) regions identified by computational fluid dynamics (CFD) predicted clot formation in vivo. Revised designs based on CFD demonstrated superior performance, illustrating the importance of a multipronged approach for a successful design process.

Published
2018
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