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2. Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report

Author

Mohiuddin, Muhammad M, Singh, Avneesh K, Scobie, Linda, Goerlich, Corbin E, Grazioli, Alison, Saharia, Kapil, Crossan, Claire, Burke, Allen, Drachenberg, Cinthia, Oguz, Cihan, Zhang, Tianshu, Lewis, Billeta, Hershfeld, Alena, Sentz, Faith, Tatarov, Ivan, Mudd, Sarah, Braileanu, Gheorghe, Rice, Kathryn, Paolini, John F, Bondensgaard, Kent, Vaught, Todd, Kuravi, Kasinath, Sorrells, Lori, Dandro, Amy, Ayares, David, Lau, Christine, and Griffith, Bartley P

Published
2023
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6. Long-Term IgG Response to Porcine Neu5Gc Antigens without Transmission of PERV in Burn Patients Treated with Porcine Skin Xenografts

Author

Scobie, Linda, Padler-Karavani, Vered, Le Bas-Bernardet, Stephanie, Crossan, Claire, Blaha, Josef, Matouskova, Magda, Hector, Ralph D, Cozzi, Emanuele, Vanhove, Bernard, Charreau, Beatrice, Blancho, Gilles, Bourdais, Ludovic, Tallacchini, Mariachiara, Ribes, Juan M, Yu, Hai, Chen, Xi, Kracikova, Jitka, Broz, Ludomir, Hejnar, Jiri, Vesely, Pavel, Takeuchi, Yasuhiro, Varki, Ajit, and Soulillou, Jean-Paul

Subjects
Biotechnology, Prevention, Clinical Research, Autoimmune Disease, Adolescent, Adult, Aged, Animals, Antigens, Heterophile, Burns, Child, Endogenous Retroviruses, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunoglobulin G, Infant, Male, Middle Aged, RNA, Viral, Reverse Transcriptase Polymerase Chain Reaction, Sialic Acids, Skin Transplantation, Swine, Transplantation, Heterologous, Immunology
Abstract

Acellular materials of xenogenic origin are used worldwide as xenografts, and phase I trials of viable pig pancreatic islets are currently being performed. However, limited information is available on transmission of porcine endogenous retrovirus (PERV) after xenotransplantation and on the long-term immune response of recipients to xenoantigens. We analyzed the blood of burn patients who had received living pig-skin dressings for up to 8 wk for the presence of PERV as well as for the level and nature of their long term (maximum, 34 y) immune response against pig Ags. Although no evidence of PERV genomic material or anti-PERV Ab response was found, we observed a moderate increase in anti-αGal Abs and a high and sustained anti-non-αGal IgG response in those patients. Abs against the nonhuman sialic acid Neu5Gc constituted the anti-non-αGal response with the recognition pattern on a sialoglycan array differing from that of burn patients treated without pig skin. These data suggest that anti-Neu5Gc Abs represent a barrier for long-term acceptance of porcine xenografts. Because anti-Neu5Gc Abs can promote chronic inflammation, the long-term safety of living and acellular pig tissue implants in recipients warrants further evaluation.

Published
2013

10. Large‐gap peripheral nerve repair using xenogeneic transplants in rhesus macaques

Author

Holzer, Paul, primary, Chang, Elizabeth J., additional, Rogers, Kaitlyn, additional, Tarlton, Jamie, additional, Lu, Diana, additional, Gillespie, Natasha, additional, Adkins, Jon, additional, Metea, Monica, additional, LaRochelle, Alan, additional, Wicks, Joan, additional, Onel, Buket, additional, Gullans, Steve, additional, Doloff, Joshua C., additional, Scobie, Linda, additional, Cetrulo, Curtis L., additional, and Monroy, Rod, additional

Published
2023
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11. The role of p53 in cell transformation by BPV-4

Author

Scobie, Linda

Subjects
572.8, Cancer, Papillomaviruses, Tumour suppressor
Abstract

Bovine papillomavirus-type 4 is associated with benign papillomas which can progress to carcinoma in cattle grazing on bracken fern. Bracken is known to contain immunosuppressants and cocarcinogens which can act as cofactors and these are known to be required for progression in vivo. One of the best characterised of these cofactors is the mutagen quercetin. BPV-4 has been shown to be capable of partially transforming primary bovine fibroblasts (PalF) cells in vitro in the presence of an activated ras and when these cells are additionally treated with quercetin they become tumourigenic in nude mice. The transforming functions of BPV-4 are encoded by the E7 and the E8 ORF's. BPV-4 is unusual in that it does not possess an E6 ORF. E6 has been shown to be one of the major transforming oncoproteins of the human papillomaviruses and is known to bind and degrade the tumour suppressor protein p53. This abrogation of the p53 protein is known to contribute to tumour progression by the high risk papillomaviruses such as HPV-16 and 18. As BPV-4 does not encode E6 functions, this would suggest that if p53 dysfunction is important in BPV-4 cell transformation, it may occur by alteration of the cellular gene. In order to look at possible p53 mutations in alimentary cancer of cattle, a 14kb genomic clone containing wild type p53 sequence was isolated from a bovine liver genomic DNA library and sequenced. This clone was used to localise bovine p53 to chromosome 19q15 which is known to be syntenic with human chromosome 17 and mouse chromosome 11 both of which harbour the p53 gene. Immunocytochemical analysis of BPV-4 derived lesions demonstrated that elevated levels of p53 protein were detectable in papillomas but not in carcinomas. BPV-4 E7 was found to be present at all stages of papillomatosis as was BPV-4 viral DNA as detected by in-situ hybridisation. Neither viral DNA nor BPV-4 E7 were detected in normal palatine tissue or in carcinomas which is coincident with the loss of viral DNA previously reported for tumours in vivo. The elevated levels of p53 in some of the papillomas were shown to be a result of the presence of mutations in p53 exon 7 as determined by SSCP-PCR and sequencing. Mutant p53 was also detected in two metastases of upper alimentary canal tumours. The addition of mutant p53 to PalF cells in vitro in the presence of BPV-4, ras and HPV-16E6 caused these cells to become tumourigenic in nude mice. In these tumorigenic PalF cell lines, mRNA expression of the BPV-4 viral oncoprotein E8 was shown to be elevated. Cotransfected mutant p53 mRNA expression was also detectable. This would suggest that p53 mutation plays a role in tumourigenic progression by BPV-4 both in vivo and in vitro. In this study we demonstrate that the lack of an E6 in BPV-4 may be compensated by the presence of a mutated p53 gene in BPV-4 induced carcinomas. These p53 mutations may arise due to cofactors present in bracken fern, and p53 mutations were detected in BPV-4 and ras transfected PalF cells that had been treated with quercetin. However, p53 mutations were detected in transfected PalF cells which had not been exposed to quercetin treatment. We also demonstrate that the additional functions provided by HPV-16 E6 (16E6) in vitro are at least in part, independent of the p53 binding and degradation function. The data suggests that an exogenous 16E6 can supplement in vitro other functions of BPV-4 which are responsible for progression in vivo. HPV-16 E6 was also demonstrated to possess a function confering anchorage independence, which mapped to the cysteines present in the zinc finger motifs of the protein. This study has demonstrated BPV-4 lacks more than one function that can be provided by an exogeneous E6 oncoprotein and that these functions may be independent of p53. In addition, p53 mutations were shown to be present in BPV-4 induced papillomas and carcinomas.

Published
1996

15. Large-gap Peripheral Nerve Repair Using Xenogeneic Transplants in Rhesus Macaques

Author

Holzer, Paul, primary, Chang, Elizabeth J., additional, Tarlton, Jamie, additional, Lu, Diana, additional, Gillespie, Natasha, additional, Rogers, Kaitlyn, additional, Adkins, Jon, additional, Metea, Monica, additional, LaRochelle, Alan, additional, Wicks, Joan, additional, Onel, Buket, additional, Gullans, Steve, additional, Doloff, Joshua C., additional, Scobie, Linda, additional, Cetrulo, Curtis L., additional, and Monroy, Rod, additional

Published
2022
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17. Large-gap Peripheral Nerve Repair Using Xenogeneic Transplants in Primates

Author

Holzer, Paul, primary, Chang, Elizabeth, additional, Tarlton, Jamie, additional, Lu, Diana, additional, Gillespie, Natasha, additional, Rogers, Kaitlyn, additional, Adkins, Jon, additional, Metea, Monica, additional, LaRochelle, Alan, additional, Wicks, Joan, additional, Onel, Buket, additional, Gullans, Steve, additional, Doloff, Joshua, additional, Scobie, Linda, additional, Cetrulo, Curt, additional, and Monroy, Rod, additional

Published
2021
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22. The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of xenocorneal transplantation

Author

Kim, Mee Kum, Choi, Hyuk Jin, Kwon, Ivo, Pierson, Richard N., III, Cooper, David K. C., Soulillou, Jean-Paul, OʼConnell, Philip J., Vabres, Bertrand, Maeda, Naoyuki, Hara, Hidetaka, Scobie, Linda, Gianello, Pierre, Takeuchi, Yasuhiro, Yamada, Kazuhiko, Hwang, Eung-Soo, Kim, Sang Joon, and Park, Chung-Gyu

Published
2014
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23. Analyses of pig genomes provide insight into porcine demography and evolution

Author

Groenen, Martien A. M., Archibald, Alan L., Uenishi, Hirohide, Tuggle, Christopher K., Takeuchi, Yasuhiro, Rothschild, Max F., Rogel-Gaillard, Claire, Park, Chankyu, Milan, Denis, Megens, Hendrik-Jan, Li, Shengting, Larkin, Denis M., Kim, Heebal, Frantz, Laurent A. F., Caccamo, Mario, Ahn, Hyeonju, Aken, Bronwen L., Anselmo, Anna, Anthon, Christian, Auvil, Loretta, Badaoui, Bouabid, Beattie, Craig W., Bendixen, Christian, Berman, Daniel, Blecha, Frank, Blomberg, Jonas, Bolund, Lars, Bosse, Mirte, Botti, Sara, Bujie, Zhan, Bystrom, Megan, Capitanu, Boris, Carvalho-Silva, Denise, Chardon, Patrick, Chen, Celine, Cheng, Ryan, Choi, Sang-Haeng, Chow, William, Clark, Richard C., Clee, Christopher, Crooijmans, Richard P. M. A., Dawson, Harry D., Dehais, Patrice, De Sapio, Fioravante, Dibbits, Bert, Drou, Nizar, Du, Zhi-Qiang, Eversole, Kellye, Fadista, João, Fairley, Susan, Faraut, Thomas, Faulkner, Geoffrey J., Fowler, Katie E., Fredholm, Merete, Fritz, Eric, Gilbert, James G. R., Giuffra, Elisabetta, Gorodkin, Jan, Griffin, Darren K., Harrow, Jennifer L., Hayward, Alexander, Howe, Kerstin, Hu, Zhi-Liang, Humphray, Sean J., Hunt, Toby, Hornshøj, Henrik, Jeon, Jin-Tae, Jern, Patric, Jones, Matthew, Jurka, Jerzy, Kanamori, Hiroyuki, Kapetanovic, Ronan, Kim, Jaebum, Kim, Jae-Hwan, Kim, Kyu-Won, Kim, Tae-Hun, Larson, Greger, Lee, Kyooyeol, Lee, Kyung-Tai, Leggett, Richard, Lewin, Harris A., Li, Yingrui, Liu, Wansheng, Loveland, Jane E., Lu, Yao, Lunney, Joan K., Ma, Jian, Madsen, Ole, Mann, Katherine, Matthews, Lucy, McLaren, Stuart, Morozumi, Takeya, Murtaugh, Michael P., Narayan, Jitendra, Truong Nguyen, Dinh, Ni, Peixiang, Oh, Song-Jung, Onteru, Suneel, Panitz, Frank, Park, Eung-Woo, Park, Hong-Seog, Pascal, Geraldine, Paudel, Yogesh, Perez-Enciso, Miguel, Ramirez-Gonzalez, Ricardo, Reecy, James M., Rodriguez-Zas, Sandra, Rohrer, Gary A., Rund, Lauretta, Sang, Yongming, Schachtschneider, Kyle, Schraiber, Joshua G., Schwartz, John, Scobie, Linda, Scott, Carol, Searle, Stephen, Servin, Bertrand, Southey, Bruce R., Sperber, Goran, Stadler, Peter, Sweedler, Jonathan V., Tafer, Hakim, Thomsen, Bo, Wali, Rashmi, Wang, Jian, Wang, Jun, White, Simon, Xu, Xun, Yerle, Martine, Zhang, Guojie, Zhang, Jianguo, Zhang, Jie, Zhao, Shuhong, Rogers, Jane, Churcher, Carol, and Schook, Lawrence B.

Published
2012
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38. Organ transplants of the future: planning for innovations including xenotransplantation.

Author

Cozzi, Emanuele, Schneeberger, Stefan, Bellini, Maria Irene, Berglund, Erik, Böhmig, Georg, Fowler, Kevin, Hoogduijn, Martin, Jochmans, Ina, Marckmann, Georg, Marson, Lorna, Neuberger, James, Oberbauer, Rainer, Pierson, Richard N., Reichart, Bruno, Scobie, Linda, White, Colin, and Naesens, Maarten

Subjects
TRANSPLANTATION of organs, tissues, etc., XENOTRANSPLANTATION, CLINICAL medicine, XENOGRAFTS, GENETIC models
Abstract

Summary: The future clinical application of animal‐to‐human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to cell, tissue and solid organ xenotransplants have been obtained from many animal models utilizing genetic engineering and protocols of pathogen‐free husbandry. Findings have reached a tipping point, and xenotransplantation of solid organs is approaching clinical evaluation, the process of which now requires close deliberation. Such discussions include considering when there is sufficient evidence from preclinical animal studies to start first‐in‐human xenotransplantation trials. The present article is based on evidence and opinions formulated by members of the European Society for Organ Transplantation who are involved in the Transplantation Learning Journey project. The article includes a brief overview of preclinical concepts and biology of solid organ xenotransplantation, discusses the selection of candidates for first‐in‐human studies and considers requirements for study design and conduct. In addition, the paper emphasizes the need for a regulatory framework for xenotransplantation of solid organs and the essential requirement for input from public and patient stakeholders. [ABSTRACT FROM AUTHOR]

Published
2021
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39. 'The 2018 Changsha Communiqué' The 10-Year Anniversary of The International Consultation on Xenotransplantation

Author

Hawthorne, Wayne J., Cowan, Peter J., Bühler, Léo H., Yi, Shounan, Bottino, Rita, Pierson, Richard N. III, Ahn, Curie, Azimzadeh, Agnes, Cozzi, Emanuele, Gianello, Pierre, Lakey, Jonathan R.T., Luo, Minhua, Miyagawa, Shuji, Mohiuddin, Muhammad M., Park, Chung-Gyu, Schuurman, Henk-Jan, Scobie, Linda, Sykes, Megan, Tector, Joseph, Tönjes, Ralf Reinhard, Wolf, Eckard, Nunez, José R., Wang, Wei, Third WHO Global Consultation on Regulatory Requirements for Xenotransplantation Clinical Trials, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, and UCL - (SLuc) Service de chirurgie et transplantation abdominale

Published
2019

42. GENE THERAPY: X-SCID transgene leukaemogenicity

Author

Thrasher, Adrian J., Gaspar, H. Bobby, Baum, Christopher, Modlich, Ute, Schambach, Axel, Candotti, Fabio, Otsu, Makoto, Sorrentino, Brian, Scobie, Linda, Cameron, Ewan, Blyth, Karen, Neil, Jim, Abina, Salima Hacein-Bey, Cavazzana-Calvo, Marina, and Fischer, Alain

Published
2006

43. Hepatitis E virus genotype 3 in shellfish, United Kingdom

Author

Crossan, Claire, Baker, Paul J., Craft, John, Takeuchi, Yasu, Dalton, Harry R., and Scobie, Linda

Subjects
Hepatitis E -- Health aspects, Pork industry -- Health aspects, Food contamination -- Health aspects, Health
Abstract

To the Editor: Bivalve mollusks (shellfish), such as mussels and oysters, are filter feeders; they concentrate microorganisms of human and animal origin (up to 100x) from the surrounding environment. Several [...]

Published
2012

46. ThirdWHOGlobal Consultation on Regulatory Requirements for Xenotransplantation Clinical Trials, Changsha, Hunan, China December 12–14, 2018

Author

Hawthorne, Wayne J., primary, Cowan, Peter J., additional, Bühler, Léo H., additional, Yi, Shounan, additional, Bottino, Rita, additional, Pierson, Richard N., additional, Ahn, Curie, additional, Azimzadeh, Agnes, additional, Cozzi, Emanuele, additional, Gianello, Pierre, additional, Lakey, Jonathan R. T., additional, Luo, Minhua, additional, Miyagawa, Shuji, additional, Mohiuddin, Muhammad M., additional, Park, Chung‐Gyu, additional, Schuurman, Henk‐Jan, additional, Scobie, Linda, additional, Sykes, Megan, additional, Tector, Joseph, additional, Tönjes, Ralf Reinhard, additional, Wolf, Eckhard, additional, Nuñez, José R., additional, and Wang, Wei, additional

Published
2019
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47. Cover Image, Volume 26, Issue 2

Author

Hawthorne, Wayne J., primary, Cowan, Peter J., additional, Bühler, Léo H., additional, Yi, Shounan, additional, Bottino, Rita, additional, Pierson, Richard N., additional, Ahn, Curie, additional, Azimzadeh, Agnes, additional, Cozzi, Emanuele, additional, Gianello, Pierre, additional, Lakey, Jonathan R. T., additional, Luo, Minhua, additional, Miyagawa, Shuji, additional, Mohiuddin, Muhammad M., additional, Park, Chung‐Gyu, additional, Schuurman, Henk‐Jan, additional, Scobie, Linda, additional, Sykes, Megan, additional, Tector, Joseph, additional, Tönjes, Ralf Reinhard, additional, Wolf, Eckhard, additional, Nuñez, José R., additional, and Wang, Wei, additional

Published
2019
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