| 1. |
- Längin, Matthias, et al.
(författare)
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Consistent success in life-supporting porcine cardiac xenotransplantation
- 2018
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 564:7736, s. 430-433
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Tidskriftsartikel (refereegranskat)abstract
- Heart transplantation is the only cure for patients with terminal cardiac failure, but the supply of allogeneic donor organs falls far short of the clinical need1–3. Xenotransplantation of genetically modified pig hearts has been discussed as a potential alternative4. Genetically multi-modified pig hearts that lack galactose-α1,3-galactose epitopes (α1,3-galactosyltransferase knockout) and express a human membrane cofactor protein (CD46) and human thrombomodulin have survived for up to 945 days after heterotopic abdominal transplantation in baboons5. This model demonstrated long-term acceptance of discordant xenografts with safe immunosuppression but did not predict their life-supporting function. Despite 25 years of extensive research, the maximum survival of a baboon after heart replacement with a porcine xenograft was only 57 days and this was achieved, to our knowledge, only once6. Here we show that α1,3-galactosyltransferase-knockout pig hearts that express human CD46 and thrombomodulin require non-ischaemic preservation with continuous perfusion and control of post-transplantation growth to ensure long-term orthotopic function of the xenograft in baboons, the most stringent preclinical xenotransplantation model. Consistent life-supporting function of xenografted hearts for up to 195 days is a milestone on the way to clinical cardiac xenotransplantation7.
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| 2. |
- Mold, Jeff E., et al.
(författare)
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Divergent clonal differentiation trajectories establish CD8(+) memory T cell heterogeneity during acute viral infections in humans
- 2021
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 35:8
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Tidskriftsartikel (refereegranskat)abstract
- The CD8(+) T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogeneous repertoire of effector and memory cells. How individual T cell clones contribute to this heterogeneity throughout immune responses remains largely unknown. In this study, we longitudinally track human CD8(+) T cell clones expanding in response to yellow fever virus (YFV) vaccination at the single-cell level. We observed a drop in clonal diversity in blood from the acute to memory phase, suggesting that clonal selection shapes the circulating memory repertoire. Clones in the memory phase display biased differentiation trajectories along a gradient from stem cell to terminally differentiated effector memory fates. In secondary responses, YFV- and influenza-specific CD8(+) T cell clones are poised to recapitulate skewed differentiation trajectories. Collectively, we show that the sum of distinct clonal phenotypes results in the multifaceted human T cell response to acute viral infections.
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| 3. |
- Wassermann, Stella, et al.
(författare)
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p16INK4a is a beta-catenin target gene and indicates low survival in human colorectal tumors
- 2009
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 136:1, s. 196-205.e2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Human colorectal carcinomas display an infiltrative front of invasion where tumor cells undergo an epithelomesenchymal transition associated with low survival. Epithelomesenchymal transition is regulated by a nuclear beta-catenin accumulation, and subsequently, activation of beta-catenin/TCF4 target genes similar to CYCLIN D(1). Unexpectedly, these tumor cells are characterized by low proliferation, which correlates with the expression of the cell cycle inhibitor p16(INK4A). Therefore, we investigated the molecular mechanism of the transcriptional regulation of p16(INK4A) in colorectal cancer and its correlation with survival. METHODS: Molecular biological techniques were used for investigating the transcriptional mechanisms of the p16(INK4A) gene regulation. Moreover, p16(INK4A) expression was correlated with the 10-year survival of patients with colorectal carcinomas. RESULTS: In colorectal carcinomas, expression of the p16(INK4A) gene is regulated by beta-catenin/TCF4 and correlates with low survival rates of patients with tumors displaying an infiltrative front of invasion. CONCLUSIONS: beta-catenin/TCF4 regulates cell cycle promoting (c-MYC, CYCLIN D(1)) and inhibiting genes (p16(INK4A)) at the same time in the mesenchymally differentiated tumor cells at the front of invasion. The function of p16(INK4A) seems to supersede in this context thus leading to low proliferation. Moreover, these tumor cells seem to govern the outcome of colorectal cancer independently of their proliferation.
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