| 1. |
- Cooper, David K. C., et al.
(författare)
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First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes - Chapter 4 : pre-clinical efficacy and complication data required to justify a clinical trial
- 2016
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Ingår i: Xenotransplantation. - : Wiley. - 0908-665X .- 1399-3089. ; 23:1, s. 46-52
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Tidskriftsartikel (refereegranskat)abstract
- In 2009, the International Xenotransplantation Association (IXA) published a consensus document that provided guidelines and recommendations (not regulations) for those contemplating clinical trials of porcine islet transplantation. These guidelines included the IXA's opinion on what constituted rigorous pre-clinical studies using the most relevant animal models and were based on non-human primate testing. We now report our discussion following a careful review of the 2009 guidelines as they relate to pre-clinical testing. In summary, we do not believe there is a need to greatly modify the conclusions and recommendations of the original consensus document. Pre-clinical studies should be sufficiently rigorous to provide optimism that a clinical trial is likely to be safe and has a realistic chance of success, but need not be so demanding that success might only be achieved by very prolonged experimentation, as this would not be in the interests of patients whose quality of life might benefit immensely from a successful islet xenotransplant. We believe these guidelines will be of benefit to both investigators planning a clinical trial and to institutions and regulatory authorities considering a proposal for a clinical trial. In addition, we suggest consideration should be given to establishing an IXA Clinical Trial Advisory Committee that would be available to advise (but not regulate) researchers considering initiating a clinical trial of xenotransplantation.
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| 2. |
- Enge, Martin, et al.
(författare)
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Single-cell analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns
- 2017
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 171:2, s. 321-330.e14
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Tidskriftsartikel (refereegranskat)abstract
- As organisms age, cells accumulate genetic and epigenetic errors that eventually lead to impaired organ function or catastrophic transformation such as cancer. Because aging reflects a stochastic process of increasing disorder, cells in an organ will be individually affected in different ways, thus rendering bulk analyses of postmitotic adult cells difficult to interpret. Here, we directly measure the effects of aging in human tissue by performing single-cell transcriptome analysis of 2,544 human pancreas cells from eight donors spanning six decades of life. We find that islet endocrine cells from older donors display increased levels of transcriptional noise and potential fate drift. By determining the mutational history of individual cells, we uncover a novel mutational signature in healthy aging endocrine cells. Our results demonstrate the feasibility of using single-cell RNA sequencing (RNA-seq) data from primary cells to derive insights into genetic and transcriptional processes that operate on aging human tissue.
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| 3. |
- Peiris, Heshan, et al.
(författare)
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Discovering human diabetes-risk gene function with genetics and physiological assays
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. However, in vivo systems for efficiently discovering T2D risk gene functions relevant to human cells are currently lacking. Here we describe powerful interdisciplinary approaches combining Drosophila genetics and physiology with human islet biology to address this fundamental gap in diabetes research. We identify Drosophila orthologs of T2D-risk genes that regulate insulin output. With human islets, we perform genetic studies and identify cognate human T2D-risk genes that regulate human beta cell function. Loss of BCL11A, a transcriptional regulator, in primary human islet cells leads to enhanced insulin secretion. Gene expression profiling reveals BCL11A-dependent regulation of multiple genes involved in insulin exocytosis. Thus, genetic and physiological systems described here advance the capacity to identify cell-specific T2D risk gene functions.
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