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- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 2. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 5. |
- Yan, C., et al.
(författare)
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Size-dependent influence of NOx on the growth rates of organic aerosol particles
- 2020
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:22
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric new-particle formation (NPF) affects climate by contributing to a large fraction of the cloud condensation nuclei (CCN). Highly oxygenated organic molecules (HOMs) drive the early particle growth and therefore substantially influence the survival of newly formed particles to CCN. Nitrogen oxide (NOx) is known to suppress the NPF driven by HOMs, but the underlying mechanism remains largely unclear. Here, we examine the response of particle growth to the changes of HOM formation caused by NOx. We show that NOx suppresses particle growth in general, but the suppression is rather nonuniform and size dependent, which can be quantitatively explained by the shifted HOM volatility after adding NOx. By illustrating how NOx affects the early growth of new particles, a critical step of CCN formation, our results help provide a refined assessment of the potential climatic effects caused by the diverse changes of NOx level in forest regions around the globe.
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| 7. |
- Brenner, P., et al.
(författare)
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Worldwide First Successful and Reproducable Long-Term Survival up to Half a Year : Completed Preclinical Study with Life-Supporting Orthotopic Pig-to-Baboon Cardiac Xenotransplantation (oXHTx) Fullfilling the ISHLT Prerequisite for Clinical Cardiac Xenotransplantation
- 2020
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Ingår i: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. - : Elsevier BV. - 1557-3117. ; 39:4, s. 12-12
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Konferensbidrag (refereegranskat)abstract
- PURPOSE: Major hurdles in oXHTx are the delayed xenograft rejection, the early perioperative cardiac xenograft dysfunction (PCXD) and the pig heart overgrowth, which were solved in this study with a costimulation blockade, a new non-ischemic cold preservation and a growth inhibition by anti-proliferative drugs. Aim was to achieve a 90-days-survival of minimal 60% (6 of 10 baboons) in this life-supporting orthotopic pig-to-baboon model (oXHTx), because this is the recommendation of the ISHLT to begin a clinical cardiac XT program. METHODS: We transplanted 8 GalKO/hCD46/hTM transgenic (tg) pig hearts orthotopically into baboons with using a basic immunosuppression consisting of ATG, rituximab, mycophenolate (MMF), cortisone and a costimulation blockade CD40mAb (high dose: 50 mg/kg). To prevent PCXD, we used instead of the crystalloid solution a new non-ischemic 8°C cold perfusion technique with oxygenated erythrocytes. Additional antihypertensive drugs and an mTOR inhibitor (temsirolimus) were applied to inhibit pig xenograft growth and hypertrophy. RESULTS: In comparison to our previous group with crystalloid cardioplegia (Längin et al. Nature. 2018;564:430-433) in this group with cold perfusion preservation (non-ischemic) no PCXD was found. One baboon died of a pancreatitis on day 14, another of sepsis on day 26. By using the antiproliferative therapy, 6 of 8 recipient baboons reached the end of study, were long-term surviving (4 were actively terminated after 90 days according to the guidelines of our government). With special permit two further experiments could be prolonged to half a year and the animals were terminated on day 182 and 195. All baboons lived under excellent physical conditions and no hyperacute rejection or DXR occurred. CONCLUSION: First time in a life-supporting oXHT of multi-tg pig hearts here was a consistent reproduceable long-term survival of 3 - 6 months achieved, which is a major progress after 25 years of research. This is an essential milestone and breakthrough and meets the prerequisite according to the ISHLT to begin a clinical phase I study with patients in terminal heart failure. This paves the way to clinical cardiac XT in the next 2 to 5 years.
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