| 1. |
- Bravo, L, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Tabiri, S, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
- 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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| 4. |
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| 5. |
- Delios, A., et al.
(författare)
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Examining the generalizability of research findings from archival data
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:30
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Tidskriftsartikel (refereegranskat)abstract
- This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability-for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples.
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| 6. |
- Lee, Chunsik, et al.
(författare)
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VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway
- 2023
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Ingår i: SIGNAL TRANSDUCTION AND TARGETED THERAPY. - : SPRINGERNATURE. - 2095-9907 .- 2059-3635. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases.
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| 7. |
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| 8. |
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| 9. |
- Lin, Ang
(författare)
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Regulation of vaccine immunity : from myeloid cell functions to antibody responses
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The generation of vaccine-induced protection against infections relies on a well-coordinated network of innate immune responses, adaptive cellular responses, and humoral responses. Sufficient stimulation of the innate immune system by vaccination is critical to subsequently induce effective pathogen-specific T cell and B cell responses. The magnitude, characteristics and functions of the T cell and B cell response will further determine the protective effect of the vaccines. This thesis has investigated aspects of both the early innate immune response as well as the adaptive T cell and B cell response after vaccination. Specifically, the first part focuses on the functions of different innate myeloid cell subsets in regulating vaccine responses. The second part focuses on the antibody responses induced by a new live pertussis vaccine compared to the currently used acellular pertussis vaccine (aPV). Neutrophils are the major circulating myeloid cells. Heterogeneity and plasticity of neutrophils have received much attention during the past years. In Paper I, we show that neutrophils can present antigens to antigen-specific memory CD4+ T cells. This is dependent on the upregulation of MHC-II and costimulatory molecules on neutrophils which can occur in the presence of antigens and autologous antigen-specific memory CD4+ T cells. Furthermore, we found that neutrophils isolated from lymph nodes draining vaccine injection sites of rhesus macaques can present vaccine antigens to antigen-specific CD4+ T cells. Neutrophils may therefore play a role in the induction and regulation of vaccine-specific T cell responses through antigen presentation. There have been efforts trying to understand how vaccines induce immune responses but much less is known about immune suppressive regulation. In Paper II, we demonstrate that myeloid-derived suppressor cells (MDSCs), which is a unique population of myeloid cells with suppressive functions particularly on T cells, accumulate transiently after vaccination. We found that monocytic (M)-MDSCs and polymorphonuclear (PMN)-MDSCs are present in rhesus blood and possess inherent suppressive effects on T cells. The frequency of M-MDSCs rapidly and transiently increased in the blood, and these cells infiltrated the injection sites after vaccination. We speculate that MDSCs contribute with an immune-balancing role to prevent excessive immune activation and inflammation upon vaccine exposure. In Paper III, we evaluated the immune responses in humans receiving the live attenuated Bordetella pertussis vaccine BPZE1 in a clinical trial. A single intranasal immunization of BPZE1 induced well-detectable plasmablasts, activated circulating T follicular helper cells, vaccine-specific Th1-polarized CD4+ T cells, memory B cells and antibodies. In contrast to the antibodies induced by the currently used aPV, BPZE1-induced antibodies showed substantially broader specificities to several B. pertussis antigens, many of which were identified for the first time. The BPZE1-induced antibodies were also more potent in mediating bacterial opsonization to stimulate reactive oxygen species production in neutrophils, which further led to enhanced bactericidal function. Collectively, these studies help in the understanding of how myeloid cells dictate immune responses and how the quality and specificities of antibody responses can be influenced by different pertussis vaccine platforms. This information will ultimately aid in the development of better future vaccines.
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| 10. |
- Metzakopian, E, et al.
(författare)
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Genome-wide characterization of Foxa2 targets reveals upregulation of floor plate genes and repression of ventrolateral genes in midbrain dopaminergic progenitors
- 2012
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Ingår i: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 139:14, s. 2625-2634
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factors Foxa1 and Foxa2 promote the specification of midbrain dopaminergic (mDA) neurons and the floor plate. Whether their role is direct has remained unclear as they also regulate the expression of Shh, which has similar roles. We characterized the Foxa2 cis-regulatory network by chromatin immunoprecipitation followed by high-throughput sequencing of mDA progenitors. This identified 9160 high-quality Foxa2 binding sites associated with 5409 genes, providing mechanistic insights into Foxa2-mediated positive and negative regulatory events. Foxa2 regulates directly and positively key determinants of mDA neurons, including Lmx1a, Lmx1b, Msx1 and Ferd3l, while negatively inhibiting transcription factors expressed in ventrolateral midbrain such as Helt, Tle4, Otx1, Sox1 and Tal2. Furthermore, Foxa2 negatively regulates extrinsic and intrinsic components of the Shh signaling pathway, possibly by binding to the same enhancer regions of co-regulated genes as Gli1. Foxa2 also regulates the expression of floor plate factors that control axon trajectories around the midline of the embryo, thereby contributing to the axon guidance function of the floor plate. Finally, this study identified multiple Foxa2-regulated enhancers that are active in the floor plate of the midbrain or along the length of the embryo in mouse and chick. This work represents the first comprehensive characterization of Foxa2 targets in mDA progenitors and provides a framework for elaborating gene regulatory networks in a functionally important progenitor population.
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