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Sökning: WFRF:(Hutter D. J.)

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71.
  • Cortes-Ciriano, I, et al. (författare)
  • Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing
  • 2020
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:3, s. 331-
  • Tidskriftsartikel (refereegranskat)abstract
    • Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.
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72.
  • Li, YL, et al. (författare)
  • Patterns of somatic structural variation in human cancer genomes
  • 2020
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 112-
  • Tidskriftsartikel (refereegranskat)abstract
    • A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes1–7. Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types8. Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.
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73.
  • Akdemir, KC, et al. (författare)
  • Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer
  • 2020
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:3, s. 294-
  • Tidskriftsartikel (refereegranskat)abstract
    • Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.
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74.
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75.
  • Bimbot, F, et al. (författare)
  • An overwiev of the CAVE project research activities in speaker verification
  • 2000
  • Ingår i: Speech Communication. - 0167-6393 .- 1872-7182. ; 31:2-3, s. 155-180
  • Tidskriftsartikel (refereegranskat)abstract
    • This article presents an overview of the research activities carried out in the European CAVE project, which focused on text-dependent speaker verification on the telephone network using whole word Hidden Markov Models. It documents in detail various aspects of the technology and the methodology used within the project. In particular, it addresses the issue of model estimation in the context of limited enrollment data and the problem of a posteriori decision threshold setting. Experiments are carried out on the realistic telephone speech database SESP. State-of-the-art performance levels are obtained, which validates the technical approaches developed and assessed during the project as well as the working infrastructure which facilitated cooperation between the partners.
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76.
  • Borgenvik, Anna, 1987-, et al. (författare)
  • Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
  • 2022
  • Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 82:24, s. 4586-4603
  • Tidskriftsartikel (refereegranskat)abstract
    • Relapse is the leading cause of death in patients with medulloblas-toma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse.Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.
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77.
  • Nakawesi, J, et al. (författare)
  • αvβ8 integrin-expression by BATF3-dependent dendritic cells facilitates early IgA responses to Rotavirus
  • 2021
  • Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 9:2, s. 53-67
  • Tidskriftsartikel (refereegranskat)abstract
    • Secretory intestinal IgA can protect from re-infection with rotavirus (RV), but very little is known about the mechanisms that induce IgA production during intestinal virus infections. Classical dendritic cells (cDCs) in the intestine can facilitate both T cell-dependent and -independent secretory IgA. Here, we show that BATF3-dependent cDC1, but not cDC2, are critical for the optimal induction of RV-specific IgA responses in the mesenteric lymph nodes. This depends on the selective expression of the TGFβ-activating integrin αvβ8 by cDC1. In contrast, αvβ8 on cDC1 is dispensible for steady state immune homeostasis. Given that cDC2 are crucial in driving IgA during steady state but are dispensable for RV-specific IgA responses, we propose that the capacity of DC subsets to induce intestinal IgA responses reflects the context, as opposed to an intrinsic property of individual DC subsets.
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78.
  • Peterziel, H, et al. (författare)
  • Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM
  • 2022
  • Ingår i: NPJ precision oncology. - : Springer Science and Business Media LLC. - 2397-768X. ; 6:1, s. 94-
  • Tidskriftsartikel (refereegranskat)abstract
    • The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.
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79.
  • Pierrot, J-B, et al. (författare)
  • A comparison of a priori threshold setting procedures for speaker verification in the CAVE project
  • 1998
  • Konferensbidrag (refereegranskat)abstract
    • The issue of a priori threshold setting in speaker verification is a key problem for field applications. In the context of the CAVE project, we compared several methods for estimating speaker-independent and speaker-dependent decision thresholds. Relevant parameters are estimated from development data only, i.e. without resorting to additional client data. The various approaches are tested on the Dutch SESP database.
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80.
  • Abdi-Jalebi, Mojtaba, et al. (författare)
  • Maximizing and stabilizing luminescence from halide perovskites with potassium passivation
  • 2018
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 555, s. 497-501
  • Tidskriftsartikel (refereegranskat)abstract
    • Metal halide perovskites are of great interest for various high-performance optoelectronic applications. The ability to tune the perovskite bandgap continuously by modifying the chemical composition opens up applications for perovskites as coloured emitters, in building-integrated photovoltaics, and as components of tandem photovoltaics to increase the power conversion efficiency. Nevertheless, performance is limited by non-radiative losses, with luminescence yields in state-of-the-art perovskite solar cells still far from 100 per cent under standard solar illumination conditions. Furthermore, in mixed halide perovskite systems designed for continuous bandgap tunability2 (bandgaps of approximately 1.7 to 1.9 electronvolts), photoinduced ion segregation leads to bandgap instabilities. Here we demonstrate substantial mitigation of both non-radiative losses and photoinduced ion migration in perovskite films and interfaces by decorating the surfaces and grain boundaries with passivating potassium halide layers. We demonstrate external photoluminescence quantum yields of 66 per cent, which translate to internal yields that exceed 95 per cent. The high luminescence yields are achieved while maintaining high mobilities of more than 40 square centimetres per volt per second, providing the elusive combination of both high luminescence and excellent charge transport. When interfaced with electrodes in a solar cell device stack, the external luminescence yield—a quantity that must be maximized to obtain high efficiency—remains as high as 15 per cent, indicating very clean interfaces. We also demonstrate the inhibition of transient photoinduced ion-migration processes across a wide range of mixed halide perovskite bandgaps in materials that exhibit bandgap instabilities when unpassivated. We validate these results in fully operating solar cells. Our work represents an important advance in the construction of tunable metal halide perovskite films and interfaces that can approach the efficiency limits in tandem solar cells, coloured-light-emitting diodes and other optoelectronic applications.
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