| 1. |
- George, Julie, et al.
(författare)
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Comprehensive genomic profiles of small cell lung cancer
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 524:7563, s. 47-U73
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Tidskriftsartikel (refereegranskat)abstract
- We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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| 2. |
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| 3. |
- Baranasic, D, et al.
(författare)
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Multiomic atlas with functional stratification and developmental dynamics of zebrafish cis-regulatory elements
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:7, s. 1037-
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Tidskriftsartikel (refereegranskat)abstract
- Zebrafish, a popular organism for studying embryonic development and for modeling human diseases, has so far lacked a systematic functional annotation program akin to those in other animal models. To address this, we formed the international DANIO-CODE consortium and created a central repository to store and process zebrafish developmental functional genomic data. Our data coordination center (https://danio-code.zfin.org) combines a total of 1,802 sets of unpublished and re-analyzed published genomic data, which we used to improve existing annotations and show its utility in experimental design. We identified over 140,000 cis-regulatory elements throughout development, including classes with distinct features dependent on their activity in time and space. We delineated the distinct distance topology and chromatin features between regulatory elements active during zygotic genome activation and those active during organogenesis. Finally, we matched regulatory elements and epigenomic landscapes between zebrafish and mouse and predicted functional relationships between them beyond sequence similarity, thus extending the utility of zebrafish developmental genomics to mammals.
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| 4. |
- Klau, Gunnar W., et al.
(författare)
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Integer linear programming approaches for non-unique probe selection
- 2007
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Ingår i: Discrete Applied Mathematics. - : Elsevier BV. - 0166-218X. ; 155, s. 840-856
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Tidskriftsartikel (refereegranskat)abstract
- In addition to their prevalent use for analyzing gene expression, DNA microarrays are an efficient tool for biological, medical, and industrial applications because of their ability to assess the presence or absence of biological agents, the targets, in a sample. Given a collection of genetic sequences of targets one faces the challenge of finding short oligonucleotides, the probes, which allow detection of targets in a sample by hybridization experiments. The experiments are conducted using either unique or non-unique probes, and the problem at hand is to compute a minimal design, i.e., a minimal set of probes that allows to infer the targets in the sample from the hybridization results. If we allow to test for more than one target in the sample, the design of the probe set becomes difficult in the case of non-unique probes. Building upon previous work on group testing for microarrays we describe the first approach to select a minimal probe set for the case of non-unique probes in the presence of a small number of multiple targets in the sample. The approach is based on an integer linear programming formulation and a branch-and-cut algorithm. Our implementation significantly reduces the number of probes needed while preserving the decoding capabilities of existing approaches. © 2006 Elsevier B.V. All rights reserved.
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| 5. |
- Klau, Gunnar W, et al.
(författare)
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Optimal robust non-unique probe selection using Integer Linear Programming.
- 2004
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Ingår i: Bioinformatics (Oxford, England). - : Oxford University Press (OUP). - 1367-4811 .- 1367-4803 .- 1460-2059. ; 20 Suppl 1
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Tidskriftsartikel (refereegranskat)abstract
- Besides their prevalent use for analyzing gene expression, microarrays are an efficient tool for biological, medical and industrial applications due to their ability to assess the presence or absence of biological agents, the targets, in a sample. Given a collection of genetic sequences of targets one faces the challenge of finding short oligonucleotides, the probes, which allow detection of targets in a sample. Each hybridization experiment determines whether the probe binds to its corresponding sequence in the target. Depending on the problem, the experiments are conducted using either unique or non-unique probes and usually assume that only one target is present in the sample. The problem at hand is to compute a design, i.e. a minimal set of probes that allows to infer the targets in the sample from the result of the hybridization experiment. If we allow to test for more than one target in the sample, the design of the probe set becomes difficult in the case of non-unique probes.Building upon previous work on group testing for microarrays, we describe the first approach to select a minimal probe set for the case of non-unique probes in the presence of a small number of multiple targets in the sample. The approach is based on an ILP formulation and a branch-and-cut algorithm. Our preliminary implementation greatly reduces the number of probes needed while preserving the decoding capabilities.http://www.inf.fu-berlin.de/inst/ag-bio
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