297 results on '"Hovig, E."'
Search Results
2. Computational approaches in cancer multidrug resistance research: Identification of potential biomarkers, drug targets and drug-target interactions
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Tolios, A., De Las Rivas, J., Hovig, E., Trouillas, P., Scorilas, A., and Mohr, T.
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- 2020
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3. Toward semantic standard and process ontology for Additive manufacturing.
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Gouttebroze, S, Friis, J, Hovig, E W, and Boivie, K
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- 2023
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4. 213P Unlocking cancer treatment opportunities by population-based advanced diagnostics in Norway
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Russnes, H.E.G., Nilsen, H.L., Jebens, M., Janssen, E., Wold, R.M., Meza-Zepeda, L.A., Hovig, E., Lien, T., Nygaard, V., Niehusmann, P., Ersland, K.M., Forthun, R., Haugland, H.K., Wennerström, A.B., Lüders, T., Randen, U., Dai, H.Y., Granlund, A.V.B., Skjulsvik, A.J., and Hovland, R.
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- 2023
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5. Associations between gene expressions in breast cancer and patient survival
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Jenssen, T.-K., Kuo, W., Stokke, T., and Hovig, E.
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- 2002
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6. Increased expression of IRF4 and ETS1 in CD4+ cells from patients with intermittent allergic rhinitis
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Bruhn, S., Barrenäs, F., Mobini, R., Andersson, B. A., Chavali, S., Egan, B. S., Hovig, E., Sandve, G. K., Langston, M. A., Rogers, G., Wang, H., and Benson, M.
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- 2012
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7. Disentangling the perturbational effects of amino acid substitutions in the DNA-binding domain of p53
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Wacey, A. I., Cooper, D. N., Liney, D., Hovig, E., and Krawczak, M.
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- 1999
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8. CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer
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Ågesen, T H, Berg, M, Clancy, T, Thiis-Evensen, E, Cekaite, L, Lind, G E, Nesland, J M, Bakka, A, Mala, T, Hauss, H J, Fetveit, T, Vatn, M H, Hovig, E, Nesbakken, A, Lothe, R A, and Skotheim, R I
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- 2011
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9. Challenging pattern recognition cross-talk: A gene profiling perspective of human Gram-negative bacteriaemia: P77
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Lau, C. L., Nygård, S., Fure, H., Lappegård, K. T., Brekke, O. L., Hovig, E., and Mollnes, T. E.
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- 2011
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10. 1315O Key learnings from building: A precision cancer medicine implementation initiative for Norway
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Tasken, K., Russnes, H.G., Aas, E., Bjorge, L., Blix, E.S., Enerly, E., Fagereng, L., Flobak, Å., Gilje, B., Gjertsen, B.T., Guren, T.K.K., Heix, J., Hovig, E., Hovland, R., Lonning, P.E., Mæhle, P.M., Nilsen, H.L., Thoresen, S., Smeland, S., and Helland, A.
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- 2022
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11. The BRCA1 syndrome and other inherited breast or breast–ovarian cancers in a Norwegian prospective series
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Møller, P., Borg, A., Heimdal, K., Apold, J., Vallon-Christersson, J., Hovig, E., and Mæhle, L.
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- 2001
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12. Genetic epidemiology of BRCA1 mutations in Norway
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Møller, P, Heimdal, K, Apold, J, Fredriksen, Å, Borg, Å, Hovig, E, Hagen, A, Hagen, B, Pedersen, J.C, and Mæhle, L
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- 2001
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13. Patterns of genomic evolution in advanced melanoma.
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Birkeland, E., Zhang, S., Poduval, D., Geisler, J., Nakken, S., Vodak, D., Meza-Zepeda, L. A., Hovig, E., Myklebost, O., Knappskog, S., and Lønning, P. E.
- Abstract
Genomic alterations occurring during melanoma progression and the resulting genomic heterogeneity between metastatic deposits remain incompletely understood. Analyzing 86 metastatic melanoma deposits from 53 patients with whole-exome sequencing (WES), we show a low branch to trunk mutation ratio and little intermetastatic heterogeneity, with driver mutations almost completely shared between lesions. Branch mutations consistent with UV damage indicate that metastases may arise from different subclones in the primary tumor. Selective gain of mutated BRAF alleles occurs as an early event, contrasting whole-genome duplication (WGD) occurring as a late truncal event in about 40% of cases. One patient revealed elevated mutational diversity, probably related to previous chemotherapy and DNA repair defects. In another patient having received radiotherapy toward a lymph node metastasis, we detected a radiotherapy-related mutational signature in two subsequent distant relapses, consistent with secondary metastatic seeding. Our findings add to the understanding of genomic evolution in metastatic melanomas. [ABSTRACT FROM AUTHOR]
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- 2018
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14. P1.02-028 Pathways Involved in Early Stage Lung Cancers
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Haakensen, V., Nygårad, S., Nygaard, V., Jørgensen, L., Solberg, S., Hovig, E., Brustugun, O.T., Lingjærde, O.C., and Helland, Å.
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- 2017
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15. High number of kinome-mutations in non-small cell lung cancer is associated with reduced immune response and poor relapse-free survival.
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Helland, Å., Brustugun, O. T., Nakken, S., Halvorsen, A. R., Dønnem, T., Bremnes, R., Busund, L. T., Sun, J., Lorenz, S., Solberg, S. K., Jørgensen, L. H., Vodak, D., Myklebost, O., Hovig, E., and Meza‐Zepeda, L. A.
- Abstract
Lung cancer is the leading cause of cancer related death, and the past years' improved insight into underlying molecular events has significantly improved outcome for specific subsets of patients. In particular, several new therapies that target protein kinases have been implemented, and many more are becoming available. We have investigated lung cancer specimens for somatic mutations in a targeted panel of 612 human genes, the majority being protein kinases. The somatic mutation profiles were correlated to profiles of immune cell infiltration as well as relapse-free survival. Targeted deep sequencing was performed on 117 tumour/normal pairs using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons and untranslated regions of all known kinases, kinase receptors and selected cancer-related genes (612 genes in total). CD8 staining was determined using Ventana Benchmark. Survival analyses were performed using SPSS. The number of mutations per sample ranged from 0 to 50 (within the 612 genes tested), with a median of nine. The prognosis was worse for patients with more than the median number of mutations. A significant correlation was found between mutations in one of selected DNA-repair genes and the total number of mutations in that tumour ( p < 0.001). There was a significant inverse correlation between the number of infiltrating stromal CD8+ lymphocytes and the presence of EGFR mutations. [ABSTRACT FROM AUTHOR]
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- 2017
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16. Increased expression of IRF4 and ETS1 in CD4+ cells from patients with intermittent allergic rhinitis.
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Bruhn, S., Barrenäs, F., Mobini, R., Andersson, B. A., Chavali, S., Egan, B. S., Hovig, E., Sandve, G. K., Langston, M. A., Rogers, G., Wang, H., and Benson, M.
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RESPIRATORY allergy ,ALLERGIC rhinitis ,TRANSCRIPTION factors ,GENE expression ,CYTOKINES ,CHROMATIN ,PATIENTS - Abstract
To cite this article: Bruhn S, Barrenäs F, Mobini R, Andersson BA, Chavali S, Egan BS, Hovig E, Sandve GK, Langston MA, Rogers G, Wang H, Benson M. Increased expression of IRF4 and ETS1 in CD4
+ cells from patients with intermittent allergic rhinitis. Allergy 2012; 67: 33-40. Abstract Background: The transcription factor (TF) IRF4 is involved in the regulation of Th1, Th2, Th9, and Th17 cells, and animal studies have indicated an important role in allergy. However, IRF4 and its target genes have not been examined in human allergy. Methods: IRF4 and its target genes were examined in allergen-challenged CD4+ cells from patients with IAR, using combined gene expression microarrays and chromatin immunoprecipitation chips (ChIP-chips), computational target prediction, and RNAi knockdowns. Results: IRF4 increased in allergen-challenged CD4+ cells from patients with IAR, and functional studies supported its role in Th2 cell activation. IRF4 ChIP-chip showed that IRF4 regulated a large number of genes relevant to Th cell differentiation. However, neither Th1 nor Th2 cytokines were the direct targets of IRF4. To examine whether IRF4 induced Th2 cytokines via one or more downstream TFs, we combined gene expression microarrays, ChIP-chips, and computational target prediction and found a putative intermediary TF, namely ETS1 in allergen-challenged CD4+ cells from allergic patients. ETS1 increased significantly in allergen-challenged CD4+ cells from patients compared to controls. Gene expression microarrays before and after ETS1 RNAi knockdown showed that ETS1 induced Th2 cytokines as well as disease-related pathways. Conclusions: Increased expression of IRF4 in allergen-challenged CD4+ cells from patients with intermittent allergic rhinitis leads to activation of a complex transcriptional program, including Th2 cytokines. [ABSTRACT FROM AUTHOR]- Published
- 2012
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17. Connectivity can be used to identify key genes in DNA microarray data: a study based on gene expression in nasal polyps before and after treatment with glucocorticoids.
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Benson, M., Steenhoff Hov, D. A., Clancy, T., Hovig, E., Rudemo, M., and Cardell, L. O.
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DNA microarrays ,GENE expression ,NASAL polyps ,THERAPEUTIC use of glucocorticoids ,ANTI-inflammatory agents ,TONSILS - Abstract
Conclusions. The presented analysis of nasal polyposis using connectivity based on the PubGene literature co-citation network demonstrates that this tool can be used to identify key genes in DNA microarray studies of human polygenic diseases. Objectives: DNA microarray studies of complex diseases may reveal differential expression of hundreds of genes. According to network theory and studies of yeast cells, genes that are connected with several other genes appear to have key regulatory roles. This study aimed to examine if this principle can be translated to DNA microarray studies of human disease, using nasal polyposis as a base for the analysis. Materials and methods. The connectivity of differentially expressed genes from a previously described microarray study of nasal polyposis before and after treatment with glucocorticoids was determined. This was done using the literature co-citation network PubGene. Results. In all, 166genes were differentially expressed; 39 of these were previously defined as inflammatory and considered important for nasal polyposis. The connectivity of all differentially expressed genes was analysed using the PubGene literature co-citation network. Seventy-four of the 166genes were connected to other genes. By contrast, the average number of connected genes among 100sets of 166 randomly chosen genes was 31.5. A small number of the differentially expressed genes were highly connected, while most genes had few or no connections. This indicated a scale-free network. The most connected gene was interleukin-8, an inflammatory gene of known importance for nasal polyposis. Twenty-eight of the 74 connected genes were inflammatory (38%), compared with 11 of the 92 unconnected genes (12%), p<0.0001. Since most evidence suggests that nasal polyps are inflammatory in their nature, this supports the hypothesis that connected genes have more disease relevance than unconnected genes. [ABSTRACT FROM AUTHOR]
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- 2007
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18. BRCA1 mutations in ovarian cancer and borderline tumours in Norway: a nested case-control study.
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Bjørge, T, Lie, A K, Hovig, E, Gislefoss, R E, Hansen, S, Jellum, E, Langseth, H, Nustad, K, Tropé, C G, and Dørum, A
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CANCER in women ,GENETIC mutation ,CYSTS (Pathology) ,BLOOD plasma ,TUMORS ,CANCER patients - Abstract
The aims of the present study were to find the frequency of the most common BRCA1 mutations in women with ovarian tumours identified from a population-based cancer registry and in the general population, to estimate the relative risk of ovarian tumours among the mutation carriers, and to explore the value of using CA125 as a prediagnostic test. The study was designed as a nested case-control study within a cohort mainly consisting of participants in population-based health examinations. The data files of The Cancer Registry of Norway and the Janus serum bank were linked to identify cases with ovarian cancer and borderline tumours. Hereditary BRCA1 mutations were determined using archived serum samples and capillary electrophoresis. Altogether 478 ovarian cancer patients and 190 patients with borderline tumours were identified, and 1421 and 568 matching controls were selected. Odds ratios (OR) of developing ovarian cancer and borderline tumours in the presence of BRCA1 mutations and CA125 level were derived from conditional logistic regression models. Among the 478 ovarian cancer patients, 19 BRCA1 mutations were identified (1675delA, 1135insA, 816delGT and 3347delAG), none among the patients with borderline tumours. Only two of the 1989 controls were BRCA1 mutation carriers (0.10%). The risk of ovarian cancer among the mutation carriers was strongly elevated (OR=29, 95%CI=6.6-120). CA125 was a marker for ovarian cancer, but the sensitivity was low. This study showed that BRCA1 mutation carriers have a very high risk of ovarian cancer. However, since the prevalence of BRCA1 mutations in the Norwegian population was low, the proportion of ovarian cancers due to BRCA1 mutations seemed to be low, about 4%. The sensitivity of using CA125 only as a screening test for ovarian cancer was low.British Journal of Cancer (2004) 91, 1829-1834. doi:10.1038/sj.bjc.6602199 www.bjcancer.com Published online 12 October 2004 [ABSTRACT FROM AUTHOR]
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- 2004
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19. Interferon-? suppresses S100A4 transcription independently of apoptosis or cell cycle arrest.
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Andersen, K, Smith-Sorensen, B, Pedersen, K B, Hovig, E, Myklebost, O, Fodstad, O, and Malandsmo, G M
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MAMMARY gland cancer ,COLON cancer ,OSTEOSARCOMA - Abstract
The S100A4 protein has been associated with increased metastatic capacity of cancer cells, and recent studies have suggested a correlation between the expression level of S100A4 and the prognostic outcome for patients with various types of cancer. The knowledge about the mechanisms underlying the metastasis-promoting effects is still limited, and the aim of the present study was to elucidate signal transduction pathways involved in the regulation of S100A4. After treatment of human carcinoma cells with interferon-gamma (IFN-γ), we observed downregulation of S100A4 both at mRNA and protein levels. The effect was not dependent on IFN-γ-induced apoptosis or IFN-γ-mediated cell cycle arrest. Moreover, IFN-γ-mediated decrease in mRNA stability could not account for the observed decrease in S100A4 transcript level. Finally, microarray analysis suggests ISGF3G, ETV5, ZNF133 and CEBPG as possible candidate genes involved in IFN-γ-mediated repression of S100A4. [ABSTRACT FROM AUTHOR]
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- 2003
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20. Database of p53 gene somatic mutations in human tumors and cell lines: updated compilation and future prospects.
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Hainaut, P., Soussi, T., Shomer, B., Hollstein, M., Greenblatt, M., Hovig, E., Harris, C. C., and Montesano, R.
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- 1997
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21. Somatic Point Mutations in the p53 Gene of Human Tumors and Cell Lines: Updated Compilation.
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Hollstein, M., Shomer, B., Greenblatt, M., Soussi, T., Hovig, E., Montesano, R., and Harris, C.C.
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- 1996
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22. Involvement of the pRb/p16/cdk4/cyclin D1 pathway in the tumorigenesis of sporadic malignant melanomas.
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Maelandsmo, G M, Flørenes, V A, Hovig, E, Oyjord, T, Engebraaten, O, Holm, R, Børresen, A L, and Fodstad, O
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- 1996
23. Involvement of the pRb/p16/cdk4/cyclin D1 pathway in the tumorigenesis of sporadic malignant melanomas.
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Mælandsmo, GM, Flørenes, VA, Hovig, E, Øyjord, T, Engebraaten, O, Holm, R, Børresen, A-L, and Fodstad, Ø
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- 1996
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24. Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas - relationship to amplification and mRNA levels of CDK4 and CCND1.
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Maelandsmo, GM, Berner, J-M, Flørenes, VA, Forus, A, Hovig, E, Fodstad, Ø, and Myklebost, O
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- 1995
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25. P04.80 Diagnostic potential of the IgM igOme (IgM repertoire) biomarkers for brain tumors.
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Kostov, V, Ferdinandov, D, Shivarov, V, Vassilev, T, Hovig, E, and Pashov, A
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- 2018
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26. Gene-expression profiling in breast cancer.
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Jenssen T and Hovig E
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- 2005
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27. 919P Predictive multi-omic signature in locally advanced laryngeal/hypopharyngeal (LH) squamous cell carcinoma (SCC) treated with induction chemotherapy (IC).
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Bossi, P., Mattavelli, D., Chiocca, S., Gurizzan, C., Compagnoni, M., Dietz, A., Hovig, E., Kalogerini, M., Khelik, K., Lorini, L., Mesia Nin, R., Plana Serrahima, M., Ravanelli, M., Rondi, P., Smussi, D., Wichmann, G., Yinxhiu, Z., and Calza, S.
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- 2024
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28. P17.94 GLIOMA GWAS HITS - MARKERS FOR RISK OR FOR PROGNOSIS?
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Wibom, C., Spaeth, F., Dahlin, A., Langseth, H., Hovig, E., Rajaraman, P., Andersson, U., and Melin, B.
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- 2014
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29. Genetic epidemiology of BRCA mutations--family history detects less than 50% of the mutation carriers.
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Møller P, Hagen AI, Apold J, Maehle L, Clark N, Fiane B, Løvslett K, Hovig E, and Vabø A
- Abstract
Ten BRCA mutations were demonstrated to be frequent in the Norwegian population. We present maps verifying the uneven distribution of prevalences according to municipality. We tested incident breast cancer cases treated in Mid-Norway from 1999 onwards for these mutations. Uptake of testing was 97% and 2.5% were demonstrated to be mutation carriers. Ten (77%) were outside families previously known to carry a mutation. Ten (77%) did not meet clinical criteria to be selected for mutation testing. We tested incident ovarian cancer cases in South-West Norway from 2001 onwards. Uptake of testing was 80% and 23% were mutation carriers. Twenty-one (88%) were outside families previously known. Twelve (67%) did not meet clinical criteria to be selected for testing. All patients with mutation collaborated actively to give our offer of predictive genetic testing to their relatives. No complaint on the activity was received. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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30. Denaturing gradient gel electrophoresis: A method for separation of DNA fragments differing by single base-pair substitution
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Børresen, A.-L., Hovig, E., and Brøgger, A.
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- 1988
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31. Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma.
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Bai B, Wise JF, Vodák D, Nakken S, Sharma A, Blaker YN, Brodtkorb M, Hilden V, Trøen G, Ren W, Lorenz S, Lawrence MS, Myklebost O, Kimby E, Pan-Hammarström Q, Steen CB, Meza-Zepeda LA, Beiske K, Smeland EB, Hovig E, Lingjærde OC, Holte H, and Myklebust JH
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- Humans, Female, Male, Middle Aged, Aged, Adult, Exome Sequencing, DNA Copy Number Variations, CREB-Binding Protein genetics, Longitudinal Studies, Aged, 80 and over, Multiomics, Lymphoma, Follicular genetics, Lymphoma, Follicular pathology, Mutation, Genomics methods
- Abstract
Follicular lymphoma (FL) is the most common indolent type of B-cell non-Hodgkin lymphoma. Advances in treatment have improved overall survival, but early relapse or transformation to aggressive disease is associated with inferior outcome. To identify early genetic events and track tumor clonal evolution, we performed multi-omics analysis of 94 longitudinal biopsies from 44 FL patients; 22 with transformation (tFL) and 22 with relapse without transformation (nFL). Deep whole-exome sequencing confirmed recurrent mutations in genes encoding epigenetic regulators (CREBBP, KMT2D, EZH2, EP300), with similar mutational landscape in nFL and tFL patients. Calculation of genomic distances between longitudinal samples revealed complex evolutionary patterns in both subgroups. CREBBP and KMT2D mutations were identified as genetic events that occur early in the disease course, and cases with CREBBP KAT domain mutations had low risk of transformation. Gains in chromosomes 12 and 18 (TCF4), and loss in 6q were identified as early and stable copy number alterations. Identification of such early and stable genetic events may provide opportunities for early disease detection and disease monitoring. Integrative analysis revealed that tumors with EZH2 mutations exhibited reduced gene expression of numerous histone genes, including histone linker genes. This might contribute to the epigenetic dysregulation in FL., (© 2024. The Author(s).)
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- 2024
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32. Finemap-MiXeR: A variational Bayesian approach for genetic finemapping.
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Akdeniz BC, Frei O, Shadrin A, Vetrov D, Kropotov D, Hovig E, Andreassen OA, and Dale AM
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- Humans, Polymorphism, Single Nucleotide genetics, Models, Genetic, Quantitative Trait Loci, Bayes Theorem, Genome-Wide Association Study methods, Algorithms, Linkage Disequilibrium
- Abstract
Genome-wide association studies (GWAS) implicate broad genomic loci containing clusters of highly correlated genetic variants. Finemapping techniques can select and prioritize variants within each GWAS locus which are more likely to have a functional influence on the trait. Here, we present a novel method, Finemap-MiXeR, for finemapping causal variants from GWAS summary statistics, controlling for correlation among variants due to linkage disequilibrium. Our method is based on a variational Bayesian approach and direct optimization of the Evidence Lower Bound (ELBO) of the likelihood function derived from the MiXeR model. After obtaining the analytical expression for ELBO's gradient, we apply Adaptive Moment Estimation (ADAM) algorithm for optimization, allowing us to obtain the posterior causal probability of each variant. Using these posterior causal probabilities, we validated Finemap-MiXeR across a wide range of scenarios using both synthetic data, and real data on height from the UK Biobank. Comparison of Finemap-MiXeR with two existing methods, FINEMAP and SuSiE RSS, demonstrated similar or improved accuracy. Furthermore, our method is computationally efficient in several aspects. For example, unlike many other methods in the literature, its computational complexity does not increase with the number of true causal variants in a locus and it does not require any matrix inversion operation. The mathematical framework of Finemap-MiXeR is flexible and may also be applied to other problems including cross-trait and cross-ancestry finemapping., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. AMD is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc. and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict-of-interest policies. Dr. OAA is a consultant for cortechs.ai, and received speaker’s honorarium from Janssen, Lundbeck and Sunovion unrelated to the topic of this study. The remaining authors have no competing interest., (Copyright: © 2024 Akdeniz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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33. Is precision medicine the solution to improve organ preservation in laryngeal/hypopharyngeal cancer? A position paper by the Preserve Research Group.
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Mattavelli D, Wichmann G, Smussi D, Paderno A, Plana MS, Mesia RN, Compagnoni M, Medda A, Chiocca S, Calza S, Zhan Y, Rognoni C, Tarricone R, Stucchi E, Lorini L, Gurizzan C, Khelik K, Hovig E, Dietz A, Piazza C, and Bossi P
- Abstract
In locally advanced (LA) laryngeal/hypopharyngeal squamous cell carcinoma (LHSCC), larynx preservation (LP) strategies aim at the cure of the disease while preserving a functional larynx, thus avoiding total laryngectomy and the associated impact on the quality of life. In the last decades, apart from transoral and open-neck organ preservation approaches, several non-surgical regimens have been investigated: radiotherapy alone, alternate, concurrent or sequential chemoradiation, and bioradiotherapy. Despite major progress, the identification of reliable and effective predictors for treatment response remains a clinical challenge. This review examines the current state of LP in LA-LHSCC and the need for predictive factors, highlighting the importance of the PRESERVE trial in addressing this gap. The PRESERVE trial represents a pivotal initiative aimed at finding the optimal therapy for laryngeal preservation specific to each patient through a retrospective analysis of data from previous LP trials and prospectively validating findings. The goal of the PRESERVE trial is to develop a comprehensive predictive classifier that integrates clinical, molecular, and multi-omics data, thereby enhancing the precision and efficacy of patient selection for LP protocols., Competing Interests: PB: participation in an advisory board or conference honoraria for: Merck, Sanofi-Regeneron, Merck Sharp & Dohme, Glaxo Smith Kline, Merus, Pfizer, Sun Pharma, Angelini, Nestlè. MP: Eisai, Invited Speaker, MSD, Invited Speaker, Travel grants. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mattavelli, Wichmann, Smussi, Paderno, Plana, Mesia, Compagnoni, Medda, Chiocca, Calza, Zhan, Rognoni, Tarricone, Stucchi, Lorini, Gurizzan, Khelik, Hovig, Dietz, Piazza and Bossi.)
- Published
- 2024
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34. High-throughput molecular assays for inclusion in personalised oncology trials - State-of-the-art and beyond.
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Edsjö A, Russnes HG, Lehtiö J, Tamborero D, Hovig E, Stenzinger A, and Rosenquist R
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- Humans, High-Throughput Nucleotide Sequencing, Clinical Trials as Topic, Medical Oncology methods, Medical Oncology trends, Precision Medicine methods, Neoplasms genetics, Neoplasms therapy, Neoplasms diagnosis, Neoplasms drug therapy, Biomarkers, Tumor
- Abstract
In the last decades, the development of high-throughput molecular assays has revolutionised cancer diagnostics, paving the way for the concept of personalised cancer medicine. This progress has been driven by the introduction of such technologies through biomarker-driven oncology trials. In this review, strengths and limitations of various state-of-the-art sequencing technologies, including gene panel sequencing (DNA and RNA), whole-exome/whole-genome sequencing and whole-transcriptome sequencing, are explored, focusing on their ability to identify clinically relevant biomarkers with diagnostic, prognostic and/or predictive impact. This includes the need to assess complex biomarkers, for example microsatellite instability, tumour mutation burden and homologous recombination deficiency, to identify patients suitable for specific therapies, including immunotherapy. Furthermore, the crucial role of biomarker analysis and multidisciplinary molecular tumour boards in selecting patients for trial inclusion is discussed in relation to various trial concepts, including drug repurposing. Recognising that today's exploratory techniques will evolve into tomorrow's routine diagnostics and clinical study inclusion assays, the importance of emerging technologies for multimodal diagnostics, such as proteomics and in vivo drug sensitivity testing, is also discussed. In addition, key regulatory aspects and the importance of patient engagement in all phases of a clinical trial are described. Finally, we propose a set of recommendations for consideration when planning a new precision cancer medicine trial., (© 2024 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)
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- 2024
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35. Identification of Transcripts with Shared Roles in the Pathogenesis of Postmenopausal Osteoporosis and Cardiovascular Disease.
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Reppe S, Gundersen S, Sandve GK, Wang Y, Andreassen OA, Medina-Gomez C, Rivadeneira F, Utheim TP, Hovig E, and Gautvik KM
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- Humans, Female, Aged, Middle Aged, Aged, 80 and over, Gene Expression Profiling, RNA, Messenger genetics, RNA, Messenger metabolism, MicroRNAs genetics, Osteoporosis, Postmenopausal genetics, Osteoporosis, Postmenopausal pathology, Cardiovascular Diseases genetics, Cardiovascular Diseases pathology, Polymorphism, Single Nucleotide, Bone Density genetics, Transcriptome
- Abstract
Epidemiological evidence suggests existing comorbidity between postmenopausal osteoporosis (OP) and cardiovascular disease (CVD), but identification of possible shared genes is lacking. The skeletal global transcriptomes were analyzed in trans-iliac bone biopsies (n = 84) from clinically well-characterized postmenopausal women (50 to 86 years) without clinical CVD using microchips and RNA sequencing. One thousand transcripts highly correlated with areal bone mineral density (aBMD) were further analyzed using bioinformatics, and common genes overlapping with CVD and associated biological mechanisms, pathways and functions were identified. Fifty genes (45 mRNAs, 5 miRNAs) were discovered with established roles in oxidative stress, inflammatory response, endothelial function, fibrosis, dyslipidemia and osteoblastogenesis/calcification. These pleiotropic genes with possible CVD comorbidity functions were also present in transcriptomes of microvascular endothelial cells and cardiomyocytes and were differentially expressed between healthy and osteoporotic women with fragility fractures. The results were supported by a genetic pleiotropy-informed conditional False Discovery Rate approach identifying any overlap in single nucleotide polymorphisms (SNPs) within several genes encoding aBMD- and CVD-associated transcripts. The study provides transcriptional and genomic evidence for genes of importance for both BMD regulation and CVD risk in a large collection of postmenopausal bone biopsies. Most of the transcripts identified in the CVD risk categories have no previously recognized roles in OP pathogenesis and provide novel avenues for exploring the mechanistic basis for the biological association between CVD and OP.
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- 2024
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36. Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated "Big Bang" pathway to CRC in three of the four Lynch syndromes.
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Møller P, Haupt S, Ahadova A, Kloor M, Sampson JR, Sunde L, Seppälä T, Burn J, Bernstein I, Capella G, Evans DG, Lindblom A, Winship I, Macrae F, Katz L, Laish I, Vainer E, Monahan K, Half E, Horisberger K, da Silva LA, Heuveline V, Therkildsen C, Lautrup C, Klarskov LL, Cavestro GM, Möslein G, Hovig E, and Dominguez-Valentin M
- Abstract
Background: Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes., Materials and Methods: We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms., Results: Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers., Conclusions: Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports., (© 2024. The Author(s).)
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- 2024
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37. COSGAP: COntainerized Statistical Genetics Analysis Pipelines.
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Akdeniz BC, Frei O, Hagen E, Filiz TT, Karthikeyan S, Pasman J, Jangmo A, Bergstedt J, Shorter JR, Zetterberg R, Meijsen J, Sønderby IE, Buil A, Tesli M, Lu Y, Sullivan P, Andreassen OA, and Hovig E
- Abstract
Summary: The collection and analysis of sensitive data in large-scale consortia for statistical genetics is hampered by multiple challenges, due to their non-shareable nature. Time-consuming issues in installing software frequently arise due to different operating systems, software dependencies, and limited internet access. For federated analysis across sites, it can be challenging to resolve different problems, including format requirements, data wrangling, setting up analysis on high-performance computing (HPC) facilities, etc. Easier, more standardized, automated protocols and pipelines can be solutions to overcome these issues. We have developed one such solution for statistical genetic data analysis using software container technologies. This solution, named COSGAP: "COntainerized Statistical Genetics Analysis Pipelines," consists of already established software tools placed into Singularity containers, alongside corresponding code and instructions on how to perform statistical genetic analyses, such as genome-wide association studies, polygenic scoring, LD score regression, Gaussian Mixture Models, and gene-set analysis. Using provided helper scripts written in Python, users can obtain auto-generated scripts to conduct the desired analysis either on HPC facilities or on a personal computer. COSGAP is actively being applied by users from different countries and projects to conduct genetic data analyses without spending much effort on software installation, converting data formats, and other technical requirements., Availability and Implementation: COSGAP is freely available on GitHub (https://github.com/comorment/containers) under the GPLv3 license., Competing Interests: Dr. Andreassen has received speaker fees from Lundbeck, Janssen, Otsuka, and Sunovion and is a consultant to Cortechs.ai. and Precision Health. Dr. Frei is a consultant to Precision Health., (© The Author(s) 2024. Published by Oxford University Press.)
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- 2024
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38. Roadmap for a European cancer data management and precision medicine infrastructure.
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Nikolski M, Hovig E, Al-Shahrour F, Blomberg N, Scollen S, Valencia A, and Saunders G
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- Humans, Data Management, Precision Medicine, Biomedical Research, Neoplasms
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- 2024
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39. Histology independent drug development - Is this the future for cancer drugs?
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Billingham L, Brown L, Framke T, Greystoke A, Hovig E, Mathur S, Page P, Pean E, Barjesteh van Waalwijk van Doorn-Khosrovani S, Vonk R, Wissink S, Zander H, and Plummer R
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- Humans, Drug Development, Medical Oncology, Biomarkers, Tumor, Antineoplastic Agents therapeutic use, Neoplasms drug therapy
- Abstract
The Cancer Drug Development Forum (CDDF)'s 'Histology independent drug development - is this the future for cancer drugs?' workshop was set up to explore the current landscape of histology independent drug development, review the current regulatory landscape and propose recommendations for improving the conduct of future trials. The first session considered lessons learnt from previous trials, including innovative solutions for reimbursement. The session explored why overall survival represents the most valuable endpoint, and the importance of duration of response, which can be captured with swimmer and spider plots. The second session on biomarker development and treatment optimisation considered current regulations for companion diagnostics, FDA guidance on histology independent drug development in oncology, and the need to establish cut-offs for the biomarker of tumour mutational burden to identify the patients most likely to benefit from PDL1 treatment. The third session reviewed novel trial designs, including basket, umbrella and platform trials, and statistical approaches of hierarchical modelling where homogeneity between study cohorts enables information to be borrowed between cohorts. The discussion highlighted the need to agree 'common assessment standards' to facilitate pooling of data across studies. In the fourth session, the sharing of data sets was recognised as a key step for improving equity of access to precision medicines across Europe. The session considered how the European Health Data Space (EHDS) could streamline access to medical records, emphasizing the importance of introducing greater accountability into the digital space. In conclusion the workshop proposed 11 recommendations to facilitate histology agnostic drug development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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40. JASPAR 2024: 20th anniversary of the open-access database of transcription factor binding profiles.
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Rauluseviciute I, Riudavets-Puig R, Blanc-Mathieu R, Castro-Mondragon JA, Ferenc K, Kumar V, Lemma RB, Lucas J, Chèneby J, Baranasic D, Khan A, Fornes O, Gundersen S, Johansen M, Hovig E, Lenhard B, Sandelin A, Wasserman WW, Parcy F, and Mathelier A
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- Animals, Humans, Mice, Plants genetics, Databases, Genetic standards, Databases, Genetic trends, Protein Binding, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
JASPAR (https://jaspar.elixir.no/) is a widely-used open-access database presenting manually curated high-quality and non-redundant DNA-binding profiles for transcription factors (TFs) across taxa. In this 10th release and 20th-anniversary update, the CORE collection has expanded with 329 new profiles. We updated three existing profiles and provided orthogonal support for 72 profiles from the previous release's UNVALIDATED collection. Altogether, the JASPAR 2024 update provides a 20% increase in CORE profiles from the previous release. A trimming algorithm enhanced profiles by removing low information content flanking base pairs, which were likely uninformative (within the capacity of the PFM models) for TFBS predictions and modelling TF-DNA interactions. This release includes enhanced metadata, featuring a refined classification for plant TFs' structural DNA-binding domains. The new JASPAR collections prompt updates to the genomic tracks of predicted TF binding sites (TFBSs) in 8 organisms, with human and mouse tracks available as native tracks in the UCSC Genome browser. All data are available through the JASPAR web interface and programmatically through its API and the updated Bioconductor and pyJASPAR packages. Finally, a new TFBS extraction tool enables users to retrieve predicted JASPAR TFBSs intersecting their genomic regions of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2024
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41. Comprehensive interrogation of gene lists from genome-scale cancer screens with oncoEnrichR.
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Nakken S, Gundersen S, Bernal FLM, Polychronopoulos D, Hovig E, and Wesche J
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- Humans, Computational Biology methods, Software, Proteomics, Neoplasms genetics
- Abstract
Genome-scale screening experiments in cancer produce long lists of candidate genes that require extensive interpretation for biological insight and prioritization for follow-up studies. Interrogation of gene lists frequently represents a significant and time-consuming undertaking, in which experimental biologists typically combine results from a variety of bioinformatics resources in an attempt to portray and understand cancer relevance. As a means to simplify and strengthen the support for this endeavor, we have developed oncoEnrichR, a flexible bioinformatics tool that allows cancer researchers to comprehensively interrogate a given gene list along multiple facets of cancer relevance. oncoEnrichR differs from general gene set analysis frameworks through the integration of an extensive set of prior knowledge specifically relevant for cancer, including ranked gene-tumor type associations, literature-supported proto-oncogene and tumor suppressor gene annotations, target druggability data, regulatory interactions, synthetic lethality predictions, as well as prognostic associations, gene aberrations and co-expression patterns across tumor types. The software produces a structured and user-friendly analysis report as its main output, where versions of all underlying data resources are explicitly logged, the latter being a critical component for reproducible science. We demonstrate the usefulness of oncoEnrichR through interrogation of two candidate lists from proteomic and CRISPR screens. oncoEnrichR is freely available as a web-based service hosted by the Galaxy platform (https://oncotools.elixir.no), and can also be accessed as a stand-alone R package (https://github.com/sigven/oncoEnrichR)., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
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- 2023
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42. Chromosomal instability and a deregulated cell cycle are intrinsic features of high-risk gastrointestinal stromal tumours with a metastatic potential.
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Namløs HM, Khelik K, Nakken S, Vodák D, Hovig E, Myklebost O, Boye K, and Meza-Zepeda LA
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- Humans, Imatinib Mesylate therapeutic use, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local drug therapy, Cell Cycle, Recurrence, Gastrointestinal Stromal Tumors drug therapy, Antineoplastic Agents therapeutic use
- Abstract
Patients with localised, high-risk gastrointestinal stromal tumours (GIST) benefit from adjuvant imatinib treatment. Still, approximately 40% of patients relapse within 3 years after adjuvant therapy and the clinical and histopathological features currently used for risk classification cannot precisely predict poor outcomes after standard treatment. This study aimed to identify genomic and transcriptomic profiles that could be associated with disease relapse and thus a more aggressive phenotype. Using a multi-omics approach, we analysed a cohort of primary tumours from patients with untreated, resectable high-risk GISTs. We compared patients who developed metastatic disease within 3 years after finishing adjuvant imatinib treatment and patients without disease relapse after more than 5 years of follow-up. Combining genomics and transcriptomics data, we identified somatic mutations and deregulated mRNA and miRNA genes intrinsic to each group. Our study shows that increased chromosomal instability (CIN), including chromothripsis and deregulated kinetochore and cell cycle signalling, separates high-risk samples according to metastatic potential. The increased CIN seems to be an intrinsic feature for tumours that metastasise and should be further validated as a novel prognostic biomarker for high-risk GIST., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
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- 2023
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43. Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement.
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Møller P, Seppälä TT, Ahadova A, Crosbie EJ, Holinski-Feder E, Scott R, Haupt S, Möslein G, Winship I, Broeke SWB, Kohut KE, Ryan N, Bauerfeind P, Thomas LE, Evans DG, Aretz S, Sijmons RH, Half E, Heinimann K, Horisberger K, Monahan K, Engel C, Cavestro GM, Fruscio R, Abu-Freha N, Zohar L, Laghi L, Bertario L, Bonanni B, Tibiletti MG, Lino-Silva LS, Vaccaro C, Valle AD, Rossi BM, da Silva LA, de Oliveira Nascimento IL, Rossi NT, Dębniak T, Mecklin JP, Bernstein I, Lindblom A, Sunde L, Nakken S, Heuveline V, Burn J, Hovig E, Kloor M, Sampson JR, and Dominguez-Valentin M
- Abstract
The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer., (© 2023. BioMed Central.)
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- 2023
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44. A Breast Cancer Polygenic Risk Score Is Feasible for Risk Stratification in the Norwegian Population.
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Akdeniz BC, Mattingsdal M, Dominguez-Valentin M, Frei O, Shadrin A, Puustusmaa M, Saar R, Sõber S, Møller P, Andreassen OA, Padrik P, and Hovig E
- Abstract
Background: Statistical associations of numerous single nucleotide polymorphisms with breast cancer (BC) have been identified in genome-wide association studies (GWAS). Recent evidence suggests that a Polygenic Risk Score (PRS) can be a useful risk stratification instrument for a BC screening strategy, and a PRS test has been developed for clinical use. The performance of the PRS is yet unknown in the Norwegian population., Aim: To evaluate the performance of PRS models for BC in a Norwegian dataset., Methods: We investigated a sample of 1053 BC cases and 7094 controls from different regions of Norway. PRS values were calculated using four PRS models, and their performance was evaluated by the area under the curve (AUC) and the odds ratio (OR). The effect of the PRS on the age of onset of BC was determined by a Cox regression model, and the lifetime absolute risk of developing BC was calculated using the iCare tool., Results: The best performing PRS model included 3820 SNPs, which yielded an AUC = 0.625 and an OR = 1.567 per one standard deviation increase. The PRS values of the samples correlate with an increased risk of BC, with a hazard ratio of 1.494 per one standard deviation increase (95% confidence interval of 1.406-1.588). The individuals in the highest decile of the PRS have at least twice the risk of developing BC compared to the individuals with a median PRS. The results in this study with Norwegian samples are coherent with the findings in the study conducted using Estonian and UK Biobank samples., Conclusion: The previously validated PRS models have a similar observed accuracy in the Norwegian data as in the UK and Estonian populations. A PRS provides a meaningful association with the age of onset of BC and lifetime risk. Therefore, as suggested in Estonia, a PRS may also be integrated into the screening strategy for BC in Norway.
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- 2023
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45. hGSuite HyperBrowser: A web-based toolkit for hierarchical metadata-informed analysis of genomic tracks.
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Kalyanasundaram S, Lefol Y, Gundersen S, Rognes T, Alsøe L, Nilsen HL, Hovig E, Sandve GK, and Domanska D
- Subjects
- Genomics methods, Genome, Internet, Software, Metadata
- Abstract
Many high-throughput sequencing datasets can be represented as objects with coordinates along a reference genome. Currently, biological investigations often involve a large number of such datasets, for example representing different cell types or epigenetic factors. Drawing overall conclusions from a large collection of results for individual datasets may be challenging and time-consuming. Meaningful interpretation often requires the results to be aggregated according to metadata that represents biological characteristics of interest. In this light, we here propose the hierarchical Genomic Suite HyperBrowser (hGSuite), an open-source extension to the GSuite HyperBrowser platform, which aims to provide a means for extracting key results from an aggregated collection of high-throughput DNA sequencing data. The hGSuite utilizes a metadata-informed data cube to calculate various statistics across the multiple dimensions of the datasets. With this work, we show that the hGSuite and its associated data cube methodology offers a quick and accessible way for exploratory analysis of large genomic datasets. The web-based toolkit named hGsuite Hyperbrowser is available at https://hyperbrowser.uio.no/hgsuite under a GPLv3 license., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kalyanasundaram et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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46. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database.
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Dominguez-Valentin M, Haupt S, Seppälä TT, Sampson JR, Sunde L, Bernstein I, Jenkins MA, Engel C, Aretz S, Nielsen M, Capella G, Balaguer F, Evans DG, Burn J, Holinski-Feder E, Bertario L, Bonanni B, Lindblom A, Levi Z, Macrae F, Winship I, Plazzer JP, Sijmons R, Laghi L, Della Valle A, Heinimann K, Dębniak T, Fruscio R, Lopez-Koestner F, Alvarez-Valenzuela K, Katz LH, Laish I, Vainer E, Vaccaro C, Carraro DM, Monahan K, Half E, Stakelum A, Winter D, Kennelly R, Gluck N, Sheth H, Abu-Freha N, Greenblatt M, Rossi BM, Bohorquez M, Cavestro GM, Lino-Silva LS, Horisberger K, Tibiletti MG, Nascimento ID, Thomas H, Rossi NT, Apolinário da Silva L, Zaránd A, Ruiz-Bañobre J, Heuveline V, Mecklin JP, Pylvänäinen K, Renkonen-Sinisalo L, Lepistö A, Peltomäki P, Therkildsen C, Madsen MG, Burgdorf SK, Hopper JL, Win AK, Haile RW, Lindor N, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo J, Buchanan DD, Thibodeau SN, von Knebel Doeberitz M, Loeffler M, Rahner N, Schröck E, Steinke-Lange V, Schmiegel W, Vangala D, Perne C, Hüneburg R, Redler S, Büttner R, Weitz J, Pineda M, Duenas N, Vidal JB, Moreira L, Sánchez A, Hovig E, Nakken S, Green K, Lalloo F, Hill J, Crosbie E, Mints M, Goldberg Y, Tjandra D, Ten Broeke SW, Kariv R, Rosner G, Advani SH, Thomas L, Shah P, Shah M, Neffa F, Esperon P, Pavicic W, Torrezan GT, Bassaneze T, Martin CA, Moslein G, and Moller P
- Abstract
Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants ( path_MMR ) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time., Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender., Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers., Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome., Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017., Competing Interests: R.B. has received honoraria for lectures and advisory boards from AbbVie, Amgen, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Illumina, Lilly, Merck-Serono, MSD, Novartis, Qiagen, Pfizer, Roche, and Targos MP Inc. R.B. is a Co-Founder and Scientific Advisor for Targos Mol. Pathology Inc. Kassel/Germany. T.T.S. is the CEO and co-owner of Healthfund Finland Oy and reports consultation fees from Boehringer Ingelheim Finland and Amgen. FB is supported by JANSSEN PHARMACEUTICALS (clinical trial for Familial Adenomatous polyposis). RH is supported by the 10.13039/501100002424Fujifilm Germany and Janssen-Pharmaceuticals. LK is consultant of Sandoz, Novartis and Abbott. GM reports consultancy fees from Johnson & Johnson., (© 2023 The Author(s).)
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- 2023
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47. Cooperative induction of receptor tyrosine kinases contributes to adaptive MAPK drug resistance in melanoma through the PI3K pathway.
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Alver TN, Heintz KM, Hovig E, and Bøe SL
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- Humans, Vemurafenib therapeutic use, Indoles pharmacology, Indoles therapeutic use, Sulfonamides pharmacology, Sulfonamides therapeutic use, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Proto-Oncogene Proteins B-raf therapeutic use, Receptor Protein-Tyrosine Kinases genetics, Receptor Protein-Tyrosine Kinases metabolism, Receptor Protein-Tyrosine Kinases therapeutic use, Drug Resistance, Neoplasm genetics, Tyrosine therapeutic use, Phosphatidylinositol 3-Kinases therapeutic use, Melanoma drug therapy
- Abstract
Vemurafenib-induced drug resistance in melanoma has been linked to receptor tyrosine kinase (RTK) upregulation. The MITF and SOX10 genes play roles as master regulators of melanocyte and melanoma development. Here, we aimed to explore the complex mechanisms behind the MITF/SOX10-controlled RTK-induced drug resistance in melanoma. To achieve this, we used a number of molecular techniques, including melanoma patient data from TCGA, vemurafenib-resistant melanoma cell lines, and knock-down studies. The melanoma cell lines were classified as proliferative or invasive based upon their MITF/AXL expression activity. We measured the change of expression activity for MITF/SOX10 and their receptor (AXL/ERBB3) and ligand (NRG1/GAS6) targets known to be involved in RTK-induced drug resistance after vemurafenib treatment. We find that melanoma cell lines characterized as proliferative (high MITF low AXL), transform into an invasive (low MITF, high AXL) cell state after vemurafenib resistance, indicating novel feedback loops and advanced compensatory regulation mechanisms between the master regulators, receptors, and ligands involved in vemurafenib-induced resistance. Together, our data disclose fine-tuned mechanisms involved in RTK-facilitated vemurafenib resistance that will be challenging to overcome by using single drug targeting strategies against melanoma., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)
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- 2023
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48. The genetic history of Scandinavia from the Roman Iron Age to the present.
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Rodríguez-Varela R, Moore KHS, Ebenesersdóttir SS, Kilinc GM, Kjellström A, Papmehl-Dufay L, Alfsdotter C, Berglund B, Alrawi L, Kashuba N, Sobrado V, Lagerholm VK, Gilbert E, Cavalleri GL, Hovig E, Kockum I, Olsson T, Alfredsson L, Hansen TF, Werge T, Munters AR, Bernhardsson C, Skar B, Christophersen A, Turner-Walker G, Gopalakrishnan S, Daskalaki E, Omrak A, Pérez-Ramallo P, Skoglund P, Girdland-Flink L, Gunnarsson F, Hedenstierna-Jonson C, Gilbert MTP, Lidén K, Jakobsson M, Einarsson L, Victor H, Krzewińska M, Zachrisson T, Storå J, Stefánsson K, Helgason A, and Götherström A
- Subjects
- Humans, Europe, Genetic Variation, Scandinavian and Nordic Countries, United Kingdom, White People genetics, White People history, Human Migration, Genome, Human
- Abstract
We investigate a 2,000-year genetic transect through Scandinavia spanning the Iron Age to the present, based on 48 new and 249 published ancient genomes and genotypes from 16,638 modern individuals. We find regional variation in the timing and magnitude of gene flow from three sources: the eastern Baltic, the British-Irish Isles, and southern Europe. British-Irish ancestry was widespread in Scandinavia from the Viking period, whereas eastern Baltic ancestry is more localized to Gotland and central Sweden. In some regions, a drop in current levels of external ancestry suggests that ancient immigrants contributed proportionately less to the modern Scandinavian gene pool than indicated by the ancestry of genomes from the Viking and Medieval periods. Finally, we show that a north-south genetic cline that characterizes modern Scandinavians is mainly due to the differential levels of Uralic ancestry and that this cline existed in the Viking Age and possibly earlier., Competing Interests: Declaration of interests A.H., K.H.S.M., K.S., and S.S.E. are employees of deCODE genetics., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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49. screenwerk: a modular tool for the design and analysis of drug combination screens.
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Hanes R, Ayuda-Durán P, Rønneberg L, Nakken S, Hovig E, Zucknick M, and Enserink JM
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- Drug Combinations, Data Analysis, High-Throughput Screening Assays, Software, Documentation
- Abstract
Motivation: There is a rapidly growing interest in high-throughput drug combination screening to identify synergizing drug interactions for treatment of various maladies, such as cancer and infectious disease. This creates the need for pipelines that can be used to design such screens, perform quality control on the data and generate data files that can be analyzed by synergy-finding bioinformatics applications., Results: screenwerk is an open-source, end-to-end modular tool available as an R-package for the design and analysis of drug combination screens. The tool allows for a customized build of pipelines through its modularity and provides a flexible approach to quality control and data analysis. screenwerk is adaptable to various experimental requirements with an emphasis on precision medicine. It can be coupled to other R packages, such as bayesynergy, to identify synergistic and antagonistic drug interactions in cell lines or patient samples. screenwerk is scalable and provides a complete solution for setting up drug sensitivity screens, read raw measurements and consolidate different datasets, perform various types of quality control and analyze, report and visualize the results of drug sensitivity screens., Availability and Implementation: The R-package and technical documentation is available at https://github.com/Enserink-lab/screenwerk; the R source code is publicly available at https://github.com/Enserink-lab/screenwerk under GNU General Public License v3.0; bayesynergy is accessible at https://github.com/ocbe-uio/bayesynergy. Selected modules are available through Galaxy, an open-source platform for FAIR data analysis at https://oncotools.elixir.no., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)
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- 2023
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50. T cell receptor repertoire sequencing reveals chemotherapy-driven clonal expansion in colorectal liver metastases.
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Høye E, Dagenborg VJ, Torgunrud A, Lund-Andersen C, Fretland ÅA, Lorenz S, Edwin B, Hovig E, Fromm B, Inderberg EM, Greiff V, Ree AH, and Flatmark K
- Subjects
- Humans, Receptors, Antigen, T-Cell genetics, Liver Neoplasms drug therapy, Liver Neoplasms genetics, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics
- Abstract
Background: Colorectal liver metastasis (CLM) is a leading cause of colorectal cancer mortality, and the response to immune checkpoint inhibition (ICI) in microsatellite-stable CRC has been disappointing. Administration of cytotoxic chemotherapy may cause increased density of tumor-infiltrating T cells, which has been associated with improved response to ICI. This study aimed to quantify and characterize T-cell infiltration in CLM using T-cell receptor (TCR) repertoire sequencing. Eighty-five resected CLMs from patients included in the Oslo CoMet study were subjected to TCR repertoire sequencing. Thirty-five and 15 patients had received neoadjuvant chemotherapy (NACT) within a short or long interval, respectively, prior to resection, while 35 patients had not been exposed to NACT. T-cell fractions were calculated, repertoire clonality was analyzed based on Hill evenness curves, and TCR sequence convergence was assessed using network analysis., Results: Increased T-cell fractions (10.6% vs. 6.3%) were detected in CLMs exposed to NACT within a short interval prior to resection, while modestly increased clonality was observed in NACT-exposed tumors independently of the timing of NACT administration and surgery. While private clones made up >90% of detected clones, network connectivity analysis revealed that public clones contributed the majority of TCR sequence convergence., Conclusions: TCR repertoire sequencing can be used to quantify T-cell infiltration and clonality in clinical samples. This study provides evidence to support chemotherapy-driven T-cell clonal expansion in CLM in a clinical context., (© The Author(s) 2023. Published by Oxford University Press GigaScience.)
- Published
- 2022
- Full Text
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