| 1. |
- Braekeveldt, Noémie, et al.
(författare)
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Patient-derived xenograft models reveal intratumor heterogeneity and temporal stability in neuroblastoma
- 2018
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Ingår i: Cancer Research. - 0008-5472. ; 78:20, s. 5958-5969
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Tidskriftsartikel (refereegranskat)abstract
- Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research.
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| 2. |
- Hammenhag, Cecilia, et al.
(författare)
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Identification of genes regulating traits targeted for domestication of field cress (Lepidium campestre) as a biennial and perennial oilseed crop
- 2018
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: The changing climate and the desire to use renewable oil sources necessitate the development of new oilseed crops. Field cress (Lepidium campestre) is a species in the Brassicaceae family that has been targeted for domestication not only as an oilseed crop that produces seeds with a desirable industrial oil quality but also as a cover/catch crop that provides valuable ecosystem services. Lepidium is closely related to Arabidopsis and display significant proportions of syntenic regions in their genomes. Arabidopsis genes are among the most characterized genes in the plant kingdom and, hence, comparative genomics of Lepidium-Arabidopsis would facilitate the identification of Lepidium candidate genes regulating various desirable traits.Results: Homologues of 30 genes known to regulate vernalization, flowering time, pod shattering, oil content and quality in Arabidopsis were identified and partially characterized in Lepidium. Alignments of sequences representing field cress and two of its closely related perennial relatives: L. heterophyllum and L. hirtum revealed 243 polymorphic sites across the partial sequences of the 30 genes, of which 95 were within the predicted coding regions and 40 led to a change in amino acids of the target proteins. Within field cress, 34 polymorphic sites including nine nonsynonymous substitutions were identified. The phylogenetic analysis of the data revealed that field cress is more closely related to L. heterophyllum than to L. hirtum.Conclusions: There is significant variation within and among Lepidium species within partial sequences of the 30 genes known to regulate traits targeted in the present study. The variation within these genes are potentially useful to speed-up the process of domesticating field cress as future oil crop. The phylogenetic relationship between the Lepidium species revealed in this study does not only shed some light on Lepidium genome evolution but also provides important information to develop efficient schemes for interspecific hybridization between different Lepidium species as part of the domestication efforts.
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| 3. |
- Walter, Abigail, et al.
(författare)
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RNA seq analysis of potato cyst nematode interactions with resistant and susceptible potato roots
- 2018
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Ingår i: European Journal of Plant Pathology. - : Springer Science and Business Media LLC. - 0929-1873 .- 1573-8469. ; 152, s. 531-539
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Tidskriftsartikel (refereegranskat)abstract
- Potato cyst nematodes (PCN) are important pests in crop production, especially since they persist in the soil and may affect further potato production for many years. Little is known about putative resistance and susceptibility targets as well as the general signaling in potato after interactions with PCN. Here we characterize a new potato breeding clone, SW-1015, found to harbor resistance to Globodera rostochiensis pathotype Ro1/4, the main PCN pathotype present in Sweden. SW-1015 contains the H1 resistance gene. We then describe susceptible and resistant reactions of potato infested by G. rostochiensis Ro1/4 in a global potato RNA-seq analysis. Only the resistant clone reacted to PCN infection quickly (8 hpi), and the reaction included up-regulation of a TSRF1 transcription factor. 48h after PCN infection, massive RNA reprograming was evident in both resistant and susceptible clones. In the resistant interaction, several genes were up-regulated including germins and a cysteine protease, as well as a laccase. In contrast, the susceptible interaction involved up-regulation of genes for auxin transport and homeobox binding. Enriched GO terms for kinase activity, calmodulin, and Ca2+ ion binding in susceptible potato might reflect the initiation of nematode feeding structures. A TIR receptor like protein member was induced in the susceptible interaction only, making this a putative susceptibility factor. The RNA data is deposited at ArrayExpress with the number E-MTAB-5215.
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| 4. |
- Willforss, Jakob
(författare)
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Interpretation of variation in omics data : Applications in proteomics for sustainable agriculture
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Biomarkers are used in molecular biology to predict characteristics of interest and are applied in agriculture to accelerate the breeding of target traits. Proteomics has emerged as a promising technology for improved markers by providing a closer view to the phenotype than conventional genome-based approaches. However, a major challenge for biomarker development is that the identified biological patterns often cannot be reproduced in other studies. One piece of the puzzle to alleviate this problem is improved software approaches to distinguish biological variation from noise in the data.In this work, two new pieces of software are introduced to facilitate interpretation of data from omic experiments. NormalyzerDE (Paper I) helps the user to perform an informed selection of a well-performing normalization technique, presents a new type of normalization for electrospray intensity variation biases and gives a user-friendly approach to performing subsequent statistical analysis. OmicLoupe (Paper II) provides interactive visualizations of up to two omics datasets, introduces novel approaches for the comparison of different datasets and provides the ability to rapidly inspect individual features. These pieces of software were applied together with existing methods to study three agricultural organisms. Firstly, a proteogenomic approach was used to study Fusarium head blight in oat. This study provided the deepest proteomic resource to date in this organism (Paper III) and identified proteins related to a differential resistance towards Fusarium head blight. It can contribute towards the development of commercial varieties with improved resistance towards this pathogen. Secondly, bull seminal plasma was studied to identify proteins correlated with fertility, which are also robust to seasonal variation (Paper IV). This study contributes towards ensuring maintained high fertility in livestock. Finally, potato grown at sites in northern and southern Sweden (Paper V) were studied to identify proteins linked to the different growth conditions at the two locations. This study contributes towards a better understanding of the molecular physiology in the agricultural field and the selection of varieties better adapted to the different growth conditions.In conclusion, these results contribute towards improved analyses of omics data and to biomarkers with potential applications in accelerated breeding in the studied organisms. Together, this could provide tools for the development of a more sustainable agriculture.
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| 5. |
- Willforss, Jakob, et al.
(författare)
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NormalyzerDE : Online Tool for Improved Normalization of Omics Expression Data and High-Sensitivity Differential Expression Analysis
- 2019
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 18:2, s. 732-740
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Tidskriftsartikel (refereegranskat)abstract
- Technical biases are introduced in omics data sets during data generation and interfere with the ability to study biological mechanisms. Several normalization approaches have been proposed to minimize the effects of such biases, but fluctuations in the electrospray current during liquid chromatography-mass spectrometry gradients cause local and sample-specific bias not considered by most approaches. Here we introduce a software named NormalyzerDE that includes a generic retention time (RT)-segmented approach compatible with a wide range of global normalization approaches to reduce the effects of time-resolved bias. The software offers straightforward access to multiple normalization methods, allows for data set evaluation and normalization quality assessment as well as subsequent or independent differential expression analysis using the empirical Bayes Limma approach. When evaluated on two spike-in data sets the RT-segmented approaches outperformed conventional approaches by detecting more peptides (8-36%) without loss of precision. Furthermore, differential expression analysis using the Limma approach consistently increased recall (2-35%) compared to analysis of variance. The combination of RT-normalization and Limma was in one case able to distinguish 108% (2597 vs 1249) more spike-in peptides compared to traditional approaches. NormalyzerDE provides widely usable tools for performing normalization and evaluating the outcome and makes calculation of subsequent differential expression statistics straightforward. The program is available as a web server at http://quantitativeproteomics.org/normalyzerde.
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| 6. |
- Willforss, Jakob, et al.
(författare)
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OmicLoupe : facilitating biological discovery by interactive exploration of multiple omic datasets and statistical comparisons
- 2021
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Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Visual exploration of gene product behavior across multiple omic datasets can pinpoint technical limitations in data and reveal biological trends. Still, such exploration is challenging as there is a need for visualizations that are tailored for the purpose. Results: The OmicLoupe software was developed to facilitate visual data exploration and provides more than 15 interactive cross-dataset visualizations for omics data. It expands visualizations to multiple datasets for quality control, statistical comparisons and overlap and correlation analyses, while allowing for rapid inspection and downloading of selected features. The usage of OmicLoupe is demonstrated in three different studies, where it allowed for detection of both technical data limitations and biological trends across different omic layers. An example is an analysis of SARS-CoV-2 infection based on two previously published studies, where OmicLoupe facilitated the identification of gene products with consistent expression changes across datasets at both the transcript and protein levels. Conclusions: OmicLoupe provides fast exploration of omics data with tailored visualizations for comparisons within and across data layers. The interactive visualizations are highly informative and are expected to be useful in various analyses of both newly generated and previously published data. OmicLoupe is available at quantitativeproteomics.org/omicloupe
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