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Veröffentlichungen der HSWT

Die chronologische Liste zeigt aktuelle Veröffentlichungen aus dem Forschungsbetrieb der Hochschule Weihenstephan-Triesdorf. Zuständig ist das Zentrum für Forschung und Wissenstransfer (ZFW).

8 Ergebnisse

  • Peter Brown, . ..., Prof. Dr. Dominik Grimm, . ..., Yaoqi Zhou

    • Berechtigungen:  Open Access
    • Berechtigungen:  Peer Reviewed

    Large expert-curated database for benchmarking document similarity detection in biomedical literature search (2019) Database 2019 . DOI: 10.1093/database/baz085

    AbstractDocument recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcHconsortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.

  • Elena Castellanos-Rizaldos, Xuan Zhang, Vasisht R. Tadigotla, Prof. Dr. Dominik Grimm, Chris Karlovich, Luis E. Raez, Johan K. Skog

    • Berechtigungen:  Open Access
    • Berechtigungen:  Peer Reviewed

    Exosome-based detection of activating and resistance EGFR mutations from plasma of non-small cell lung cancer patients (2019) Oncotarget 10 (30), S. 2911-2920. DOI: 10.18632/oncotarget.26885

    Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer and its molecular landscape has been extensively studied. The most common genetic alterations in NSCLC are mutations within the epidermal growth factor receptor (EGFR) gene, with frequencies between 10-40%. There are several molecular targeted therapies for patients harboring these mutations.Liquid biopsies constitute a flexible approach to monitor these mutations in real time as opposed to tissue biopsies that represent a single snap-shot in time. However, interrogating cell free DNA (cfDNA) has inherent biological limitations, especially at early or localized disease stages, where there is not enough tumor material released into the patient’s circulation.We developed a qPCR- based test (ExoDx EGFR) that interrogates mutations within EGFR using Exosomal RNA/DNA and cfDNA (ExoNA) derived from plasma in a cohort of 110 NSCLC patients.The performance of the assay yielded an overall sensitivity of 90% for L858R, 83% for T790M and 73% for exon 19 indels with specificities of 100%, 100%, and 96% respectively. In a subcohort of patients with extrathoracic disease (M1b and MX) the sensitivities were 92% (L858R), 95% (T790M), and 86% (exon 19 indels) with specificity of 100%, 100% and 94% respectively.

  • Anja Gumpinger, Damian Roqueiro, Prof. Dr. Dominik Grimm, Karsten Borgwardt

    Methods and Tools in Genome-Wide Association Studies (2018) Computational Cell Biology . DOI: 10.1007/978-1-4939-8618-7_5

  • Elena Castellanos-Rizaldos, Prof. Dr. Dominik Grimm, Vasisht R. Tadigotla, James Hurley, John Healy, Patricia L. Neal, Mia Sher, Raajdeep Venkatesan, Chris Karlovich, Mitch Raponi, Anne Krug, Mikkel Noerholm, Jihane Tannous, Bakhos A. Tannous, Luis E. Raez, Johan K. Skog

    • Berechtigungen:  Open Access
    • Berechtigungen:  Peer Reviewed

    Exosome-Based Detection of EGFR T790M in Plasma from Non–Small Cell Lung Cancer Patients (2018) Clinical Cancer Research 24 (12), S. 2944-2950. DOI: 10.1158/1078-0432.CCR-17-3369

    Purpose: About 60% of non–small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third-generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a noninvasive option to detect the mutation; however, sensitivity is low as many patients have too few detectable copies in circulation. Here, we have developed and validated a novel test that overcomes the limited abundance of the mutation by simultaneously capturing and interrogating exosomal RNA/DNA and cfDNA (exoNA) in a single step followed by a sensitive allele-specific qPCR.Experimental Design: ExoNA was extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) and T790M-negative (N = 108) samples. The T790M mutation status was determined using an analytically validated allele-specific qPCR assay in a Clinical Laboratory Improvement Amendment laboratory.Results: Detection of the T790M mutation on exoNA achieved 92% sensitivity and 89% specificity using tumor biopsy results as gold standard. We also obtained high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), for whom detection by liquid biopsy has been particularly challenging.Conclusions: The combination of exoRNA/DNA and cfDNA for T790M detection has higher sensitivity and specificity compared with historical cohorts using cfDNA alone. This could further help avoid unnecessary tumor biopsies for T790M mutation testing.

  • Jan M. Falcke, Neelanjan Bose, Alexander B. Artyukhin, Christian Rödelsperger, Gabriel V. Markov, Joshua J. Yim, Prof. Dr. Dominik Grimm, Marc H. Claassen, Oishika Panda, Joshua A. Baccile, Ying K. Zhang, Henry H. Le, Dino Jolic, Frank C. Schroeder, Ralf J. Sommer

    • Berechtigungen:  Open Access
    • Berechtigungen:  Peer Reviewed

    Linking Genomic and Metabolomic Natural Variation Uncovers Nematode Pheromone Biosynthesis (2018) Cell Chemical Biology 25 (6), S. 787-796. DOI: 10.1016/j.chembiol.2018.04.004

    In the nematodes Caenorhabditis elegans and Pristionchus pacificus, a modular library of small molecules control behavior, lifespan, and development. However, little is known about the final steps of their biosynthesis, in which diverse building blocks from primary metabolism are attached to glycosides of the dideoxysugar ascarylose, the ascarosides. We combine metabolomic analysis of natural isolates of P. pacificuswith genome-wide association mapping to identify a putative carboxylesterase, Ppa-uar-1, that is required for attachment of a pyrimidine-derived moiety in the biosynthesis of ubas#1, a major dauer pheromone component. Comparative metabolomic analysis of wild-type and Ppa-uar-1 mutants showed that Ppa-uar-1 is required specifically for the biosynthesis of ubas#1 and related metabolites. Heterologous expression of Ppa-UAR-1 in C. elegans yielded a non-endogenous ascaroside, whose structure confirmed that Ppa-uar-1 is involved in modification of a specific position in ascarosides. Our study demonstrates the utility of natural variation-based approaches for uncovering biosynthetic pathways.

  • Moises Exposito-Alonso, Claude Becker, Verena J. Schuenemann, Ella Reiter, Claudia Setzer, Radka Slovak, Benjamin Brachi, Jörg Hagmann, Prof. Dr. Dominik Grimm, Jiahui Chen, Wolfgang Busch, Joy Bergelson, Rob W. Ness, Detlef Weigel

    • Berechtigungen:  Open Access
    • Berechtigungen:  Peer Reviewed

    The rate and potential relevance of new mutations in a colonizing plant lineage (2018) PLoS Genetics 14 (2). DOI: 10.1371/journal.pgen.1007155

    By following the evolution of populations that are initially genetically homogeneous, much can be learned about core biological principles. For example, it allows for detailed studies of the rate of emergence of de novo mutations and their change in frequency due to drift and selection. Unfortunately, in multicellular organisms with generation times of months or years, it is difficult to set up and carry out such experiments over many generations. An alternative is provided by “natural evolution experiments” that started from colonizations or invasions of new habitats by selfing lineages. With limited or missing gene flow from other lineages, new mutations and their effects can be easily detected. North America has been colonized in historic times by the plant Arabidopsis thaliana, and although multiple intercrossing lineages are found today, many of the individuals belong to a single lineage, HPG1. To determine in this lineage the rate of substitutions—the subset of mutations that survived natural selection and drift–, we have sequenced genomes from plants collected between 1863 and 2006. We identified 73 modern and 27 herbarium specimens that belonged to HPG1. Using the estimated substitution rate, we infer that the last common HPG1 ancestor lived in the early 17th century, when it was most likely introduced by chance from Europe. Mutations in coding regions are depleted in frequency compared to those in other portions of the genome, consistent with purifying selection. Nevertheless, a handful of mutations is found at high frequency in present-day populations. We link these to detectable phenotypic variance in traits of known ecological importance, life history and growth, which could reflect their adaptive value. Our work showcases how, by applying genomics methods to a combination of modern and historic samples from colonizing lineages, we can directly study new mutations and their potential evolutionary relevance.

  • Matteo Togninalli, Ümit Seren, Dazhe Meng, Joffrey Fitz, Magnus Nordborg, Detlef Weigel, Karsten Borgwardt, Arthur Korte, Prof. Dr. Dominik Grimm

    • Berechtigungen:  Open Access
    • Berechtigungen:  Peer Reviewed

    The AraGWAS Catalog: a curated and standardized Arabidopsis thaliana GWAS catalog (2018) Nucleic Acids Research 46 (1), S. 1150-1156. DOI: 10.1093/nar/gkx954

    The abundance of high-quality genotype and phenotype data for the model organism Arabidopsis thaliana enables scientists to study the genetic architecture of many complex traits at an unprecedented level of detail using genome-wide association studies (GWAS). GWAS have been a great success in A. thaliana and many SNP-trait associations have been published. With the AraGWAS Catalog (https://aragwas.1001genomes.org) we provide a publicly available, manually curated and standardized GWAS catalog for all publicly available phenotypes from the central A. thaliana phenotype repository, AraPheno. All GWAS have been recomputed on the latest imputed genotype release of the 1001 Genomes Consortium using a standardized GWAS pipeline to ensure comparability between results. The catalog includes currently 167 phenotypes and more than 222 000 SNP-trait associations with P < 10−4, of which 3887 are significantly associated using permutation-based thresholds. The AraGWAS Catalog can be accessed via a modern web-interface and provides various features to easily access, download and visualize the results and summary statistics across GWAS.

  • Anne Krug, Daniel Enderle, Chris Karlovich, Tina Priewasser, Stefan Bentink, Alexandra Spiel, Kay Brinkmann, Jennifer N. Emenegger, Prof. Dr. Dominik Grimm, Elena Castellanos-Rizaldos, Jonathan W. Goldman, Lecia Van Dam Sequist, Jean-Charles Soria, David Ross Camidge, S. M. Gadgeel, Heather A. Wakelee, Mitch Raponi, Mikkel Noerholm, Johan K. Skog

    • Berechtigungen:  Open Access
    • Berechtigungen:  Peer Reviewed

    Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma (2017) Annals of Oncology 29 (3), S. 700-706. DOI: 10.1093/annonc/mdx765

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