| 1. |
- Demichev, Vadim, et al.
(author)
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A time-resolved proteomic and prognostic map of COVID-19
- 2021
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In: Cell Systems. - : Elsevier BV. - 2405-4712 .- 2405-4720. ; 12:8, s. 780-794.e7
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Journal article (peer-reviewed)abstract
- COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.
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| 2. |
- Rollings, N., et al.
(author)
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Sperm telomere length correlates with blood telomeres and body size in red-sided garter snakes, Thamnophis sirtalis parietalis
- 2020
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In: Journal of Zoology. - : Wiley. - 0952-8369 .- 1469-7998. ; 312:1, s. 21-31
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Journal article (peer-reviewed)abstract
- Telomeres, tandem repeats of TTAGGG at the ends of chromosomes, are highly dynamic structures that shorten in response to a variety of factors, including organismal stress and tissue-specific growth rates. Cell turnover rates are frequently linked to their functions, resource availability and telomere dynamics. Using male red-sided garter snakes, Thamnophis sirtalis parietalis, as a model, we investigated the relationship between telomere length in sperm cells, blood cells telomere length and a growth proxy (age-adjusted body length and mass). This relationship is interesting because snakes exhibit indeterminate growth and because these garter snakes have a dissociated reproductive cycle where spermatogenesis occurs months prior to the mating season. In this study, we determined sperm telomere length (STL) and male age using qPCR and skeletochronology, respectively. Sperm telomere length correlated positively with snout-vent length (SVL) and with age-adjusted SVL as a proxy for growth rate (residuals of size against age regression, hereafter growth), but not with age. Although an individual's STL is correlated with blood telomere length (BTL), sperm telomeres are 60% longer than blood telomeres. In previous work, we have shown that BTL is shorter in older males and unrelated to SVL or any growth rate proxies. We hypothesized that STL is related to growth and SVL because growth and sperm production both occur during summer when resources are most abundant and stress lowest. This study is the first to compare telomere dynamics between cell types in a snake and supports growing evidence that telomere dynamics may be highly tissue-specific and driven by the life-history strategy of an organism.
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| 3. |
- Schöpf, Julia, et al.
(author)
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Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions
- 2024
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In: Nature Communications. - 2041-1723. ; 15, s. 1-17
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Journal article (peer-reviewed)abstract
- Linking clinical multi-omics with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling demonstrates a close relationship with undifferentiated sarcomas. In two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, indicating stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers.
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