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Germany's national genomDE strategy
No full textGermany is paving the way toward genomics-based personalized healthcare and translational research
Reproducibility assessment of biventricular strain derived from long-axis feature tracking in travelling volunteers - a study in the Berlin research network for cardiovascular magnetic resonance (BER-CMR)
Get PDFPURPOSE: To evaluate the reproducibility of biventricular global longitudinal strain (GLS) assessment using cardiovascular magnetic resonance in a multicenter study of travelling volunteers. METHODS: Twenty travelling volunteers were prospectively scanned at four sites with same-vendor scanners at 3.0T (sites I, II, III) and 1.5T (site IV). Cine imaging in three long-axis views was performed using a segmented balanced steady-state free precession sequence with 30 cardiac phases except site II with 25 phases. RESULTS: Imaging and post-processing were carried out successfully for 18 volunteers in a core lab setting. Pairwise comparisons revealed significant differences in left ventricular (LV) GLS between sites I and II (p < 0.001) and sites II and IV (p = 0.013), as well as in right ventricular (RV) GLS between sites I and IV (p = 0.027). RV GLS values were significantly higher at 3.0T (p = 0.024), whereas field strength had no significant impact on LV GLS (p = 0.153). Conversely, the use of 25 cardiac phases at site II was associated with significantly lower LV GLS values (p < 0.001), while RV GLS remained unaffected (p = 0.825). CONCLUSION: When applying feature tracking-based strain in a multicenter study, careful consideration should be given to the temporal resolution for LV longitudinal strain and to magnetic field strength for RV longitudinal strain
Extrachromosomal circular DNA promotes inflammation and hepatocellular carcinoma development
Get PDFTwo decades after the initial report on increased micronuclei in human chronic liver disease (CLD) and hepatocellular carcinoma (HCC), their role in HCC development is still poorly understood. Here, we show that micronuclei in hepatocytes trigger a hepatic immune response and promote HCC development via an increased level of extrachromosomal circular DNA (eccDNA). Livers of a CLD model (Mcl1(Δhep) mice) show increased micronuclei and eccDNA levels. Circular sequencing confirms higher eccDNA levels in micronuclei compared to primary nuclei. The nuclei-segregated DNA fiber (NuSeF) assay we developed demonstrates that micronuclei are more susceptible to replication stress, exhibiting increased replication fork slowing. Comparing different murine liver disease models reveals that high eccDNA correlates with an increased tumor incidence. eccDNA is a strong immunostimulant and promotes a cross-talk between hepatocytes and immune cells through the cGAS-STING pathway. Deletion of Sting1 in Mcl1(Δhep) mice reduces immune cell chemotaxis and tumor incidence. Our findings suggest that eccDNA from micronuclei mediates inflammation-driven liver carcinogenesis in CLD
Can synthetic data reproduce real-world findings in epidemiology? A replication study using tree-based generative AI
No full textGenerative artificial intelligence for synthetic data generation holds substantial potential to address practical challenges in epidemiology. However, many current methods suffer from limited quality, high computational demands, and complexity for non-experts. Furthermore, common evaluation strategies for synthetic data often fail to directly reflect statistical utility. Against this background, a critical underexplored question is whether synthetic data can reliably reproduce key findings from epidemiological research. We propose the use of adversarial random forests (ARF) as an efficient and convenient method for synthesizing tabular epidemiological data. To evaluate its performance, we replicated statistical analyses from six epidemiological publications and compared original with synthetic results. These publications cover blood pressure, anthropometry, myocardial infarction, accelerometry, loneliness, and diabetes, based on data from the German National Cohort (NAKO Gesundheitsstudie), the Bremen STEMI Registry U45 Study, and the Guelph Family Health Study. Additionally, we assessed the impact of dimensionality and variable complexity on synthesis quality by limiting datasets to variables relevant for individual analyses, including necessary derivations. Across all replicated original studies, results from multiple synthetic data replications consistently aligned with original findings. Even for datasets with relatively low sample size-to-dimensionality ratios, the replication outcomes closely matched the original results across various descriptive and inferential analyses. Reducing dimensionality and pre-deriving variables further enhanced both quality and stability of the results. In summary, ARF reliably generates high-quality synthetic data that replicate epidemiological study findings across diverse scenarios, supporting its practical use for applications such as rapid prototyping and data sharing under appropriate privacy and regulatory considerations
Cell-based immune anticipation of the omicron variant in SARS-CoV-2 triple-vaccinated cancer patients
Get PDFSARS-CoV-2 infections affect healthcare systems worldwide. Patients with cancer, a particularly vulnerable group, and oncology care takers were offered early access to mRNA-based vaccinations. We report the dynamics of humoral and cellular immune response parameters of 74 patients with cancer and 12 control participants after two basal vaccinations and a booster six months later. Upon booster vaccination, 78% of patients with tumor under active therapy (versus 50.8% prior to the boost) exhibited humoral and cellular spike protein responses, as compared to 100% and 73.3%, respectively, in those without active therapy. Conducted prior to the emergence of the Omicron variant of concern, we found Wuhan-Hu-1 spike-encoding mRNA vaccination to evoke T cell responses against peptides outside and within the Omicron-mutated region of the spike protein. The vast majority of patients with cancer achieved significant antibody titers upon repeated vaccinations. Accordingly, patients with tumor appeared well-protected, indicated by asymptomatic or mild breakthrough infections during the Omicron wave
Spatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets
No full textHigh-grade serous ovarian cancer (HGSOC) is often detected at an advanced stage, where curative treatment options are limited. Recent advances in ultrasensitive mass spectrometry-based spatial proteomics have provided a unique opportunity to uncover molecular drivers of early tumorigenesis and novel therapeutic targets. Here, we present a comprehensive proteomic analysis of serous tubal intraepithelial carcinoma (STIC), the HGSOC precursor lesion, and concurrent invasive carcinoma, covering more than 10,000 proteins from ultra-low input archival tissue. STIC and HGSOC showed highly similar proteomes, clustering into two subtypes with distinct tumor immune microenvironments and common remodelling of the extracellular matrix. We discovered cell-of-origin signatures from secretory fallopian tube epithelial cells in STICs and identified early dysregulated pathways of therapeutic relevance. Targeting cholesterol biosynthesis by inhibiting the terminal steps via DHCR7 showed therapeutic effects in ovarian cancer cell lines and synergized with standard-of-care carboplatin treatment. This study demonstrates the power of spatially resolved quantitative proteomics in understanding early carcinogenesis and provides a rich resource for biomarker and drug target research
Microglia from patients with multiple sclerosis display a cell-autonomous immune activation state
Get PDFAberrant and sustained activation of microglia is implicated in the progression and severity of multiple sclerosis (MS). However, whether intrinsic alterations in microglial function impact the pathogenesis of this disease remains unclear. We conducted transcriptomic and functional analyses of microglia-like cells (iMGLs) differentiated from induced pluripotent stem cells (iPSCs) from patients with MS (pwMS) to answer this question. The pwMS showed increased innate immune cell activity via 18-kDa translocator protein positron emission tomography imaging. After confirming that the differentiated iMGLs transcriptional profile is determined by the microglial cell type, comparative studies were performed to identify the transcriptional and functional differences between iMGLs from pwMS and healthy controls. Importantly, MS iMGLs presented cell-autonomous differences in their regulation of inflammation, both in the basal state and following inflammatory lipopolysaccharide challenge. Through transcriptomic profiling, we showed that MS iMGLs display increased expression of genes upregulated in MS pathology. Furthermore, upregulated genes in MS iMGLs were associated with immune receptor activation, antigen presentation, and the complement system. MS iMGLs demonstrated transcriptional similarities to lesion-specific microglia in MS, marked by upregulation of immune-related genes and pathways, including those involved in antigen presentation. Finally, functional analyses indicated that the transcriptional changes in MS iMGLs corresponded with modulation of cytokine secretion and increased phagocytosis. Together, our results provide evidence of putative cell-autonomous microglial activation in pwMS and identify transcriptomic and functional changes that recapitulate the phenotypes observed in vivo in microglia from pwMS. These findings indicate that MS disease-specific iPSCs are valuable tools for studying disease-specific microglial activation in vitro and highlight microglia as potential therapeutic targets in MS
Bisulphite MLT1F2
No full textMLT1F2 sanger sequencing results after bisulphite treatment in healthy and EO-PE placentas
Spatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets
No full textHigh-grade serous ovarian cancer (HGSOC) is a devastating disease that is frequently detected at an incurable stage. Advances in ultrasensitive mass spectrometry-based spatial proteomics have provided a unique opportunity to uncover early molecular events in tumorigenesis and common dysregulated pathways with high therapeutic potential. Here, we present a comprehensive proteomic analysis of serous tubal intraepithelial carcinoma (STIC), the HGSOC precursor lesion, covering more than 10,000 proteins. We found that STICs and concurrent invasive carcinomas were indistinguishable at the global proteomic level, revealing a similar level of molecular heterogeneity. Using cell-type-resolved tissue proteomics, we revealed strong cell-of-origin signatures preserved in STICs and invasive tumors and identified early dysregulated pathways of therapeutic relevance, such as an onco-metabolic increase in cholesterol biosynthesis. Finally, we uncovered substantial remodeling of the co-evolving tumor microenvironment, affecting approximately one-third of the stromal proteome, and derived a common signature associated with progressive immunosuppression and extracellular matrix restructuring. In summary, our study highlights the power of spatially resolved quantitative proteomics to dissect the molecular underpinnings of early carcinogenesis and provides a rich proteomic resource for future biomarker and drug target research in ovarian cancer