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Subclonal immune evasion in non-small cell lung cancer
Get PDFCancers rarely respond completely to immunotherapy. While tumors consist of multiple genetically distinct clones, whether this affects the potential for immune escape remains unclear due to an inability to isolate and propagate individual subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived organoid – T cell co-culture platform that allows the functional analysis of subclonal immune escape at single clone resolution. We establish organoid lines from 11 separate tumor regions from three patients, followed by isolation of 81 individual clonal sublines. Co-culture with tumor infiltrating lymphocytes (TIL) or natural killer (NK) cells reveals cancer-intrinsic and subclonal immune escape in all 3 patients. Immune evading subclones represent genetically distinct lineages with a unique evolutionary history. This indicates that immune evading and non-evading subclones can be isolated from the same tumor, suggesting that subclonal tumor evolution directly affects immune escape
Cross-sectional study of health impairment related to post COVID-19 condition among participants of a large population-based cohort in Germany
Get PDFPost COVID-19 condition (PCC) is a substantial burden for patients, society, and the healthcare system. Participants of the German National Cohort (NAKO) were asked in an online survey about their self-perceived health, symptoms related to PCC, and infection status. PCC was defined as reporting symptoms for the time window 4–12 months after infection. Of 110,375 respondents (73% response), 86,833 were included in this analysis. Of these, 44,451 (51%) did not report a SARS-CoV-2 infection (no infection), 26,726 (31%) reported an infection but no symptoms 4–12 months after infection (infection/no PCC), and 15,656 (18%) reported an infection and symptoms (PCC). The median number of current symptoms at the time of the survey was two for the "no infection" and the "infection/no PCC" group, and five for the "PCC" group. Participants with PCC had a substantially higher probability of having worse self-perceived health (OR 1.84, 95% CI [1.75; 1.93] compared to the "no infection" group, adjusting for sex, age, education and chronic diseases with elevated risk for developing PCC. After adjusting for the number of current symptoms related to PCC, this difference disappeared, suggesting that the symptoms collected explain the impairment of self-perceived health in the PCC group
DNA virus infections shape transposable elements activity in vitro and in vivo
Get PDFTransposable elements (TEs) are implicated in a variety of processes including placental and preimplantation development and a variety of human diseases. TEs are known to be activated in the context of some viral infections, but the mechanisms and consequences are not understood. We show strong activation of TEs upon DNA virus infection, in particular the MLT- and THE1-class of LTR-containing retrotransposons as well as a subset of LINE-1-, Alu-elements and HERVs. Mechanistically, two key pathways induce TEs upregulation: inhibition of the KAP1/TRIM28 repressive complex by phosphorylation, and expression of the pioneer transcription factor double-homeobox 4 (DUX4), which is known to be involved in TE-induction during zygotic genome activation in embryonic development. DUX4 is induced by DNA viruses, it binds to TEs upon infection and analysis of genes adjacent to TEs shows pathways that are important for DNA virus infections. Analysis of knockdown, knockout and overexpression data reveal that almost all TEs expressed upon herpesviral infection are regulated by KAP1/TRIM28 and DUX4. Interestingly, analysis of single cell sequencing data from patients with DNA virus-associated cancers showed that in vivo TEs expression strongly correlates with virus infection, indicating a possible role in viral oncogenesis
Barriers in healthcare to the use of optical coherence tomography angiography in multiple sclerosis
Get PDFOptical coherence tomography angiography (OCT-A) is a state-of-the-art imaging technique for the retinal vasculature to accurately segment the capillary network and assign it to retinal layers. OCT-A is a promising technique to better understand neurological diseases with visual system manifestations, such as multiple sclerosis (MS), and to identify and characterize vascular biomarkers. Initial studies suggested vascular changes in MS and its differential diagnoses such as myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD). Here we review clinical and technical aspects of OCT-A imaging and discuss the potential for the MS field as well as barriers that need to be overcome before OCT-A can be established in clinical application
Stem cell markers LGR5, LGR4 and their immediate signalling partners are dysregulated in preeclampsia
No full textLeucine-rich repeat-containing G protein-coupled receptors 5/4 (LGR5/LGR4) are critical stem cell markers in epithelial tissues including intestine. They agonise wingless-related integration site (WNT) signalling. Until now, LGR5/LGR4 were uncharacterised in placenta, where analogous functions may exist. We characterised LGR5/LGR4, their ligands/targets in human placenta, with further assessments on dysregulation in preeclampsia/fetal growth restriction (FGR). LGR5 mRNA was unaltered in first trimester (n = 11), preterm (n = 9) and term (n = 11) placental lysate. LGR5 was enriched in human trophoblast stem cells (hTSCs) and downregulated with differentiation to extravillous trophoblasts (p < 0.0215) and syncytiotrophoblasts (p < 0.0350). In situ hybridisation localised LGR5 to unique, proliferative MKI67 + mononuclear trophoblasts underlying syncytium which concurred with proposed progenitor identities in single-cell transcriptomics. LGR5 expression was significantly reduced in placentas from early-onset preeclampsia (p < 0.0001, n = 81 versus n = 19 controls), late-onset preeclampsia (p = 0.0046, n = 20 versus n = 33 controls) and FGR (p = 0.0031, n = 34 versus n = 17 controls). LGR4 was elevated in first trimester versus preterm and term placentas (p = 0.0412), in placentas with early-onset preeclampsia (p = 0.0148) and in FGR (p = 0.0417). Transcriptomic analysis and in vitro hTSC differentiation to both trophoblast lineages suggested LGR4 increases with differentiation. Single-nucleus RNA sequencing of placental villous samples supported LGR5 and LGR4 localisation findings. Hypoxia/proinflammatory cytokine treatment modelling elements experienced by the placenta in placental insufficiency pathogenesis did not significantly alter LGR5/LGR4. Ligands R-spondins 1/3/4, and neutralising targets ring finger protein 43 (RNF43) and zinc and ring finger 3 (ZNRF3) were also reduced in placentas from preeclamptic pregnancies. This study is the first to describe LGR5/LGR4 and their signalling partner expression in human placenta. Their dysregulations in the preeclamptic placenta allude to disruptions to integral trophoblast stem cell function/differentiation that may occur during placental development related to WNT signalling
Effects of a 6-week treadmill training with and without virtual reality on frailty in people with multiple sclerosis: Frailty rehabilitation in multiple sclerosis
Get PDFOBJECTIVE: To examine the effects of a cognitive-motor rehabilitation program consisting of treadmill training augmented by virtual reality (TT+VR) on frailty in people with multiple sclerosis (pwMS). DESIGN: Secondary analysis from a multi-center randomized controlled trial investigating the effects of TT+VR, compared to treadmill training (TT) only, on measures of mobility and cognitive function in pwMS. SETTING: Four university research laboratories in Israel, the United States, and Germany. PARTICIPANTS: A total of 124 pwMS were randomized into the parent trial. Here, we studied a subset of 83 participants (mean age=49.4±9.3 years, 73.5% female, EDSS range=2.0-6.0), who completed the intervention and had complete pre- and post-intervention frailty data. INTERVENTION: Participants were randomly allocated to TT+VR (n=44) or to TT (n=39). Both groups trained three times a week for six weeks. MAIN OUTCOME MEASURES: Frailty was assessed using a 40-item frailty index (FI) through standard validated procedures and represented the primary study outcome. Two exploratory frailty indices were also computed by isolating health-related deficits involving the cognitive (FI-physical) or physical (FI-cognitive) domains from the main FI. The assessments were performed at baseline and after six weeks, upon intervention completion. RESULTS: The mean FI of study participants at baseline was 0.33±0.13, indicating a moderate average level of frailty. FI scores improved in both TT+VR and TT participants (pooled mean ΔFI=0.024, 95%CI=0.010-0.038, F=10.49, p=0.002, ηp(2)=0.115), without any group-by-time interaction (F=0.82, p=0.367, ηp(2)=0.010). However, a significant group-by-time interaction was found for pre- and post-training changes in FI-cognitive (F=5.74, p=0.019, ηp(2)=0.066), suggesting a greater improvement for TT+VR participants than for TT participants. CONCLUSION: Treadmill training with or without virtual reality can reduce frailty levels in pwMS. While both TT and TT+VR had a positive impact on overall frailty, only TT+VR improved cognitive aspects of frailty and may represent an appropriate strategy for counteracting frailty in pwMS
Structural basis for membrane targeting and secretion of legionella SidE ubiquitin ligases
Get PDFSidE family effectors from Legionella pneumophila catalyze serine ubiquitination of host proteins via phospho-ribose (PR) linkages, disrupting host compartments, facilitating the formation of Legionella-containing vacuoles (LCVs) and blocking xenophagy. Upon infection, SidE proteins are injected into the cytosol and recruited to host membranes. Here we present structural and functional insights into a previously uncharacterized C-terminal domain (CTD) of SidE effectors. The crystal structure reveals a banana-shape resembling eukaryotic BAR-domain dimers, with an amphipathic helix and electropositive patch mediating membrane association. Membrane targeting to ER and Golgi confers substrate specificity for PR-ubiquitination. We further show that the CTD binds the IcmS-IcmW-DotL complex, acting as a secretion signal for the Type IV secretion system. Our findings establish membrane localization and secretion as critical determinants of SidE effector function during Legionella infection
The 2025 ESC Guidelines for Myocarditis and Pericarditis and the Evolving Role of Cardiovascular Magnetic Resonance
No full textSomatic Hdac4-902fs mutations lead to loss of HDAC4 function through nonsensemediated mRNA degradation
No full textHistone deacetylases (HDACs) are essential chromatin regulators and are involved in the regulation of gene expression by removing acetyl groups from histone and non-histone proteins. Histone deacetylase 4 (HDAC4) is known to regulate the process of endochondral ossification in mice by non-enzymatic repression of the activity of the RUNX2 transcription factor (TF) and to control cardiac metabolism in physiological stress situations. In this study, we examined the function of somatic HDAC4-902 frameshift (fs) mutations that are frequently observed in gastric and colon adenocarcinoma patients. Whether these mutations lead to a gain- or a loss-of-function is currently unknown. Here we generated a murine model bearing a germline HDAC4- methionine (M) amino acid (AA) 902-to-histidine (H) frameshift (M902Hfs) mutation. HDAC4-M902Hfs mice phenocopied HDAC4 null mice and present with premature ossification and early postnatal death. Mechanistically, we found that the HDAC4-M902Hfs mutation induced nonsense-mediated mRNA decay, resulting in loss of HDAC4 protein. This loss-of-function (LOF) effect was further supported by increased mRNA and protein expression of runt-related transcription factor-2 (RUNX2) and reduced class IIa HDAC enzymatic activity, indicating that HDAC4 contributes significantly to endogenous class IIa HDAC activity. Patient-derived data suggest that the HDAC4-902fs mutation is associated with reduced mRNA expression of HDAC4. In conclusion, our study identify that HDAC4-902fs mutation is a loss-of-function mutation, but raises the new question whether the loss of nonenzymatic mechanisms or the reduction in class IIa HDAC activity contributes to tumor progression