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Datasets associated with: Unwinding of a eukaryotic origin of replication visualized by cryo-EM
No full textDatasets associated with: Henrikus, S. S., Gross, M. H., Willhoft, O., Pühringer, T., Lewis, J. S., McClure, A. W., ... & Costa, A. (2024). Unwinding of a eukaryotic origin of replication visualized by cryo-EM. Nature structural & molecular biology, 31(8), 1265-1276.</p
Long-term real-world survival outcomes with dual immune checkpoint blockade in synchronous metastatic renal cell carcinoma: Implications for the design of prospective cytoreductive nephrectomy trials
No full textBackground and objective: Patients with synchronous metastatic renal cell carcinoma (s-mRCC) increasingly undergo systemic therapy with their primary tumour in situ. We report long-term survival outcomes and deferred cytoreductive nephrectromy (dCN) rates in an unselected real-world s-mRCC cohort of patients treated with nivolumab + ipilimumab. Methods: This was a retrospective cohort study of 287 patients with s-mRCC treated with nivolumab + ipilimumab between 2018 and 2024 at five European institutions. Data were collected for International mRCC Database Consortium (IMDC) risk, overall survival (OS), progression-free survival (PFS), treatment responses, and dCN rates. Key findings and limitations: At median follow-up of 23.5 mo, median OS was 29.0 mo (95% confidence interval [CI] 20.1–36.2) for the overall cohort (n = 287), and 49.8 mo (95% CI 33.1–not reached) for the intermediate-risk group (n = 144, 50%) versus 16.3 mo (95% CI 13.5–26.3) for the poor-risk group (n = 143, 50%; hazard ratio [HR] 0.50, 95% CI 0.35–0.71; p 0.9). Conclusions and clinical implications: Real-world treatment of s-mRCC with nivolumab + ipilimumab yields encouraging OS, especially in patients with intermediate IMDC risk and CR/nCR at metastatic sites. Trials investigating dCN following immunotherapy may be impacted by this lower-than-expected event rate, which could potentially affect their estimated sample sizes. Patient summary: We looked at outcomes for patients with metastatic kidney cancer who were treated with immunotherapy while their kidney tumour was still in place. Patients who responded well to immunotherapy were likely to survive for a long time, whether or not they then had surgery to remove their kidney tumour. Our results will help in the design of analyses for clinical trials that are already testing the role of delayed surgery for metastatic kidney tumours
Mycobacterial α-glucans hijack dectin-1 to facilitate intracellular bacterial survival.
No full textMycobacteria have a cell envelope that can act as a shield against host defense. This study shows that mycobacteria survive in host macrophages by targeting the innate host receptor dectin-1 through a noncanonical ligand. Compared with wild-type (WT) mice, dectin-1-deficient mice were more resistant to infection to mycobacteria. Dectin-1-deficient mice presented with substantially reduced bacterial burdens, inflammatory cytokines, and infiltrating myeloid cells, such as neutrophils and macrophages. Intracellular survival of these bacteria was reduced in macrophages derived from dectin-1-deficient mice compared with those from WT mice. Cellular characterization of mycobacteria-infected macrophages indicated that the presence of dectin-1 altered phagosomal maturation and association with markers of autophagy. Activity-based purification and nuclear magnetic resonance spectrometry identified branched α-glucan as the dectin-1 mycobacterial ligand. This branched glucan was essential for activating dectin-1. These results show that mycobacterial α-glucan targets dectin-1 to facilitate intracellular bacterial survival
Impact of first SARS-CoV-2 infection variant on serological responses against Omicron: Findings from the SIREN study.
No full textINTRODUCTION: Despite the existing hybrid immunity, a sharp increase in SARS-CoV-2 reinfections was observed worldwide following Omicron variant emergence. We investigated whether the first infecting variant indelibly shapes serological responses against Omicron (BA.1 and BA.2) reinfection. METHODS: Participants with a sequence-confirmed Alpha (n = 23) or Delta (n = 10) first infection before third vaccine dose (V3) that subsequently had a BA.1 or BA.2 reinfection were selected. Sera were tested for anti-SARS-CoV-2 spike (anti-S) and live virus microneutralisation (LV-N) against Ancestral, Alpha, Delta, Omicron BA.1 and BA.2. Antibody responses and waning post-V3 were compared by first infection variant using mixed-effect models, as well as inferred titres days before reinfections. Individual's neutralisation responses were compared 12 weeks post-V3, among those with Alpha and Delta primary infection. RESULTS: After V3, those with Delta first infection had higher LV-N Omicron BA.1 titres (fold difference (FD) = 2.7, p = 0.05) compared to Alpha primary infection. Participants with Delta first infection presented higher LV-N BA.1 (FD = 1.89, p = 0.004) and LV-N BA.2 (FD = 2.06, p = 0.001) titres pre-Omicron reinfections. Individuals' neutralisation responses against Ancestral were higher than any other subsequent variants, regardless of first infection variant. CONCLUSIONS: A previous Delta SARS-CoV-2 infection induced a higher serological response against a subsequent Omicron infection when compared to Alpha first infections
Centromeric protein CENP-C depletion during early stages of Drosophila spermatogenesis results in reduced levels of the centromere-specific histone CENP-A in mature sperm
No full textPoster presented as part of the Crick BioImage Analysis Symposium 2025.Permission has been given by authors to upload to Crick Figshare. Copyright remains with the original authors.</p
Assessing PARP trapping dynamics in ovarian cancer using a CRISPR-engineered FRET biosensor.
No full textPoly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment of ovarian high-grade serous carcinoma (HGSC), particularly in homologous recombination-deficient tumors. However, the emergence of resistance poses a critical challenge, as over 50% of patients relapse within 3 years. The mechanisms underlying changes in PARP trapping, a central aspect of PARPi efficacy, are not well understood, as current experimental methodologies lack resolution and throughput. To address this, we develop an intramolecular fluorescence resonance energy transfer (FRET)-based biosensor by CRISPR-Cas9 dual labeling of endogenous PARP1 with EGFP and mCherryFP in OVCAR4 cells. This biosensor enables real-time, single-cell analysis of PARP trapping dynamics. Using fluorescence lifetime imaging microscopy (FLIM), we reveal dose-dependent PARP trapping, differentiate the trapping efficiencies of four clinically approved PARPi, and observe reduced trapping in PARPi-resistant models in vitro and in vivo. This biosensor provides critical insights into PARPi resistance mechanisms, with implications for developing more effective therapies and advancing personalized treatment for ovarian cancer patients
Capturing gene-cell duality in a cat's cradle.
No full textSUMMARY: CatsCradle is an R package for single-cell analysis that exploits the duality between cells and the genes they express. Our package provides tools to cluster genes, visualise relationships between them, and to explore relationships between gene clusters (programmes) and cell clusters (cell types). AVAILABILITY AND IMPLEMENTATION: CatsCradle is available freely as an R Bioconductor package (https://bioconductor.org/packages/CatsCradle) and interfaces directly with Seurat and SingleCellExperiment data structures. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online
Cross-presentation of dead cell-associated antigens shapes the neoantigenic landscape of tumor immunity.
No full textType 1 conventional dendritic cells (cDC1s) acquire and cross-present tumor antigens to prime CD8⁺ T cells. Whether this selects for specific neoantigens is unclear. DNGR-1 (CLEC9A), a cDC1 receptor for F-actin exposed on dead cells, promotes cross-presentation of cell-associated antigens. Here we show that DNGR-1-deficient mice develop chemically induced tumors more rapidly and at higher incidence, and these are more frequently rejected on transplantation into wild-type recipients. Whole-exome sequencing reveals enrichment of predicted neoantigens derived from mutated F-actin-binding proteins. Consistent with this observation, tethering model antigens to F-actin enhances DNGR-1-dependent cross-presentation. These results suggest that DNGR-1-mediated recognition of F-actin exposed by dead cancer cells favors priming of CD8⁺ T cells specific for cytoskeletal neoantigens, which can then drive immune escape of cancer cells lacking or reverting those mutations. Thus, neoantigen cross-presentation by cDC1 can determine the immune visibility of the tumor mutational landscape and sculpt cancer evolution by immunoediting
Tumor-associated macrophages enhance peripheral nerve tumor infiltration and spinal cord repair.
No full textTumor-associated macrophages (TAMs) enhance cancer progression by promoting angiogenesis, extracellular matrix remodeling, and immune suppression. Nerve infiltration also contributes to tumor growth. However, the role of TAMs in promoting intratumoral nerve growth remains unclear. In this study, we have shown that TAMs express a distinct neural growth gene signature. TAMs actively enhanced neural growth within tumors and directly promoted in vitro neurite outgrowth. We identified secreted phosphoprotein 1 (SPP1) as a required mediator of TAM-driven neural growth and mTORC2 activation. Leveraging this TAM-neural growth function, we explored TAM neuroregenerative potential. Adoptive transfer of TAMs in severe complete-compressive-contusive spinal cord injury (scSCI) increased neuronal survival, axonal regrowth, and motor function recovery. Moreover, TAMs healed scSCI microenvironment and remodeled the cyst. Functional and proteomic analyses confirmed SPP1 and neural Rictor as necessary molecular mediators for TAM-induced regeneration. Our data unveil a role for TAMs in tumor innervation and neural tissue repair
Pan-cancer evolution signatures link clonal expansion to dynamic changes in the tumor immune microenvironment.
No full textCancer is an evolutionary process characterized by profound intratumor heterogeneity (ITH), which can be quantified using in silico estimates of cancer cell fractions (CCFs) of tumor-specific somatic mutations. We demonstrate a data-driven approach based on CCF distributions to identify 4 robust pan-cancer evolutionary signatures from 4,146 tumors across 17 cancer types in The Cancer Genome Atlas (TCGA). These signatures define a continuum of cancer cell fractions reflecting neutral evolution, clonal expansion, and clonal fixation. Correlating evolutionary signatures with mutational and biological programs reveals that tumors enriched for clonal expansion and fixation are associated with immune evasion and distinct changes in the tumor immune microenvironment. Our analysis reveals a dynamic shift from adaptive to innate immune programs as tumors progress toward clonal fixation and escape immune surveillance, accompanied by the clonal expansion of driver genes modulating tumor-stroma interactions. These evolutionary dynamic subtypes are further associated with clinical outcomes and immunotherapy responses