24036 research outputs found
Sort by
Targeting Runx1 protects against heart failure with preserved ejection fraction
Get PDFHeart failure with preserved ejection fraction (HFpEF) is a public health problem and an elusive illness for which there are few treatment options. HFpEF is a systemic condition with a broad phenotype including diastolic dysfunction, pulmonary oedema, exercise intolerance, and left ventricular (LV) hypertrophy, collectively resulting in enhanced morbidity and mortality. Master-regulator transcription factor RUNX1 has recently been identified as a mediator of pathological changes in many cardiac diseases, however its role in HFpEF was unknown. Here we show that inhibition of Runx1 limits adverse cardiac remodelling in a clinically relevant mouse model of HFpEF. Cardiomyocyte-specific tamoxifen-inducible Runx1-deficient mice with HFpEF are protected, with preservation of diastolic function, and attenuation of pulmonary oedema, exercise intolerance, and hypertrophy. Furthermore, targeting Runx1 in HFpEF by using gene transfer or small molecule inhibitors improves diastolic function, both in female and male mice. Overall, our research enhances our understanding of RUNX1 in cardiac disease and demonstrates a novel translational target for the treatment of HFpEF
Anti-CD19 CAR T cell therapy induces antibody seroconversion and complete B cell depletion in the bone marrow of a therapy-refractory patient with ANCA-associated vasculitis
No full textEpithelial OPA1 links mitochondrial fusion to inflammatory bowel disease
No full textDysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation. We found reduced expression of mitochondrial fusion–related genes, such as the dynamin-related guanosine triphosphatase (GTPase) optic atrophy 1 (OPA1), and fragmented mitochondrial networks in crypt IECs of patients with IBD. Mice with Opa1 deficiency in the gut epithelium (Opa1(i∆IEC)) spontaneously developed chronic intestinal inflammation with mucosal ulcerations and immune cell infiltration. Intestinal inflammation in Opa1(i∆IEC) mice was driven by microbial translocation and associated with epithelial progenitor cell death and gut barrier dysfunction. Opa1-deficient epithelial cells and human organoids exposed to a pharmacological OPA1 inhibitor showed disruption of the mitochondrial network with mitochondrial fragmentation and changes in mitochondrial size, ultrastructure, and function, resembling changes observed in patient samples. Pharmacological inhibition of the GTPase dynamin-1–like protein in organoids derived from Opa1(i∆IEC) mice partially reverted this phenotype. Together, our data demonstrate a role for epithelial OPA1 in regulating intestinal immune homeostasis and epithelial barrier function. Our data provide a mechanistic explanation for the observed mitochondrial dysfunction in IBD and identify mitochondrial fusion as a potential therapeutic target in this disease
Flow-cytometric quantification of urine kidney epithelial cells specifically reflects tubular damage in acute kidney diseases
Get PDFINTRODUCTION: Tubular injury is one of the main mechanisms driving acute kidney injury (AKI); however, clinicians still have a limited diagnostic repertoire to precisely monitor damage to tubular epithelial cells (TECs). In our previous study, we used single-cell sequencing to identify TEC subsets as the main components of the urine signature of AKI. This study aimed to establish TECs as clinical markers of tubular damage. METHODS: A total of 243 patients were analyzed. For sequencing, we collected 8 urine samples from patients with AKI and glomerular disease. We developed a protocol for the flow cytometric quantification of CD10/CD13(+) proximal TECs (PTECs) and CD227/CD326(+) distal TECs (DTECs) in urine by aligning urinary single-cell transcriptomes and TEC surface proteins using Cellular Indexing of Transcriptome and Epitope Sequencing (CITE-Seq). Marker combinations were confirmed in kidney biopsies. We validated our approach in 4 cohorts of 235 patients as follows: patients with AKI (n = 63), COVID-19 infection (n = 47), antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) with active disease or stable remission (n = 110), and healthy controls (n = 15). RESULTS: Our findings demonstrated that CD10/CD13 and CD227/CD326 adequately identified PTECs and DTECs, respectively. Distal urinary TEC counts correlate with the severity of AKI based on Kidney Disease: Improving Global Outcomes (KDIGO) stage and acute estimated glomerular filtration rate (GFR) loss in 2 separate cohorts and can successfully discriminate AKI from healthy controls and glomerular disease. CONCLUSION: We propose that urinary CD227/CD326(+) TEC count is a specific, noninvasive marker for tubular injury in AKI. Our protocol provides a basis for a deeper phenotypic analysis of urinary TECs
Rapid brain tumor classification from sparse epigenomic data
Get PDFAlthough the intraoperative molecular diagnosis of the approximately 100 known brain tumor entities described to date has been a goal of neuropathology for the past decade, achieving this within a clinically relevant timeframe of under 1 h after biopsy collection remains elusive. Advances in third-generation sequencing have brought this goal closer, but established machine learning techniques rely on computationally intensive methods, making them impractical for live diagnostic workflows in clinical applications. Here we present MethyLYZR, a naive Bayesian framework enabling fully tractable, live classification of cancer epigenomes. For evaluation, we used nanopore sequencing to classify over 200 brain tumor samples, including 10 sequenced in a clinical setting next to the operating room, achieving highly accurate results within 15 min of sequencing. MethyLYZR can be run in parallel with an ongoing nanopore experiment with negligible computational overhead. Therefore, the only limiting factors for even faster time to results are DNA extraction time and the nanopore sequencer’s maximum parallel throughput. Although more evidence from prospective studies is needed, our study suggests the potential applicability of MethyLYZR for live molecular classification of nervous system malignancies using nanopore sequencing not only for the neurosurgical intraoperative use case but also for other oncologic indications and the classification of tumors from cell-free DNA in liquid biopsies
Endothelial deletion of adipose triglyceride lipase protects against heart failure with preserved ejection fraction
Get PDFHighlights from the plenary session: cellular and molecular mechanisms of disease (I)
No full textIn this plenary session of the Vasculitis Workshop 2024, pioneering translational research on autoimmune vasculitis, particularly ANCA-associated vasculitis (AAV), was presented, highlighting advancements in our understanding of disease mechanisms and promising therapeutic prospects. Advances in elucidating molecular pathways, such as IL-17 and IFN-I, pave the way for specific treatments. Preclinical studies have revealed the gut microbiome's role in the pathogenesis of MPO-AAV and demonstrate the therapeutic potential of dietary interventions. Furthermore, research into the protective role of Tregs has shed light on potential new targets for therapeutic interventions. Innovative approaches, such as CAR-T cell therapy and Deoxy Mab DX-1/DX-3, show significant promise in mitigating AAV pathology. These advancements underscore the transformative potential of translational research. By enhancing our understanding of disease mechanisms, these findings pave the way for the development of personalized and effective therapies, ultimately enhancing patient outcomes
The IBEX Knowledge-Base: a central resource for multiplexed imaging techniques
Get PDFMultiplexed imaging is a powerful approach in spatial biology, although it is complex, expensive and labor-intensive. Here, we present the IBEX Knowledge-Base, a central resource for reagents, protocols and more, to enhance knowledge sharing, optimization and innovation of spatial proteomics techniques
Rhabdomyosarcoma of head and neck varies in aggressiveness depending on the specific site of origin
Get PDFOBJECTIVE: To evaluate predictive impact of granular subsites of head/neck rhabdomyosarcoma in a cross-age evaluation of the population-based SEER-program. DESIGN: Data were obtained for cases 0-90+ years, newly diagnosed with rhabdomyosarcoma at head/neck, registered in SEER17 2000-2020. Disease-specific survival (DSS) and overall survival (OS) were the endpoints, using the Kaplan-Meier estimator and Cox proportional hazards regression model. A granular site categorization was established. RESULTS: Median age of 1114 cases was 11 years. 5-year OS and DSS were 59.1 %±3.1 (95 %CI) and 62.4 %±3.1 with median follow-up for 662 survivors of 8.6 years. Increasing age was independently associated with worse prognosis. The rate of affected subsites varied considerably. Age, histology, tumor size, disease stage, the proportion of pathologically examined and affected lymph nodes differed significantly according to granular subsite. Granular subsites were of independent predictive impact when adjusted for age, size, histology, stage, and pathological lymph node status. While rhabdomyosarcoma at orbit, parotid gland, and ear correlated with best survival, larynx, oral cavity, paranasal sinuses, brain, pharynx, and nose were associated with adverse survival. In contrast to all other subsites, nasal and paranasal sinus rhabdomyosarcoma were predominantly alveolar, large, distant spread, and with the highest proportion of affected lymph nodes. Rhabdomyosarcoma of nose/paranasal sinuses exhibit high potential of spreading not only suggesting different biology but thorough staging including pathological lymph node assessment. CONCLUSION AND RELEVANCE: Granular head/neck subsites show different characteristics between subsites and highly varying outcomes. Understanding the impact of granular head/neck subsites on outcome may inform risk-adapted and novel approaches to rhabdomyosarcoma