Microbiome signatures of diagnosis and aggressiveness of a neurovascular disease, cavernous angioma
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PROVIDER: PRJEB37514 | ENA |
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Project description:Microbiome signatures of diagnosis and aggressiveness of a neurovascular disease, cavernous angioma
| PRJEB35505 | ENA
Project description:Background: Cerebral cavernous angiomas with a symptomatic hemorrhage (CASH) have a high-risk of recurrent hemorrhage and serious morbidity. Methods: Eighteen plasma molecules with postulated mechanistic roles in cavernous angioma (CA) pathobiology were investigated in 114 patients and 12 healthy subjects. The diagnostic biomarker of a CASH in the prior year was derived as minimizing the Akaike Information Criterion (AIC) and validated using machine-learning, and then compared to the prognostic CASH biomarker predicting bleeding in the subsequent year. Both biomarkers were longitudinally followed in a subset of cases. The biomarkers were queried in the transcriptome of human lesional micro-dissected neurovascular units (NVUs) and in relation to plasma miRNAs from CASH and non-CASH patients. Results: The diagnostic CASH biomarker included a weighted combination of four molecules (sCD14, VEGF, CRP, and IL-10) distinguishing CASH patients with 76% sensitivity and 80% specificity (p=0.0003). The prognostic CASH biomarker included two of these molecules (sCD14 and VEGF) and two others (IL-1β and sROBO-4) was confirmed to predict a bleed in the subsequent year, with 83% sensitivity and 93% specificity (p=0.001). Genes associated with the diagnostic and prognostic CASH biomarkers were differentially expressed in CASH lesional NVUs. Thirteen miRNAs were also differentially expressed in the plasma of CASH patients compared to non-CASH. Conclusion: There are shared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in CA, and are mechanistically linked to the lesional transcriptome and miRNA regulation. The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice.
2019-05-13 | GSE130174 | GEO
Project description:Background: Cerebral cavernous angiomas with a symptomatic hemorrhage (CASH) have a high-risk of recurrent hemorrhage and serious morbidity. Methods: Eighteen plasma molecules with postulated mechanistic roles in cavernous angioma (CA) pathobiology were investigated in 114 patients and 12 healthy subjects. The diagnostic biomarker of a CASH in the prior year was derived as minimizing the Akaike Information Criterion (AIC) and validated using machine-learning, and then compared to the prognostic CASH biomarker predicting bleeding in the subsequent year. Both biomarkers were longitudinally followed in a subset of cases. The biomarkers were queried in the transcriptome of human lesional micro-dissected neurovascular units (NVUs) and in relation to plasma miRNAs from CASH and non-CASH patients. Results: The diagnostic CASH biomarker included a weighted combination of four molecules (sCD14, VEGF, CRP, and IL-10) distinguishing CASH patients with 76% sensitivity and 80% specificity (p=0.0003). The prognostic CASH biomarker included two of these molecules (sCD14 and VEGF) and two others (IL-1β and sROBO-4) was confirmed to predict a bleed in the subsequent year, with 83% sensitivity and 93% specificity (p=0.001). Genes associated with the diagnostic and prognostic CASH biomarkers were differentially expressed in CASH lesional NVUs. Thirteen miRNAs were also differentially expressed in the plasma of CASH patients compared to non-CASH. Conclusion: There are shared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in CA, and are mechanistically linked to the lesional transcriptome and miRNA regulation. The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice.
2019-05-13 | GSE130175 | GEO
Project description:Biomarkers of Cavernous Angioma with Symptomatic Hemorrhage (CASH)
| PRJNA534216 | ENA
Project description:Biomarkers of Cavernous Angioma with Symptomatic Hemorrhage (CASH) [RNA-seq]
| PRJNA534219 | ENA
Project description:Biomarkers of Cavernous Angioma with Symptomatic Hemorrhage (CASH) [small RNA-seq]
| PRJNA534220 | ENA
Project description:Purpose: To investigate the regulatory role of microRNA (miR)-148a-3p in mouse corpus cavernous pericyte (MCPs)-derived extracellular vesicles (EVs) in the treatment of diabetes-induced erectile dysfunction (ED). Materials and Methods: Mouse corpus cavernous tissue was used for MCPs primary culture and EVs isolation. Small RNA sequencing analysis was performed to assess the type and content of miRs in MCPs-EVs. Four groups of mice were used: control nondiabetic mice and streptozotocin-induced diabetic mice receiving two intracavernous injections (days -3 and 0) of phosphate buffered saline, MCPs-EVs transfected with regent control, or MCPs-EVs transfected with miR-148a-3p inhibitor. The function of miR-148a-3p in MCPs-EVs was evaluated by tube formation assay, migration assay, TUNEL assay, intracavernous pressure, immunofluorescence staining, and western blot experiments. Results: We extracted EVs from MCPs and by small RNA sequencing analysis we found that miR-148a-3p is enriched in MCPs-EVs. Exogenous administration of MCPs-EVs can effectively promote mouse cavernous endothelial cell (MCECs) tube formation, migration, proliferation, and reduce MCECs apoptosis under high-glucose conditions. However, these effects are significantly attenuated in miR-148a-3p-depleted MCPs-EVs, which is extracted after inhibiting miR-148a-3p expression in MCPs. Repeated intracavernous injections of MCPs-EVs improves erectile function by inducing cavernous neurovascular regeneration in diabetic mice. Through online bioinformatics databases and luciferase report assays, we predict Pyruvate dehydrogenase kinase-4 (PDK4) is a potential target gene of miR-148a-3p. Conclusions: Our findings provide new and reliable evidence that miR-148a-3p in MCPs-EVs significantly enhances cavernous neurovascular regeneration by inhibiting PDK4 in diabetic mice.
2023-12-19 | GSE195533 | GEO
Project description:Cavernous angiomas (CA) are common vascular anomalies causing brain hemorrhage. Based on mouse studies, roles of gram-negative bacteria and altered intestinal homeostasis have been implicated in CA pathogenesis, and pilot study had suggested potential microbiome differences between non-CA and CA individuals based on 16S rRNA gene sequencing. We here assess microbiome differences in a larger cohort of human subjects with and without CA, and among subjects with different clinical features, and conduct more definitive microbial analyses using metagenomic shotgun sequencing. Relative abundance of distinct bacterial species in CA patients is shown, consistent with postulated permissive microbiome driving CA lesion genesis via lipopolysaccharide signaling, in humans as in mice. Other microbiome differences are related to CA clinical behavior. Weighted combinations of microbiome signatures and plasma inflammatory biomarkers enhance associations with disease severity and hemorrhage. This is the first demonstration of a sensitive and specific diagnostic microbiome in a human neurovascular disease.
| S-EPMC7253448 | biostudies-literature
Project description:BackgroundCavernous angiomas (CAs) affect 0.5% of the population, predisposing to serious neurologic sequelae from brain bleeding. A leaky gut epithelium associated with a permissive gut microbiome, was identified in patients who develop CAs, favoring lipid polysaccharide producing bacterial species. Micro-ribonucleic acids along with plasma levels of proteins reflecting angiogenesis and inflammation were also previously correlated with CA and CA with symptomatic hemorrhage.MethodsThe plasma metabolome of CA patients and CA patients with symptomatic hemorrhage was assessed using liquid-chromatography mass spectrometry. Differential metabolites were identified using partial least squares-discriminant analysis (p < 0.05, FDR corrected). Interactions between these metabolites and the previously established CA transcriptome, microbiome, and differential proteins were queried for mechanistic relevance. Differential metabolites in CA patients with symptomatic hemorrhage were then validated in an independent, propensity matched cohort. A machine learning-implemented, Bayesian approach was used to integrate proteins, micro-RNAs and metabolites to develop a diagnostic model for CA patients with symptomatic hemorrhage.ResultsHere we identify plasma metabolites, including cholic acid and hypoxanthine distinguishing CA patients, while arachidonic and linoleic acids distinguish those with symptomatic hemorrhage. Plasma metabolites are linked to the permissive microbiome genes, and to previously implicated disease mechanisms. The metabolites distinguishing CA with symptomatic hemorrhage are validated in an independent propensity-matched cohort, and their integration, along with levels of circulating miRNAs, enhance the performance of plasma protein biomarkers (up to 85% sensitivity and 80% specificity).ConclusionsPlasma metabolites reflect CAs and their hemorrhagic activity. A model of their multiomic integration is applicable to other pathologies.
| S-EPMC9984539 | biostudies-literature
Project description:A cavernous hemangioma, well-known as vascular malformation, is present at birth, grows proportionately with the child, and does not undergo regression. Although a cavernous hemangioma has well-defined histopathological characteristics, its origin and formation remain unknown. In the present study, we characterized the cellular heterogeneity of cavernous hemangioma using single-cell RNA sequencing (scRNA-seq). The main contribution of the present study is the discovery of mesenchymal stem cells (MSCs) that cause cavernous hemangioma formation and may be abnormally or incompletely differentiated from epiblast stem cells. EGFR inhibitors are the potential drugs to treat cavernous hemangiomas. Other new findings include the responsive ACKR1 positive endothelial cell (ACKR1+EC) and BTNL9 positive endothelial cell (BTNL9+EC) and the BTNL9-caused checkpoint blockade enhanced by the CXCL12-CXCR4 signalling. The activated CD8+T and NK cells may highly express CCL5 for their infiltration in cavernous hemangiomas, independent on the tumor cell-derived CCL5-IFNG-CXCL9 pathway. The plasmacytoid dendritic cells (pDCs) function for anti-tumour as CD8+T cells in cavernous hemangiomas. The oxidised low-density lipoprotein (oxLDL) and scavenger receptors (SRs) may play an important role in the immune responses in the tumour microenvironment of cavernous hemangiomas. Notably, we propose that oxLDL induces the oxLDL-OLR1-NLRP3 pathway in M1-like macrophages via the over-expression of OLR1, whereas oxLDL induces the oxLDL-SRs-C1q pathway in M2-like macrophages via the over-expression of many SRs (LILRB5, etc) except OLR1. The highly expressed EREG in M1-like macrophages and the highly expressed EGFR in MSCs may cause MSC proliferation and the tumour progression. The present study revealed the origin of cavernous hemangiomas and reported the marker genes, cell types and molecular mechanisms, which are associated with the origin, formation, progression, diagnosis or therapy of cavernous hemangiomas. Our discoveries facilitate the development of gold standards for molecular diagnosis and effective drugs for treatment, and enrich the fundamental knowledge in the research field of immune, cancer and even cell biology.
2021-11-17 | GSE188515 | GEO