Plasma proteomics analysis reveals potential biomarkers for intracranial aneurysm formation and rupture.

The aim of this study was to investigate the plasma proteome in individuals with intracranial aneurysms (IAs) and identify biomarkers associated with the formation and rupture of IAs. Proteomic profiles (N = 1069 proteins) were assayed in plasma (N = 120) collected from patients with ruptured and unruptured intracranial aneurysms (RIA and UIA), traumatic subarachnoid hemorrhage (tSAH), and healthy controls (HC) using tandem mass tag (TMT) labeling quantitative proteomics analysis. Gene ontology (GO) and pathway analysis revealed that these relevant proteins were involved in immune response and extracellular matrix organization pathways. Seven candidate biomarkers were verified by ELISA in a completely separate cohort for validation (N = 90). Among them, FN1, PON1, and SERPINA1 can be utilized as diagnosis biomarkers of IA, with a combined area under the ROC curve of 0.891. The sensitivity was 93.33%, specificity was 75.86%, and accuracy was 87.64%. PFN1, ApoA-1, and SERPINA1 can serve as independent risk factors for predicting aneurysm rupture. The combined prediction of aneurysm rupture yielded an area under the ROC curve of 0.954 with a sensitivity of 96.15%, specificity of 81.48%, and accuracy of 88.68%. This prediction model was more effective than PHASES score. In conclusion, high-throughput proteomics analysis with population validation was performed to assess blood-based protein expression characteristics. This revealed the potential mechanism of IA formation and rupture, facilitating the discovery of biomarkers. SIGNIFICANCE: Although the annual rupture rate of small unruptured aneurysms is believed to be minimal, studies have indicated that ruptured aneurysms typically have an average size of 6.28 mm, with 71.8% of them being <7 mm in diameter. Hence, evaluating the possibility of rupture in UIA and making a choice between aggressive treatment and conservative observation emerges as a significant challenge in the management of UIA. No biomarker or scoring system has been able to satisfactorily address this issue to date. It would be significant to develop biomarkers that could be used for early diagnosis of IA as well as for prediction of IA rupture. After TMT proteomics analysis and ELISA validation in independent populations, we found that FN1, PON1, and SERPINA1 can be utilized as diagnostic biomarkers for IA, and PFN1, ApoA-1, and SERPINA1 can serve as independent risk factors for predicting aneurysm rupture. Especially, when combined with ApoA-1, SERPINA1, and PFN1 for predicting IA rupture, the area under the curve (AUC) was 0.954 with a sensitivity of 96.15%, specificity of 81.48%, and accuracy of 88.68%. This prediction model was more effective than PHASES score.

Intracranial aneurysm circulating exosome-derived LncRNA ATP1A1-AS1 promotes smooth muscle cells phenotype switching and apoptosis.

Exosomal long non-coding RNAs (LncRNAs) play a crucial role in the pathogenesis of cerebrovascular diseases. However, the expression profiles and functional significance of exosomal LncRNAs in intracranial aneurysms (IAs) remain poorly understood. Through high-throughput sequencing, we identified 1303 differentially expressed LncRNAs in the plasma exosomes of patients with IAs and healthy controls. Quantitative real-time polymerase chain reaction (qRT-PCR) verification confirmed the differential expression of LncRNAs, the majority of which aligned with the sequencing results. ATP1A1-AS1 showed the most significant upregulation in the disease group. Importantly, subsequent in vitro experiments validated that ATP1A1-AS1 overexpression induced a phenotype switching in vascular smooth muscle cells, along with promoting apoptosis and upregulating MMP-9 expression, potentially contributing to IAs formation. Furthermore, expanded-sample validation affirmed the high diagnostic value of ATP1A1-AS1. These findings suggest that ATP1A1-AS1 is a potential therapeutic target for inhibiting IAs progression and serves as a valuable clinical diagnostic marker.

Causal association between circulating inflammatory cytokines and intracranial aneurysm and subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The causal association between inflammatory cytokines and the development of intracranial aneurysm (IA), unruptured IA (uIA) and subarachnoid hemorrhage (SAH) lacks clarity. METHODS: The summary-level datasets for inflammatory cytokines were extracted from a genome-wide association study of the Finnish Cardiovascular Risk in Young Adults Study and the FINRISK survey. The summary statistics datasets related to IA, uIA and SAH were obtained from the genome-wide association study meta-analysis of the International Stroke Genetics Consortium and FinnGen Consortium. The primary method employed for analysis was inverse variance weighting (false discovery rate), supplemented by sensitivity analyses to address pleiotropy and enhance robustness. RESULTS: In the International Stroke Genetics Consortium, 10, six and eight inflammatory cytokines exhibited a causal association with IA, uIA and SAH, respectively (false discovery rate, p < 0.05). In FinnGen datasets, macrophage Inflammatory Protein-1 Alpha (MIP_1A), MIP_1A and interferon γ-induced protein 10 (IP_10) were verified for IA, uIA and SAH, respectively. In the reverse Mendelian randomization analysis, the common cytokines altered by uIA and SAH were vascular endothelial growth factor (VEGF), MIP_1A, IL_9, IL_10 and IL_17, respectively. The meta-analysis results show that MIP_1A and IP_10 could be associated with the decreased risk of IA, and MIP_1A and IP_10 were associated with the decreased risk of uIA and SAH, respectively. Notably, the levels of VEGF, MIP_1A, IL_9, IL_10 and TNF_A were increased with uIA. Comprehensive heterogeneity and pleiotropy analyses confirmed the robustness of these results. CONCLUSION: Our study unveils a bidirectional association between inflammatory cytokines and IA, uIA and SAH. Further investigations are essential to validate their relationship and elucidate the underlying mechanisms.

The association between hematologic traits and aneurysm-related subarachnoid hemorrhage: a two-sample mendelian randomization study.

Several hematologic traits have been suggested to potentially contribute to the formation and rupture of intracranial aneurysms (IA). The purpose of this study is to explore the causal association between hematologic traits and the risk of IA. To explore the causal association between hematologic traits and the risk of IA, we employed two-sample Mendelian randomization (MR) analysis. Two independent summary-level GWAS data were used for preliminary and replicated MR analyses. The inverse variance weighted (IVW) method was employed as the primary method in the MR analyses. The stabilities of the results were further confirmed by a meta-analysis. In the preliminary MR analysis, hematocrit, hemoglobin concentration (p = 0.0047), basophil count (p = 0.0219) had a suggestive inverse causal relationship with the risk of aneurysm-associated subarachnoid hemorrhage (aSAH). The monocyte percentage of white cells (p = 0.00956) was suggestively positively causally correlated with the risk of aSAH. In the replicated MR analysis, only the monocyte percentage of white cells (p = 0.00297) remained consistent with the MR results in the preliminary analysis. The hematocrit, hemoglobin concentration, and basophil count no longer showed significant causal relationship (p > 0.05). Meta-analysis results further confirmed that only the MR result of monocyte percentage of white cells reached significance in the random effect model and fixed effect model. None of the 25 hematologic traits was causally associated with the risk of unruptured intracranial aneurysms (uIA). This study revealed a suggestive positive association between the monocyte percentage of white cells and the risk of aSAH. This finding contributes to a better understanding that monocytes/macrophages could participate in the risk of aSAH.

Immunological alterations in intracranial aneurysm: a prospective study on selected biomarker profiles in blood collected during endovascular neurointervention.

INTRODUCTION: Previous studies showed that the concentrations of selected chemokines are locally elevated in samples collected from the lumen of intracranial aneurysms (IA). Our objective was to determine whether the observed differences in analyte concentrations were influenced by the origin of the blood samples (i.e. cerebral versus peripheral), thus providing insight into the localised nature of these alterations and their significance in IA pathogenesis. MATERIAL AND METHODS: This prospective study included 24 patients with IA who underwent endovascular embolisation. Concentrations of selected analytes were analysed in blood samples from the IA lumen, feeding artery, and aorta. The analytes included MPO, Lipocalin-2/NGAL, sICAM-1, sVCAM-1, and serum amyloid A. RESULTS: Higher median plasma concentrations of MPO, lipocalin-2/NGAL, sVCAM-1, and SAA were found in samples obtained from the IA lumen and the feeding artery compared to the aorta. The concentration of sICAM-1 was significantly higher in the IA compared to the aorta, but did not differ between the proximal artery and the aorta. No significant differences in any analyte concentration were observed between the IA and the proximal artery. CONCLUSIONS: These findings suggest that the IA and the proximal vessel share similarities in the local immunological environment, which is different from that observed in the aorta. Further studies are needed to fully understand and elucidate these observations.

A Computational Model of Blood D-Dimer, Cystatin C, and CRP Levels Predicts the Risk of Intracranial Aneurysms and their Rupture.

Objective: The aim of this study is to construct a computational model of blood D-dimer, cystatin C, and CRP levels and to predict the risk of intracranial aneurysms and their rupture. Methods: A total of 69 intracranial aneurysms patients were selected as the case group, including 28 cases in the ruptured group and 41 cases in the unruptured group. Another 64 non-intracranial aneurysm patients were selected as the control group. The detection results of serum D-dimer, cystatin C, and CRP were collected. The logistic regression computational model was used to analyze the occurrence and risk factors of intracranial aneurysms. The receiver operating curves (ROC) of serum D-dimer, cystatin C, and C reactive protein (CRP) levels for predicting intracranial aneurysms and their rupture were drawn, and the area under the curve (AUC), sensitivity, and specificity were calculated. Results: The serum levels of D-dimer, cystatin C, and CRP in patients with intracranial aneurysms were significantly higher than those in the control group and the differences were statistically significant (P < 0.05). The serum levels of D-dimer, cystatin C, and CRP in patients with ruptured intracranial aneurysms were higher than those in patients with unruptured intracranial aneurysms, and the differences were also statistically significant (P < 0.05). The combined detection of serum D-dimer, cystatin C, and CRP levels has a higher AUC (0.9014) for predicting intracranial aneurysms and higher AUC (0.9412) for predicting ruptured intracranial aneurysms than D-dimer (0.7118 and 0.8750, respectively), cystatin C (0.6489 and 0.6180, respectively), and CRP (0.7764 and 0.6551, respectively) independent detection; the combined detection had a sensitivity of 93.75% and 87.80 for predicting the occurrence and rupture of intracranial aneurysms, and the specificity was 68.12% and 92.86%, respectively. Conclusion: The combined detection of serum D-dimer, cystatin C, and CRP levels is a very valuable indicator for predicting the occurrence and rupture of intracranial aneurysms, and combined detection can provide scientific evidence-based guidance for clinical prediction of the occurrence and rupture of intracranial aneurysms.

Subarachnoid Hemorrhage and Extracorporeal Blood Purification with HA-380 and High-Volume Hemofiltration: A New Therapeutic Challenge at the Neurocritical Care Unit? A Case Report.

We present the case of a patient with subarachnoid hemorrhage (SAH) secondary to a ruptured cerebral aneurysm and a refractory shock with high doses of vasopressors without a proven source of infection. This patient received therapy with high-volume hemofiltration plus adsorption, resolving the hemodynamic deterioration and with good neurological evolution. Our clinical case proposes that extracorporeal therapies may have a feasibility role in the management of complications of SAH.

CircRNA_0079586 and circRNA_RanGAP1 are involved in the pathogenesis of intracranial aneurysms rupture by regulating the expression of MPO.

Several circRNAs have been reported to be dysregulated in human endothelial cells through sponging miRNAs. Previous reports demonstrated that MPO not only contributed to the formation and rupture of cerebral aneurysm but was also correlated with the degenerative remodeling predisposition to saccular intracranial aneurysm wall rupture, although its underlying mechanisms remain to be explored. Microarray screening was performed to compare the differential expression of circRNAs in the endothelial cells collected from UIAs and RIAs patients. Luciferase assays were used to explore the regulatory relationship between circRNAs and miRNAs, and between miRNAs and their target genes. Microarray screening analysis found a batch of up-regulated circRNAs in the endothelial cells harvested from RIAs patients, including circRNA-0079586 and circRNA-RanGAP1. Luciferase assays revealed the suppressive role of miR-183-5p/miR-877-3p in the expression of circRNA-0079586/circRNA-RanGAP1/MPO. And the expression of circRNA-0079586 and circRNA-RanGAP1 was respectively suppressed by the overexpression of miR-183-5p and miR-877-3p. And both the transfection of miR-183-5p and miR-877-3p mimics suppressed the relative expression level of MPO mRNA. The expression of circRNA-0079586, circRNA-RanGAP1 and MPO was significantly activated in the endothelial cells collected from RIAs patients when compared with UIAs patients, whereas the expression of miR-183-5p and miR-877-3p was remarkably suppressed in the endothelial cells collected from RIAs patients when compared with UIAs patients. We further altered the expression of circRNA-0079586 and circRNA-RanGAP1 using siRNA and overexpression in HUVECS, and the expression of circRNA-0079586 and circRNA-RanGAP1 was significantly and negatively correlated with the expression of miR-183-5p and miR-877-3p, but positively correlated with the expression of MPO under different conditions. In this study, we established two MPO-modulating signaling pathways of circRNA_0079586/miR-183-5p/MPO and circRNA_RanGAP1/miR-877-3p/MPO. These two signaling pathways are involved in the pathogenesis of intracranial aneurysms rupture.

Simvastatin increases circulating endothelial progenitor cells and inhibits the formation of intracranial aneurysms in rats with diet-induced hyperhomocysteinemia.

BACKGROUND AND PURPOSE: Endothelial dysfunction triggers early pathological changes in artery, leading to the formation of intracranial aneurysm (ICA). Increase in plasma homocysteine (Hcy) impairs endothelium and endothelial progenitor cells (EPCs) are critical in repairing damaged endothelium. The aim of this study was to assess the impact of simvastatin on ICA formation in rats with hyperhomocysteinemia (HHcy). METHODS: ICAs were induced in Male Sprague-Dawley rats after surgical induction in the presence of HHcy induced by a high L-methionine diet with or without oral simvastatin treatment. The size and media thickness of ICAs were evaluated 2 months after aneurysm induction. EPCs and serum vascular endothelial grow factor (VEGF) were measured be flow cytometry and ELISA respectively. Plasma Hcy levels and expression of VEGF, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2), and MMP-9 in aneurysmal walls were examined and correlated with ICA formation. RESULTS: HHcy accelerates ICA formation and rats treated with simvastatin exhibited a significant increase in media thickness and a reduction in aneurysmal size. Simvastatin increased levels of circulating EPCs and decreased iNOS, MMP-2, MMP-9 and VEGF mRNA levels, while increased eNOS mRNA in aneurysmal tissue. CONCLUSION: In a rat model, HHcy reduces circulating EPCs and accelerates ICA formation. Simvastatin treatment increases circulating EPCs and inhabits the formation of ICA. We have shown a close association among circulating EPCs, biochemical markers related to vascular remodeling and the formation of ICA.

Association of Serum Magnesium Levels With Risk of Intracranial Aneurysm: A Mendelian Randomization Study.

OBJECTIVE: Magnesium has been implicated in regulating blood pressure and vascular endothelial cell function, but its role in the pathophysiology of intracranial aneurysm is not known. Here we performed a Mendelian randomization analysis to investigate the association between serum magnesium concentration and risk of intracranial aneurysm. METHODS: Five single-nucleotide polymorphisms strongly associated with serum magnesium concentrations in a genome-wide association study in 23,829 individuals of European ancestry were used as genetic instruments. Genetic association estimates for intracranial aneurysm were obtained from a genome-wide association study in 79,429 individuals (7,495 cases and 71,934 controls). The inverse variance weighted method was used in the primary analyses to obtain the causal estimates. RESULTS: Higher genetically predicted serum magnesium concentrations were associated with lower risk of intracranial aneurysm. The odds ratios per 0.1 mmol/L increment in genetically predicted serum magnesium concentrations were 0.66 (95% confidence interval [CI] 0.49-0.91) for intracranial aneurysm (unruptured and ruptured combined), 0.57 (95% CI 0.30-1.06) for unruptured intracranial aneurysm, and 0.67 (95% CI 0.48-0.92) for aneurysmal subarachnoid hemorrhage. CONCLUSION: This study provides evidence to support that increased serum magnesium concentrations reduce the risk of intracranial aneurysm and associated hemorrhage.

The relationship between the level of vitamin D and ruptured intracranial aneurysms.

The purpose of our research is to explore whether vitamin D levels were associated with the rupture of intracranial aneurysms. In this retrospective study, 105 patients diagnosed with ruptured intracranial aneurysms (RIAs) and 185 patients diagnosed with unruptured intracranial aneurysms (UIAs) at The First Affiliated Hospital of Zhengzhou University were recruited from September 2019 to September 2020. Patients' demographic and clinical information, including vitamin D levels, were recorded and compared. Univariate analysis showed that patients with UIAs had higher vitamin D levels than RIAs (p = 0.019). In addition, there were significant differences in aneurysm location (p < 0.001), aspirin use (p = 0.001), and comorbid diabetes mellitus (p = 0.037) between patients with UIAs and RIAs. Binary logistic regression analysis showed that the level of vitamin D was independently associated with RIAs [odds ratio (OR) 0.960; 95% confidence intervals (CI), 0.926-0.996, p = 0.028].

Non-Coding RNAs as Circulating Biomarkers for the Diagnosis of Intracranial Aneurysm: A Systematic Review and Meta-Analysis.

BACKGROUND: Early diagnosis of intracranial aneurysm (IA) is arduous in the current situation, and no biomarker is available for the screening of IA. We here systematically evaluate the diagnostic value of circulating non-coding RNA (ncRNA) for the diagnosis of IA. METHODS: We searched PubMed, Web of Science, Embase, Scopus and Cochrane Library databases from inception to June 2020. We included studies that investigated the diagnostic performance of circulating ncRNAs for the diagnosis of IA. We performed Random-effect meta-analyses for the diagnostic test accuracy to calculate pooled estimates. Subgroup analyses and sensitivity analyses were conducted to explore the source of heterogeneity. RESULTS: Thirteen studies, including 1,105 patients and 28 ncRNAs, were included. The pooled sensitivity and specificity were 0.80 (95% confidence interval [CI], 0.76-0.83) and 0.80 (95% CI, 0.76-0.84), respectively, and the area under the hierarchical summary receiver operating characteristic curve was 0.87 (95% CI, 0.84-0.89). The pooled positive and negative likelihood ratios were 3.97 (95% CI, 3.17-4.98) and 0.25 (95% CI, 0.21-0.31), corresponding with a diagnostic odds ratio of 15.63 (95% CI, 10.41-23.47). Subgroup analyses revealed that the diagnostic accuracy of miRNA, lncRNA and circRNA were not significantly different (p > 0.05). Circulating ncRNAs showed higher diagnostic accuracy for patients with unruptured IA than those with ruptured IA (p = 0.0122). CONCLUSION: Current evidence suggests that the circulating ncRNA test could be an effective method for universal IA screening. Future clinical studies need to confirm the diagnostic role of specific ncRNAs.

Clinical application values of neutrophil-to-lymphocyte ratio in intracranial aneurysms.

Inflammation plays an important role in the pathogenesis and growth of intracranial aneurysms (IAs). We investigated the clinical value of the neutrophil-to-lymphocyte ratio (NLR) as a marker of systemic subclinical inflammation in patients with IAs. Consecutive patients with IAs who underwent endovascular treatment (EVT) were enrolled in the study. The evaluation indicators were aneurysm size and rupture, a poor outcome at 3 to 6 months, and delayed cerebral ischemia (DCI) during hospitalization. In total, 532 patients with IAs underwent EVT (mean age, 54.0 years; 62.4% female). Among patients with ruptured IAs, those with a higher NLR had an increased risk of a poor outcome at 3 to 6 months and DCI during hospitalization than those with a lower NLR. A higher NLR was significantly more strongly associated with the size of unruptured aneurysms and aneurysm rupture than a lower NLR. The NLR and C-reactive protein concentration showed similar predictive ability for aneurysm size and treatment prognosis. The NLR was lower at discharge than admission for patients with ruptured IAs and DCI. An elevated NLR was significantly associated with the size of unruptured IAs, an increased risk of a poor outcome, and DCI in patients with ruptured IAs.

Can we improve the prediction of complications and outcome in aneurysmal subarachnoid hemorrhage? The clinical implications of serum proteomics.

Aneurysmal subarachnoid hemorrhage is a devastating condition, often leading to a debilitating outcome. Delayed ischemic neurological deficits are considered the feared sequelae. Proteomics is a large-scale study of proteins incorporating structural and functional properties in complex biological fluids. Analysis of proteomes has led to identifying relevant complex proteins related to specific pathophysiological processes reflecting the severity and extent of diseases. Proteomics has evolved in the past few years; more biomarkers are deemed clinically relevant to diagnose, monitor, and define prognosis in patients with aneurysmal subarachnoid hemorrhage. Despite the absence of candidate biomarkers in the clinical routine, many have shown promising results. The complexity of proteins implicated in aneurysmal subarachnoid hemorrhage rendered these biomarkers' clinical use paved with various pitfalls and technical difficulties, especially when data about the perfect timing and values are lacking. We review the latest literature concerning serum proteomics and their clinical utility regarding the prediction of cerebral vasospasm and other complications of aneurysmal subarachnoid hemorrhage, as well as the clinical outcome. Future prospective studies will allow changing the disease's course, label patients according to their prognosis to provide earlier and better management and improve outcomes.

Whole blood transcriptome biomarkers of unruptured intracranial aneurysm.

BACKGROUND: The rupture of an intracranial aneurysm (IA) causes devastating subarachnoid hemorrhages, yet most IAs remain undiscovered until they rupture. Recently, we found an IA RNA expression signature of circulating neutrophils, and used transcriptome data to build predictive models for unruptured IAs. In this study, we evaluate the feasibility of using whole blood transcriptomes to predict the presence of unruptured IAs. METHODS: We subjected RNA from peripheral whole blood of 67 patients (34 with unruptured IA, 33 without IA) to next-generation RNA sequencing. Model genes were identified using the least absolute shrinkage and selection operator (LASSO) in a random training cohort (n = 47). These genes were used to train a Gaussian Support Vector Machine (gSVM) model to distinguish patients with IA. The model was applied to an independent testing cohort (n = 20) to evaluate performance by receiver operating characteristic (ROC) curve. Gene ontology and pathway analyses investigated the underlying biology of the model genes. RESULTS: We identified 18 genes that could distinguish IA patients in a training cohort with 85% accuracy. This SVM model also had 85% accuracy in the testing cohort, with an area under the ROC curve of 0.91. Bioinformatics reflected activation and recruitment of leukocytes, activation of macrophages, and inflammatory response, suggesting that the biomarker captures important processes in IA pathogenesis. CONCLUSIONS: Circulating whole blood transcriptomes can detect the presence of unruptured IAs. Pending additional testing in larger cohorts, this could serve as a foundation to develop a simple blood-based test to facilitate screening and early detection of IAs.

Characterization of Long Non-coding RNA Signatures of Intracranial Aneurysm in Circulating Whole Blood.

BACKGROUND AND OBJECTIVE: Long non-coding RNAs (lncRNAs) may serve as biomarkers for complex disease states, such as intracranial aneurysms. In this study, we investigated lncRNA expression differences in the whole blood of patients with unruptured aneurysms. METHODS: Whole blood RNA from 67 subjects (34 with aneurysm, 33 without) was used for next-generation RNA sequencing. Differential expression analysis was used to define a signature of intracranial aneurysm-associated lncRNAs. To estimate the signature's ability to classify aneurysms and to identify the most predictive lncRNAs, we implemented a nested cross-validation pipeline to train classifiers using linear discriminant analysis. Ingenuity pathway analysis was used to study potential biological roles of differentially expressed lncRNAs, and lncRNA ontology was used to investigate ontologies enriched in signature lncRNAs. Co-expression correlation analysis was performed to investigate associated differential protein-coding messenger RNA expression. RESULTS: Of 4639 detected lncRNAs, 263 were significantly different (p < 0.05) between the two groups, and 84 of those had an absolute fold-change ≥ 1.5. An eight-lncRNA signature (q < 0.35, fold-change ≥ 1.5) was able to separate patients with and without aneurysms on principal component analysis, and had an estimated accuracy of 70.9% in nested cross-validation. Bioinformatics analyses showed that networks of differentially expressed lncRNAs (p < 0.05) were enriched for cell death and survival, connective tissue disorders, carbohydrate metabolism, and cardiovascular disease. Signature lncRNAs shared ontologies that reflected regulation of gene expression, signaling, ubiquitin processing, and p53 signaling. Co-expression analysis showed correlations with messenger RNAs related to inflammatory responses. CONCLUSIONS: Differential expression in whole blood lncRNAs is detectable in patients harboring aneurysms, and reflects expression/signaling regulation, and ubiquitin and p53 pathways. Following validation in larger cohorts, these lncRNAs may be potential diagnostic targets for aneurysm detection by blood testing.

Clinical Relevance of Changes in Peripheral Blood Cells After Intracranial Aneurysm Rupture.

BACKGROUND: The rupture of an intracranial aneurysm (IA) causes a systemic response that involves an immune/inflammatory reaction. We sought to characterize the systemic response to IA rupture. METHODS: We included 19 patients in the acute phase of IA rupture and 20 control subjects. Flow cytometry was used to analyze alterations in the level of mononuclear leukocytes. Cell-related parameters, including the neutrophil-to-lymphocyte ratio (NL-R), lymphocyte-to-monocyte ratio (LM-R), platelet-to-lymphocyte ratio (PL-R), and systemic immune-inflammation index (SII), were calculated, and the relationship between the analyzed hematological parameters and clinical status was investigated. RESULTS: Patients with ruptured IAs presented with significantly higher white blood cells (WBC) and neutrophil counts but lower lymphocyte counts than control subjects. NL-R and SII values were higher and the LM-R was lower in the acute phase after IA rupture. Analyzing the severity of clinical status and the outcome of patients with subarachnoid hemorrhage, we found that patients with poor clinical status, as measured by the Glasgow Coma Scale (GCS) and the Hunt and Hess scale, had significantly lower lymphocyte counts and higher NL-R, PL-R and SII values than those with good clinical status. Additionally, patients with lower GCS scores presented a lower proportion of CD3+CD4-CD8- cells. Worse outcomes assessed at discharge were associated with lower lymphocyte counts but higher PL-R values. CONCLUSIONS: The current study pointed to the significance of systemic immune and inflammatory responses after IA rupture and the potential clinical utility of hematological parameters, which can be easily calculated. In particular, the role of DN T cells and the significance of the SII as a marker related to clinical status should be further investigated.

Bioinformatics analysis of microRNA profiles and identification of microRNA-mRNA network and biological markers in intracranial aneurysm.

Intracranial aneurysm (IA) is a kind of cerebrovascular disorder, which may result in the subarachnoid hemorrhage with high lethality and disability. The purpose of this study was to reveal the pathogenesis and identify novel biomarkers in IA.We processed the raw microRNA (miRNA) expression profile data of IA obtained from Gene Expression Omnibus. Then weighted correlation network analysis was performed to identify the hub miRNAs in IA. Target genes of hub miRNAs were predicted using multiR package. In addition, a protein-protein network as well as miRNA-mRNA network was constructed and functional and pathway enrichment analyses were done. Finally, the prediction value of hub miRNAs in IA was tested in validation set.Two modules that had relation with IA were identified and 10 hub miRNAs in each module with higher gene-module association were selected. The protein-protein network and miRNA-mRNA network contained 243 nodes and 1496 edges. Functional and pathway enrichment analyses showed that they were mainly enriched in cell cycle, cell proliferation, and PI3K/Akt signaling pathways. Besides, hsa-miR-191-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-425-3p were proven to be valuable in prediction IA occurrence.In a word, this study reveals hub miRNAs, target genes and pathways potentially participating in formation and development of IA and screens out some candidate biomarkers. Our findings provide some new perspectives for research and treatment of IA.

Identification of potential key pathways, genes and circulating markers in the development of intracranial aneurysm based on weighted gene co-expression network analysis.

Background: Intracranial aneurysm (IA) is a disease resulted from weak brain control, characterized by local expansion or dilation of brain artery. This study aimed to construct a gene co-expression network by Weighted Gene Correlation Network Analysis (WGCNA) to explore the potential key pathways and genes for the development of IA.Method: Six IA-related gene expression data sets were downloaded from the Gene Expression Omnibus (GEO) database for identifying differentially expressed genes (DEGs). WGCNA was used to identify modules associated with IA. Functional enrichment analysis was used to explore the potential biological functions. ROC analysis was used to find markers for predicting IA.Results: Purple, greenyellow and yellow modules were significantly associated with unruptured intracranial aneurysms, while blue and turquoise modules were significantly associated with ruptured intracranial aneurysms. Functional modules significantly related to IA were enriched in Ribosome, Glutathione metabolism, cAMP signalling pathway, Lysosome, Glycosaminoglycan degradation and other pathways. CD163, FCEREG, FPR1, ITGAM, NLRC4, PDG, and TYROBP were up-regulated ruptured intracranial aneurysms and serum, these genes were potential circulating markers for predicting IA rupture.Conclusions: Potential IA-related key pathways, genes and circulating markers were identified for predicting IA rupture by WGCNA analysis.

Preclinical safety and efficacy evaluation of the Pipeline Vantage Embolization Device with Shield Technology.

BACKGROUND: The Pipeline Vantage Embolization Device with Shield Technology is a next generation flow diverter developed to improve aneurysm occlusion and implant endothelialization in addition to lowering thrombogenicity. We report here the in vivo biocompatibility and in vitro hemocompatibility performance of the Pipeline Vantage Embolization Device with Shield Technology (Vantage) compared with the Pipeline Flex Embolization Device (Flex). METHODS: Biocompatibility (via histology), aneurysm occlusion and vessel patency (via angiography), and endothelial coverage (via scanning electron microscopy (SEM)) for the Vantage and Flex devices were assessed in the rabbit elastase aneurysm model at 90 days (n=29) and 180 days (n=27). In vitro thrombogenicity for Flex and Vantage (n=16) was assessed using a human blood flow loop model at low heparin concentration (0.6 U/mL) with thrombin generation, platelet activation and thrombus visualization as outputs. RESULTS: Raymond Roy Occlusion Classification grade 1 was higher for Vantage (61%) compared with Flex (46%), but was not statistically significant (p>0.05). All branch vessels were patent. Histological measures for both devices were similar (p>0.05). Endothelial coverage of the implant was significantly better for Vantage compared with Flex (p<0.05). In vitro measurements of thrombin generation (thrombin-antithrombin complex (µg/mL): Vantage 0.49±0.45; Flex 10.57±9.84) and platelet activation (ß-thromboglobulin (IU/µl): Vantage 0.41±0.19; Flex 4.14±2.38) were both statistically lower (p<0.05) for Vantage compared with Flex. High resolution microscopy showed less accumulation of thrombus on Vantage as compared with Flex. CONCLUSION: Vantage improved aneurysm occlusion and implant endothelialization and had significantly lower thrombogenicity as compared with Flex, while preserving the biocompatibility safety profile of Flex.