The Role of Long Noncoding RNAs in Vascular Smooth Muscle Cell Phenotype and the Pathogenesis of Cardiovascular and Cerebrovascular Aneurysms.

ABSTRACT: Aneurysms are localized dilations of blood vessels, which can expand to 50% of the original diameter. They are more common in cardiovascular and cerebrovascular vessels. Rupture is one of the most dangerous complications. The pathophysiology of aneurysms is complex and diverse, often associated with progressive vessel wall dysfunction resulting from vascular smooth muscle cell death and abnormal extracellular matrix synthesis and degradation. Multiple studies have shown that long noncoding RNAs (lncRNAs) play a significant role in the progression of cardiovascular and cerebrovascular diseases. Therefore, it is necessary to find and summarize them. LncRNAs control gene expression and disease progression by regulating target mRNA or miRNA and are biomarkers for the diagnosis and prognosis of aneurysmal cardiovascular and cerebrovascular diseases. This review explores the role, mechanism, and clinical value of lncRNAs in aneurysms, providing new insights for a deeper understanding of the pathogenesis of cardiovascular and cerebrovascular aneurysms.

Tenofovir alafenamide or tenofovir disoproxil fumarate in pregnancy to prevent HBV transmission: Maternal ALT trajectory and infant outcomes.

BACKGROUND: The use of antiviral agents, specifically tenofovir disoproxil fumarate (TDF), in pregnant women to prevent mother-to-child HBV transmission is a key step towards hepatitis elimination. However, data on using tenofovir alafenamide (TAF) is insufficient. The frequent occurrence of postpartum ALT flares may impact the clinical implementation. METHODS: The maternal and infant outcomes were compared in multi-centre trials of high viral load HBsAg/HBeAg+ pregnant women receiving TAF or TDF from the third trimester until 2 weeks postpartum with intensive follow-ups. To explore the dynamic pre- and postpartum changes in ALT levels, we used a group-based trajectory model for analysing data of 332 women from three prospective studies. RESULTS: After treatment, the maternal HBV DNA levels significantly decreased from baseline to delivery: 7.87 ± 0.59 to 3.99 ± 1.07 Log10 IU/mL TAF (n = 78) and 8.30 ± 0.36 to 4.47 ± 0.86 Log10 IU/mL (TDF, n = 53), with viral load reductions of 3.87 versus 3.83 Log10 IU/mL. The HBsAg-positive rates among 12-month-old infants were 1.28% (1/78) versus 1.82% (1/55) respectively (p = 1.00). Of the TAF or TDF-treated mothers, 25.64% versus 16.98% experienced ALT > 2X ULN, and 11.54% versus 1.89% received extended antiviral treatment. Our model revealed four distinct ALT patterns: stable ALT (87.2%), moderate (8.0%) or marked (2.4%) postpartum flares, or prepartum elevations (2.4%). CONCLUSIONS: TAF effectively reduces mother-to-child HBV transmission, but prophylaxis failure still occurred in few cases. Postpartum ALT flares are common in women receiving TAF or TDF during pregnancy. Approximately 12.8% of mothers may require extended postpartum antiviral treatment. CLINICAL TRIAL NUMBER: NCT03695029 (ClinicalTrials.gov).

Revealing Novel Genes Related to Parkinson's Disease Pathogenesis and Establishing an associated Model.

Parkinson's disease (PD) represents a multifaceted neurological disorder whose genetic underpinnings warrant comprehensive investigation. This study focuses on identifying genes integral to PD pathogenesis and evaluating their diagnostic potential. Initially, we screened for differentially expressed genes (DEGs) between PD and control brain tissues within a dataset comprising larger number of specimens. Subsequently, these DEGs were subjected to weighted gene co-expression network analysis (WGCNA) to discern relevant gene modules. Notably, the yellow module exhibited a significant correlation with PD pathogenesis. Hence, we conducted a detailed examination of the yellow module genes using a cytoscope-based approach to construct a protein-protein interaction (PPI) network, which facilitated the identification of central hub genes implicated in PD pathogenesis. Employing two machine learning techniques, including XGBoost and LASSO algorithms, along with logistic regression analysis, we refined our search to three pertinent hub genes: FOXO3, HIST2H2BE, and HDAC1, all of which demonstrated a substantial association with PD pathogenesis. To corroborate our findings, we analyzed two PD blood datasets and clinical plasma samples, confirming the elevated expression levels of these genes in PD patients. The association of the genes with PD, as reflected by the area under the curve (AUC) values for FOXO3, HIST2H2BE, and HDAC1, were moderate for each gene. Collectively, this research substantiates the heightened expression of FOXO3, HIST2H2BE, and HDAC1 in both PD brain and blood samples, underscoring their pivotal contribution to the pathogenesis of PD.

ADORA3: A Key Player in the Pathogenesis of Intracranial Aneurysms and a Potential Diagnostic Biomarker.

BACKGROUND: The effects of genes on the development of intracranial aneurysms (IAs) remain to be elucidated, and reliable blood biomarkers for diagnosing IAs are yet to be established. This study aimed to identify genes associated with IAs pathogenesis and explore their diagnostic value by analyzing IAs datasets, conducting vascular smooth muscle cells (VSMC) experiments, and performing blood detection. METHODS: IAs datasets were collected and the differentially expressed genes were analyzed. The selected genes were validated in external datasets. Autophagy was induced in VSMC and the effect of selected genes was determined. The diagnostic value of selected gene on the IAs were explored using area under curve (AUC) analysis using IAs plasma samples. RESULTS: Analysis of 61 samples (32 controls and 29 IAs tissues) revealed a significant increase in expression of ADORA3 compared with normal tissues using empirical Bayes methods of "limma" package; this was further validated by two external datasets. Additionally, induction of autophagy in VSMC lead to upregulation of ADORA3. Conversely, silencing ADORA3 suppressed VSMC proliferation and autophagy. Furthermore, analysis of an IAs blood sample dataset and clinical plasma samples demonstrated increased ADORA3 expression in patients with IA compared with normal subjects. The diagnostic value of blood ADORA3 expression in IAs was moderate when analyzing clinical samples (AUC: 0.756). Combining ADORA3 with IL2RB or CCR7 further enhanced the diagnostic ability for IAs, with the AUC value over 0.83. CONCLUSIONS: High expression of ADORA3 is associated with IAs pathogenesis, likely through its promotion of VSMC autophagy. Furthermore, blood ADORA3 levels have the potential to serve as an auxiliary diagnostic biomarker for IAs.

Diagnosis of Middle Cerebral Artery Stenosis Using Transcranial Doppler Images Based on Convolutional Neural Network.

BACKGROUND: The purpose of this study was to explore the diagnostic value of convolutional neural networks (CNNs) in middle cerebral artery (MCA) stenosis by analyzing transcranial Doppler (TCD) images. METHODS: Overall, 278 patients who underwent cerebral vascular TCD and cerebral angiography were enrolled and classified into stenosis and non-stenosis groups based on cerebral angiography findings. Manual measurements were performed on TCD images. The patients were divided into a training set and a test set, and the CNN architecture was used to classify TCD images. The diagnostic accuracies of manual measurements, CNNs, and TCD parameters for MCA stenosis were calculated and compared. RESULTS: Overall, 203 patients without stenosis and 75 patients with stenosis were evaluated. The sensitivity, specificity, and area under the curve (AUC) for manual measurements of MCA stenosis were 0.80, 0.83, and 0.81, respectively. After 24 iterations of the running model in the training set, the sensitivity, specificity, and AUC of the CNNs in the test set were 0.84, 0.86, and 0.80, respectively. The diagnostic value of CNNs differed minimally from that of manual measurements. Two parameters of TCD, peak systolic velocity and mean flow velocity, were higher in patients with stenosis than in those without stenosis; however, their diagnostic values were significantly lower than those of CNNs (P < 0.05). CONCLUSIONS: The diagnostic value of CNNs for MCA stenosis based on TCD images paralleled that of manual measurements. CNNs could be used as an auxiliary diagnostic tool to improve the diagnosis of MCA stenosis.

Co-expression Network Analysis Reveals Novel Genes Underlying Alzheimer's Disease Pathogenesis.

Background: The pathogenesis of Alzheimer's disease (AD) remains to be elucidated. This study aimed to identify the hub genes in AD pathogenesis and determine their functions and pathways. Methods: A co-expression network for an AD gene dataset with 401 samples was constructed, and the AD status-related genes were screened. The hub genes of the network were identified and validated by an independent cohort. The functional pathways of hub genes were analyzed. Results: The co-expression network revealed a module that related to the AD status, and 101 status-related genes were screened from the trait-related module. Gene enrichment analysis indicated that these status-related genes are involved in synaptic processes and pathways. Four hub genes (ENO2, ELAVL4, SNAP91, and NEFM) were identified from the module, and these hub genes all participated in AD-related pathways, but the associations of each gene with clinical features were variable. An independent dataset confirmed the different expression of hub genes between AD and controls. Conclusions: Four novel genes associated with AD pathogenesis were identified and validated, which provided novel therapeutic targets for AD.

Predictive factors for early hypothyroidism following the radioactive iodine therapy in Graves' disease patients.

BACKGROUND: Radioactive iodine (RAI) therapy is an important treatment option for Graves' disease (GD), the main side effect of RAI treatment is hypothyroidism, and the factors resulting in hypothyroidism are still controversial. The purpose of this retrospective study was to clarify the possible risk factors of early hypothyroidism after RAI therapy in Graves' disease. METHODS: We reviewed 312 GD patients treated with RAI between January 2017 to December 2018, collected the potential risk factors, and analyzed the relationship between these variables and early hypothyroidism. RESULTS: After 6 months' follow-up, 218 (69.87%) patients were evaluated as early hypothyroid. Male gender, shorter duration of disease, smaller thyroid weight, lower 2-h radioactive iodine uptake (RAIU), 6-h RAIU, 24-h RAIU and 6/24-h uptake ratio, lower administered dosages were significantly associated with early hypothyroidism. Logistics regression analysis showed that male gender, smaller thyroid weight and lower 6-h RAIU were associated with early hypothyroidism. Multi-factors combined ROC curve analysis suggested that the predictive power of male gender, smaller thyroid weight and lower 6-h RAIU for early hypothyroidism was 0.711. CONCLUSIONS: Our results show that RAI is an effective therapy for GD and most of the cured patients became to hypothyroid within 6 months. Male gender, smaller thyroid weight and lower 6-h RAIU are the main risk factors for early hypothyroidism.

LncRNA MIAT sponges miR-149-5p to inhibit efferocytosis in advanced atherosclerosis through CD47 upregulation.

Atherosclerotic cardio-cerebrovascular disease and death remain the leading cause of morbidity and mortality worldwide. Defective efferocytosis, the clearance of apoptotic cells by macrophages, is thought to lead to increased inflammation and necrotic core formation in atherosclerotic lesions. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here we show that lncRNA myocardial infarction associated transcript (MIAT) was markedly elevated in the serum of patients with symptoms of vulnerable atherosclerotic plaque and the macrophages of necrotic cores in an advanced atherosclerosis mouse model. MIAT knockdown attenuated atherosclerosis progression, reduced necrotic core size, and increased plaque stability in vivo. Furthermore, MIAT knockdown promoted clearance of apoptotic cells by macrophages in vivo and in vitro. Mechanistic studies revealed that MIAT acted as a micro RNA (miRNA) sponge to positively modulate the expression of anti-phagocytic molecule CD47 through sponging miR-149-5p. Together, these findings identified a macrophage MIAT/miR-149-5p /CD47 pathway as a key factor in the development of necrotic atherosclerotic plaques.

Expression of long non­coding RNA and mRNA in the hippocampus of mice with type 2 diabetes.

Long non­coding RNAs (lncRNAs) serve key roles in cell growth, development and various diseases associated with the central nervous system. However, differential expression profiles of lncRNAs in type 2 diabetes have not been reported. The present study aimed to analyze the expression pattern of lncRNA­mRNA in a type 2 diabetic mouse model using microarray analysis. The mouse model of type 2 diabetes was established and the total RNAs were extracted from the hippocampus of the mice used in the present study. The total RNAs were then examined by the GeeDom human lncRNA + mRNA V4.0 expression profile and analyzed through comparing Gene Ontology (GO) enrichment analysis and signal pathway analysis with the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. There were statistically significant differences between the expression of IncRNAs and mRNA in the healthy mice and that of the diabetic mice. In the diabetic mice, 130 different lncRNAs were expressed with 126  significantly upregulated and 4 significantly downregulated and 49 different mRNAs were detected with 45 significantly upregulated and 4 downregulated. GO analysis indicated that the mRNAs that are affected are involved in transport, cell adhesion, ion transport and metabolic processes. KEGG and Reactome enrichment analysis indicated that mRNAs impact on cholinergic synapses, nuclear factor­kB pathway, Toll like receptor 4 cascade and zinc transporter are correlated with cognitive dysfunction in type 2 diabetes. A dynamic lncRNA­mRNA network was constructed containing 123 lncRNAs and 48 mRNAs, which can elucidate the interaction between lncRNA and mRNA. Overall, this is the first study to indicate that lncRNAs are differentially expressed in the type 2 diabetic mice.

Association between serum uric acid level and multiple system atrophy: A meta-analysis.

OBJECTIVES: Lower serum uric acid (UA) levels are considered to be related to the risk to develop many neurodegenerative disorders. However, the association between serum UA level and multiple system atrophy (MSA) remains controversial. The aim of this meta-analysis was to evaluate the relationship between serum UA level and MSA. PATIENTS AND METHODS: PubMed, Web of Science, Embase, Cochrane Library and China National Knowledge Infrastructure (CNKI) were searched for eligible studies. Standardized mean difference (SMD) and 95% confidence intervals (95% CI) were calculated in a fixed-effects model or a random-effects model when appropriate. Subgroup analyses were carried out based on gender. A total of 6 eligible studies involving 547 MSA patients and 637 healthy individuals were identified. RESULTS: Meta-analysis results revealed that individuals with MSA had lower sera levels of UA as compared with healthy controls (pooled SMD is -0.51, 95%CI: -0.88 to -0.14; p = 0.006). The subgroup analysis to detect sex differences showed that the pooled SMD was -0.61 (95% CI: -0.82 to -0.40; p < 0.0001) for males and -0.22 (95% CI: -0.55 to 0.10; p = 0.18) for females compared with healthy controls. CONCLUSION: Our meta-analysis revealed that lower serum level of UA is associated with an increased risk of MSA and the relationship is significant in men but not in women.

Long-term Nucleos(t)ides Analogues for Chronic Hepatitis B Improve Liver and Spleen Size: A Noninvasive Sonographic Study.

BACKGROUND: Histological improvement and regression of liver fibrosis after long-term use of nucleos(t)ides analogues (NUCs) have been documented. The aim of the present investigation was to evaluate the usefulness of traditional sonography to detect hepatic and splenic changes during NUC therapy in chronic hepatitis B (CHB) patients. METHODS: A total of 181 CHB patients receiving NUC treatment were enrolled in this study. The study population was divided into three groups 72 cirrhotic, 58 noncirrhotic CHB, and 51 nonreplicative hepatitis B virus carriers. All patients had blood chemistries taken and sonography at baseline and during the NUC treatment period. The changes in liver size, liver edge, spleen size, platelet count, and platelet count/spleen diameter (PC/SD) ratio were compared among the three groups of patients. RESULTS: CHB Patients with and without cirrhosis have improved clinical features during NUC therapy with lower aspartate aminotransferase, alanine aminotransferase, international normalized ratio, hepatitis B virus DNA, and spleen size and higher platelet, liver edge, liver size, and PC/SD ratio compared with the baseline data (p < 0.05). The differences in liver edge, liver size, spleen size, and PC/SD ratio are higher in the cirrhosis group than in the non-cirrhotic group (p < 0.001). A decrease in spleen size exhibited a linear relationship with treatment duration (R2 = 0.905). CONCLUSIONS: Traditional sonography is helpful to monitor changes in liver fibrosis of CHB patients under NUC therapy.Abbreviations: AFP, α-fetoprotein; ALT, alanine transaminase; AST, aspartate transaminase; CHB, chronic hepatitis B; Hb, hemoglobin; HBV, hepatitis B virus; INR, international normalized ratio; NUCs, nucleos(t)ides analogues; PC/SD, platelet count/spleen diameter; WBC, white blood cells.

Association of smoking with restenosis and major adverse cardiac events after coronary stenting: A meta-analysis.

BACKGROUND AND OBJECTIVE: The association between smoking and clinical outcomes after coronary stenting is controversial. The aim of this meta-analysis was to assess the association between smoking and in stent restenosis (ISR), major adverse cardiac events (MACE), or major adverse cardiac and cerebrovascular events (MACCE) after coronary stenting. METHODS: A search for studies published before December 2014 was conducted in PubMed, Embase, and Cochrane library. An inverse random weighted meta-analysis was conducted using logarithm of the odds ratio (OR) and its standard error for each study. RESULTS: Ten studies investigated the association between smoking and ISR. Overall, smoking was not associated with ISR (OR: 1.05, 95% CI: 0.79-1.41; I(2) = 47.8%). Subgroup analysis also failed to show a significant association between smoking and ISR risk regardless of bare metal stent (BMS) and drug-eluting stent (DES) implantation. Eight studies explored the association between smoking and MACE, but no association was found (OR: 0.92, 95% CI: 0.77-1.10; I(2) = 25.5%), and subgroup analysis revealed that no distinct difference was found between BMS and DES implantation. Three studies investigated the association between smoking and MACCE and significant association was found (OR: 2.09, 95% CI: 1.43-3.06; I(2) = 21.6%). CONCLUSIONS: Our results suggest that in patients undergoing percutaneous coronary intervention with stent implantation, smoking is not associated with ISR and MACE; however, smoking is an independent risk factor for MACCE.

Meta-Analysis of Prognostic and Clinical Significance of CD44v6 in Esophageal Cancer.

CD44v6 is a cell adhesion molecule that plays an important role in the development and progression of esophageal cancer. However, the prognostic value and clinical significance of CD44v6 in esophageal cancer remains controversial. In the present study, we aimed to clarify these relationships through a meta-analysis.We performed a comprehensive search of studies from PubMed, EMBASE, Ovid library database, Google scholar, and Chinese National Knowledge Infrastructure databases that were published before June 2015. The odds ratio (OR) and pooled hazard ratio (HR) with the 95% confidence intervals (CI) were used to estimate the effects.Twenty-one studies including 1504 patients with esophageal cancer were selected to assess the prognostic value and clinical significance of CD44v6 in these patients. The results showed that the expression of CD44v6 was higher in esophageal cancer tissue than in normal colorectal tissue (OR=9.19, 95% CI=6.30-13.42). Moreover, expression of CD44v6 was higher in patients with lymphoid nodal metastasis, compared to those without (OR=6.91, 95% CI=4.81-9.93). The pooled results showed that CD44v6 was associated with survival in patients with esophageal cancer (HR = 2.47, 95% CI = 1.56-3.92). No significant difference in CD44v6 expression was found in patients with different histological types and tumor stages (both P>0.05). Moreover, no publication bias was found among the studies (all P > 0.05).This meta-analysis demonstrates that CD44v6 is associated with the metastasis of esophageal cancer and a poor prognosis, but is not associated with the histological types and tumor stages.

Egg consumption and risk of bladder cancer: a meta-analysis.

The findings of epidemiologic studies on the association between egg consumption and bladder cancer risk remain conflicting. We conducted a meta-analysis to clarify the potential association between egg consumption and bladder cancer risk. Four cohort studies and 9 case-control studies in the PubMed database through February 2012 were identified on egg consumption and risk of bladder cancer involving 2715 cases and 184,727 participants. Random-effects models were used to calculate the summary relative risk estimates (SRRE) based on the highest compared with the lowest category of egg consumption. In addition, we performed stratified analyses and sensitivity and dose-response analyses to examine the association. Overall, no significant association was observed between egg consumption and bladder cancer (SRRE = 1.11 95% CI: 0.90-1.35). However, increased risk of bladder cancer was detected in North/South America (SRRE = 1.40 95% CI: 1.05-1.86) and, moreover, fried egg intake positively associated with bladder cancer as well (SRRE = 2.04, 95% CI: 1.41-2.95). In conclusion, our findings suggest no significant association between egg consumption and bladder cancer risk, except for a possible positive relationship with the intake of fried eggs based on the limited number of studies. Additional studies, especially large prospective cohort studies, are warranted to confirm these findings.