Supra-Blan2 t score as a multisystem-based risk score to predict poor 3-month outcome in acute ischemic stroke patients with intravenous thrombolysis.

AIM: To develop and validate a novel weighted score integrating multisystem laboratory and clinical variables to predict poor 3-month outcome (mRS score of 3-6) in acute ischemic stroke (AIS) patients with intravenous thrombolysis (IVT) therapy. METHODS: We retrospectively analyzed data from Trial of Revascularization Treatment for Acute Ischemic Stroke study. The Supra-Blan2 t score was derived using the data on age, the National Institutes of Health Stroke Scale score, history of atrial fibrillation, blood sugar level, neutrophil count, direct bilirubin level, platelet-lymphocyte ratio, and TnI level in the derivation cohort of 433 patients, and validated in a cohort of 525 patients. Furthermore, we compared the performance of the Supra-Blan2 t score with DRAGON, TURN, and SPAN-100 scores. RESULTS: The discrimination capacity in the derivation and validation cohorts was good for poor 3-month outcome (the area under the curve was 0.821 and 0.843, respectively). The cumulative incidence of poor 3-month outcome significantly increased across risk categories in the derivation (low-risk, 9.2%; medium-risk, 17.4%; and high-risk, 58.8%) and validation cohorts (12.7%, 36.5%, and 73.6%, respectively). The performance of the Supra-Blan2 t score was similar to or superior to DRAGON, TURN, and SPAN-100 scores. CONCLUSION: The Supra-Blan2 t score, based on easily available multisystem laboratory and clinical variables, reliably predicted poor 3-month functional outcome in AIS patients treated with IVT therapy featuring good calibration and discrimination.

Association of white matter hyperintensities with long-term EGFR-TKI treatment and prediction of progression risk.

PURPOSE: The purpose of this study was to test the hypothesis that brain white matter hyperintensities (WMH) are more common in patients receiving epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and identify clinical risk factors associated with WMH. EXPERIMENTAL DESIGN: This multiple-center, prospective cohort study was conducted from March 2017 to July 2020. Two groups of patients with non-small cell lung cancer (NSCLC) who received or did not receive EGFR-TKI were included and followed up for more than 24 months. The progression of WMH was defined as an increase of ≥1 point on the Fazekas visual rating scale between the baseline and at the 2-year follow-up. A modified Poisson regression model was performed to evaluate risk factors on increased WMH load. RESULTS: Among 286 patients with NSCLC, 194 (68%) patients with NSCLC who received EGFR-TKI and 92 (32%) patients with NSCLC without EGFR-TKI treatment were analyzed. Modified Poisson regression analysis showed that EGFR-TKI treatment was independently associated with the WMH progression (EGFR-TKI: aRR 2.72, 95% confidence interval [CI] 1.46-5.06, p = .002). Interleukin (IL)-2, IL-4, and IL-10 were associated with increased WMH in the adjusted model (IL-2: aRR 1.55 [95% CI 1.06-2.25], p = .023; IL-4: aRR 1.66 [95% CI 1.13-2.43], p = .010; IL-10: aRR 1.48 [95% CI 1.06-2.06], p = .020). CONCLUSION: Patients with NSCLC who received EGFR-TKI may be at higher risk of developing WMH or worsening of WMH burden. The impact of increased WMH lesions in these patients is to be further assessed. IL-2, IL-4, and IL-10 may be used as potential biomarkers to monitor the risk of increased WMH burden.

CNS-LAND score: predicting early neurological deterioration after intravenous thrombolysis based on systemic responses and injury.

Importance: Early neurological deterioration (END) is a critical complication in acute ischemic stroke (AIS) patients receiving intravenous thrombolysis (IVT), with a need for reliable prediction tools to guide clinical interventions. Objective: This study aimed to develop and validate a rating scale, utilizing clinical variables and multisystem laboratory evaluation, to predict END after IVT. Design setting and participants: The Clinical Trial of Revascularization Treatment for Acute Ischemic Stroke (TRAIS) cohort enrolled consecutive AIS patients from 14 stroke centers in China (Jan 2018 to Jun 2022). Outcomes: END defined as NIHSS score increase >4 points or death within 24 h of stroke onset. Results: 1,213 patients (751 in the derivation cohort, 462 in the validation cohort) were included. The CNS-LAND score, a 9-point scale comprising seven variables (CK-MB, NIHSS score, systolic blood pressure, LDH, ALT, neutrophil, and D-dimer), demonstrated excellent differentiation of END (derivation cohort C statistic: 0.862; 95% CI: 0.796-0.928) and successful external validation (validation cohort C statistic: 0.851; 95% CI: 0.814-0.882). Risk stratification showed END risks of 2.1% vs. 29.5% (derivation cohort) and 2.6% vs. 31.2% (validation cohort) for scores 0-3 and 4-9, respectively. Conclusion: CNS-LAND score is a reliable predictor of END risk in AIS patients receiving IVT.

The Role of Oxidative Stress in Acute Ischemic Stroke-Related Thrombosis.

Acute ischemic stroke is a serious life-threatening disease that affects almost 600 million people each year throughout the world with a mortality of more than 10%, while two-thirds of survivors remain disabled. However, the available treatments for ischemic stroke are still limited to thrombolysis and/or mechanical thrombectomy, and there is an urgent need for developing new therapeutic target. Recently, intravascular oxidative stress, derived from endothelial cells, platelets, and leukocytes, has been found to be tightly associated with stroke-related thrombosis. It not only promotes primary thrombus formation by damaging endothelial cells and platelets but also affects thrombus maturation and stability by modifying fibrin components. Thus, oxidative stress is expected to be a novel target for the prevention and treatment of ischemic stroke. In this review, we first discuss the mechanisms by which oxidative stress promotes stroke-related thrombosis, then summarize the oxidative stress biomarkers of stroke-related thrombosis, and finally put forward an antithrombotic therapy targeting oxidative stress in ischemic stroke.

Characterization of two constitutive promoters RPS28 and EIF1 for studying soybean growth, development, and symbiotic nodule development.

Native promoters that can drive high and stable transgene expression are important tools for modifying plant traits. Although several such promoters have been reported in soybean (Glycine max), few of them function at multiple growth and development stages and during nodule development. Here, we report that the promoters of 40S RIBOSOMAL PROTEIN SMALL SUBUNIT S28 (RPS28) and EUKARYOTIC TRANSLATION INITIATION FACTOR 1 (EIF1) are ideal for high expression of transgene. Through bioinformatic analysis, we determined that RPS28 and EIF1 were highly expressed during soybean growth and development, nodule development, and various biotic and abiotic stresses. Fusion of both RPS28 and EIF1 promoters, with or without their first intron, with the reporter gene ß-GLUCURONIDASE (uidA) in transgenic soybean, resulted in high GUS activity in seedlings, seeds, and nodules. Fluorimetric GUS assays showed that the RPS28 promoter and the EIF1 promoter yielded high expression, comparable to the soybean Ubiquitin (GmUbi) promoter. RPS28 and EIF1 promoters were also highly expressed in Arabidopsis thaliana and Nicotiana benthamiana. Our results indicate the potential of RPS28 and EIF1 promoters to facilitate future genetic engineering and breeding to improve the quality and yield of soybean, as well as in a wide variety of other plant species. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-022-00073-6.

Comprehensive Expression Profiling and Molecular Basis of CDC28 Protein Kinase Regulatory Subunit 2 in Cervical Cancer.

More and more evidence suggests the oncogenic function of overexpressed CDC28 protein kinase regulatory subunit 2 (CKS2) in various human cancers. However, CKS2 has rarely been studied in cervical cancer. Herein, taking advantage of massive genetics data from multicenter RNA-seq and microarrays, we were the first group to perform tissue microarrays for CKS2 in cervical cancer. We were also the first to evaluate the clinical significance of CKS2 with large samples (980 cervical cancer cases and 422 noncancer cases). We further excavated the mechanism of the tumor-promoting activities of CKS2 in cervical cancer through analysis of genetic mutation profiles, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) significant enrichment of genes coexpressed with CKS2. According to the results, expression data from multilevels unanimously supported the overexpression of CKS2 in cervical cancer. Patients with cervical cancer in stage II from inhouse microarrays had significantly higher expression of CKS2, and CKS2 overexpression had an adverse impact on the disease-free survival status of cervical cancer patients in GSE44001. Both mutation types of mRNA high and mRNA low appeared in cervical cancer cases from the TCGA Firehose project. Gene coexpressed with CKS2 participated in pathways including the cell cycle, estrogen signaling pathway, and DNA replication. In summary, upregulated CKS2 is closely associated with the malignant clinical development of cervical cancer and might serve as a valuable therapeutic target in cervical cancer.

Full-Length Transcriptome Sequencing Reveals Alternative Splicing and lncRNA Regulation during Nodule Development in Glycine max.

Alternative splicing (AS) is a ubiquitous phenomenon among eukaryotic intron-containing genes, which greatly contributes to transcriptome and proteome diversity. Here we performed the isoform sequencing (Iso-Seq) of soybean underground tissues inoculated and uninoculated with Rhizobium and obtained 200,681 full-length transcripts covering 26,183 gene loci. It was found that 80.78% of the multi-exon loci produced more than one splicing variant. Comprehensive analysis of these identified 7874 differentially splicing events with highly diverse splicing patterns during nodule development, especially in defense and transport-related processes. We further profiled genes with differential isoform usage and revealed that 2008 multi-isoform loci underwent stage-specific or simultaneous major isoform switches after Rhizobium inoculation, indicating that AS is a vital way to regulate nodule development. Moreover, we took the lead in identifying 1563 high-confidence long non-coding RNAs (lncRNAs) in soybean, and 157 of them are differentially expressed during nodule development. Therefore, our study uncovers the landscape of AS during the soybean-Rhizobium interaction and provides systematic transcriptomic data for future study of multiple novel directions in soybean.

Use of Single Cell Transcriptomic Techniques to Study the Role of High-Risk Human Papillomavirus Infection in Cervical Cancer.

High-risk human papillomavirus (hrHPV) infection has been associated with a higher probability of progression to cervical cancer. However, several extensive studies have reported that the presence of hrHPV can lead to a better prognosis, but the mechanism of how this occurs is unclear. In this study, microbiological analysis was used to identify HPV infection as a factor for the prognosis of patients with cervical squamous cell carcinoma (CSCC). Comparing the interactions of HPV+ and HPV- malignant cells with immune cells as well as the trajectory of malignant cells either with or without HPV, we found that most of the HPV+ cells are well differentiated while HPV- cells appear to be hypo-fractionated. Using transcriptomic and immunostaining data, we validated a set of unfavourable molecules in the HPV- CSCC cells, including KRT16, ITGB1, CXCR1, VEGFA, CRCT1 and TNFRSF10B/DR5. This study provides a basis for the development of a rational post-operative follow-up programme and the development of an appropriate treatment plan for patients with cervical cancer.

Endothelial ETS1 inhibition exacerbate blood-brain barrier dysfunction in multiple sclerosis through inducing endothelial-to-mesenchymal transition.

Blood-brain barrier (BBB) dysfunction has been recognized as an early pathological feature and contributing factor in multiple sclerosis. Endothelial-to-mesenchymal transition is a process associated with endothelial dysfunction leading to the disruption of vessel stability and barrier function, yet its functional consequence in multiple sclerosis remains unclear. Here, we demonstrated that endothelial-to-mesenchymal transition accompanied the blood-brain barrier dysfunction in several neurological disorders, especially in multiple sclerosis. The activity of transcription factor ETS1, which is highly expressed in endothelial cells (ECs) and responded to an inflammatory condition, is suppressed in the central nervous system (CNS) ECs in MS and its animal model experimental autoimmune encephalomyelitis. We identify ETS1 as a central regulator of endothelial-to-mesenchymal transition (EndMT) associated with the compromise of barrier integrity. These phenotypical and functional alterations can further induce high permeability, immune infiltration, and organ fibrosis in multiple sclerosis, thus promoting disease progression. Together, these results demonstrate a functional role of EndMT in blood-brain barrier dysfunction and propose ETS1 as a potential transcriptional switch of EndMT to target the development of multiple sclerosis.

Elevated Serum Lactate Dehydrogenase Predicts Unfavorable Outcomes After rt-PA Thrombolysis in Ischemic Stroke Patients.

Background and Purpose: Currently, acute ischemic stroke (AIS) is one of the most common and serious diseases in the world and is associated with very high mortality and morbidity even after thrombolysis therapy. This study aims to research the relationship between lactic dehydrogenase (LDH) and prognosis in AIS patients treated with intravenous rtPA. Method: This study (a Multicenter Clinical Trial of Revascularization Treatment for Acute Ischemic Stroke, TRAIS) included 527 AIS patients in 5 cooperative medical institutions in China from January 2018 to February 2021. The primary outcome was major disability and death within 3 months (mRS score of 3-6), and the secondary outcomes were early neurological improvement (ENI), early neurological deterioration (END), moderate-severe cerebral edema (CE), and symptomatic intracranial hemorrhage (sICH). Results: The mean age of the 527 patients was 65.6 ± 11.7 years, and the median baseline NIHSS score was 4 (interquartile range, 2-7). The median serum LDH level was 184 U/L (interquartile range, 163-212 U/L). In total, 287 (54.5%) patients acquired ENI, 68 (13.0%) patients suffered END, 53 (12.1%) patients were observed with moderate-severe CE, and 28 (6.2%) patients showed sICH. Within 3 months, 127 (25.15%) patients experienced the primary outcome and 42 (8.3%) patients died. Serum LDH levels before thrombolysis showed an independent association with the risk of primary outcome [adjusted odds ratio, 3.787; (95% CI, 1.525-9.404); P = 0.014]. When log-transformed LDH increased each standard deviation, the risk of primary outcome was raised by 80.1% (95% CI, 28.9-251.7%). A positive linear dependence between the risk of primary outcome and serum LDH levels (P of linearity = 0.0248, P of non-linearity = 0.8284) was shown in multivariable-adjusted spline regression models. Pre-thrombolysis LDH quartile also provided a conventional risk model and significant improvement of the prediction for clinical outcomes, with a net reclassification improvement index (NRI) = 41.86% (P < 0.001) and integrated discrimination improvement (IDI) = 4.68% (P < 0.001). Conclusions: Elevated serum LDH levels predicted unfavorable clinical outcomes after intravenous thrombolysis in AIS patients.

Genome assembly of the JD17 soybean provides a new reference genome for comparative genomics.

Cultivated soybean (Glycine max) is an important source for protein and oil. Many elite cultivars with different traits have been developed for different conditions. Each soybean strain has its own genetic diversity, and the availability of more high-quality soybean genomes can enhance comparative genomic analysis for identifying genetic underpinnings for its unique traits. In this study, we constructed a high-quality de novo assembly of an elite soybean cultivar Jidou 17 (JD17) with chromosome contiguity and high accuracy. We annotated 52,840 gene models and reconstructed 74,054 high-quality full-length transcripts. We performed a genome-wide comparative analysis based on the reference genome of JD17 with 3 published soybeans (WM82, ZH13, and W05), which identified 5 large inversions and 2 large translocations specific to JD17, 20,984-46,912 presence-absence variations spanning 13.1-46.9 Mb in size. A total of 1,695,741-3,664,629 SNPs and 446,689-800,489 Indels were identified and annotated between JD17 and them. Symbiotic nitrogen fixation genes were identified and the effects from these variants were further evaluated. It was found that the coding sequences of 9 nitrogen fixation-related genes were greatly affected. The high-quality genome assembly of JD17 can serve as a valuable reference for soybean functional genomics research.

Predictive value of different bilirubin subtypes for clinical outcomes in patients with acute ischemic stroke receiving thrombolysis therapy.

AIMS: To explore the association of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL) levels with, as well as the incremental predictive value of different bilirubin subtypes for, poor outcomes in acute ischemic stroke patients after thrombolysis. METHODS: We analyzed 588 individuals out of 718 AIS participants, and all patients were followed up at 3 months after thrombolysis. The primary outcome was 3-month death and major disability (modified Rankin Scale (mRS) score of 3-6). The secondary outcomes were 3-month mortality (mRS score of 6), moderate-severe cerebral edema, and symptomatic intracranial hemorrhage (sICH), respectively. RESULTS: Elevated DBIL pre-thrombolysis was associated with an increased risk of primary outcome (OR 3.228; 95% CI 1.595-6.535; p for trend = 0.014) after fully adjustment. Elevated TBIL pre-thrombolysis showed the similar results (OR 2.185; 95% CI 1.111-4.298; p for trend = 0.047), while IBIL pre-thrombolysis was not significantly associated with primary outcome (OR 1.895; 95% CI 0.974-3.687; p for trend = 0.090). Multivariable-adjusted spline regression model showed a positive linear dose-response relationship between DBIL pre-thrombolysis and risk of primary outcome (p for linearity = 0.004). Adding DBIL pre-thrombolysis into conventional model had greater incremental predictive value for primary outcome, with net reclassification improvement (NRI) 95% CI = 0.275 (0.084-0.466) and integrated discrimination improvement (IDI) 95% CI = 0.011 (0.001-0.024). Increased DBIL post-thrombolysis had an association with primary outcome (OR 2.416; 95%CI 1.184-4.930; p for trend = 0.039), and it also elevated the incremental predictive value for primary outcome, with NRI (95% CI) = 0.259 (0.066-0.453) and IDI (95% CI) = 0.025 (0.008-0.043). CONCLUSION: Increased DBIL pre-thrombolysis had a stronger association with, as well as greater incremental predictive value for, poor outcomes than TBIL and IBIL did in AIS patients after thrombolysis, which should be understood in the context of retrospective design. The effect of DBIL on targeted populations should be investigated in further researches.

Morinda officinalis oligosaccharides alleviate depressive-like behaviors in post-stroke rats via suppressing NLRP3 inflammasome to inhibit hippocampal inflammation.

AIMS: Morinda officinalis oligosaccharides (MOOs), a traditional Chinese medicine, have been used to treat mild and moderate depressive episodes. In this study, we investigated whether MOOs can ameliorate depressive-like behaviors in post-stroke depression (PSD) rats and further explored its mechanism by suppressing microglial NLRP3 inflammasome activation to inhibit hippocampal inflammation. METHODS: Behavioral tests were performed to evaluate the effect of MOOs on depressive-like behaviors in PSD rats. The effects of MOOs on the expression of IL-18, IL-1ß, and nucleotide-binding domain leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3) inflammasome were measured in both PSD rats and lipopolysaccharide (LPS) and adenosine triphosphate (ATP) stimulated primary rat microglia by reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence and Western blot analysis. Adeno-associated virus (AAV) was injected into the hippocampus to regulate NLRP3 inflammasome expression. The detailed molecular mechanism underlying the effects of MOOs was analyzed by Western blot and immunofluorescence. RESULTS: MOOs can alleviate depressive-like behaviors in PSD rats. PSD rats showed increased expression of IL-18, IL-1ß, and NLRP3 inflammasome in the ischemic hippocampus, while MOOs reversed the elevation. NLRP3 downregulation ameliorated depressive-like behaviors and hippocampal inflammation response in PSD rats, while NLRP3 upregulation inhibited the effect of MOOs on depressive-like behaviors and hippocampal inflammation response in PSD rats. Moreover, we found that NLRP3 was mainly expressed on microglia. In vitro, MOOs effectively inhibited the expression of IL-18, IL-1ß, and NLRP3 inflammasome in LPS + ATP treated primary rat microglia. We also showed that modulation of NLRP3 inflammasome by MOOs was associated with the IκB/NF-κB p65 signaling pathway. CONCLUSION: Overall, our study reveals the antidepressive effect of MOOs on PSD rats through modulation of microglial NLRP3 inflammasome. We also provide a novel insight into hippocampal inflammation response in PSD pathology and put forward NLRP3 inflammasome as a potential therapeutic target for PSD.

The role of leukocytes in acute ischemic stroke-related thrombosis: a notable but neglected topic.

Ischemic stroke is one of the most serious diseases today, and only a minority of patients are provided with effective clinical treatment. Importantly, leukocytes have gradually been discovered to play vital roles in stroke thrombosis, including promoting the activation of thrombin and the adhesion and aggregation of platelets. However, they have not received enough attention in the field of acute ischemic stroke. It is possible that we could not only prevent stroke-related thrombosis by inhibiting leukocyte activation, but also target leukocyte components to dissolve thrombi in the cerebral artery. In this review, we expound the mechanisms by which leukocytes are activated and participate in the formation of stroke thrombus, then describe the histopathology of leukocytes in thrombi of stroke patients and the influence of leukocyte composition on vascular recanalization effects and patient prognosis. Finally, we discuss the relevant antithrombotic strategies targeting leukocytes.

pH-Sensitive, Cerebral Vasculature-Targeting Hydroxyethyl Starch Functionalized Nanoparticles for Improved Angiogenesis and Neurological Function Recovery in Ischemic Stroke.

Angiogenesis, an essential restorative process following ischemia, is a promising therapeutic approach to improve neurological deficits. However, overcoming the blood-brain barrier (BBB) and effective drug enrichment are challenges for conventional drug delivery methods, which has limited the development of treatment strategies. Herein, a dual-targeted therapeutic strategy is reported to enable pH-sensitive drug release and allow cerebral ischemia targeting to improve stroke therapeutic efficacy. Targeted delivery is achieved by surface conjugation of Pro-His-Ser-Arg-Asn (PHSRN) peptides, which binds to integrin α5 ß1 enriched in the cerebral vasculature of ischemic tissue. Subsequently, smoothened agonist (SAG), an activator of sonic hedgehog (Shh) signaling, is coupled to PHSRN-HES by pH-dependent electrostatic adsorption. SAG@PHSRN-HES nanoparticles can sensitively release more SAG in the acidic environment of ischemic brain tissue. More importantly, SAG@PHSRN-HES exerts the synergistic mechanisms of PHSRN and SAG to promote angiogenesis and BBB integrity, thus improving neuroplasticity and neurological function recovery. This study proposes a new approach to improve the delivery of medications in the ischemic brain. Dual-targeted therapeutic strategies have excellent potential to treat patients suffering from cerebral infarction.

Neurologists' attitudes and options for anticoagulation therapy in central China.

AIMS: We aim to find out the factors affecting the use of anticoagulants and the intensity of their choices, and to establish a basis for improving neurologists' effective implementation of the guidelines. METHODS: A cross-sectional study is conducted in Hubei province in central China. Each neurologist completes a standard-structured anonymous questionnaire through face-to-face interviews. The problems include the attitude and options about anticoagulant therapy. RESULTS: A total of 611 neurologists from 38 hospitals respond to this survey. For the best treatment of atrial fibrillation, more than 80% of physicians choose anticoagulant therapy. For patients with atrial fibrillation and cerebral infarction, physicians think that Warfarin is the preferred drug as high as 93.8%. Among the anticoagulant drugs ever used by clinicians, the use rate of Warfarin is 93.8%, but the use rate of direct oral anticoagulants is insufficient. The use of direct oral anticoagulants is related to the educational level and the geographical location of the hospital. Bleeding risk is the first reason influencing clinicians' choice of Warfarin, accounts for 88.9%. 97.7% of the clinicians recommend patients with Warfarin to regularly monitor the INR, but the frequency of monitoring is inconsistent. Clinicians have a high willingness to learn about AF, but the proportion of hospitals that carry out appropriate training is low. CONCLUSIONS: There are still some gaps with the guidelines on the choice of anticoagulant drugs. Neurologists have positive attitude towards anticoagulant therapy and a strong willingness to learn, but the corresponding training is lacking. Continuous professional training is necessary.

Prognostic value of neutrophil to lymphocyte ratio in acute ischemic stroke after reperfusion therapy.

The purpose of this study was to investigate whether baseline neutrophil to lymphocyte ratio (NLR) was an independent predictor for early symptomatic intracranial hemorrhage (sICH), poor functional outcome and mortality at 3 months after reperfusion therapy in acute ischemic stroke (AIS) patients. Using PubMed and EMBASE, we searched for literature published before January 19th, 2019. Two reviewers independently confirmed each study's eligibility, assessed risk of bias, and extracted data. One reviewer combined studies using random effects meta-analysis. 9 studies with 3651 patients were pooled in the meta-analysis. Overall, baseline NLR levels were greater in patients with poor outcome. The standardized mean difference (SMD) in the NLR levels between patients with poor functional outcome (mRS > 2) and good functional outcome (mRS ≤ 2) was 0.54 units (95% credible interval [CI] [0.38, 0.70]). Heterogeneity test showed that there were significant differences between individual studies (p = 0.02; I2 = 72.8%). The NLR levels were associated with sICH in four included studies (n = 2003, SMD = 0.78, 95% [CI] [0.18, 1.38], I2 = 73.9%). Higher NLR levels were positively correlated with 3-month mortality (n = 1389, ES = 1.71, 95% CI [1.01,2.42], p < 0.01, I2 = 0%) when data were used as categorical variables. Our meta-analysis suggests that increased NLR levels are positively associated with greater risk of sICH, 3-month poor functional outcome and 3-month mortality in AIS patients undergoing reperfusion treatments. Although there are some deficits in this study, it may be feasible to predict the prognosis of reperfusion therapy in AIS patients with NLR levels.

Synergistic inflammatory signaling by cGAS may be involved in the development of atherosclerosis.

Inappropriate activation or overactivation of cyclic GMP-AMP synthase (cGAS) by double-stranded deoxyribonucleic acid (dsDNA) initiates a regulatory signaling cascade triggering a variety of inflammatory responses, which are a great threat to human health. This study focused on identifying the role of cGAS in atherosclerosis and its potential mechanisms. The relationship between cGAS and atherosclerosis was identified in an ApoE -/- mouse model. Meanwhile, RNA sequencing (RNA-seq) analysis of the underlying mechanisms of atherosclerosis in RAW264.7 macrophages treated with cGAS inhibition was conducted. Results showed that cGAS was positively correlated with atherosclerotic plaque area, and was mainly distributed in macrophages. RNA-seq analysis revealed that inflammatory response, immune response and cytokine-cytokine receptor interaction may play important roles in the development of atherosclerosis. Real-time quantitative polymerase chain reaction (RT-qPCR) results showed that the expression of the pro-inflammatory factors, signal transducer and activator of transcription (Stat), interferon regulatory factor (Irf), toll-like receptors (Tlrs), and type I interferons (Ifns) were synergistically reduced when cGAS was inhibited. Furthermore, cGAS inhibition significantly inhibited RAW264.7 macrophage M1 polarization. These results demonstrate that cGAS may contribute to the development of atherosclerosis through synergistic inflammatory signaling of TLRs, STAT/IRF as well as IFNs, leading to macrophage M1 polarization.