Prolonged increased neutrophil-to-lymphocyte ratio is associated with mortality after successful revascularization for treatment of acute ischemic stroke.

BACKGROUND: To determine the association between dynamic neutrophil-to-lymphocyte ratio (NLR) during hospitalization and mortality 1 month after ischemia reperfusion in patients undergoing endovascular treatment (EVT) with successful revascularization for acute large vessel occlusion stroke. METHODS: This retrospective study included patients who had undergone successful EVT. Information was collected regarding patients' clinical characteristics, imaging data, and mortality at 1 month. Univariate and multivariate logistic regression models were applied to assess the association between NLR and mortality. We used a generalized additive model and a generalized additive mixed model to compare trends in NLR over time between survivors and nonsurvivors. RESULTS: A total of 237 patients were included. During the 1-month follow-up, 42 of these patients (17.7%) died. The multivariate analysis demonstrated that NLR obtained within 12 to 24 hours (odds ratio [OR] = 1.18; 95% confidence interval [CI]: 1.04, 1.33; P = 0.008), 24 to 48 hours (OR = 1.16; 95% CI: 1.01, 1.35; P = 0.044), and 48 to 72 hours (OR = 1.23; 95% CI: 1.03, 1.47; P = 0.021) after EVT were independently associated with mortality at 1 month. In addition, there was a trend for NLR to decrease gradually over time for both survivors and nonsurvivors; however, NLR in survivors decreased by an average of 0.29 daily than in nonsurvivors. CONCLUSIONS: Increased NLR in the early period after EVT was associated with an increased risk of mortality, and a continued trend toward higher NLR over time was also linked with a higher mortality risk.

Early Neutrophil-to-Lymphocyte Ratio Is a Prognostic Marker in Acute Ischemic Stroke After Successful Revascularization.

OBJECTIVE: To explore the association between early neutrophil-to-lymphocyte ratio (ENLR) and prognosis of anterior circulation large-vessel occlusion stroke (LVOS) after patients undergo endovascular treatment (EVT) with successful revascularization. METHODS: Patients who experienced acute anterior circulation LVOS and underwent EVT at Changzhou Second People's Hospital Affiliated to Nanjing Medical University between May 2017 and May 2020 were included in this retrospective study. We collected information about patients' baseline characteristics, medical history, laboratory test results, imaging data, and endovascular treatment outcomes, as well as data from follow-up at 3 months. Univariate and multivariate logistic regression models were used to evaluate the association between ENLR and functional disease prognosis. A piecewise linear regression model was also applied to compute the threshold effect of ENLR on poor prognosis (defined as modified Rankin Scale score 3-6) at 3 months using a smoothing plot. RESULTS: Of 224 patients who received EVT during the study period, 160 patients were included in the analysis. After adjustments were made for potential confounders, multivariate analysis demonstrated a significant association between ENLR and poor prognosis at 3 months (odds radio 1.19; 95% confidence interval 1.07-1.32; P = 0.0016). An ENLR ≥9.75 was found to be significantly associated with poor prognosis at 3 months (odds ratio 1.54; 95% confidence interval 1.19-2.00; P = 0.0119). CONCLUSIONS: Increased ENLR after successful revascularization is independently associated with poor prognosis. These findings suggest that ENLR could be used to inform treatment strategies for patients who experience anterior circulation LVOS.

A novel tailored immune gene pairs signature for overall survival prediction in lower-grade gliomas.

Lower-grade gliomas (LGGs) have a good prognosis with a wide range of overall survival (OS) outcomes. An accurate prognostic system can better predict survival time. An RNA-Sequencing (RNA-seq) prognostic signature showed a better predictive power than clinical predictor models. A signature constructed using gene pairs can transcend changes from biological heterogeneity, technical biases, and different measurement platforms. RNA-seq coupled with corresponding clinical information were extracted from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). Immune-related gene pairs (IRGPs) were used to establish a prognostic signature through univariate and multivariate Cox proportional hazards regression. Weighted gene co-expression network analysis (WGCNA) was used to evaluate module eigengenes correlating with immune cell infiltration and to construct gene co-expression networks. Samples in the training and testing cohorts were dichotomized into high- and low-risk groups. Risk score was identified as an independent predictor, and exhibited a closed relationship with prognosis. WGCNA presented a gene set that was positively correlated with age, WHO grade, isocitrate dehydrogenase (IDH) mutation status, 1p/19 codeletion, risk score, and immune cell infiltrations (CD4 T cells, B cells, dendritic cells, and macrophages). A nomogram comprising of age, WHO grade, 1p/19q codeletion, and three gene pairs (BIRC5|SSTR2, BMP2|TNFRSF12A, and NRG3|TGFB2) was established as a tool for predicting OS. The IPGPs signature, which is associated with immune cell infiltration, is a novel tailored tool for individual-level prediction.

The expression patterns of Septin-9 after traumatic brain injury in rat brain.

Septins are a novel group of GTPases, which are first identified in yeast and more recently found in a wide range of animal cells. Septin-9, a novel septin family member, is expressed ubiquitously and involved in an increasing number of signaling cascades. However, information regarding its distribution and possible function in the central nervous system (CNS) is limited. In this study, western blot analysis and immunohistochemistry showed a significant upregulation of Septin-9 in the ipsilateral peritrauma cortex compared with the sham group. Immunofluorescent labeling indicated that Septin-9 was localized strikingly in the cytoplasm of neurons, but not astrocytes and oligodendrocytes. The co-localization of Septin-9 and active caspase-3 was also examined in the ipsilateral cortex. In addition, the expression patterns of active caspase-3 were parallel with that of Septin-9. Quantitative real-time RT-PCR also was used to detect Seption-9 mRNA level. Based on our data, we speculated that traumatic brain injury may be a stimulus to induce the Septin-9 expression, and Septin-9 might play an important role in the pathophysiology process in the CNS after traumatic brain injury. Taken together, this is the first description of Septin-9 expression changes during the central nervous system lesion and repair, but further studies are needed to understand the cell signaling pathway which can direct the exact role of Septin-9 following traumatic brain injury.

Detection of serum Alu element hypomethylation for the diagnosis and prognosis of glioma.

Global genomic hypomethylation is a hallmark of cancer in humans. In the present study, the feasibility of measuring hypomethylation of Alu elements (Alu) in serum and its clinical utility were investigated. Tumor tissues and matched serum specimens from 65 glioma patients and serum samples from 30 healthy controls were examined for Alu hypomethylation by bisulfite sequencing. The median serum Alu methylation level was 47.30 % in patients (interquartile range (IQR), 35.40-54.25 %) and 57.90 % in the controls (IQR, 55.25-61.45 %). The median Alu methylation level in tumor samples was 40.30 % (IQR, 36.80-54.20 %), which shows the correlation of Alu hypomethylation between tumor and serum samples (r = 0.882) in the study group. The methylation level was higher in the low-grade glioma group than in the high-grade group both in tumor and serum samples. A correlation between high methylation level and longer survival time was detected in tumor and serum samples. Receiver operating characteristic curve analysis showed that the area under the curve for diagnosis was 0.861 (95 % confidence interval, 0.789-0.933), suggesting that Alu hypomethylation in serum may be of diagnostic value. Our results indicate that the detection of Alu hypomethylation in serum may be clinically useful for the diagnosis and prognosis of glioma.

SCY1-like 1 binding protein 1 (SCYL1-bp1) interacts with p53-induced RING H2 protein (Pirh2) after traumatic brain injury in rats.

Traumatic brain injury (TBI) triggers a complex series of neurochemical and signaling changes that lead to neuronal dysfunction and overreactive astrocytes. In the current study, we showed that interactions between SCYL1-bp1 and Pirh2 are involved in central nervous system (CNS) injury and repair. Western blot and immunohistochemical analysis of an acute traumatic brain injury model in adult rats revealed significantly increased levels of SCYL1-bp1 and Pirh2 in the ipsilateral brain cortex, compared to contralateral cerebral cortex. Immunofluorescence double-labeling analyses further revealed that SCYL1-bp1 is mainly co-expressed with NeuN. Terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling staining data supported the involvement of SCYL1-bp1 and Pirh2 in neuronal apoptosis after brain injury. We additionally examined the expression profiles of active caspase-3, which were altered in correlation with the levels of SCYL1-bp1 and Pirh2. Notably, both SCYL1-bp1 and Pirh2 were colocalized with active caspase-3, and all three proteins participated in neuronal apoptosis. Immunoprecipitation experiments further revealed interactions of these proteins with each other in the pathophysiology process. To our knowledge, this is the first study to report interactions between SCYL1-bp1 and Pirh2 in traumatic brain. Our data collectively indicate that SCYL1-bp1 and Pirh2 play important roles in CNS pathophysiology after TBI.

Upregulation of CRM1 relates to neuronal apoptosis after traumatic brain injury in adult rats.

Traumatic brain injury (TBI) initiates a complex series of neurochemical and signaling changes that leads to neuronal dysfunction and over-reactive astrocytes. There is increasing evidence that CRM1 mediated P27(Kip1), which is a potent inhibitor of G1 cyclin-dependent kinases complexes, nuclear export-dependent or -independent Jab1/CSN5, and cytoplasmic degradation in cells. Up to now, the function of CRM1 in central nervous system (CNS) is still with limited acquaintance. In our study, to investigate whether CRM1 is involved in CNS lesion, we performed a TBI model in adult rats. Western blot and RT-PCR analysis revealed that the level of protein and mRNA of CRM1 increased in ipsilateral brain cortex in comparison to the contralateral. Immunohistochemistry and immunofluorescence double labeling indicated that CRM1 was shutting into nucleus around the wound, and increased CRM1 co-localized with P27(Kip1). Terminal deoxynucleotidyl transferase deoxy-UTP-nick end labeling (TUNEL) staining suggested that CRM1 was involved in neuronal apoptosis after brain injury. We also investigated co-localization of CRM1 and active-caspase-3 in the ipsilateral brain cortex. In addition, the expression patterns of Bax and active-caspase-3 were parallel with that of CRM1. Based on our data, we suggested that CRM1 might play an important role in neuronal apoptosis following TBI, and might provide a basis for the further study on its role in regulating the expression of P27(Kip1) and cell cycle re-entry in TBI.

Increased expression of AGS3 in rat brain cortex after traumatic brain injury.

Receptor-independent activators of G protein signaling (AGS) offer alternative modes of signal processing for the G protein signaling system that has broad mechanistic and functional significance. Previous studies have demonstrated that AGS3, which belongs to the AGS family, is involved in a number of different cellular activities. However, the distribution and function of AGS3 in the central nervous system (CNS) remain unclear. To investigate whether AGS3 is involved in CNS injury and repair, we used an acute traumatic brain injury (TBI) model in adult rats. Western blot analysis and immunohistochemistry showed a significant upregulation of AGS3 in ipsilateral peritrauma cortex. Double immunofluorescence staining showed that AGS3 was coexpressed with NeuN but rarely with glial fibrillary acidic protein. In addition, we detected that active caspase-3 had colocalization with NeuN and AGS3, suggesting that AGS3 might be involved in the neuron apoptosis after TBI. To investigate the potential function of AGS3 further, a neuronal cell line, PC12, was employed to establish a cell apoptosis model. Western blot analysis indicated that AGS3 shared a similar dynamic variation in animal experiments, and phosphorylated cyclic AMP response element-binding protein (CREB) increased in parallel. Additionally, knocking down AGS3 with siRNA partially attenuated the protein level of phosphorylated CREB in PC12 stimulated by H2 O2 , while reinforcing active caspase-3 expression, demonstrating a probable antiapoptotic role through CREB played by AGS3 in neuronal apoptosis. We hypothesize that AGS3 might play an important antiapoptotic role through enhancing phosphorylation of CREB. © 2013 Wiley Periodicals, Inc.

Different functions of HIPK2 and CtBP2 in traumatic brain injury.

Traumatic brain injury (TBI) initiates a complex series of neurochemical and signaling changes that lead to neuronal dysfunction and over-reactive astrocytes. In our study, homeodomain interacting protein kinase 2 (HIPK2) can interact with C-terminal binding protein 2 (CtBP2) in rat brain, which is a component of Wnt-regulated transcription. Up to now, the functions of HIPK2 and CtBP2 in CNS are still with limited acquaintance. In our study, we found that the interaction between HIPK2 and CtBP2 was involved in central nervous system (CNS) injury and repair. We performed an acute TBI model in adult rats. Western blot and immunohistochemistry analysis revealed that both HIPK2 and CtBP2 significantly increased in the peritrauma brain cortex in comparison to contralateral cerebral cortex. And immunofluorescence double-labeling revealed that HIPK2 was mainly co-expressed with NeuN but less GFAP. Meanwhile, we also examined that the expression profiles of active-caspase-3 was correlated with the expression of HIPK2 and the expression profiles of the proliferating cell nuclear antigen (PCNA) was correlated with the expression of CtBP2. HIPK2 participated in apoptosis of neurons, but CtBP2 was associated with the activation and proliferation of astrocytes. Immunoprecipitation further showed that they enhanced the interaction with each other in the pathophysiology process. In conclusion, this was the first description that HIPK2 interacted with CtBP2 in traumatic brains. Our data suggest that HIPK2 and CtBP2 might play important roles in CNS pathophysiology after TBI, and might provide a basis for the further study on their roles in regulating the prognosis after TBI.

Increased expression of actin filament-stabilizing protein tropomyosin after rat traumatic brain injury.

Tropomyosin (TM), is a coiled-coil dimmer which modulates actin filament properties, has been implicated in the control of actin filament dynamics during cell migration, morphogenesis, and cytokinesis. However, the expressions and possible functions of tropomyosin in central nervous system (CNS) lesion remain unknown. In this study, we found the expression of tropomyosin gradually increased in rat brains subjected to traumatic brain injury (TBI). Double immunofluorescence staining showed tropomyosin was expressed in neurons and reactive astrocytes following TBI but not in quiescent astrocytes in normal brains. Furthermore, we detected that proliferating cell nuclear antigen (PCNA) had the co-localization with GFAP, and tropomyosin. In conclusion, this was the first description of tropomyosin expression in rat traumatic brain. Our date suggested that tropomyosin might be involved in the astrocytes proliferation following TBI.