Characterizing the relationship between MRI radiomics and AHR expression and deriving a predictive model for prognostic assessment in glioblastoma.

PURPOSE: Aryl hydrocarbon receptor (AHR), a crucial molecular marker associated with glioma, is a potential therapeutic target. We aimed to establish a non-invasive predictive model for AHR through radiomics. METHODS: Contrast-enhanced T1-weighted (T1W) MRI and the corresponding and clinical variables of glioblastoma patients from The Cancer Genome Atlas (TCGA) and The Cancer Imaging Archive (TCIA) were obtained for analysis. KM curves and Cox regression analyses were used to assess the prognostic value of AHR expression. The radiomics features were screened by Max-Relevance and Min-Redundancy (mRMR) and recursive feature elimination (RFE), followed by the construction of two predictive models using logistic regression (LR) and a support vector machine (SVM). RESULTS: The expression levels of AHR in tumour patients were significantly higher than those in the control group, and higher AHR expression was associated with worse prognosis (P<0.05). AHR remained a risk factor for poor prognosis in glioblastoma after multivariate adjustment (HR: 1.61, 95% CI: 1.085-2.39, P<0.05). The radiomics models constructed using LR and SVM based on three selected features achieved area under the curve (AUC) values of 0.887 and 0.872, respectively. Radiomics score emerged as a key factor influencing overall survival (OS) after multivariate adjustment in the Cox model (HR: 3.931, 95% CI: 1.272-12.148, P < 0.05). CONCLUSION: The radiomics models could effectively distinguish the expression levels of AHR and predict prognosis in patients with glioblastoma, which may serve as a powerful tool to assist clinical assessment and precision treatment.

Machine learning models reveal the critical role of nighttime systolic blood pressure in predicting functional outcome for acute ischemic stroke after endovascular thrombectomy.

Background: Blood pressure (BP) is a key factor for the clinical outcomes of acute ischemic stroke (AIS) receiving endovascular thrombectomy (EVT). However, the effect of the circadian pattern of BP on functional outcome is unclear. Methods: This multicenter, retrospective, observational study was conducted from 2016 to 2023 at three hospitals in China (ChiCTR2300077202). A total of 407 patients who underwent endovascular thrombectomy (EVT) and continuous 24-h BP monitoring were included. Two hundred forty-one cases from Beijing Hospital were allocated to the development group, while 166 cases from Peking University Shenzhen Hospital and Hainan General Hospital were used for external validation. Postoperative systolic BP (SBP) included daytime SBP, nighttime SBP, and 24-h average SBP. Least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), Boruta were used to screen for potential features associated with functional dependence defined as 3-month modified Rankin scale (mRS) score ≥ 3. Nine algorithms were applied for model construction and evaluated using area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. Results: Three hundred twenty-eight of 407 (80.6%) patients achieved successful recanalization and 182 patients (44.7%) were functional independent. NIHSS at onset, modified cerebral infarction thrombolysis grade, atrial fibrillation, coronary atherosclerotic heart disease, hypertension were identified as prognostic factors by the intersection of three algorithms to construct the baseline model. Compared to daytime SBP and 24-h SBP models, the AUC of baseline + nighttime SBP showed the highest AUC in all algorithms. The XGboost model performed the best among all the algorithms. ROC results showed an AUC of 0.841 in the development set and an AUC of 0.752 in the validation set for the baseline plus nighttime SBP model, with a brier score of 0.198. Conclusion: This study firstly explored the association between circadian BP patterns with functional outcome for AIS. Nighttime SBP may provide more clinical information regarding the prognosis of patients with AIS after EVT.

Potential causal association between gut microbiome and posttraumatic stress disorder.

BACKGROUND: The causal effects of gut microbiome and the development of posttraumatic stress disorder (PTSD) are still unknown. This study aimed to clarify their potential causal association using mendelian randomization (MR). METHODS: The summary-level statistics for gut microbiome were retrieved from a genome-wide association study (GWAS) of the MiBioGen consortium. As to PTSD, the Freeze 2 datasets were originated from the Psychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group (PGC-PTSD), and the replicated datasets were obtained from FinnGen consortium. Single nucleotide polymorphisms meeting MR assumptions were selected as instrumental variables. The inverse variance weighting (IVW) method was employed as the main approach, supplemented by sensitivity analyses to evaluate potential pleiotropy and heterogeneity and ensure the robustness of the MR results. We also performed reverse MR analyses to explore PTSD's causal effects on the relative abundances of specific features of the gut microbiome. RESULTS: In Freeze 2 datasets from PGC-PTSD, eight bacterial traits revealed a potential causal association between gut microbiome and PTSD (IVW, all P < 0.05). In addition, Genus.Dorea and genus.Sellimonas were replicated in FinnGen datasets, in which eight bacterial traits revealed a potential causal association between gut microbiome and the occurrence of PTSD. The heterogeneity and pleiotropy analyses further supported the robustness of the IVW findings, providing additional evidence for their reliability. CONCLUSION: Our study provides the potential causal impact of gut microbiomes on the development of PTSD, shedding new light on the understanding of the dysfunctional gut-brain axis in this disorder. Our findings present novel evidence and call for investigations to confirm the association between their links, as well as to illuminate the underlying mechanisms.

The association of glaucoma with ischemic stroke and functional outcome after ischemic stroke from the perspective of causality.

INTRODUCTION: Glaucoma may be related to ischemic stroke (IS) and poor outcomes after IS in observational studies, while the causal association remains unclear. METHODS: We obtained single nucleotide polymorphisms (SNPs) related to glaucoma from the gene-wide association study (GWAS) conducted by the FinnGen consortium. The GWAS included a total of 13,614 cases and 295,540 controls. The summary-level of datasets regarding IS were collected from the MEGASTROKE consortium, including 34,217 cases and 406,111 controls. Furthermore, we acquired summary statistics datasets for functional outcomes following IS from the GWAS meta-analysis conducted by the GISCOME consortium, which involved 6,021 individuals. The genetic association estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Score (mRS), including 3,741 cases with good functional outcomes (mRS=0-2) and 2,280 subjects with poor functional outcomes post-stroke (mRS=3-6). Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. RESULTS: Genetically, glaucoma is associated with an increased risk of IS (odds ratio [OR]=1.08, 95% confidence interval [CI] = 1.02-1.14, P = 0.0039), as well as poor prognosis after IS with adjustment for severity (OR=1.64; 95% CI=1.27-2.13, P=0.0001) and functional outcome after IS (OR=1.45, 95% CI=1.12-1.87, P=0.0038). Through sensitivity analyses, we confirmed the robustness of the results. In addition, we did not identify any causal association between IS, functional outcome after IS, and glaucoma in reverse analysis. CONCLUSION: Our study provides evidence suggesting a potential genetic causal relationship between glaucoma and an increased risk of IS, as well as a poor functional outcome following IS. Future studies are necessary to confirm these findings.

Causal Association of Iron Status With Functional Outcome After Ischemic Stroke.

BACKGROUND: Iron status has been associated with functional outcomes after ischemic stroke (IS). Nonetheless, this association may be affected by confounders. We perform Mendelian randomization to clarify the causal association between iron status and functional outcome after IS. METHODS: We obtained summary-level statistics related to iron status biomarkers from a meta-analysis of a gene-wide association study conducted by the Genetics of Iron Status Consortium, which included 11 discovery cohorts and 8 replication cohorts. We also took genetic variants related to 4 biomarkers of iron status from combining gene-wide association study results of Iceland, the United Kingdom, and Denmark to perform a replicate Mendelian randomization analysis. This data set included 4 iron status biomarkers, namely, ferritin, total iron binding capacity, iron, and transferrin saturation (TSAT). The confounders in these data sets have been adjusted to mitigate the collider bias. We acquired summary statistics data sets for functional outcomes following IS from the gene-wide association study meta-analysis conducted by the Genetics of Ischemic Stroke Functional Outcome Consortium. The genetic estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Scale score, including 3741 cases with good functional outcomes (modified Rankin Scale score, 0-2) and 2280 subjects with poor functional outcomes poststroke (modified Rankin Scale score, 3-6). Inverse variance weighting was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. RESULTS: Reported with odds ratios (ORs) of stroke outcome with per SD unit increase in genetically determined iron status biomarker, TSAT and iron were associated with poor functional outcome after IS (TSAT: OR, 1.36 [95% CI, 1.23-1.50]; P=2.27×10-9; iron: OR, 1.44 [95% CI, 1.13-1.85]; P=0.0033). In replicate Mendelian randomization analysis, the detrimental effects of iron on poor functional outcome after IS remained stable (OR, 1.60 [95% CI, 1.24-2.08]; P=0.0003). In the meta-analysis, iron and TSAT were associated with poor functional outcomes after IS (TSAT: ORmeta, 1.35 [95% CI, 1.23-1.48]; iron: ORmeta, 1.51 [95% CI, 1.27-1.81]). Through sensitivity analyses and reverse Mendelian randomization analyses, we confirmed the robustness of the results. CONCLUSIONS: Our study provides evidence suggesting a potential causal relationship between iron status and poor functional outcomes after IS. Future studies are required to illuminate the underlying mechanism.

Levofloxacin alleviates blood-brain barrier disruption following cerebral ischemia and reperfusion via directly inhibiting A-FABP.

Reperfusion therapy is currently the most effective treatment for acute ischemic stroke, but often results in secondary brain injury. Adipocyte fatty acid-binding protein (A-FABP, FABP4, or aP2) was shown to critically mediate cerebral ischemia/reperfusion (I/R) injury by exacerbating blood-brain barrier (BBB) disruption. However, no A-FABP inhibitors have been approved for clinical use due to safety issues. Here, we identified the therapeutic effect of levofloxacin, a widely used antibiotic displaying A-FABP inhibitory activity in vitro, on cerebral I/R injury and determined its target specificity and action mechanism in vivo. Using molecular docking and site-directed mutagenesis, we showed that levofloxacin inhibited A-FABP activity through interacting with the amino acid residue Asp76, Gln95, Arg126 of A-FABP. Accordingly, levofloxacin significantly inhibited A-FABP-induced JNK phosphorylation and expressions of proinflammatory factors and matrix metalloproteinase 9 (MMP-9) in mouse primary macrophages. In wild-type mice with transient middle cerebral artery occlusion, levofloxacin substantially mitigated BBB disruption and neuroinflammation, leading to reduced cerebral infarction, alleviated neurological outcomes, and improved survival. Mechanistically, levofloxacin decreased MMP-9 expression and activity, and thus reduced degradation of extracellular matrix and endothelial tight junction proteins. Importantly, the BBB- and neuro-protective effects of levofloxacin were abolished in A-FABP or MMP-9 knockout mice, suggesting that the therapeutic effects of levofloxacin highly depended on specific targeting of the A-FABP-MMP-9 axis. Overall, our study demonstrates that levofloxacin alleviates A-FABP-induced BBB disruption and neural tissue injury following cerebral I/R, and unveils its therapeutic potential for the treatment of ischemic stroke.

A machine learning-based integrated clinical model for predicting prognosis in atypical meningioma patients.

PURPOSE: Atypical meningioma (AM) recurs in up to half of patients after surgical resection and may require adjuvant therapy to improve patient prognosis. Various clinicopathological features have been shown to have prognostic implications in AM, but an integrated prediction model is lacking. Thus, in this study, we aimed to develop and validate an integrated prognostic model for AM. METHODS: A retrospective cohort of 528 adult AM patients surgically treated at our institution were randomly assigned to a training or validation group in a 7:3 ratio. Sixteen baseline demographic, clinical, and pathological parameters, progression-free survival (PFS), and overall survival (OS) were analysed. Sixty-five combinations of machine learning (ML) algorithms were used for model training and validation to predict tumour recurrence and patient mortality. RESULTS: The random survival forest (RSF) model was the best model for predicting recurrence and death. Primary or secondary tumour, Ki-67 index, extent of resection, tumour size, brain involvement, tumour necrosis, and age contributed significantly to the model. The C-index value of the RSF recurrence prediction model reached 0.8080. The AUCs for 1-, 3-, and 5-year PFS were 0.83, 0.82, and 0.86, respectively. The C-index value of the RSF death prediction model reached 0.8890. The AUCs for 3-year and 5-year OS were 0.88 and 0.89, respectively. CONCLUSION: A high-performing integrated RSF predictive model for AM recurrence and patient mortality was proposed that may guide therapeutic decision-making and long-term monitoring.

LC-MS/MS based metabolomic analysis of serum from patients with cerebrovascular stenosis.

Cerebrovascular stenosis (CVS) is the main cause of ischemic stroke, which greatly threatens human life. Hence, it's important to perform early screenings for CVS. Metabolomics is an emerging omics approach that has great advantages in disease screening and diagnosis. Therefore, we aim to elucidate the correlation between CVS and metabolomics, which can aid in conducting CVS screening at an early stage. Patients with CVS in Beijing Hospital were included in the study. A total of 36 participants, including 18 patients diagnosed with CVS and 18 healthy individuals, were recruited at Beijing Hospital between May 2022 and October 2021. The serum samples were analyzed for liquid chromatography-tandem mass spectrometry (LC-MS/MS). Then, multivariate statistical methods, including principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were performed. Differential metabolites were obtained and demonstrated by volcano plot and heatmap. The study recruited 36 participants, including 18 patients with CVS and 18 healthy participants. A total of 150 metabolites were identified. Multivariate statistical analysis revealed significant differences between patients and healthy participants. Furthermore, 30 serum metabolites levels differed significantly between two groups. Differential metabolites were enriched in phenylalanine, tyrosine, and tryptophan biosynthesis; primary bile acid biosynthesis, and other pathways. This study identified differential metabolites in patients with CVS and elucidated the relevant metabolic pathways. Thus, these findings aid in the study of the pathogenesis of CVS and its early diagnosis. DATA AVAILABILITY STATEMENT: The datasets generated for this study are available on request to the corresponding author.

Integrative analyses identify HIF-1α as a potential protective role with immune cell infiltration in adamantinomatous craniopharyngioma.

Craniopharyngiomas (CPs) are histologically benign tumors located in the sellar-suprasellar region. Although the transcriptome development in recent years have deepened our knowledge to the tumorigenesis process of adamantinomatous craniopharyngioma (ACP), the peritumoral immune infiltration of tumor is still not well understood. In this study, weighted gene coexpression network analysis (WGCNA) was applied to identify different gene modules based on clinical characteristics and gene expression, and then, the protein-protein interaction (PPI) network with the Cytohubba plug-in were performed to screen pivotal genes. In addition, immune cell infiltration (ICI) analysis was used to evaluate the immune microenvironment of ACP patients. In total, 8,568 differential expression genes were identified based on our datasets and two microarray profiles from the public database. The functional enrichment analysis revealed that upregulated genes were mainly enriched in immune-related pathways while downregulated genes were shown in the hormone and transduction of signaling pathways. The WGCNA investigated the most relevant modules, and 1,858 hub genes was detected, from which the PPI network identified 14 pivotal genes, and the Hypoxia-inducible factor 1-alpha (HIF-1α) pathway including four critical genes may be involved in the development of ACP. Moreover, naïve CD4+ and CD8+ T cells were decreased while specific subtypes of T cells were significantly increased in ACP patients according to ICI analysis. Validation by immunofluorescence staining revealed a higher expression of HIF-1α in ACP (ACP vs. control) and adult-subtype (adult vs. children), suggesting a possible state of immune system activation. Notably, children with low HIF-1α scores were related to the hypothalamus involvement and hydrocephalus symptoms. In this study, we successfully identified HIF-1α as a key role in the tumorigenesis and development of ACP through comprehensive integrated analyses and systematically investigated the potential relationship with immune cells in ACP. The results may provide valuable resources for understanding the underlying mechanisms of ACP and strengthen HIF-1α as a potential immunotherapeutic target in clinical application.

Pulmonary infection and baseline mRS scores predict poor prognosis in anti-GABABR encephalitis.

Purpose: Anti-gamma-aminobutyric-acid type B receptor (anti-GABABR) encephalitis is a rare autoimmune condition caused by the presence of GABABR antibodies in the limbic system. However, its clinical features and prognostic factors are poorly understood. In this study, we aimed to explore factors that affect the response to first-line treatment in patients with anti-GABABR encephalitis. Methods: Thirty-four patients with an initial diagnosis of anti-GABABR encephalitis were retrospectively enrolled from December 2015 to June 2021. Clinical features and experimental data recorded within 24 h of admission were extracted from the patients' medical records. The modified Rankin Scale (mRS) was utilized to assess disease severity at admission and functional recovery after immunotherapy. Independent prognostic factors were determined by ordinal logistic regression analysis. Results: Of the 34 anti-GABABR encephalitis patients, 12 (35%) presented with cancer; all of these patients had lung cancer. According to multivariate regression analysis, the cancer group exhibited a decrease in the peripheral blood absolute lymphocyte count (ALC) (odds ratio [OR]: 0.063, 95% confidence interval [CI]: 0.006-0.639, P=0.019) and hyponatremia (OR: 9.268, 95% CI: 1.054-81.502, 0.045). In addition, the neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR) and platelet/lymphocyte ratio (PLR) did not significantly differ according to mRS scores in patients receiving first-line treatment. No patients with mild or moderate mRS scores (0-2) at admission developed symptoms after treatment; in contrast, only 11 patients with a severe mRS scores (≥3, 11/18) experienced symptom alleviation. Ordinal regression analysis indicated that worse prognosis was associated with pulmonary infection (OR=9.885, 95% CI: 1.106-88.323, P=0.040) and baseline mRS scores (OR= 24.047, 95% CI: 3.294-175.739, P=0.002) in the adjusted model. Conclusion: Our findings demonstrate that pulmonary infection and baseline mRS scores are independent risk factors for poor prognosis in patients with anti-GABABR encephalitis after first-line treatment. ALC and hyponatremia are potential biomarkers for anti-GABABR encephalitis cases accompanied by lung cancer.

Unusual presentation of epilepsy of germinoma located in the frontal-lobe: case report and literature review.

Germinoma is rare in peripheral lobar locations in the brain, with only 10 cases of primary frontal lobe germinoma having been reported in the previous literature. Epilepsy is a rare manifestation of germinomas. We describe an unusual case of a primary frontal germinoma in a 21-year-old man who presented with epilepsy. A presumptive diagnosis of abscess or cystic glioma was made, and then, we performed microsurgery under magnetic resonance imaging (MRI) neuronavigation guidance. Postoperative histopathologic examination identified the tumour as a rare germinoma. Subsequently, adjuvant radiotherapy and chemotherapy programmes were adopted in the present case, and there were no recurrence and postoperative seizure symptoms observed in the follow-up 6 months after operation.

Postoperative Adjuvant Radiotherapy in Atypical Meningioma Patients: A Meta-Analysis Study.

BACKGROUND AND PURPOSE: Consensus regarding the need for adjuvant radiotherapy (RT) in patients with atypical meningiomas (AMs) is lacking. We compared the effects of adjuvant RT after surgery, gross total resection (GTR), and subtotal resection (STR) on progression-free survival (PFS) and overall survival (OS) in patients with AMs, respectively. METHODS: We performed a systematic review and meta-analysis of the literature published in PubMed, Embase, and the Cochrane Library from inception to February 1, 2021, to identify articles comparing the PFS and OS of patients receiving postoperative RT after surgery, GTR and STR. RESULTS: We identified 2307 unique studies; 24 articles including 3078 patients met the inclusion criteria. The sensitivity analysis results showed that for patients undergoing undifferentiated surgical resection, adjuvant RT reduced tumor recurrence (HR=0.70, p<0.0001) with no significant effect on survival (HR=0.89, p=0.49). Postoperative RT significantly increased PFS (HR=0.69, p=0.01) and OS (HR=0.55, p=0.007) in patients undergoing GTR. The same improvement was observed in patients undergoing STR plus RT (PFS: HR=0.41, p<0.00001; OS: HR=0.47, p=0.01). A subgroup analysis of RT in patients undergoing GTR showed no change in PFS in patients undergoing Simpson grade I and II resection (HR=1.82, p=0.22) but significant improvement in patients undergoing Simpson grade III resection (HR=0.64, p=0.02). CONCLUSION: Regardless of whether GTR or STR was performed, postoperative RT improved PFS and OS to varying degrees. Especially for patients undergoing Simpson grade III or IV resection, postoperative RT confers the benefits for recurrence and survival.

Development and Validation of Predicting Nomograms for Craniopharyngioma: A Retrospective, Multiple-Center, Cohort Study.

Craniopharyngiomas (CPs) are benign tumors arising from the sellar region. However, little is known about their clinical features and long-term recurrence due to low morbidity and the lack of large cohort studies. Thus, we aimed to develop nomograms to accurately predict the extent of resection and tumor recurrence using clinical parameters. A total of 545 patients diagnosed with CP between 2009 and 2019 were examined: 381 in the development cohort and 164 in the validation cohort. Least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were performed to establish two nomograms. Receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA) and Kaplan-Meier (KM) curves were used to evaluate their predictive performance and discriminative power, respectively, in the two cohorts. In addition, the EORTC QLQ-BN20 questionnaire was used to assess neuropsychological status in the follow-up. In the development cohort, the area under the curve (AUC) and C-index were 0.760 and 0.758, respectively, for predicting the extent of resection and 0.78 and 0.75, respectively, for predicting 3-year progression-free survival (PFS) and 5-year PFS. Additionally, the model had a predictive accuracy of 0.785. Both nomograms showed acceptable discrimination in the two cohorts. Moreover, DCA demonstrated excellent clinical benefits from the two nomograms. Finally, participants were classified into two distinct risk groups according to the risk score, and an online calculator was created for convenient clinical use. During long term follow-up, hypothyroidism (77.61%) and hypocortisolism (76.70%) were the most common endocrine dysfunction after surgery and significant deficits were observed concerning visual disorder, motor dysfunction and seizures in the recurrent groups. In particular, better quality of life was associated with gross total resection (GTR), postoperative radiation, anterior interhemispheric (AI) approach and transsphenoidal approach. To our knowledge, these are the first nomograms based on a very large cohort of patients with CP that show potential benefits for guiding treatment decisions and long-term surveillance. The current study demonstrated the online calculator serve as the practical tool for individual strategies based on the patient's baseline characteristics to achieve a better prognosis.

Analysis of Approaches in the Microsurgical Treatment of 102 Cases of Petroclival Meningioma in a Single Center.

Objectives: We identified the optimal approaches for treating the diverse tumor subtypes of petroclival meningioma (PM) by analyzing the clinical benefits of various surgical approaches adopted for each subtype. Methods: Tumors in 102 PM patients from a single center who underwent surgical treatment were classified as upper clivus (UC), cavernous sinus (CS), tentorium (TE), or petrous apex (PA) types based on the attachment site of the tumor base and the displacement of the trigeminal nerve. The therapeutic effects of different surgical approaches among the subtypes were evaluated according to the patient outcomes. Results: The subtemporal (33.33%), retrosigmoid (16.67%), and Kawase approaches (50%) were used for the UC type. Simpson I/II resection was achieved in 46.66% of patients with the Kawase approach. Significant differences were found between the other two approaches (P = 0.044) and in the follow-up Karnofsky performance scale (KPS) scores (P = 0.008). The subtemporal (60%) and Kawase approaches (40%) were used for the CS type; neither approach achieved Simpson I/II resection. The retrosigmoid (25.81%) and Kawase approaches (74.19%) were used for the TE type. The Simpson I/II resection rates of the two approaches were 55.55 and 86.95%, respectively, and a significant difference was observed between them (P = 0.039). The retrosigmoid (43.75%) and Kawase approaches (56.25%) were used for the PA type. The Simpson I/II resection rates of the two approaches were 31.25 and 50%, respectively. The resection degrees of the two approaches and the KPS scores at follow-up were significantly different (P = 0.034). Conclusion: The individual microsurgical approaches adopted for the various PM tumor subtypes can provide maximal safe resection and good KPS scores. The Kawase approach is more suitable for PM, especially for UC- and PA-type PM tumors.

Sphingosine-1-phosphate receptor 3 is implicated in BBB injury via the CCL2-CCR2 axis following acute intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a catastrophic cerebrovascular disease with high morbidity and mortality. Evidence demonstrated that sphingosine-1-phosphate receptor (S1PR) plays a vital role in inflammatory damage via the upregulation of CCL2 expression. However, whether S1PR3 is involved in blood-brain barrier (BBB) breakdown via CCL2 activation after ICH has not been described. METHODS: We investigated the expression profiles of all S1PRs using high-throughput RNA-seq analysis and RT-PCR. The potential role of S1PR3 and interaction between S1PR3 and CCL2 were evaluated via Western blotting, immunofluorescence, and flow cytometry. BBB disruption was examined via magnetic resonance imaging, transmission electron microscopy, and Evans blue extravasation. Microglial activation, proliferation, and polarization were assessed via histopathological analysis. The expression levels of CCL2, p-p38 MAPK, ICAM-1, and ZO-1 were examined in vitro and in vivo. RESULTS: The present results showed that the levels of S1PR3 and its ligand, sphingosine 1-phosphate (S1P), were dramatically increased following ICH, which regulated the expression of CCL2 and p38MAPK. Moreover, reductions in brain edema volume, amelioration of BBB integrity, and improvements in behavioral deficits were achieved after the administration of CAY10444, an S1PR3 antagonist, to rats. Remarkably increased CCL2, p-p38MAPK, and ICAM-1 expression and decreased ZO-1 expression were observed in cocultured human astrocytes (HAs) and hCMEC/D3 cells after S1P stimulation. However, the expression levels of CCL2, p-p38 MAPK, and ICAM-1 were decreased and ZO-1 expression was increased after S1PR3 inhibition. In addition, microglial proliferation and M1 polarization were attenuated after CAY10444 administration. CONCLUSION: To the best of our knowledge, this is the first demonstration of the neuroprotective role of S1PR3 modulation in maintaining BBB integrity by inhibiting the S1PR3-CCL2 axis after ICH, providing a novel treatment for ICH by targeting S1PR3.

Identification and Characterization of TF-lncRNA Regulatory Networks Involved in the Tumorigenesis and Development of Adamantinomatous Craniopharyngioma.

Craniopharyngiomas (CPs) are rare tumors arising from the sellar region. Although the best outcome for patients with one subtype, adamantinomatous craniopharyngioma (ACP), is obtained by gross total resection, little is known about the roles of long noncoding RNAs (lncRNAs) and transcription factors (TFs) in ACP tumorigenesis. In total, 12 human ACP and 5 control samples were subjected to transcriptome-level sequencing. We built an integrated algorithm for identifying lncRNAs and TFs regulating the CP-related pathway. Furthermore, ChIP-Seq datasets with binding domain information were used to further verify and identify TF-lncRNA correlations. RT-PCR and immunohistochemistry staining were performed to validate the potential targets. Five pathways associated with ACP were identified and defined by an extensive literature search. Based on the specific pathways and the whole gene expression profile, 266 ACP-related lncRNAs and 39 TFs were identified by our integrating algorithm. Comprehensive analysis of the ChIP-Seq datasets revealed that 29 TFs were targeted by 12000 lncRNAs in a wide range of tissues, including 161 ACP-related lncRNAs that were identified by the computational method. These 29 TFs and 161 lncRNAs, constituting 1004 TF-lncRNA pairs, were shown to potentially regulate different ACP-related pathways. A total of 232 TF-lncRNA networks were consequently established based on differential gene expression. Validation by RT-PCR and immunohistochemistry staining revealed positive expression of the ACP-related TFs E2F2 and KLF5 in ACP. Moreover, the expression of the lncRNA RP11-360P21.2 was shown to be upregulated in ACP tissues. In this study, we introduced an integrated algorithm for identifying lncRNAs and TFs regulating the ACP-related pathway. This is the first comprehensive study to systematically investigate the potential TF and lncRNA regulatory network in ACP. The resulting data serve as a valuable resource for understanding the mechanisms underlying ACP-related lncRNAs and TFs.

Primary large B-cell lymphoma involving the cerebellopontine angle: a case report.

Primary large B-cell lymphomas involving the cerebellopontine angle (CPA) are uncommon. Fewer than 20 cases of large B-cell lymphoma at the CPA have been reported worldwide. Herein, we report a rare case of B-cell lymphoma in a 67-year-old woman who presented with dysphagia and dizziness and showed a lesion involving the right CPA on magnetic resonance imaging (MRI). The primary diagnosis was metastatic tumor; however, postoperative pathology confirmed a diffuse large B-cell lymphoma. The initial symptoms were resolved completely at the 2-month postoperative follow-up, and the postoperative course was uneventful. Large B-cell lymphoma should be included in the differential diagnosis of CPA lesions.

Intracranial Metastases Originating From Pediatric Primary Spinal Cord Glioblastoma Multiforme: A Case Report and Literature Review.

Primary spinal cord glioblastoma multiforme (scGBM) is an uncommon entity in pediatrics, and intracranial metastasis originating in spinal cord gliomas is very rare. A 7-year-old female presented with weakness in the limbs, paralysis of the lower limbs and incontinence. The initial MRI of the spinal cord revealed expansion and abnormal signals from T2 to T5. She was initially diagnosed with Neuromyelitis optica spectrum disorders and treated with high-dose glucocorticoid and gamma globulin. Four months later, her symptoms worsened and follow-up imaging showed multiple intracranial mass lesions. We performed a subtotal resection of the right thalamic basal ganglia tumor and gross total resection of the right frontal lobe tumor under microscopic examination. Histopathology revealed scGBM with intracranial metastasis and the molecular pathology diagnosis suggested H3K27M mutant diffuse midline glioma WHO grade IV, which had previously been misdiagnosed as a Neuromyelitis optica spectrum disorders. We review the literature of intracranial metastases originating from pediatric primary spinal cord glioblastoma multiforme and summarize possible methods of differentiation, including changes in muscle strength or tone, intramedullary heterogeneously enhancing solitary mass lesions and cord expansion in MRI. Finally, we emphasize that in unexpected radiological changes or disadvantageous response to the treatment, a biopsy to achieve a pathological diagnosis is necessary to discard other diseases, especially neoplasms.

Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) remains a devastating type of stroke that lacks an effective treatment. Recent evidence has demonstrated that CCL2 is involved in the blood-brain barrier (BBB) disruption and propagermanium (PG) as a CCL2 receptor inhibitor is neuroprotective in ischemic stroke. However, whether PG therapy exert effective role in acute ICH still unclear. In this study, our goal was to investigate the potential role of CCL2 and the effects of PG in ICH. Differentially expressed RNAs including CCL2 were detected in human ICH. CCL2 and the activation of p-p38 MAPK and AQP4 expression were analyzed in rats after ICH. Brain water content and BBB integrity as well as neurological function were also examined after PG administration. In addition, the mechanism by which CCL2-mediated BBB injury was further investigated by cell coculture. Our findings showed that PG could effectively reduce brain edema and improve neurobehavioral functions. p-p38 MAPK and AQP4 expression were significantly inhibited by PG in vivo and in vitro. To the best of our knowledge, this is the first demonstration of PG in neuroprotecting the BBB integrity by inhibition of CCL2-CCR2-p38 MAPK pathway following ICH, targeting CCL2 could be developed as a novel treatment for hemorrhagic stroke.

Clinicopathological Features and Microsurgical Management of Lesions Located in the Cavernous Sinus: Analysis of 66 Cases.

AIM: To investigate the clinicopathological features and related factors affecting microsurgical resection of lesions in the cavernous sinus. MATERIAL AND METHODS: Clinical data of 66 patients undergoing microsurgery for lesions located in the cavernous sinus from January 2011 to December 2017 were retrospectively reviewed. RESULTS: Histopathological examination revealed benign lesions in 60 (90.9%) patients, the most common histopathological types were meningiomas, schwannomas, and cavernous hemangiomas. Only six (9.1%) patients had malignant lesions. The gross total resection rate was 33%, subtotal resection rate was 21%, substantial partial resection rate was 26%, and partial resection rate was 20%. Factors influencing the extent of lesion resection included the presence of cavernous sinus syndrome prior to surgery, the size of the lesion, the site of origin, and the surrounding of the internal carotid artery, all of which detrimentally influenced total excision (p < 0.05). CONCLUSION: Most lesions involving the cavernous sinus are histopathologically benign. Preoperative cavernous sinus syndrome, the size of the lesion, the site of origin, and the surrounding of the internal carotid artery all detrimentally influence the extent of lesion resection.