Global hyperperfusion after successful endovascular thrombectomy is linked to worse outcome in acute ischemic stroke.

Patients with stroke may develop hyperperfusion after a successful endovascular thrombectomy (EVT). However, the relationship between post-EVT hyperperfusion and clinical outcomes remains unclear and requires further clarification. We reviewed consecutive patients with anterior circulation occlusion who were successfully recanalized with EVT. Based on post-EVT arterial spin-labeling images, hyperperfusion was categorized as follows: global hyperperfusion (GHP), increased cerebral blood flow (CBF) in ≥ 50% of the culprit vessel territory; focal hyperperfusion (FHP), increased CBF in < 50% of the culprit vessel territory; no hyperperfusion (NHP), no discernible CBF increase. Factors associated with hyperperfusion were assessed, and clinical outcomes were compared among patients under different hyperperfusion categories. Among 131 patients, 25 and 40 patients developed GHP and FHP, respectively. Compared to other groups, the GHP group had worse National Institutes of Health Stroke Scale score (GHP vs. NHP/FHP, 18.1 ± 7.4 vs. 12.3 ± 6.0; p < 0.001), a larger post-EVT infarct volume (98.9 [42.3-132.7] vs. 13.5 [5.0-34.1] mL; p < 0.001), and a worse 90-day outcome (modified Rankin Scale, 3 [1-4] vs. 2 [0-3]; p = 0.030). GHP was independently associated with infarct volume (B = 0.532, standard error = 0.163, p = 0.001), and infarct volume was a major mediator of the association of GHP with unfavorable outcomes (total effect: ß = 0.176, p = 0.034; direct effect: ß = 0.045, p = 0.64; indirect effect: ß = 0.132, p = 0.017). Patients presenting with post-EVT GHP had poorer neurological prognosis, which is likely mediated by a large infarct volume.

The immunologic phenotype of thrombi is associated with future vascular events after cerebral infarction.

BACKGROUND: Thrombi retrieved from patients with acute ischemic stroke may contain prognostic information. OBJECTIVE: To investigate the relationship between the immunologic phenotype of thrombi and future vascular events in patients with a stroke. METHODS: This study included patients with acute ischemic stroke who underwent endovascular thrombectomy at Chung-Ang University Hospital in Seoul, Korea, between February 2017 and January 2020. Laboratory and histological variables were compared between patients with and without recurrent vascular events (RVEs). Kaplan-Meier analysis followed by the Cox proportional hazards model was used to identify factors related to RVE. Receiver operating characteristic (ROC) analysis was conducted to evaluate the performance of the immunologic score by combining immunohistochemical phenotypes to predict RVE. RESULTS: A total of 46 patients were included in the study with 13 RVEs (mean±SD age, 72.8±11.3 years; 26 (56.5%) men). Thrombi with a lower percentage of programmed death ligand-1 expression (HR=11.64; 95% CI 1.60 to 84.82) and a higher number of citrullinated histone H3 positive cells (HR=4.19; 95% CI 0.81 to 21.75) were associated with RVE. The presence of high-mobility group box 1 positive cell was associated with reduced risk of RVE, but the association was lost after adjustment for stroke severity. The immunologic score, which consists of the three immunohistochemical phenotypes, showed good performance in predicting RVE (area under the ROC curve, 0.858; 95% CI 0.758 to 0.958). CONCLUSIONS: The immunological phenotype of thrombi could provide prognostic information after stroke.

Clonal Hematopoiesis and Acute Ischemic Stroke Outcomes.

OBJECTIVE: The effect of clonal hematopoiesis of indeterminate potential (CHIP) on the manifestation and clinical outcomes of acute ischemic stroke (AIS) has not been fully elucidated. METHODS: Patients with AIS were included from a prospective registry coupled with a DNA repository. Targeted next-generation sequencing on 25 genes that are frequently mutated in hematologic neoplasms was performed. The prevalence of CHIP was compared between patients with AIS and age-matched healthy individuals. A multivariate linear or logistic regression model was used to assess the association among CHIP and stroke severity, hemorrhagic transformation, and functional outcome at 90 days. RESULTS: In total, 380 patients with AIS (mean age = 67.2 ± 12.7 years; 41.3% women) and 446 age-matched controls (mean age = 67.2 ± 8.7 years; 31.4% women) were analyzed. The prevalence of CHIP was significantly higher in patients with AIS than in the healthy controls (29.0 vs 22.0%, with variant allele frequencies of 1.5%, p = 0.024). PPM1D was found to be most significantly associated with incident AIS (adjusted odds ratio [aOR] = 7.85, 95% confidence interval [CI] = 1.83-33.63, p = 0.006). The presence of CHIP was significantly associated with the initial National Institutes of Health Stroke Scale (NIHSS) score (ß = 1.67, p = 0.022). Furthermore, CHIP was independently associated with the occurrence of hemorrhagic transformation (65/110 clonal hematopoiesis positive [CH+] vs 56/270 CH negative [CH-], aOR = 5.63, 95% CI = 3.24-9.77, p < 0.001) and 90-day functional disability (72/110 [CH+] vs 99/270 [CH-], aOR = 2.15, 95% CI = 1.20-3.88, p = 0.011). INTERPRETATION: CH was significantly associated with incident AIS. Moreover, particularly, sequence variations in PPM1D, TET2, and DNMT3A represent a new prognostic factor for AIS. ANN NEUROL 2023;94:836-847.

Ultrasmall polymer-coated cerium oxide nanoparticles as a traumatic brain injury therapy.

No medication has been approved for secondary injuries after traumatic brain injury (TBI). While free radicals are considered a major mediator of secondary injury, conventional antioxidants only have modest clinical efficacy. Here, we synthesized CX201 consisting of core cerium oxide nanoparticles coated with 6-aminocaproic acid and polyvinylpyrrolidone in aqueous phase. CX201 with 3.49 ± 1.11 nm of core and 6.49 ± 0.56 nm of hydrodynamic diameter showed multi-enzymatic antioxidant function. Owing to its excellent physiological stability and cell viability, CX201 had a neuroprotective effect in vitro. In a TBI animal model, an investigator-blinded randomized experiment showed a single intravenously injected CX201 significantly improved functional recovery compared to the control. CX201 reduced lipid peroxidation and inflammatory cell recruitment at the damaged brain. These suggest ultrasmall CX201 can efficiently reduce secondary brain injuries after TBI. Given the absence of current therapies, CX201 may be proposed as a novel therapeutic strategy for TBI.

Neuroimaging features of antiphospholipid antibody-related stroke compared with atrial fibrillation-related stroke.

Recognizing the lesion pattern of antiphospholipid antibody-related stroke (aPL-stroke) may contribute to establishing the cause in patients with cryptogenic stroke. We aimed to describe the neuroimaging features of aPL-stroke compared with atrial fibrillation-related stroke (AF-stroke), a major hidden cause of cryptogenic stroke. Using a prospective stroke registry, we identified consecutive aPL- and AF-stroke patients without other potential causes of stroke. Neuroimaging features based on diffusion-weighted imaging and angiographic findings at admission were compared. A total of 56 and 333 patients were included in the aPL- and AF-stroke groups, respectively. aPL-stroke patients more often presented with single small lesions (aPL-stroke, 30.4% vs. AF-stroke, 7.5%, p < 0.001), while the predominant pattern in AF-stroke patients was large territorial lesions (26.8% vs. 56.5%, p < 0.001). aPL-stroke patients had smaller infarct volume (1.58 mL [0.45; 9.41] vs. 11.32 mL [2.82; 33.08], p < 0.001) and less experience of relevant artery occlusion (17.9% vs. 54.7%, p < 0.001). The proportion of multi-territory lesions, an embolic pattern, was similar between the two groups (28.6% vs. 22.8%, p = 0.44). In comparison only including patients with multi-territory lesions as well, aPL-stroke patients showed small lesion dominance and smaller infarct volume. Multivariate analyses showed independent associations between mild neuroimaging features (small lesion prevalence, smaller infarct volume, and absence of relevant artery occlusion) and aPL-stroke. Patterns of small lesion prevalence, small infarct volume, and absence of relevant artery occlusion were suggestive of aPL-stroke rather than AF-stroke. Cryptogenic stroke patients with such neuroimaging features may benefit from aPL testing for a precise diagnosis.

Ceria Nanoparticles Synthesized With Aminocaproic Acid for the Treatment of Subarachnoid Hemorrhage.

Background and Purpose- Despite early aneurysm repair and aggressive management for complications, subarachnoid hemorrhage (SAH) results in at least 25% mortality rate and 50% persistent neurological deficit. We investigated whether ceria nanoparticles which have potent antioxidative activities can protect against subarachnoid hemorrhage via attenuating fatal brain injuries. Methods- Uniform, 3 nm, water-dispersed ceria nanoparticles were prepared from short sol-gel reaction of cerium (III) ions with aminocaproic acid in aqueous phase. SAH was induced by endovascular perforation of middle cerebral artery of rats. A single dose of ceria nanoparticles (0.5 mg Ce/kg) or saline control was randomly administered intravenously at an hour post-SAH. Neuronal death, macrophage infiltration, SAH grade, and brain edema were evaluated at 72 hours. Mortality and neurological function were assessed for 14 days. Results- The obtained ceria nanoparticles with high Ce3+ to Ce4+ ratio demonstrated potent antioxidative, cytoprotective, and anti-inflammatory activities in vitro. In rodent SAH models, the severity of hemorrhage was comparable between the ceria nanoparticles- and saline-treated groups. However, ceria nanoparticles significantly reduced neuronal death, macrophage infiltration, and brain edema after SAH. Ceria nanoparticles successfully improved survival rates (88.2% in the ceria nanoparticles group versus 21.1% in the control group; P<0.001) and neurological outcomes (modified Garcia score: 12.1±0.5 in the ceria nanoparticles group versus 4.4±0.5 in the control group; P<0.001) of the animals with SAH. Conclusions- Ceria nanoparticles, totally synthesized in aqueous phase using aminocaproic acid, demonstrated promising results against SAH via potent antioxidative, neuroprotective and anti-inflammatory activities. Given the obvious limitations of current therapies for SAH, ceria nanoparticles can be a potential therapeutic agent which might result in a paradigm shift in SAH treatment.

Transcription factors Sp1 and Sp3 regulate expression of human ABCG2 gene and chemoresistance phenotype.

ABCG2 is a member of the ATP binding cassette (ABC) transmembrane proteins that plays an important role in stem cell biology and drug resistance of cancer cells. In this study, we investigated how expression of human ABCG2 gene is regulated in lung cancer A549 cells. Binding of Sp1 and Sp3 transcription factors to the ABCG2 promoter in vitro and in vivo was elucidated by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. The ABCG2 promoter activity was impaired when Sp1 sites were mutated but was enhanced by overexpression of Sp1 or Sp3 proteins. Knockdown of Sp1 or Sp3 expression by short interfering RNA significantly decreased the expression of ABCG2 mRNA and protein, resulting in attenuated formation of the side population in A549 cells. In addition, Sp1 inhibition in vivo by mithramycin A suppressed the percentage of the side population fraction and sphere forming activities of A549 cells. Moreover, inhibiting Sp1- or Sp3-dependent ABCG2 expression caused chemosensitization to the anticancer drug cisplatin. Collectively, our results demonstrate that Sp1 and Sp3 transcription factors are the primary determinants for activating basal transcription of the ABCG2 gene and play an important role in maintaining the side population phenotype of lung cancer cells.

Accessible chromatin structure permits factors Sp1 and Sp3 to regulate human TGFBI gene expression.

Transforming growth factor beta 1-induced (TGFBI) protein is an extracellular matrix (ECM) protein that is associated with other ECM proteins and functions as a ligand for various types of integrins. In this study, we investigated how human TGFBI expression is regulated in lung and breast cancer cells. We observed that the TGFBI promoter in A549 and MBA-MD-231 cells, which constitutively express TGFBI, existed in an open chromatin conformation associated with transcriptionally permissive histone modifications. Moreover, we found that TGFBI expression required Sp1 transcription elements that can bind transcription factors Sp1 and Sp3 in vitro. Occupancy of the TGFBI promoter by Sp1 and Sp3 in vivo was only observed in TGFBI-expressing cells, indicating that open chromatin conformation might facilitate the binding of Sp1 and Sp3 to the TGFBI promoter region. TGFBI promoter activity was impaired when Sp1 elements were mutated, but was increased when Sp1 or Sp3 factors was overexpressed. Furthermore, Sp1 inhibition in vivo by mithramycin A, as well as knockdown of Sp1 and/or Sp3 expression by short interfering RNA, significantly reduced TGFBI mRNA and protein levels. Thus, our data demonstrated that the expression of TGFBI is well correlated with chromatin conformation at the TGFBI promoter, and that factors Sp1 and Sp3 are the primary determinants for the control of constitutive expression of TGFBI gene.