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Background: Covert atrial fibrillation (AF) is a major cause of cryptogenic stroke. This study investigated whether a dose-dependent relationship exists between the frequency of premature atrial contractions (PACs) and AF detection in patients with cryptogenic stroke using an insertable cardiac monitor (ICM)., Methods: We enrolled consecutive patients with cryptogenic stroke who underwent ICM implantation between October 2016 and September 2020 at 8 stroke centers in Japan. Patients were divided into 3 groups according to the PAC count on 24-hour Holter ECG: ≤200 (group L), >200 to ≤500 (group M), and >500 (group H). We defined a high AF burden as above the median of the cumulative duration of AF episodes during the entire monitoring period. We evaluated the association of the frequency of PACs with AF detection using log-rank trend test and Cox proportional hazard model and with high AF burden using logistic regression model, adjusting for age, sex, CHADS 2 score., Results: Of 417 patients, we analyzed 381 patients with Holter ECG and ICM data. The median age was 70 (interquartile range, 59.5-76.5), 246 patients (65%) were males, and the median duration of ICM recording was 605 days (interquartile range, 397-827 days). The rate of new AF detected by ICM was higher in groups with more frequent PAC (15.5%/y in group L [n=277] versus 44.0%/y in group M [n=42] versus 71.4%/y in group H [n=62]; log-rank trend P <0.01). Compared with group L, the adjusted hazard ratios for AF detection in groups M and H were 2.11 (95% CI, 1.24-3.58) and 3.23 (95% CI, 2.07-5.04), respectively, and the adjusted odds ratio for high AF burden in groups M and H were 2.57 (95% CI, 1.14-5.74) and 4.25 (2.14-8.47), respectively., Conclusions: The frequency of PACs was dose-dependently associated with AF detection in patients with cryptogenic stroke., Competing Interests: Disclosures Dr Todo reports lecture fees from Pfizer, Bristol-Myers Squibb, Daiichi-Sankyo, Bayer, Medtronic, Abbott, and Otsuka Pharmaceutical. Dr Doijiri reports lecture fees from Medtronic, Abbott, Biotronic, Daiichi Sankyo, Bristol-Myers Squibb, and Bayer. Dr Yamazaki reports lecture fees from Medtronic, Abbott, Daiichi Sankyo, Bristol-Myers Squibb, and Bayer. Dr Iwata reports lecture fees from Daiichi-Sankyo, and Medtronic. Dr Sonoda reports lecture fees from Medtronic, Abbott, and Daiichi-Sankyo. Dr Koge reports lecture fees from Medtronic. Dr Koga reports honoraria from Daiichi-Sankyo and research support from Daiichi-Sankyo. Dr Nagata reports lecture fees from Otsuka Pharmaceutical, Daiichi-Sankyo, Eli Lilly, and Amgen. Dr Ueno reports research funds from Bristol-Myers Squibb. Dr Yamagami reports lecture fees from Medtronic, Abbott, Daiichi-Sankyo, Bristol-Myers Squibb, and Bayer, and grant support from Bristol-Myers Squibb. Dr Gon reports lecture fees from Eisai, Kyowa Kirin, and Pfizer. The other authors report no conflicts.

Although low-dose direct oral anticoagulants (DOACs) are recommended for patients at high risk of bleeding complications, it remains unclear whether the dose reduction in real-world setting is also appropriate in patients after large-vessel occlusion (LVO) stroke. This study hypothesized that patients with atrial fibrillation (AF) and LVO receiving low-dose DOACs have an increased risk of ischemic and hemorrhagic events. The study aimed to assess 1 year morbidity and mortality in patients treated with standard-dose and low-dose apixaban after LVO stroke. A post hoc analysis was performed using the acute LVO registry data, which enrolled patients with AF and LVO who received apixaban within 14 days of stroke onset. The incidences of ischemic events (ischemic stroke, acute coronary syndrome, acute myocardial infarction, and systemic embolism), major bleeding events, and death from any cause were compared between patients receiving standard- and low-dose apixaban. Of 643 patients diagnosed with LVO, 307 (47.7%) received low-dose apixaban. After adjustment for clinically relevant variables, no significant differences were observed in the incidence of ischemic events (adjusted hazard ratio [aHR]: 2.12, 95% confidence interval [CI] 0.75-6.02), major bleeding events (aHR: 1.17, 95% CI 0.50-2.73), and death from any cause (aHR: 1.95, 95% CI 0.78-4.89) between patients receiving standard- and low-dose apixaban. No significant differences were observed in the incidence of ischemic events, major bleeding events, or death from any cause between patients with AF and LVO receiving standard- and low-dose apixaban., (© 2024. The Author(s).)

Background: Atrial fibrillation (AF) is known to be a strong risk factor for stroke. However, the risk of stroke recurrence in patients with cryptogenic stroke with AF detected after stroke by an insertable cardiac monitor (ICM) is not well known. We sought to evaluate the risk of ischemic stroke recurrence in patients with cryptogenic stroke with and without ICM-detected AF., Methods and Results: We retrospectively reviewed patients with cryptogenic stroke who underwent ICM implantation at 8 stroke centers in Japan. Cox regression models were developed using landmark analysis and time-dependent analysis. We set the target sample size at 300 patients based on our estimate of the annualized incidence of ischemic stroke recurrence to be 3% in patients without AF detection and 9% in patients with AF detection. Of the 370 patients, 121 were found to have AF, and 110 received anticoagulation therapy after AF detection. The incidence of ischemic stroke recurrence was 4.0% in 249 patients without AF detection and 5.8% in 121 patients with AF detection ( P =0.45). In a landmark analysis, the risk of ischemic stroke recurrence was not higher in patients with AF detected ≤90 days than in those without (hazard ratio, 1.47 [95% CI, 0.41-5.28]). In a time-dependent analysis, the risk of ischemic stroke recurrence did not increase after AF detection (hazard ratio, 1.77 [95% CI, 0.70-4.47])., Conclusions: The risk of ischemic stroke recurrence in patients with cryptogenic stroke with ICM-detected AF, 90% of whom were subsequently anticoagulated, was not higher than in those without ICM-detected AF.

Background: Patients with acute ischemic stroke and active cancer have more severe neurological symptoms, elevated risks of stroke recurrence, and death compared with the general population. We examined whether von Willebrand factor (vWF) antigen levels at stroke onset were associated with the poor outcomes of patients with stroke and cancer., Methods and Results: Using data from 90 patients with acute ischemic stroke and active cancer who were registered in the SCAN (Ischemic Stroke in Patients With Cancer and Neoplasia) study, a prospective multicenter, observational study in Japan, we divided patients into 2 groups according to their median vWF antigen levels (high, n=46; or low, n=44). The high-vWF group had a significantly higher initial National Institutes of Health Stroke Scale score (median, 7 [interquartile range, 3-11.25] versus 3 [interquartile range, 1-8.5]; P <0.05) and a significantly higher incidence of cryptogenic stroke (32 [70%] versus 16 [36%]; P <0.01) and venous thromboembolism (7 [15%] versus 0 [0%]; P <0.01), as well as multiple lesions (28 [62%] versus 12 [27%]; P <0.001), than the low-vWF group. We observed no significant difference in the rate of stroke recurrence within 1 year between the groups. However, increased vWF levels were an independent predictor of death within 1 year of stroke onset, after adjusting for potential confounders (odds ratio, 6.77 [95% CI, 1.49-30.78]; P <0.05)., Conclusions: Elevated vWF antigen levels were associated with adverse outcomes in patients with cancer-associated stroke and may represent a useful biomarker to guide future therapeutic interventions.

Background: The effect of nutritional status on survival in ischemic stroke patients with active cancer remains unclear., Methods: This study retrospectively evaluated ischemic stroke patients with active cancer admitted to a university hospital in Japan between 2006 and 2016. Patients were followed for 2 years after stroke. The controlling nutritional status (CONUT) score was used to classify undernutrition degree into 4 groups: normal, light, moderate, and severe. Survival rates were compared using the Kaplan-Meier method. Hazard ratio (HR) and 95 % confidence intervals (CIs) for mortality were calculated using Cox regression models., Results: A total of 158 patients (31 % women; median age: 71 years) were analyzed. Of these, 47 % had distant metastasis. The median (interquartile range) National Institute of Health Stroke Scale and CONUT scores were 4 (1-10) and 5 (3-7), respectively. Kaplan-Meier curve indicated that patients with poorer nutritional status had worse outcomes (overall log-rank test, p < 0.001). The univariable Cox regression analysis showed that the HR (95 % CI) for the light, moderate, and severe groups were 1.14 (0.45-2.86), 3.01 (1.27-7.12), and 2.94 (1.10-7.84), respectively. This statistical significance did not persist after adjustment for potential confounders (HR [95 % CI] for the light, moderate, and severe groups were 0.95 [0.36-2.49], 1.56 [0.57-4.28], and 1.34 [0.37-4.92], respectively). Past stroke, distant metastasis, and plasma D-dimer levels on admission were independent predictors of prognosis., Conclusions: This single-center, retrospective study suggests that nutritional status serves as a prognostic indicator for ischemic stroke patients with active cancer. However, the effect is not statistically independent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The incidence of cancer-associated stroke has increased with the prolonged survival times of cancer patients. Recent genetic studies have led to progress in cancer therapeutics, but relationships between oncogenic mutations and stroke remain elusive. Here, we focused on the driver gene KRAS, which is the predominant RAS isoform mutated in multiple cancer types, in cancer associated stroke study. KRAS G13D/- and parental human colorectal carcinoma HCT116 cells were inoculated into mice that were then subjected to a photochemically-induced thrombosis model to establish ischemic stroke. We found that cancer inoculation exacerbated neurological deficits after stroke. Moreover, mice inoculated with KRAS G13D/- cells showed worse neurological deficits after stroke compared with mice inoculated with parental cells. Stroke promoted tumor growth, and the KRAS G13D/- allele enhanced this growth. Brain RNA sequencing analysis and serum ELISA showed that chemokines and cytokines mediating pro-inflammatory responses were upregulated in mice inoculated with KRAS G13D/- cells compared with those inoculated with parental cells. STAT3 phosphorylation was promoted following ischemic stroke in the KRAS G13D/- group compared with in the parental group, and STAT3 inhibition significantly ameliorated stroke outcomes by mitigating microglia/macrophage polarization. Finally, we compared the prognosis and mortality of colorectal cancer patients with or without stroke onset between 1 January 2007 and 31 December 2020 using a hospital-based cancer registry and found that colorectal cancer patients with stroke onset within 3 months after cancer diagnosis had a worse prognosis. Our work suggests an interplay between KRAS and ischemic stroke that may offer insight into future treatments for cancer-associated stroke., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background Limited data exist on the prognostic factors for patients with ischemic stroke and active cancer. Methods and Results We conducted a prospective, multicenter, observational study in Japan, including patients with acute ischemic stroke and active cancer, to investigate the prognostic factors. We followed up the patients for 1 year after stroke onset. The patients were divided into 2 groups according to cryptogenic stroke and known causes (small-vessel occlusion, large-artery atherosclerosis, cardioembolism, and other determined cause), and survival was compared. The hazard ratios (HRs) and 95% CIs for mortality were calculated using Cox regression models. We identified 135 eligible patients (39% women; median age, 75 years). Of these patients, 51% had distant metastasis. A total of 65 (48%) and 70 (52%) patients had cryptogenic stroke and known causes, respectively. Patients with cryptogenic stroke had significantly shorter survival than those with known causes (HR [95% CI], 3.11 [1.82-5.32]). The multivariable Cox regression analysis revealed that distant metastasis, plasma D-dimer levels, venous thromboembolism (either deep venous thrombosis or pulmonary embolism) complications at stroke onset were independent predictors of mortality after adjusting for potential confounders. Cryptogenic stroke was associated with prognosis in univariable analysis but was not significant in multivariable analysis. The plasma D-dimer levels stratified the prognosis of patients with ischemic stroke and active cancer. Conclusions The prognosis of patients with acute ischemic stroke and active cancer varied considerably depending on stroke mechanism, distant metastasis, and coagulation abnormalities. The present study confirmed that coagulation abnormalities were crucial in determining the prognosis of such patients.

Background: Although stimulation of Wnt/β-catenin signaling is an important strategy to treat ischemic stroke, its signaling pathway has not been fully clarified yet. Recently, RSPO3 (R-spondin 3)/LGR4 (leucine-rich repeat-containing G protein-coupled receptor 4) signaling has resolved TLR4 (toll-like receptor 4)-induced inflammation in lung injury; however, whether this signal is critical in the ischemic brain remains unknown. Therefore, we investigated the role of RSPO3/LGR4 signaling in the ischemic brain., Methods: BALB/c mice were exposed to permanent distal middle cerebral artery and common carotid artery occlusion. Temporal RSPO3 and LGR4 expressions were examined, and the mice were randomly assigned to receive vehicle or recombinant RSPO3. The underlying mechanisms were investigated using microglial cell lines and primary mixed glia-endothelia-neuron and primary neuronal cultures., Results: In the ischemic brain, RSPO3 and LGR4 were expressed in endothelial cells and microglia/macrophages and neurons, respectively. Stimulation of RSPO3/LGR4 signaling by recombinant RSPO3 recovered neurological deficits with decreased Il1β and iNOS mRNA on day 3 and increased Gap43 on day 9. In cultured cells, LGR4 was expressed in neuron and microglia, whereas RSPO3 promoted nuclear translocation of β-catenin. Neuroprotective effects with reduced expression of inflammatory cytokines were observed in lipopolysaccharide-stimulated glia-endothelium-neuron cultures but not in glutamate-, CoCl 2 -, H 2 O 2 -, or oxygen glucose deprivation-stimulated neuronal cultures, indicating that RSPO3/LGR4 can protect neurons by regulating inflammatory cytokines. LGR4-Fc chimera, which was used to block endogenous RSPO3/LGR4 signaling, increased LPS-induced production of inflammatory cytokines, suggesting that endogenous RSPO3 suppresses inflammation. RSPO3 decreased TLR4-related inflammatory cytokine expression by decreasing TLR4 expression without affecting the M1/M2 phenotype. RSPO3 also inhibited TLR2- and TLR9-induced inflammation but not TLR7-induced inflammation, and promoted neurite outgrowth., Conclusions: RSPO3/LGR4 signaling plays a critical role in regulating TLR-induced inflammation and neurite outgrowth in the ischemic brain. Enhancing this signal will be a promising approach for treating ischemic stroke., Competing Interests: Disclosures The Department of Health Development and Medicine is an endowed department supported by AnGes, Daicel, and FunPep and collaborates with these companies. The Department of Clinical Gene Therapy is financially supported by Novartis, AnGes, Shionogi, Boehringer, Fancl, Rohto, and FunPep. Dr Morishita is a stockholder of AnGes and Funpep and receives an honorarium at AnGes. Dr Nakagami is a scientific advisor to FunPep. The Department of Gene & Stem Cell Regenerative Therapy is an endowed department supported by AS medical support.

Background Immune cells play a vital role in the pathology of ischemic stroke. Neutrophils and polymorphonuclear myeloid-derived suppressor cells share a similar phenotype and have attracted increasing attention in immune regulation research, yet their dynamics in ischemic stroke remain elusive. Methods and Results Mice were randomly divided into 2 groups and intraperitoneally treated with anti-Ly6G (lymphocyte antigen 6 complex locus G) monoclonal antibody or saline. Distal middle cerebral artery occlusion and transient middle cerebral artery occlusion were applied to induce experimental stroke, and mice mortality was recorded until 28 days after stroke. Green fluorescent nissl staining was used to measure infarct volume. Cylinder and foot fault tests were used to evaluate neurological deficits. Immunofluorescence staining was conducted to confirm Ly6G neutralization and detect activated neutrophils and CD11b + Ly6G + cells. Fluorescence-activated cell sorting was performed to evaluate polymorphonuclear myeloid-derived suppressor cell accumulation in brains and spleens after stroke. Anti-Ly6G antibody successfully depleted Ly6G expression in mice cortex but did not alter cortical physiological vasculature. Prophylactic anti-Ly6G antibody treatment ameliorated ischemic stroke outcomes in the subacute phase. Moreover, using immunofluorescence staining, we found that anti-Ly6G antibody suppressed activated neutrophil infiltration into parenchyma and decreased neutrophil extracellular trap formation in penumbra after stroke. Additionally, prophylactic anti-Ly6G antibody treatment reduced polymorphonuclear myeloid-derived suppressor cell accumulation in the ischemic hemisphere. Conclusions Our study suggested a protective effect of prophylactic anti-Ly6G antibody administration against ischemic stroke by reducing activated neutrophil infiltration and neutrophil extracellular trap formation in parenchyma and suppressing polymorphonuclear myeloid-derived suppressor cell accumulation in the brain. This study may provide a novel therapeutic approach for ischemic stroke.

Blood-brain barrier (BBB) disruption contributes to brain injury and neurological impairment. Tight junctions (TJs) and cell-cell adhesion complexes develop between endothelial cells in the brain to establish and maintain the BBB. Occludin, the first transmembrane protein identified in TJs, has received intense research interest because numerous in vitro studies have suggested its importance in maintaining BBB integrity. However, its role in maintaining BBB integrity after ischemic stroke is less clear owing to the lack of in vivo evidence. This study aimed to investigate the dynamics and function of occludin across the acute and chronic phases after stroke using occludin-deficient mice. By photochemically induced thrombosis model, the expression of occludin was decreased in brain endothelial cells from ischemic lesions. The neurological function of occludin-deficient mice was continuously impaired compared to that of wild-type mice. BBB integrity evaluated by Evans blue and 0.5-kDa fluorescein in the acute phase and by 10-kDa fluorescein isothiocyanate-labeled dextran in the chronic phase was decreased to a greater extent after stroke in occludin-deficient mice. Furthermore, occludin-deficient mice showed decreased claudin-5 and neovascularization after stroke. Our study reveals that occludin plays an important role from the acute to the chronic phase after ischemic stroke in vivo., (© 2023. The Author(s).)

Mdmx and Mdm2 are two major suppressor factors for the tumor suppressor gene p53. In central nervous system, Mdmx suppresses the transcriptional activity of p53 and enhances the binding of Mdm2 to p53 for degradation. But Mdmx dynamics in cerebral infarction remained obscure. Here we investigated the role of Mdmx under ischemic conditions and evaluated the effects of our developed small-molecule Protein-Protein Interaction (PPI) inhibitors, K-181, on Mdmx-p53 interactions in vivo and in vitro. We found ischemic stroke decreased Mdmx expression with increased phosphorylation of Mdmx Serine 367, while Mdmx overexpression by AAV-Mdmx showed a neuroprotective effect on neurons. The PPI inhibitor, K-181 attenuated the neurological deficits by increasing Mdmx expression in post-stroke mice brain. Additionally, K-181 selectively inhibited HDAC6 activity and enhanced tubulin acetylation. Our findings clarified the dynamics of Mdmx in cerebral ischemia and provide a clue for the future pharmaceutic development of ischemic stroke., (© 2022. The Author(s).)

A 53-year-old woman with severe coronavirus disease 2019 (COVID-19) pneumonia was admitted and treated with intravenous unfractionated heparin for thromboprophylaxis under general anesthesia with mechanical ventilation. She developed right hemiparesis after hospitalization due to a large hemorrhagic infarction. Her platelet count decreased from 243,000/μL at administration to 121,000/μL. Anti-platelet factor 4-heparin antibody testing was positive according to a latex immunoturbidimetric assay. She was therefore diagnosed with heparin-induced thrombocytopenia. We immediately stopped the heparin and started argatroban; the platelet count recovered, and thrombosis did not relapse. Physicians should consider heparin-induced thrombocytopenia as a cause of ischemic stroke in patients with COVID-19 infection.

Background: Thrombosis is a dynamic process, and a thrombus undergoes physical and biochemical changes that may alter its response to reperfusion therapy. This study assessed whether thrombus age influenced reperfusion quality and outcomes after mechanical thrombectomy for cerebral embolism., Methods: We retrospectively evaluated 185 stroke patients and thrombi that were collected during mechanical thrombectomy at three stroke centers. Thrombi were pathologically classified as fresh or older based on their granulocytes' nuclear morphology and organization. Thrombus components were quantified, and the extent of NETosis (the process of neutrophil extracellular trap formation) was assessed using the density of citrullinated histone H3-positive cells. Baseline patient characteristics, thrombus features, endovascular procedures, and functional outcomes were compared according to thrombus age., Results: Fresh thrombi were acquired from 43 patients, and older thrombi were acquired from 142 patients. Older thrombi had a lower erythrocyte content ( p  < 0.001) and higher extent of NETosis ( p  = 0.006). Restricted mean survival time analysis revealed that older thrombi were associated with longer puncture-to-reperfusion times (difference: 15.6 minutes longer for older thrombi, p  = 0.002). This association remained significant even after adjustment for erythrocyte content and the extent of NETosis (adjusted difference: 10.8 minutes, 95% confidence interval [CI]: 0.6-21.1 minutes, p  = 0.039). Compared with fresh thrombi, older thrombi required more device passes before reperfusion ( p  < 0.001) and were associated with poorer functional outcomes (adjusted common odds ratio: 0.49; 95% CI: 0.24-0.99)., Conclusion: An older thrombus delays reperfusion after mechanical thrombectomy for ischemic stroke. Adding therapies targeting thrombus maturation may improve the efficacy of mechanical thrombectomy., Competing Interests: Dr. Kitano reports lecture fees from Stryker. Dr. Nakamura reports lecture fees from Johnson & Johnson, Medtronic, and Stryker. Dr. Todo reports lecture fees from Medtronic. The other authors have no conflicts relevant to the contents of this article to disclose., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objectives: As the number of patients with left ventricular assist device (LVAD) implantation has been increasing, treatment of LVAD-related ischemic stroke is becoming a critical issue. We sought to clarify the features of mechanical thrombectomy in LVAD-related stroke with large vessel occlusion., Methods: In a multi-center, retrospective case-control study, we compared 20 LVAD-related strokes with 33 non-LVAD strokes, all of which had large vessel occlusion in the anterior circulation treated with mechanical thrombectomy. A comparative histopathological examination of the retrieved thrombi was also performed., Results: Successful reperfusion was achieved in 75% of the LVAD-related strokes. The time from onset to reperfusion was similar to that of non-LVAD strokes, but the total number of device passes required for reperfusion (median, 2.5 versus 1, P = 0.01) and the incidences of post-procedural parenchymal and subarachnoid hemorrhage (25% versus 3%, P = 0.02 and 55% versus 15%, P = 0.01, respectively) were higher in LVAD-related strokes. Symptomatic intracranial hemorrhage occurred in 4 patients (20%) with LVAD-related strokes. The histopathological analysis revealed that the ratio of erythrocyte components was significantly lower in thrombi retrieved from patients with LVAD-related stroke than in those with non-LVAD stroke (19 ± 6% versus 41 ± 17%, P = 0.01)., Conclusions: Mechanical thrombectomy is feasible in patients with LVAD-related stroke. However, repetitive device passes are needed to achieve successful reperfusion mainly because of the structurally organized thrombi, and the higher risk of hemorrhagic complications should be considered, while offering this therapeutic alternative., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Although T cells play important roles in the pathophysiology of ischemic stroke, the dynamics of T cells remains unclear. In cancer, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) contribute to the maintenance of the tumor microenvironment by suppressing T cells. However, the presence of these cells has never been examined in ischemic brain. Therefore, we examined the temporal and spatial profiles of PMN-MDSCs, which are defined as the CD11b+Ly6ClowLy6G+ cells with higher expression levels of Nox2 and C/EBP Homologous Protein (CHOP) mRNA than normal neutrophil. Fluorescence-activated cell sorter (FACS) analysis showed that the count of CD11b+Ly6ClowLy6G+ cells was increased in the ischemic hemisphere and bone marrow at 72 hours, as well as in the spleen 24 hours after transient middle cerebral artery occlusion in mice. In contrast, the contralateral hemisphere, normal bone marrow, and normal spleen contained few CD11b+Ly6ClowLy6G+ cells. Real-time reverse transcription polymerase chain reaction revealed that CD11b+Ly6ClowLy6G+ cells sorted from brain and spleen 72 hours after ischemia had greater expression of Nox2 and CHOP mRNA than neutrophils in bone marrow, suggesting that these cells constitute PMN-MDSCs. Immunohistochemistry showed that CD11b+Ly6G+ cells were located in the ischemic core and border zone, indicating that PMN-MDSCs might be endemic to these regions. Although neutrophils are believed to invade infarct regions 48–72 hours after ischemia, the present study suggested that some of these cells are in fact PMN-MDSCs. Further studies on the function of PMN-MDSCs might unveil the unknown mechanisms of T cell activation and recruitment in ischemic stroke. [ABSTRACT FROM AUTHOR]

• We performed Ingenuity Pathway Analysis (IPA) using RNA extracted from the whole blood of four healthy controls, six minor acute ischemic stroke patients, and six severe acute ischemic stroke patients on admission. • miRNA-targeted mRNA expressions could be utilized to distinguish between MS and SS groups. • Multiple microRNAs comprehensively controlled the pathophysiology of stroke. • In severe acute stroke, integration of mRNA and microRNA analysis showed activated macrophage-stimulating protein-recepteur d'origine nantais signaling in macrophages is a key pathway. • The canonical pathway analysis of miRNA-targeted mRNA between SS and MS patients showed that the most inhibited were TFNR1 and apoptosis signaling. The roles of mRNA and microRNA (miRNA) are well known in many diseases, including ischemic stroke; thus, integration analysis using mRNA and miRNA is important to elucidate pathogenesis. However, their contribution, especially that of miRNA-targeted mRNA, to the severity of acute ischemic stroke remains unclear. Therefore, we examined mRNA and miRNA integration analysis targeted for acute ischemic stroke to clarify the pathway related to acute stroke severity. We performed Ingenuity Pathway Analysis (IPA) using RNA extracted from the whole blood of four healthy controls, six minor acute ischemic stroke patients (MS; National Institutes of Health Stroke Scale [NIHSS] < 8), and six severe acute ischemic stroke patients (SS; NIHSS ≥ 8) on admission. mRNA and miRNA were measured using RNA sequencing and RNA expression variation; canonical pathway analysis (CPA) and upstream regulator analyses were performed. Acute ischemic stroke patients demonstrated different RNA expressions to healthy controls. Compared to MS patients, in the SS patients, 1222 mRNA, 96 miRNA, and 935 miRNA-targeted mRNA expressions were identified among differentially expressed RNA expressions (p<0.05, |log2 fold change| >1.1). CPA by IPA using mRNAs or miRNA-targeted mRNAs showed that macrophage-stimulating protein (MSP)-recepteur d'origine nantais (RON) signaling was mostly activated in SS patients compared to in MS patients. In addition, upstream regulator analysis in IPA showed that most mRNAs located upstream are miRNAs. In severe acute stroke, integration of mRNA and microRNA analysis showed activated MSP-RON signaling in macrophages, and multiple miRNAs comprehensively controlled the overall pathophysiology of stroke. [ABSTRACT FROM AUTHOR]

Background: The present study aimed to examine whether variables including D-dimer, high-sensitivity C-reactive protein (hsCRP), hemoglobin, platelet count, and nutritional status mediate the pathway between cancer and ischemic stroke outcomes.Methods: We reviewed data from consecutive patients with ischemic stroke admitted to Osaka University Hospital between January 1, 2006, and December 31, 2016. Patients with ischemic stroke were grouped according to the presence of cancer. Nutritional status was assessed using Controlling Nutritional Status (CONUT) scores. Mediation analyses were utilized to address the study aims.Results: Among 1,570 patients with ischemic stroke, 185 (12%) had active cancer. Relative to patients with ischemic stroke in the non-cancer group, those in the cancer group exhibited higher National Institutes of Health Stroke Scale scores on admission, higher D-dimer and hsCRP levels, lower hemoglobin levels and platelet counts, higher CONUT scores, and poorer modified Rankin Scale scores at discharge. Mediation analysis revealed that D-dimer, hsCRP, hemoglobin, platelet count, and CONUT scores acted as mediators of poor prognosis in the cancer group. The association between the exposure and outcome variables was no longer significant in the models containing D-dimer and CONUT scores as mediator variables, suggesting that they were strong mediators. Regarding the association between the mediator and outcome variables, hemoglobin, platelet count, and CONUT exhibited non-linearity (p for non-linearity < 0.001).Conclusions: D-dimer, hsCRP, hemoglobin, platelet count, and CONUT score act as mediators of poor prognosis in patients with ischemic stroke with comorbid cancer. Such abnormalities can help to predict ischemic stroke outcomes. [ABSTRACT FROM AUTHOR]