Association of Serum Macrophage Migration Inhibitory Factor with 3-Month Poor Outcome and Malignant Cerebral Edema in Patients with Large Hemispheric Infarction.

BACKGROUND: We aimed to investigate the associations of macrophage migration inhibitory factor (MIF), toll-like receptors 2 and 4 (TLR2/4), and matrix metalloproteinase 9 (MMP9) with 3-month poor outcome, death, and malignant cerebral edema (MCE) in patients with large hemispheric infarction (LHI). METHODS: Patients with LHI within 24 h of onset were enrolled consecutively. Serum MIF, TLR2/4, and MMP9 concentrations on admission were measured. Poor outcome was defined as a modified Rankin Scale score of ≥ 3 at 3 months. MCE was defined as a decreased level of consciousness, anisocoria and midline shift > 5 mm or basal cistern effacement, or indications for decompressive craniectomy during hospitalization. The cutoff values for MIF/MMP9 were obtained from the receiver operating characteristic curve. RESULTS: Of the 130 patients with LHI enrolled, 90 patients (69.2%) had 3-month poor outcome, and MCE occurred in 55 patients (42.3%). Patients with serum MIF concentrations ≤ 7.82 ng/mL for predicting 3-month poor outcome [adjusted odds ratio (OR) 2.827, 95% confidence interval (CI) 1.144-6.990, p = 0.024] also distinguished death (adjusted OR 4.329, 95% CI 1.841-10.178, p = 0.001). Similarly, MMP9 concentrations ≤ 46.56 ng/mL for predicting 3-month poor outcome (adjusted OR 2.814, 95% CI 1.236-6.406, p = 0.014) also distinguished 3-month death (adjusted OR 3.845, 95% CI 1.534-9.637, p = 0.004). CONCLUSIONS: Lower serum MIF and MMP9 concentrations at an early stage were independently associated with 3-month poor outcomes and death in patients with LHI. These findings need further confirmation in larger sample studies.

Heart-Rate-to-Blood-Pressure Ratios Correlate with Malignant Brain Edema and One-Month Death in Large Hemispheric Infarction: A Cohort Study.

INTRODUCTION: Large hemispheric infarction (LHI) can lead to fatal complications such as malignant brain edema (MBE). We aimed to investigate the correlation between heart-rate-to-blood-pressure ratios and MBE or one-month death after LHI. METHODS: We prospectively included LHI patients from a registered cohort. Hourly heart-rate-to-blood-pressure ratios were recorded as a variation of the traditional shock index (SI), SIs and SId (systolic and diastolic pressures, respectively), and calculated for mean and variability (standard deviation) in 24 h and two 12 h epochs (1-12 h and 13-24 h) after onset of symptoms. MBE was defined as neurological deterioration symptoms with imaging evidence of brain swelling. We employed a generalized estimating equation to compare the trend in longitudinal collected SIs and SId between patients with and without MBE. We used multivariate logistic regression to investigate the correlation between SIs, SId and outcomes. RESULTS: Of the included 162 LHI patients, 28.4% (46/162) developed MBE and 25.3% (40/158) died within one month. SIs and SId increased over baseline in all patients, with a similar ascending profile during the first 12 h epoch and a more intensive increase in the MBE group during the second 12 h epoch (p < 0.05). During the overall 24 h, patients with greater SId variability had a significantly increased MBE risk after adjustment (OR 3.72, 95%CI 1.38-10.04). Additionally, during the second 12 h epoch (13-24 h after symptom onset), patients developing MBE had a significantly higher SId level (OR 1.18, 95%CI 1.00-1.39) and greater SId variability (OR 3.16, 95%CI 1.35-7.40). Higher SId and greater SId variability within 24 h independently correlated with one-month death (all p < 0.05). Within the second 12 h epoch, higher SIs, higher SId and greater SId variability independently correlated with one-month death (all p < 0.05). No significant correlation was observed in the first 12 h epoch. CONCLUSIONS: Higher and more fluctuated heart-rate-to-blood-pressure ratios independently correlated with MBE development and one-month death in LHI patients, especially during the second 12 h (13-24 h) epoch after onset.

Pathological Changes of Small Vessel Disease in Intracerebral Hemorrhage: a Systematic Review and Meta-analysis.

In intracerebral hemorrhage (ICH) with pathology-proven etiology, we performed a systematic review and meta-analysis to elucidate the association between cerebral amyloid angiopathy (CAA) and arteriolosclerosis, and directly compared MRI and pathological changes of markers of cerebral small vessel disease (CSVD). Studies enrolling primary ICH who had received an etiological diagnosis through biopsy or autopsy were searched using Ovid MEDLINE, PubMed, and Web of Science from inception to June 8, 2022. We extracted pathological changes of CSVD for each patient whenever available. Patients were grouped into CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis subgroups. Of 4155 studies identified, 28 studies with 456 ICH patients were included. The frequency of lobar ICH (p<0.001) and total microbleed number (p=0.015) differed among patients with CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis. Concerning pathology, severe CAA was associated with arteriolosclerosis (OR 6.067, 95% CI 1.107-33.238, p=0.038), although this association was not statistically significant after adjusting for age and sex. Additionally, the total microbleed number (median 15 vs. 0, p=0.006) was higher in ICH patients with CAA evidence than those without CAA. The pathology of CSVD imaging markers was mostly investigated in CAA-ICH. There was inconsistency concerning CAA severity surrounding microbleeds. Small diffusion-weighted imaging lesions could be matched to acute microinfarct histopathologically. Studies that directly correlated MRI and pathology of lacunes, enlarged perivascular spaces, and atrophy were scarce. Arteriolosclerosis might be associated with severe CAA. The pathological changes of CSVD markers by ICH etiology are needed to be investigated further.

Increased Serum EphrinA1 Is Associated with Parenchymal Hematoma after Ischemic Stroke.

INTRODUCTION: Previous preclinical studies reported that the level of serum EphrinA1 was associated with blood-brain barrier disruption; however, its role in predicting parenchymal hematoma (PH) after ischemic stroke is underexplored. We aimed to explore the association between the level of serum EphrinA1 and PH in patients with ischemic stroke. METHODS: Patients with ischemic stroke after onset from West China Hospital, Sichuan University, were prospectively enrolled between January 2017 and December 2019. The level of serum EphrinA1 at baseline was measured after admission. PH was diagnosed as hematoma within the infarct territory detected on the brain CT/MRI scans within 7 days after onset but not on the initial scan according to European Cooperative Acute Stroke Study (ECASS) III criteria. The association between the level of serum EphrinA1 and PH after ischemic stroke was assessed by multiple logistic regression analysis. RESULTS: A total of 667 patients were included in the final analysis. The mean age was 67.20 ± 14.31 years, and 57.87% (368/667) were males. Of the 667 patients, 65 (9.75%) patients had PH. The median of EphrinA1 on admission was 82.83 ng/mL (IQR, 70.11-93.75 ng/mL). Compared with patients without PH, those with PH had a higher level of serum EphrinA1 (p = 0.024). Patients were divided into 3 categories based on EphrinA1 tertiles (T1, <79.11 ng/mL, n = 223; T2, 79.11-93.75 ng/mL, n = 222; and T3, >93.75 ng/mL, n = 222). After adjusting for age, sex, atrial fibrillation, smoking, statins, antiplatelets, Trail of Org 10172 in Acute Stroke Treatment (TOAST) classification and National Institutes of Health Stroke Scale (NIHSS) score ≥15, patients in the second and third EphrinA1 tertiles showed a significant increase in PH compared with those in the lowest tertile (OR 2.44, 95% CI: 1.10-5.40, p = 0.028; OR 2.61, 95% CI: 1.19-5.74, p = 0.017, respectively). Additionally, adjusting for reperfusion therapy (thrombolysis and/or endovascular therapy), only patients in the highest group (tertile 3) had a significantly higher risk of PH compared to the lowest group (OR 2.30, 95% CI: 1.03-5.13, p = 0.042). CONCLUSION: Higher serum EphrinA1 is independently associated with a higher risk of PH after ischemic stroke. Future studies with larger sample sizes are needed to validate our findings and elucidate the potential role of EphrinA1 in PH.

Serum microRNA miR-491-5p/miR-206 Is Correlated with Poor Outcomes/Spontaneous Hemorrhagic Transformation after Ischemic Stroke: A Case Control Study.

BACKGROUND: It is unclear whether miR-491-5p, miR-206, miR-21-5p or miR-3123 are associated with functional outcomes and hemorrhagic transformation (HT) after acute ischemic stroke (AIS). In this study, we aimed to investigate the correlation between these four microRNAs and functional outcomes, as well as spontaneous HT after AIS; Methods: We included 215 AIS patients and retrospectively assayed for miR-21-5p, miR-206, miR-3123 and miR-491-5p levels in serum. Poor functional outcome was defined as a modified Rankin Scale score ≥ 3. Spontaneous HT referred to hemorrhage detected in follow-up brain imaging but not on admission, without reperfusion therapies. Logistic regression, generalized additive model and 2-piecewise regression model were used to explore the independent, non-linear correlation between miRNA expression levels and outcomes; Results: We included 215 AIS patients. Higher miR-491-5p level independently reduced the risk of poor functional outcomes at 1 year (OR 0.90, 95% CI 0.82-0.98, corrected p value = 0.044). Higher miR-206 level significantly increased the risk of spontaneous HT (OR 1.64, 95% CI 1.17-2.30, corrected p value = 0.016). There was a nonlinear correlation found between miR-491-5p level and 1 year outcome with an inflection point of 2.180, while an approximately linear correlation was observed with an inflection point of 2.037 between miR-206 level and spontaneous HT; Conclusions: Higher serum miR-491-5p level independently reduced risk of 1-year poor functional outcome of AIS patients. Higher serum miR-206 level independently increased the risk of spontaneous HT in AIS patients. These two miRNAs may be as the potential biomarkers for improving prognosis after AIS.

Stemness Related Genes Revealed by Network Analysis Associated With Tumor Immune Microenvironment and the Clinical Outcome in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the leading fatal malignancy with high morbidity and mortality worldwide. However, due to its complicated mechanism and lack of effective clinical therapeutics, early diagnosis and prognosis are still unsatisfactory. Most of the previous studies focused on cancer stem cells (CSCs), the relationship between cancer stemness (stem-like characteristics) and anti-tumor immunity has not been clearly revealed. Therefore, this study aimed to comprehensively analyze the role of cancer stemness and tumor microenvironment (TME) in LUAD using weighted gene co-expression network analysis (WGCNA). We constructed a gene co-expression network, identified key modules, and hub genes, and further explored the relationship between hub gene expression and cancer immunological characteristics through a variety of algorithms, including Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) and Gene Set Enrichment Analysis (GSEA). The hub genes were renamed stemness related genes (SRGs), whose functions were examined at the transcription and protein levels through survival analysis with additional samples, Oncomine database, immunohistochemistry, single cell RNA sequencing (scRNA-seq) and single-sample Gene Set Enrichment Analysis (ssGSEA). Subsequently, Tumor Immune Dysfunction and Exclusion (TIDE) and Connectivity Map (CMap) were implemented for treatment and prognosis analyses. As a result, 15 co-expressed SRGs (CCNA2, CCNB1, CDC20, CDCA5, CDCA8, FEN1, KIF2C, KPNA2, MCM6, NUSAP1, RACGAP1, RRM2, SPAG5, TOP2A, and TPX2) were identified. The overexpression of which was discovered to be associated with reduced immune infiltration in LUAD. It was discovered that there was a general negative correlation between cancer stemness and immunity. The expression of SRGs could probably affect our tumor occurrence, progression, the efficacy of chemotherapy and immunotherapy, and clinical outcomes. In conclusion, the 15 SRGs reported in our study may be used as potential candidate biomarkers for prognostic indicators and therapeutic targets after further validation.

HPV infection related immune infiltration gene associated therapeutic strategy and clinical outcome in HNSCC.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumor in human. Research has shown that HPV status HNSCC is a unique prognosis factor, which may due to its immune infiltration landscape. But the underlying mechanism is unclear. METHODS: In this study, we used a combination of several bioinformatics tools, including WCGNA, ssGSEA, CIBERSORT, TIDE,etc., to explore significant genes both related to HPV infection status and immune cell infiltration in HNSCC patients. RESULTS: Combined with several bioinformatics algorithms, eight hub genes were identified, including LTB, CD19, CD3D, SKAP1, KLRB1, CCL19, TBC1D10C and ARHGAP4. In HNSCC population, the hub genes had a stable co-expression, which was related to immune cell infiltration, especially CD8+ T cells, and the infiltrative immune cells were in a dysfunctional status. Samples with high hub genes expression presented with better response to immune check point block (ICB) therapy and sensitivity to bleomycin and methotrexate. CONCLUSIONS: The eight hub genes we found presented with a stable co-expression in immune cell infiltration of HPV + ve HNSCC population. The co-expression of hub genes related to an immune microenvironment featuring an increase in immune cells but high degree of immune dysfunction status. Patients with high hub gene expression had a better response to ICB treatment, bleomycin and methotrexate. The co-expression of hub genes may be related to immune infiltration status in patients. The concrete molecular mechanism of hub genes function demands further exploration.

Enhancement of all-trans retinoic acid-induced differentiation by pH-sensitive nanoparticles for solid tumor cells.

Cancer differentiation therapy is an attractive concept and has been clinically used to treat leukemia. However, it is limited to date for solid tumors. In this study, the pH-sensitive nanoparticles based on poly(amidoamine) (PAMAM) dendrimers are synthesized by coupling 3,4,5,6-tetrahydrophthalic anhydride with the first generation PAMAM. The modified dendrimers can self-assemble in aqueous solution to form nanoparticles with a diameter of 125-435 nm. The nanoparticles are relatively stable at physiological pH (pH 7.4) but dissociated in acidic environments (pH 5.0 or 6.0). The present studies show that the proliferation inhibition and albumin secretion of hepatoma carcinoma cells are enhanced with all-trans retinoic acid (ATRA) encapsulated in the nanoparticles. The enhancement of induced differentiation is due to the high internalization of ATRA in the cells by the nanoparticles. These experimental results demonstrate that pH-sensitive nanoparticles may be efficient for improving the differentiation therapy for solid tumor.