Simultaneous ischemic regions targeting and BBB crossing strategy to harness extracellular vesicles for therapeutic delivery in ischemic stroke.

Extracellular vesicles (EVs) derived from adipose-derived stem cells (ADSC-EVs) hold great promise for ischemic stroke treatment, but their therapeutic efficacy is greatly limited due to insufficient targeting ability. Previous reports focused on single ischemic targeting or blood-brain barrier (BBB) penetration, precise delivery to the brain parenchyma has not been fully considered. This study leveraged the targeting ability of RGD peptide and the cell penetrating ability of Angiopep-2 peptide to deliver ADSC-EVs precisely to the impaired brain parenchyma. We found that dual-modified EVs (RA-EVs) significantly enhanced the transcellular permeability across BBB in vitro, and not only targeted ischemic blood vessels but also achieved rapid accumulation in the ischemic lesion area after intravenous administration in vivo. RA-EVs further decreased the infarct volume, apoptosis, BBB disruption, and neurobehavioral deficits. RNA sequencing revealed the molecular regulation mechanism after administration. These findings demonstrate that dual-modification optimizes brain parenchymal targeting and highlights the significance of recruitment and penetration as a previously unidentified strategy for harnessing EVs for therapeutic delivery in ischemic stroke.

Post-operative neutrophil-to-lymphocyte ratio and outcome after thrombectomy in acute ischemic stroke.

Background: Neutrophil to lymphocyte ratio (NLR) is a novel inflammatory marker to predict adverse cardiovascular events. However, there is a lack of data on hemorrhagic transformation (HT) and neurological outcome after mechanical thrombectomy in acute ischemic stroke (AIS). We investigated whether NLR before and after thrombectomy for patients with AIS was associated with HT and neurological outcomes. Methods: We performed a retrospective analysis of consecutive patients with anterior circulation AIS who underwent thrombectomy. HT was evaluated by CT within 24 h after thrombectomy. Clinical data had been collected retrospectively; laboratory data were extracted from our electronic hospital information system. NLR was obtained at admission (NLR1) and immediately after thrombectomy (NLR2). The main outcomes were post-interventional intracranial hemorrhage and unfavorable functional status (modified Rankin scale scores of 3-6) 3 months post-stroke. Results: A total of 258 patients with AIS, according to the NIHSS (median 14), were included. NLR2 was higher in patients who developed HT after thrombectomy and unfavorable neurological outcomes 3 months post-stroke (p < 0.001) than in those without HT or favorable outcomes, even after correction for co-factors [Odds Ratio (OR) 1.35 for HT, 95% confidence interval (CI)1.16-1.57, p < 0.001, and 1.85 for unfavorable outcome, 95%CI 1.57-2.17, p < 0.001]. The optimal cutoff value for the NLR2 as an indicator for auxiliary diagnosis of HT and the unfavorable outcome was 8.4 and 8.8, respectively. Conclusion: NLR immediately after thrombectomy is a readily available biomarker of HT and neurological outcomes in patients with AIS.

The proportion of 3 classes of lateral throat form.

The aim of this study was to investigate the proportion of 3 Neil's classifications of lateral throat forms and the difference in the length of the lateral throat form between the dentures and the patient's actual anatomy. The classification of lateral throat form was determined by the patient's functional movements, and an implant depth gauge was used to measure the length of the lateral throat form in the patient's mouth and compare it to that of the dentures. One hundred mandibular edentulous patients were measured. The proportion of Neil's Class I lateral throat form was 70%, the proportion of Class II was 25%, and the proportion of Class III was 5%. The mean difference between the actual lateral throat forms and the dentures was 6.7 +/- 2.9 mm at the anterior point of measurement (from the anterior part of the retromolar pad to the mouth floor) and 10.0 +/- 3.7 mm at the posterior point (from the middle of the retromolar pad to the mouth floor). The difference in length between the ridge height of the mouth and the denture was statistically significant (P < .001).

[Correlation between the expression of angiopoietins and their receptor and angiogenesis in gastric cancers].

OBJECTIVE: To explore the effects of angiopoietins (Ang-1 and Ang-2) and Tie-2 expression on microvessel density (MVD) in gastric cancers. METHODS: By using semiquantitative RT-PCR, immunohistochemistry and image analysis system, the expression of Ang-1, Ang-2, Tie-2 mRNA and their proteins were detected in 68 primary gastric cancers and their adjacent normal tissues. Microvessel density (MVD) was figured out based on CD34 immunohistochemical staining. RESULTS: The expression of all Ang-1, Ang -2, Tie-2 mRNA and their proteins was detected in gastric cancers and their paired adjacent gastric mucosa tissues. A negative correlation between Ang-1 protein, Tie-2 mRNA and MVD in gastric cancers was observed (r = -0.440, r = -0.267; P < 0.05), while the relation between Ang-2 mRNA and its protein, Ang-2/Ang-1 protein ratio with MVD were positive (r = 0.319, r = 0.729, r = 0.739; P < 0.05). It was found that MVD in groups with Ang-2 mRNA T/N ratio over 1.2 (the ratio of Ang-2 mRNA in gastric cancers and its adjacent normal mucosa) was higher than that in those with a ratio under 1.2, revealed by analysing the effects of Ang-1 and Ang-2 mRNA T/N ratio on MVD in gastric cancers. CONCLUSION: Ang-1 activates Tie-2 receptor, whereas Ang-2 antagonizes Ang-1 in the angiogenesis, and the Ang-2/Ang-1 ratio determines angiogenesis and tumor growth in gastric cancers. When the expression of Ang-2 is high and Ang-1 is low, the angiogenesis in gastric cancers is promoted, otherwise oppositely. The role of Ang-2 is dominant in the effect of Angs and their receptor on angiogenesis in gastric cancers.

[Dual effect of angiopoietin-2 on angiogenesis in gastric cancer].

OBJECTIVE: To explore the effect of Ang-2 on angiogenesis in gastric cancer. METHODS: The expression of Ang-2 mRNA was analyzed by RT-PCR and the expression of VEGF and CD34 was detected by immunohistochemistry in 36 cases of gastric cancer tissues and their paired adjacent gastric mucosa. RESULTS: The expression of Ang-2 mRNA was found both in gastric cancer and their paired adjacent gastric mucosa; the correlationship between the general expression levels of Ang-2 mRNA and microvessel density (MVD) in gastric cancer tissues was not found. However, in 27 cases whose Ang-2 mRNA expression levels in cancer tissues were lower than those in adjacent gastric mucosa. A significant positive correlation between the expression level of Ang-2 mRNA and MVD in the tumor tissues was found (r = 0.411, P < 0.05). In these 27 cases, the MVD in the gastric cancer tissues with positive VEGF expression (45.45 +/- 10.30) was higher than that with negative VEGF expression (30.15 +/- 8.69, P < 0.05), whereas in the other 9 cases whose expression levels of Ang-2 mRNA in cancer tissues were higher than those in adjacent gastric mucosa, a significant negative correlation between expression level of Ang-2 mRNA and MVD in the tumor tissues (r = -0.758, P < 0.05), but without correlation between the MVD and VEGF. CONCLUSION: Under the conditions that the expression of Ang-2 mRNA in cancer tissues was lower than that in adjacent gastric mucosa, VEGF could promote the sprouting of new vessels along with Ang-2 upregulation. But under the conditions that the expression of Ang-2 mRNA in cancer tissues was higher than that in adjacent gastric mucosa, Ang-2 inhibited angiogenesis. Angiopoietin-2 may play a dual effect on angiogenesis in gastric cancer.