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IntroductionModeling the blood-brain barrier has long been a challenge for pharmacological studies. Up to the present, numerous attempts have been devoted to recapitulating the endothelial barrier in vitro to assess drug delivery vehicles’ efficiency for brain disorders. In the current work, we presented a new approach for analyzing the morphometric parameters of the cells of an insert co-culture blood-brain barrier model using rat brain astrocytes, rat brain microvascular endothelial cells, and rat brain pericytes. This analytical approach could aid in getting further information on drug trafficking through the blood-brain barrier and its impact on the brain indirectly.MethodsIn the current work, we cultured rat brain astrocytes, rat brain microvascular endothelial cells, and rat brain pericytes and then used an insert well to culture the cells in contact with each other to model the blood-brain barrier. Then, the morphometric parameters of the porous membrane of the insert well, as well as each cell type were imaged by digital holographic microscopy before and after cell seeding. At last, we performed folate conjugation on the surface of the EVs we have previously tested for glioma therapy in our previous work called VEGF-A siDOX-EVs and checked how the trafficking of EVs improves after folate conjugation as a clathrin-mediated delivery setup. the trafficking and passage of EVs were assessed by flow cytometry and morphometric analysis of the digital holographic microscopy holograms.ResultsOur results indicated that EVs successfully entered through the proposed endothelial barrier assessed by flow cytometry analysis and furthermore, folate conjugation significantly improved EV passage through the blood-brain barrier. Moreover, our results indicated that the VEGF-A siDOX-EVs insert cytotoxic impact on the cells of the bottom of the culture plate.Conclusionfolate-conjugation on the surface of EVs improves their trafficking through the blood-brain barrier and by using digital holographic microscopy analysis, we could directly assess the morphometric changes of the blood-brain barrier cells for pharmacological purposes as an easy, label-free, and real-time analysis.

Introduction Glial brain tumours are highly mortal and are noted as major neurosurgical challenges due to frequent recurrence or progression. Despite standard-of-care treatment for gliomas, the prognosis of patients with higher-grade glial tumours is still poor, and hence empowering antitumour immunity against glioma is a potential future oncological prospect. This review is designed to improve our understanding of the efficacy of cell-based immunotherapies for glioma.Methods and analysis This systematic review will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search of main electronic databases: PubMed/MEDLINE, Scopus, ISI Web of Science EMBASE and ProQuest will be done on original articles, followed by a manual review of review articles. Only records in English and only clinical trials will be encountered for full-text review. All the appropriate studies that encountered the inclusion criteria will be screened, selected and then will undergo data extraction step by two independent authors. For meta-analyses, data heterogeneity for each parameter will be first evaluated by Cochran’s Q and I2 statistics. In case of possible heterogeneity, a random-effects meta-analysis will be performed and for homogenous data, fixed-effects models will be selected for reporting the results of the proportional meta-analysis. Bias risk will be assessed through Begg’s and Egger’s tests and will also be visualised by Funnel plots.Ethics and dissemination As this study will be a systematic review without human participants’ involvement, no ethical registration is required and meta-analysis will be presented at a peer-reviewed journal.PROSPERO registration number CRD42022373297

Abstract Background Spalt-like transcription factor 4 (SALL4) and aldehyde dehydrogenase1 family member A1 (ALDH1A1) expressing cells have been characterized as possessing stem cell-like properties known as cancer stem cell marker in serous ovarian carcinoma (SOC). Methods The association between SALL4 and ALDH1A1 was observed based on literature review and bioinformatics tools. Therefore, this study aimed to investigate the association between the co-expression of SALL4/ALDH1A1 proteins and clinicopathological parameters and their prognostic value in SOC patients using immunohistochemical staining on tissue microarrays (TMAs). Furthermore, benign tumors and normal tissue samples were compared with the expression of the tumor tissue samples. Results Increased co-expression of SALL4/ALDH1A1 was found to be significantly associated with the advanced FIGO stage (P = 0.047), and distant metastasis (P = 0.028). The results of Kaplan–Meier survival analysis indicated significant differences between disease- specific survival (DSS; P = 0.034) or progression-free survival (PFS; P = 0.018) and the patients with high and low co-expression of SALL4/ALDH1A1, respectively. Furthermore, high level co-expression of SALL4/ALDH1A1 was a significant predictor of worse DSS and PFS in the univariate analysis. The data also indicated that the co-expression of SALL4/ALDH1A1 was an independent prognostic factor affecting PFS. Moreover, the co-expression of SALL4/ALDH1A1 added prognostic values of DSS in patients with SOC who had grade III versus grade I in multivariate analysis. Conclusions Our data demonstrated that high co-expression of SALL4/ALDH1A1 was found to be significantly associated with tumor aggressiveness and worse DSS or PFS in SOC patients. Therefore, co-expression of SALL4/ALDH1A1 may serve as a potential prognostic biomarker of cancer progression in these cases.

Glioblastoma (grade IV glioma) is the most aggressive histopathological subtype of glial tumors with inordinate microvascular proliferation as one of its key pathological features. Extensive angiogenesis in the tumor microenvironment supplies oxygen and nutrients to tumoral cells; retains their survival under hypoxic conditions; and induces an immunosuppressive microenvironment. Anti-angiogenesis therapy for high-grade gliomas has long been studied as an adjuvant immunotherapy strategy to overcome tumor growth. In the current review, we discussed the underlying molecular mechanisms contributing to glioblastoma aberrant angiogenesis. Further, we discussed clinical applications of monoclonal antibodies, tyrosine kinase inhibitors, and aptamers as three major subgroups of anti-angiogenic immunotherapeutics and their limitations. Moreover, we reviewed clinical and preclinical applications of small interfering RNAs (siRNAs) as the next-generation anti-angiogenic therapeutics and summarized their potential advantages and limitations. siRNAs may serve as next-generation anti-angiogenic therapeutics for glioma. Additionally, application of nanoparticles as a delivery vehicle could increase their selectivity and lower their off-target effects.

Brain gliomas are major neurosurgical challenges due to high mortality and morbidity. Hence, development of novel biomarkers is of great value to plan appropriate treatment strategy. Evaluation of the molecular content of extracellular vesicles (EVs) as novel non-invasive biomarker repertoires can provide a real-time portrait of disease status. This study aims to provide a systematic, comprehensive and critical report of the diagnostic and prognostic significance of EV biomarkers (proteins, DNAs and RNAs) for brain gliomas, discuss their biogenesis and passage through the blood brain barrier, and also highlight the high throughput methods used for EV biomarker discovery; as well as discussing potential limitations of EV isolation and characterization methods as glioma diagnostic, prognostic or treatment response biomarkers. Moreover, we critically appraise the bias risk in the previous studies, discuss the limitations EV biomarker discovery faces to enter neurosurgical practice in the future, and highlight the need for more optimized protocols for EV isolation and biomarker discovery in high throughput studies. The current systematic review was conducted upon PRISMA guidelines [10].