Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor-Initiating Cells.

Glioblastomas (GBM) are aggressive brain tumors with extensive intratumoral heterogeneity that contributes to treatment resistance. Spatial characterization of GBMs could provide insights into the role of the brain tumor microenvironment in regulating intratumoral heterogeneity. Here, we performed spatial transcriptomic and single-cell analyses of the mouse and human GBM microenvironment to dissect the impact of distinct anatomical regions of brains on GBM. In a syngeneic GBM mouse model, spatial transcriptomics revealed that numerous extracellular matrix (ECM) molecules, including biglycan, were elevated in areas infiltrated with brain tumor-initiating cells (BTIC). Single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing showed that ECM molecules were differentially expressed by GBM cells based on their differentiation and cellular programming phenotypes. Exogeneous biglycan or overexpression of biglycan resulted in a higher proliferation rate of BTICs, which was associated mechanistically with low-density lipoprotein receptor-related protein 6 (LRP6) binding and activation of the Wnt/ß-catenin pathway. Biglycan-overexpressing BTICs developed into larger tumors and displayed mesenchymal phenotypes when implanted intracranially in mice. This study points to the spatial heterogeneity of ECM molecules in GBM and suggests that the biglycan-LRP6 axis could be a therapeutic target to curb tumor growth. SIGNIFICANCE: Characterization of the spatial heterogeneity of glioblastoma identifies regulators of brain tumor-initiating cells and tumor growth that could serve as candidates for therapeutic interventions to improve the prognosis of patients.

The Fragility of Statistically Significant Results in Gynaecologic Surgery: A Systematic Review.

OBJECTIVE: To use the fragility index (FI) to evaluate the robustness of gynaecologic surgery trials that report statistically significant results. The FI defines the minimum number of patients who must have an alternative outcome to alter statistical significance. DATA SOURCES: We searched MEDLINE, Web of Science, Embase, and ClinicalTrials.gov from 2011 to 2021 to identify gynaecologic surgery randomized controlled trials (RCTs). STUDY SELECTION: A total of 4775 trials were screened for eligibility. All included studies evaluated benign gynaecologic surgery interventions or peri-operative medical interventions. Only 2-arm RCTs with statistically significant dichotomous primary outcomes were included. Ninety-three trials were ultimately included for analysis. DATA EXTRACTION AND SYNTHESIS: Data from the included studies, including sample size, loss to follow-up, and number of events, were recorded. The FI of each study was calculated using a predefined technique. The overall FI and FIs by subgroup (clinical subspecialty, country of origin, and statistical test used) are reported as medians alongside their interquartile ranges (IQRs). The Kruskal-Wallis test was applied to find possible statistically significant relationships between FI and the nominal subgroups. Among this cohort, the median FI was 3 (IQR 1-7). The FI was 0 in 13 trials (14%), and in 39 trials (42%), the number of patients lost to follow-up was greater than the FI. The median FI within clinical subspecialty groups (general gynaecology, anaesthesia, urogynaecology, and fertility) did not differ (P = 0.122). CONCLUSION: Statistically significant results of RCTs in gynaecologic surgery are fragile, suggesting that clinicians should interpret results with caution. This is particularly true when the number of patients lost to follow-up is greater than the FI. The FI serves as a quality metric that can be used to evaluate robustness of results when applying the outcomes of RCTs to clinical practice or guideline development.

COVID-19 basics and vaccine development with a Canadian perspective.

The ongoing coronavirus disease 2019 (COVID-19) pandemic is a rapidly evolving situation. New discoveries about COVID-19 and its causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continue to deepen the understanding of this novel disease. As there is currently no COVID-19 specific treatment, isolation is the most effective method to prevent transmission. Moreover, development of a safe and effective COVID-19 vaccine will be instrumental in reinstating pre-COVID-19 conditions. As of 31 July 2020, there are at least 139 vaccine candidates from around the globe in preclinical evaluation, with another 26 undergoing clinical evaluation. This paper aims to review the basics of COVID-19, including epidemiology, basic biology of SARS-CoV-2, and transmission. We also review COVID-19 vaccine development, including animal models, platforms under development, and vaccine development in Canada.