The dual PI3K/mTOR inhibitor dactolisib elicits anti-glioma activity in glioblastoma cell lines The dual PI3K/mTOR inhibitor dactolisib elicits anti-glioma activity in glioblastoma cell lines

Background. Decreased 25-hydroxyvitamin D [25(OH)D] has been reported to be related to increased risk of cerebrovascular disease. We aimed to investigate whether an association exists between 25(OH)D levels and cerebral small vessel disease (cSVD). Method. Patients with first-ever minor ischemic stroke or transient ischemic attack were recruited prospectively during Jan 2017 to Dec 2017. Serum 25(OH)D levels were measured at admission in all patients. Magnetic resonance imaging (MRI) was performed to determine the presence of cSVD, including silent lacunar infarcts (SLIs), white matter lesions (WMLs), cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVs). The severity of cSVD was evaluated by total MRI cSVD burden, an ordinal score from 0 to 4. The association between the baseline 25(OH)D level and cSVD was analyzed by multiple logistic regression models. Results. Of 234 patients included, the median 25(OH)D level was 39.2 nmol/L. The proportions of patients with 0 to 4 cSVD features were 8.5%, 29.1%, 42.3%, 16.2%, and 3.8%, respectively. After adjusting for potential confounders, multiple logistic regression analysis demonstrated that patients with 25(OH)D level in its first quartile, compared with those in its fourth quartile, were more likely to have severe WMLs [odds ratio (OR), 3.31; 95% confidence interval (CI) 1.74–9.67; P = 0.004], severe EPVs (OR, 2.35; 95% CI 1.11–6.02, P = 0.046] and increasing total MRI cSVD burden (OR, 3.00; 95% CI 1.36–6.53, P = 0.006). Conclusions. Lower levels of 25(OH)D is associated with greater total MRI cSVD burden in ischemic stroke patients.

It is becoming increasingly clear that N6-methyladenosine (m6A) plays a key role in post-transcriptional modification of eukaryotic RNAs in cancer. The regulatory mechanism of m6A modifications in prostate cancer is still not completely elucidated. Heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), an m6A reader, has been revealed to function as an oncogenic RNA-binding protein. However, its contribution to prostate cancer progression remains poorly understood. Here, we found that HNRNPA2B1 was highly overexpressed and correlated with a poor prognosis in prostate cancer. In vitro and in vivo functional experiments demonstrated that HNRNPA2B1 knockout impaired proliferation and metastasis of prostate cancer. Mechanistic studies indicated that HNRNPA2B1 interacted with primary miRNA-93 and promoted its processing by recruiting DiGeorge syndrome critical region gene 8 (DGCR8), a key subunit of the Microprocessor complex, in an METTL3-dependent mechanism, while HNRNPA2B1 knockout significantly restored miR-93-5p levels. HNRNPA2B1/miR-93-5p downregulated FERM domain-containing protein 6 (FRMD6), a cancer suppressor, and enhanced proliferation and metastasis in prostate cancer. In conclusion, our findings identified a novel oncogenic axis, HNRNPA2B1/miR-93-5p/FRMD6, that stimulates prostate cancer progression via an m6A-dependent manner.