No abstract

No abstract

Background Medulloblastoma (MB) is the most common malignant brain tumour in children but also rarely occur in adults. Sonic Hedgehog (SHH) driven MB is associated with aberrant activation of the SHH signalling pathway. SMO inhibitors, sonidegib and vismodegib, have been used as selective antagonist of the hedgehog pathway that acts by binding to SMO, and inhibits activation of the downstream hedgehog target genes. Several clinical trials investigating SMO inhibitors for the treatment of relapsed MB patients have been published. Methods We conducted a systemic review and meta-analysis among these Phase I and II clinical trials. The pooled effect of SMO inhibitors in relapsed MB were analysed using Reviewer Manager 5.3 software. The clinical efficacy of SMO inhibitors on SHH subtype of MB were measured by the objective response rate. The risk difference was obtained by comparing the ORR between SHH and non-SHH subtypes of MB. Results The five studies all had clear criteria for patient recruitment, adequate follow-up time for endpoint assessment and clear definition of tumour responses. MB patients had good compliance in the trials. The pooled objective response rate (ORR) of SMO inhibitor was 37% and 0 against SHH-driven and other MBs. The pooled ORR of sonidegib was 55% among MB SHH and 0 among MB non-SHH subgroup. Vismodegib also had no efficacy on non-SHH subtype of MB. The sonidegib against SHH-driven MB produced the ORR 1.87-fold higher than that of vismodegib (95%CI 1.23, 6.69). Among paediatric patients, the efficacy of sonidegib was 3.67-fold higher than vismodegib ( p < 0.05). A total of 320 cases received SMO inhibitor therapy and 36 cases reported grade 3/4 dose-limiting toxicity (DLT). The rate of grade 3/4 DLT was similar between patients receiving vismodegib and sonidegib (11.6% vs. 11.2%). Conclusion Sonidegib and vismodegib were well tolerated and demonstrated anti-tumour activity in SHH-driven paediatric and adult MB by effectively inhibiting Hh signalling. These results support the ongoing clinical trials using SMO inhibitors in combination with conventional chemotherapies for the treatment of relapsed MB SHH .

No abstract

Mitochondrial dysfunction is considered a crucial therapeutic target for early brain injury following subarachnoid hemorrhage (SAH). Emerging evidence indicates that docosahexaenoic acid (DHA), an essential omega-3 fatty acid, protects mitochondria in various chronic diseases. This study aimed to investigate the neuroprotective effects of DHA on mitochondrial dynamic dysfunction after EBI using in vivo and in vitro approaches. For in vivo experiments, the rat endovascular perforation SAH model was performed, whereby DHA was administered intravenously 1 h after induction of SAH. Primary cultured neurons treated with oxyhemoglobin (OxyHb) for 24 h were used to mimic SAH in vitro. Our results demonstrated that DHA improved neurological deficits and reduced brain edema in rats with SAH, and attenuated OxyHb-induced neuronal death in primary cultured cells. DHA reduced the amount of reactive oxygen species-positive cells and improved cell viability when compared to the SAH + vehicle group in vitro. DHA attenuated malondialdehyde levels and superoxide dismutase stress, increased Bcl2 and Bcl-xl, and decreased Bax and cleaved caspase-3 in vivo. Additionally, DHA ameliorated mitochondrial dysfunction, upregulated the mitochondrial fusion-related protein Optic Atrophy 1, and downregulated the mitochondrial fission-related protein Dynamin-Related-Protein 1 (Drp1) and Serine 616 phosphorylated Drp1 after SAH both in vitro and in vivo. Taken together, our current study demonstrates that DHA might prevent oxidative stress-based apoptosis after SAH. The characterization of the underlying molecular mechanisms may further improve mitochondrial dynamics-related signaling pathways.

No abstract

Purpose. The immune checkpoint inhibitor is approved for breast cancer treatment, but the low expression of PD-L1 limits the immunotherapy. CD155 is another immune checkpoint protein in cancers and interacts with ligands to regulate immune microenvironment. This study is aimed at investigating the expression of CD155 and the association with prognosis and pathological features of breast cancer. Methods. 126 patients were recruited this cohort study consecutively, and CD155 expression on tumor cells was detected by immunohistochemistry. The Kaplan-Meier survival curve and Cox hazard regression model were used to estimate the association. Results. 38.1% patients had an overexpression of CD155, and the proportion of tumor cells with CD155 overexpression was 17%, 39%, 37%, and 62% among Luminal A, Luminal B, HER2-positive, and triple negative breast cancer cases, respectively (p<0.05). Patients with CD155 overexpression had the Ki-67 index significantly higher than that of patients with low expression (42% vs. 26%). Though the number of tumor-infiltrating lymphocytes was higher among patients with CD155 overexpression (144/HPF vs. 95/HPF), the number of PD-1+ lymphocytes was significantly higher (52/HPF vs. 25/HPF, p<0.05). Patients of CD155 overexpression had the disease-free and overall survival decreased by 13 months and 9 months, respectively (p<0.05). CD155 overexpression was associated with an increased relapse (HR=13.93, 95% CI 2.82, 68.91) and death risk for breast cancer patients (HR=5.47,1.42,20.99). Conclusions. Overexpression of CD155 was correlated with more proliferative cancer cells and a dysfunctional immune microenvironment. CD155 overexpression introduced a worse relapse-free and overall survival and might be a potential immunotherapy target for breast cancer.

The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) was discovered to possess antitumor activity, revealing its potential value in future chemotherapy. However, its poor water solubility makes it difficult for intravenous administration. In this study, the monomethyl poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) copolymer was applied to prepare nanoassemblies of fisetin by a self-assembly procedure. The prepared fisetin micelles gained a mean particle size of 22 ± 3 nm, polydisperse index of 0.163 ± 0.032, drug loading of 9.88 ± 0.14%, and encapsulation efficiency of 98.53 ± 0.02%. Compared with free fisetin, fisetin micelles demonstrated a sustained and prolonged in vitro release behavior, as well as enhanced cytotoxicity, cellular uptake, and fisetin-induced apoptosis in CT26 cells. As for in vivo studies, fisetin micelles were more competent for suppressing tumor growth and prolonging survival time than free fisetin in the subcutaneous CT26 tumor model. Furthermore, histological analysis, terminal deoxynucleotidyl transferase-mediated nick-end labeling assay, immunohistochemical detection of Ki-67, and microvessel density detection were conducted, demonstrating that fisetin micelles gained increased tumor apoptosis induction, proliferation suppression, and antiangiogenesis activities. In conclusion, we have successfully produced a MPEG-PCL-based nanocarrier encapsulating fisetin with enhanced antitumor activity.