The causal relationship between sleep traits and the risk of schizophrenia: a two-sample bidirectional Mendelian randomization study.

BACKGROUND: Observational studies suggest that sleep disturbances are commonly associated with schizophrenia. However, it is uncertain whether this relationship is causal. To investigate the bidirectional causal relation between sleep traits and schizophrenia, we performed a two-sample bidirectional Mendelian randomization (MR) study with the fixed effects inverse-variance weighted (IVW) method. METHODS: As genetic variants for sleep traits, we selected variants from each meta-analysis of genome-wide association studies (GWASs) conducted using data from the UK Biobank (UKB). RESULTS: We found that morning diurnal preference was associated with a lower risk of schizophrenia, while long sleep duration and daytime napping were associated with a higher risk of schizophrenia. Multivariable MR analysis also showed that sleep duration was associated with a higher risk of schizophrenia after adjusting for other sleep traits. Furthermore, genetically predicted schizophrenia was negatively associated with morning diurnal preference and short sleep duration and was positively associated with daytime napping and long sleep duration. CONCLUSIONS: Therefore, sleep traits were identified as a potential treatment target for patients with schizophrenia.

A synthetic dsRNA, as a TLR3 pathwaysynergist, combined with sorafenib suppresses HCC in vitro and in vivo.

BACKGROUND: Recent studies have demonstrated that synthetic dsRNAs may produce therapeutic effects in a target-independent manner through stimulation of the toll-like receptor-3 (TLR3)/interferon pathway; as a result, angiogenesis and proliferation of tumor cells are inhibited. Thus, this pathway may become a potential target of dsRNA in tumor suppression. In this study, we evaluated the role of synthetic dsRNA as a TLR3 synergist and by combining with sorafenib in anti-hepatocellular carcinoma (HCC) in vitro and in vivo. METHODS: Four dsRNAs were designed and synthesized. One of them that was capable of activating TLR3 most effectively in human HCC cell line (HepG2.2.15) was selected as a TLR3 synergist (called BM-06). Subsequently, the expression of proteins relating to TLR3 signaling pathway, such as NF-κB, caspase 8 survivin, bcl-2 and PCNA affected by BM-06, sorafenib alone or in combination, was compared. The migration, proliferation and apoptosis of HepG2.2.15 cells were evaluated in presence of BM-06, sorafenib alone or in combination of both. The similar treatments were also applied in an SD rat primary HCC model. RESULTS: qRT-PCR data showed that the expression of TLR3 and NF-κB in HepG2.2.15 cells was enhanced. BM-06 was selected as a TLR3 synergist capable of activating the TLR3/interferon pathway most effective among 4 synthetic dsRNAs. The migration and proliferation were significantly inhibited in treated HepG2.2.15 cells with BM-06 or Sorafenib alone as compared with PBS-sham control (P<0.01). However, the role of combination BM-06 with Sorafenib was the most prominent. Tumor cell apoptotic rate was increased by BM-06 or combination when compared to PBS or poly(I:C) (P<0.05). Similarly, in orthotopic HCC SD rats, the effect of the combination was superior to either agent alone on the inhibition of tumor growth and induction of HCC cell apoptosis (P<0.05). CONCLUSIONS: dsRNA alone was capable of inhibiting the proliferation of HepG2.2.15 cells and tumor growth of orthotopic HCC SD rats, but the effect of combination of dsRNA with sorafenib was more prominent. These findings implicate the potential role of combined use of a dsRNA, a TLR3 synergist, and sorafenib in inhibition of HCC.