Acute lung injury (ALI) or its more severe form, known as acute respiratory distress syndrome (ARDS), is characterized by an initial exudative phase, expression of proinflammatory mediators, activation of inflammatory leukocytes, and impairment of the lung endothelium and epithelium. Despite numerous, novel therapeutic strategies have been developed regarding the pathophysiology of ALI, current treatment is mainly supportive, as specific therapies have not been established in the past few decades. The MAP kinase-interacting kinases (MNK1 and MNK2) are serine threonine kinases which are activated by mitogen-activated protein kinases (MAPKs), regulate protein synthesis by phosphroylating eukaryotic translation initiation factor 4E (eIF4E). Although studies have shown that MAPKs pathway is involved in anti-inflammatory and preventing tissue injury processes, the role of MNKs in ALI has, until now, remained relatively unexplored. Here, we investigated whether partial inhibition of MAPKs pathway by targeting MNKs was effective in the prevention and treatment of ALI. C57BL6 mice were pretreated with MNK1 and MNK2 inhibitor (CGP57380, 30 mg/kg) for 30 min and then challenged with 5 mg/kg LPS for 6 h. The results showed that pretreatment with CGP57380 not only significantly attenuated LPS-induced lung wet/dry ratio, as well as protein content, total cells and neutrophils in bronchoalveolar lavage fluid (BALF), but also decreased the production of pro-inflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) and keratinocyte-derived chemoattractant (KC). In addition, CGP57380 was observed to significantly suppress LPS-stimulated phosphorylation of eIF4E and MAPKs in the mouse bone marrow-derived macrophages (BMDMs). The involvement of MNK2 in lung injury was further evident by MNK2 knockout mice. MNK2 deficiency resulted in the attenuated lung histopathological changes, as also reflected by reductions in neutrophil counts, and the less LPS-induced the production of IL-6, TNF-α and KC in mouse BALF. Taken together, these findings demonstrated for the first time that MNK inhibition could effectively reduce the LPS-induced ALI in mice, suggesting a novel and potential application for MNK-based therapy to treat this serious disease.

This study aimed to clarify the association between serum total cholesterol (TC) levels and overall cancer risk. Study-specific relative risks (RR) and 95% confidence intervals (CI) were pooled using a random-effects model, and dose-response relation was also evaluated. Twelve prospective studies were identified with a total of 1,926,275 participants and 13,1676 cases. High levels of serum TC showed an inverse association with overall cancer risk (RR for the highest versus the lowest category: 0.87, 95% CI: 0.83 ∼ 0.90; I2 = 52.5%). A linear dose-response relation between serum TC levels and overall cancer risk was found (p = .004 for Wald test; I2 = 49.6%), and the pooled RR was 0.92 (95% CI: 0.89 ∼ 0.94) for 3 mmol/L, 0.86 (95% CI: 0.81 ∼ 0.90) for 5 mmol/L, 0.80 (95% CI: 0.74 ∼ 0.87) for 7 mmol/L. Our dose-response meta-analysis of 12 prospective studies indicated that higher serum TC levels were significantly associated with reduced cancer risk.

In order to assess the effect of long-term versus short-term intravesical chemotherapy in preventing the recurrence of patients with non-muscle-invasive bladder cancer, we searched several databases with words as mesh terms and free text words to find all eligible randomized clinical trials (RCTs) for the comparison of the two strategies of instillation durations. “Observed-Expected events research (O-E)” and “Variance (V)” for calculating hazard ratio (HR) were used in Revman 5.2 software recommended by Cochrane Collabration for data analysis. Sensitivity and subgroup analysis were selected to minish heterogeneity. GRADEpro 3.6 profile recommended by Cochrane Collabration was employed for quality assessment of analyses. Finally, 13 eligible RCTs with 4216 patients were included in this review and 16 comparisons from 13 trials were involved for analysis. The pooled analysis revealed no significant difference between long-term and short-term duration [HR=0.99, 95% CI (0.89, 1.11), P=0.89]. Within the subgroup analysis, patients benefited from long-term instillations with a start regimen of one immediate instillation [HR=0.83, 95% CI (0.69, 1.00), P=0.05]. But patients were not suitable to receive long-term instillations with epirubicin (EPI) [HR=1.01, 95% CI (0.91, 1.13), P=0.78]. The progression rate was not reduced after long-term instillations [HR=0.96, 95% CI (0.66, 1.39), P=0.82]. From our results, patients should not receive introvesical chemotherapy more than half a year. In contrast, patients with one immediate instillation are preferred to have a long-term duration at least one year. Long-term instillations can not reduce the progression rate.

AIMTo assess the effects of the fixed combination of 0.005% latanoprost and 0.5% timolol (FCLT) vs their individual components for primary open angle glaucoma (POAG) and ocular hypertension (OHT).METHODSAfter searched PubMed, EMBASE, the Cochrane Library and SCI, all randomized controlled clinical trials (RCTs) and cross-over studies were included. The control groups were the mono therapy or the concomitant therapy of latanoprost and timolol. The outcomes were visual field defect, optic atrophy, mean intraocular pressure (IOP) and IOP fluctuation. The analysis was carried out in RevMan version 5.1 software.RESULTSThe post-intervention mean IOP of FCLT was significantly lower compared to timolol [mean difference (MD) -2.92, 95%CI -3.28 to -2.55, P<0.00001] and latanoprost (MD -1.11, 95%CI -1.51 to -0.72, P<0.00001). The post-intervention IOP fluctuation was also significantly lower compared to timolol (MD -0.88, 95%CI -1.23 to -0.53, P<0.00001) and latanoprost (MD -0.63, 95%CI -1.04 to -0.22, P=0.002). The mean IOP was higher in FCLT morning dose group than the one in unfixed combination of 0.005% latanoprost and 0.5% timolol (UFCLT) (MD 1.10, 95%CI 0.81 to 1.39, P<0.00001). Otherwise, there was no difference between FCLT evening dose group and UFCLT (MD 0.34, 95% CI -0.01 to 0.69, P=0.06). There was no statistical difference for the incidence of visual field defect and optic atrophy between FCLT and the monotherapy of components.CONCLUSIONA better IOP lowering effect has been demonstrated for FCLT compared to the mono therapy of components. The IOP lowering effect was worse for FCLT morning dose and almost same for FCLT evening dose compared to the UFCLT. We need more long-term high quality RCTs to demonstrate the outcomes of visual field defect and optic atrophy.