Rationale: Platelets are believed to contribute to acute respiratory distress syndrome (ARDS) pathogenesis through inflammatory coagulation pathways. We recently reported that leucine-rich repeat-containing 16A (LRRC16A) modulates baseline platelet counts to mediate ARDS risk.Objectives: To examine the role of LRRC16A in ARDS survival and its mediating effect through platelets.Methods: A total of 414 cases with ARDS from intensive care units (ICUs) were recruited who had exome-wide genotyping data, detailed platelet counts, and follow-up data during ICU hospitalization. Association of LRRC16A single-nucleotide polymorphisms (SNPs) and ARDS prognosis, and the mediating effect of SNPs through platelet counts were analyzed. LRRC16A mRNA expression levels for 39 cases with ARDS were also evaluated. Patients with ΔPLT were associated with favorable ARDS outcomes. Mediation analysis indicated that the SNP prognostic effect was mediated through ΔPLT within 28 days (28-day survival: HR Indirect , 0.937; 95% CI, 0.91820.957; P = 0.0009, 11.53% effects mediated; 60-day survival: HR Indirect , 0.919; 95% CI, 0.90120.936; P = 0.0001, 14.35% effects mediated). Functional exploration suggested that this SNP reduced LRRC16A expression at ICU admission, which was associated with a lesser ΔPLT during ICU hospitalization.Conclusions: LRRC16A appears to mediate ΔPLT after ICU admission to affect the prognosis in patients with ARDS.

Kaposi’s sarcoma (KS) is the most common AIDS-associated malignancy etiologically caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). KS is a highly disseminated and vascularized tumor comprised of poorly differentiated spindle-shaped endothelial cells. KSHV encodes 12 pre-microRNAs (pre-miRNAs) that yield 25 mature miRNAs, but their roles in KSHV-induced tumor dissemination and angiogenesis remain largely unknown. KSHV-encoded miR-K12-6 (miR-K6) can produce two mature miRNAs, miR-K6-3p and miR-K6-5p. Recently, we have shown that miR-K6-3p promoted cell migration and angiogenesis by directly targeting SH3 domain binding glutamate-rich protein (SH3BGR) (PLoS Pathog. 2016;12(4):e1005605). Here, by using mass spectrometry, bioinformatics analysis and luciferase reporter assay, we showed that miR-K6-5p directly targeted the coding sequence (CDS) of CD82 molecule (CD82), a metastasis suppressor. Ectopic expression of miR-K6-5p specifically inhibited the expression of endogenous CD82 and strongly promoted endothelial cells invasion in vitro and angiogenesis in vivo. Overexpression of CD82 significantly inhibited cell invasion and angiogenesis induced by miR-K6-5p. Mechanistically, CD82 directly interacted with c-Met to inhibit its activation. MiR-K6-5p directly repressed CD82, relieving its inhibition on c-Met activation and inducing cell invasion and angiogenesis. Deletion of miR-K6 from KSHV genome abrogated KSHV suppression of CD82 resulting in compromised KSHV activation of c-Met pathway, and KSHV-induced invasion and angiogenesis. In conclusion, these results show that by inhibiting CD82, KSHV miR-K6-5p promotes cell invasion and angiogenesis by activating the c-Met pathway. Our findings illustrate that KSHV miRNAs may play an essential role in the dissemination and angiogenesis of KSHV-induced malignancies.

The objective of the study was to assess the associations of dyslipidaemia, combined oral contraceptive (COC) use and their interaction on the risk of hypertension in Chinese women. In a case-control study, we evaluated 665 hypertensive women and 665 normotensive women matched on region and age in China. Hypertensive women had a higher prevalence of dyslipidaemia and higher levels of total cholesterol, triglyceride, low-density lipoprotein-cholesterol and lipoprotein a than normotensive ones (Po0.05). The risk of hypertension gradually increased with the increasing cumulative time of COC use in women (P ¼ 0.0043), especially significantly increased among those with cumulative time of COC use15-20 and X20 years (adjusted odds ratio (OR) ¼ 1.46, 95% confidence interval (CI): 1.00-2.15; OR ¼ 1.49, 95% CI: 1.06-2.11), but gradually decreased from stopping use of COC (Po0.0001). The multiplicative interaction between dyslipidaemia and accumulative time of COC use X15 years, dyslipidaemia and family history of hypertension, or family history of hypertension and accumulative time of COC use X15 years was confirmed and the interaction analyses showed that they can significantly increased the risk of hypertension (adjusted OR ¼ 2.82, 95% CI: 1.59-3.27; OR ¼ 4.33, 95% CI: 3.10-6.06; OR ¼ 4.56, 95% CI: 3.07-6.77). It is concluded that dyslipidaemia, accumulative time of COC use X15 years and their interaction increased the risk of hypertension.

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