miR-100 and miR-125b Contribute to Enhanced 3D Growth and Invasiveness and can be Functionally Transferred to Silence Target Genes in Recipient Cells.

Extracellular communication via the transfer of vesicles and nanoparticles is now recognized to play an important role in tumor microenvironment interactions. Cancer cells upregulate and secrete abundant levels of miR-100 and miR-125b that can alter gene expression by both cell- and non-cell-autonomous mechanisms. We previously showed that these miRNAs activate Wnt signaling in colorectal cancer (CRC) through noncanonical pairing with 5 negative regulators of Wnt signaling. To identify additional targets of miR-100 and miR-125b , we used bioinformatic approaches comparing multiple CRC cell lines, including knockout lines lacking one or both of these miRNAs. From an initial list of 96 potential mRNA targets, we tested 15 targets with 8 showing significant downregulation in the presence of miR-100 and miR-125b . Among these, Cingulin (CGN) and Protein tyrosine phosphatase receptor type-R (PTPRR) are downregulated in multiple cancers, consistent with regulation by increased levels of miR-100 and miR-125b. We also show that increased cellular levels of miR-100 and miR-125b enhance 3D growth and invasiveness in CRC and glioblastoma cell lines. Lastly, we demonstrate that extracellular transfer of miR-100 and miR-125b can silence both reporter and endogenous mRNA targets in recipient cells and also increase the invasiveness of recipient spheroid colonies when grown under 3D conditions in type I collagen.

The impact of bystander relation and medical training on out-of-hospital cardiac arrest outcomes.

AIM: In this study, we investigate the impact of bystander relation and medical training on survival to hospital discharge in out-of-hospital cardiac arrest (OHCA) patients receiving bystander cardiopulmonary resuscitation (CPR). METHODS: A retrospective analysis was performed on non-traumatic OHCA patients receiving bystander CPR and Emergency Medical Service (EMS) attempted resuscitation from 2015 through 2017. Adjusted logistic regression was used to assess the association between related versus unrelated and layperson versus medically trained bystander CPR providers and survival to hospital discharge. RESULTS: A total of 4464 OHCA were eligible for inclusion, of which 2385 (53.4%) received CPR from a relative, 468 (10.5%) from a work colleague or friend and 1611 (36.1%) from a stranger. Layperson's provided CPR in 3703 (83.0%) OHCA and medically trained professionals in 761 (17.0%). After adjustment for arrest characteristics, there was no difference in survival to hospital discharge between related versus unrelated CPR (adjusted odds ratio [AOR] 0.92, 95% confidence interval [CI]: 0.68-1.23, p = 0.555). However, bystander CPR by a medically trained provider rather than a layperson, was associated with an increase in the odds of survival by 47% (AOR 1.47, 95% CI: 1.09-2.00, p = 0.012) in the overall population and 73% (AOR 1.73, 95% CI: 1.21-2.49; p = 0.003) in patients with an initial shockable arrest. Adjusting for public access defibrillation significantly attenuated the effect of medically trained bystander CPR in initial shockable arrests (AOR 1.42, 95% CI: 0.97-2.07; p = 0.073). CONCLUSION: This study supports ongoing efforts to crowdsource a larger number of first responders with medical training to OHCA patients to assist with the provision of CPR and early defibrillation.