Bone marrow fibroblasts overexpress miR-27b and miR-214 in step with multiple myeloma progression, dependent on tumour cell-derived exosomes.

Aberrant microRNA (miR) expression has an important role in tumour progression, but its involvement in bone marrow fibroblasts of multiple myeloma patients remains undefined. We demonstrate that a specific miR profile in bone marrow fibroblasts parallels the transition from monoclonal gammopathy of undetermined significance (MGUS) to myeloma. Overexpression of miR-27b-3p and miR-214-3p triggers proliferation and apoptosis resistance in myeloma fibroblasts via the FBXW7 and PTEN/AKT/GSK3 pathways, respectively. Transient transfection of miR-27b-3p and miR-214-3p inhibitors demonstrates a cooperation between these two miRNAs in the expression of the anti-apoptotic factor MCL1, suggesting that miR-27b-3p and miR-214-3p negatively regulate myeloma fibroblast apoptosis. Furthermore, myeloma cells modulate miR-27b-3p and miR-214-3p expression in fibroblasts through the release of exosomes. Indeed, tumour cell-derived exosomes induce an overexpression of both miRNAs in MGUS fibroblasts not through a simple transfer mechanism but by de novo synthesis triggered by the transfer of exosomal WWC2 protein that regulates the Hippo pathway. Increased levels of miR-27b-3p and miR-214-3p in MGUS fibroblasts co-cultured with myeloma cell-derived exosomes enhance the expression of fibroblast activation markers αSMA and FAP. These data show that the MGUS-to-myeloma transition entails an aberrant miRNA profile in marrow fibroblasts and highlight a key role of myeloma cells in modifying the bone marrow microenvironment by reprogramming the marrow fibroblasts' behaviour. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Strong release of viruses in fracture flow in response to a perturbation in ionic strength: Filtration/retention tests and modeling.

Effluents derived from a municipal wastewater treatment plant were used for virus filtration/retention experiments by using a horizontal laboratory filter. Filtration tests were performed to examine how soil geochemical heterogeneity and fracture patterns affected the transport of viruses in groundwater in order to model the influence of reductive perturbations in ionic strength (IS) during wastewater filtration. Although perturbations of IS and velocity are known to result in resuspension of colloids, we found that the effect of soil geochemical heterogeneity can produce strong and instantaneous virus releases in fractured aquifers, likely an internal additional source of viruses. Sixteen limestone slabs were packed in a PVC box filter at the Bari Laboratory (South Italy) to replicate wastewater filtration throughout a fractured medium similar to the Bari carbonate aquifer. Terra rossa, which is an aggregate of sand, silt and clay, was unevenly spread on the surface of each limestone slab within the filter. Since the mineralogical composition of terra rossa includes iron (hematite, magnetite, and goethite) oxides, the soil exhibited localized unfavorable colloid/collector interactions for attachment. In contrast, soil-free parts of the fracture surfaces maintained favorable colloid/collector interactions. We found in our experiments that the lowering of IS due to the reduction of water salt content, which could occur during runoff injections after rainfall, might be sufficient to cause strong detachment of viruses from fracture surfaces, allowing further migration into the groundwater. The model in this work can predict the count and pathways of released viruses in groundwater fractures under soil geochemical heterogeneity and originated by reductions of IS, by using analytical solutions.