Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Prognosis is poor, and therapeutic options are limited. MicroRNAs (miRNAs) have emerged as potential therapeutic molecules against cancer. Here, we investigated the therapeutic efficacy of miR-199a-3p, an miRNA highly expressed in normal liver and downregulated in virtually all HCCs. The therapeutic value of miR-199a-3p mimic molecules was assayed in the TG221 mouse, a transgenic model highly predisposed to the development of liver cancer. Administration of miR-199a-3p mimics in the TG221 transgenic mouse showing liver cancer led to a significant reduction of number and size of tumor nodules compared to control animals. In vivo delivery confirmed protein downregulation of the miR-199a-3p direct targets, mechanistic target of rapamycin (MTOR) and p21 activated kinase 4 (PAK4), ultimately leading to the repression of FOXM1. Remarkably, the anti-tumor activity of miR-199a-3p mimics was comparable to that obtained with sorafenib. These results suggested that miR-199a-3p may be considered a promising HCC therapeutic option.

This work is an overview of the oxidative potential (OP) values up to date measured in Italy, with the aim to provide a picture of the spatial and seasonal variability of OP in the various geographical areas across Italy. The summarized works used the common acellular assays-based dithiothreitol (OP DTT ), ascorbic acid (OP AA ), glutathione (OP GSH ), and 2 ,7 -dichlorodfluorescein (OP DCFH ) assays. The paper describes the association of OP responses with PM chemical composition, the sensitivity of various acellular OP assays to PM components and emission sources, and PM size distribution of the measured OP values. Our synthesis indicates that crustal and transition metals (e.g., Fe, Ni, Cu, Cr, Mn, Zn, and V), secondary ions and carbonaceous components (elemental carbon, EC, organic carbon, OC and water soluble carbon, WSOC) show significant correlations with OP across different urban and rural areas and size ranges. These chemical species are mainly associated with various PM sources, including residual/fuel oil combustion, traffic emissions, and secondary organic aerosol formation. Although the OP assays are sensitive to the same redox-active species, they differ in the association with PM chemical components. The DDT assay is mainly sensitive to the organic compounds that are mostly accumulated in the fine PM fraction, i.e., tracers of burning sources, and redox active organics associated with other markers of photochemical aging. In contrast, OP AA and OP GSH were mostly responsive to metals, mainly those related to non-exhaust traffic emissions (Cu, Zn, Cr, Fe, Ni, Mn, Sn, Cd, Pb), that are mainly accumulated in the coarse PM. Among the investigated sites, our synthesis shows larger OP values in Trentino region and the Po Valley, that may be explained by the high density of anthropogenic sources, and the orographic and meteorological characteristics, that favor the pollutants accumulation and aerosol photo-oxidative aging. ). The acellular version of the 2 ,7 -dichlorodfluorescein (DCFH) assay uses the enzymatic production of the fluorescent probe largely used for the evaluation of oxidative stress in living cells.The present work summarizes the PM oxidative properties up to date measured in Italy using OP acellular assays, with the aim of giving a general insight of PM OP across the Italian territory, that has not been reported yet, in spite of the increasing number of OP measurements carried out in Europe [6,[19][20][21][22]. In addition, the study reviews the association described in previous studies between OP from different assays with several inorganic ad organic components, that effect PM oxidative properties, i.e., metals, ions, and carbonaceous components. The aim is to give a picture of the spatial and seasonal variability of different contributions to OP in the various geographical areas across Italy. The relevance of such an investigation is based on the large variability in the chemical composition of different PM size fractions in various locations across Italy, as a consequence of the stron...

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Interactions between the splicing machinery and RNA Polymerase II (RNA Pol II) increase protein-coding gene transcription. Similarly, exons and splicing signals of enhancer-generated lncRNAs (elncRNAs) augment enhancer activity. However, elncRNAs are inefficiently spliced, suggesting that compared to protein-coding genes they contain qualitatively different exons with a limited ability to drive splicing. We show here that the inefficiently spliced first exons of elncRNAs as well as promoter-antisense lncRNAs (pa-lncRNAs) in human and mouse cells trigger a transcription termination checkpoint that requires WDR82, an RNA Pol II-binding protein, and its RNA-binding partner of previously unknown function, ZC3H4. We propose that the first exons of elncRNAs and pa-lncRNAs are an intrinsic component of a regulatory mechanism that on the one hand maximizes the activity of these cis-regulatory elements by recruiting the splicing machinery, and on the other contains elements that suppress pervasive extragenic transcription.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms