Oncolytic viruses are designed for cancer treatment. Cell-virus interactions are key determinants for successful viral replication. Therefore, the extensive reprogramming of gene expression that occurs in tumor cells might create a hurdle for viral propagation. We used a replication-based approach of a microRNA (miRNA) adenoviral library encoding up to 243 human miRNAs as a bioselection strategy to identify miRNAs that facilitate adenoviral oncolytic activity in pancreatic ductal adenocarcinoma. We identify two miRNAs, miR-99b and miR-485, that function as enhancers of adenoviral oncolysis by improving the intra-and extracellular yield of mature virions. An increased adenoviral activity is the consequence of enhanced E1A and late viral protein expression, which is probably mediated by the downregulation of the transcriptional repressors ELF4, MDM2, and KLF8, which we identify as miR-99b or miR-485 target genes. Arming the oncolytic adenovirus ICOVIR15 with miR-99b or miR-485 enhances its fitness and its antitumoral activity. Our results demonstrate the potential of this strategy to improve oncolytic adenovirus potency, and they highlight miR-99b and miR-485 as sensitizers of adenoviral replication.

In chronic granulomatous disease, pain from a thickened gallbladder disappears after oral treatment with glucocorticoids and antibiotics.

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Although urban historians have recently begun to study the city and the senses, relatively few have investigated the aural environment experienced by the ear. To a certain extent, towns are thus characterized as silent societies and sounds of whatever kind are not viewed as an integral part of urban life. This article, based on a small Spanish town called Jaca, aims to describe some of its most notable sounds during the ancien régime and to explore how inhabitants perceived them. Such an approach provides a deeper and more comprehensive insight into the totality of the urban experience of townspeople of the period, and also suggests some new lines of enquiry for future musicological research.

This article aims to provide the first large-scale description of current trends in classical music programming. The purpose is to analyze an issue commonly associated with the critical state of concert venues today, which is to say, the predominantly conservative aesthetic of performed repertoires. This paper attempts to go further than previous studies by looking at a larger group of repertoires and institutions, examining data from some 4,700 concerts performed between 2010 and 2015, randomly gathered by the database www.bachtrack.com. No other source in this field enjoys its sheer size and wide variety. The first section demonstrates that an extremely small handful of composers dominate the musical landscape, and that patterns of association between programmed composers within individual concerts are highly predictable. Against this problematic backdrop, the second section proposes possible remedies to balance this disproportionate concentration of specific styles, composers, and associations by focusing as a case study on the innovative music program at the Juan March Foundation in Madrid. The overall results are both original and valuable, as they reveal otherwise undetected trends in music programming, while providing practical strategies to re-engage audiences and encourage different cultural policies at concert halls.