Antitumoral effects of attenuated Listeria monocytogenes in a genetically engineered mouse model of melanoma

Attenuated Listeria monocytogenes (Lmat-LLO) represents a valuable anticancer vaccine and drug delivery platform. Here we show that in vitro Lmat-LLO causes ROS production and, in turn, apoptotic killing of a wide variety of melanoma cells, irrespectively of their stage, mutational status, sensitivity to BRAF inhibitors or degree of stemness. We also show that, when administered in the therapeutic setting to Braf/Pten genetically engineered mice, Lmat-LLO causes a strong decrease in the size and volume of primary melanoma tumors, as well as a reduction of the metastatic burden. At the molecular level, we confirm that the anti-melanoma activity exerted in vivo by Lmat-LLO depends also on its ability to potentiate the immune response of the organism against the infected tumor. Our data pave the way to the preclinical testing of listeria-based immunotherapeutic strategies against metastatic melanoma, using a genetically engineered mouse rather than xenograft models

The landscape of BRAF transcript and protein variants in human cancer

Background: The BRAF protein kinase is widely studied as a cancer driver and therapeutic target. However, the regulation of its expression is not completely understood. Results: Taking advantage of the RNA-seq data of more than 4800 patients belonging to 9 different cancer types, we show that BRAF mRNA exists as a pool of 3 isoforms (reference BRAF, BRAF-X1, and BRAF-X2) that differ in the last part of their coding sequences, as well as in the length (BRAF-ref: 76 nt; BRAF-X1 and BRAF-X2: up to 7 kb) and in the sequence of their 3'UTRs. The expression levels of BRAF-ref and BRAF-X1/X2 are inversely correlated, while the most prevalent among the three isoforms varies from cancer type to cancer type. In melanoma cells, the X1 isoform is expressed at the highest level in both therapy-naïve cells and cells with acquired resistance to vemurafenib driven by BRAF gene amplification or expression of the Δ[3-10] splicing variant. In addition to the BRAF-ref protein, the BRAF-X1 protein (the full length as well as the Δ[3-10] variant) is also translated. The expression levels of the BRAF-ref and BRAF-X1 proteins are similar, and together they account for BRAF functional activities. In contrast, the endogenous BRAF-X2 protein is hard to detect because the C-terminal domain is selectively recognized by the ubiquitin-proteasome pathway and targeted for degradation. Conclusions: By shedding light on the repertoire of BRAF mRNA and protein variants, and on the complex regulation of their expression, our work paves the way to a deeper understanding of a crucially important player in human cancer and to a more informed development of new therapeutic strategies

Framing alleged Islamist plots: a case study of British press coverage since 9/11

In the decade post 9/11 , the UK terrorist threat was associated with a series of high profile counter terrorism operations, linked to specific plots. These terrorism related episodes received significant media attention and, as a consequence, were a visible sign of the contemporary terrorist threat. This paper seeks to identify the dominant frames rendered in news media reporting on these episodes. Through a longitudinal study of UK press coverage, the analysis reveals that two prominent frames were present, an inevitability and preparedness frame, with alleged plots serving to underline the risk posed by contemporary terrorism,and a belonging and responsibility frame, which cast later episodes as belonging to the Muslim communities disrupted by polic

Vascular deaths in elderly neurological patients with leukoaraiosis.

OBJECTIVES: The prognostic significance of leukoaraiosis is still not completely elucidated. The objective was to examine survival and causes of death among elderly neurological patients with leukoaraiosis. METHODS: From 1 January 1994, vital status and causes of death were drawn from municipality lists and death certificates of 216 patients (mean age (SD) 70.6 (8.3) years) admitted to a geriatric unit who underwent cranial CT between 1 January 1984 and 31 December 1986 (mean observation period (SD) 8.4 (0.8) years). These patients had been enrolled for a study of clinical predictors of leukoaraiosis. Based on the presence of leukoaraiosis on CT, this group had been divided into two subgroups of patients, with and without leukoaraiosis. The difference in survival and causes of death between these groups formed the objective of the study. RESULTS: Survival time was shorter among the 90 patients with leukoaraiosis than among the 126 patients without (median survival time 4.07 v 7.78 years, log rank test P < 0.001). After controlling for age and other major death predictors, the risk of death remained significantly increased (relative risk (RR) = 1.64, 95% confidence interval (95% CI) 1.15-2.34) among patients with leukoaraiosis. Moreover, patients with leukoaraiosis had an almost threefold higher risk of dying from vascular causes than patients without (RR = 2.81, 95% CI 1.74-4.53). CONCLUSION: Leukoaraiosis is a predictor of vascular deaths in elderly neurological patients. Careful diagnostic evaluation and attention to preventive measures are required in patients with leukoaraiosis

Faith, language and identity : Muslim migrants in Scotland and northern Ireland

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Flavonoids mixture (diosmin, troxerutin, hesperidin) in the treatment of acute hemorrhoidal disease: a prospective, randomized, triple-blind, controlled trial

Background: The role of a mixture of phlebotonics in the treatment of acute hemorrhoid crisis is investigated to test their efficacy. Methods: One hundred and thirty-four consecutive patients with an acute hemorrhoidal crisis recruited in five colorectal units entered the study. Sixty-six of them were randomized to receive a mixture of diosmin, troxerutin and hesperidin (group A), and 68 a placebo (group B). The main symptoms, the use of oral painkillers and the Bristol scale score were recorded at each scheduled visit and compared using both Student’s t test for independent samples and the ANOVA models for repeated measures. The presence of edema, prolapse and thrombosis were also recorded and compared using the Chi-square test. Furthermore, the trend of proportions during the time of the evaluations was assessed by the Chi-square test for linear trend. Results: Pain, bleeding and the proportion of patients who reported persistence of edema and thrombosis decreased significantly after 12 days of treatment in group A. After 6 days, the number of paracetamol tablets taken by patients in groupA was significantly lower than the amount of flavonoid mixture. Conclusions: The use of a mixture of diosmin, troxerutin and hesperidin is a safe and effective mean of managing symptoms of acute hemorrhoidal disease. Furthermore, in patients receiving treatment, there was faster control and lower persistence of edema and thrombosis

A eutherian-specific microRNA controls the translation of Satb2 in a model of cortical differentiation

none16noCerebral cortical development is controlled by key transcription factors that specify the neuronal identities in the different layers. The mechanisms controlling their expression in distinct cells are only partially known. We investigated the expression and stability of Tbr1, Bcl11b, Fezf2, Satb2, and Cux1 mRNAs in single developing mouse cortical cells. We observe that Satb2 mRNA appears much earlier than its protein and in a set of cells broader than expected, suggesting an initial inhibition of its translation, subsequently released during development. Mechanistically, Satb2 3′UTR modulates protein translation of GFP reporters during mouse corticogenesis. We select miR-541, a eutherian-specific miRNA, and miR-92a/b as the best candidates responsible for SATB2 inhibition, being strongly expressed in early and reduced in late progenitor cells. Their inactivation triggers robust and premature SATB2 translation in both mouse and human cortical cells. Our findings indicate RNA interference as a major mechanism in timing cortical cell identities.openMartins M.; Galfre S.; Terrigno M.; Pandolfini L.; Appolloni I.; Dunville K.; Marranci A.; Rizzo M.; Mercatanti A.; Poliseno L.; Morandin F.; Pietrosanto M.; Helmer-Citterich M.; Malatesta P.; Vignali R.; Cremisi F.Martins, M.; Galfre, S.; Terrigno, M.; Pandolfini, L.; Appolloni, I.; Dunville, K.; Marranci, A.; Rizzo, M.; Mercatanti, A.; Poliseno, L.; Morandin, F.; Pietrosanto, M.; Helmer-Citterich, M.; Malatesta, P.; Vignali, R.; Cremisi, F