Re: Jonas Hugosson, Monique J. Roobol, Marianne Månsson, et al. A 16-yr Follow-up of the European Randomized Study of Screening for Prostate Cancer. Eur Urol 2019;76:43-51: Mortality in the Age Group ≥70 yr and the Case of Italy.

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Comment on Itoh et al. Intensive Treat-to-Target Statin Therapy in High-Risk Japanese Patients With Hypercholesterolemia and Diabetic Retinopathy: Report of a Randomized Study. Diabetes Care 2018;41:1275–1284

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Oncogenomic Approaches in Exploring Gain of Function of Mutant p53

Cancer is caused by the spatial and temporal accumulation of alterations in the genome of a given cell. This leads to the deregulation of key signalling pathways that play a pivotal role in the control of cell proliferation and cell fate. The p53 tumor suppressor gene is the most frequent target in genetic alterations in human cancers. The primary selective advantage of such mutations is the elimination of cellular wild type p53 activity. In addition, many evidences in vitro and in vivo have demonstrated that at least certain mutant forms of p53 may possess a gain of function, whereby they contribute positively to cancer progression. The fine mapping and deciphering of specific cancer phenotypes is taking advantage of molecular-profiling studies based on genome-wide approaches. Currently, high-throughput methods such as array-based comparative genomic hybridization (CGH array), single nucleotide polymorphism array (SNP array), expression arrays and ChIP-on-chip arrays are available to study mutant p53-associated alterations in human cancers. Here we will mainly focus on the integration of the results raised through oncogenomic platforms that aim to shed light on the molecular mechanisms underlying mutant p53 gain of function activities and to provide useful information on the molecular stratification of tumor patients

Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages

Background: As crucial regulators of the immune response against pathogens, macrophages have been extensively shown also to be important players in several diseases, including cancer. Specifically, breast cancer macrophages tightly control the angiogenic switch and progression to malignancy. ID4, a member of the ID (inhibitors of differentiation) family of proteins, is associated with a stem-like phenotype and poor prognosis in basal-like breast cancer. Moreover, ID4 favours angiogenesis by enhancing the expression of pro-angiogenic cytokines interleukin-8, CXCL1 and vascular endothelial growth factor. In the present study, we investigated whether ID4 protein exerts its pro-angiogenic function while also modulating the activity of tumour-associated macrophages in breast cancer. Methods: We performed IHC analysis of ID4 protein and macrophage marker CD68 in a triple-negative breast cancer series. Next, we used cell migration assays to evaluate the effect of ID4 expression modulation in breast cancer cells on the motility of co-cultured macrophages. The analysis of breast cancer gene expression data repositories allowed us to evaluate the ability of ID4 to predict survival in subsets of tumours showing high or low macrophage infiltration. By culturing macrophages in conditioned media obtained from breast cancer cells in which ID4 expression was modulated by overexpression or depletion, we identified changes in the expression of ID4-dependent angiogenesis-related transcripts and microRNAs (miRNAs, miRs) in macrophages by RT-qPCR. Results: We determined that ID4 and macrophage marker CD68 protein expression were significantly associated in a series of triple-negative breast tumours. Interestingly, ID4 messenger RNA (mRNA) levels robustly predicted survival, specifically in the subset of tumours showing high macrophage infiltration. In vitro and in vivo migration assays demonstrated that expression of ID4 in breast cancer cells stimulates macrophage motility. At the molecular level, ID4 protein expression in breast cancer cells controls, through paracrine signalling, the activation of an angiogenic programme in macrophages. This programme includes both the increase of angiogenesis-related mRNAs and the decrease of members of the anti-angiogenic miR-15b/107 group. Intriguingly, these miRNAs control the expression of the cytokine granulin, whose enhanced expression in macrophages confers increased angiogenic potential. Conclusions: These results uncover a key role for ID4 in dictating the behaviour of tumour-associated macrophages in breast cancer

Paracrine signaling from breast cancer cells causes activation of ID4 expression in tumor-associated macrophages

Background: Tumor-associated macrophages (TAMs) constitute a major portion of the leukocyte infiltrate found in breast cancer (BC). BC cells may reprogram TAMs in a pro-angiogenic and immunosuppressive sense. We previously showed that high expression of the ID4 protein in triple-negative BC cells leads to the induction of a proangiogenic program in TAMs also through the downregulation of miR-107. Here, we investigated the expression and function of the ID4 protein in TAMs. Methods: Human macrophages obtained from peripheral blood-derived monocytes (PBDM) and mouse RAW264.7 cells were used as macrophage experimental systems. ID4-correlated mRNAs of the TCGA and E-GEOD-18295 datasets were analyzed. Results: We observed that BC cells determine a paracrine induction of ID4 expression and activation of the ID4 promoter in neighboring macrophages. Interestingly, ID4 expression is higher in macrophages associated with invasive tumor cells compared to general TAMs, and ID4-correlated mRNAs are involved in various pathways that were previously reported as relevant for TAM functions. Selective depletion of ID4 expression in macrophages enabled validation of the ability of ID4 to control the expression of YAP1 and of its downstream targets CTGF and CYR61. Conclusion: Collectively, our results show that activation of ID4 expression in TAMs is observed as a consequence of BC cell paracrine activity and could participate in macrophage reprogramming in BC

Air pollution: a study of citizen's attitudes and behaviors using different information sources

Background: From November 2015 to January 2016, the routine air monitoring showed a peak of air pollution (in particular of PM10) that caused alarm in many Italian cities and was widely reported by mass media. After some weeks from this alarm, we tried to evaluate the citizen awareness and interest towards air pollution together with their positive behaviors, using different information sources. Methods: From September 2015 to March 2016, in parallel with the number of exceedances of the PM10 in Italy we evaluated the press coverage, the average monthly searches on Google and the interest on Twitter. Moreover, a qualitative content analysis on daily newspapers was conducted and a self-compiled questionnaire on the attitudes and behaviors about environmental issues and their determinants was administered to 598 parents involved in the project MAPEC_LIFE (LIFE12 ENV/IT/00614). Results: The media coverage of the theme of air pollution was very high from the end of 2015 to the beginning of 2016, as well as internet searches and twitter messages. Our qualitative analysis highlighted that only a small portion of articles included information about positive behaviors and environmental awareness. Despite the high media coverage and the satisfactory self-perceived knowledge, the majority of respondents judged negatively the received information (as untrue and incomplete) and declared a limited adoption of pro-environmental behaviors.  Conclusion: The parallel study of mass media information and people’s attitudes and behaviors seem to indicate that the high media coverage was not followed by a very high motivation towards pro-environmental behaviors

The mutant p53-ID4 complex controls VEGFA isoforms by recruiting lncRNA MALAT1

The abundant, nuclear-retained, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been associated with a poorly differentiated and aggressive phenotype of mammary carcinomas. This long non-coding RNA (lncRNA) localizes to nuclear speckles, where it interacts with a subset of splicing factors and modulates their activity. In this study, we demonstrate that oncogenic splicing factor SRSF1 bridges MALAT1 to mutant p53 and ID4 proteins in breast cancer cells. Mutant p53 and ID4 delocalize MALAT1 from nuclear speckles and favor its association with chromatin. This enables aberrant recruitment of MALAT1 on VEGFA pre-mRNA and modulation of VEGFA isoforms expression. Interestingly, VEGFA-dependent expression signatures associate with ID4 expression specifically in basal-like breast cancers carrying TP53 mutations. Our results highlight the key role for MALAT1 in control of VEGFA isoforms expression in breast cancer cells expressing gain-of-function mutant p53 and ID4 proteins

Tre tipi di wh in situ nei dialetti lombardi

The paper deals with the syntax of interrogatives in Lombard dialects. It mainly focuses on novel data from an Alpine and an Eastern Lombard variety; respectively, the dialect of Cavergno (Valle Maggia, CH) and Comun Nuovo (Bergamo, IT). These dialects show three different types of wh in situ, which could be analysed in three different ways: (i) without wh-movement; (ii) with partial wh-movement, and (iii) with wh-movement. 1. Introduzione Questo articolo verte sulle strutture interrogative attestate in alcune varietà lombarde che consentono di lasciare il sintagma interrogativo (wh) in situ, ovvero nella posizione che tale sintagma occuperebbe nella corrispondente frase dichiarativa. Il fenomeno è presente in varie aree del settentrione; in area lombarda si tratta soprattutto di alcune varietà della Svizzera italiana e di alcuni dialetti lombardo-orientali, quali bergamasco e bresciano, si veda Lurà (1987); Manzini / Savoia (2005); Poletto / Pollock (2009). In molte di queste varietà-e diversamente dall'italiano-il wh in situ è la strategia di interrogazione pragmaticamente non marcata. I dati qui presentati derivano in parte da Donzelli (2015) e in parte sono stati raccolti in seno al progetto AIS, reloaded, 1 mediante inchieste dialettali nelle 18 località AIS 2 della Svizzera italiana. Questo lavoro sul campo ha permesso di indagare la (micro-)variazione sia all'interno di circoscritte aree linguistiche, sia in ciascuna delle varietà indagate. In questa sede la nostra analisi si concentrerà sul dialetto di Cavergno 3 (CA), varietà lombardo-alpina parlata in Valle Maggia (Canton Ticino), e sul dialetto di Comun Nuovo (CN), varietà lombardo-orientale parlata in provincia di Bergamo. L'ipotesi centrale del presente lavoro è che, sebbene entrambi i dialetti lombardi qui presi in considerazione presentino il fenomeno del wh in situ, esistono almeno tre differenti strutture sintattiche caratterizzate dall'ordine in situ, che, anticipando le nostre conclusioni, possono essere classificate nel modo seguente: 1 [SNF 100012_162482] periodo di ricerca: 2016-2019. 2 Acronimo per lo Sprach-und Sachatlas Italiens und der Südschweiz, si veda Jaberg / Jud (1928). 3 Per una classificazione esaustiva si veda Salvio

Tre tipi di wh in situ nei dialetti lombardi

International audienceThe paper deals with the syntax of interrogatives in Lombard dialects. It mainly focuses on novel data from an Alpine and an Eastern Lombard variety; respectively, the dialect of Cavergno (Valle Maggia, CH) and Comun Nuovo (Bergamo, IT). These dialects show three different types of wh in situ, which could be analysed in three different ways: (i) without wh-movement; (ii) with partial wh-movement, and (iii) with wh-movement. 1. Introduzione Questo articolo verte sulle strutture interrogative attestate in alcune varietà lombarde che consentono di lasciare il sintagma interrogativo (wh) in situ, ovvero nella posizione che tale sintagma occuperebbe nella corrispondente frase dichiarativa. Il fenomeno è presente in varie aree del settentrione; in area lombarda si tratta soprattutto di alcune varietà della Svizzera italiana e di alcuni dialetti lombardo-orientali, quali bergamasco e bresciano, si veda Lurà (1987); Manzini / Savoia (2005); Poletto / Pollock (2009). In molte di queste varietà-e diversamente dall'italiano-il wh in situ è la strategia di interrogazione pragmaticamente non marcata. I dati qui presentati derivano in parte da Donzelli (2015) e in parte sono stati raccolti in seno al progetto AIS, reloaded, 1 mediante inchieste dialettali nelle 18 località AIS 2 della Svizzera italiana. Questo lavoro sul campo ha permesso di indagare la (micro-)variazione sia all'interno di circoscritte aree linguistiche, sia in ciascuna delle varietà indagate. In questa sede la nostra analisi si concentrerà sul dialetto di Cavergno 3 (CA), varietà lombardo-alpina parlata in Valle Maggia (Canton Ticino), e sul dialetto di Comun Nuovo (CN), varietà lombardo-orientale parlata in provincia di Bergamo. L'ipotesi centrale del presente lavoro è che, sebbene entrambi i dialetti lombardi qui presi in considerazione presentino il fenomeno del wh in situ, esistono almeno tre differenti strutture sintattiche caratterizzate dall'ordine in situ, che, anticipando le nostre conclusioni, possono essere classificate nel modo seguente: 1 [SNF 100012_162482] periodo di ricerca: 2016-2019. 2 Acronimo per lo Sprach-und Sachatlas Italiens und der Südschweiz, si veda Jaberg / Jud (1928). 3 Per una classificazione esaustiva si veda Salvion