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

Argonaute 2 drives miR-145-5p-dependent gene expression program in breast cancer cells

To perform their regulatory functions, microRNAs (miRNAs) must assemble with any of the four mammalian Argonaute (Ago) family of proteins, Ago1–4, into an effector complex known as the RNA-induced silencing complex (RISC). While the mature miRNA guides the RISC complex to its target mRNA, the Ago protein represses mRNA translation. The specific roles of the various Ago members in mediating miRNAs activity, however, haven’t been clearly established. In this study, we investigated the contribution of Ago2, the only human Ago protein endowed with nuclease activity, to the function of tumor-suppressor miR-145-5p in breast cancer (BC). We show that miR-145-5p and Ago2 protein are concomitantly downregulated in BC tissues and that restoration of miR-145-5p expression in BC cells leads to Ago2 protein induction through the loosening of Ago2 mRNA translational repression. Functionally, miR-145-5p exerts its inhibitory activity on cell migration only in presence of Ago2, while, upon Ago2 depletion, we observed increased miR-145/Ago1 complex and enhanced cell motility. Profiling by microarray of miR-145-5p target mRNAs, in BC cells depleted or not of Ago2, revealed that miR-145-5p drives Ago2-dependent and -independent activities. Our results highlight that the Ago2 protein in cancer cells strictly dictates miR-145-5p tumor suppressor activity

Contribution of miR-145-5p/Ago2 complex to the regulation of epithelial-mesenchymal transition

The epithelial-mesenchymal transition (EMT) is essential for cell fate determination during development but it is involved in pathological processes like cancer as well, being one of the first steps in the mechanisms leading to metastasis. miR-145-5p is one of the most widely recognized tumor-suppressor miRNAs, able to regulate cell migration and EMT through the contribution of the RISC complex in which Argonaute (Ago) proteins are required for target recognition and gene silencing [1]. Ago2 is an important member of the Ago family and its overexpression correlates with a transformed phenotype in breast cancer cells [2]. With the aim to unravel miR-145-5p/Ago2 contribution to the suppression of cancer progression in epithelial tumors, here we show that: i) miR-145-5p and Ago2 are down-regulated in breast tumor vs normal tissues; ii) the restored expression of miR-145-5p in breast cancer cell lines results in the reduction of tumor phenotype; iii) Ago2 expression is positively and specifically regulated by miR-145-5p; iv) miR-145-5p-dependent Ago2 induction is necessary for the inhibition of cell migration; v) when Ago2 is depleted, the formation of an alternative miR-145-5p/Ago1 active complex redirects miR-145-5p tumor suppressor function and correlates with a more invasive phenotype in breast cancer cells. These results open to the identification of miR-145-5p/Ago2-dependent molecular networks involved in the maintenance and progression of cancer phenotype

Efficacy of neuropsychological rehabilitation on numerical and calculation abilities: A developmental case study

Present single case proves the effectiveness of a theory-based cognitive treatment on numerical and calculation abilities in developmental age. Both evaluation and treatment were designed on the bases of current models of numerical cognition, in particular Von Aster's developmental model. At the age of 7.4 years, HT was referred for a serious delay in the acquisition of numerical skills involving all numerical and calculation skills (written calculations, numerical knowledge, accuracy, rapidity). Following the rules of neuropsychological rehabilitation, HT was submitted to an early, intensive, HT-tailored treatment based on analogic representation of amount. After 12 months of treatment, HT showed statistically significant increasing in all the investigated variables: however, even if he correctly performed various numerical tasks, he remained significantly slower compared to his peers. Present case demonstrated the efficacy of theory-based, individually-tailored developmental dyscalculia. Early diagnosis and early intervention are urgently needed to get clinically significant change and to prevent behavioral and emotional symptoms

Cambiamenti nello sviluppo semantico in bambini di 3, 4 e 5 anni.

In questo lavoro presentiamo una batteria di test che valuta le seguenti componenti dell’abilita’ semantica: la capacità di categorizzare oggetti utilizzando relazioni tassonomiche; la conoscenza di legami associativi tra oggetti e situazioni; l’abilità di memorizzare legami tra oggetti e parole; l’abilità di rappresentare esplicitamente categorizzazioni e significati delle parole. Abbiamo somministrato la batteria a 150 bambini di 3, 4, e 5 anni. I risultati mostrano, al crescere dell'età, un aumento statisticamente significativo sia delle relazioni tassonomiche numero con cui gli oggetti vengono correttamente raggruppati sia del numero di oggetti che vengono correttamente associati a una situazione. Il recupero mnestico di un legame oggetto-parola si sviluppa in termini di efficienza ma i profili di facilitazione sono costanti: in ogni fascia di età i legami associativi permettono un miglior recupero delle parole target, seguiti dalle relazioni tassonomiche e infine da quelle arbitrarie. Il numero delle risposte con cui vengono esplicitate le categorizzazioni tassonomiche o con cui vengono definite parole target utilizzando termini o relazioni linguistiche aumenta in maniera statisticamente significativa solo nel gruppo dei bambini di 5 anni

Semantic abilities predict expressive lexicon in children with typical and atypical language development

In this study we used a semantic battery assessing the conceptual, lexical, and metacognitive level in semantic relationships to predict expressive lexicon in preschool children with typical and atypical language development. Our regression analyses showed that the tests of our semantic battery altogether accounted for 24% of variance in expressive lexicon after controlling for age and phonological short-term memory. The ability to memorize picture-cue/word pairs that were linked by taxonomic relations made a unique contribution to the expressive lexicon, and was a reliable marker of delayed expressive vocabulary in a group of children with specific language impairment. © 2010 Psychology Press

L’insorgenza delle malattie professionali negli operatori addetti alla coltivazione e manipolazione dei funghi: una revisione

The paper presents a review on health hazards involving operators that cultivate and handle mushrooms. Intensive production of edible and medicinal fungi is a common agricultural management all over the world and involves a number of operators whose health must be safeguarded due the number of risks. Growth techniques and environmental conditions for producing and handling mushrooms expose workers to several types of allergens that possibly cause occupational diseases. Namely, mushroom workers suffer from allergic pulmonary diseases and, more rarely, from forms of contact dermatitis. The cause of these clinical manifestations may be found in the exposure to several factors, such as the peculiar production conditions leading to the presence of many allergens (bacteria, moulds, mycotoxins, endotoxins) and the direct contact of workers with some fungal species, which are themselves allergens.La produzione intensiva di funghi commestibili e medicinali è un'attività agricola comune in tutto il mondo e coinvolge un gran numero di operatori la cui salute deve essere salvaguardata poiché potrebbero esserci dei rischi. Le tecniche di crescita e le condizioni ambientali richieste per la produzione e la lavorazione dei funghi espongono i lavoratori a diversi tipi di allergeni che causano l'insorgenza di una serie di condizioni classificabili come malattie professionali. Vale a dire, i lavoratori di funghi soffrono di malattie polmonari allergiche e, più raramente, di forme di dermatite da contatto. La causa di queste manifestazioni cliniche si può riscontrare nell'esposizione a diversi fattori, come le particolari condizioni di produzione che portano allo sviluppo di molti allergeni (batteri, muffe, micotossine, endotossine) e il contatto diretto con alcune specie fungine, che sono esse stesse allergeni

Esposizione alle aflatossine dei lavoratori dell'industria agro-alimentare

Aflatoxins are mycotoxins produced by some Aspergillus species. They are remarkably toxic and included among the most known carcinogenic substances. Article 139 of the Italian presidential decree of 30 June 1965, no. 1204 and subsequent amendments, includes hepatocellular carcinoma due to exposure to aflatoxin B1 the list of diseases for which reporting is mandatory. Aflatoxins could contaminate food of plant and animal origin, therefore the areas of work most at risk are the agro-food and, in general, all the activities carried out in humid and poorly ventilated areas, subject to fungal contamination. Although the procedures for controlling aflatoxins in food are now fairly well established, there is still no full knowledge of the risk of workplace exposure. A review of the risks relating to exposure to aflatoxin of workers in the agri-food sector is presented here based on bibliographic data and surveys conducted in some Italian regions by local health authorities and by the National Institute for Insurance against Accidents at Work. To protect the health of workers in the sectors considered, we therefore consider it necessary to evaluate the presence of aflatoxins and inform workers about the application of good prevention practices and the use of adequate personal protective equipment.Le aflatossine sono micotossine prodotte da alcune specie di Aspergillus. Esse sono notevolmente tossiche e sono incluse tra le sostanze cancerogene più conosciute. L’Articolo 139 del D.P.R. del 30 giugno 1965, n. 1204 e successive modifiche, include il carcinoma epatocellulare dovuto all'esposizione all'aflatossina B1 nell'elenco delle malattie per le quali è obbligatoria la segnalazione. Le aflatossine potrebbero infatti contaminare alimenti di origine vegetale e animale, pertanto le aree di lavoro più a rischio sono del settore agroalimentare e, in generale, tutte le attività svolte in aree umide e scarsamente ventilate, soggette a contaminazione fungina. Sebbene le procedure per il controllo delle aflatossine negli alimenti siano ormai abbastanza consolidate, non esiste ancora una piena conoscenza del rischio alla loro esposizione sul luogo di lavoro. Una rassegna dei rischi relativi all'esposizione alle aflatossine dei lavoratori nel settore agroalimentare è presentata qui sulla base di dati bibliografici e indagini condotte in alcune regioni italiane dalle autorità sanitarie locali e dall'Istituto Nazionale per l'assicurazione contro gli infortuni sul lavoro (INAIL). Per proteggere la salute dei lavoratori nei settori considerati, riteniamo pertanto necessario che venga valutata la presenza di aflatossine e vengano informati i lavoratori sull'applicazione di buone pratiche di prevenzione e sull'uso di adeguati dispositivi di protezione individuale

Contribution of right hemisphere to visual imagery: A visual working memory impairment?

Visual Imagery is the ability to generate mental images in the absence of perception, that is, "seeing with the mind's eye." We describe a patient, IM, who suffered from an acute ischemic stroke in the right anterior choroidal artery who appeared to demonstrate relatively isolated impairment in visual imagery. Her cognitive function, including her performance on tests of semantic function, was at ceiling, apart from a deficit in visual memory. IM failed in tasks involving degraded stimuli, object decision involving reality judgments on normal animals. and drawings from memory. By contrast, site was able to match objects seen from an unfamiliar viewpoint and to perform tasks of semantic and visual association. We hypothesize that IM has a visual working memory deficit that impairs her ability to generate full visual representations of objects given their names, individual feature, or partial representations. The deficit appears to be the result of damage to connections between the right thalamus and the right temporal lobe. Our findings may help to clarify the role of the thalamus in the cortical selective engagement processes that underlie working memory