Extracellular vesicles in anti-tumor immunity

To what extent extracellular vesicles (EVs) can impact anti-tumor immune responses has only started to get unraveled. Their nanometer dimensions, their growing number of subtypes together with the difficulties in defining their origin hampers their investigation. The existence of tumor cell lines facilitated advance in cancer EV understanding, while capturing information about phenotypes and functions of immune cell EVs in this context is more complex. The advent of immunotherapy with immune checkpoint inhibitors has further deepened the need to dissect the impact of EVs during immune activation and response, not least to contribute unraveling and preventing the generation of resistance occurring in the majority of patients. Here we discuss the factors that influence/drive the immune response in cancer patients in the context of cancer therapeutics and the roles or possible functions EVs can have in this scenario. With immune cell-derived EVs as leitmotiv we will journey from EV discovery and subtypes through their physiological and pathological non-cancer functions to their similarities with cancer EVs and on how to revert their detrimental consequences on immune responses to cancer

miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators

BACKGROUND: Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance.METHODS: The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy.RESULTS: miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor.CONCLUSIONS: Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment. Video Abstract

Development of a Nomogram Predicting the Risk of Persistence/Recurrence of Cervical Dysplasia

Background: Cervical dysplasia persistence/recurrence has a great impact on women's health and quality of life. In this study, we investigated whether a prognostic nomogram may improve risk assessment after primary conization. Methods: This is a retrospective multi-institutional study based on charts of consecutive patients undergoing conization between 1 January 2010 and 31 December 2014. A nomogram assessing the importance of different variables was built. A cohort of patients treated between 1 January 2015 and 30 June 2016 was used to validate the nomogram. Results: A total of 2966 patients undergoing primary conization were analyzed. The median (range) patient age was 40 (18-89) years. At 5-year of follow-up, 6% of patients (175/2966) had developed a persistent/recurrent cervical dysplasia. Median (range) recurrence-free survival was 18 (5-52) months. Diagnosis of CIN3, presence of HR-HPV types, positive endocervical margins, HPV persistence, and the omission of HPV vaccination after conization increased significantly and independently of the risk of developing cervical dysplasia persistence/recurrence. A nomogram weighting the impact of all variables was built with a C-Index of 0.809. A dataset of 549 patients was used to validate the nomogram, with a C-index of 0.809. Conclusions: The present nomogram represents a useful tool for counseling women about their risk of persistence/recurrence after primary conization. HPV vaccination after conization is associated with a reduced risk of CIN2+

Epistolari dal Due al Seicento. Modelli, questioni ecdotiche, edizioni, cantieri aperti (Gargnano del Garda, 29 settembre - 1° ottobre 2014)

Nei secoli passati, la lettera era l'unico mezzo di comunicazione: familiare, amichevole, d'ufficio o di servizio, ma anche strumento di dibattito politico e culturale. Lo studio degli epistolari dei singoli ma anche delle reti di comunicazione e di scambio è uno dei grandi temi della ricerca europea contemporanea. Vi si inserisce questo secondo volume dei "Quaderni di Gargnano", che - volgendosi sia alla produzione latina sia a quella volgare dal Due al Seicento - si sofferma su problemi metodologici e casi significativi, con impostazioni e tagli diversi: dall'ecdotica alla filologia, dall'archivistica, alla storia, alla storia delle discipline

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Il teatro sociale alla prova dei “risvegli”: un’esperienza di ricerca

L’articolo illustra i risultati di una ricerca condotta in relazione alle attività di un laboratorio teatrale rivolto a persone con cerebrolesioni acquisite. Gli autori, avendo verificato con gli esperti medici l'impraticabilità di una indagine valutativa sull'impatto terapeutico di tipo fisico, si sono chiesti se e come tale attività abbia o no reso possibile per soggetti colpiti da gravi deprivazioni polisensoriali un miglioramento nella qualità della vita quotidiana, concentrando l'attenzione sulle opportunità di costruire una scena condivisa in cui comunicare. Date le caratteristiche dei soggetti coinvolti, l'indagine ha adottato strumenti diversi di rilevazione qualitativa: osservazione; conversazioni di gruppo; interviste semi-strutturate a operatori, familiari e spettatori. I risultati hanno evidenziato un indubbio effetto socializzante derivante dall’importanza del lavoro di gruppo e dagli aspetti di intrattenimento tipici del teatro. Il laboratorio costituisce per i partecipanti una rottura ludica della routine, motivando un maggiore impegno riabilitativo, e quindi risultando utile nel medio-lungo periodo anche per il piano di riabilitazione terapeutica, sia per i pazienti sia per i caregivers. Cruciale è, in particolare, il lavoro di recitazione in squadra, che favorisce regole d’interazione resilienti, portando a costruire indizi simbolici d'interesse anche per lo studio della comunicazione in situazioni di forte disabilità. La solidità del gruppo e l’espressività sono aspetti evidenti anche per gli operatori e, cosa altrettanto importante, per gli spettatori, che hanno valutato positivamente l’esperienza.The article describes a research on a theatre workshop aimed at people with acquired brain injuries. The authors wondered if and how this activity has made it possible, even for subjects affected by severe multi-sensory deprivation, to construct a shared scene in which to communicate. Given the characteristics of the subjects involved, the authors adopted different qualitative research tools: observation; group conversations; semi-structured interviews with operators, family members and spectators. The results highlighted the importance of the group and of the entertainment related to the theatre. The laboratory constitutes a playful break from the routine, motivating a greater rehabilitation effort. Team acting is crucial, which enhances resilient rules of interaction. The solidity of the group and expressiveness are also evident aspects for operators and spectators, who have positively evaluated the experience

Indoor Air Quality Real-Time Monitoring in Airport Terminal Areas: An Opportunity for Sustainable Management of Micro-Climatic Parameters

Indoor air quality (IAQ) management in public spaces is assuming a remarkable importance. Busy environments, like airport terminals, are currently regarded as possible hotspots and IAQ is a crucial element for passengers and staff protection, as well as a key aspect of airport passenger experience. A one-month monitoring period has been performed on IAQ in the airport of Bologna (Italy), as prototypal example of large regional airport. Four strategic areas within the airport have been equipped with electronic monitoring platforms, including different contaminants and two microclimatic sensors. Data suggest that daily variation in IAQ parameters typically follow the activity pattern of the different environments under study (i.e., passengers\u2019 flows) for gaseous contaminants, where particulate matter counts oscillate in a definite range, with a significant role played by ventilation system. Gaseous contaminants show a correlation between indoor and outdoor concentrations, mainly due to airside activities. Micro-climatic comfort parameters have been tested to match with standards for commercial environments. As results appears in line with typical households IAQ values, the current air ventilation system appears to be adequate. Nevertheless, an integrated air management system, based on real-time monitoring, would lead to optimization and improvement in environmental and economical sustainability

Spatial distribution of tumour immune infiltrate predicts outcomes of patients with high-risk soft tissue sarcomas after neoadjuvant chemotherapy

Anthracycline; Neoadjuvant chemotherapy; Soft tissue sarcomasAntraciclina; Quimioterapia neoadyuvante; Sarcomas de tejidos blandosAntraciclina; Quimioteràpia neoadjuvant; Sarcomes de teixits tousBackground: Anthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis. Methods: The ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS). Findings: Tumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI. Interpretation: The different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS.Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5 × 1000 Funds—2016, Italian Ministry of Health; AIRC Grant [ID#28546]

Scienze della sostenibilità. Energia - Risorse - Città - Acqua - Ecosistemi - Diritto. Con e-book

L’Agenda 2030 dell’ONU definisce 17 obiettivi di sviluppo sostenibile da raggiungere in tutti i Paesi e a tutti i livelli entro il 2030, sfide globali che puntano a far sì che la vita sulla Terra sia pacifica, giusta, inclusiva, prospera e in armonia con la natura e che, ora come ora, sono addirittura cruciali per la sopravvivenza dell’umanità. Depauperamento delle risorse, riscaldamento globale, inquinamento di acqua, suolo e aria, perdita della biodiversità sono infatti alcuni tra i più importanti mali che affliggono il nostro pianeta con intensità crescente e che, per essere affrontati, hanno bisogno del coinvolgimento di tutti i Paesi e di tutte le parti in causa, di investimenti nella ricerca e nell’innovazione tecnologica come nell’educazione delle nuove generazioni. L’università come luogo di formazione e di ricerca ha quindi la responsabilità di porsi come punto di riferimento culturale nella transizione verso la sostenibilità sociale, economica e ambientale. Scienze della sostenibilità raccoglie la sfida e propone un compendio degli aspetti energetici, ambientali, urbanistici e giuridici della sostenibilità da un punto di vista tecnico. Il libro è suddiviso in sei capitoli, ciascuno dei quali fornisce un inquadramento generale su una tematica legata alla sostenibilità e correlata a determinati obiettivi dell’Agenda 2030: - Sostenibilità energetico-ambientale (obiettivi 7, 11, 12 e 13) - Materie prime e riciclo (obiettivi 12, 7, 8, 11, 13, 14 e 15) - Mobilità sostenibile (obiettivi 11, 3 e 13) - Idroclimatologia (obiettivi 6, 11, 13, 14 e 15) - Ecologia e servizi ecosistemici (obiettivi 15, 3, 11, 13 e 14) - Diritto dello sviluppo sostenibile (obiettivi 16, 7, 11, 12, 13, 14 e 15)