Role of extracellular vesicle-based cell-to-cell communication in multiple myeloma progression

Multiple myeloma (MM) progression closely depends on the bidirectional crosstalk between tumor cells and the surrounding microenvironment, which leads to the creation of a tumor supportive niche. Extracellular vesicles (EVs) have emerged as key players in the pathological interplay between the malignant clone and near/distal bone marrow (BM) cells through their biologically active cargo. Here, we describe the role of EVs derived from MM and BM cells in reprogramming the tumor microenvironment and in fostering bone disease, angiogenesis, immunosuppression, drug resistance, and, ultimately, tumor progression. We also examine the emerging role of EVs as new therapeutic agents for the treatment of MM, and their potential use as clinical biomarkers for early diagnosis, disease classification, and therapy monitoring

MicroRNAs as a Potential New Preventive Approach in the Transition from Asymptomatic to Symptomatic Multiple Myeloma Disease

Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bonemarrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact onMMtumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions

FuturAP - Rapporto sul Futuro e l'innovazione dell'Amministrazione Pubblica

Il volume raccoglie e analizza i principali fattori di cambiamento e innovazione dell'Amministrazione Pubblica italiana attorno a 5 macro-tematiche: Etica, trasparenza e protezione dati; innovazione resiliente; performance e capitale umano; enti locali e sfide globali; welfare sostenibil

Pre-Feasibility Analysis of Electric Vehicle Public Charging Infrastructure in Ontario, Canada

This study aims to evaluate the integration of charging stations on the Toronto-Ottawa ON-401E motorway located in Ontario, Canada. Firstly, there is a discussion of general aspects of the Canadian electric distribution system and an overview of public charging stations. Next is analysis of a real case scenario. From assessing vehicle data and distances along the journey, a comparison is made between five different models of electric vehicles (EVs). Starting with optimal charging station collocation and coverage evaluation for route infrastructure, this work offers an evaluation of the main factors that influence EV performance, that is, autonomy, charging time and energy required

APO(a) variants and lipoprotein(a) in men with or without myocardial infarction

The lipoprotein Lp(a) with high plasma concentration is an independent genetic determinant for cardiovascular diseases. It was investigated as a quantitative factor of risk for myocardial infarction. A total Of 345 Italian subjects, 127 Cases and 218 Controls, were studied. Lipids and lipoproteins were compared. Cases had atherogenic traits, such as lower HDL cholesterol and higher triglycerides than Controls. In particular, they had Lp(a) concentrations over the risk threshold, (median, 27 mg/dl in Cases vs 17 mg/dl in Controls; P = 0.0075, Mann-Whitney test) which confirmed the association of this parameter with the disease. Two main functional variants of the apo(a) gene, KringleIV and penta-nucleotide repeat, (PNR) were analyzed. Allele and genotype frequency distributions differed between Cases and Controls. Lp(a) concentrations differed according to PNR genotypes in Controls: subjects having alleles >8 showed lower Lp(a). This was not found in Cases. They had a higher prevalence of the smaller KringleIV alleles, the high Lp(a)-expressing ones. In Cases, genotypes consisting of two small KringleIV alleles were prevalently associated to PNR 8/9 and 8/10, thus preventing Lp(a) lowering. The putative apo(a) enhancer within LINE1 in the apo(a)-plasminogen intergenic region was investigated for functional polymorphisms. No variants that could be associated to the Lp(a) variability were found

Helicobacter pylori is associated with modified lipid profile: impact on Lipoprotein(a)

Objectives: Helicobacter pylori is a controversial risk factor for atherosclerosis. We investigated whether the bacterium persistent inflammation or the expression of the cytotoxin-associated gene A (CagA) may affect serum lipids as well as Lipoprotein(a). Design and methods: Two hundred-eleven healthy volunteers were evaluated for lipids and Lipoprotein(a). Helicobacter pylori was characterized by Urea Breath Test and IgG-anti-CagA. apo(a) Kringle-IV polymorphism was genotyped. Results: Prevalence of the infection was 72%; 43% of subjects expressed CagA reactivity. Infected subjects showed increased levels of cholesterol, LDL-cholesterol, and cholesterol/HDL-cholesterol atherogenic index. Association with the Helicobacter pylori CagA(-) strains persisted after the adjustment for covariates. Significant difference between infected and uninfected subjects was found in Lipoprotein(a) levels. This difference did not arise from the Kringle-IV genotype. Conclusions: The infection per se significantly modified serum lipid and Lipoprotein(a) concentrations. CagA does not seem to be a reliable marker of pathogenicity for the atherogenic complications of H. pylori infection

“Exosomes-Mediate Crosstalk in Multiple Myeloma progression and drug Resistance”

Purpose: Exosomes (EXOs) mediate local and systemic cell-tocell communication and regulate cell behavior by transferring mRNA, miRNAs and proteins to recipient cells. Recently, we demonstrated that bone marrow (BM) cancer associated fibroblasts (CAFs) promote tumor progression and drug resistance (DR) in multiple myeloma (MM) (1-3). In this study, we analysed the effect of MM-derived EXOs on CAFs in MGUS to MM transition and, in turn, the effect of CAFs-derived EXOs on endothelial (ECs) and MM cells. Methods: EXOs isolation was performed from conditioned medium (CM) of CAFs purified from BM aspirates of 8 active MM patients and from CM of cultured RPMI8226 and U266 MM cells. Electron microscopy (TEM), dual immunofluorescence-confocal laser-scanning microscopy, western blot (WB), flow cytometry (FC) and qRT-PCR studies were performed to evaluate the CAFsand MM-derived EXOs phenotypes, their miRs content and their mutual effect. Results: TEM analysis of CAFs- and MM-derived EXOs showed a vesicles population with heterogeneous aspect, 50-100 nm sized. WB analysis defined the expression of commonly used EXOs surface markers as CD63, Hsp70 for CAFs and CD63, Hsp70, Alix for MM cells. Confocal microscopy showed the ability both CAFs and MM cells to uptake respectively MM- and CAFs-derived EXOs labelled with fluorescent dyes. Functional studies showed that MM-derived EXOs induce a specific miRNA profile as overexpression of miR-27b-3p, -125b-5p, -214-3p and activated phenotype, as expression of FAP+ and SMA+ antigens, in MGUS and MM CAFs. In turn, MM CAFs released EXOs containing miR-27b-3p, -125b-5p, -214-3p are swallowed by MM cells and ECs. Functional studies also showed that CAFsderived EXOs are able to stimulate angiogenic ability in ECs and to induce bortezomib-resistance in MM cells. Discussions and Conclusions: Overall results suggest an important exosomal crosstalk among tumor cells, CAFs and ECs which lead to BM microenvironmental modifications, favouring MM progression and DR. References 1. Frassanito MA et al. Leukemia 2014; 28: 904-16. 2. Frassanito MA et al. Leukemia 2016; 30: 640-8. 3. Di Marzo L et al. Oncotarget 2016; 7: 60698-711