On-line hemodiafiltration modulates atherosclerosis signaling in peripheral lymphomonocytes of hemodialysis patients.

BACKGROUND: Hemodialysis patients present a dramatic increase in cardiovascular morbidity/mortality. Circulating immune cells, activated by both uremic milieu and dialysis, play a key role in the pathogenesis of dialysis-related vascular disease. The aim of our study was to identify, through a high-throughput approach, differences in gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of patients treated with on-line hemodiafiltration and bicarbonate hemodialysis. METHODS: The transcriptomic profile was investigated in PBMCs isolated from eight patients on on-line hemodiafiltration and eight patients on bicarbonate hemodialysis by microarray analysis. The results were evaluated by statistical and functional pathway analysis and validated by real time PCR (qPCR) in an independent cohort of patients (on-line hemodiafiltration N = 20, bicarbonate hemodialysis n = 20). RESULTS: Eight hundred and forty-seven genes were differentially expressed in patients treated with  on-line hemodiafiltration and bicarbonate hemodialysis. Thirty-seven functional gene networks were identified and atherosclerosis signaling was the top canonical pathway regulated by on-line hemodiafiltration. Among the genes of this pathway, on-line hemodiafiltration was associated with a reduced expression of Platelet-derived growth factor A chain (PDGF A), Clusterin, Monoamine Oxidase A, Interleukin-6 (IL-6) and Vascular Endothelial Growth Factor C (VEGF-)C and with an increase of Apolipoprotein E. qPCR confirmed the microarray results. Platelet derived growth factor AA (PDGF-AA), IL-6 and VEGF-C serum levels were significantly lower in the on-line hemodiafiltration group. Finally, 10 patients previously on bicarbonate hemodialysis  were switched to on-line hemodiafiltration and PBMCs were harvested after 6 months. The qPCR results from this perspective group confirmed the modulation of atherosclerotic genes observed in the cross-sectional analysis. CONCLUSIONS: Our data suggest that type of dialysis (on-line hemodiafiltration versus bicarbonate hemodialysis) may modulate the expression of several genes involved in the pathogenesis of atherosclerotic disease.

Understanding Discomfort in Order to Appropriately Treat Fever.

Although national and international guidelines on the management of childhood and adolescent fever are available, some inadequate practices persist, both from parents and healthcare professionals. The main goal of bringing children's temperature back to normal can lead to the choice of inappropriate drugs or non-necessary combination/alternation of antipyretic treatments. This behavior has been described in the last 35 years with the concept of fever-phobia, caused also by the dissemination of unscientific information and social media. It is therefore increasingly important that pediatricians continue to provide adequate information to parents in order to assess the onset of signs of a possible condition of the child's discomfort rather than focusing only on temperature. In fact, there is no clear and unambiguous definition of discomfort in literature. Clarifying the extent of the feverish child's discomfort and the tools that could be used to evaluate it would therefore help recommend that antipyretic treatment is appropriate only if fever is associated with discomfort.

FZD10 Carried by Exosomes Sustains Cancer Cell Proliferation.

Extracellular vesicles (EVs) are involved in intercellular communication during carcinogenesis, and cancer cells are able to secrete EVs, in particular exosomes containing molecules, that can be transferred to recipient cells to induce pathological processes and significant modifications, as metastasis, increase of proliferation, and carcinogenesis evolution. FZD proteins, a family of receptors comprised in the Wnt signaling pathway, play an important role in carcinogenesis of the gastroenteric tract. Here, a still unknown role of Frizzled 10 (FZD10) protein was identified. In particular, the presence of FZD10 and FZD10-mRNA in exosomes extracted from culture medium of the untreated colorectal, gastric, hepatic, and cholangio cancer cell lines, was detected. A substantial reduction in the FZD10 and FZD10-mRNA level was achieved in FZD10-mRNA silenced cells and in their corresponding exosomes. Concomitantly, a significant decrease in viability of the silenced cells compared to their respective controls was observed. Notably, the incubation of silenced cells with the exosomes extracted from culture medium of the same untreated cells promoted the restoration of the cell viability and, also, of the FZD10 and FZD10-mRNA level, thus indicating that the FZD10 and FZD10-mRNA delivering exosomes may be potential messengers of cancer reactivation and play an active role in long-distance metastatization.

TGF-ß as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives.

Therapeutic attempts to treat hepatocellular carcinoma (HCC) frequently result in a poor response or treatment failure. The efficacy of approved drugs and survival expectancies is affected by an ample degree of variability that can be explained at least in part by the enormous between-patient cellular and molecular heterogeneity of this neoplasm. Transforming growth factor-ß (TGF-ß) is hyperactivated in a large fraction of HCCs, where it influences complex interactive networks covering multiple cell types and a plethora of other local soluble ligands, ultimately establishing several malignancy traits. This cytokine boosts the invasiveness of cancerous epithelial cells through promoting the epithelial-to-mesenchymal transition program, but also skews the phenotype of immune cells toward a tumor-supporting status. Here, we discuss recent strategies pursued to offset TGF-ß-dependent processes that promote metastatic progression and immune surveillance escape in solid cancers, including HCC. Moreover, we report findings indicating that TGF-ß reduces the expression of the proinflammatory factors CCL4 and interleukin-1ß (IL-1ß in human ex vivo treated HCC tissues. While this is consistent with the anti-inflammatory properties of TGF-ß, whether it is an outright tumor promoter or suppressor is still a matter of some debate. Indeed, IL-1ß has also been shown to support angiogenesis and cell invasiveness in some cancers. In addition, we describe an inhibitory effect of TGF-ß on the secretion of CCL2 and CXCL1 by HCC-derived fibroblasts, which suggests the existence of an indirect stroma-mediated functional link between TGF-ß and downstream immunity.