Novel pathways involved in cisplatin resistance identified by a proteomics approach in non-small-cell lung cancer cells.

Although platinum-based chemotherapy remains the standard-of-care for most patients with advanced non-small-cell lung cancer (NSCLC), acquired resistance occurs frequently predicting poor prognosis. To examine the mechanisms underlying platinum resistance, we have generated and characterized by proteomic approach the resistant A549 CDDP-resistant (CPr-A549) and their parental A549 cells, identifying 15 proteins differentially expressed (13 upregulated and 2 downregulated in CPr-A549). In details, we highlighted a coherent network of proteins clustering together and involved in altered protein folding and endoplasmic reticulum stress, correlated with epithelial to mesenchymal transition process and cancer stem cell markers, where vimentin played a hierarchical role, ultimately resulting in increased aggressive features. By using publicly available databases we showed that the modulated proteins could contribute to NSCLC carcinogenesis and correlate with NSCLC patients prognosis and survival probability, suggesting that they can be used as novel potential prognostic/predictive biomarkers or therapeutic targets to overcome platinum-resistance.

HSP90 identified by a proteomic approach as druggable target to reverse platinum resistance in ovarian cancer.

Acquired resistance to platinum (Pt)-based therapies is an urgent unmet need in the management of epithelial ovarian cancer (EOC) patients. Here, we characterized by an unbiased proteomics method three isogenic EOC models of acquired Pt resistance (TOV-112D, OVSAHO, and MDAH-2774). Using this approach, we identified several differentially expressed proteins in Pt-resistant (Pt-res) compared to parental cells and the chaperone HSP90 as a central hub of these protein networks. Accordingly, up-regulation of HSP90 was observed in all Pt-res cells and heat-shock protein 90 alpha isoform knockout resensitizes Pt-res cells to cisplatin (CDDP) treatment. Moreover, pharmacological HSP90 inhibition using two different inhibitors [17-(allylamino)-17-demethoxygeldanamycin (17AAG) and ganetespib] synergizes with CDDP in killing Pt-res cells in all tested models. Mechanistically, genetic or pharmacological HSP90 inhibition plus CDDP -induced apoptosis and increased DNA damage, particularly in Pt-res cells. Importantly, the antitumor activities of HSP90 inhibitors (HSP90i) were confirmed both ex vivo in primary cultures derived from Pt-res EOC patients ascites and in vivo in a xenograft model. Collectively, our data suggest an innovative antitumor strategy, based on Pt compounds plus HSP90i, to rechallenge Pt-res EOC patients that might warrant further clinical evaluation.

Influence of Pasture on Stearoyl-CoA Desaturase and miRNA 103 Expression in Goat Milk: Preliminary Results.

The effect of pasture on the stearoyl-CoA desaturase (SCD) and miRNA 103 expression was evaluated on dairy goats divided into two homogeneous groups (G, grazing, and S, stable). Group S was housed in a stall and received alfalfa hay as forage, while group G was led to pasture. The goats of both the groups received the same amount of concentrate. Milk yield did not differ statistically between the groups. Group G showed significantly higher fat (4.10% vs. 2.94%, p < 0.01) and protein percentage (3.43% vs. 3.25%; p < 0.05) than group S. Among milk fatty acids, group S showed significantly higher levels of saturated fatty acids (SFA) and lower values of mono-unsaturated fatty acid (MUFA). The percentages of polyunsaturated fatty acid (PUFA) were not different between groups even if pasture significantly affected the percentages of C18:3 and total omega 3. In group G, total CLAs were twice than in group S (0.646% vs. 0.311%; p < 0.01) mainly due to the differences in CLA cis9 trans 11 (0.623% vs. 0.304%; p < 0.01). Milk total CLA in grazing group was significantly (p < 0.01) higher in August according to the highest value of both linoleic and α-linolenic acids in the pasture. In grazing animals, SCD expression decreased from April to June, increased in July and decreased again in August, while it was almost unvaried along the trial in group S. By contrast, the expression of miRNA 103 showed a similar trend for both groups, decreasing from April to June, increasing in July and falling down in August. To our knowledge, this is the first observation of the effects of pasture on miRNA expression in milk from ruminant species.

Diet effect on short- and long-term glycaemic response in adult healthy cats.

In the paper the short- and long-term glycaemic response after 4 diet programmes was evaluated. Each diet programme was alternatively administered to 6 healthy cats for 30 days. At the end of each period cats were weighed and underwent blood sampling for glucose and fructosamine determination. Glycaemia was measured every 2 hours for 24 hours using an automated glucometer. Very high protein level and low starch (VHP÷LS) and high protein and moderate starch level (HP÷LS) diets showed glucose (Mean and Peak) and fructosamine values signi cantly lower compared to the moderate protein and high starch diets (MP/HS). It is likely that these results are due to the contemporary e ect of the following nutritional characteristics: protein level, protein/starch ratio and dietary bre. All these parameters were higher in VHP/LS and HP/MS diets. These preliminary results suggest that the use of diets with high protein/starch ratio and soluble bre levels favours the carbohydrate metabolism of healthy cats.