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Background: The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective gamma-secretase inhibitor in patients with advanced triple-negative breast cancer. Methods: The dose-finding part was based on a 2×3 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination. Results and Conclusions: The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m2. At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients (N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%])., SCOPUS: ar.j, info:eu-repo/semantics/published

The thin brown perisperm (skin) that envelops hazelnut kernels is usually removed after roasting process, leading a phenolic-rich by-product. Principal aim of this work was to characterise the total antioxidant activity of phenolic extracts obtained from roasted “Nocciola Piemonte PGI” hazelnuts skin. Different extraction solvents (methanol, acidified methanol, ethanol, acidified ethanol, and acetone/water) and different protocols (cold solvent-assisted extraction and semi-automated Soxhlet extraction) were employed. The influence of different roasting degree (180 °C/10 min and 180 °C/20 min) was also investigated. DPPHradical dot and ABTSradical dot+ radical-scavenging methods, ferrous ions chelation activity and inhibition of lipid peroxidation investigated in this study demonstrated significant antioxidant properties for hazelnut skin phenolics. The main mechanism involved appeared the antiradical activity, strictly related to the total phenolic content (r = −0.8798 and −0.8285 for DPPHradical dot and ABTSradical dot+ assays, respectively). The acidification of extraction solvents led to a significant decrease of antiradical activity, whilst the different roasting conditions significantly influenced the chelation activity and the inhibition of lipid peroxidation, showing higher effectiveness for high-roasted hazelnut skin extracts. Conversely, the direct measure of the antioxidant capacity of defatted hazelnut skins revealed higher ABTSradical dot+ scavenging properties for medium-roasted sample., info:eu-repo/semantics/published

info:eu-repo/semantics/nonPublished

info:eu-repo/semantics/nonPublished