Survival with nal-IRI (liposomal irinotecan) plus 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in per-protocol and non-per-protocol populations of NAPOLI-1 : expanded analysis of a global phase 3 trial

Background: In the phase 3 randomised NAPOLI-1 clinical study, a 45% increase in median overall survival (OS) was shown with liposomal irinotecan, 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) versus 5-FU/LV in patients with metastatic pancreatic cancer progressing after gemcitabine-based therapy. Here, we report data from a pre-specified, expanded analysis of outcomes in the per-protocol (PP) population. Materials and methods: The PP population comprised patients receiving ≥80% of planned treatment during the first 6 weeks, with no major protocol violations. A post-hoc analysis of the non-PP population was also performed. Results: For PP patients, median OS was 8.9 (95% confidence interval: 6.4–10.5) months with nal-IRI+5-FU/LV (n = 66) vs 5.1 (4.0–7.2) months with 5-FU/LV (n = 71; unstratified hazard ratio [HR] 0.57, p = 0.011). For non-PP patients, it was 4.4 (3.3–5.3) months with nal-IRI+5-FU/LV (n = 51) vs 2.8 (1.7–3.2) months with 5-FU/LV (n = 48; unstratified HR 0.64, p = 0.0648). Conclusion: A statistically significant survival advantage was observed with nal-IRI+5-FU/LV vs 5-FU/LV in the PP patient population

Simulation, Experiment, and Evolution: Understanding Nucleation in Protein S6 Folding

In this study, we explore nucleation and the transition state ensemble of the ribosomal protein S6 using a Monte Carlo Go model in conjunction with restraints from experiment. The results are analyzed in the context of extensive experimental and evolutionary data. The roles of individual residues in the folding nucleus are identified and the order of events in the S6 folding mechanism is explored in detail. Interpretation of our results agrees with, and extends the utility of, experiments that shift f-values by modulating denaturant concentration and presents strong evidence for the realism of the mechanistic details in our Monte Carlo Go model and the structural interpretation of experimental f-values. We also observe plasticity in the contacts of the hydrophobic core that support the specific nucleus. For S6, which binds to RNA and protein after folding, this plasticity may result from the conformational flexibility required to achieve biological function. These results present a theoretical and conceptual picture that is relevant in understanding the mechanism of nucleation in protein folding.Comment: PNAS in pres

Geometric observation for the Bures fidelity between two states of a qubit

In this Brief Report, we present a geometric observation for the Bures fidelity between two states of a qubit.Comment: 4 pages, 1 figure, RevTex, Accepted by Phys. Rev.