2,188 research outputs found
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
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