PurposeCPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML).Patients and MethodsIn this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival.ResultsCPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60.ConclusionCPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

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Viroporins are virally encoded, membrane-active proteins, which enhance viral replication and assist in egress of viruses from host cells. The 2B proteins in the picornaviridae family are known to have viroporin-like properties, and play critical roles during virus replication. The 2B protein of Hepatitis A Virus (2B), an unusual picornavirus, is somewhat dissimilar from its analogues in several respects. HAV 2B is approximately 2.5 times the length of other 2B proteins, and does not disrupt calcium homeostasis or glycoprotein trafficking. Additionally, its membrane penetrating properties are not yet clearly established. Here we show that the membrane interacting activity of HAV 2B is localized in its C-terminal region, which contains an alpha-helical hairpin motif. We show that this region is capable of forming small pores in membranes and demonstrates lipid specific activity, which partially rationalizes the intracellular localization of full-length 2B. Using a combination of biochemical assays and molecular dynamics simulation studies, we also show that HAV 2B demonstrates a marked propensity to dimerize in a crowded environment, and probably interacts with membranes in a multimeric form, a hallmark of other picornavirus viroporins. In sum, our study clearly establishes HAV 2B as a bona fide viroporin in the picornaviridae family.

Experimental values of density, viscosity, and refractive index at (298.15, 303.15, and 308.15) K and the speed of sound data at 298.15 K for the binary mixtures of dimethyl carbonate with methanol, chloroform, carbon tetrachloride, cyclohexane, and dichloromethane are presented over the whole range of mixture composition. From these data, excess molar volume, deviations in viscosity, speed of sound, isentropic compressibility, and Lorenz−Lorentz molar refractivity have been calculated. These results are fit to the Redlich−Kister type polynomial equation of the third degree to derive the binary coefficients. The standard error values are estimated between the calculated and experimental data points.

Experimental values of density, viscosity, and refractive index at 298.15, 303.15, and 308.15 K, and the speed of sound at 298.15 K, for the binary mixtures of 2-chloroethanol with n-alkanols (C1−C6) are presented over the entire mole fraction range. Using these data, excess molar volume and deviations in viscosity, Δη, speed of sound, Δu, and isentropic compressibility, Δk S, have been calculated. Excess quantities and deviations have been fitted to the Redlich−Kister equation to derive the binary coefficients with the standard errors between the experimental and calculated quantities. Sign and magnitude of the mixing quantities have been discussed to study the nature of molecular interactions in binary mixtures.