Extreme resilience in cochleate nanoparticles

Cochleates, prospective nanoscale drug delivery vehicles, are rolls of negatively-charged phospholipid membrane layers. The membrane layers are held together by calcium ions; however, neither the magnitude of membrane-interaction forces, nor the overall mechanical properties of cochleates have been known. Here we manipulated individual nanoparticles with atomic force microscopy to characterize their nanomechanical behavior. Their stiffness (4.2-12.5 N/m) and membrane-rupture forces (45.3-278 nN) are orders magnitude greater than those of the tough viral nanoshells. Even though the fundamental building material of cochleates is a fluid membrane, the combination of supramolecular geometry, the cross-linking action of calcium and the tight packing of the ions apparently lead to extreme mechanical resilience. The supramolecular design of cochleates may provide efficient protection for encapsulated materials and give clues to understanding biomolecular structures of similar design, such as the myelinated axon

Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax

The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10−4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax–rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL