How Can One Controllably Use of Natural Delta pH in Polyelectrolyte Multilayers?

Most natural and synthetic polyelectrolytes (PEs) possess dissociable groups, and therefore the corresponding structures depend on pH. This enables manipulation of their properties, in special permeability, elasticity and swelling, and this can be made use of in many applications. The effect of individual polymer composition on the dissociation equilibrium is discussed. Different concentrations and pH values during the PE assembly affect concentration of charged groups per molecule on the dissociation equilibrium. Ionic strength also influences the protonation/deprotonation behavior of PE, that can be changed by adding different salt concentration but also varies with the concentration of charged groups in the polymer molecules. Electrostatic interactions of the polymer molecules strongly affect the dissociation equilibrium of weak PEs and, thus, layers architecture and properties that can be regulated by natural pH changes in such processes as self-healing, corrosion and antifouling, drug storage and delivery, etc.ope

Survey of ex vivo drug combination effects in chronic lymphocytic leukemia reveals synergistic drug effects and genetic dependencies

Drug combinations that target critical pathways are a mainstay of cancer care. To improve current approaches to combination treatment of chronic lymphocytic leukemia (CLL) and gain insights into the underlying biology, we studied the effect of 352 drug combination pairs in multiple concentrations by analysing ex vivo drug response of 52 primary CLL samples, which were characterized by "omics" profiling. Known synergistic interactions were confirmed for B-cell receptor (BCR) inhibitors with Bcl-2 inhibitors and with chemotherapeutic drugs, suggesting that this approach can identify clinically useful combinations. Moreover, we uncovered synergistic interactions between BCR inhibitors and afatinib, which we attribute to BCR activation by afatinib through BLK upstream of BTK and PI3K. Combinations of multiple inhibitors of BCR components (e.g., BTK, PI3K, SYK) had effects similar to the single agents. While PI3K and BTK inhibitors produced overall similar effects in combinations with other drugs, we uncovered a larger response heterogeneity of combinations including PI3K inhibitors, predominantly in CLL with mutated IGHV, which we attribute to the target's position within the BCR-signaling pathway. Taken together, our study shows that drug combination effects can be effectively queried in primary cancer cells, which could aid discovery, triage and clinical development of drug combinations