Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20 Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCP-ALL) is a high-risk subtype of acute lymphoblastic leukemia characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab, an anti-CD20 monoclonal antibody is administered to adult BCP-ALL patients with ≥20% CD20+ blasts.

Advancements in cancer immunotherapies targeting CD20: from pioneering monoclonal antibodies to chimeric antigen receptor-modified T cells.

CD20 located predominantly on the B cells plays a crucial role in their development, differentiation, and activation, and serves as a key therapeutic target for the treatment of B-cell malignancies. The breakthrough of monoclonal antibodies directed against CD20, notably exemplified by rituximab, revolutionized the prognosis of B-cell malignancies. Rituximab, approved across various hematological malignancies, marked a paradigm shift in cancer treatment.

Concomitant inhibition of the thioredoxin system and nonhomologous DNA repair potently sensitizes Philadelphia-positive lymphoid leukemia to tyrosine kinase inhibitors.

Breakpoint cluster region-Abelson () gene fusion is an essential oncogene in both chronic myeloid leukemia (CML) and Philadelphia-positive (Ph) B-cell acute lymphoblastic leukemia (B-ALL). While tyrosine kinase inhibitors (TKIs) are effective in up to 95% of CML patients, 50% of Ph B-ALL cases do not respond to treatment or relapse. This calls for new therapeutic approaches for Ph B-ALL.

Overlapping stimulation of subthalamic nucleus and dentato-rubro-thalamic tract in Parkinson's disease after deep brain stimulation.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces tremor, rigidity, and akinesia. According to the literature, the dentato-rubro-thalamic tract (DRTt) is verified target for DBS in essential tremor; however, its role in the treatment of Parkinson's disease is only vaguely described. The aim of our study was to identify the relationship between symptom alleviation in PD patients and the distance of the DBS electrode electric field (EF) to the DRTt.

Lipid shape and packing are key for optimal design of pH-sensitive mRNA lipid nanoparticles.

The ionizable-lipid component of RNA-containing nanoparticles controls the pH-dependent behavior necessary for an efficient delivery of the cargo-the so-called endosomal escape. However, it is still an empirical exercise to identify optimally performing lipids. Here, we study two well-known ionizable lipids, DLin-MC3-DMA and DLin-DMA using a combination of experiments, multiscale computer simulations, and electrostatic theory.

pH-dependent structural transitions in cationic ionizable lipid mesophases are critical for lipid nanoparticle function.

Lipid nanoparticles (LNPs) are advanced core-shell particles for messenger RNA (mRNA) based therapies that are made of polyethylene glycol (PEG) lipid, distearoylphosphatidylcholine (DSPC), cationic ionizable lipid (CIL), cholesterol (chol), and mRNA. Yet the mechanism of pH-dependent response that is believed to cause endosomal release of LNPs is not well understood. Here, we show that eGFP (enhanced green fluorescent protein) protein expression in the mouse liver mediated by the ionizable lipids DLin-MC3-DMA (MC3), DLin-KC2-DMA (KC2), and DLinDMA (DD) ranks MC3 ≥ KC2 > DD despite similar delivery of mRNA per cell in all cell fractions isolated.

Titanium Prostheses for Treating Posttraumatic Ossicular Chain Disruption.

Background: Posttraumatic chain disruption may be caused by blunt head trauma, barotrauma, or a penetrating foreign body. In cases of severe damage to the incus, or its absence, a titanium prosthesis is a good option for reconstructing the ossicular chain.

Methods: A retrospective analysis was performed on 24 cases of posttraumatic ossicular chain disruption that had been treated with a titanium partial or total ossicular replacement prosthesis.

Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein.

Lipid nanoparticles (LNPs) are the most clinically advanced delivery system for RNA-based drugs but have predominantly been investigated for intravenous and intramuscular administration. Subcutaneous administration opens the possibility of patient self-administration and hence long-term chronic treatment that could enable messenger RNA (mRNA) to be used as a novel modality for protein replacement or regenerative therapies. In this study, we show that subcutaneous administration of mRNA formulated within LNPs can result in measurable plasma exposure of a secreted protein.

Assembling responsive microgels at responsive lipid membranes.

Directed colloidal self-assembly at fluid interfaces can have a large impact in the fields of nanotechnology, materials, and biomedical sciences. The ability to control interfacial self-assembly relies on the fine interplay between bulk and surface interactions. Here, we investigate the interfacial assembly of thermoresponsive microgels and lipogels at the surface of giant unilamellar vesicles (GUVs) consisting of phospholipids bilayers with different compositions.

Interfacial properties of lipid sponge-like nanoparticles and the role of stabilizer on particle structure and surface interactions.

The advantage of using nonlamellar lipid liquid crystalline phases has been demonstrated in many applications, such as drug delivery, protein encapsulation and crystallisation. We have recently reported that a mixture of mono- and diglycerides is able to form sponge-like nanoparticles (L3-NPs) with large enough aqueous pores to encapsulate macromolecules such as proteins. Here we use small angle neutron scattering (SANS) to reveal morphology, structural and chemical composition of these polysorbate 80 (P80) stabilized sponge phase nanoparticles, not previously known.

Nanowires for Biosensing: Lightguiding of Fluorescence as a Function of Diameter and Wavelength.

Semiconductor nanowires can act as nanoscaled optical fibers, enabling them to guide and concentrate light emitted by surface-bound fluorophores, potentially enhancing the sensitivity of optical biosensing. While parameters such as the nanowire geometry and the fluorophore wavelength can be expected to strongly influence this lightguiding effect, no detailed description of their effect on in-coupling of fluorescent emission is available to date. Here, we use confocal imaging to quantify the lightguiding effect in GaP nanowires as a function of nanowire geometry and light wavelength.

Successful reprogramming of cellular protein production through mRNA delivered by functionalized lipid nanoparticles.

The development of safe and efficacious gene vectors has limited greatly the potential for therapeutic treatments based on messenger RNA (mRNA). Lipid nanoparticles (LNPs) formed by an ionizable cationic lipid (here DLin-MC3-DMA), helper lipids (distearoylphosphatidylcholine, DSPC, and cholesterol), and a poly(ethylene glycol) (PEG) lipid have been identified as very promising delivery vectors of short interfering RNA (siRNA) in different clinical phases; however, delivery of high-molecular weight RNA has been proven much more demanding. Herein we elucidate the structure of hEPO modified mRNA-containing LNPs of different sizes and show how structural differences affect transfection of human adipocytes and hepatocytes, two clinically relevant cell types.

Direct comparison between in vivo and in vitro microsized particle phagocytosis assays in Drosophila melanogaster.

The effects of micro and nanoparticles on the innate immune system have been widely investigated and a general lack of agreement between in vivo and in vitro assays has been observed. In order to determine the origin of these discrepancies, there is a need for comparing the results of in vivo and in vitro phagocytosis assays obtained using the same particles and same immune cells. Here, we establish an in vivo polystyrene microsized particle phagocytosis assay in Drosophila melanogaster and compare it with an in vitro assay consisting of exposing the same immune cells in culture to the same particles.

Supported Fluid Lipid Bilayer as a Scaffold to Direct Assembly of RNA Nanostructures.

RNA architectonics offers the possibility to design and assemble RNA into specific shapes, such as nanoscale 3D solids or nanogrids. Combining the minute size of these programmable shapes with precise positioning on a surface further enhances their potential as building blocks in nanotechnology and nanomedicine. Here we describe a bottom-up approach to direct the arrangement of nucleic acid nanostructures by using a supported fluid lipid bilayer as a surface scaffold.

Temperature responsive lipid liquid crystal layers with embedded nanogels.

Polymer nanogels are embedded within layers consisting of a nonlamellar liquid crystalline lipid phase to act as thermoresponsive controllers of layer compactness and hydration. As the nanogels change from the swollen to the collapsed state via a temperature trigger, they enable on-demand release of water from the mixed polymer-lipid layer while the lipid matrix remains intact. Combining stimuli-responsive polymers with responsive lipid-based mesophase systems opens up new routes in biomedical applications such as functional biomaterials, bioanalysis and drug delivery.

Interfacial properties of POPC/GDO liquid crystalline nanoparticles deposited on anionic and cationic silica surfaces.

Reversed lipid liquid crystalline nanoparticles (LCNPs) of the cubic micellar (I) phase have high potential in drug delivery applications due to their ability to encapsulate both hydrophobic and hydrophilic drug molecules. Their interactions with various interfaces, and the consequences for the particle structure and integrity, are essential considerations in their effectiveness as drug delivery vehicles. Here, we have studied LCNPs formed of equal fractions of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and glycerol dioleate in the presence of different fractions of the stabilizer Polysorbate 80.

Diffusion through Pig Gastric Mucin: Effect of Relative Humidity.

Mucus covers the epithelium found in all intestinal tracts, where it serves as an important protecting barrier, and pharmaceutical drugs administrated by the oral, rectal, vaginal, ocular, or nasal route need to penetrate the mucus in order to reach their targets. Furthermore, the diffusion in mucus as well as the viscosity of mucus in the eyes, nose and throat can change depending on the relative humidity of the surrounding air. In this study we have investigated how diffusion through gels of mucin, the main protein in mucus, is affected by changes in ambient relative humidity (i.

Surface nanostructures for fluorescence probing of supported lipid bilayers on reflective substrates.

The fluorescence interference contrast (FLIC) effect prevents the use of fluorescence techniques to probe the continuity and fluidity of supported lipid bilayers on reflective materials due to a lack of detectable fluorescence. Here we show that adding nanostructures onto reflective surfaces to locally confer a certain distance between the deposited fluorophores and the reflecting surface enables fluorescence detection on the nanostuctures. The nanostructures consist of either deposited nanoparticles or epitaxial nanowires directly grown on the substrate and are designed such that they can support a lipid bilayer.

Model-free estimation of the effective correlation time for C-H bond reorientation in amphiphilic bilayers: (1)H-(13)C solid-state NMR and MD simulations.

Molecular dynamics (MD) simulations give atomically detailed information on structure and dynamics in amphiphilic bilayer systems on timescales up to about 1 μs. The reorientational dynamics of the C-H bonds is conventionally verified by measurements of (13)C or (2)H nuclear magnetic resonance (NMR) longitudinal relaxation rates R1, which are more sensitive to motional processes with correlation times close to the inverse Larmor frequency, typically around 1-10 ns on standard NMR instrumentation, and are thus less sensitive to the 10-1000 ns timescale motion that can be observed in the MD simulations. We propose an experimental procedure for atomically resolved model-free estimation of the C-H bond effective reorientational correlation time τe, which includes contributions from the entire range of all-atom MD timescales and that can be calculated directly from the MD trajectories.

Association of anionic surfactant and physisorbed branched brush layers probed by neutron and optical reflectometry.

Pre-adsorbed branched brush layers were formed on silica surfaces by adsorption of a diblock copolymer consisting of a linear cationic block and an uncharged bottle-brush block. The charge of the silica surface was found to affect the adsorption, with lower amounts of the cationic polyelectrolyte depositing on less charged silica. Cleaning under basic conditions rendered surfaces more negatively charged (more negative zeta-potential) than acid cleaning and was therefore used to increase polyelectrolyte adsorption.

Non-lamellar lipid liquid crystalline structures at interfaces.

The self-assembly of lipids leads to the formation of a rich variety of nano-structures, not only restricted to lipid bilayers, but also encompassing non-lamellar liquid crystalline structures, such as cubic, hexagonal, and sponge phases. These non-lamellar phases have been increasingly recognized as important for living systems, both in terms of providing compartmentalization and as regulators of biological activity. Consequently, they are of great interest for their potential as delivery systems in pharmaceutical, food and cosmetic applications.

Assembly of RNA nanostructures on supported lipid bilayers.

The assembly of nucleic acid nanostructures with controlled size and shape has large impact in the fields of nanotechnology, nanomedicine and synthetic biology. The directed arrangement of nano-structures at interfaces is important for many applications. In spite of this, the use of laterally mobile lipid bilayers to control RNA three-dimensional nanostructure formation on surfaces remains largely unexplored.