Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies.

Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN.

Nanoliter Scale Parallel Liquid-Liquid Extraction for High-Throughput Purification on a Droplet Microarray.

In the current drug discovery process, the synthesis of compound libraries is separated from biological screenings both conceptually and technologically. One of the reasons is that parallel on-chip high-throughput purification of synthesized compounds is still a major challenge. Here, on-chip miniaturized high-throughput liquid-liquid extraction in volumes down to 150 nL with efficiency comparable to or better than large-scale extraction utilizing separation funnels is demonstrated. The method is based on automated and programmable merging of arrays of aqueous nanoliter droplets with organic droplets. Multi-step extraction performed simultaneously or with changing conditions as well as handling of femtomoles of compounds are demonstrated. In addition, the extraction efficiency is analyzed with a fast optical readout as well as matrix-assisted laser desorption ionization-mass spectrometry on-chip detection. The new massively parallel and miniaturized purification method adds another important tool to the chemBIOS concept combining chemical combinatorial synthesis with biological screenings on the same miniaturized droplet microarray platform, which will be essential to accelerate drug discovery.

Equilibrium droplet shapes on chemically patterned surfaces: theoretical calculation, phase-field simulation, and experiments.

HYPOTHESIS: Droplet wetting on a solid substrate is affected by the surface heterogeneity. Introducing patterned wettability on the solid substrate is expected to engender anisotropic wetting morphologies, thereby manipulating droplet wetting behaviors. However, when the droplet size is comparable with that of the surface heterogeneity, the wetting morphologies cannot be depicted by the quintessential Cassie's theory but should be possible to be predicted from the perspective of thermodynamics via surface energy minimization. METHODS: Here, we investigate the equilibrium droplet shapes on chemically patterned substrates by using an analytical model, phase-field simulations, and experiments. The former two methods are sharp and diffuse interface treatments, respectively, which both are based on minimizing the free energy of the system. The experimental results are obtained by depositing droplets on chemically patterned glass substrates. FINDINGS: Various anisotropic wetting shapes are found from the three methods. Excellent agreement is observed between different methods, showing the possibility to quantify the anisotropic wetting droplet morphologies on patterned substrates by present methods. We also address a series of non-rotationally symmetric droplet shapes, which is the first resport about these special wetting morphologies. Furthermore, we reveal the anisotropic wetting shapes in a quasi-equilibrium evaporation process.

Designing Inherently Photodegradable Cell-Adhesive Hydrogels for 3D Cell Culture.

Light-based microfabrication techniques constitute an indispensable approach to fabricate tissue assemblies, benefiting from noncontact spatially and temporarily controlled manipulation of soft matter. Light-triggered degradation of soft materials, such as hydrogels, is important in tissue engineering, bioprinting, and related fields. The photoresponsiveness of hydrogels is generally not intrinsic and requires complex synthetic procedures wherein photoresponsive crosslinking groups are incorporated into the hydrogel. This paper demonstrates a novel biocompatible and inherently photodegradable poly(ethylene glycol) methacrylate (PEGMA)-based gelatin-methacryloyl (GelMA)-containing hydrogel that can be used to culture cells in 3D for at least 14 d. These gels are conveniently and quickly degraded via UV irradiation for 10 min to produce structured hydrogels of various geometries, sizes, and free-standing cell-laden hydrogel particles. These structures can be flexibly produced on demand. In particular, photodegradation can be temporarily delayed from photopolymerization, offering an alternative to hydrogel array production via photopolymerization with a photomask. The paper investigates the influences of hydrogel composition and swelling liquid on both its photodegradability and biocompatibility.

Liquid Wells as Self-Healing, Functional Analogues to Solid Vessels.

Liquids are traditionally handled and stored in solid vessels. Solid walls are not functional, adaptive, or self-repairing, and are difficult to remove and re-form. Liquid walls can overcome these limitations, but cannot form free-standing 3D walls. Herein, a liquid analogue of a well, termed a "liquid well" is introduced. Water tethered to a surface with hydrophobic-hydrophilic core-shell patterns forms stable liquid walls capable of containing another immiscible fluid, similar to fluid confinement by solid walls. Liquid wells with different liquids, volumes, and shapes are prepared and investigated by confocal and Raman microscopy. The confinement of various low-surface-tension liquids (LSTLs) on surfaces by liquid wells can compete with or be complementary to existing confinement strategies using perfluorinated surfaces, for example, in terms of the shape and height of the confined LSTLs. Liquid wells show unique properties arising from their liquid aggregate state: they are self-healing, dynamic, and functional, that is, not restricted to a passive confining role. Water walls can be easily removed and re-formed, making them interesting as sacrificial templates. This is demonstrated in a process termed water-templated polymerization (WTP). Numerical phase-field model simulations are performed to scrutinize the conditions required for the formation of stable liquid wells.