A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia

B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders.     

Migration of specific planar grain boundaries in bicrystals: application of magnetic fields and mechanical stresses

Recent research on the dynamics of planar grain boundaries is reviewed. Novel measuring techniques developed for in situ observation and recording of magnetically and stress driven grain boundary migration are presented. The results of migration measurements obtained on bismuth, zinc and aluminum bicrystals are addressed. The experiments revealed that the inclination of a 〈112〉 tilt boundary in Bi has a very strong influence on its mobility. The migration of planar 〈10$ \bar 1 $ \bar 1 0〉 tilt grain boundaries with different misorientation angles was measured in situ in bicrystals of high purity zinc. The results proved that there is a pronounced misorientation dependence of grain boundary mobility in the investigated angular range. The shear stress induced migration of planar symmetric 〈100〉 tilt boundaries in aluminum bicrystals was observed to be accompanied by a lateral translation of the adjacent grains. The coupling between boundary motion and shearing is not confined to low angle and some low Σ high angle boundaries, but occurs also for noncoincidence high angle 〈100〉 tilt boundaries. It has been found that also for stress induced grain boundary motion there is a misorientation dependence of the migration activation parameters. Lower values of the activation enthalpy and the pre-exponential mobility factor can be associated with boundaries with tilt angles close to low Σ CSL orientation relationships.     

Injection of Microporous Annealing Particle (MAP) Hydrogels in the Stroke Cavity Reduces Gliosis and Inflammation and Promotes NPC Migration to the Lesion

With the number of deaths due to stroke decreasing, more individuals are forced to live with crippling disability resulting from the stroke. To date, no therapeutics exist after the first 4.5 h after the stroke onset, aside from rest and physical therapy. Following stroke, a large influx of astrocytes and microglia releasing proinflammatory cytokines leads to dramatic inflammation and glial scar formation, affecting brain tissue's ability to repair itself. Pathological conditions, such as a stroke, trigger neural progenitor cells (NPCs) proliferation and migration toward the damaged site. However, these progenitors are often found far from the cavity or the peri‐infarct tissue. Poststroke tissue remodeling results in a compartmentalized cavity that can directly accept a therapeutic material injection. Here, this paper shows that the injection of a porous hyaluronic acid hydrogel into the stroke cavity significantly reduces the inflammatory response following stroke while increasing peri‐infarct vascularization compared to nonporous hydrogel controls and stroke only controls. In addition, it is shown that the injection of this material impacts NPCs proliferation and migration at the subventricular zone niche and results, for the first time, in NPC migration into the stroke site.     

Analysis of microstructure and microhardness of Zr-2.5Nb processed by High-Pressure Torsion (HPT)

Nanostructured materials have been widely studied due to the improvement of their mechanical properties comparing to those of coarse grain materials. The present work intended to analyze the microstructure and microhardness of Zr-2.5Nb processed by high-pressure torsion (HPT), one of the severe plastic deformation techniques. The deformations were carried out at room temperature using a pressure of 5?GPa and 5 anvil turns. Vickers indentation was used to evaluate the microhardness of the samples. Transmission electron microscopy and X-ray diffraction were used to analyze the microstructure. The results showed a significant refinement from the initial microstructure achieving nanometric grain size around 50?nm and phase transformation α?→?ω?+?β_I induced by shear. The Vickers microhardness values of the material submitted to HPT technique were significantly higher than those of non-deformed material. Also, HPT procedure resulted in a huge grain refinement of the material and in phase transformation.     

Fullerene: biomedical engineers get to revisit an old friend

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The occurrence of perchlorate during drinking water electrolysis using BDD anodes

Electrochemical studies were carried out to estimate the risks of perchlorate formation in drinking water disinfected by direct electrolysis. Boron Doped Diamond (BDD) anodes were used in laboratory and commercially available cells at 20 °C. The current density was changed between 50 and 500 A m⁻². For comparison, other anode materials such as platinum and mixed oxide were also tested. It was found that BDD anodes have a thousandfold higher perchlorate formation potential compared with the other electrode materials that were tested. In long-term discontinuous experiments all the chloride finally reacted to form perchlorate. The same result was obtained when probable oxychlorine intermediates (OCl⁻, ClO₂⁻, ClO₃⁻) were electrolysed in synthetic waters in the ppm range of concentrations. The tendency to form perchlorate was confirmed when the flow rate of drinking water was varied between 100 and 300 L h⁻¹ and the temperature increased to 30 °C. In a continuous flow mode of operation a higher chloride concentration in the water resulted in a lower perchlorate formation. This can be explained by reaction competition of species near and on the anode surface for experiments both with synthetic and local drinking waters. It is concluded that the use of electrodes producing highly reactive species must be more carefully controlled in hygienically and environmentally oriented applications.     

Artificial gravity loading increases the effects of the glutamate transporter inhibitors on the glutamate release and uptake in rat brain nerve terminals

The present study evaluated the effect of artificial gravity loading on transporter-mediated uptake and release of L-glutamate using the inhibitors of glutamate transporters as tools. The competitive nontransportable, DL-threo-beta-benzyloxyaspartate (DL-TBOA), and transportable, DL-threo-beta-hydroxyaspartate (DL-THA), inhibitors were demonstrated to better inhibit the L-[¹⁴C]glutamate uptake under centrifuge-induced hypergravity compared with the normal gravity control. The effect of DL-TBOA on depolarization-induced carrier-mediated L-[¹⁴C]glutamate release also increased after hypergravity loading in Na⁺- and low [Na⁺] NMDG- supplemented media. 10 µM DL-TBOA-induced decrease in L-[¹⁴C]glutamate release in Na⁺ — supplemented medium was 15.2±2.2 % in the control experiments and 26.2±3.9 % after centrifuge-induced loading (P≤0,05) and in low [Na⁺] medium was 37.0±2.5 % and 45.0±3.4 %, respectively.     

New proposal in the thermodynamic analysis of complex heat regeneration systems

This paper presents a new approach for analyzing and/or synthesizing the heat regeneration system, which has many applications in various energy conversion plants (ECP) and between ones. The method is applied for optimizing heat exchanger networks (HENs) operating below ambient temperature conditions as an application for refrigeration machines. Exergy and exergoeconomic methods are adapted for the optimization of three-flow heat exchangers. Few cases are illustrated and discussed. Also, the heuristic rules and design criteria for pinch analysis for an optimized HEN are presented.