Sulfonamide Inhibitors of β-Catenin Signaling as Anticancer Agents with Different Output on c-MYC

The Wnt/β-catenin pathway is often found deregulated in cancer. The aberrant accumulation of β-catenin in the cell nucleus results in the development of various malignancies. Specific drugs against this signaling pathway for clinical treatments have not been approved yet. Herein we report inhibitors of β-catenin signaling of potential therapeutic value as anticancer agents. Ethyl 4-((4-(trifluoromethyl)phenyl)sulfonamido)benzoate (compound 14 ) inhibits the effect on Wnt reporter with an IC₅₀ value of 7.0 μM, significantly reduces c-MYC levels, inhibits HCT116 colon cancer cell growth (IC₅₀ 20.2 μM), does not violate Lipinski and Veber rules, and shows predicted Caco-2 and MDCK cell permeability P_app>500 nm s⁻¹. Compound 14 seems to have potential for the development of new anticancer therapies.     

Oxidation state and local structure of plutonium reacted with magnetite, mackinawite, and chukanovite

Due to their redox reactivity, surface sorption characteristics, and ubiquity as corrosion products or as minerals in natural sediments, iron(II)-bearing minerals control to a large extent the environmental fate of actinides. Pu-L(III)-edge XANES and EXAFS spectra were used to investigate reaction products of aqueous (242)Pu(III) and (242)Pu(V) reacted with magnetite, mackinawite, and chukanovite under anoxic conditions. As Pu concentrations in the liquid phase were rapidly below detection limit, oxidation state and local structure of Pu were determined for Pu associated with the solid mineral phase. Pu(V) was reduced in the presence of all three minerals. A newly identified, highly specific Pu(III)-sorption complex formed with magnetite. Solid PuO(2) phases formed in the presence of mackinawite and chukanovite; in the case of chukanovite, up to one-third of plutonium was also present as Pu(III). This highlights the necessity to consider, under reducing anoxic conditions, Pu(III) species in addition to tetravalent PuO(2) for environmental risk assessment. Our results also demonstrate the necessity to support thermodynamic calculations with spectroscopic data.     

Identification of beta-amyloid-binding sites on transthyretin

Transthyretin (TTR) binds to the Alzheimer-related peptide beta-amyloid (Aβ), and may protect against Aβ-induced neurotoxicity. In this work, the specific domains on TTR involved with binding to Aβ were probed. An array was constructed of peptides derived from overlapping sequences from TTR. Strong binding of Aβ to TIAALLSPYSYS (residues 106-117) was detected, corresponding to strand G on the inner β-sheet of TTR. Aβ bound weakly to four contiguous peptides spanning residues 59-83, which includes strand E through the E/F helix and loop. To further pinpoint specific residues on TTR involved with Aβ binding, nine alanine mutants were generated: I68A, I73A, K76A, L82A, I84A, S85A, L17A, T106A and L110A. Aβ binding was significantly inhibited only in L82A and L110A, indicating that Aβ binding to TTR is mediated through these bulky hydrophobic leucines. Aβ binding to L17A and S85A was significantly higher than to wild-type TTR. Enhancement of binding in L17A is postulated to arise from reduced steric restriction to the interior L110 site, since these two residues are adjacent in the native protein. The S85A mutation caused a reduction in TTR tetramer stability; increased Aβ binding is postulated to be a direct consequence of the reduced quaternary stability.     

The effects of target and distractor familiarity on visual search in de novo Parkinson's disease patients: Latent inhibition and novel pop-out.

De novo Parkinson's disease (PD) patients identified presence or absence of a unique shape presented with homogeneous distractors. Response time (RT) was examined as a function of prior experience with target and/or distractor assessing latent inhibition (LI; slower RTs to a target that was formerly a distractor against a background of distractors that were formerly targets as compared with a novel target with distractors that were formerly targets) and novel pop-out effects. PD patients were slower than controls in detecting test-phase targets compared with preexposure-phase targets. Female PD patients with right-side motor symptoms had elevated LI compared with female controls and female PD patients with left-side symptoms. Male PD patients with right-side symptoms did not exhibit LI. Results are discussed in terms of the dopamine hypothesis and the reciprocal relationship between PD and schizophrenia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Characterisation of 3D Bioprinted Human Breast Cancer Model for In Vitro Drug and Metabolic Targeting

Monolayer cultures, the less standard three-dimensional (3D) culturing systems, and xenografts are the main tools used in current basic and drug development studies of cancer research. The aim of biofabrication is to design and construct a more representative in vivo 3D environment, replacing two-dimensional (2D) cell cultures. Here, we aim to provide a complex comparative analysis of 2D and 3D spheroid culturing, and 3D bioprinted and xenografted breast cancer models. We established a protocol to produce alginate-based hydrogel bioink for 3D bioprinting and the long-term culturing of tumour cells in vitro. Cell proliferation and tumourigenicity were assessed with various tests. Additionally, the results of rapamycin, doxycycline and doxorubicin monotreatments and combinations were also compared. The sensitivity and protein expression profile of 3D bioprinted tissue-mimetic scaffolds showed the highest similarity to the less drug-sensitive xenograft models. Several metabolic protein expressions were examined, and the in situ tissue heterogeneity representing the characteristics of human breast cancers was also verified in 3D bioprinted and cultured tissue-mimetic structures. Our results provide additional steps in the direction of representing in vivo 3D situations in in vitro studies. Future use of these models could help to reduce the number of animal experiments and increase the success rate of clinical phase trials.     

The Effect of Duration of Amidation of Fatty Acids with Diethanolamine on the Surfactant Properties

The effects of the duration of direct amidation of fatty acids (FA) with diethanolamine on the composition of the products obtained, their surface-active properties, and ability to stabilize water-in-oil emulsions are studied using the example of tall oil distillate. A certain range of synthesis time that corresponds to the maximum content of diethanolamides in the reaction products, and, as a consequence, the highest surface-active and emulsifying properties of the products is shown to exist. An increase in the synthesis duration time leads to a deterioration of these properties due to accumulation of the products of secondary reactions. A new mechanism of the amidation process that includes secondary transformations of diethanolamine and its condensation products with FA into 1,4-bis(2-hydroxyethyl)piperazine derivatives is proposed. The structures of by-products are confirmed using high-performance liquid chromatography-mass spectrometry (HPLC–MS), infrared (IR), and nuclear magnetic resonance (NMR) spectroscopy methods. It is concluded that the acid value of the product as well as the amount of water released during the synthesis cannot serve as a reliable criterion for completion of the process.     

NMR evaluation of montmorillonite's d-spacings on the formation of phosphocarbonaceous species in intumescent systems

To further investigate the influence of the d-spacing of montmorillonite types derived from Cloisite Na on the process of the intumescent layer formation, composites of poly(ethylene-co-butylacrylate), EBA-30, with an intumescent formulation consisting of ammonium polyphosphate and pentaerythritol were processed and heated at different temperatures. The residues were analyzed by ¹³C, ³¹P, and ²⁷Al solid-state nuclear magnetic resonance (NMR). ¹³C NMR peaks in the aromatic range of 100–150 ppm for samples heated at 350 °C suggest that the montmorillonites with smaller d-spacing (13.5 and 21.8 Å) accounted for the greater amounts of condensed aromatic structures, leading to the char. For d-spacing of 35 Å, the condensation of the polyaromatic structures occurs more slowly, retarding the char formation. The ²⁷Al NMR peak around −15 ppm for samples heated at 280 °C indicates the destruction of montmorillonite structure, producing aluminophosphate species, meaning that the d-spacing influences the reactions under this temperature. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 48053.     

Micrograded ceramic-metal composites

The article shows new designed cermets and processes concerning primary to applications as thermal insulation materials with low emissivity. A new projected microstructure was obtained where dense regions (micropellets) rest inside the main porous pellet. The feature resembles a frozen hypercube, therefore such architecture is called hyper-pellet/ cermet. The processing method to obtain the hyper-cermet is based on sequential tape castings and sintering techniques. Ni-zirconia lamellae were prepared by a special mechanochemical process followed by sintering, which remain inside the main pellets as a dense region. The whole pellet is turned to be porous by employing pore-forming additives. All the constituents and porosity shapes are aligned along the disc/ flake planes. Thermal conductivity is estimated for the materials up to 800 °C by a flash diffusivimeter. Ceramographic analyses show graded density regions with directional constituents and pores. Applications of such materials are foreseen as temperature insulation materials and thermal radiation shields.     

Microstructure design by mechanical alloying

Mixing and coprecipitation processes are, often, not enough in order to reach materials holding several functional components, like selective catalysts that must work simultaneously. Even though when a homogeneous and fine distribution of the constituents is obtained, the affinity between equal phase particles leads to coarsening during the consolidation (sintering) process, as well as on application, such as the material can loose high reactivity. The present work proposes a new consolidation route – sintering by activated surface (SAS) – that employs sacrificial metal layers to avoid coarsening and to increase the diffusion profiles during sintering, once high activity surfaces are exposed during the first sintering step. Regarding limited oxygen potential is established in the sintering atmosphere, the SAS effect is engaged when a specific projected powder microstructure obtained by mechanical alloying (MA) processing is provided. The MA is driven in such a way that yields cermet powders particles with lamellar pod-like like structures, as shown in the SEM image. This projected morphology comprises the ceramic round particles plated by thin metal layers or embedded on them.Porous nickel–zirconia based cermets are studied with Cu and some selected refractory metal additives. The refractory metals are expected to repeal Cu, which remains in pure state at the cermet. By its turn, Cu addition is postulated to prevent coking when fuel-reforming reactions are involved at the application (e.g. in solid oxide fuel cells). Furthermore, Cu is desired since it promotes shrinkage and lower the sintering temperatures. The SAS process running under argon atmospheres with controlled oxygen partial pressure is found to further reduce the sintering temperature by 100–300 °C, for cermets final densities above 60%TD. The sintering behaviour depends on the chosen additive, being Ag, Cu and Mo the most effective ones. The resulted sintered parts attain a suitable density and phase dispersion for catalysis applications.