Chemical Antibody Mimics Inhibit Cadherin-Mediated Cell–Cell Adhesion: A Promising Strategy for Cancer Therapy

One of the most promising strategies to treat cancer is the use of therapeutic antibodies that disrupt cell–cell adhesion mediated by dysregulated cadherins. The principal site where cell–cell adhesion occurs encompasses Trp2 found at the N-terminal region of the protein. Herein, we employed the naturally exposed highly conserved peptide Asp1-Trp2-Val3-Ile4-Pro5-Pro6-Ile7, as epitope to prepare molecularly imprinted polymer nanoparticles (MIP-NPs) to recognize cadherins. Since MIP-NPs target the site responsible for adhesion, they were more potent than commercially available therapeutic antibodies for inhibiting cell–cell adhesion in cell aggregation assays, and for completely disrupting three-dimensional tumor spheroids as well as inhibiting invasion of HeLa cells. These biocompatible supramolecular anti-adhesives may potentially be used as immunotherapeutic or sensitizing agents to enhance antitumor effects of chemotherapy.     

Divergent and Overlapping Roles for Selected Phytochemicals in the Regulation of Pathological Cardiac Hypertrophy

Plant-based foods, like fruits, vegetables, whole grains, legumes, nuts, seeds and other foodstuffs, have been deemed as heart healthy. The chemicals within these plant-based foods, i.e., phytochemicals, are credited with protecting the heart. However, the mechanistic actions of phytochemicals, which prevent clinical endpoints, such as pathological cardiac hypertrophy, are still being elucidated. We sought to characterize the overlapping and divergent mechanisms by which 18 selected phytochemicals prevent phenylephrine- and phorbol 12-myristate 13-acetate-mediated cardiomyocyte enlargement. Of the tested 18 compounds, six attenuated PE- and PMA-mediated enlargement of neonatal rat ventricular myocytes. Cell viability assays showed that apigenin, baicalein, berberine hydrochloride, emodin, luteolin and quercetin dihydrate did not reduce cell size through cytotoxicity. Four of the six phytochemicals, apigenin, baicalein, berberine hydrochloride and emodin, robustly inhibited stress-induced hypertrophy and were analyzed further against intracellular signaling and genome-wide changes in mRNA expression. The four phytochemicals differentially regulated mitogen-activated protein kinases and protein kinase D. RNA-sequencing further showed divergence in gene regulation, while pathway analysis demonstrated overlap in the regulation of inflammatory pathways. Combined, this study provided a comprehensive analysis of cardioprotective phytochemicals. These data highlight two defining observations: (1) that these compounds predominantly target divergent gene pathways within cardiac myocytes and (2) that regulation of overlapping signaling and gene pathways may be of particular importance for the anti-hypertrophic actions of these phytochemicals. Despite these new findings, future works investigating rodent models of heart failure are still needed to understand the roles for these compounds in the heart.     

Theoretical optimization of Irinotecan-based anticancer strategies in the case of drug-induced efflux

The anticancer drug Irinotecan (CPT11) is known to trigger the induction of ATP-Binding Cassette (ABC) transporters, responsible for the efflux of the drug and its metabolites outside of the cells. The drug-modulated overexpression of those transporters prevents its accumulation in the intracellular medium, therefore decreasing its efficacy. A critical clinical concern lies in the design of CPT11-based therapeutic strategies which eradicate a maximum number of cancer cells despite their ability to become resistant. In order to address this issue, we supplemented an existing mathematical model of CPT11 molecular pharmacokinetics–pharmacodynamics (PK–PD) with a new model of CPT11-induced overexpression of ABC transporters. We then theoretically optimized exposure to CPT11 given as a single agent or combined either with ABC transporter inhibitors, or with inhibitors of nuclear factors whose activation is responsible for transporter overexpression. We firstly considered a cancer cell population endowed with the ability of inducing their transporters. For any drug combination, we concluded that the highest concentration of CPT11 should be administered in order to kill a maximum number of cancer cells, despite the triggering of resistance. We then considered a population of healthy cells which were assumed to be identical to cancer cells except that they were not able to become resistant. Optimal schemes were defined as the ones which maximized DNA damage in cancer cells under the constraint of DNA damage in healthy cells not exceeding a tolerability threshold. The optimal therapeutic strategy consisted in combining CPT11 with ABC transporter inhibitors as it achieved a complete reversal of resistance by means of the lowest concentrations of CPT11.     

Is it True That the Normal Valence‐Length Correlation Is Irrelevant for Metal–Metal Bonds?

The most intriguing feature of metal–metal bonds in inorganic compounds is an apparent lack of correlation between the bond order and the bond length. In this study, we combine a variety of literature data obtained by quantum chemistry and our results based on the empirical bond valence model (BVM), to confirm for the first time the existence of a normal exponential correlation between the effective bond order (EBO) and the length of the metal–metal bonds. The difference between the EBO and the formal bond order is attributed to steric conflict between the (TM)_n cluster (TM=transition metal) and its environment. This conflict, affected mainly by structural type, should cause high lattice strains, but electron redistribution around TM atoms, evident from the BVM calculations, results in a full or partial strain relaxation.     

Measurement of B0-B-0 flavor oscillations in hadronic B0 decays

Flavor oscillations of neutral B mesons have been studied in e+e- annihilation data collected with the BABAR detector at center-of-mass energies near the upsilon(4S) resonance. The data sample used for this purpose consists of events in which one B0 meson is reconstructed in a hadronic decay mode, while the flavor of the recoiling B0 is determined with a tagging algorithm that exploits the correlation between the flavor of the heavy quark and the charges of its decay products. From the time development of the observed mixed and unmixed final states, we determine the B0-B-0 oscillation frequency deltamd to be 0.516+/-0.016(stat)+/-0.010(syst) ps-1.     

Measurement of B --> K*gamma branching fractions and charge asymmetries

The branching fractions of the exclusive decays B0-->K(*0)gamma and B+-->K(*+)gamma are measured from a sample of (22.74+/-0.36)x10(6) BB decays collected with the BABAR detector at the PEP-II asymmetric e(+)e(-) collider. We find B (B0-->K(*0)gamma) = [4.23+/-0.40(stat)+/-0.22(syst)]x10(-5), B(B+-->K(*+)gamma) = [3.83+/-0.62(stat)+/-0.22(syst)]x10(-5) and constrain the CP-violating charge asymmetry to be -0.170K(*)gamma)<0.082 at 90% C.L.     

Normality and paracompactness of the Fell topology

Let be a Hausdorff topological space and the hyperspace of all closed nonempty subsets of . We show that the Fell topology on is normal if and only if the space is Lindelöf and locally compact. For the Fell topology normality, paracompactness and Lindelöfness are equivalent.

     

Electrothermal atomic absorption spectrometric techniques for the determination of zinc and copper in microliter and submicroliter volumes of aqueous and serum matrices

Two electrothermal atomic absorption techniques which provide linear working functions over wide concentration ranges, and are suitable for the determination of zinc and copper in aqueous and 10-fold diluted blood serum matrices are evaluated. The first technique is based on modification of the furnace tube to provide a significant decrease of the atomic absorption signal when microliter and larger volumes of sample are injected. The second technique involves a delivery system capable of dispensing micro- and submicroliter sample volumes to the furnace tube. The precision of the two techniques is about 98%.     

Structural direction of hydrogenation of some Δ4(5)-6-ketopyranosteroids

Conclusions The structural direction of the hydrogenation of steroidal 3-acetoxy-⁴-6-ketones depends on the substitution at C¹⁷, and due to this it becomes possible to approach the 5H analogs from the 5-hydroxy-6-keto-17-desoxysteroids.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 713–716, March, 1984.     

The preparation of avidin microspheres using the sonochemical method and the interaction of the microspheres with biotin

Avidin microspheres were prepared using the sonochemical method. It was found that avidin microspheres can bind biotin, but to a lesser degree than the native protein. The binding of the biotin molecules to the avidin microspheres was probed primarily by TPD measurements.