The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule expressed in many cell types, including triple-negative and non-triple-negative breast cancer cells. It affects breast ...cancer growth and crosstalk with estrogen receptor signaling. Normally, this receptor is degraded shortly after ligand activation via the 26S proteasome. Here, we report that AHR undergoes chaperone-mediated autophagy in MDA-MB-468 triple-negative breast cancer cells. This lysosomal degradation of AHR exhibits the following characteristics: (1) it is triggered by 6 amino-nicotinamide, starvation, and piperazinylpyrimidine compound Q18; (2) it is not observed in non-triple-negative breast cancer cells (MCF-7, T47D, and MDA-MB-361); (3) it can be inhibited by progesterone receptor B but not estrogen receptor alpha; (4) it can be reversed by chloroquine but not MG132; (5) it requires LAMP2A; and (6) it involves AHR-HSC70 and AHR-LAMP2A interactions. The NEKFF sequence localized at amino acid 558 of human AHR appears to be a KFERQ-like motif of chaperone-mediated autophagy, responsible for the LAMP2A-mediated AHR protein degradation.
Cyclin-dependent kinase 8 (CDK8) has been identified as a colon cancer oncogene. Since this initial observation, CDK8 has been implicated as a potential driver of other cancers including acute ...myelogenous leukemia (AML) and some breast cancers. Here, we observed different biological responses to CDK8 inhibition among colon cancer cell lines and the triple-negative breast cancer (TNBC) cell line MDA-MB-468. When treated with CDK8 inhibitor
, all treated cell lines responded with decreased cell viability and increased apoptosis. In the MDA-MB-468 cell line, the decrease in cell viability was dependent on increased phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is not observed in the colon cancer cell lines. Furthermore, increased STAT3 phosphorylation in
treated MDA-MB-468 cells was dependent on increased transcription factor E2F1 protein. These results are consistent with previous reports of exogenous expression of E2F1-induced apoptosis in MDA-MB-468 cells.
Abstract
The stocks of bog oak taken from the bottom of reservoirs are increasingly used to preserve growing valuable species of wood, primarily oak. English oak (
Quercus pedunculata
Ehrh.) is a ...hard-drying species. Drying modes of oak boards have been well developed for both convection and microwave drying. The interest in bog oak, rose out from water bodies, sharply increased, but it turned out to be impossible to dry it using known methods other than microwave drying. Cracking defects are 70% at a thickness of 30 mm and 100% at a cross section of 60 mm. The article analyzes the results of bog oak drying in laboratory-type microwave chambers. The distance between magnetrons was 0.5 m, and a length of boards was 1.2 m. A semicommercial plant with a loading volume of 2 m
3
and total power of 30 kW was used. Total drying time for boards with a total loading volume of 0.2 m
3
was from 3 to 5 days. Cracking defects reduced to 20% for a thickness of 30 mm and to 32% for a thickness of 60 mm (with additional treatment by 40% carbamide solution). Board warping was not noticed.
A multiple analysis of the impact of the endocrine disruptor nonylphenol on the number of microorganisms, taxonomic structure of the microbial community, and phytotoxicity of a loamy soddy-podzolic ...soil (Eutric Albic Retisol (Abruptic, Loamic, Aric, Ochric)) was performed in model experiments for the first time. The upper horizons of a loamy soddy-podzolic soil from Leningrad oblast were analyzed. The number and group composition of the soil microbiota were determined by the inoculation of soil suspensions on standard nutrient media. The taxonomic composition of the microbial community was studied using the pyrosequencing method (Illumina MiSeq). The content of nonylphenol in soil samples was determined by high-performance liquid chromatography. The phytotoxicity of the soil samples was evaluated in relation to the test culture of soft wheat (
Tríticum aestívum
). It was found that nonylphenol induces dose- and time-dependent changes in the number of the main physiological groups of soil microorganisms. In the presence of nonylphenol, a significant increase in the number of heterotrophic and oligotrophic microorganisms, as well as of bacteria tolerant to nonylphenol was observed. Actinomycetes and spore-forming bacteria proved to be most sensitive to this chemical. Under the impact of nonylphenol, the species diversity of the soil microbial cenosis decreased.
Proteobacteria
became the dominant phylum (78%) in the taxonomic structure of the microbial community. In the soil polluted by nonylphenol, the intensity of microbiological mineralization of nitrogen-containing organic substances decreased, and nitrogen immobilization processes were inhibited. The phytotoxicity of the soil samples with a high dose of nonylphenol (300 mg/kg soil) manifested itself during a month-long incubation. The obtained results can be used in developing a scientifically grounded methodology for bioremediation of soils contaminated with endocrine disruptors. Changes in the phylogenetic structure of soil microbial cenoses can serve as a sensitive bioindicator of the ecological soil state.
The effect of the endocrine disruptor nonylphenol on the biological activity of loamy soddy-podzolic soil (Eutric Albic Retisol (Abruptic, Loamic, Aric, Ochric)) was studied in model experiments. The ...upper horizons of loamy soddy-podzolic soil sampled in Leningrad oblast were the object of this study. The number of soil microorganisms, the activity of soil enzymes, and soil respiration were determined with the methods commonly used in soil microbiology and biochemistry. The content of nonylphenol in soil samples was determined using high-performance liquid chromatography. Soil contamination with nonylphenol was shown to cause time- and dose-dependent changes in the activity of the pool of nitrogen, carbohydrates, and redox enzymes and increases the basal respiration. The results obtained are an important stage necessary for risk assessment of soil contamination with alkylphenols, and can be used in the development of a remediation methodology for soils contaminated with endocrine disruptors.
NF-kB is a transcription factor protein complex that can be found in almost all animal cell types and is a key player in some cancers and inflammatory responses. It can enhance the proliferation ...rate, reduce apoptosis, as well as creating more blood flow to ensure the survival of cancer, thus blocking the NF-kB pathway has potential therapeutic benefit. We designed a series of compounds based on a quinazoline scaffold pharmacophore model which may have high binding affinity with the p50 subunit of NF-kB. The compound series with phenyl substitution at the 2 position of the quinazoline proved to be more effective at inhibiting NF-kB function both theoretically and experimentally. These compounds also reduce the proliferation of numerous tumor cell lines and the mean GI50 for compound 2a is 2.88μM against the NCI-60 cell line. At the same time, compound 2a can induce significant apoptosis in EKVX cell line at the concentration of 1μM.
Many difficulties may arise during the modeling of the time course of Hamilton Rating Scale for Depression (HAMD) scores in clinical trials for the evaluation of antidepressant drugs: (i) flexible ...designs, used to increase the chance of selecting more efficacious doses, (ii) dropout events, and (iii) adverse effects related to the experimental compound. It is crucial to take into account all these factors when designing an appropriate model of the HAMD time course and to obtain a realistic description of the dropout process. In this work, we propose an integrated approach to the modeling of a double‐blind, flexible‐dose, placebo‐controlled, phase II depression trial that comprises response, tolerability, and dropout. We investigate three different dropout mechanisms in terms of informativeness. Goodness of fit is quantitatively assessed with respect to response (HAMD score) and dropout data. We show that dropout is a complex phenomenon that may be influenced by HAMD evolution, dose changes, and occurrence of drug‐related adverse effects.
Clinical Pharmacology & Therapeutics (2012); 91 5, 863–871. doi:10.1038/clpt.2011.322
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•An optimized PDGFR family kinase inhibitor is described.•The optimized analog demonstrates binding to wild-type and mutant PDGFR family kinases with kds in the low to sub-nM ...range.•Cellular target engagement for the optimized analog is demonstrated in a mutant KIT tumor cell-line.•In vivo activity of the optimized analog is suggested in a mouse model.
Aberrant expression of wild-type and mutant forms of the platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases has been implicated in various oncologic indications such as leukemias, gliomas, and soft tissue sarcomas. Clinically used kinase inhibitors imatinib and sunitinib are potent inhibitors of wild-type PDGFR family members, but show reduced binding to mutant forms. Here we describe compound 5 which binds to both wild-type and oncogenic mutant forms of PDGFR family members, and demonstrates both cellular and in vivo activity.
The e-CALLISTO (Compound Astronomical Low-cost Low-frequency Instrument for Spectroscopy and Transportable Observatory) is a worldwide radio-spectrograph network with 24 hours a day solar radio burst ...monitoring. The e-CALLISTO network is led by the Swiss Federal Institute of Technology Zurich (ETHZ Zurich), which work up collaborations with local host institutions. In 2013 the University of Alcalá joined the e-CALLISTO network with the installation of two Solar Radio Telescopes (SRT): the EA4RKU-SRT that was located at the University of Alcalá from January 2013 till June 2013 and the Melibea-SRT that is located at Peralejos de las Truchas (Guadalajara) in operation from June 2013. The Spanish e-Callisto SRTs provide routine data to the network. We present examples of type III and type II radio-bursts observed by Melibea during its first year of operation and study their relation with soft X-ray flares observed by GOES and Coronal Mass Ejections (CMEs) and Solar Energetic Particle (SEP) events observed by space-borne instrumentation.
Summary An hypothesis is presented which seeks to explain the anti-cancer activity of thiazolidinediones (TZDs), a class of drugs currently used to treat type 2 diabetes mellitus. Empirical data from ...the scientific literature is used to support the hypothesis that TZDs are inhibitors of microtubule assembly. The similarities between the affects of TZDs on cellular processes and known inhibitors of tubulin polymerization are identified. Similarities between TZDs and currently used inhibitors of microtubule assembly, such as cell cycle arrest in G1 phase, anti-angiogenesis activity, and inhibition of cell motility, are striking. In addition to the similarities in biological function, certain molecular structure similarities are also identified. The possibility that TZDs inhibit the polymerization of actin is presented as an alternative interpretation of the available data. Finally suggestions for testing the hypothesis, by using commercially available tubulin polymerization assays and fluorescence based binding assays, as well as isothermal titration calorimetry, are given. Considering TZD position as third-line therapy for treatment of type 2 diabetes mellitus and the potential loss of market share to newly introduced inhalable insulin, a better understanding of TZD anti-cancer activity may lead to revival for this drug class in cancer treatment.
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