High Precision Measurements of Resonance Frequency of Ozone Rotational Transition J = 6_1,5–6_0,6 in the Real Atmosphere

Ground-based passive measurements of downwelling atmospheric radiation at ~110.836 GHz allow extracting the spectra of ozone self-radiation (rotational transition J = 61,5–60,6) coming from the low stratosphere–mesosphere and retrieving vertical profiles of ozone concentration at these altitudes. There is a notable (several hundred kHz) ambiguity in the determination of the resonance frequency of this important ozone line. We carried out long-term ground-based measurements of atmospheric microwave radiation in this range using upgraded apparatus with high technical accuracy and spectral resolution (~12 kHz). The obtained brightness temperature spectra allowed us to determine the frequency of this ozone line to be 110,835.909 ± 0.016 MHz. We verified that the Doppler frequency shift by horizontal wind as well as the variations of the tropospheric absorption had little effect on the obtained result. The found value was 131 ± 16 kHz less than that measured in the laboratory and differed from modern model calculations. At the same time, it was close to the results of early semiempirical calculations made more than 40 years ago. The applications where precise knowledge about the resonance frequency of this ozone line can be important were discussed in this paper

Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance

Aim: The study aims to analyze the effect of long-term incubation of ERα-positive MCF7 breast cancer cells with 4-hydroxytamoxifen (HT) on their sensitivity to tubulin polymerization inhibitor docetaxel.Methods: The analysis of cell viability was performed by the MTT method. The expression of signaling proteins was analyzed by immunoblotting and flow cytometry. ERα activity was evaluated by gene reporter assay. To establish hormone-resistant subline MCF7, breast cancer cells were treated with 4-hydroxytamoxifen for 12 months.Results: The developed MCF7/HT subline has lost sensitivity to 4-hydroxytamoxifen, and the resistance index was 2. Increased Akt activity (2.2-fold) and decreased ERα expression (1.5-fold) were revealed in MCF7/HT cells. The activity of the estrogen receptor α was reduced (1.5-fold) in MCF7/HT. Evaluation of class III β-tubulin expression (TUBB3), a marker associated with metastasis, revealed the following trends: higher expression of TUBB3 was detected in triple-negative breast cancer MDA-MB-231 cells compared to hormone-responsive MCF7 cells (P < 0.05). The lowest expression of TUBB3 was found in hormone-resistant MCF7/HT cells (MCF7/HT < MCF7 < MDA-MB-231, approximately 1:2:4). High TUBB3 expression strongly correlated with docetaxel resistance: IC50 value of docetaxel for MDA-MB-231 cells was greater than that for MCF7 cells, whereas resistant MCF7/HT cells were the most sensitive to the drug. The accumulation of cleaved PARP (a 1.6-fold increase) and Bcl-2 downregulation (1.8-fold) were more pronounced in docetaxel-treated resistant cells (P < 0.05). The expression of cyclin D1 decreased (2.8-fold) only in resistant cells after 4 nM docetaxel treatment, while this marker was unchanged in parental MCF7 breast cancer cells.Conclusion: Further development of taxane-based chemotherapy for hormone-resistant cancer looks highly promising, especially for cancers with low TUBB3 expression

The Phenomenon of the Cross-Resistance of Breast Cancer to Target and Hormonal Drugs: The Role of Epigenetic Reconstruction

The rearrangement of molecular pathways and the activation of bypass signaling determine the progression of tumor cell resistance to various drugs that specifically block target signaling proteins. The present work was performed on the MCF-7 breast cancer cells and established sublines, resistant to mTOR inhibitor rapamycin or antiestrogen tamoxifen, developed under prolonged cell treatment with rapamycin or tamoxifen, respectively. We have shown that both resistant sublines demonstrate the cross-resistance to rapamycin and tamoxifen and are characterized with the common signaling changes, namely—blocking of the estrogen receptor α (ERα) transcriptional activity and constitutive activation of Akt signaling. Analysis of the epigenetic machinery revealed the drastic suppression of the level of DNA methyltransferase 3A (DNMT3A) in both the resistant sublines that were correlated with the demethylation of the LINE-1 repeats. Knockdown of the DNMT3A via siRNA results in the progression of partial resistance of MCF-7 cells to both tamoxifen and rapamycin, supporting the important role of DNA methylation in the formation of the resistant phenotype. Totally, the results obtained highlight the possible mechanism of the tumor cell resistance to targeting/hormonal drugs based on the rearrangement of DNA methylation profile and activation of the bypass signaling pathways

Exosome-Mediated Transfer of Cancer Cell Resistance to Antiestrogen Drugs

Exosomes are small vesicles which are produced by the cells and released into the surrounding space. They can transfer biomolecules into recipient cells. The main goal of the work was to study the exosome involvement in the cell transfer of hormonal resistance. The experiments were performed on in vitro cultured estrogen-dependent MCF-7 breast cancer cells and MCF-7 sublines resistant to SERM tamoxifen and/or biguanide metformin, which exerts its anti-proliferative effect, at least in a part, via the suppression of estrogen machinery. The exosomes were purified by differential ultracentrifugation, cell response to tamoxifen was determined by MTT test, and the level and activity of signaling proteins were determined by Western blot and reporter analysis. We found that the treatment of the parent MCF-7 cells with exosomes from the resistant cells within 14 days lead to the partial resistance of the MCF-7 cells to antiestrogen drugs. The primary resistant cells and the cells with the exosome-induced resistance were characterized with these common features: decrease in ERα activity and parallel activation of Akt and AP-1, NF-κB, and SNAIL1 transcriptional factors. In general, we evaluate the established results as the evidence of the possible exosome involvement in the transferring of the hormone/metformin resistance in breast cancer cells