Ultrafast magnetoacoustics in Galfenol nanostructures.

Phonons and magnons are prospective information carriers to substitute the transfer of charge in nanoscale communication devices. Our ability to manipulate them at the nanoscale and with ultimate speed is examined by ultrafast acoustics and femtosecond optomagnetism, which use ultrashort laser pulses for generation and detection of the corresponding coherent excitations. Ultrafast magnetoacoustics merges these research directions and focuses on the interaction of optically generated coherent phonons and magnons. In this review, we present ultrafast magnetoacoustic experiments with nanostructures based on the alloy (Fe,Ga) known as Galfenol. We demonstrate how broad we can manipulate the magnetic response on an optical excitation by controlling the spectrum of generated coherent phonons and their interaction with magnons. Resonant phonon pumping of magnons, formation of magnon polarons, driving of a magnetization wave by a guided phonon wavepacket are demonstrated. The presented experimental results have great application potential in emerging areas of modern nanoelectronics.

Light-driven photoswitching of quinazoline analogues of combretastatin A-4 as an effective approach for targeting skin cancer cells.

A novel quinazoline series of photoswitchable combretastatin A-4 (CA-4) analogues were synthesized and their photochemical properties and antiproliferative activity against A431 epidermoid carcinoma cells were studied. It was found that quinazoline analogues, in contrast to the majority of the known CA-4, exhibit high antiproliferative activity in the E-form as well. Photoswitching of the E-form to the Z-form resulted in a multiple (9-fold) increase in antiproliferative activity. 1H NMR monitoring showed that these compounds are very resistant to UV (λ = 365 nm) or sunlight irradiation and do not undergo photodegradation with a loss of antiproliferative activity that is inherent in heterocyclic analogues of CA-4. Similar photoswitching and an increase in antiproliferative activity are observed on exposure to sunlight. A selected compound (1a-Z51) in sub-micromolar concentrations induced apoptosis in A431 cells, while rad50/ATM/p53 were not involved in cell death. The growth of A431 cells was significantly inhibited after combination treatment with compound 1a-Z51 and chemotherapy drugs (cisplatin or 5-fluorouracil). In summary, the quinazoline analogues of CA-4 represent a promising strategy to achieve a photoswitchable potency for the treatment of cancers, including the development of combination therapies.

Snail-Family Proteins: Role in Carcinogenesis and Prospects for Antitumor Therapy.

The review analyzes Snail family proteins, which are transcription factors involved in the regulation of the epithelial-mesenchymal transition (EMT) of tumor cells. We describe the structure of these proteins, their post-translational modification, and the mechanisms of Snail-dependent regulation of genes. The role of Snail proteins in carcinogenesis, invasion, and metastasis is analyzed. Furthermore, we focus on EMT signaling mechanisms involving Snail proteins. Next, we dissect Snail signaling in hypoxia, a condition that complicates anticancer treatment. Finally, we offer classes of chemical compounds capable of down-regulating the transcriptional activity of Snails. Given the important role of Snail proteins in cancer biology and the potential for pharmacological inhibition, Snail family proteins may be considered promising as therapeutic targets.

[BRCA1 and Estrogen Receptor α Expression Regulation in Breast Cancer Cells].

BRCA1 (breast cancer 1) protein is involved in the genome stability maintenance participating in homologous recombination-dependent DNA repair. Disruption of BRCA1 functioning is associated with breast and ovarian cancer. Despite the important role of BRCA1 in DNA repair in all cell types, the development of BRCA1-associated cancer takes place mainly in estrogen-dependent tissues such as breast and ovarian ones. Using breast cancer cell line MCF-7 it was demonstrated in in vitro experiments that the estrogen 17ß-estradiol (E2), phytoestrogens (genistein and apigenin) and antiestrogens (tamoxifen and fulvestrant) inhibited estrogen receptor (ERα) expression while only genistein influenced BRCA1 increasing its expression. In hypoxia, that is an important factor of solid tumors progression, the decrease of BRCA1 and ERα expression was demonstrated in MCF-7 cells. Therefore, hypoxia influences both BRCA1-dependent DNA repair and hormonal regulation of breast cancer cell growth. Taken together, obtained results demonstrate a relationship between BRCA1 and steroid hormones signal transduction pathways in breast cancer cells and point out to the importance of complex BRCA1 and ERa expression regulation mechanisms studies including epigenetic gene expression regulation.

Horizontal Transfer of Tamoxifen Resistance in MCF-7 Cell Derivates: Proteome Study.

Using estrogen-dependent MCF-7 breast cancer cells and tamoxifen-resistant MCF-7/T subline we have shown that their co-cultivation lead to increase in tamoxifen resistance in the parent MCF-7 cells. The proteome analysis of MCF-7/T cells and new-generated resistant cells revealed 21 common proteins differently expressed in both the resistant cell lines, among them - 6 proteins were associated with the drug or hormonal resistance. Both resistant lines were characterized with suppression of estrogen receptor and activation of SNAIL1-signaling - mesenchymal pathway playing an important role in the down-regulation of estrogen receptor and maintaining of the estrogen-independent phenotype.

[Cytotoxic activity and molecular modeling of progestins - pregna-D'-pentarans]. / Tsitotoksicheskaia aktivnost' i molekuliarnoe modelirovanie progestinov - pregna-D'-pentaranov.

The cytotoxic activity of synthetic progestins (pregna-D'-pentaranes) II-V full agonists of the progesterone receptor (PR) for PR-positive and PR-negative cells of human breast carcinoma was studied. These compounds were more active in the PR-positive MCF-7 cells than in the PR-negative MDA-MB-453 cells. Cytotoxic effects of tested compounds against normal epithelial MDCK cells were not found. Molecular modeling of studied steroids with PR showed that all progestins with close energy values can bind to the ligand binding domain (LBD) of PR and the magnitude of the energy exceeds the value estimated for the progesterone molecule. Thus, the studied progestins are active against different molecular subtypes of breast cancer and represent a promising class of chemical compounds for oncology.

Regulatory Proteins of Epithelial-Mesenchymal Transition and Some Components of VEGF Signaling Pathway in Breast Cancer.

Immunohistochemical method was used to assay for Snail family regulatory proteins of epithelial-mesenchymal transition, their NF-κB coactivator, and the components of VEGF signaling pathway (VEGF and its receptors VEGFR1 and VEGFR2) in 157 specimens of breast tumors. Most tumors did not express SNAI1, while 65% tumors demonstrated mid- or high-level SNAI2 expression. There were significant correlations between the expression of SNAI1, SNAI2, and their NF-κB co-activator. Correlation was also detected between expression of Snail and VEGFR1 protein families in the tumors. In addition, the study revealed tumoral co-expression of SNAI2 and VEGFR2. The data attest to coordinated activation of regulatory proteins of epithelial-mesenchymal transition and the major components of VEGF signaling pathway in breast tumors.

The Mechanism of Adaptation of Breast Cancer Cells to Hypoxia: Role of AMPK/mTOR Signaling Pathway.

We studied the mechanisms of adaptation of human breast cancer cells MCF-7 to hypoxia and analyzed the role of AMPK/mTOR signaling pathway in the maintenance of cell proliferation under hypoxic conditions. It was found that long-term culturing (30 days or more) of MCF-7 cells under hypoxic conditions induced their partial adaptation to hypoxia. Cell adaptation to hypoxia was associated with attenuation of hypoxia-dependent AMPK induction with simultaneous constitutive activation of mTOR and Akt. These findings suggest that these proteins can be promising targets for targeted therapy of tumors developing under hypoxic conditions.

Apigenin Inhibits Growth of Breast Cancer Cells: The Role of ERα and HER2/neu.

Phytoestrogens are a group of plant-derived compounds with an estrogen-like activity. In mammalians, phytoestrogens bind to the estrogen receptor (ER) and participate in the regulation of cell growth and gene transcription. There are several reports of the cytotoxic effects of phytoestrogens in different cancer cell lines. The aim of this study was to measure the phytoestrogen activity against breast cancer cells with different levels of ER expression and to elucidate the molecular pathways regulated by the leader compound. Methods used in the study include immunoblotting, transfection with a luciferase reporter vector, and a MTT test. We demonstrated the absence of a significant difference between ER+ and ER- breast cancer cell lines in their response to cytotoxic stimuli: treatment with high doses of phytoestrogens (apigenin, genistein, quercetin, naringenin) had the same efficiency in ER-positive and ER-negative cells. Incubation of breast cancer cells with apigenin revealed the highest cytotoxicity of this compound; on the contrary, naringenin treatment resulted in a low cytotoxic activity. It was shown that high doses of apigenin (50 µM) do not display estrogen-like activity and can suppress ER activation by 17ß-estradiol. Cultivation of HER2-positive breast cancer SKBR3 cells in the presence of apigenin resulted in a decrease in HER2/neu expression, accompanied by cleavage of an apoptosis substrate PARP. Therefore, the cytotoxic effects of phytoestrogens are not associated with the steroid receptors of breast cancer cells. Apigenin was found to be the most effective phytoestrogen that strongly inhibits the growth of breast cancer cells, including HER2-positive ones.

Picosecond acoustics in semiconductor optoelectronic nanostructures.

We overview the results of three recently performed experiments, where the picosecond acoustic technique was applied to semiconductor devices with quantum wells or quantum dots embedded in an optical microcavity. In these experiments, high amplitude picosecond strain pulses are injected into such a device and the resulting changes in the response of the optical resonance are monitored. First, in quantum well devices we observe the generation of THz sidebands in optical reflectivity near the polariton resonance. Second, for certain conditions we detect the destruction and recurrence of excitons by acoustic shock waves on picosecond time scales. Third, in a vertical cavity surface emitting laser with a quantum dot layer the injection of the picosecond strain pulses induces the giant increase of the laser output. All these effects are governed by nonadiabatic processes in the interaction between a strain pulse and the electronic quantum confined states. Their observation became possible due to the possibility of generating very short strain pulses with sufficiently high amplitude.

Molecular mechanisms of hormone resistance of breast cancer.

More than 70% malignant mammary tumors contain steroid hormone receptors; this suggests the possibility of hormone therapy in the majority of patients with breast cancer (BC). The main cause of inefficiency of hormone therapy in BC is hormone resistance (tumor resistance to hormonal cytostatics). Here we discuss the main mechanisms of hormone resistance of BC and the mechanisms underlying the formation of hormone resistance of the tumors are analyzed at the molecular level. The data on the signal pathways of estrogen receptors (ER), the key regulators of BC cell proliferation, are presented. The most important factors of BC hormone resistance are: high activity/expression of receptor tyrosine kinases; high activity of proteins regulating cell defense mechanisms (Akt PI3K, mTOR); changes in the activities of cell cycle regulator proteins (Myc, c-Fos, Cyclin D1). Our experiments have demonstrated that estrogen-independent BC cell growth is supported by VEGF/VEGFR2 and EGF/EGFR mitogenic signal pathways. Our data indicate that NF-kappaB transcription factor is directly involved in the regulation of hormone-resistant BC cell growth and survival, while NF-kappaB suppression determines cell sensitivity to apoptotic activity of antitumor compounds. On the whole, the results indicate good prospects of using EGFR, HER-2/neu, mTOR, VEGFR, PI3K/Akt molecular pathways as targets for BC therapy, including therapy for BC resistant forms.

Picosecond opto-acoustic interferometry and polarimetry in high-index GaAs.

By means of a metal opto-acoustic transducer we generate quasi-longitudinal and quasi-transverse picosecond strain pulses in a (311)-GaAs substrate and monitor their propagation by picosecond acoustic interferometry. By probing at the sample side opposite to the transducer the signals related to the compressive and shear strain pulses can be separated in time. In addition to conventional monitoring of the reflected probe light intensity we monitor also the polarization rotation of the optical probe beam. This polarimetric technique results in improved sensitivity of detection and provides comprehensive information about the elasto-optical anisotropy. The experimental observations are in a good agreement with a theoretical analysis.

beta-catenin signaling pathway and the tolerance of breast cancer cells to hypoxic conditions.

We have previously shown that Snail, a regulator of epithelial-mesenchymal transition, is activated in the hypoxia-resistant breast cancer cell line HBL100. The purpose of this study was to evaluate the role of beta-catenin signaling pathway in the maintenance of breast cancer cells 'tolerance to hypoxia. The breast cancer cell lines MCF-7 and HBL-100 were used in this study; HBL-100 cells were characterized by increased resistance to hypoxia. We have demonstrated that the transcription factor beta-catenin is activated in hypoxic conditions and the beta-catenin activity is supported by Snail, a regulator of epithelial-mesenchymal transition. The activated beta-catenin regulates the expression of genes of the cell response to hypoxia and thus, it maintains the growth of breast cancer in the reduced oxygen conditions. The coordinated activation of Snail/beta-catenin/HIF-1alpha proteins in cell may be considered as an important factor of tumor resistance to hypoxia.

The expression and DNA-binding activity of NF-κB nuclear transcription factor in the tumors of patients with breast cancer.

The content and DNA-binding activity of NF-κB nuclear transcription factor subunit p65 (NF-κBp65) were evaluated by quantitative enzyme immunoassay in tumors and histologically intact tissues of 119 patients with breast cancer. DNA-binding activity of NF-κBp65 in the tumors was higher than in adjacent tissue in 97% cases. This elevation was paralleled by an increase in total protein content in the majority of cases. No significant relationship of the parameter with the disease stage, tumor size and histology, and degree of lymph node involvement was detected. However, the content of NF-κBp65 in tumors of malignancy degree III was significantly higher than in tumors of malignancy degree II. An increase in total expression of NF-κBp65 protein was found in HER-2+ tumors. This increase was not related to steroid hormone receptor status and was not paralleled by elevation of DNA-binding activity, which was maximum in tumors with the "triple negative" receptor status (RE-RP-HER-2-).

Coherent magnetization precession in ferromagnetic (Ga,Mn)As induced by picosecond acoustic pulses.

We show that the magnetization of a thin ferromagnetic (Ga,Mn)As layer can be modulated by picosecond acoustic pulses. In this approach a picosecond strain pulse injected into the structure induces a tilt of the magnetization vector M, followed by the precession of M around its equilibrium orientation. This effect can be understood in terms of changes in magnetocrystalline anisotropy induced by the pulse. A model where only one anisotropy constant is affected by the strain pulse provides a good description of the observed time-dependent response.

In vitro effect of Knotolan, a new lignan from Abies sibirica, on the growth of hormone-dependent breast cancer cells.

Here we present antiestrogenic effects of Knotolan, a new dietary lignan from Abies sibirica raw material. Knotolan abolished growth-stimulating effects of 17ß-estradiol on hormone-dependent MCF-7 cells.

NF-kappaB suppression provokes the sensitization of hormone-resistant breast cancer cells to estrogen apoptosis.

The progression of breast cancer cells to estrogen-independent growth may be accompanied with the paradoxical cell sensitization to estrogen apoptotic action; however, the mechanism of this phenomenon is still unclear. In the present study, we have shown that the sensitization of hormone-resistant breast cancer cells to estrogen apoptotic action is accompanied with the gradual NF-kappaB suppression. Using the chemical inhibitors of NF-kappaB as well as the dominant-negative NF-kappaB constructs, we have proved the sufficiency of NF-kappaB inhibition for the sensitization of the resistant cells to estrogen apoptosis. Estradiol treatment results in the additional suppression of NF-kappaB, demonstrating the possible NF-kappaB involvement in the regulation of cell response to estrogens. Totally, the results presented suggest that the constitutive NF-kappaB suppression in the estrogen-independent cells may be considered as one of the factors resulting in a imbalance between pro- and anti-apoptotic pathways and enhancement in estrogen apoptotic action in the cells.

Chirping of an optical transition by an ultrafast acoustic soliton train in a semiconductor quantum well.

Acoustic solitons formed during the propagation of a picosecond strain pulse in a GaAs crystal with a ZnSe/ZnMgSSe quantum well on top lead to exciton resonance energy shifts of up to 10 meV, and ultrafast frequency modulation, i.e., chirping, of the exciton transition. The effects are well described by a theoretical analysis based on the Korteweg-de Vries equation and accounting for the properties of the excitons in the quantum well.

Mechanism of estrogen-induced apoptosis in breast cancer cells: role of the NF-kappaB signaling pathway.

The ability of sex steroid hormones to up-regulate the apoptotic signaling proteins is well documented; however, the apoptotic potential of sex hormones is not remarkable and fully compensated by their growth stimulatory action to target cells. In the present study using the long-term cultivation of estrogen-dependent MCF-7 breast cancer cells in steroid-free medium, we have established a cell subline, designed as MCF-7/LS, which was characterized by the resistance to growth stimulatory estradiol action and hypersensitivity to estrogen-induced apoptosis. We have demonstrated that estrogen treatment of the cells does not influence on the level of TNF-R1 or Fas, but dramatically decreases the transcriptional activity of NF-kappaB. Importantly, the MCF-7/LS cells, which are insensitive to growth stimulatory estrogen action, retain the ability to decrease in the NF-kappaB activity in response to estrogen stimulus. Furthermore, the significant increase in the basal (in the absence of ligand) estrogen receptor (ER)-dependent transcriptional activity in the MCF-7/LS cells was revealed and reciprocal transcriptional antagonism between ER and NF-kappaB was demonstrated. Finally, we proved the possible involvement of phosphatidylinositol-3 kinase (PI3K) in the ligand-independent ER activation. In general, the results presented suggest that long-term growth of MCF-7 breast cancer cells in steroid-free medium is accompanied with the increase in the basal ER-dependent transcriptional activity as well as the maintenance of the negative regulatory loop ER-NF-kappaB. The latter may be considered as one of the factors resulting in a disbalance between pro- and anti-apoptotic pathways and enhancement in estrogen apoptotic action in the cells.

Ultrafast band-gap shift induced by a strain pulse in semiconductor heterostructures.

The conventional piezospectroscopic effect is extended to picosecond time scales by using ultrashort strain pulses injected into semiconductor heterostructures. The strain pulses with durations of approximately 10 ps are generated in a metal transducer film by intense femtosecond laser pulses. They propagate coherently in the GaAs/(Al,Ga)As heterostructure over a distance of 100 microm and shift the band gaps by several meV as detected optically for quantum well exciton resonances by pump-probe techniques and time-resolved photoluminescence.