By using theoretical predictions based on first-principle calculations, we explore an interface engineering approach to stabilize polarization states in ferroelectric heterostructures with a thickness of just several nanometers.
The mTOR (mammalian target of rapamycin) inhibitor rapamycin caused growth arrest in both androgendependent and androgen-independent prostate cancer cells; however, long-term treatment induced resistance to the drug. The aim of this study was to investigate methods that can overcome this resistance. Here, we show that rapamycin treatment stimulated androgen receptor (AR) transcriptional activity, whereas suppression of AR activity with the antiandrogen bicalutamide sensitized androgen-dependent, as well as AR-sensitive androgenindependent prostate cancer cells, to growth inhibition by rapamycin. Further, the combination of rapamycin and bicalutamide, but not the individual drugs, induced significant levels of apoptosis in prostate cancer cells. The net effect of rapamycin is determined by its individual effects on the mTOR complexes mTORC1 (mTOR/ raptor/GbL) and mTORC2 (mTOR/rictor/sin1/GbL). Inhibition of both mTORC1 and mTORC2 by rapamycin-induced apoptosis, whereas rapamycin-stimulation of AR transcriptional activity resulted from the inhibition of mTORC1, but not mTORC2. The effect of rapamycin on AR transcriptional activity was mediated by the phosphorylation of the serine/threonine kinase Akt, which also partially mediated apoptosis induced by rapamycin and bicalutamide. These results indicate the presence of two parallel cell-survival pathways in prostate cancer cells: a strong Akt-independent, but rapamycin-sensitive pathway downstream of mTORC1, and an AR-dependent pathway downstream of mTORC2 and Akt, that is stimulated by mTORC1 inhibition. Thus, the combination of rapamycin and bicalutamide induce apoptosis in prostate cancer cells by simultaneously inhibiting both pathways and hence would be of therapeutic value in prostate cancer treatment.
Live attenuated lentivirus immunization is the only vaccine strategy that elicits consistent protection against intravaginal challenge with pathogenic simian immunodeficiency virus (SIV). To determine the mechanism of protection in rhesus monkeys infected with attenuated simian-human immunodeficiency virus (SHIV)89.6, a detailed analysis of SIV Gag-specific T-cell responses in several tissues including the genital tract was performed. Six months after SHIV infection, antiviral T-cell responses were rare in the cervix; however, polyfunctional, cytokine-secreting, and degranulating SIV Gag-specific CD4(+) T cells were consistently found in the vagina of the immunized macaques. SIV-specific CD8(+) T cells were also detected in the vagina, blood, and genital lymph nodes of most of the animals. Thus, an attenuated SHIV vaccine induces persistent antiviral T cells in tissues, including the vagina, where these effector T-cell responses may mediate the consistent protection from vaginal SIV challenge observed in this model.
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