TLR3 engagement induces IRF-3-dependent apoptosis in androgen-sensitive prostate cancer cells and inhibits tumour growth in vivo

Toll-like receptors (TLRs) are a family of highly conserved transmembrane proteins expressed in epithelial and immune cells that recognize pathogen associated molecular patterns. Besides their role in immune response against infections, numerous studies have shown an important role of different TLRs in cancer, indicating these receptors as potential targets for cancer therapy. We previously demonstrated that the activation of TLR3 by the synthetic double-stranded RNA analogue poly I:C induces apoptosis of androgen-sensitive prostate cancer (PCa) LNCaP cells and, much less efficiently, of the more aggressive PC3 cell line. Therefore, in this study we selected LNCaP cells to investigate the mechanism of TLR3-mediated apoptosis and the in vivo efficacy of poly I:C-based therapy. We show that interferon regulatory factor-3 (IRF-3) signalling plays an essential role in TLR3-mediated apoptosis in LNCaP cells through the activation of the intrinsic and extrinsic apoptotic pathways. Interestingly, hardly any apoptosis was induced by poly I:C in normal prostate epithelial cells RWPE-1. We also demonstrate for the first time the direct anticancer effect of poly I:C as a single therapeutic agent in a well-established human androgen-sensitive PCa xenograft model, by showing that tumour growth is highly impaired in poly I:C-treated immunodeficient mice. Immunohistochemical analysis of PCa xenografts highlights the antitumour role of poly I:C in vivo both on cancer cells and, indirectly, on endothelial cells. Notably, we show the presence of TLR3 and IRF-3 in both human normal and PCa clinical samples, potentially envisaging poly I:C-based therapy for PCa

Entanglement Evolution in the Presence of Decoherence

The entanglement of two qubits, each defined as an effective two-level, spin 1/2 system, is investigated for the case that the qubits interact via a Heisenberg XY interaction and are subject to decoherence due to population relaxation and thermal effects. For zero temperature, the time dependent concurrence is studied analytically and numerically for some typical initial states, including a separable (unentangled) initial state. An analytical formula for non-zero steady state concurrence is found for any initial state, and optimal parameter values for maximizing steady state concurrence are given. The steady state concurrence is found analytically to remain non-zero for low, finite temperatures. We also identify the contributions of global and local coherence to the steady state entanglement.Comment: 12 pages, 4 figures. The second version of this paper has been significantly expanded in response to referee comments. The revised manuscript has been accepted for publication in Journal of Physics

Resonance structures in the multichannel quantum defect theory for the photofragmentation processes involving one closed and many open channels

The transformation introduced by Giusti-Suzor and Fano and extended by Lecomte and Ueda for the study of resonance structures in the multichannel quantum defect theory (MQDT) is used to reformulate MQDT into the forms having one-to-one correspondence with those in Fano's configuration mixing (CM) theory of resonance for the photofragmentation processes involving one closed and many open channels. The reformulation thus allows MQDT to have the full power of the CM theory, still keeping its own strengths such as the fundamental description of resonance phenomena without an assumption of the presence of a discrete state as in CM.Comment: 7 page

High-order harmonic generation in Xe, Kr, and Ar driven by a 2.1-\mu m source: high-order harmonic spectroscopy under macroscopic effects

We experimentally and numerically study the atomic response and pulse propagation effects of high-order harmonics generated in Xe, Kr, and Ar driven by a 2.1-\mu m infrared femtosecond light source. The light source is an optical parametric chirped-pulse amplifier, and a modified strong-field approximation and 3-dimensional pulse propagation code are used for the numerical simulations. The extended cutoff in the long-wavelength driven high-harmonic generation has revealed the spectral shaping of high-order harmonics due to the atomic structure (or photo-recombination cross-section) and the macroscopic effects, which are the main factors of determining the conversion efficiency besides the driving wavelength. Using precise numerical simulations to determine the macroscopic electron wavepacket, we are able to extract the photo-recombination cross-sections from experimental high-order harmonic spectra in the presence of macroscopic effects. We have experimentally observed that the macroscopic effects shift the observed Cooper minimum of Kr from 80 eV to 60-70 eV and wash out the Cooper minimum of Ar. Measured high-harmonic conversion efficiencies per harmonic near the cutoff are ~10^{-9} for all three gases.Comment: 19 pages, 8 figure

Stem-like and highly invasive prostate cancer cells expressing CD44v8-10 marker originate from CD44-negative cells

In human prostate cancer (PCa), the neuroendocrine cells, expressing the prostate cancer stem cell (CSC) marker CD44, may be resistant to androgen ablation and promote tumor recurrence. During the study of heterogeneity of the highly aggressive neuroendocrine PCa cell lines PC3 and DU-145, we isolated and expanded in vitro a minor subpopulation of very small cells lacking CD44 (CD44neg). Unexpectedly, these sorted CD44neg cells rapidly and spontaneously converted to a stable CD44high phenotype specifically expressing the CD44v8-10 isoform which the sorted CD44high subpopulation failed to express. Surprisingly and potentially interesting, in these cells expression of CD44v8-10 was found to be induced in stem cell medium. CD44 variant isoforms are known to be more expressed in CSC and metastatic cells than CD44 standard isoform. In agreement, functional analysis of the two sorted and cultured subpopulations has shown that the CD44v8-10pos PC3 cells, resulting from the conversion of the CD44neg subpopulation, were more invasive in vitro and had a higher clonogenic potential than the sorted CD44high cells, in that they produced mainly holoclones, known to be enriched in stem-like cells. Of interest, the CD44v8-10 is more expressed in human PCa biopsies than in normal gland. The discovery of CD44v8-10pos cells with stem-like and invasive features, derived from a minoritarian CD44neg cell population in PCa, alerts on the high plasticity of stem-like markers and urges for prudency on the approaches to targeting the putative CSC

Relativistic transition wavelenghts and probabilities for spectral lines of Ne II

Transition wavelengths and probabilities for several 2p4 3p - 2p4 3s and 2p4 3d - 2p4 3p lines in fuorine-like neon ion (NeII) have been calculated within the multiconfiguration Dirac-Fock (MCDF) method with quantum electrodynamics (QED) corrections. The results are compared with all existing experimental and theoretical data

Atomic photoionization experiment by harmonic-generation spectroscopy

Citation: Frolov, M. V., Sarantseva, T. S., Manakov, N. L., Fulfer, K. D., Wilson, B. P., Tross, J., . . . Trallero-Herrero, C. A. (2016). Atomic photoionization experiment by harmonic-generation spectroscopy. Physical Review A, 93(3), 5. doi:10.1103/PhysRevA.93.031403Measurements of the high-order-harmonic generation yield of the argon (Ar) atom driven by a strong elliptically polarized laser field are shown to completely determine the field-free differential photoionization cross section of Ar, i.e., the energy dependence of both the angle-integrated photoionization cross section and the angular distribution asymmetry parameter

Overexpression of the nerve growth factor-inducible PC3 immediate early gene is associated with growth inhibition

PC3 (pheochromocytoma cell-3) is an immediate early gene isolated as sequence induced in the rat PC12 cell line during neuronal differentiation by nerve growth factor (NGF). PC3, which is expressed in vivo in the neuroblast when it ceases proliferating and differentiates into a neuron, has partial homology with two antiproliferative genes, BTG1 and Tob. Here we report that overexpression of PC3 in NIH3T3 and PC12 cells leads to marked inhibition of cell proliferation. In stable NIH3T3 clones expressing PC3, the transition from G1 to S phase was impaired, whereas the retinoblastoma (RB) protein was detected as multiple isoforms of M(r) 105,000-115,000 (indicative of a hyperphosphorylated state) only in low-density cultures. Such findings are consistent with a condition of growth inhibition. Thus, PC3 might be a negative regulator of cell proliferation, possibly acting as a transducer of factors influencing cell growth and/or differentiation, such as NGF, by a RB-dependent pathway. This is the first evidence of a NGF-inducible immediate early gene displaying antiproliferative activity

Nontunneling high-order harmonics from ultra-intense laser-driven tightly bound systems

High-order harmonic emission is investigated by numerical solution of the weakly relativistic, two-dimensional Schrödinger equation for the case of ultra-intense laser-driven tightly bound systems (for example, multiply charged ions such as O7+ exposed to laser fields of the order of 1018 W cm-2 at 248 nm). In contrast to their usual substantial decrease, the low-order harmonics having an energy less than the ionization potential exhibit a high efficiency (i.e. intense) plateau with a well defined cutoff. The shape of this plateau is found to depend on the shape of the binding potential. A classical “surfing” mechanism for the generation of these harmonics is proposed that does not involve tunneling and that nevertheless explains the observed cutoff. Thus we call them “nontunneling harmonics.” The significance of relativistic effects for these harmonics is investigated and found to be small, despite the high laser intensity, because of the absence of tunneling

Transfected poly(I:C) activates different dsRNA receptors leading to apoptosis or immunoadjuvant response in androgen-independent prostate cancer cells.

Despite the effectiveness of surgery or radiation therapy for the treatment of early-stage of prostate cancer (PCa), there is currently no effective strategy for late-stage disease. New therapeutic targets are emerging, in particular dsRNA receptors Toll-like Receptor 3 (TLR3) and cytosolic helicases expressed by cancer cells once activated exert a pro-apoptotic effect in different tumors. We previously demonstrated that the synthetic analogue of dsRNA poly(I:C) induces apoptosis in the androgen-dependent PCa cell line LNCaP in a TLR3-dependent fashion, whereas only a weak apoptotic effect is observed in more aggressive and androgen-independent PCa cells PC3 and DU145. In this paper we characterize the receptors and the signalling pathways involved in the remarkable apoptosis induced by poly(I:C) transfected by lipofectamine [in-poly(I:C)] compared to twelve-fold higher free poly(I:C) concentration in PC3 and DU145 cells. By using genetic inhibition of different poly(I:C) receptors, we demonstrate the crucial role of TLR3 and Src in in-poly(I:C)-induced apoptosis. Therefore, we show that the increased in-poly(I:C) apoptotic efficacy is due to a higher binding of endosomal TLR3. On the other hand, we show that in-poly(I:C) binding to cytosolic receptors MDA5 and RIG-I triggers IRF3-mediated signaling leading uniquely to the upregulation of IFN-β, that likely in turn induces increased TLR3, MDA5 and RIG-I proteins. To sum up, in-poly(I:C) activates two distinct anti-tumor pathways in PC3 and DU145 cells: one mediated by the TLR3/Src/STAT1 axis, leading to apoptosis and the other one mediated by MDA5/RIG-I/IRF3, leading to immunoadjuvant IFN-β expression