The Wigner function associated to the Rogers-Szego polynomials

We show here that besides the well known Hermite polynomials, the q-deformed harmonic oscillator algebra admits another function space associated to a particular family of q-polynomials, namely the Rogers-Szego polynomials. Their main properties are presented, the associated Wigner function is calculated and its properties are discussed. It is shown that the angle probability density obtained from the Wigner function is a well-behaved function defined in the interval [-Pi,Pi), while the action probability only assumes integer values greater or equal than zero. It is emphasized the fact that the width of the angle probability density is governed by the free parameter q characterizing the polynomial.Comment: 12 pages, 2 (mathemathica) figure

Veneziano Amplitudes, Spin Chains and String Models

In a series of recently published papers we reanalyzed the existing treatments of Veneziano and Veneziano-like amplitudes and the models associated with these amplitudes. In this work we demonstrate that the already obtained new partition function for these amplitudes can be exactly mapped into that for the Polychronakos-Frahm (P-F) spin chain model. This observation allows us to recover many of the existing string-theoretic models, including the most recent ones.Comment: 38 page

Generalized squeezing operators, bipartite Wigner functions and entanglement via Wehrl's entropy functionals

We introduce a new class of unitary transformations based on the su(1,1) Lie algebra that generalizes, for certain particular representations of its generators, well-known squeezing transformations in quantum optics. To illustrate our results, we focus on the two-mode bosonic representation and show how the parametric amplifier model can be modified in order to generate such a generalized squeezing operator. Furthermore, we obtain a general expression for the bipartite Wigner function which allows us to identify two distinct sources of entanglement, here labelled by dynamical and kinematical entanglement. We also establish a quantitative estimate of entanglement for bipartite systems through some basic definitions of entropy functionals in continuous phase-space representations.Comment: 16 page

Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib With Regorafenib Induces Enhanced Anti-tumor Effects in Hepatocarcinoma Cell Lines

Advanced hepatocarcinoma (HCC) is an aggressive malignancy with poor prognosis and limited treatment options. Alterations of the cyclin D-CDK4/6-Rb pathway occur frequently in HCC, providing the rationale for its targeting at least in a molecular subset of HCC. In a panel of HCC cell lines, we investigated whether the CDK4/6 inhibitor palbociclib might improve the efficacy of regorafenib, a powerful multi-kinase inhibitor approved as second-line treatment for advanced HCC after sorafenib failure and currently under clinical investigation as first-line therapy in combination with immunotherapy. In Rb-proficient cells, the simultaneous drug combination, but not the sequential schedules, inhibited cell proliferation, either in short or in long-term experiments, and induced cell death more strongly than individual treatments. Moreover, the combination significantly reduced spheroid cell growth and inhibited cell migration/invasion. The superior efficacy of palbociclib plus regorafenib emerged also under hypoxia and was associated with a significant down-regulation of CDK4/6-Rb-myc and mTORC1/p70S6K signaling. Moreover, regorafenib suppressed palbociclib-induced expression of cyclin D1 contributing to the cytotoxic effects of the combination. Besides these inhibitory effects on cell viability/proliferation, palbociclib and regorafenib reduced glucose uptake, although this effect was dependent on the cell model and on the oxygen availability (normoxia or hypoxia). Palbociclib and regorafenib combination impaired glucose uptake and utilization, down-regulating basal and hypoxia-induced expression of HIF-1α, HIF-2α, GLUT-1, and MCT4 proteins as well as the activity/expression of glycolytic enzymes (HK2, PFKP, aldolase A, PKM2). In addition, regorafenib alone reduced mitochondrial respiration. The combined treatment impaired glucose metabolism and respiration without enhancing the effects of the single agents. Our findings provide pre-clinical evidence for the effectiveness of palbociclib and regorafenib combination in HCC cell models

Dual inhibition of CDK4/6 and PI3K/AKT/mTOR signaling impairs energy metabolism in MPM cancer cells

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination

Efficacy of the cdk4/6 dual inhibitor abemaciclib in egfr-mutated nsclc cell lines with different resistance mechanisms to osimertinib

Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or-independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senes-cence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment

Secondary metabolites from the sponges Aplysina fistularis and Dysidea sp. and the antituberculosis activity of 11-ketofistularin-3

The present investigation reports the isolation of aeroplysinin-2, 2-(3,5-dibromo-4-methoxyphenyl)-N,N,N-trimethyletanamonium, 7,9-dibromo-10-hydroxy-8-methoxy-1-oxa-2-azaspiro[4.5]deca-2,6,8-trien-3-carboxylic acid and its methyl ester, 11-oxoaerothionin, aerothionin, 11-keto-12-hydroxyaerothionin, 11-ketofistularin-3 and fistularin-3 from Aplysina fistularis, as well as of furodysinin lactone and 9α,11α-epoxicholest-7-en-3β,5α,6α,10-tetrol-6-acetate from Dysidea sp. Although the extracts of both sponges displayed antituberculosis activity, only 11-ketofistularin-3 isolated from A. fistularis displayed antimycobacterial activity against Mycobacterium tuberculosis H34Rv, with MIC at 16 μg/mL and SI of 40, a result that reinforce that fistularin-3 derivatives are interesting leads for the development of antituberculosis drugs.American Society of Pharmacognosy FoundationFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)BIOTA/FAPESP - BIOprospecTAUSP - PIBIC/CNPqFAPES

Pemetrexed enhances membrane PD-L1 expression and potentiates T cell-mediated cytotoxicity by anti-PD-L1 antibody therapy in non-small-cell lung cancer

Immunotherapy has significantly changed the treatment landscape for advanced non-small-cell lung cancer (NSCLC) with the introduction of drugs targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1). In particular, the addition of the anti-PD-1 antibody pembrolizumab to platinum-pemetrexed chemotherapy resulted in a significantly improved overall survival in patients with non-squamous NSCLC, regardless of PD-L1 expression. In this preclinical study, we investigated whether chemotherapy can modulate PD-L1 expression in non-squamous NSCLC cell lines, thus potentially affecting immunotherapy efficacy. Among different chemotherapeutic agents tested, only pemetrexed increased PD-L1 levels by activating both mTOR/P70S6K and STAT3 pathways. Moreover, it also induced the secretion of cytokines, such as IFN-γ and IL-2, by activated peripheral blood mononuclear cells PBMCs that further stimulated the expression of PD-L1 on tumor cells, as demonstrated in a co-culture system. The anti-PD-1/PD-L1 therapy enhanced T cell-mediated cytotoxicity of NSCLC cells treated with pemetrexed and expressing high levels of PD-L1 in comparison with untreated cells. These data may explain the positive results obtained with pemetrexed-based chemotherapy combined with pembrolizumab in PD-L1-negative NSCLC and can support pemetrexed as one of the preferable chemotherapy partners for immunochemotherapy combination regimens