494 research outputs found

    Credit and banking in a DSGE model of the euro area

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    This paper studies the role of credit-supply factors in business cycle fluctuations. For this purpose, we introduce an imperfectly competitive banking sector into a DSGE model with financial frictions. Banks issue collateralized loans to both households and firms, obtain funding via deposits and accumulate capital from retained earnings. Margins charged on loans depend on bank capital-to-assets ratios and on the degree of interest rate stickiness. Bank balance-sheet constraints establish a link between the business cycle, which affects bank profits and thus capital, and the supply and cost of loans. The model is estimated with Bayesian techniques using data for the euro area. The analysis delivers the following results. First, the existence of a banking sector partially attenuates the effects of demand shocks, while it helps propagate supply shocks. Second, shocks originating in the banking sector explain the largest share of the fall of output in 2008 in the euro area, while macroeconomic shocks played a limited role. Third, an unexpected destruction of bank capital has a substantial impact on the real economy and particularly on investment.collateral constraints, banks, banking capital, sticky interest rates

    Targeting the phosphatidylinositol 3-kinase/Akt/mechanistic target of rapamycin signaling pathway in B-lineage acute lymphoblastic leukemia: An update

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    Despite considerable progress in treatment protocols, B-lineage acute lymphoblastic leukemia (B-ALL) displays a poor prognosis in about 15‚Äď20% of pediatric cases and about 60% of adult patients. In addition, life-long irreversible late effects from chemo- and radiation therapy, including secondary malignancies, are a growing problem for leukemia survivors. Targeted therapy holds promising perspectives for cancer treatment as it may be more effective and have fewer side effects than conventional therapies. The phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway is a key regulatory cascade which controls proliferation, survival and drug-resistance of cancer cells, and it is frequently upregulated in the different subtypes of B-ALL, where it plays important roles in the pathophysiology, maintenance and progression of the disease. Moreover, activation of this signaling cascade portends a poorer prognosis in both pediatric and adult B-ALL patients. Promising preclinical data on PI3K/Akt/mTOR inhibitors have documented their anticancer activity in B-ALL and some of these novel drugs have entered clinical trials as they could lead to a longer event-free survival and reduce therapy-associated toxicity for patients with B-ALL. This review highlights the current status of PI3K/Akt/mTOR inhibitors in B-ALL, with an emphasis on emerging evidence of the superior efficacy of synergistic combinations involving the use of traditional chemotherapeutics or other novel, targeted agents

    Redistribution of DNA topoisomerase II beta after in vitro stabilization of human erythroleukemic nuclei by heat or Cu++ revealed by confocal microscopy.

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    Using confocal laser scanning microscope and a monoclonal antibody we have examined by means of indirect immunofluorescence techniques the distribution of DNA topoisomerase II beta (the 180-kDa nucleolar isoform of topoisomerase II) following stabilization of isolated nuclei by exposure to moderate heat (37 degrees or 42 degrees C) or Cu++. In intact cells the antibody specifically decorated the nucleoli. The same pattern was maintained if nuclei were incubated at 0 degree C in a buffer containing spermine/spermidine/KCl or stabilized by means of 0.5 mM Cu++ for 10 minutes at 0 degree C in the same buffer. On the contrary, if stabilization was performed by incubating the nuclei either at 37 degrees or 42 degrees C, the immunoreactivity dispersed all over the nucleus, forming numerous speckles. This phenomenon was not detected if, in addition to spermine/spermidine/KCl, the incubation buffer also contained 5 mM Mg++ and the temperature was 37 degrees C. If the stabilization was performed at 42 degrees C, Mg++ failed to maintain the original distribution of DNA topoisomerase II beta, as seen in intact cells. The analysis on 2-D optical section showed the alteration of the nucleolar profile, particularly at 37 degrees C, even when the samples were treated with Mg++. The 3-D reconstruction figured out the irregularity of the surface at 37 degrees C and the variations of the volume occupied by the fluorescent figures. These were in close proximity to each other both in intact cells and in 0 degree C incubated nuclei; they showed a certain degree of shrinkage in 0 degree C plus Cu++ exposed samples (-20\% of the volume), and, on the contrary, the labeled structures were scattered in a volume increased two- or threefold when exposed to 37 degrees or 42 degrees C, respectively. The addition of Mg++ restored the original spatial relationship and volume at 37 degrees C, but not at 42 degrees C, where the volumetric analysis showed an increase of about 50\%. Our results demonstrate that heat stabilization of isolated nuclei in a buffer without Mg++ (i.e., a technique often employed to prepare the nuclear matrix or scaffold) cannot be considered an optimal procedure to maintain the original distribution of protein within the nucleus

    miRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment

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    microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, including tumor microenvironment. Cancer cells cooperate with stromal cells and elements of the extracellular matrix (ECM) to establish a comfortable niche to grow, to evade the immune system, and to expand. Within the tumor microenvironment, cells release ECmiRNAs and other factors in order to influence and hijack the physiological processes of surrounding cells, fostering tumor progression. Here, we discuss the role of miRNAs in the pathogenesis of multicomplex diseases, such as Alzheimer's disease, obesity, and cancer, focusing on the contribution of both intracellular miRNAs, and of released ECmiRNAs in the establishment and development of cancer niche. We also review growing evidence suggesting the use of miRNAs as novel targets or potential tools for therapeutic applications

    Nuclear Diacylglycerol Produced by Phosphoinositide-specific Phospholipase C Is Responsible for Nuclear Translocation of Protein Kinase C-őĪ

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    It is well established that an independent inositide cycle is present within the nucleus, where it is involved in the control of cell proliferation and differentiation. Previous results have shown that when Swiss 3T3 cells are treated with insulin-like growth factor-I (IGF-I) a rapid and sustained increase in mass of diacylglycerol (DAG) occurs within the nuclei, accompanied by a decrease in the levels of both phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate. However, it is unclear whether or not other lipids could contribute to this prolonged rise in DAG levels. We now report that the IGF-I-dependent increase in nuclear DAG production can be inhibited by the specific phosphatidylinositol phospholipase C inhibitor 1-O-octadeyl-2-O-methyl-sn-glycero-3-phosphocholine or by neomycin sulfate but not by the purported phosphatidylcholine-phospholipase C specific inhibitor D609 or by inhibitors of phospholipase D-mediated DAG generation. Treatment of cells with 1-O-octadeyl-2-O-methyl-sn-glycero-3-phosphocholine or neomycin sulfate inhibited translocation of protein kinase C-alpha to the nucleus. Moreover, exposure of cells to 1-O-octadeyl-2-O-methyl-sn-glycero-3-phosphocholine, but not to D609, dramatically reduced the number of cells entering S-phase upon stimulation with IGF-I. These results suggest that the only phospholipase responsible for generation of nuclear DAG after IGF-I stimulation of 3T3 cells is PI-PLC. When this activity is inhibited, neither DAG rise is seen nor PKC-alpha translocation to the nucleus occurs. Furthermore, this PI-PLC activity appears to be essential for the G0/G1 to S-phase transition

    Controlateral Symmetrisation in SRM for Breast Cancer: Now or Then? Immediate versus Delayed Symmetrisation in a Two-Stage Breast Reconstruction

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    Introduction: The timing of contralateral symmetrisation in patients with large and ptotic breasts undergoing a unilateral skin-reducing mastectomy (SRM) is one of the most debated topics in the reconstructive field. There is no evidence to support the advantage of immediate or delayed symmetrisation to help surgeons with this decision. The aim of this study was to investigate the clinical and aesthetic outcomes of immediate symmetrisation. Methods: A randomised observational study was conducted on patients who underwent an SRM for unilateral breast cancer. Based on a simple randomisation list, patients were divided into two groups: a delayed symmetrisation group versus an immediate symmetrisation group. The postoperative complications, BREAST-Q outcomes and reoperations were compared. Results: Out of a total of 84 patients undergoing an SRM between January 2018 and January 2021, 42 patients underwent immediate symmetrisation and 42 patients had delayed symmetrisation. Three implant losses (7.2%) were observed and we reported three wound dehiscences; one of these was in a contralateral breast reconstruction in the immediate symmetrisation group. The BREAST-Q patient-reported outcome measures recorded better aesthetic outcomes and a high patient satisfaction for the immediate symmetrisation group. Conclusions: Simultaneous controlateral symmetrisation is a good alternative to achieve better satisfaction and quality of life for patients; from a surgical point of view, it does not excessively impact on the second time of reconstruction

    Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation

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    The PI3K/Akt/mTOR signaling cascade is a key regulatory pathway controlling cell growth and survival, and its dysregulation is a reported feature of B-precursor acute lymphoblastic leukemia (B-pre ALL). Torin-2 is a novel, second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. It has been shown that Torin-2 displayed dramatic antiproliferative activity across a panel of cancer cell lines. To investigate if Torin-2 could represent a new option for the treatment of B-pre ALL, we tested its activity on a panel of B-pre ALL cell lines. In all of them Torin-2 showed a powerful cytotoxic activity, inhibiting the growth of each cell line in a dose-dependent manner, with an IC50 in the nanomolar range. Torin-2 caused both apoptosis and autophagy, induced cell cycle arrest in G0/G1 phase and affected both mTORC1 and mTORC2 activities as assessed by their specific substrate dephosphorylation. Torin-2 alone suppressed feedback activation of PI3K/Akt, whereas the mTORC1 inhibitor RAD001 required the addition of the Akt inhibitor MK-2206 to achieve the same effect. These pharmacological strategies targeting PI3K/Akt/mTOR at different points of the signaling pathway cascade might represent a new promising therapeutic strategy for treatment of B-pre ALL patients

    DInSAR Analysis and Analytical Modeling of Mount Etna Displacements: The December 2018 Volcano‚ÄźTectonic Crisis

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    We investigate the 24‚Äď27 December 2018 eruption of Mount Etna occurred from fissures located on the volcano eastern flank and accompanied by a seismic swarm, which was triggered by the magma intrusion and continued for weeks after the end of the eruption. Moreover, this swarm involved some of the shallow volcano‚Äźtectonic structures located on the Mount Etna flanks and culminated on 26 December with the strongest event (ML 4.8), occurred along the Fiandaca Fault. In this work, we analyze seismological data and Sentinel‚Äź1 Differential Interferometric Synthetic Aperture Radar (DInSAR) measurements, the latter inverted through analytical modeling. Our results suggest that a dike source intruded, promoting the opening of the eruptive fissures fed by a shallower dike. Moreover, our findings indicate that the activation of faults in different sectors of the volcano may be considered as a response to accommodate the deformations induced by the magma volumes injection.Published5817-58275V. Processi eruttivi e post-eruttiviJCR Journa

    Optimal network topologies: Expanders, Cages, Ramanujan graphs, Entangled networks and all that

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    We report on some recent developments in the search for optimal network topologies. First we review some basic concepts on spectral graph theory, including adjacency and Laplacian matrices, and paying special attention to the topological implications of having large spectral gaps. We also introduce related concepts as ``expanders'', Ramanujan, and Cage graphs. Afterwards, we discuss two different dynamical feautures of networks: synchronizability and flow of random walkers and so that they are optimized if the corresponding Laplacian matrix have a large spectral gap. From this, we show, by developing a numerical optimization algorithm that maximum synchronizability and fast random walk spreading are obtained for a particular type of extremely homogeneous regular networks, with long loops and poor modular structure, that we call entangled networks. These turn out to be related to Ramanujan and Cage graphs. We argue also that these graphs are very good finite-size approximations to Bethe lattices, and provide almost or almost optimal solutions to many other problems as, for instance, searchability in the presence of congestion or performance of neural networks. Finally, we study how these results are modified when studying dynamical processes controlled by a normalized (weighted and directed) dynamics; much more heterogeneous graphs are optimal in this case. Finally, a critical discussion of the limitations and possible extensions of this work is presented.Comment: 17 pages. 11 figures. Small corrections and a new reference. Accepted for pub. in JSTA

    Roles of GSK-3 and microRNAs on epithelial mesenchymal transition and cancer stem cells

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    Various signaling pathways exert critical roles in the epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs). The Wnt/beta-catenin, PI3K/PTEN/ Akt/mTORC, Ras/Raf/MEK/ERK, hedgehog (Hh), Notch and TP53 pathways elicit essential regulatory influences on cancer initiation, EMT and progression. A common kinase involved in all these pathways is moon-lighting kinase glycogen synthase kinase-3 (GSK-3). These pathways are also regulated by micro-RNAs (miRs). TP53 and components of these pathways can regulate the expression of miRs. Targeting members of these pathways may improve cancer therapy in those malignancies that display their abnormal regulation. This review will discuss the interactions of the multi-functional GSK-3 enzyme in the Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, Hh, Notch and TP53 pathways. The regulation of these pathways by miRs and their effects on CSC generation, EMT, invasion and metastasis will be discussed
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