Holographic dual of the Standard Model on the throat

We apply recent techniques to construct geometries, based on local Calabi-Yau manifolds, leading to warped throats with 3-form fluxes in string theory, with interesting structure at their bottom. We provide their holographic dual description in terms of RG flows for gauge theories with almost conformal duality cascades and infrared confinement. We describe a model of a throat with D-branes at its bottom, realizing a 3-family Standard Model like chiral sector. We provide the explicit holographic dual gauge theory RG flow, and describe the appearance of the SM degrees of freedom after confinement. As a second application, we describe throats within throats, namely warped throats with discontinuous warp factor in different regions of the radial coordinate, and discuss possible model building applications.Comment: 46 pages, 21 figures, reference adde

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/\u3b2-catenin signaling and \u3b2-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-\u3baB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth

The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells

Hepatocellular carcinoma (HCC) is one of the most common lethal human malignancies worldwide and its advanced status is frequently resistant to conventional chemotherapeutic agents and radiation. We evaluated the cytotoxic effect of the orally bioavailable dual PI3K/mTOR inhibitor, NVP-BGT226, on a panel of HCC cell lines, since hyperactivated PI3K/Akt/mTOR signaling pathway could represent a biomolecular target for Small Inhibitor Molecules in this neoplasia. We analyzed the drug activity in both normoxia and hypoxia conditions, the latter playing often a relevant role in the induction of chemoresistance and angiogenesis. In normoxia NVP-BGT226 caused cell cycle arrest in the G0/G1 phase of the cell cycle, induced apoptosis and autophagy at low concentrations. Interestingly the drug inactivated p-Akt and p-S6 at < 10 nM concentration. In hypoxia NVP-BGT226 maintained its cytotoxic efficacy at the same concentration as documented by MTT assays and Western blot analysis. Moreover, the drug showed in hypoxia inhibitory properties against angiogenesis by lowering the expression of the transcription factor HIF-1α and of VEGF. Our results indicate that NVP-BGT226 has a potent cytotoxic effect on HCC cell lines also in hypoxia condition, thus emerging as a potential candidate for cancer treatment in HCC targeted therap

Three hits are superior than one: multiple Akt inhibition as a new therapeutic strategy in T-ALL

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder of T lymphocytes characterized by a poor clinical outcome, especially for relapsed patients [1]. The PI3K/Akt/mTOR signaling pathway is crucial for cell growth and survival in many types of solid and blood tumors, including T-ALL, influencing the response to therapeutic treatments [2]. The PI3K/Akt/mTOR network is often hyperactivated in T-ALL and therefore could constitute a target of inhibitory strate- gies, such as those that use small molecules inhibitors (SMI). The combined administration of multiple drugs is an attractive attempt to overcome drug resistance and to improve clinical outcome [3]. We tested in a panel of T-ALL cell lines three drugs directed against Akt with totally different modes of action: GSK690693, ATP- competitive, MK-2206, allosteric, and Perifosine, alkylphospholipid-Akt inhibitor. We showed that multiple Akt inhibition with this drug combination in T-ALL cell lines was cytotoxic and displayed a synergistic effect which was also related to the timing and the sequence of every drug administration. In fact, our findings showed that 6h of Perifosine pre-treatment followed by the combined administration of MK-2206 and GSK690693 for 30 min was necessary for the complete switch off of the activated protein. This combination caused a potent cell cycle arrest in G0/G1 phase and induced apoptosis and autophagy with more efficacy than single or double drug administration. In conclusion, our data demonstrated that this pharmacological strategy could represent a new promising treatment for patients affected by T-ALL with hyperacti- vated PI3K/Akt/mTOR signaling pathway

Cytotoxic activity of the novel dual PI3K/mTOR inhibitor NVP-BGT226 in both normoxic and hypoxic hepatocarcinoma cells

Hepatocellular carcinoma (HCC) is one of the most common lethal human malig- nancies worldwide. One of the most prevalent causes for the high mortality rate in patients with HCC is the lack of effective treatment, especially for patients with advanced disease (1). For this reason, an effective and well-tolerated pharmaceutical profile for the treatment of advanced HCC is requested to introduce new, potential therapeutic approaches. We evaluated the cytotoxic effect of the orally bioavailable dual PI3K/mTOR inhibitor, NVP-BGT226, on a panel of HCC cell lines, since hyperac- tivated PI3K/Akt/mTOR signaling pathway could represent a biomolecular target for Small Inhibitor Molecules in this neoplasia (2). We analyzed the activity of the drug in both normoxia and hypoxia conditions, which play often a relevant role in the induc- tion of chemoresistance and angiogenesis. Indeed, it has been recently demonstrated that PI3K/Akt signaling pathway regulates VEGF and HIF-1α expression, and inhibitors targeting PI3K p110α decrease both VEGF expression and angiogenesis in an vitro HCC model. In normoxia NVP-BGT226 caused cell cycle arrest in the G0/G1 phase of the cell cycle and induced apoptosis and autophagy at low concentrations. Interestingly, the drug inactivated p-Akt and p-S6 at a concentration lower than 10 nM. In hypoxia NVP-BGT226 maintained its cytotoxic efficacy at the same concentration, as documented by MTT assays and Western blot analysis. Moreover, in hypoxia the drug showed inhibitory properties against angiogenesis by lowering the expression of the transcription factor HIF-1α and of VEGF. Our results indicate that NVP-BGT226 has a potent cytotoxic effect on HCC cell lines also in hypoxia condition, thus emerging as a potential candidate for cancer treatment in HCC targeted therapy

Age-dependent increase of oxidative stress regulates microRNA-29 family preserving cardiac health.

The short-lived turquoise killifish Nothobranchius furzeri (Nfu) is a valid model for aging studies. Here, we investigated its age-associated cardiac function. We observed oxidative stress accumulation and an engagement of microRNAs (miRNAs) in the aging heart. MiRNA-sequencing of 5 week (young), 12-21 week (adult) and 28-40 week (old) Nfu hearts revealed 23 up-regulated and 18 down-regulated miRNAs with age. MiR-29 family turned out as one of the most up-regulated miRNAs during aging. MiR-29 family increase induces a decrease of known targets like collagens and DNA methyl transferases (DNMTs) paralleled by 5´methyl-cytosine (5mC) level decrease. To further investigate miR-29 family role in the fish heart we generated a transgenic zebrafish model where miR-29 was knocked-down. In this model we found significant morphological and functional cardiac alterations and an impairment of oxygen dependent pathways by transcriptome analysis leading to hypoxic marker up-regulation. To get insights the possible hypoxic regulation of miR-29 family, we exposed human cardiac fibroblasts to 1% O &lt;sub&gt;2&lt;/sub&gt; levels. In hypoxic condition we found miR-29 down-modulation responsible for the accumulation of collagens and 5mC. Overall, our data suggest that miR-29 family up-regulation might represent an endogenous mechanism aimed at ameliorating the age-dependent cardiac damage leading to hypertrophy and fibrosis

Semiclassical strings in Sasaki-Einstein manifolds and long operators in N=1 gauge theories

We study the AdS/CFT relation between an infinite class of 5-d Ypq Sasaki-Einstein metrics and the corresponding quiver theories. The long BPS operators of the field theories are matched to massless geodesics in the geometries, providing a test of AdS/CFT for these cases. Certain small fluctuations (in the BMN sense) can also be successfully compared. We then go further and find, using an appropriate limit, a reduced action, first order in time derivatives, which describes strings with large R-charge. In the field theory we consider holomorphic operators with large winding numbers around the quiver and find, interestingly, that, after certain simplifying assumptions, they can be described effectively as strings moving in a particular metric. Although not equal, the metric is similar to the one in the bulk. We find it encouraging that a string picture emerges directly from the field theory and discuss possible ways to improve the agreement.Comment: 44 pages, LaTeX, 9 figures. v2: References adde

Specific V-ATPase expression sub-classifies IDHwt lower-grade gliomas and impacts glioma growth in vivo

Background: Cancer cells use specific V-ATPase subunits to activate oncogenic pathways. Therefore, we investigated V-ATPase deregulation in aggressive gliomas and associated signaling. Methods: V-ATPase genes expression and associated pathways were analyzed in different series of glioma available from public databases, as well as in patients\u2019 cohort. Activation of pathways was analyzed at gene and protein expression levels. A genetic model of glioma in Drosophila melanogaster and mice with GBM patients-derived orthotopic xenografts were used as in vivo models of disease. Findings: GBM and recurrent gliomas display a specific V-ATPase signature. Such signature resolves the heterogeneous class of IDH-wild type lower-grade gliomas, identifying the patients with worse prognosis independently from clinical and molecular features (p = 0\ub703, by Cox proportional-hazards model). In vivo, V-ATPase subunits deregulation significantly impacts tumor growth and proliferation. At the molecular level, GBM-like V-ATPase expression correlates with upregulation of Homeobox genes. Interpretation: Our data identify a V-ATPase signature that accompanies glioma aggressiveness and suggest new entry points for glioma stratification and follow-up. Fund: This work was supported by Fondazione Cariplo (2014\u20131148 to VV), Fondazione IRCCS Ca\u2019 Granda, and Fondazione INGM Grant in Molecular Medicine 2014 (to VV)

A GBM-like V-ATPase signature directs cell-cell tumor signaling and reprogramming via large oncosomes

Background: The V-ATPase proton pump controls acidification of intra and extra-cellular milieu in both physiological and pathological conditions. We previously showed that some V-ATPase subunits are enriched in glioma stem cells and in patients with poor survival. In this study, we investigated how expression of a GBM-like V-ATPase pump influences the non-neoplastic brain microenvironment. Methods: Large oncosome (LO) vesicles were isolated from primary glioblastoma (GBM) neurospheres, or from patient sera, and co-cultured with primary neoplastic or non-neoplastic brain cells. LO transcript and protein contents were analyzed by qPCR, immunoblotting and immunogold staining. Activation of pathways in recipient cells was determined at gene and protein expression levels. V-ATPase activity was impaired by Bafilomycin A1 or gene silencing. Findings: GBM neurospheres influence their non-neoplastic microenvironment by delivering the V-ATPase subunit V1G1 and the homeobox genes HOXA7, HOXA10, and POU3F2 to recipient cells via LO. LOs reprogram recipient cells to proliferate, grow as spheres and to migrate. Moreover, LOs are particularly abundant in the circulation of GBM patients with short survival time. Finally, impairment of V-ATPase reduces LOs activity. Interpretation: We identified a novel mechanism adopted by glioma stem cells to promote disease progression via LO-mediated reprogramming of their microenvironment. Our data provide preliminary evidence for future development of LO-based liquid biopsies and suggest a novel potential strategy to contrast glioma progression. Fund: This work was supported by Fondazione Cariplo (2014-1148 to VV) and by the Italian Minister of Health-Ricerca Corrente program 2017 (to SF)

A Measurement of Coherent Neutral Pion Production in Neutrino Neutral Current Interactions in NOMAD

We present a study of exclusive neutral pion production in neutrino-nucleus Neutral Current interactions using data from the NOMAD experiment at the CERN SPS. The data correspond to $1.44 \times 10^6$ muon-neutrino Charged Current interactions in the energy range $2.5 \leq E_{\nu} \leq 300$ GeV. Neutrino events with only one visible $\pi^0$ in the final state are expected to result from two Neutral Current processes: coherent $\pi^0$ production, {\boldmath $\nu + {\cal A} \to \nu + {\cal A} + \pi^0$} and single $\pi^0$ production in neutrino-nucleon scattering. The signature of coherent $\pi^0$ production is an emergent $\pi^0$ almost collinear with the incident neutrino while $\pi^0$'s produced in neutrino-nucleon deep inelastic scattering have larger transverse momenta. In this analysis all relevant backgrounds to the coherent $\pi^0$ production signal are measured using data themselves. Having determined the backgrounds, and using the Rein-Sehgal model for the coherent $\pi^0$ production to compute the detection efficiency, we obtain {\boldmath $4630 \pm 522 (stat) \pm 426 (syst)$} corrected coherent-$\pi^0$ events with $E_{\pi^0} \geq 0.5$ GeV. We measure {\boldmath $\sigma (\nu {\cal A} \to \nu {\cal A} \pi^0) = [ 72.6 \pm 8.1(stat) \pm 6.9(syst) ] \times 10^{-40} cm^2/nucleus$}. This is the most precise measurement of the coherent $\pi^0$ production to date.Comment: 23 pages, 9 figures, accepted for publication in Phys. Lett.