Physical interaction between MYCN oncogene and polycomb repressive complex 2 (PRC2) in neuroblastoma: Functional and therapeutic implications

This article is made available through the Brunel Open Access Publishing Fund. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.CLU (clusterin) is a tumor suppressor gene that we have previously shown to be negatively modulated by the MYCN proto-oncogene, but the mechanism of repression was unclear. Here, we show that MYCN inhibits the expression of CLU by direct interaction with the non-canonical E box sequence CACGCG in the 5′-flanking region. Binding of MYCN to the CLU gene induces bivalent epigenetic marks and recruitment of repressive proteins such as histone deacetylases and Polycomb members. MYCN physically binds in vitro and in vivo to EZH2, a component of the Polycomb repressive complex 2, required to repress CLU. Notably, EZH2 interacts with the Myc box domain 3, a segment of MYC known to be essential for its transforming effects. The expression of CLU can be restored in MYCN-amplified cells by epigenetic drugs with therapeutic results. Importantly, the anticancer effects of the drugs are ablated if CLU expression is blunted by RNA interference. Our study implies that MYC tumorigenesis can be effectively antagonized by epigenetic drugs that interfere with the recruitment of chromatin modifiers at repressive E boxes of tumor suppressor genes such as CLU.SPARKS, The Neuroblastoma Society, a Wellcome Trust grant (to A. S.), and the Italian Association for Cancer Research

Summary of the CMS Discovery Potential for the MSSM SUSY Higgses

This work summarises the present understanding of the expected MSSM SUSY Higgs reach for CMS. Many of the studies presented here result from detailed detector simulations incorporating final CMS detector design and response. With 30 fb-1 the h -> gamma,gamma and h -> bb channels allow to cover most of the MSSM parameter space. For the massive A,H,H+ MSSM Higgs states the channels A,H -> tau,tau and H+ -> tau,nu turn out to be the most profitable ones in terms of mass reach and parameter space coverage. Consequently CMS has made a big effort to trigger efficiently on taus. Provided neutralinos and sleptons are not too heavy, there is an interesting complementarity in the reaches for A,H -> tau,tau and A,H -> chi,chi.Comment: 19 pages, 27 figure

DC and AC Electrical Characterization of Stacks of HTS Tapes

Today the Bi-2223 tape represents a suitable candidate for the use in various HTS devices. The LHC current leads use Bi-2223 tapes soldered together in short lengths, forming stacks of rugged HTS conductors. Critical current and AC loss measurements were performed on BSCCO stacks, in the temperature range of 65 K and 77 K and in magnetic fields of up to 0.5 T. The experimental results reported in this paper give a broad description of the stacks behavior in the range of current and field values of practical interest, and provide design parameters for the optimization of current leads operating both in DC and pulsed conditions

Spinfoams in the holomorphic representation

We study a holomorphic representation for spinfoams. The representation is obtained via the Ashtekar-Lewandowski-Marolf-Mour\~ao-Thiemann coherent state transform. We derive the expression of the 4d spinfoam vertex for Euclidean and for Lorentzian gravity in the holomorphic representation. The advantage of this representation rests on the fact that the variables used have a clear interpretation in terms of a classical intrinsic and extrinsic geometry of space. We show how the peakedness on the extrinsic geometry selects a single exponential of the Regge action in the semiclassical large-scale asymptotics of the spinfoam vertex.Comment: 10 pages, 1 figure, published versio

Projection-based measurement and identification

A recently developed Projection-based Digital Image Correlation (P-DVC) method is here extended to 4D (space and time) displacement field measurement and mechanical identification based on a single radiograph per loading step instead of volumes as in standard DVC methods. Two levels of data reductions are exploited, namely, reduction of the data acquisition (and time) by a factor of 1000 and reduction of the solution space by exploiting model reduction techniques. The analysis of a complete tensile elastoplastic test composed of 127 loading steps performed in 6 minutes is presented. The 4D displacement field as well as the elastoplastic constitutive law are identified. Keywords: Image-based identification, Model reduction, Fast 4D identification, In-situ tomography measurements. INTRODUCTION Identification and validation of increasingly complex mechanical models is a major concern in experimental solid mechanics. The recent developments of computed tomography coupled with in-situ tests provide extremely rich and non-destructive analyses [1]. In the latter cases, the sample was imaged inside a tomograph, either with interrupted mechanical load or with a continuously evolving loading and on-the-fly acquisitions (as ultra-fast X-ray synchrotron tomography, namely, 20 Hz full scan acquisition for the study of crack propagation [2]). Visualization of fast transformations, crack openings, or unsteady behavior become accessible. Combined with full-field measurements, in-situ tests offer a quantitative basis for identifying a broad range of mechanical behavior.Comment: SEM 2019, Jun 2019, Reno, United State

Many-nodes/many-links spinfoam: the homogeneous and isotropic case

I compute the Lorentzian EPRL/FK/KKL spinfoam vertex amplitude for regular graphs, with an arbitrary number of links and nodes, and coherent states peaked on a homogeneous and isotropic geometry. This form of the amplitude can be applied for example to a dipole with an arbitrary number of links or to the 4-simplex given by the compete graph on 5 nodes. All the resulting amplitudes have the same support, independently of the graph used, in the large j (large volume) limit. This implies that they all yield the Friedmann equation: I show this in the presence of the cosmological constant. This result indicates that in the semiclassical limit quantum corrections in spinfoam cosmology do not come from just refining the graph, but rather from relaxing the large j limit.Comment: 8 pages, 4 figure

BAFF Index and CXCL13 levels in the cerebrospinal fluid associate respectively with intrathecal IgG synthesis and cortical atrophy in multiple sclerosis at clinical onset

Abstract Background B lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology. The in vivo analysis of intrathecally produced B cell-related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS. Methods Paired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21. 3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh). Results Compared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes ( p \u2009<\u20090.01), lower values of BAFF Index (11.9\u2009\ub1\u20096.1 vs 17.5\u2009\ub1\u20095.2, p \u2009<\u20090.01), and higher CSF CXCL13 levels (27.7\u2009\ub1\u200933.5 vs 0.9\u2009\ub1\u20091.5, p \u2009<\u20090.005). In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis ( r \u2009>\u20090.5 and p \u2009<\u20090.05 for all correlations). CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB\u2212 ( p \u2009<\u20090.05) and HC ( p \u2009<\u20090.01), and correlated to CSF CXCL13 concentrations ( r 0.77, p \u2009<\u20090.001). The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41\u2009\ub1\u20090.1 vs 2.49\u2009\ub1\u20090.1\ua0mm, p \u2009<\u20090.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB\u2212. Conclusions The intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13. These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS). In this study, CXCL13 identifies a subgroup of MS patients characterized by ..

Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of &gt;2 years of follow-up.

BackgroundNovel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045.Patients and methodsAdult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR.ResultsA total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy.ConclusionsLong-term results (&gt;2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC.Trial registrationClinicalTrials.gov: NCT02256436

On the Ultraviolet Behaviour of Newton's constant

We clarify a point concerning the ultraviolet behaviour of the Quantum Field Theory of gravity, under the assumption of the existence of an ultraviolet Fixed Point. We explain why Newton's constant should to scale like the inverse of the square of the cutoff, even though it is technically inessential. As a consequence of this behaviour, the existence of an UV Fixed Point would seem to imply that gravity has a built-in UV cutoff when described in Planck units, but not necessarily in other units.Comment: 8 pages; CQG class; minor changes and rearrangement