Network Working Group K. Rosenbrock Request for Comments: 3113 3GPP PCG Chair Category: Informational R. Sanmugam Ericsson

Abstract This document describes the standardization collaboration between 3GPP and IETF

Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors

Fragments based on the VEGFR2i Semaxanib (SU5416, (vascular endothelial growth factor receptor-2 inhibitor) and the HDACi (histone deacetylase inhibitor) SAHA (suberanilohydroxamic acid) have been merged to form a range of low molecular weight dual action hybrids. Vindication of this approach is provided by SAR, docking studies, in vitro cancer cell line and biochemical enzyme inhibition data as well as in vivo Xenopus data for the lead molecule (Z)-N1-(3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-5-yl)- N8-hydroxyoctanediamide 6

Light tracking through ice and water -- Scattering and absorption in heterogeneous media with Photonics

In the field of neutrino astronomy, large volumes of optically transparent matter like glacial ice, lake water, or deep ocean water are used as detector media. Elementary particle interactions are studied using in situ detectors recording time distributions and fluxes of the faint photon fields of Cherenkov radiation generated by ultra-relativistic charged particles, typically muons or electrons. The Photonics software package was developed to determine photon flux and time distributions throughout a volume containing a light source through Monte Carlo simulation. Photons are propagated and time distributions are recorded throughout a cellular grid constituting the simulation volume, and Mie scattering and absorption are realised using wavelength and position dependent parameterisations. The photon tracking results are stored in binary tables for transparent access through ANSI-C and C++ interfaces. For higher-level physics applications, like simulation or reconstruction of particle events, it is then possible to quickly acquire the light yield and time distributions for a pre-specified set of light source and detector properties and geometries without real-time photon propagation. In this paper the Photonics light propagation routines and methodology are presented and applied to the IceCube and Antares neutrino telescopes. The way in which inhomogeneities of the Antarctic glacial ice distort the signatures of elementary particle interactions, and how Photonics can be used to account for these effects, is described.Comment: 22 pages, 8 Postscript figures, uses elsart.cl

Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies

First published online: April 23, 2015Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa.Siu Chiu Chan, Luke A. Selth, Yingming Li, Michael D. Nyquist, Lu Miao, James E. Bradner, Ganesh V. Raj, Wayne D. Tilley and Scott M. Deh

An epigenomic approach to therapy for tamoxifen-resistant breast cancer

Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERα remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERα signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ERα signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERα gene by the BET protein BRD3/4, and facilitates ERα gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERα signaling pathway and the growth of Tam-R breast cancer cells in culture. Using a Tam-R breast cancer xenograft mouse model, we demonstrated in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ER degrader fulvestrant. Taken together, we provide evidence that the epigenomic proteins BRD3/4 and WHSC1 are essential regulators of estrogen receptor signaling and are novel therapeutic targets for treatment of Tam-R breast cancer

Acoustic and optical variations during rapid downward motion episodes in the deep north-western Mediterranean Sea

An Acoustic Doppler Current Profiler (ADCP) was moored at the deep-sea site of the ANTARES neutrino telescope near Toulon, France, thus providing a unique opportunity to compare high-resolution acoustic and optical observations between 70 and 170 m above the sea bed at 2475 m. The ADCP measured downward vertical currents of magnitudes up to 0.03 m s-1 in late winter and early spring 2006. In the same period, observations were made of enhanced levels of acoustic reflection, interpreted as suspended particles including zooplankton, by a factor of about 10 and of horizontal currents reaching 0.35 m s-1. These observations coincided with high light levels detected by the telescope, interpreted as increased bioluminescence. During winter 2006 deep dense-water formation occurred in the Ligurian subbasin, thus providing a possible explanation for these observations. However, the 10-20 days quasi-periodic episodes of high levels of acoustic reflection, light and large vertical currents continuing into the summer are not direct evidence of this process. It is hypothesized that the main process allowing for suspended material to be moved vertically later in the year is local advection, linked with topographic boundary current instabilities along the rim of the 'Northern Current'.Comment: 30 pages, 7 figure

The specificity of phage testing for MAP — where might it fit into the diagnostic armoury?

The current individual tools available for the diagnosis of Johne's disease are far from suitable to tackle this endemic disease. Culture, polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) tests, when used together can be useful in managing the disease in the later stages of infection at a herd level. They are, however, ill-suited to detecting the causative agent Mycobacterium avium subsp. paratuberculosis (MAP) at the early stages of infection and at an individual level. Phage technology offers another tool in the attempt to better manage and control this disease. Phage-technology has been demonstrated to rapidly and sensitively detect and specifically identify viable MAP in the milk and blood of cattle. Although in relatively-early stages of development phage technology offers a strong addition to the armoury of tests used to detect MAP in blood and milk, and may go on to be part of ongoing control measures to reduce the burden of disease to farmers and veterinarians

Active medulloblastoma enhancers reveal subgroup-specific cellular origins

Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins