The E2F1/DNMT1 axis is associated with the development of AR negative castration resistant prostate cancer

BACKGROUND Research on castration resistant prostate cancer (CRPC) has focused primarily on functional alterations of the androgen receptor (AR). However, little is known about the loss of AR gene expression itself and the possible contribution of AR negative cells to CRPC. METHODS Human and murine prostate cancer tissue microarrays (TMAs) were evaluated with antibodies specific for E2F1, DNA methyltransferase 1 or AR. The human prostate cancer TMA consisted of clinical samples ranging from normal tissue to samples of metastatic disease. The murine TMA was comprised of benign, localized or metastatic prostate cancer acquired from TRAMP mice treated with castration and/or 5′‐Aza‐2′‐deoxycytidine (5Aza). RESULTS Immunohistochemical analysis revealed increased nuclear DNMT1 staining in localized PCa ( P  < 0.0001) and metastatic PCa ( P  < 0.0001) compared to normal tissue. Examination of specific diagnoses revealed that Gleason seven tumors exhibited greater nuclear DNMT1 staining than Gleason six tumors ( P  < 0.05) and that metastatic tissue exhibited greater levels of nuclear DNMT1 than Gleason seven tumors ( P  < 0.01). Evaluation of the murine tissue cores revealed that 8.2% and 8.1% of benign tissue cores stained positive for E2F1 and DNMT1 respectively, while 97.0% were AR positive. Conversely, 81% and 100% of tumors were positive for E2F1and DNMT1 respectively. This was in stark contrast to only 18% of tumors positive for AR. Treatment of mice with 5Aza reduced DNMT1 staining by 30%, while AR increased by 27%. CONCLUSIONS These findings demonstrate that the E2F1/DNMT1 inhibitory axis of AR transcription is activated during the emergence of CRPC. Prostate 73:1776–1785, 2013 . © 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100341/1/pros22715.pd

The fine-grained phase-space structure of Cold Dark Matter halos

We present a new and completely general technique for calculating the fine-grained phase-space structure of dark matter throughout the Galactic halo. Our goal is to understand this structure on the scales relevant for direct and indirect detection experiments. Our method is based on evaluating the geodesic deviation equation along the trajectories of individual DM particles. It requires no assumptions about the symmetry or stationarity of the halo formation process. In this paper we study general static potentials which exhibit more complex behaviour than the separable potentials studied previously. For ellipsoidal logarithmic potentials with a core, phase mixing is sensitive to the resonance structure, as indicated by the number of independent orbital frequencies. Regions of chaotic mixing can be identified by the very rapid decrease in the real space density of the associated dark matter streams. We also study the evolution of stream density in ellipsoidal NFW halos with radially varying isopotential shape, showing that if such a model is applied to the Galactic halo, at least $10^5$ streams are expected near the Sun. The most novel aspect of our approach is that general non-static systems can be studied through implementation in a cosmological N-body code. Such an implementation allows a robust and accurate evaluation of the enhancements in annihilation radiation due to fine-scale structure such as caustics. We embed the scheme in the current state-of-the-art code GADGET-3 and present tests which demonstrate that N-body discreteness effects can be kept under control in realistic configurations.Comment: 20 pages, 24 figures, submitted to MNRA

Estimation of Combinatoric Background in SeaQuest using an Event-Mixing Method

All experiments observing dilepton pairs (e.g. $e^+e^-$, $\mu^+\mu^-$) must confront the existence of a combinatoric background caused by the combining of tracks not arising from the same physics vertex. Some method must be devised to calculate and remove this background. In this document we describe a particular event-mixing method relying on many of the unique aspects of the SeaQuest spectrometer and data. The method described here calculates the combinatoric background with correct normalization; i.e., there is no need to assign a floating normalization factor that is then determined in a subsequent fitting procedure. Numerous tests are applied to demonstrate the reliability of the method.Comment: Submitted to JINST; revised due to second round of referee comment

Psycho-education programme for temporomandibular disorders: a pilot study

BACKGROUND: Temporomandibular disorders (TMDs) are by far the most predominant condition affecting the temporomandibular joint (TMJ), however many patients have mild self-limiting symptoms and should not be referred for specialist care. The aim of this pilot study was to develop a simple, cost-effective management programme for TMDs using CD-ROM. 41 patients (age 18–70) participated in this study, patients were divided into three groups: the 1st group were involved in an attention placebo CD-ROM (contain anatomical information about the temporomandibular system), the 2nd group received information on CD-ROM designed to increase their control and self efficacy, while the 3rd group received the same programme of the 2nd group added to it an introduction to self-relaxing techniques followed by audio tape of progressive muscle relaxation exercises. Each of the groups was asked to complete a number of questionnaires on the day of initial consultation and six weeks afterwards. RESULTS: The two experimental groups (2nd & 3rd) were equally effective in reducing pain, disability and distress, and both were more effective than the attention placebo group (1st), however the experimental groups appeared to have improved at follow-up relative to the placebo-group in terms of disability, pain and depressed mood. CONCLUSION: This pilot study demonstrates the feasibility and acceptability of the design. A full, randomized, controlled trial is required to confirm the efficacy of the interventions developed here

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers

Strong Lensing in Abell 1703: Constraints on the Slope of the Inner Dark Matter Distribution

In this article, we apply strong lensing techniques in Abell 1703, a massive X-ray luminous galaxy cluster at z=0.28. Our analysis is based on imaging data both from space and ground in 8 bands, complemented with a spectroscopic survey. Abell 1703 looks rather circular from the general shape of its multiply imaged systems and present a dominant giant elliptical cD galaxy in its centre. This cluster exhibits a remarkable bright 'central ring' formed by 4 bright images at z_{spec}=0.888 located very close to the cD galaxy, providing observational constraints that are potentially very interesting to probe the central mass distribution. The stellar contribution from the cD galaxy (~1.25 10^{12} M_{sun} within 7") is accounted for in our parametric mass modelling, and the underlying smooth dark matter component distribution is described using a generalized NFW profile parametrized with a central logarithmic slope \alpha. We find that within the range where observational constraints are present (from ~5" to ~50"), the slope of the dark matter distribution in Abell1703 is equal to 1.09^{+0.05}_{-0.11} (3\sigma confidence level). The concentration parameter is equal to c_{200} ~ 3.5, and the scale radius is constrained to be larger than the region where observational constraints are available. Within this radius, the 2D mass is equal to M(50")=2.4 10^{14} M_{\sun}. We cannot draw any conclusions on cosmological models at this point since we lack results from realistic numerical simulations containing baryons to make a proper comparison. We advocate the need for a sample of observed and simulated unimodal relaxed galaxy clusters in order to make reliable comparisons, and potentially provide a test of cosmological models.Comment: Accepted for publication, conclusion unchanged but strengthened by a serie of tests suggested by a constructive referee report. Higher resolution available at http://www.dark-cosmology.dk/~marceau/1703.php.htm

Physics of Neutron Star Crusts

The physics of neutron star crusts is vast, involving many different research fields, from nuclear and condensed matter physics to general relativity. This review summarizes the progress, which has been achieved over the last few years, in modeling neutron star crusts, both at the microscopic and macroscopic levels. The confrontation of these theoretical models with observations is also briefly discussed.Comment: 182 pages, published version available at <http://www.livingreviews.org/lrr-2008-10

High transverse momentum eta meson production in p+p, d+Au and Au+Au collisions at sqrt(s_NN) = 200 GeV

Inclusive transverse momentum spectra of eta mesons in the range p_T~2-12 GeV/c have been measured at mid-rapidity (|\eta| < 0,35) by the PHENIX experiment at RHIC in p+p, d+Au and Au+Au collisions at sqrt(s_NN) = 200 GeV. The eta mesons are reconstructed through their eta--> \gamma\gamma channel for the three colliding systems as well as through the eta-->pi^0 pi+ pi- decay mode in p+p and d+Au collisions. The nuclear modification factor in d+Au collisions, R_dAu(p_T~1.0-1.1, suggests at most only modest p_T broadening ("Cronin enhancement"). In central Au+Au reactions, the eta yields are significantly suppressed, with R_AuAu(pT)~0.2. The ratio of eta to pi^0 yields is approximately constant as a function of p_T for the three colliding systems in agreement with the high-p_T world average of R_eta/pi^0 \approx 0.5 in hadron-hadron, hadron-nucleus, and nucleus-nucleus collisions for a wide range of center-of-mass energies [sqrt(s_NN)~3-1800 GeV] as well as, for high scaled momentum x_p, in e+e- annihilations at sqrt(s)=91.2 GeV. These results are consistent with a scenario where high-p_T eta production in nuclear collisions at RHIC is largely unaffected by initial-state effects, but where light-quark mesons (pi^0;eta) are equally suppressed due to final-state interactions of the parent partons in the dense medium produced in Au+Au reactions.Comment: 391 authors, NN pages text, RevTeX4, figures, tables. Submitted to Physical Review C. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm