Calcium regulation of androgen receptor expression in the human prostate cancer cell line LNCaP

Elevation of intracellular calcium levels in the presence of normal androgen levels has been implicated in apoptotic prostate cell death. Since the androgen receptor (AR) plays a critical role in the regulation of growth and differentiation of the prostate, it was of interest to determine whether Ca2+ would affect the expression of androgen receptor messenger RNA (mRNA) and protein, thus affecting the ability of androgens to control prostate function. AR-positive human prostate cancer cells, LNCaP, were incubated with either the calcium ionophore A23187 or the intracellular endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin. Subsequently, AR mRNA and protein levels were assessed by Northern and Western blot analysis. Both A23187 and thapsigargin were found to down-regulate steady state AR mRNA levels in a time- and dose-dependent manner. AR mRNA began to decrease after 6-8 h of incubation with 10(-6) M A23187 or 10(-7) M thapsigargin, reaching a nadir at 16 and 10 h of incubation, respectively. In contrast, control mRNA (glyceraldehyde 3-phosphate dehydrogenase) did not change significantly during the treatments with either A23187 or thapsigargin. AR protein levels were found to be decreased after 12 h of incubation with either 10(-6) M A23187 or 10(-7) M thapsigargin. The decrease in AR mRNA and protein seemed to precede apoptosis, since neither A23187 (24 h) nor thapsigargin (30 h) was found to alter cell morphology within the treatment time. Cycloheximide and actinomycin D were unable to change the calcium-mediated decrease in AR mRNA, ruling out the necessity for de novo protein synthesis or a change in mRNA stability. Moreover, the decrease in AR mRNA induced by calcium does not seem to involve protein kinase C- or calmodulin-dependent pathways, since inhibitors of these cellular components had no effect. Nuclear run-on assays demonstrated little or no effects of either A23187 or thapsigargin treatment on AR gene transcription (8 h and 10 h). In conclusion, these studies show that intracellular calcium seems to be a potent regulator of AR gene expression in LNCaP cells

The role of atmospheric CO2 in controlling sea surface temperature change during the Pliocene

We present the role of CO2 forcing in controlling Late Pliocene sea surface temperature (SST) change using six models from Phase 2 of the Pliocene Model Intercomparison Project (PlioMIP2) and palaeoclimate proxy data from the PlioVAR working group. At a global scale, SST change in the Late Pliocene relative to the pre-industrial is predominantly driven by CO2 forcing in the low and mid-latitudes and non-CO2 forcing in the high latitudes. We find that CO2 is the dominant driver of SST change at the vast majority of proxy data sites assessed (17 out of 19), but the relative dominance of this forcing varies between all proxy sites, with CO2 forcing accounting for between 27 % and 82 % of the total change seen. The dearth of proxy data sites in the high latitudes means that only two sites assessed here are predominantly forced by non-CO2 forcing (such as changes to ice sheets and orography), both of which are in the North Atlantic Ocean. We extend the analysis to show the seasonal patterns of SST change and its drivers at a global scale and at a site-specific level for three chosen proxy data sites. We also present a new estimate of Late Pliocene climate sensitivity using site-specific proxy data values. This is the first assessment of site-specific drivers of SST change in the Late Pliocene and highlights the strengths of using palaeoclimate proxy data alongside model outputs to further develop our understanding of the Late Pliocene. We use the best available proxy and model data, but the sample sizes remain limited, and the confidence in our results would be improved with greater data availability

The Fezzan Project 2001: Preliminary report on the fifth season of work

AbstractThe Fezzan Project completed its five-year fieldwork cycle in 2001. The geographical research team located numerous additional palaeolake sites within the Edeyen Ubari, using a combination of Remote Sensing technology and field visits. Additional samples were taken for analysis and dating from many lake edge locations, relating to both the large Pleistocene lake and to the numerous smaller Holocene lakes that have been identified by the team. The excavations at Old Germa were taken down through Garamantian occupation levels to the natural subsoil below the earliest cultural horizon. The earliest activity, represented by a few mudbrick walls and hearths built directly on the natural soil, is believed to date toc. 400-300 BC. Traces of several phases of Garamantian buildings were uncovered, along with numerous rubbish pits, which yielded a rich assemblage of finds, including, for the first time, examples of Garamantian figurines, small 3-D sculptures of humans and animals. Work on the various classes of finds (pottery, small finds, lithics and other stone artefacts, metallurgical evidence, etc.) complemented the excavation work. In addition, a small amount of further survey work was carried out on sites in the Wadi al-Ajal, along with a contour survey of Old Germa and standing building survey at a number of other sites.</jats:p

Pliocene Model Intercomparison Project Phase 3 (PlioMIP3) – Science plan and experimental design

The Pliocene Model Intercomparison Project (PlioMIP) was initiated in 2008. Over two phases PlioMIP has helped co-ordinate the experimental design and publication strategy of the community, which has included an increasing number of climate models and modelling groups from around the world. It has engaged with palaeoenvironmental scientists to foster new data synthesis supporting the construction of new model boundary conditions, as well as to facilitate new data-model comparisons. The work has advanced our understanding of Pliocene climates and environments, enhanced our knowledge regarding the ability of complex climate and Earth System models to accurately simulate climate change, and helped to refine our estimates of how sensitive the climate system is to forcing conditions. In this community protocol paper, we outline the scientific plan for PlioMIP Phase 3 (PlioMIP3). This plan provides the required guidance to participating modelling groups from around the world to successfully set up and perform PlioMIP3 climate model experiments. The project is open to new participants from the scientific community (both from the climate modelling and geosciences communities). In PlioMIP3, we retain the PlioMIP2 Core experiments (Eoi400, E280) and extend the Core requirements to include either an experiment focussed on the Early Pliocene or an alternative Late Pliocene simulation (or both). These additions (a) allow a comparison of Early and Late Pliocene warm intervals and help build research connections and synergy with the MioMIP (Miocene Model Intercomparison Project - also known as DeepMIP-Miocene) and PlioMioVAR projects (Pliocene-Miocene Variability Working Group), and (b) create an alternative time slice simulation for 3.205 Ma (MIS KM5c) through removal of some of the largest palaeogeographic differences introduced between PlioMIP1 and 2 resulting in minimal land-sea mask variations from the modern. In addition, we present ten optional experiments designed to enhance our assessment of climate sensitivity and to explore the uncertainty in greenhouse gas-related forcing. For the first time, we introduce orbital sensitivity experiments into the science plan, as well as simulations incorporating dynamic vegetation-climate feedbacks and an experiment designed to examine the potential significance of East Antarctic Ice Sheet boundary condition uncertainty. These changes enhance palaeo-to-future scientific connections and enable an exploration of the significance of palaeogeographic uncertainties on climate simulations

Nonperturbative renormalization group approach to frustrated magnets

This article is devoted to the study of the critical properties of classical XY and Heisenberg frustrated magnets in three dimensions. We first analyze the experimental and numerical situations. We show that the unusual behaviors encountered in these systems, typically nonuniversal scaling, are hardly compatible with the hypothesis of a second order phase transition. We then review the various perturbative and early nonperturbative approaches used to investigate these systems. We argue that none of them provides a completely satisfactory description of the three-dimensional critical behavior. We then recall the principles of the nonperturbative approach - the effective average action method - that we have used to investigate the physics of frustrated magnets. First, we recall the treatment of the unfrustrated - O(N) - case with this method. This allows to introduce its technical aspects. Then, we show how this method unables to clarify most of the problems encountered in the previous theoretical descriptions of frustrated magnets. Firstly, we get an explanation of the long-standing mismatch between different perturbative approaches which consists in a nonperturbative mechanism of annihilation of fixed points between two and three dimensions. Secondly, we get a coherent picture of the physics of frustrated magnets in qualitative and (semi-) quantitative agreement with the numerical and experimental results. The central feature that emerges from our approach is the existence of scaling behaviors without fixed or pseudo-fixed point and that relies on a slowing-down of the renormalization group flow in a whole region in the coupling constants space. This phenomenon allows to explain the occurence of generic weak first order behaviors and to understand the absence of universality in the critical behavior of frustrated magnets.Comment: 58 pages, 15 PS figure

Decomposition of physical processes controlling EASM precipitation changes during the mid-Piacenzian: new insights into data–model integration

The mid-Piacenzian warm period (MPWP, ~3.264–3.025 Ma) has gained widespread interest due to its partial analogy with future climate. However, quantitative data–model comparison of East Asian Summer Monsoon (EASM) precipitation during the MPWP is relatively rare, especially due to problems in decoding the imprint of physical processes to climate signals in the records. In this study, pollen-based precipitation records are reconstructed and compared to the multi-model ensemble mean of the Pliocene Model Intercomparison Project Phase 2 (PlioMIP2). We find spatially consistent precipitation increase in most simulations but a spatially divergent change in MPWP records. We reconcile proxy data and simulation by decomposing physical processes that control precipitation. Our results 1) reveal thermodynamic control of an overall enhancement of EASM precipitation and 2) highlight a distinct control of thermodynamic and dynamical processes on increases of tropical and subtropical EASM precipitation, reflecting the two pathways of water vapor supply that enhance EASM precipitation, respectively

Energy conservation and maintenance through retrofit measures 3 case studies in coal-fired schools

SIGLEAvailable from British Library Document Supply Centre- DSC:7761.3412(DES-ABB-RR--1) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Noninvasive imaging and radiovirotherapy of prostate cancer using an oncolytic measles virus expressing the sodium iodide symporter

Prostate cancer cells overexpress the measles virus (MV) receptor CD46. Herein, we evaluated the antitumor activity of an oncolytic derivative of the MV Edmonston (MV-Edm) vaccine strain engineered to express the human sodium iodide symporter (NIS; MV-NIS virus). MV-NIS showed significant cytopathic effect (CPE) against prostate cancer cell lines in vitro. Infected cells effectively concentrated radioiodide isotopes as measured in vitro by Iodide-125 ( 125I) uptake assays. Virus localization and spread in vivo could be effectively followed by imaging of 123 I uptake. In vivo administration of MV-NIS either locally or systemically (total dose of 9 × 106 TCID50) resulted in significant tumor regression (P&amp;lt;0.05) and prolongation of survival (P&amp;lt;0.01). Administration of 131 I further enhanced the antitumor effect of MV-NIS virotherapy (P 0.05). In conclusion, MV-NIS is an oncolytic vector with significant antitumor activity against prostate cancer, which can be further enhanced by 131 I administration. The NIS transgene allows viral localization and monitoring by noninvasive imaging which can facilitate dose optimization in a clinical setting. © The American Society of Gene &amp;amp; Cell Therapy

p300 Acetyltransferase Regulates Androgen Receptor Degradation and PTEN-Deficient Prostate Tumorigenesis

Item does not contain fulltextOverexpression of the histone acetyltransferase p300 is implicated in the proliferation and progression of prostate cancer, but evidence of a causal role is lacking. In this study, we provide genetic evidence that this generic transcriptional coactivator functions as a positive modifier of prostate tumorigenesis. In a mouse model of PTEN deletion-induced prostate cancer, genetic ablation of p300 attenuated expression of the androgen receptor (AR). This finding was confirmed in human prostate cancer cells in which PTEN expression was abolished by RNA interference-mediated attenuation. These results were consistent with clinical evidence that the expression of p300 and AR correlates positively in human prostate cancer specimens. Mechanistically, PTEN inactivation increased AR phosphorylation at serine 81 (Ser81) to promote p300 binding and acetylation of AR, thereby precluding its polyubiquitination and degradation. In support of these findings, in PTEN-deficient prostate cancer in the mouse, we found that p300 was crucial for AR target gene expression. Taken together, our work identifies p300 as a molecular determinant of AR degradation and highlights p300 as a candidate target to manage prostate cancer, especially in cases marked by PTEN loss. Cancer Res; 74(6); 1870-80. (c)2014 AACR

CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy

Item does not contain fulltextDespite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbp(pc-/-);Pten(pc+/-) mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp(-/-); Pten(+/-) and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27(KIP1), and p21(CIP1). Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbp(pc-/-);Pten(pc+/-) mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer