ERG Induces Epigenetic Activation of Tudor Domain-Containing Protein 1 (TDRD1) in ERG Rearrangement-Positive Prostate Cancer

Background Overexpression of ERG transcription factor due to genomic ERG- rearrangements defines a separate molecular subtype of prostate tumors. One of the consequences of ERG accumulation is modulation of the cell’s gene expression profile. Tudor domain-containing protein 1 gene (TDRD1) was reported to be differentially expressed between TMPRSS2:ERG-negative and TMPRSS2:ERG-positive prostate cancer. The aim of our study was to provide a mechanistic explanation for the transcriptional activation of TDRD1 in ERG rearrangement-positive prostate tumors. Methodology/Principal Findings Gene expression measurements by real-time quantitative PCR revealed a remarkable co-expression of TDRD1 and ERG (r2 = 0.77) but not ETV1 (r2<0.01) in human prostate cancer in vivo. DNA methylation analysis by MeDIP-Seq and bisulfite sequencing showed that TDRD1 expression is inversely correlated with DNA methylation at the TDRD1 promoter in vitro and in vivo (ρ = −0.57). Accordingly, demethylation of the TDRD1 promoter in TMPRSS2:ERG-negative prostate cancer cells by DNA methyltransferase inhibitors resulted in TDRD1 induction. By manipulation of ERG dosage through gene silencing and forced expression we show that ERG governs loss of DNA methylation at the TDRD1 promoter-associated CpG island, leading to TDRD1 overexpression. Conclusions/Significance We demonstrate that ERG is capable of disrupting a tissue-specific DNA methylation pattern at the TDRD1 promoter. As a result, TDRD1 becomes transcriptionally activated in TMPRSS2:ERG-positive prostate cancer. Given the prevalence of ERG fusions, TDRD1 overexpression is a common alteration in human prostate cancer which may be exploited for diagnostic or therapeutic procedures

From reading numbers to seeing ratios: a benefit of icons for risk comprehension

Promoting a better understanding of statistical data is becoming increasingly important for improving risk comprehension and decision-making. In this regard, previous studies on Bayesian problem solving have shown that iconic representations help infer frequencies in sets and subsets. Nevertheless, the mechanisms by which icons enhance performance remain unclear. Here, we tested the hypothesis that the benefit offered by icon arrays lies in a better alignment between presented and requested relationships, which should facilitate the comprehension of the requested ratio beyond the represented quantities. To this end, we analyzed individual risk estimates based on data presented either in standard verbal presentations (percentages and natural frequency formats) or as icon arrays. Compared to the other formats, icons led to estimates that were more accurate, and importantly, promoted the use of equivalent expressions for the requested probability. Furthermore, whereas the accuracy of the estimates based on verbal formats depended on their alignment with the text, all the estimates based on icons were equally accurate. Therefore, these results support the proposal that icons enhance the comprehension of the ratio and its mapping onto the requested probability and point to relational misalignment as potential interference for text-based Bayesian reasoning. The present findings also argue against an intrinsic difficulty with understanding single-event probabilities

Phase retrieval for adaptive optics system calibration

Our objective in this report is to develop methods to determine the output pupil wavefront using intensity measurements directly from the science detector. This wavefront can then be used to determine a reference wavefront which will precorrect for the non-common-path aberrations and produce the desired wavefront at the science detector. We describe two phase retrieval algorithms that can be used and a set of simulation studies of AO system calibration. We present the initial experimental results of applying this technique in calibration of the Lick Observatory laser guidestar AO system in a later paper

DEVELOPMENT OF ADAPTIVE RESONATOR TECHNIQUES FOR HIGH-POWER LASERS

The design of an adaptive wavefront control system for a high-power Nd:Glass laser will be presented. Features of this system include: an unstable resonator in confocal configuration, a multi-module slab amplifier, and real-time intracavity adaptive phase control using deformable mirrors and high-speed wavefront sensors. Experimental results demonstrate the adaptive correction of an aberrated passive resonator (no gain)

X-ray imaging: Status and trends

There is a veritable renaissance occurring in x-ray imaging. X-ray imaging by radiography has been a highly developed technology in medicine and industry for many years. However, high resolution imaging has not generally been practical because sources have been relatively dim and diffuse, optical elements have been nonexistent for most applications, and detectors have been slow and of low resolution. Materials analysis needs have therefore gone unmet. Rapid progress is now taking place because we are able to exploit developments in microelectronics and related material fabrication techniques, and because of the availability of intense x-ray sources. This report describes the methods and uses of x-ray imaging along with a discussion of technology advances in these areas

Changes in circulating microRNA levels associated with prostate cancer

BACKGROUND: The aim of this study was to investigate the hypothesis that changes in circulating microRNAs (miRs) represent potentially useful biomarkers for the diagnosis, staging and prediction of outcome in prostate cancer. METHODS: Real-time polymerase chain reaction analysis of 742 miRs was performed using plasma-derived circulating microvesicles of 78 prostate cancer patients and 28 normal control individuals to identify differentially quantified miRs. RESULTS: A total of 12 miRs were differentially quantified in prostate cancer patients compared with controls, including 9 in patients without metastases. In all, 11 miRs were present in significantly greater amounts in prostate cancer patients with metastases compared with those without metastases. The association of miR-141 and miR-375 with metastatic prostate cancer was confirmed using serum-derived exosomes and microvesicles in a separate cohort of patients with recurrent or non-recurrent disease following radical prostatectomy. An analysis of five selected miRs in urine samples found that miR-107 and miR-574-3p were quantified at significantly higher concentrations in the urine of men with prostate cancer compared with controls. CONCLUSION: These observations suggest that changes in miR concentration in prostate cancer patients may be identified by analysing various body fluids. Moreover, circulating miRs may be used to diagnose and stage prostate cance

Technical challenges for the future of high energy lasers

The Solid-State, Heat-Capacity Laser (SSHCL) program at Lawrence Livermore National Laboratory is a multi-generation laser development effort scalable to the megawatt power levels with current performance approaching 100 kilowatts. This program is one of many designed to harness the power of lasers for use as directed energy weapons. There are many hurdles common to all of these programs that must be overcome to make the technology viable. There will be a in-depth discussion of the general issues facing state-of-the-art high energy lasers and paths to their resolution. Despite the relative simplicity of the SSHCL design, many challenges have been uncovered in the implementation of this particular system. An overview of these and their resolution are discussed. The overall system design of the SSHCL, technological strengths and weaknesses, and most recent experimental results will be presented

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer