Networks of intergenic long-range enhancers and snpRNAs drive castration-resistant phenotype of prostate cancer and contribute to pathogenesis of multiple common human disorders

Biological and mechanistic relevance of intergenic disease-associated genetic loci (IDAGL) containing highly statistically significant disease-linked SNPs remains unknown. Here we present the experimental and clinical evidence revealing important role of IDAGL in human diseases. Targeted RT-PCR screen coupled with sequencing of purified PCR products detects widespread transcription at multiple intergenic disease-associated genomic loci (IDAGL) and identifies 96 small non-coding trans-regulatory RNAs of ~ 100-300 nt in length containing SNPs associated with 21 common human disorders (snpRNAs). Functionality of snpRNAs is supported by multiple independent lines of experimental evidence demonstrating their cell-type-specific expression and evolutionary conservation of sequences, genomic coordinates, and biological effects. Analysis of chromatin state signatures, expression profiling experiments using microarray and Q-PCR technologies, and luciferase reporter assays indicate that many IDAGL are Polycomb-regulated long-range enhancers. Expression of snpRNAs in human and mouse cells markedly affects cellular behavior and induces allele-specific clinically-relevant phenotypic changes: NLRP1-locus snpRNAs exert regulatory effects on monocyte/macrophage trans-differentiation, induce prostate cancer (PC) susceptibility snpRNAs, and transform low-malignancy hormone-dependent human PC cells into highly malignant androgen-independent PC. Q-PCR analysis and luciferase reporter assays demonstrate that snpRNA sequences represent allele-specific “decoy” targets of microRNAs which function as SNP-allele-specific modifiers of microRNA expression and activity. We demonstrate that trans-acting RNA molecules facilitating androgen depletion-independent growth (ADIG) in vitro and castration-resistant (CR) phenotype in vivo of PC contain intergenic 8q24-locus SNP variants which were recently linked with increased risk of developing PC. Expression level of 8q24-locus PC susceptibility snpRNAs is regulated by NLRP1-locus snpRNAs, which are transcribed from the intergenic long-range enhancer sequence located in 17p13 region at ~ 30 kb distance from the NLRP1 gene. Q-PCR analysis of clinical PC samples reveals markedly increased snpRNA expression levels in tumor tissues compared to the adjacent normal prostate [122-fold and 45-fold in Gleason 7 tumors (p = 0.03); 370-fold and 127-fold in Gleason 8 tumors (p = 0.0001); for NLRP1-locus and 8q24-locus SnpRNAs, respectively]. Highly concordant expression profiles of the NLRP1-locus snpRNAs and 8q24 CR-locus snpRNAs (r = 0.896; p < 0.0001) in clinical PC samples and experimental evidence of trans-regulatory effects of NLRP1-locus snpRNAs on expression of 8q24-locus SnpRNAs indicate that ADIG and CR phenotype of human PC cells can be triggered by RNA molecules transcribed from the NLRP1-locus intergenic enhancer and down-stream activation of the 8q24-locus snpRNAs. Our results define the intergenic NLRP1 and 8q24 regions as regulatory loci of ADIG and CR phenotype of human PC, reveal previously unknown molecular links between the innate immunity/inflammasome system and development of hormone-independent PC, and identify novel diagnostic and therapeutic targets exploration of which should be highly beneficial for clinical management of PC

Telling Patients the Truth

This article discusses the ethical necessity of health care workers telling their patients the truth about both their diagnosis and prognosis. This necessity is based upon respect for persons, utility, and kindness. Within this ethical obligation to tell the truth, however, there are several different ways in which the truth can be told. In particular, this paper stresses that telling patients the truth is best thought of as a process that unfolds over time, and which is driven by what the patient knows and what they want

Some Ethical Issues in Treating and Caring for People with Dementia

This paper explores several issues regarding the treatment and care for patients suffering from dementia, including a discussion of the relatively low time and money spent on dementia research compared to research on cancer and cardio-vascular disease. It will also discuss the special relationship between the person suffering from dementia and their carer, who is often a loved one. The paper employs principlism and so examines these issues from a consideration of autonomy, non-maleficence, beneficence, and justice

Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease and cancer : a systematic review and meta-analysis

We thank Associate Professor Andrew Grey for helping to resolve discrepancies in data extraction and interpretation for cardiovascular events and cancer events. We thank trialists from 16 studies for clarifying or providing additional information for this review [Andrews 2011, Aveyard 2016, Bennett 2012, de Vos 2014, Finnish Diabetes Prevention Study 2009, Goodwin 2014, Green 2015, Horie 2016, Hunt (FFIT) 2014, Katula 2013, Li (Da Qing) 2014, Logue 2005, Ma 2013, O’Neil 2016, Rejeski (CLIP) 2011, Uusitupa 1993] and also others who provided information, but their trials were later found not to fulfil our inclusion criteria. Funding: The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorate.Peer reviewedPublisher PD

Investigating what level of visual information inspires trust in a user of a highly automated vehicle

The aim of this research is to investigate whether visual feedback alone can affect a driver’s trust in an autonomous vehicle, and in particular, what level of feedback (no feedback vs. moderate feedback vs. high feedback) will evoke the appropriate level of trust. Before conducting the experiment, the Human Machine Interfaces (HMI) were piloted with two sets of six participants (before and after iterations), to ensure the meaning of the displays can be understood by all. A static driving simulator experiment was conducted with a sample of 30 participants (between 18 and 55). Participants completed two pre-study questionnaires to evaluate previous driving experience, and attitude to trust in automation. During the study, participants completed a trust questionnaire after each simulated scenario to assess their trust level in the autonomous vehicle and HMI displays, and on intention to use and acceptance. The participants were shown 10 different driving scenarios that lasted approximately 2 minutes each. Results indicated that the ‘high visual feedback’ group recorded the highest trust ratings, with this difference significantly higher than for the ‘no visual feedback’ group (U = .000; p = <0.001 < α) and the ‘moderate visual feedback’ group (U = .000; p = <0.001 < α). There is an upward inclination of trust in all groups due to familiarity to both the interfaces and driving simulator over time. Participants’ trust level was also influenced by the driving scenario, with trust reducing in all displays during safety verses non-safety-critical situations

Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors.

BackgroundIn 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.ResultsPre-decitabine RhoA was higher in patients who had received their last therapy &gt;3&nbsp;months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = -0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores ≤150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P &lt;0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = -0.45, P = 0.19).ConclusionsIn conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation

The Merger Rates and Mass Assembly Histories of Dark Matter Haloes in the Two Millennium Simulations

We construct merger trees of dark matter haloes and quantify their merger rates and mass growth rates using the joint dataset from the Millennium and Millennium-II simulations. The finer resolution of the Millennium-II Simulation has allowed us to extend our earlier analysis of halo merger statistics to an unprecedentedly wide range of descendant halo mass (10^10 < M0 < 10^15 Msun), progenitor mass ratio (10^-5 < xi < 1), and redshift (0 < z < 15). We update our earlier fitting form for the mean merger rate per halo as a function of M_0, xi, and z. The overall behavior of this quantity is unchanged: the rate per unit redshift is nearly independent of z out to z~15; the dependence on halo mass is weak (M0^0.13); and it is nearly a power law in the progenitor mass ratio (xi^-2). We also present a simple and accurate fitting formula for the mean mass growth rate of haloes as a function of mass and redshift. This mean rate is 46 Msun/yr for 10^12 Msun haloes at z=0, and it increases with mass as M^{1.1} and with redshift as (1+z)^2.5 (for z > 1). When the fit for the mean mass growth rate is integrated over a halo's history, we find excellent match to the mean mass assembly histories of the simulated haloes. By combining merger rates and mass assembly histories, we present results for the number of mergers over a halo's history and the statistics of the redshift of the last major merger.Comment: 12 pages, 9 figures, accepted in MNRA