Epigenomic Regulation of Androgen Receptor Signaling: Potential Role in Prostate Cancer Therapy.

Androgen receptor (AR) signaling remains the major oncogenic pathway in prostate cancer (PCa). Androgen-deprivation therapy (ADT) is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC). Epigenetics, the study of heritable and reversible changes in gene expression without alterations in DNA sequences, is a crucial regulatory step in AR signaling. We and others, recently described the technological advance Chem-seq, a method to identify the interaction between a drug and the genome. This has permitted better understanding of the underlying regulatory mechanisms of AR during carcinogenesis and revealed the importance of epigenetic modifiers. In screening for new epigenomic modifiying drugs, we identified SD-70, and found that this demethylase inhibitor is effective in CRPC cells in combination with current therapies. The aim of this review is to explore the role of epigenetic modifications as biomarkers for detection, prognosis, and risk evaluation of PCa. Furthermore, we also provide an update of the recent findings on the epigenetic key processes (DNA methylation, chromatin modifications and alterations in noncoding RNA profiles) involved in AR expression and their possible role as therapeutic targets

Trump, Twitter, and news media responsiveness: a media systems approach

How populists engage with media of various types, and are treated by those media, are questions of international interest. In the United States, Donald Trump stands out for both his populism-inflected campaign style and his success at attracting media attention. This article examines how interactions between candidate communications, social media, partisan media, and news media combined to shape attention to Trump, Clinton, Cruz, and Sanders during the 2015–2016 American presidential primary elections. We identify six major components of the American media system and measure candidates’ efforts to gain attention from them. Our results demonstrate that social media activity, in the form of retweets of candidate posts, provided a significant boost to news media coverage of Trump, but no comparable boost for other candidates. Furthermore, Trump tweeted more at times when he had recently garnered less of a relative advantage in news attention, suggesting he strategically used Twitter to trigger coverage.Accepted manuscrip

lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs.

Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis, their potential involvement in regulated gene transcription programs remains rather poorly understood. The androgen receptor regulates a large repertoire of genes central to the identity and behaviour of prostate cancer cells, and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy. Here we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 (also known as PCAT8) and PCGEM1, bind successively to the androgen receptor and strongly enhance both ligand-dependent and ligand-independent androgen-receptor-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated androgen receptor on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the androgen receptor amino terminus that is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus 2 PHD domain enhances selective looping of androgen-receptor-bound enhancers to target gene promoters in these cells. In 'resistant' prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length androgen receptor, causing ligand-independent activation of the androgen receptor transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumour xenograft growth in vivo. Together, these results indicate that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumours

Anticoagulation in patients with atrial fibrillation and heart failure: Insights from the NCDR PINNACLE-AF registry.

BackgroundIn non-valvular atrial fibrillation (NVAF) patients, congestive heart failure (CHF) confers an increased risk of stroke or systemic thromboembolism. This risk is present in both heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). It is unclear if clinicians account for both types of CHF in their NVAF anticoagulation practices. Accordingly, we characterized current outpatient anticoagulation trends in NVAF patients with HFpEF compared to patients with HFrEF.MethodsThe outpatient NCDR PINNACLE-AF registry was analyzed to identify patients with NVAF and CHF. The study population was subdivided into HFpEF (ie, LVEF ≥ 40%) and HFrEF (LVEF < 40%). Anticoagulation rates by CHF group were compared and stratified by CHA2 DS2 -VASc score.ResultsA total of 340 127 patients with NVAF and CHF were identified, of whom 248 136 (73.0%) were classified as HFpEF and 91 991 (27.0%) as HFrEF. Patients with HFpEF had higher mean CHA2 DS2 -VASc scores and were more likely to be female, older, and have hypertension (P < 0.001). Unadjusted anticoagulation rates were significantly lower in patients with HFpEF compared to those with HFrEF (60.6% vs 64.2%, respectively). Lower rates of anticoagulation in the HFpEF group persisted after risk adjustment (RR: 0.93 [95% CI: 0.91, 0.94]). Stratification by CHA2 DS2 -VASc score demonstrated that lower rates of anticoagulation in patients with HFpEF persisted until a score of ≥5.ConclusionsPatients with NVAF and HFpEF have significantly lower anticoagulation rates when compared to their HFrEF counterparts. These findings suggest a potential underappreciation of HFpEF as a risk factor in patients with NVAF