Thresholds for surfactant use in preterm neonates: a network meta-analysis.

OBJECTIVE: To perform a network meta-analysis of randomised controlled trials of different surfactant treatment strategies for respiratory distress syndrome (RDS) to assess if a certain fraction of inspired oxygen (FiO2) is optimal for selective surfactant therapy. DESIGN: Systematic review and network meta-analysis using Bayesian analysis of randomised trials of prophylactic versus selective surfactant for RDS. SETTING: Cochrane Central Register of Controlled Trials, MEDLINE, Embase and Science Citation Index Expanded. PATIENTS: Randomised trials including infants under 32 weeks of gestational age. INTERVENTIONS: Intratracheal surfactant, irrespective of type or dose. MAIN OUTCOME MEASURES: Our primary outcome was neonatal mortality, compared between groups treated with selective surfactant therapy at different thresholds of FiO2. Secondary outcomes included respiratory morbidity and major complications of prematurity. RESULTS: Of 4643 identified references, 14 studies involving 5298 participants were included. We found no statistically significant differences between 30%, 40% and 50% FiO2 thresholds. A sensitivity analysis of infants treated in the era of high antenatal steroid use and nasal continuous positive airway pressure as initial mode of respiratory support showed no difference in mortality, RDS or intraventricular haemorrhage alone but suggested an increase in the combined outcome of major morbidities in the 60% threshold. CONCLUSION: Our results do not show a clear benefit of surfactant treatment at any threshold of FiO2. The 60% threshold was suggestive of increased morbidity. There was no advantage seen with prophylactic treatment. Randomised trials of different thresholds for surfactant delivery are urgently needed to guide clinicians and provide robust evidence. PROSPERO REGISTRATION NUMBER: CRD42020166620.

Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential.

Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients' outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.

Development of 2-(5,6,7-Trifluoro-1H-Indol-3-yl)-quinoline-5-carboxamide as a Potent, Selective, and Orally Available Inhibitor of Human Androgen Receptor Targeting Its Binding Function-3 for the Treatment of Castration-Resistant Prostate Cancer.

Prostate cancer (PCa) patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer (CRPC). Targeting the androgen receptor (AR) Binding Function-3 (BF3) site offers a promising option to treat CRPC. However, BF3 inhibitors have been limited by poor potency or inadequate metabolic stability. Through extensive medicinal chemistry, molecular modeling, and biochemistry, we identified 2-(5,6,7-trifluoro-1H-Indol-3-yl)-quinoline-5-carboxamide (VPC-13789), a potent AR BF3 antagonist with markedly improved pharmacokinetic properties. We demonstrate that VPC-13789 suppresses AR-mediated transcription, chromatin binding, and recruitment of coregulatory proteins. This novel AR antagonist selectively reduces the growth of both androgen-dependent and enzalutamide-resistant PCa cell lines. Having demonstrated in vitro efficacy, we developed an orally bioavailable prodrug that reduced PSA production and tumor volume in animal models of CRPC with no observed toxicity. VPC-13789 is a potent, selective, and orally bioavailable antiandrogen with a distinct mode of action that has a potential as novel CRPC therapeutics.

Functional mapping of androgen receptor enhancer activity.

BACKGROUND: Androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10-100× more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription. RESULTS: To characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity. CONCLUSIONS: Using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters.

A review of the propriety of thyroid ultrasound referrals and their follow-up burden.

PURPOSE: The overdiagnosis of thyroid nodules and indolent thyroid cancers represents an increasing burden on health services, with thyroid ultrasound (US) imaging often representing the initial entry point into the thyroid nodule diagnostic pathway. The aim of this study was to retrospectively review thyroid US referrals to a single Irish hospital to determine if the stated indications for imaging had been appropriate, to review the results of the scans, and to assess the follow-up required in each case. METHODS: Patient demographics, scan indications, results, and outcomes were retrospectively reviewed for all patients undergoing thyroid ultrasound from 2012 to 2016. Data were analyzed using GraphPad Prism and expressed in mean ± standard deviation. RESULTS: In total, 318 patients (mean age 53 ± 15 years, 85% female) had at least one ultrasound. Most US scans were performed for appropriate indications in order to follow up known thyroid nodular disease and/or malignancy (34.3%), to assess new thyroid goiters or discrete neck lumps (33.3%), and to follow up incidental findings from other imaging modalities (12.6%). However, scans were also requested (in the absence of any palpable goiter or mass) for choking/neck pain/swallowing complaints (12.3%), hypo/hyperthyroidism (6.6%), and miscellaneous reasons (0.6%) that were deemed either potentially or likely inappropriate. Of these scans, approximately half of the identified nodule(s) were deemed unlikely to be related to the stated symptoms, but which subsequently required follow-up imaging ± biopsy. No cases of malignancy were identified. CONCLUSIONS: In our center, a significant percentage of thyroid US scans along with their subsequent follow-up were potentially avoidable.

Chemical activation of a food deprivation signal extends lifespan.

Model organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug-like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology.