CHARACTERIZING THE EFFECTS OF ANTIANDROGENS AND SENOLYTICS TO ENHANCE THE THERAPEUTIC RESPONSE TO CASTRATION-RESISTANT PROSTATE CANCER

Prostate cancer is the most frequently diagnosed cancer in males and the second most common cause of cancer deaths. Androgen deprivation therapy, whether through surgical or chemical castration, is the mainstay for treatment of advanced prostate cancer; however, despite an initial response, most patients eventually develop a progressive PSA rise, and castration- sensitive prostate cancer gives rise to castration-resistant prostate cancer. The standard of care therapy includes the antiandrogens such as enzalutamide and abiraterone acetate as well as the microtubule poison, docetaxel, and various immunotherapies; however, while prostate cancer research is progressing, there continues to be a compelling need for new and more efficacious treatment combinations to prolong survival and offset disease progression, especially for castration-resistant disease. While the role of antiandrogens in androgen-dependent prostate cancer is well characterized, this is not the case for the involvement of these therapies in androgen-independent disease. Furthermore, successful utilization of senolytics to target senescent cells in cancer treatment has not yet been implemented or approved for clinical use. Initially, we evaluated the standard of care anti-androgens, enzalutamide and abiraterone, and their ability to induce growth arrest and possibly senescence in the PC3 and DU145 androgen-independent cell lines. While treatment with these antiandrogens produced a transient, growth arrest response, even in the case of supraclinical concentrations, neither drug induced significant senescence in either cell line. Despite these initially negative results, this did not rule out the possibility that a potential senolytic such as the BET degrader, ARV-825, could enhance the response to antiandrogens; therefore, we hypothesized that ARV-825 could potentially improve androgen independent castration-resistant prostate cancer’s response to enzalutamide. While the ARV-825 failed to enhance the response to enzalutamide in combination in PC3 cells, it had a significant effect as a monotherapy. Additional studies to understand the ineffectiveness of ARV-825 in the combination proved to be challenging, with enzalutamide inducing protective autophagy being a possible explanation. The most promising direction derived from these studies is the possible use of ARV-825 as a monotherapy in androgen-independent disease. ARV-825 as a monotherapy induced a significant prolonged growth arrest in the androgen-independent cells along with decreased levels of BRD4 and c-Myc. However, the ARV-825 did not induce significant senescence or apoptosis, despite the substantial growth arrest; therefore, the nature of this growth arrest remains to be investigated. Nevertheless, ARV-825 could prove to be a clinically relevant strategy in the treatment of castration-resistant prostate cancer

Prevalence and Prediction of Obstructive Coronary Artery Disease in Patients Referred for Valvular Heart Surgery

Current guidelines recommend a coronary evaluation before valvular heart surgery (VHS). Diagnostic coronary angiography is recommended in patients with known coronary artery disease (CAD) and those with high pretest probability of CAD. In patients with low or intermediate pretest probability of CAD, the guidelines recommend coronary computed tomographic angiography. However, there are no tools available to objectively assess a patient’s risk for obstructive CAD before VHS. To address this deficit, 5,360 patients without histories of CAD who underwent diagnostic coronary angiography as part of preoperative evaluation for VHS were identified. Obstructive CAD was defined as ≥50% stenosis in ≥1 artery. Of the patients assessed, 1,035 (19.3%) were found to have obstructive CAD. Through multivariate analysis, age, gender, diabetes, renal dysfunction, hyperlipidemia, and a family history of premature CAD were found to be associated with the presence of obstructive CAD (p \u3c0.001 for all). After adjustment, the specific dysfunctional valve was not associated with the presence of obstructive CAD. Patients were then randomly split into derivation and validation cohorts. Within the derivation cohort, using only age, gender, and the presence or absence of risk factors, a model was constructed to predict the risk for obstructive CAD (C statistic 0.766, 95% confidence interval 0.750 to 0.783). The risk prediction model performed well within the validation cohort (C statistic 0.767, 95% confidence interval 0.751 to 0.784, optimism 0.004). The bias-corrected C statistic for the model was 0.765 (95% confidence interval 0.748 to 0.782). In conclusion, this novel risk prediction tool can be used to objectively risk-stratify patients who undergo preoperative evaluation before VHS and to facilitate appropriate triage to computed tomographic angiography or diagnostic coronary angiography

Multiomics implicate gut microbiota in altered lipid and energy metabolism in Parkinson's disease

We aimed to investigate the link between serum metabolites, gut bacterial community composition, and clinical variables in Parkinson's disease (PD) and healthy control subjects (HC). A total of 124 subjects were part of the study (63 PD patients and 61 HC subjects). 139 metabolite features were found to be predictive between the PD and Control groups. No associations were found between metabolite features and within-PD clinical variables. The results suggest alterations in serum metabolite profiles in PD, and the results of correlation analysis between metabolite features and microbiota suggest that several bacterial taxa are associated with altered lipid and energy metabolism in PD.Peer reviewe

CemOrange2 fusions facilitate multifluorophore subcellular imaging in C. elegans

Due to its ease of genetic manipulation and transparency, Caenorhabditis elegans (C. elegans) has become a preferred model system to study gene function by microscopy. The use of Aequorea victoria green fluorescent protein (GFP) fused to proteins or targeting sequences of interest, further expanded upon the utility of C. elegans by labeling subcellular structures, which enables following their disposition during development or in the presence of genetic mutations. Fluorescent proteins with excitation and emission spectra different from that of GFP accelerated the use of multifluorophore imaging in real time. We have expanded the repertoire of fluorescent proteins for use in C. elegans by developing a codon-optimized version of Orange2 (CemOrange2). Proteins or targeting motifs fused to CemOrange2 were distinguishable from the more common fluorophores used in the nematode; such as GFP, YFP, and mKate2. We generated a panel of CemOrange2 fusion constructs, and confirmed they were targeted to their correct subcellular addresses by colocalization with independent markers. To demonstrate the potential usefulness of this new panel of fluorescent protein markers, we showed that CemOrange2 fusion proteins could be used to: 1) monitor biological pathways, 2) multiplex with other fluorescent proteins to determine colocalization and 3) gain phenotypic knowledge of a human ABCA3 orthologue, ABT-4, trafficking variant in the C. elegans model organism

Semiparametric Bayesian inference in smooth coefficient models

We describe procedures for Bayesian estimation and testing in cross-sectional, panel data and nonlinear smooth coefficient models. The smooth coefficient model is a generalization of the partially linear or additive model wherein coefficients on linear explanatory variables are treated as unknown functions of an observable covariate. In the approach we describe, points on the regression lines are regarded as unknown parameters and priors are placed on differences between adjacent points to introduce the potential for smoothing the curves. The algorithms we describe are quite simple to implement - for example, estimation, testing and smoothing parameter selection can be carried out analytically in the cross-sectional smooth coefficient model. We apply our methods using data from the National Longitudinal Survey of Youth (NLSY). Using the NLSY data we first explore the relationship between ability and log wages and flexibly model how returns to schooling vary with measured cognitive ability. We also examine a model of female labor supply and use this example to illustrate how the described techniques can been applied in nonlinear settings

Ancient dental calculus reveals oral microbiome shifts associated with lifestyle and disease in Great Britain

We thank C. Stringer and R. Kruszynski of the Natural History Museum, London; S. Schiffels; D. Sayer; Oxford Archaeology East; M. Farrell of the Royal College of Surgeons of England; J. Pearson of the Inverness Museum; and all of the museums for access to samples. We also thank the Museum of London for allowing us to collect and destructively analyse archaeological dental calculus samples from their collections from London, particularly J. Bekvalac and R. Redfern. We would also like to acknowledge J. VanderBerg at EnDev Geographic for producing the map used in Fig. 1. A.C., C.A. and L.W. thank the Australian Research Council for research funding (DP110105038) and Laureate (FL140100260). The work was also supported by an Australian Research Council Future Fellowship Award to L.S.W. (FT180100407). This material is also based on work supported by the National Science Foundation Graduate Research Fellowship Program awarded to A.S.G. under Grant No. DGE1255832. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.Peer reviewedPostprintPostprintPostprin

Highly Variable Extinction and Accretion in the Jet-driving Class I Type Young Star PTF 10nvg (V2492 Cyg, IRAS 20496+4354)

We report extensive new photometry and spectroscopy of the highly variable young stellar object PTF 10nvg including optical and near-infrared time series data as well as mid-infrared and millimeter data. Following the previously reported 2010 rise, during 2011 and 2012 the source underwent additional episodes of brightening and dimming events including prolonged faint states. The observed high-amplitude variations are largely consistent with extinction changes having a 220 day quasi-periodic signal. Spectral evolution includes not only changes in the spectral slope but correlated variation in the prominence of TiO/VO/CO bands and atomic line emission, as well as anticorrelated variation in forbidden line emission which, along with H_2, dominates optical and infrared spectra at faint epochs. Neutral and singly-ionized atomic species are likely formed in an accretion flow and/or impact while the origin of zero-velocity atomic LiI 6707 in emission is unknown. Forbidden lines, including several rare species, exhibit blueshifted emission profiles and likely arise from an outflow/jet. Several of these lines are also seen spatially offset from the continuum source position, presumably in a shocked region of an extended jet. CARMA maps resolve on larger scales a spatially extended outflow in mm-wavelength CO. We attribute the observed photometric and spectroscopic behavior in terms of occultation of the central star as well as the bright inner disk and the accretion/outflow zones that renders shocked gas in the inner part of the jet amenable to observation at the faint epochs. We discuss PTF 10nvg as a source exhibiting both accretion-driven (perhaps analogous to V1647 Ori) and extinction-driven (perhaps analogous to UX Ori or GM Cep) high-amplitude variability phenomena.Comment: accepted to AJ - in press (74 pages

A qualitative study of professional and carer perceptions of the threats to safe hospital discharge for stroke and hip fracture patients in the English National Health Service

Background: Hospital discharge is a vulnerable transitional stage in patient care. This qualitative study investigated the views of healthcare professionals and patients about the threats to safe hospital discharge with aim of identifying contributory and latent factors. The study was undertaken in two regional health and social care systems in the English National Health Service, each comprising three acute hospitals, community and primary care providers and municipal social care services. The study focused on the threats to safe discharge for hip fracture and stroke patients as exemplars of complex care transitions. Methods: A qualitative study involving narrative interviews with 213 representative stakeholders and professionals involved in discharge planning and care transition activities. Narratives were analysed in line with ‘systems’ thinking to identify proximal (active) and distal (latent) factors, and the relationships between them. Results: Three linked categories of commonly and consistently identified threat to safe discharge were identified:(1) ‘direct’ patient harms comprising falls, infection, sores and ulceration, medicines-related issues, and relapse; (2) proximal ‘contributing’ factors including completion of tests, assessment of patient, management of equipment and medicines, care plan, follow-up care and patient education; and distal ‘latent’ factors including discharge planning, referral processes, discharge timing, resources constraints, and organisational demands. Conclusion: From the perspective of stakeholders, the study elaborates the relationship between patient harms and systemic factors in the context of hospital discharge. It supports the importance of communication and collaboration across occupational and organisational boundaries, but also the challenges to supporting such communication with the inherent complexity of the care system