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

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

Ensuring due process in the IACUC and animal welfare setting: considerations in developing noncompliance policies and procedures for institutional animal care and use committees and institutional officials

Every institution that is involved in research with animals is expected to have in place policies and procedures for the management of allegations of noncompliance with the Animal Welfare Act and the U.S. Public Health Service Policy on the Humane Care and Use of Laboratory Animals. We present here a model set of recommendations for institutional animal care and use committees and institutional officials to ensure appropriate consideration of allegations of noncompliance with federal Animal Welfare Act regulations that carry a significant risk or specific threat to animal welfare. This guidance has 3 overarching aims: 1) protecting the welfare of research animals; 2) according fair treatment and due process to an individual accused of noncompliance; and 3) ensuring compliance with federal regulations. Through this guidance, the present work seeks to advance the cause of scientific integrity, animal welfare, and the public trust while recognizing and supporting the critical importance of animal research for the betterment of the health of both humans and animals.â Hansen, B. C., Gografe, S., Pritt, S., Jen, K.â L. C., McWhirter, C. A., Barman, S. M., Comuzzie, A., Greene, M., McNulty, J. A., Michele, D. E., Moaddab, N., Nelson, R. J., Norris, K., Uray, K. D., Banks, R., Westlund, K. N., Yates, B. J., Silverman, J., Hansen, K. D., Redman, B. Ensuring due process in the IACUC and animal welfare setting: considerations in developing noncompliance policies and procedures for institutional animal care and use committees and institutional officials. FASEB J. 31, 4216â 4225 (2017). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154293/1/fsb2fj201601250r.pd

Cognition, culture and utility:Plant classification by Paraguayan immigrant farmers in Misiones, Argentina

Background: This study was conducted in three rural communities of small farmers of Paraguayan origin living in the province of Misiones, Argentina. These Criollos (Mestizos) hail chiefly from departments located in the east of Paraguay, where the climate and flora have similar characteristics as those in Misiones. These ecological features contribute to the continuation and maintenance of knowledge and practices related to the use of plants. Methods: Fieldwork was conducted between September 2014 and August 2015. Forty five informants from three rural localities situated along the Parana River participated in an ethno-classification task. For the classification event, photographs of 30 medicinal and edible plants were chosen, specifically those yielding the highest frequency of mention among the members of that community (based on data obtained in the first stage of research in 2014). Variation in local plant classifications was examined and compared using principal component analysis and cluster analysis. Results: We found that people classify plants according to application or use (primarily medicinal, to a lesser extent as edible). Morphology is rarely taken into account, even for very similar and closely-related species such as varieties of palms. In light of our findings, we highlight a dominant functionality model at work in the process of plant cognition and classification among farmers of Paraguayan origin. Salient cultural beliefs and practices associated with rural Paraguayan plant-based medicine are described. Additionally, the manner by which residents’ concepts of plants articulate with local folk epistemology is discussed. Conclusions: Culturally constructed use patterns ultimately override morphological variables in rural Paraguayans’ ethnobotanical classification.Antecedentes: Este trabajo se realizó con pequeños agricultores de origen paraguayo, que habitan en la provincia de Misiones, Argentina. Los criollos (mestizos) en su mayoría provienen de departamentos ubicados al oriente del Paraguay, donde el clima y la flora presentan características similares a la provincia de Misiones. Estas características ecológicas contribuyen a la continuación y el mantenimiento de los conocimientos y las prácticas relacionados al uso de las plantas. Métodos El trabajo de campo se realizó entre septiembre de 2014 y agosto de 2015. En la etnoclasificación participaron 45 informantes, provenientes de tres localidades rurales, situadas a lo largo del río Paraná, frontera entre los dos países. Para la clasificación se utilizaron imágenes fotográficas de 30 especies -comestibles y medicinales- preseleccionadas como las de mayor frecuencia de mención entre los habitantes de la región (a partir de los datos obtenidos en una primera etapa de investigación en el año 2014). Por medio del análisis de componentes principales y el análisis de agrupamiento (cluster) se contrastaron y compararon las variaciones en las etnoclasificaciones locales de plantas. Resultados Se encontró que los pobladores clasifican sus plantas según su aplicación y uso (mayormente asociadas a la categoría medicinal y en menor medida a la comestible). Mientras, la morfología rara vez se tiene en cuenta, incluso en aquellas especies muy similares y estrechamente relacionadas como las palmeras. A la luz de los hallazgos, se destaca un modelo de funcionalidad dominante en el proceso de cognición y de clasificación de las plantas entre los agricultores de origen paraguayo. Se describen las principales creencias y prácticas culturales asociadas a la medicina rural paraguaya. Adicionalmente, se discuten algunos de los conceptos de las plantas que mantienen los paraguayos y su articulación con la epistemología local. Conclusiones En la clasificación etnobotánica de los pobladores de origen paraguayo los patrones de uso construidos culturalmente tienen mayor peso que las variables morfológicas.Fil: Kujawska, Monika. University Of Lodz; ArgentinaFil: Jiménez Escobar, Néstor David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Antropología de Córdoba. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Instituto de Antropología de Córdoba; ArgentinaFil: Nolan, Justin M.. University Of Arkansas; Estados UnidosFil: Arias Mutis, Daniel. University of Groningen; Países Bajo

Publisher Correction: Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.

This paper was originally published under a standard Springer Nature license

Accurate Inference of Subtle Population Structure (and Other Genetic Discontinuities) Using Principal Coordinates

Accurate inference of genetic discontinuities between populations is an essential component of intraspecific biodiversity and evolution studies, as well as associative genetics. The most widely-used methods to infer population structure are model-based, Bayesian MCMC procedures that minimize Hardy-Weinberg and linkage disequilibrium within subpopulations. These methods are useful, but suffer from large computational requirements and a dependence on modeling assumptions that may not be met in real data sets. Here we describe the development of a new approach, PCO-MC, which couples principal coordinate analysis to a clustering procedure for the inference of population structure from multilocus genotype data.PCO-MC uses data from all principal coordinate axes simultaneously to calculate a multidimensional "density landscape", from which the number of subpopulations, and the membership within subpopulations, is determined using a valley-seeking algorithm. Using extensive simulations, we show that this approach outperforms a Bayesian MCMC procedure when many loci (e.g. 100) are sampled, but that the Bayesian procedure is marginally superior with few loci (e.g. 10). When presented with sufficient data, PCO-MC accurately delineated subpopulations with population F(st) values as low as 0.03 (G'(st)>0.2), whereas the limit of resolution of the Bayesian approach was F(st) = 0.05 (G'(st)>0.35).We draw a distinction between population structure inference for describing biodiversity as opposed to Type I error control in associative genetics. We suggest that discrete assignments, like those produced by PCO-MC, are appropriate for circumscribing units of biodiversity whereas expression of population structure as a continuous variable is more useful for case-control correction in structured association studies

Mosaic Chromosomal alterations in Blood across ancestries Using Whole-Genome Sequencing

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis

Genomic Insights Into The Ixodes scapularis Tick Vector Of Lyme Disease

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retrotransposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing B57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick–host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host ‘questing’, prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent