The Landscape of Long Non-Coding RNA Dysregulation and Clinical Relevance in Muscle Invasive Bladder Urothelial Carcinoma.

Bladder cancer is one of the most common cancers in the United States, but few advancements in treatment options have occurred in the past few decades. This study aims to identify the most clinically relevant long non-coding RNAs (lncRNAs) to serve as potential biomarkers and treatment targets for muscle invasive bladder cancer (MIBC). Using RNA-sequencing data from 406 patients in The Cancer Genome Atlas (TCGA) database, we identified differentially expressed lncRNAs in MIBC vs. normal tissues. We then associated lncRNA expression with patient survival, clinical variables, oncogenic signatures, cancer- and immune-associated pathways, and genomic alterations. We identified a panel of 20 key lncRNAs that were most implicated in MIBC prognosis after differential expression analysis and prognostic correlations. Almost all lncRNAs we identified are correlated significantly with oncogenic processes. In conclusion, we discovered previously undescribed lncRNAs strongly implicated in the MIBC disease course that may be leveraged for diagnostic and treatment purposes in the future. Functional analysis of these lncRNAs may also reveal distinct mechanisms of bladder cancer carcinogenesis

Psychedelics Promote Structural and Functional Neural Plasticity.

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders

High throughput mutagenesis for identification of residues regulating human prostacyclin (hIP) receptor

The human prostacyclin receptor (hIP receptor) is a seven-transmembrane G protein-coupled receptor (GPCR) that plays a critical role in vascular smooth muscle relaxation and platelet aggregation. hIP receptor dysfunction has been implicated in numerous cardiovascular abnormalities, including myocardial infarction, hypertension, thrombosis and atherosclerosis. Genomic sequencing has discovered several genetic variations in the PTGIR gene coding for hIP receptor, however, its structure-function relationship has not been sufficiently explored. Here we set out to investigate the applicability of high throughput random mutagenesis to study the structure-function relationship of hIP receptor. While chemical mutagenesis was not suitable to generate a mutagenesis library with sufficient coverage, our data demonstrate error-prone PCR (epPCR) mediated mutagenesis as a valuable method for the unbiased screening of residues regulating hIP receptor function and expression. Here we describe the generation and functional characterization of an epPCR derived mutagenesis library compromising >4000 mutants of the hIP receptor. We introduce next generation sequencing as a useful tool to validate the quality of mutagenesis libraries by providing information about the coverage, mutation rate and mutational bias. We identified 18 mutants of the hIP receptor that were expressed at the cell surface, but demonstrated impaired receptor function. A total of 38 non-synonymous mutations were identified within the coding region of the hIP receptor, mapping to 36 distinct residues, including several mutations previously reported to affect the signaling of the hIP receptor. Thus, our data demonstrates epPCR mediated random mutagenesis as a valuable and practical method to study the structurefunction relationship of GPCRs. © 2014 Bill et al

Nurses in advanced roles as a strategy for equitable access to healthcare in the WHO Western Pacific region: a mixed methods study

BackgroundThe Western Pacific region constitutes one-quarter of the world's population and has diverse health needs. While dialogue on and promotion of advanced practice nurses are ongoing, this study investigated the current responsibilities of nurses in advanced roles, future healthcare needs, and the implications of these components for nurses' professional development within the Western Pacific region.MethodsThis study employed three phases, a descriptive survey on the current status of nurses in advanced roles in the Western Pacific region, followed by a Delphi survey, and exploratory interviews. A total of 55 national experts with clinical, academic, and/or government-related backgrounds from 18 countries participated from December 2017 - December 2018. The descriptive survey via email to identify the status of nurses in advanced roles and a working definition was developed. This formed the basis for the Delphi survey, which identified key barriers and challenges for enhancing the development of nurses in advanced roles within the country (round 1) and for the region (rounds 2 and 3). Lastly, semi-structured individual interviews were conducted to identify strategies for establishing nurses in advanced roles to improve equitable access to healthcare.ResultsThirty-seven roles and characteristics were identified and categorized for nurses performing advanced roles. Emergency care, critical care, elderly health, child health, and rural/remote communities were identified as fields with particular need for nurses in advanced roles in the Western Pacific region. Providing effective services, influencing government leadership, and advocating for health system sustainability were deemed necessary to improve equitable healthcare access. We found that nurses in advanced roles are not limited to clinical tasks within the hospital but are poised for active participation in primary healthcare, education/teaching, professional leadership, quality management, and research.ConclusionsDemand for nurses in advanced roles is high in the Western Pacific region and 15 items were identified across five core strategic areas to enhance development of nurses in advanced roles. Governmental-level recommendations include establishing legislative protection, improving systems for remuneration, strengthening supportive channels, and conducting national needs assessments

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification

Baseline albumin-bilirubin (ALBI) in Western patients with hepatocellular carcinoma treated with stereotactic body radiotherapy (SBRT)

Purpose: To assess the baseline albumin-bilirubin (ALBI) score as a predictor of toxicity and survival in a prospective cohort of Western patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT) in 2 prospective trials. Methods and Materials: The study included 102 patients with Child-Pugh class A liver disease who received 6-fraction SBRT for HCC. Univariate and multivariable logistic regression investigated factors associated with toxicity, defined as an increase in Child-Pugh score ≥ 2 within 3 months of SBRT. Univariate and multivariable Cox regression analyses investigated factors predictive of overall survival (OS). The ALBI score was analyzed as a continuous and binary variable in separate analyses. Results: On multivariable analysis of toxicity, including the ALBI score as a continuous variable, the ALBI score (odds ratio [OR] per 0.1-unit increase, 1.51; 95% confidence interval [CI] 1.23-1.85; P = .00074), mean liver dose (OR, 1.31; 95% CI 1.02-1.68; P = .036), and dose received by 800 cm3 of normal liver (OR, 1.10; 95% CI 1.01-1.20; P = .028) were significant. When the ALBI score was included as a dichotomous variable, the ALBI grade remained a significant predictor of toxicity (OR, 7.44; 95% CI 2.34-23.70; P = .00069). On multivariable analysis of OS, including the ALBI score as a continuous variable, the ALBI score (hazard ratio [HR] per 0.1-unit increase, 1.09; 95% CI 1.03-1.17; P = .004), tumor thrombus (HR, 1.94; 95% CI 1.23-3.07; P = .004), and treatment in trial 1 versus trial 2 (HR, 1.92; 95% CI 1.23-3.03; P = .004) were significant. Similarly, when the ALBI score was included as a binary variable, the ALBI grade, tumor thrombus, and trial were significant predictors of OS. When the ALBI score was considered, the Child-Pugh score (A6 vs A5) was not significant in multivariable models analyzing toxicity or survival. Concordance statistics indicated models containing the ALBI score were superior to those containing the Child-Pugh score. Conclusions: The baseline ALBI score was more discriminating than the Child-Pugh score in predicting OS and toxicity in patients with Child-Pugh class A liver disease. The ALBI score should be used as a factor for stratification in future HCC SBRT trials

Quantum Tunneling in Nuclear Fusion

Recent theoretical advances in the study of heavy ion fusion reactions below the Coulomb barrier are reviewed. Particular emphasis is given to new ways of analyzing data, such as studying barrier distributions; new approaches to channel coupling, such as the path integral and Green function formalisms; and alternative methods to describe nuclear structure effects, such as those using the Interacting Boson Model. The roles of nucleon transfer, asymmetry effects, higher-order couplings, and shape-phase transitions are elucidated. The current status of the fusion of unstable nuclei and very massive systems are briefly discussed.Comment: To appear in the January 1998 issue of Reviews of Modern Physics. 13 Figures (postscript file for Figure 6 is not available; a hard copy can be requested from the authors). Full text and figures are also available at http://nucth.physics.wisc.edu/preprints

Nutrition aspects in children receiving maintenance hemodialysis: impact on outcome

Children with end-stage renal disease (ESRD) have rates of mortality estimated to be 30-times higher than expected for age compared with those of healthy children. Physical manifestations of under-nutrition, such as body mass index (BMI) and low height standard deviation score (SDS), have been associated with increased risk of mortality. Traditional measures, such as height, weight and serum albumin concentration, may not be accurate indicators to assess the nutritional status of children receiving maintenance hemodialysis. Normalized protein catabolic rate (nPCR) has emerged as a better marker of nutritional status of such children. Meeting the special nutritional needs of these children often requires nutritional supplementation, by either the enteral or the parenteral route. Recently, in children receiving maintenance hemodialysis who are malnourished, intradialytic parenteral nutrition (IDPN) has been utilized as a means to provide additional protein and calories. This article is a state-of-the-art review of malnutrition in children receiving maintenance hemodialysis, with special focus on outcome, nPCR and IDPN

Genome sequence of an Australian kangaroo, Macropus eugenii, provides insight into the evolution of mammalian reproduction and development.

BACKGROUND: We present the genome sequence of the tammar wallaby, Macropus eugenii, which is a member of the kangaroo family and the first representative of the iconic hopping mammals that symbolize Australia to be sequenced. The tammar has many unusual biological characteristics, including the longest period of embryonic diapause of any mammal, extremely synchronized seasonal breeding and prolonged and sophisticated lactation within a well-defined pouch. Like other marsupials, it gives birth to highly altricial young, and has a small number of very large chromosomes, making it a valuable model for genomics, reproduction and development. RESULTS: The genome has been sequenced to 2 × coverage using Sanger sequencing, enhanced with additional next generation sequencing and the integration of extensive physical and linkage maps to build the genome assembly. We also sequenced the tammar transcriptome across many tissues and developmental time points. Our analyses of these data shed light on mammalian reproduction, development and genome evolution: there is innovation in reproductive and lactational genes, rapid evolution of germ cell genes, and incomplete, locus-specific X inactivation. We also observe novel retrotransposons and a highly rearranged major histocompatibility complex, with many class I genes located outside the complex. Novel microRNAs in the tammar HOX clusters uncover new potential mammalian HOX regulatory elements. CONCLUSIONS: Analyses of these resources enhance our understanding of marsupial gene evolution, identify marsupial-specific conserved non-coding elements and critical genes across a range of biological systems, including reproduction, development and immunity, and provide new insight into marsupial and mammalian biology and genome evolution