Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target

BACKGROUND: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling.

METHODS: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided.

RESULTS: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts.

CONCLUSIONS: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.

Geographical variation in inorganic arsenic in paddy field samples and commercial rice from the Iberian Peninsula

This study investigated total arsenic and arsenic speciation in rice using ion chromatography with mass spectrometric detection (IC-ICP-MS), covering the main rice-growing regions of the Iberian Peninsula in Europe. The main arsenic species found were inorganic and dimethylarsinic acid. Samples surveyed were soil, shoots and field-collected rice grain. From this information soil to plant arsenic transfer was investigated plus the distribution of arsenic in rice across the geographical regions of Spain and Portugal. Commercial polished rice was also obtained from each region and tested for arsenic speciation, showing a positive correlation with field-obtained rice grain. Commercial polished rice had the lowest i-As content in Andalucia, Murcia and Valencia while Extremadura had the highest concentrations. About 26% of commercial rice samples exceeded the permissible concentration
for infant food production as governed by the European Commission. Some cadmium data is also presented, available with ICP-MS analyses, and show low concentration in rice samples.

Validating the use of intrinsic markers in body feathers to identify inter‑individual differences in non‑breeding areas of northern fulmars

Many wildlife studies use chemical analyses to explore spatio-temporal variation in diet, migratory patterns and contaminant exposure. Intrinsic markers are particularly valuable for studying non-breeding marine predators, when direct methods of investigation are rarely feasible. However, any inferences regarding foraging ecology are dependent upon the time scale over which tissues such as feathers are formed. In this study, we validate the use of body feathers for studying non-breeding foraging patterns in a pelagic seabird, the northern fulmar. Analysis of carcasses of successfully breeding adult fulmars indicated that body feathers moulted between September and March, whereas analyses of carcasses and activity patterns suggested that wing feather and tail feather moult occurred during more restricted periods (September to October and September to January, respectively). By randomly sampling relevant body feathers, average values for individual birds were shown to be consistent. We also integrated chemical analyses of body feather with geolocation tracking data to demonstrate that analyses of δ13C and δ15N values successfully assigned 88 % of birds to one of two broad wintering regions used by breeding adult fulmars from a Scottish study colony. These data provide strong support for the use of body feathers as a tool for exploring non-breeding foraging patterns and diet in wide-ranging, pelagic seabirds.

The Importance of DNA methylation in Prostate Cancer development

After briefly reviewing the nature of DNA methylation, its general role in cancer and the tools available to interrogate it, we consider the literature surrounding DNA methylation as relating to prostate cancer. Specific consideration is given to recurrent alterations. A list of frequently reported genes is synthesised from seventeen studies that have reported on methylation changes in malignant prostate tissue, and we chart the timing of those changes in the diseases history through amalgamation of several previously published data sets. We also review associations with genetic alterations and hormone signalling, before the practicalities of investigating prostate cancer methylation using cell lines are assessed. We conclude by outlining the interplay between DNA methylation and prostate cancer metabolism and their regulation by Androgen Receptor, with a specific discussion of the mitochondria and their associations with DNA methylation.

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.

To Hell with Herbert Read

Freee write manifestos by taking a pencil (or a laptop) to an historical text, usually belonging to the entwined traditions of the avant-garde and political activism. Sometimes, as Tristan Tzara advised, we choose the text according to its length, while other times, such as in this instance, we selected the text according to the conditions of the invitation that triggered the writing of the manifesto. Our manifesto ‘To Hell with Herbert Read’ was written originally as a contribution to a conference held in Manchester that took its title from Herbert Read’s book ‘To Hell with Culture’. ‘To Hell with Culture’ is a book that cuts itself off from the world whereas ‘To Hell with Herbert Read’ relocates Read’s book in a world of cultural, social, economic and political actualities that are part of common experience. Read rejects culture because he thinks it is a useless, wasteful, elitist, puffed-up, decorative supplement to the functional, factual, palpable, purposeful world of things. He is a positivist kind of modernist who presents himself as the opposite, an enemy of the status quo. He is an anarchist of a particularly bourgeois hue: he wants us all to have decent pots and pans, not the inferior ones that are supplied by market forces cheaply. Rather than taking his aim precisely to target the dominant forces of his day - the industrial capitalists and their financiers - he rejects the world and all its inhabitants. He not only despises elitist culture but popular culture too.

To Hell with Herbert Read

Freee write manifestos by taking a pencil (or a laptop) to an historical text, usually belonging to the entwined traditions of the avant-garde and political activism. Sometimes, as Tristan Tzara advised, we choose the text according to its length, while other times, such as in this instance, we selected the text according to the conditions of the invitation that triggered the writing of the manifesto. Our manifesto ‘To Hell with Herbert Read’ was written originally as a contribution to a conference held in Manchester that took its title from Herbert Read’s book ‘To Hell with Culture’. ‘To Hell with Culture’ is a book that cuts itself off from the world whereas ‘To Hell with Herbert Read’ relocates Read’s book in a world of cultural, social, economic and political actualities that are part of common experience. Read rejects culture because he thinks it is a useless, wasteful, elitist, puffed-up, decorative supplement to the functional, factual, palpable, purposeful world of things. He is a positivist kind of modernist who presents himself as the opposite, an enemy of the status quo. He is an anarchist of a particularly bourgeois hue: he wants us all to have decent pots and pans, not the inferior ones that are supplied by market forces cheaply. Rather than taking his aim precisely to target the dominant forces of his day - the industrial capitalists and their financiers - he rejects the world and all its inhabitants. He not only despises elitist culture but popular culture too.

New Music by Young Composers, performed by Members of the Contemporary Group, December 4, 1978

Concert Program for New Music by Young composers, performed by Members of the Contemporary Group, December 4, 1978

Evaluation and Potential Cost-Effectiveness of Active Surveillance Pharmacovigilance for First-Line HAART in Namibia

Thesis (Ph.D.)--University of Washington, 2016-02

Memória do projecto cinco lugares. No exercício da sua função

Esta Memória de Projecto Cinco Lugares – No exercício da sua função funciona como um fluxo de ideias livres e inevitavelmente dispersas, que não são mais que uma consequência do pensamento sobre cada plano, cena e sequência que compõem o filme criado. A tese principal do filme, entre as várias ideias que nele se pretenderam elaborar, encontra reflexos e ressonâncias nas interpretações expressas ao longo dos vários capítulos iniciais. Assim, na Parte I (Caminhos do Tempo), faz-se uma contextualização teórica, com base nos textos de André Bazin, Gilles Deleuze e Marc Augé sobre as concepções de espaço e tempo, e analisam-se algumas das mais radicais obras do cinema contemporâneo (de Yasujirô Ozu, Robert Flaherty, Andy Warhol, Michael Snow a Victor Erice, Wang Bing, Abbas Kiarostami e James Benning). Esta contextualização e análise constituem fundamento à presente Memória, aprofundando-se a possibilidade do Tempo como categoria estrutural principal de um texto fílmico. Na Parte II, dá-se nota do percurso de Cinco Lugares, filme que congrega um conjunto de memórias sobre cinco lugares de uma cidade (Lisboa), ensurdecedora e em crescente movimento, e no qual se procurou registar, plano a plano, essas memórias pela, para usar uma expressão de Tarkovsky, “pressão do tempo no plano”. Iniciado no tempo do silêncio (público) do Pátio da Galé, o filme passou ao espaço privado e interior de uma habitação na Rua Nova do Loureiro, que a arquitectura tão naturalmente separa e resguarda do exterior. Do registo fílmico de um ritual religioso, numa Igreja de convento, transitámos para um dos lugares mais esquecidos da cidade, a Mãe d’Água/ Aqueduto das Águas Livres. Por fim, aportámos num antigo antro de loucura contida, o Pavilhão Panóptico do Hospital Miguel Bombarda, hoje museu de um conjunto de memórias – memórias que também constituem matéria de uma outra memória cinematográfica de João César Monteiro. Em comum, estes cinco lugares têm tudo e não têm nada. São arquitecturas que se estabelecem numa fronteira entre um interior e um exterior. São também matéria própria, constituída por tempos, espaços e identidades totalmente diferentes. São, ainda, cinco tipos de silêncio urbano e momentos de realidade documentados sob uma perspectiva de um mundo em aceleração. Em suma, os capítulos seguintes de ambas as Partes são uma das muitas conversas possíveis e inacabadas, qual coda num trecho musical, a ter sobre o que interessa verdadeiramente neste trabalho de projecto – o filme em si.

Nasal immunization of mice with human papillomavirus type 16 virus-like particles elicits neutralizing antibodies in mucosal secretions.

To specifically induce a mucosal antibody response to purified human papillomavirus type 16 (HPV16) virus-like particles (VLP), we immunized female BALB/c mice orally, intranasally, and/or parenterally and evaluated cholera toxin (CT) as a mucosal adjuvant. Anti-HPV16 VLP immunoglobulin G (IgG) and IgA titers in serum, saliva, and genital secretions were measured by enzyme-linked immunosorbent assay (ELISA). Systemic immunizations alone induced HPV16 VLP-specific IgG in serum and, to a lesser extent, in genital secretions but no secretory IgA. Oral immunization, even in the presence of CT, was inefficient. However, three nasal immunizations with 5 microgram of VLP given at weekly intervals to anesthetized mice induced high (>10(4)) and long-lasting (>15 weeks) titers of anti-HPV16 VLP antibodies in all samples, including IgA and IgG in saliva and genital secretions. CT enhanced the VLP-specific antibody response 10-fold in serum and to a lesser extent in saliva and genital secretions. Nasal immunization of conscious mice compared to anesthetized mice was inefficient and correlated with the absence of uptake of a marker into the lung. However, a 1-microgram VLP systemic priming followed by two 5-microgram VLP intranasal boosts in conscious mice induced both HPV16 VLP-specific IgG and IgA in secretions, although the titers were lower than in anesthetized mice given three intranasal immunizations. Antibodies in serum, saliva, and genital secretions of immunized mice were strongly neutralizing in vitro (50% neutralization with ELISA titers of 65 to 125). The mucosal and systemic/mucosal HPV16 VLP immunization protocols that induced significant titers of neutralizing IgG and secretory IgA in mucosal secretions in mice may be relevant to genital HPV VLP-based human vaccine trials.

Brock Hockey Team (1981-82)

Back Row: Paul Jackson (Asst. Coach), Paul DeGagne (Manager), Angelo Pontello, Yvan Prevost, Greg Foy, Ken Murray, Steve Ashfield, Rick Berard, Andy MacMillan, Kelly Toppazzini, Carl Van Bolderen, John Dakin, Loran Prentice, Joe Kenny (Trainer), Ron Anderson (Coach) Front Row: Logan Trafford, Mark Warren, Pat Gallagher, Phil Powers, Daryl Clancy, Ted Sawicki, Gord Christie, John Hogg, Brian Onifrichuk, Doug Riopelle, Shawn Barry Absent: Paul Hanley, Brad MacMillan, Rico Schirru, Mike Quinn (Asst. Coach)

1978 - 79 Men's Coxed Four

From left to right. Top: Pierre Nadeau, Dave Blanchard, Tony Biernacki (Coach), Kevin McLaughlin, Mike McDonald. Bottom: Andy Ness.

Enhancing Student Learning: Study of a Motivational Resource for Educators

This study surveyed practicing classroom teacher’s perceptions of a proposed educational resource “Avatar Academy” designed to enhance students’, particularly young boys, motivation and general attitude towards learning. The Avatar Academy resource is an instructional guide for implementing a classroom reward system based on common game mechanics. The resource emphasizes the modification of current pedagogies to exploit the use of game design to engage boys. A survey of recent literature indicated an opportunity to study teachers’ perceptions of the possible applications of game design mechanics to support the enhancement of student motivation and learning in the classroom. As a result the Avatar Academy handbook and blog resource were developed to assist teachers with the integration and administration of a program designed to enhance student motivation, especially boys, using avatars and a point based reward system. The resources were initially distributed to several practicing teachers for their review, and their feedback formed the basis for revisions of the Avatar Academy resource. After implementing changes to the resource based on initial teacher feedback, an updated Avatar Academy was redistributed and teacher opinions and perceptions of the tool’s possible impacts on classroom learning were collected.