Perlecan, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway

BACKGROUND: Genetic studies associated the CAPB locus with familial risk of brain and prostate cancers. We have identified HSPG2 (Perlecan) as a candidate gene for CAPB. Previously we have linked Perlecan to Hedgehog signaling in Drosophila. More recently, we have demonstrated the importance of Hedgehog signaling in humans for advanced prostate cancer. RESULTS: Here we demonstrate Perlecan expression in prostate cancer, and its function in prostate cancer cell growth through interaction and modulation of Sonic Hedgehog (SHH) signaling. Perlecan expression in prostate cancer tissues correlates with a high Gleason score and rapid cell proliferation. Perlecan is highly expressed in prostate cancer cell lines, including androgen insensitive cell lines and cell lines selected for metastatic properties. Inhibition of Perlecan expression in these cell lines decreases cell growth. Simultaneous blockade of Perlecan expression and androgen signaling in the androgen-sensitive cell line LNCaP was additive, indicating the independence of these two pathways. Perlecan expression correlates with SHH in tumor tissue microarrays and increased tumor cell proliferation based on Ki-67 immunohistochemistry. Inhibition of Perlecan expression by siRNA in prostate cancer cell lines decreases SHH signaling while expression of the downstream SHH effector GLI1 rescues the proliferation defect. Perlecan forms complexes with increasing amounts of SHH that correlate with increasing metastatic potential of the prostate cancer cell line. SHH signaling also increases in the more metastatic cell lines. Metastatic prostate cancer cell lines grown under serum-starved conditions (low androgen and growth factors) resulted in maintenance of Perlecan expression. Under low androgen, low growth factor conditions, Perlecan expression level correlates with the ability of the cells to maintain SHH signaling. CONCLUSION: We have demonstrated that Perlecan, a candidate gene for the CAPB locus, is a new component of the SHH pathway in prostate tumors and works independently of androgen signaling. In metastatic tumor cells increased SHH signaling correlates with the maintenance of Perlecan expression and more Perlecan-SHH complexes. Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions. This proteoglycan represents an important central regulator of SHH activity and presents an ideal drug target for blocking SHH effects

Cross-species global and subset gene expression profiling identifies genes involved in prostate cancer response to selenium

BACKGROUND: Gene expression technologies have the ability to generate vast amounts of data, yet there often resides only limited resources for subsequent validation studies. This necessitates the ability to perform sorting and prioritization of the output data. Previously described methodologies have used functional pathways or transcriptional regulatory grouping to sort genes for further study. In this paper we demonstrate a comparative genomics based method to leverage data from animal models to prioritize genes for validation. This approach allows one to develop a disease-based focus for the prioritization of gene data, a process that is essential for systems that lack significant functional pathway data yet have defined animal models. This method is made possible through the use of highly controlled spotted cDNA slide production and the use of comparative bioinformatics databases without the use of cross-species slide hybridizations. RESULTS: Using gene expression profiling we have demonstrated a similar whole transcriptome gene expression patterns in prostate cancer cells from human and rat prostate cancer cell lines both at baseline expression levels and after treatment with physiologic concentrations of the proposed chemopreventive agent Selenium. Using both the human PC3 and rat PAII prostate cancer cell lines have gone on to identify a subset of one hundred and fifty-four genes that demonstrate a similar level of differential expression to Selenium treatment in both species. Further analysis and data mining for two genes, the Insulin like Growth Factor Binding protein 3, and Retinoic X Receptor alpha, demonstrates an association with prostate cancer, functional pathway links, and protein-protein interactions that make these genes prime candidates for explaining the mechanism of Selenium's chemopreventive effect in prostate cancer. These genes are subsequently validated by western blots showing Selenium based induction and using tissue microarrays to demonstrate a significant association between downregulated protein expression and tumorigenesis, a process that is the reverse of what is seen in the presence of Selenium. CONCLUSIONS: Thus the outlined process demonstrates similar baseline and selenium induced gene expression profiles between rat and human prostate cancers, and provides a method for identifying testable functional pathways for the action of Selenium's chemopreventive properties in prostate cancer

Stable and Active Oxygen Reduction Catalysts with Reduced Noble Metal Loadings through Potential Triggered Support Passivation

The development of stable, cost‐efficient and active materials is one of the main challenges in catalysis. The utilization of platinum in the electroreduction of oxygen is a salient example where the development of new material combinations has led to a drastic increase in specific activity compared to bare platinum. These material classes comprise nanostructured thin films, platinum alloys, shape‐controlled nanostructures and core–shell architectures. Excessive platinum substitution, however, leads to structural and catalytic instabilities. Herein, we introduce a catalyst concept that comprises the use of an atomically thin platinum film deposited on a potential‐triggered passivating support. The model catalyst exhibits an equal specific activity with higher atom utilization compared to bulk platinum. By using potential‐triggered passivation of titanium carbide, irregularities in the Pt film heal out via the formation of insoluble oxide species at the solid/liquid interface. The adaptation of the described catalyst design to the nanoscale and to high‐surface‐area structures highlight the potential for stable, passivating catalyst systems for various electrocatalytic reactions such as the oxygen reduction reaction

Implementation of preventive strength training in residential geriatric care: a multi-centre study protocol with one year of interventions on multiple levels

<p>Abstract</p> <p>Background</p> <p>There is scientific evidence that preventive physical exercise is effective even in high age. In contrast, there are few opportunities of preventive exercise for highly aged people endangered by or actually in need of care. For example, they would not be able to easily go to training facilities; standard exercises may be too intensive and therefore be harmful to them; orientation disorders like dementia would exacerbate individuals and groups in following instructions and keeping exercises going. In order to develop appropriate interventions, these and other issues were assigned to different levels: the individual-social level (ISL), the organisational-institutional level (OIL) and the political-cultural level (PCL). Consequently, this conceptional framework was utilised for development, implementation and evaluation of a new strength and balance exercise programme for old people endangered by or actually in need of daily care. The present paper contains the development of this programme labeled "fit for 100", and a study protocol of an interventional single-arm multi-centre trial.</p> <p>Methods</p> <p>The intervention consisted of (a) two group training sessions every week over one year, mainly resistance exercises, accompanied by sensorimotor and communicative group exercises and games (ISL), (b) a sustainable implementation concept, starting new groups by instructors belonging to the project, followed by training and supervision of local staff, who stepwise take over the group (OIL), (c) informing and convincing activities in professional, administrative and governmental contexts, public relation activities, and establishing an advisory council with renowned experts and public figures (PCL). Participating institutions of geriatric care were selected through several steps of quality criteria assessment. Primary outcome measures were continuous documentation of individual participation (ISL), number of groups continued without external financial support (at the end of the project, and after one year) (OIL). Secondary outcome was measured by sensorimotor tests and care-related assessments in the beginning and every 16 weeks (ISL), by qualitative outcome descriptions 12 months after group implementation (OIL) and by analysis of media response and structured interviews with stakeholders, also after 12 months (PCL).</p> <p>Conclusion</p> <p>Exemplarily, preventive exercise has been established for a neglected target population. The multi-level approach used here seems to be helpful to overcome institutional and individual (attitude) barriers.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN55213782</p

Naturalizing Institutions: Evolutionary Principles and Application on the Case of Money

In recent extensions of the Darwinian paradigm into economics, the replicator-interactor duality looms large. I propose a strictly naturalistic approach to this duality in the context of the theory of institutions, which means that its use is seen as being always and necessarily dependent on identifying a physical realization. I introduce a general framework for the analysis of institutions, which synthesizes Searle's and Aoki's theories, especially with regard to the role of public representations (signs) in the coordination of actions, and the function of cognitive processes that underly rule-following as a behavioral disposition. This allows to conceive institutions as causal circuits that connect the population-level dynamics of interactions with cognitive phenomena on the individual level. Those cognitive phenomena ultimately root in neuronal structures. So, I draw on a critical restatement of the concept of the meme by Aunger to propose a new conceptualization of the replicator in the context of institutions, namely, the replicator is a causal conjunction between signs and neuronal structures which undergirds the dispositions that generate rule-following actions. Signs, in turn, are outcomes of population-level interactions. I apply this framework on the case of money, analyzing the emotions that go along with the use of money, and presenting a stylized account of the emergence of money in terms of the naturalized Searle-Aoki model. In this view, money is a neuronally anchored metaphor for emotions relating with social exchange and reciprocity. Money as a meme is physically realized in a replicator which is a causal conjunction of money artefacts and money emotions

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC

Nucleic acid approaches for detection and identification of biological warfare and infectious disease agents

Biological warfare agents are the most problematic of the weapons of mass destruction and terror. Both civilian and military sources predict that over the next decade the threat from proliferation of these agents will increase significantly. In this review we summarize the state of the art in detection and identification of biological threat agents based on PCR technology with emphasis on the new technology of microarrays. The advantages and limitations of real-time PCR technology and a review of the literature as it applies to pathogen and virus detection are presented. The paper covers a number of issues related to the challenges facing biological threat agent detection technologies and identifies critical components that must be overcome for the emergence of reliable PCR-based DNA technologies as bioterrorism countermeasures and for environmental applications. The review evaluates various system components developed for an integrated DNA microchip and the potential applications of the next generation of fully automated DNA analyzers with integrated sample preparation and biosensing elements. The article also reviews promising devices and technologies that are near to being, or have been, commercialized