STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.Lukas Kenner and Jan Pencik are supported by FWF, P26011 and the Genome Research-Austria project “Inflammobiota” grants. Helmut Dolznig is supported by the Herzfelder Family Foundation and the Niederösterr. Forschungs-und Bildungsges.m.b.H (nfb). Richard Moriggl is supported by grant SFB-F2807 and SFB-F4707 from the Austrian Science Fund (FWF), Ali Moazzami is supported by Infrastructure for biosciences-Strategic fund, SciLifeLab and Formas, Zoran Culig is supported by FWF, P24428, Athena Chalaris and Stefan Rose-John are supported by the Deutsche Forschungsgemeinschaft (Grant SFB 877, Project A1and the Cluster of Excellence --“Inflammation at Interfaces”). Work of the Aberger lab was supported by the Austrian Science Fund FWF (Projects P25629 and W1213), the European FP7 Marie-Curie Initial Training Network HEALING and the priority program Biosciences and Health of the Paris-Lodron University of Salzburg. Valeria Poli is supported by the Italian Association for Cancer Research (AIRC, No IG13009). Richard Kennedy and Steven Walker are supported by the McClay Foundation and the Movember Centre of Excellence (PC-UK and Movember). Gerda Egger is supported by FWF, P27616. Tim Malcolm and Suzanne Turner are supported by Leukaemia and Lymphoma Research.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms873

An integrated Bayesian analysis of LOH and copy number data

Background: Cancer and other disorders are due to genomic lesions. SNP-microarrays are able to measure simultaneously both genotype and copy number (CN) at several Single Nucleotide Polymorphisms (SNPs) along the genome. CN is defined as the number of DNA copies, and the normal is two, since we have two copies of each chromosome. The genotype of a SNP is the status given by the nucleotides (alleles) which are present on the two copies of DNA. It is defined homozygous or heterozygous if the two alleles are the same or if they differ, respectively. Loss of heterozygosity (LOH) is the loss of the heterozygous status due to genomic events. Combining CN and LOH data, it is possible to better identify different types of genomic aberrations. For example, a long sequence of homozygous SNPs might be caused by either the physical loss of one copy or a uniparental disomy event (UPD), i.e. each SNP has two identical nucleotides both derived from only one parent. In this situation, the knowledge of the CN can help in distinguishing between these two events. Results: To better identify genomic aberrations, we propose a method (called gBPCR) which infers the type of aberration occurred, taking into account all the possible influence in the microarray detection of the homozygosity status of the SNPs, resulting from an altered CN level. Namely, we model the distributions of the detected genotype, given a specific genomic alteration and we estimate the parameters involved on public referenc

Varieties of Capitalism and the Learning Firm: Contemporary Developments in EU and German Company Law - A Comment on the Strine-Bainbridge Debate About Shared Values of Corporate Management and Labor

Research in corporate governance and in labour law has been characterized by a disjuncture in the way that scholars in each field are addressing organizational questions related to the business enterprise. While labour has eventually begun to shift perspectives from aspirations to direct employee involvement in firm management, as has been the case in Germany, to a combination of \u27exit\u27 and \u27voice\u27 strategies involving pension fund management and securities litigation, it remains to be seen whether this new stream will unfold as a viable challenge to an otherwise exclusionary shareholder value paradigm. At the same time, recent suggestions made by Delaware Chancery Court Vice Chancellor Strine, to dare think about potentially shared commitments between management and labor - and UCLA\u27s Stephen Bainbridge\u27s response - underline the viability - and, the contestedness - of attempts at moving the corporate governance debate beyond the confines of corporate law proper. While such a wider view had already famously been encouraged by Dean Clarke in his 1986 treatise on Corporate Law (p. 32), mainstream corporate law does not seem to have endorsed this perspective. This paper takes the questionable divide between management and labor within the framework of a limiting corporate governance concept as starting point to explore the institutional dynamics of the corporation, hereby building on the theory of the innovative enterprise, as developed by management theorists Mary O\u27Sullivan and William Lazonick. Largely due to the sustained distance between corporate and labour law scholars, neither group has effectively addressed their common blind spot: a better understanding of the business enterprise itself. In midst of an unceasing flow of affirmations of the finance paradigm of the corporation on the one hand and \u27voice\u27 strategies by labour on the other, it seems to fall to management theorists to draw lessons from the continuing co-existence of different forms of market organization, in which companies appear to thrive. Exploring the conundrum of \u27risky\u27 business decisions within the firm, management theorists have been arguing for the need to adopt a more sophisticated organizational perspective on companies operating on locally, regionally and transnationally shaped, often highly volatile market segments. Research by comparative political economists has revealed a high degree of connectivity between corporate governance and economic performance without, however, arriving at such favourable results only for shareholder value regimes. Such findings support the view that corporate governance regimes are embedded in differently shaped regulatory frameworks, characterized by distinct institutions, both formal and informal, and enforcement processes. As a result of these findings, arguments to disassociate issues of corporate governance from those of the firm\u27s (social) responsibility [CSR] have been losing ground. Instead, CSR can be taken to be an essential part of understanding a particular business enterprise. It is the merging of a comparative political economy perspective on the corporation with one on the organizational features, structures and processes of the corporation, which can help us better understand the distribution of power and knowledge within the \u27learning firm\u27

RNAi-based biocontrol of wheat nematodes using natural poly-component biostimulants

With the growing global demands on sustainable food production, one of the biggest challenges to agriculture is associated with crop losses due to parasitic nematodes. While chemical pesticides have been quite successful in crop protection and mitigation of damage from parasites, their potential harm to humans and environment, as well as the emergence of nematode resistance, have necessitated the development of viable alternatives to chemical pesticides. One of the most promising and targeted approaches to biocontrol of parasitic nematodes in crops is that of RNA interference (RNAi). In this study we explore the possibility of using biostimulants obtained from metabolites of soil streptomycetes to protect wheat (Triticum aestivum L.) against the cereal cyst nematode Heterodera avenae by means of inducing RNAi in wheat plants. Theoretical models of uptake of organic compounds by plants, and within-plant RNAi dynamics, have provided us with useful insights regarding the choice of routes for delivery of RNAi-inducing biostimulants into plants. We then conducted in planta experiments with several streptomycete-derived biostimulants, which have demonstrated the efficiency of these biostimulants at improving plant growth and development, as well as in providing resistance against the cereal cyst nematode. Using dot blot hybridization we demonstrate that biostimulants trigger a significant increase of the production in plant cells of si/miRNA complementary with plant and nematode mRNA. Wheat germ cell-free experiments show that these si/miRNAs are indeed very effective at silencing the translation of nematode mRNA having complementary sequences, thus reducing the level of nematode infestation and improving plant resistance to nematodes. Thus, we conclude that natural biostimulants produced frommetabolites of soil streptomycetes provide an effective tool for biocontrol of wheat nematode

Role of SPI-1 Secreted Effectors in Acute Bovine Response to Salmonella enterica Serovar Typhimurium: A Systems Biology Analysis Approach

Salmonella enterica Serovar Typhimurium (S. Typhimurium) causes enterocolitis with diarrhea and polymorphonuclear cell (PMN) influx into the intestinal mucosa in humans and calves. The Salmonella Type III Secretion System (T3SS) encoded at Pathogenicity Island I translocates Salmonella effector proteins SipA, SopA, SopB, SopD, and SopE2 into epithelial cells and is required for induction of diarrhea. These effector proteins act together to induce intestinal fluid secretion and transcription of C-X-C chemokines, recruiting PMNs to the infection site. While individual molecular interactions of the effectors with cultured host cells have been characterized, their combined role in intestinal fluid secretion and inflammation is less understood. We hypothesized that comparison of the bovine intestinal mucosal response to wild type Salmonella and a SipA, SopABDE2 effector mutant relative to uninfected bovine ileum would reveal heretofore unidentified diarrhea-associated host cellular pathways. To determine the coordinated effects of these virulence factors, a bovine ligated ileal loop model was used to measure responses to wild type S. Typhimurium (WT) and a ΔsipA, sopABDE2 mutant (MUT) across 12 hours of infection using a bovine microarray. Data were analyzed using standard microarray analysis and a dynamic Bayesian network modeling approach (DBN). Both analytical methods confirmed increased expression of immune response genes to Salmonella infection and novel gene expression. Gene expression changes mapped to 219 molecular interaction pathways and 1620 gene ontology groups. Bayesian network modeling identified effects of infection on several interrelated signaling pathways including MAPK, Phosphatidylinositol, mTOR, Calcium, Toll-like Receptor, CCR3, Wnt, TGF-β, and Regulation of Actin Cytoskeleton and Apoptosis that were used to model of host-pathogen interactions. Comparison of WT and MUT demonstrated significantly different patterns of host response at early time points of infection (15 minutes, 30 minutes and one hour) within phosphatidylinositol, CCR3, Wnt, and TGF-β signaling pathways and the regulation of actin cytoskeleton pathway

Studies on the expression and distribution of Selenoprotein P

Im Rahmen der vorliegenden Arbeit wurde die Verteilung von Selenoprotein P (SePP) sowohl auf Transkript- als auch auf Proteinebene analysiert. Mit Hilfe der In-Situ-Hybridisierung konnte anhand ausgewählter muriner Organe gezeigt werden, dass SePP Gewebs- und Zell-spezifisch exprimiert wird. Diese Ergebnisse wurden mit Hilfe eines Expression-Arrays humaner Gewebe bestätigt. Ferner wurde mit Hilfe mehrerer polyklonaler Antikörper eine immunhistochemische Färbung von SePP etabliert und evaluiert. Es wurden humane zerebrale Gewebsschnitte immunhistochemisch untersucht und mit Hilfe einer Access-Datenbank eine zerebrale Protein-Karte der Normalverteilung erstellt. Hierbei zeigte sich, dass v.a. lange Bahnsysteme (z.B. im Rückenmark) in der Markscheide eine deutliche SePP-Immunreaktivität aufweisen. Ferner wiesen insbesondere große Neurone im Bereich des Cortex cerebri und des Rückenmarks eine deutliche Immunreaktivität auf. Die untersuchten neuronalen Kerngebiete (z.B. im Hirnstamm) zeigten eine differentielle SePP-Immunreaktivität. Ein postulierter Zusammenhang der SePP-Immunreaktivität mit der Neurotransmitterverteilung konnte nicht festgestellt werden. Ergänzend wurde orientierend zerebrales Gewebe von einzelnen Patienten mit unter-schiedlichen neurodegenerativen Erkrankungen untersucht (Morbus Alzheimer, multiple Sklerose, Morbus Parkinson, amyotrophe Lateralsklerose). Hierbei zeigte sich, dass bei den Herden der multiplen Sklerose die SePP-Immunreaktivität in Korrelation mit dem Verlust der Markscheiden abnimmt. Ein möglicher Zusammenhang mit dem chronischen Verlust von Axonen bei der multiplen Sklerose wurde diskutiert. Bei den untersuchten Gewebeproben von Patienten mit amyotropher Lateralsklerose zeigten die Neuronen im Bereich der Ubiquitin- positiven Motoneurone des Rückenmarkvorderhorns eine perinukleär betonte verwaschene SePP-Immunreaktivität. Bei Gewebe von Alzheimer-Patienten fanden sich im Cortex und im Bereich des entorhinalen Cortex bzw. Hippocampus Neurone mit perinukleär kräftiger SePP-Immunreaktivität. Ferner fanden sich SePP- positive Ablagungen, passend zu sog. Neurofibrillary Tangles bzw. Alzheimer- Plaques. Im Gewebe von Patienten mit Morbus Parkinson fanden sich keine Auffälligkeiten der SePP-Immunreaktivität. Ein Zusammenhang mit der Pathogenese der neurodegenerativen Erkrankungen bzw. ein möglicher protektiver Einfluß von SePP erscheint anhand dieser Daten möglich, bedarf aber der weiteren molekularen Charakterisierung.We studied the distribution of Selenoprotein P (SePP) on mRNA and protein level. Using in-situ hybridisation on selected murine tissues, we showed tissue- and cell specific SePP-mRNA distribution. These results were confirmed and correlated using a commercially available human mRNA expression array. In an effort to study SePP protein localization, we established immunohistochemical stainings using three different antibodies directed against human SePP. Distribution of SePP in the Human brain was systematically analyzed and the results were used to generate a Microsoft Access database of the non-pathologic distribution of SePP. SePP stainings showed a high and specific immunoreactivity in the myelin sheath especially of the long ascending and descending fibers of the spinal cord. Especially the larger neurons in the cortex and spinal cord demonstrated a high SePP immunoreactivity. A more diverse immunoreactivity was observed in neurons of different nuclei (e.g. of the brainstem). A postulated correlation between SePP-immunoreactivity and the different neurotransmitters was not found. Finally, brain tissues of patients with neurodegenerative and neuroinflammatory diseases (Alzheimer´s disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson´s disease) were analyzed. In multiple sclerosis a decrease in SePP immunoreactivity was found in correlation with the loss of myelin sheaths. Tissue from patients with amyotrophic lateral sclerosis showed a blurred immunoreactivity in motoneurons of the spinal cord. In the cortex and hippocampus of patients with Alzheimer´s disease SePP- immunoreactivity in neurons and perineural tissue was detected, potentially correlating to neurofibrillary tangles and plaques. In Parkinson´s disease there were no obvious changes in immunoreactivity as compared to controls. We conclude that the changes in SePP expression and localisation found in neurodegenerative or neuroinflammatory diseases are consistent with the hypothesis of a possible (neuroprotective) role of SePP in the pathology of these diseases

Corporate governance, compliance und Chinese walls

Corporate governance, compliance und Chinese walls. - Regensburg : Roderer, 2000. - XIV, 321 S. - (Theorie und Forschung ; 652 : Rechtswissenschaften ; 70). - Zugl: Augsburg, Univ., Diss, 199