COX-derived prostanoid pathways in gastrointestinal cancer development and progression : novel targets for prevention and intervention

Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies. COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers were significantly reduced by daily aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in cancer development/progression. PGE 2, which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA 2 in G.I. cancers has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD 2 and its metabolite 15d-PGJ2, PGF 1α and PGI 2. Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity.A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field. © 2011 Elsevier B.V.

Continuous remote emissions monitoring – the lynchpin for air quality management

Diesel particulate matter (DPM), in particular, has been likened in a somewhat inflammatory manner to be the ‘next asbestos’. From the business change perspective, there are three areas holding the industry back from fully engaging with the issue: 1. There is no real feedback loop in any operational sense to assess the impact of investment or application of controls to manage diesel emissions. 2. DPM are getting ever smaller and more numerous, but there is no practical way of measuring them to regulate them in the field. Mass, the current basis of regulation, is becoming less and less relevant. 3. Diesel emissions management is generally wholly viewed as a cost, yet there are significant areas of benefit available from good management. This paper discusses a feedback approach to address these three areas to move the industry forward. The six main areas of benefit from providing a feedback loop by continuously monitoring diesel emissions have been identified: 1. Condition-based maintenance. Emissions change instantaneously if engine condition changes. 2. Operator performance. An operator can use a lot more fuel for little incremental work output through poor technique or discipline. 3. Vehicle utilisation. Operating hours achieved and ratios of idling to under power affect the proportion of emissions produced with no economic value. 4. Fuel efficiency. This allows visibility into other contributing configuration and environmental factors for the vehicle. 5. Emission rates. This allows scope to directly address the required ratio of ventilation to diesel emissions. 6. Total carbon emissions - for NGER-type reporting requirements, calculating the emissions individually from each vehicle rather than just reporting on fuel delivered to a site.

Visualization of predictive distributions for discrete spatial-temporal log Cox processes approximated with MCMC

An important aspect of decision support systems involves applying sophisticated and flexible statistical models to real datasets and communicating these results to decision makers in interpretable ways. An important class of problem is the modelling of incidence such as fire, disease etc. Models of incidence known as point processes or Cox processes are particularly challenging as they are ‘doubly stochastic’ i.e. obtaining the probability mass function of incidents requires two integrals to be evaluated. Existing approaches to the problem either use simple models that obtain predictions using plug-in point estimates and do not distinguish between Cox processes and density estimation but do use sophisticated 3D visualization for interpretation. Alternatively other work employs sophisticated non-parametric Bayesian Cox process models, but do not use visualization to render interpretable complex spatial temporal forecasts. The contribution here is to fill this gap by inferring predictive distributions of Gaussian-log Cox processes and rendering them using state of the art 3D visualization techniques. This requires performing inference on an approximation of the model on a discretized grid of large scale and adapting an existing spatial-diurnal kernel to the log Gaussian Cox process context.

The effects of parental illness and other ill family members on youth caregiving experiences

Informed by a model of family role-redistribution derived from the Family Ecology Framework (Pedersen & Revenson, 2005), this study examined differences in two proposed psychological components of role-redistribution (youth caregiving experiences and responsibilities) between youth of a parent with illness and their peers from ‘healthy’ families controlling for the effects of whether a parent is ill or some other family member, illness type, and demographics. Based on self-report questionnaire data, four groups of Australian children were derived from a community sample of 2474youth (‘healthy’ family, n=1768; parental illness, n=336; other family member illness, n=254; both parental and other family member illness, n=116). The presence of any family member with a serious illness is associated with an intensification of youth caregiving experiences relative to peers from healthy families. This risk is elevated if the ill family member is a parent, if more illnesses are present, and by certain youth and family demographics, and especially by higher caregiving responsibilities. The presence of a family member, particularly a parent, with a serious medical condition has pervasive increased effects on youth caregiving compared to healthy families, and these effects are not fully accounted for by illness type, demographics or caregiving responsibilities.

The dynamics of global visual effects and games development industries: lessons for Australia’s creative industries development policy

The paper critiques the focus of creative industries policy on capability development of small and medium sized firms and the provision of regional incentives. It analyses factors affecting the competitiveness and sustainability of the games development industry and visual effects suppliers to feature films. Interviews with participants in these industries highlight the need for policy instruments to take into consideration the structure and organization of global markets and the power of lead multinational corporations. We show that although forms of economic governance in these industries may allow sustainable value capture, they are interrupted by bottlenecks in which ferocious competition among suppliers is confronted by comparatively little competition among the lead firms. We argue that current approaches to creative industries policy aimed at building self-sustaining creative industries are unlikely to be sufficient because of the globalized nature of the industries. Rather, we argue that a more profitable approach is likely to require supporting diversification of the industries as ‘feeders’ into other areas of the economy.

M. bovis BCG induced expression of COX-2 involves nitric oxide-dependent and -independent signaling pathways

In a multifaceted immunity to mycobacterial infection, induced expression of cyclooxygenase-2 (COX-2) by Mycobacterium bovis bacillus Calmette-Guerin (BCG) may act as an important influencing factor for the effective host immunity. We here demonstrate that M. bovis BCG-triggered TLR2-dependent signaling leads to COX-2 and PGE2 expression in vitro in macrophages and in vivo in mice. Further, the presence of PGE2 could be demonstrated in sera or cerebrospinal fluid of tuberculosis patients. The induced COX-2 expression in macrophages is dependent on NF-kappa B activation, which is mediated by inducible NO synthase (iNOS)/NO-dependent participation of the members of Notch1-PI-3K signaling cascades as well as iNOS-independent activation of ERK1/2 and p38 MAPKs. Inhibition of iNOS activity abrogated the M. bovis BCG ability to trigger the generation of Notch1 intracellular domain (NICD), a marker for Notch1 signaling activation, as well as activation of the PI-3K signaling cascade. On the contrary, treatment of macrophages with 3-morpholinosydnonimine, a NO donor, resulted in a rapid increase in generation of NICD, activation of PI-3K pathway, as well as the expression of COX-2. Stable expression of NICD in RAW 264.7 macrophages resulted in augmented expression of COX-2. Further, signaling perturbations suggested the involvement of the cross-talk of Notch1 with members with the PI-3K signaling cascade. These results implicate the dichotomous nature of TLR2 signaling during M. bovis BCG-triggered expression of COX-2. In this perspective, we propose the involvement of iNOS/NO as one of the obligatory, early, proximal signaling events during M. bovis BCG-induced COX-2 expression in macrophages.

Portrait of Samuel Mayer Ehrenberg ( 1773 - 1853 ).

This painting is in dedication " in honor of Meyer Ehrenberg by his students" as stated on a scroll held by the sitter. The scroll is dated October 7, 1820 and is followed by a list of names in two columns: (M.Ehrenberg, P.Ehrenberg, B. Ehrenberg, M.Imanuel M.Balke, B.Meier, L.Franck, M. Cohen, W.Fraenkel, M. Chohns, P.Goldschmidt, J.Lippoa, A. Nathan, M.Kramer, J.Fraenkel, M.Goldschmidt.) Ehrenberg was the founder of the first modern Jewish Day School in Germany, at Wolfenbuettel. Ehrenberg was the great-grandfather of the Jewish Theologian Franz Rosenzweig.

Francis Nicosia Collection.

Two photos of Nicosia.

PIM2 Induced COX-2 and MMP-9 Expression in Macrophages Requires PI3K and Notch1 Signaling

Activation of inflammatory immune responses during granuloma formation by the host upon infection of mycobacteria is one of the crucial steps that is often associated with tissue remodeling and breakdown of the extracellular matrix. In these complex processes, cyclooxygenase-2 (COX-2) plays a major role in chronic inflammation and matrix metalloproteinase-9 (MMP-9) significantly in tissue remodeling. In this study, we investigated the molecular mechanisms underlying Phosphatidyl-myo-inositol dimannosides (PIM2), an integral component of the mycobacterial envelope, triggered COX-2 and MMP-9 expression in macrophages. PIM2 triggers the activation of Phosphoinositide-3 Kinase (PI3K) and Notch1 signaling leading to COX-2 and MMP-9 expression in a Toll-like receptor 2 (TLR2)-MyD88 dependent manner. Notch1 signaling perturbations data demonstrate the involvement of the cross-talk with members of PI3K and Mitogen activated protein kinase pathway. Enforced expression of the cleaved Notch1 in macrophages induces the expression of COX-2 and MMP-9. PIM2 triggered significant p65 nuclear factor-kappa B (NF-kappa B) nuclear translocation that was dependent on activation of PI3K or Notch1 signaling. Furthermore, COX-2 and MMP-9 expression requires Notch1 mediated recruitment of uppressor of Hairless (CSL) and NF-kappa B to respective promoters. Inhibition of PIM2 induced COX-2 resulted in marked reduction in MMP-9 expression clearly implicating the role of COX-2 dependent signaling events in driving the MMP-9 expression. Taken together, these data implicate PI3K and Notch1 signaling as obligatory early proximal signaling events during PIM2 induced COX-2 and MMP-9 expression in macrophages.

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN.

Francis Watsonin teologinen hermeneutiikka

Tämän tutkimuksen tehtävänä on selvittää Francis Watsonin käsitys teologisesta hermeneutiikasta. Tutkielmassa käytetään kolmea tarkentavaa tutkimuskysymystä: Miten Watson hahmottaa tieteellisen raamatuntutkimuksen ja Raamatun teologisen tulkinnan suhteen? Miten Watson näkee raamatuntutkimuksessa historiallisen ja kirjallisen lähestymistavan suhteen toisiinsa? Miten Watson suhtautuu postmodernismiin teologisessa hermeneutiikassaan? Tutkimusmetodina on systemaattinen analyysi. Watsonin teologista hermeneutiikkaa ei ole tutkittu suomeksi ennen tätä työtä ja kansainvälistäkin tutkimusta aiheesta on hyvin vähän. Sen vuoksi tutkimuksessa on pyritty käsittelemään Watsonin teologista hermeneutiikkaa mahdollisimman kattavasti, mutta samalla on jouduttu rajaamaan työn ulkopuolelle osa Watsonin käsittelemistä teemoista, kuten Raamatun feministinen kritiikki ja VT:n ja UT:n suhde. Tutkimuksen päälähteinä ovat Watsonin kirjat Text, Church and World ja Text and Truth, joissa hän analysoi modernia historiallis-kriittistä raamatuntutkimusta, postmodernismia ja kirjallista lähestymistapaa Raamattuun. Watson kritisoi niissä näkemiään ongelmia ja kritiikkinsä pohjalta rakentaa omaa teologista hermeneutiikkaansa. Toissijaisina lähteinä tutkimuksessa on useita Watsonin artikkeleja, jotka tuovat lisävalaistusta Watsonin hermeneuttiseen ajatteluun. Päälähteiksi valitut teokset ja toissijaisiksi lähteiksi valitut artikkelit kattavat laajasti Watsonin hermeneutiikkaa käsittelevät kirjoitukset. Johdannon ja loppukatsauksen lisäksi tutkimus on jaettu neljään päälukuun. Tutkielman toisessa luvussa selvitetään Watsonin näkemys tieteellisen raamatuntutkimuksen ja Raamatun teologisen tulkinnan suhteesta ja havaitaan, että Watsonin mukaan raamatuntutkimuksen tulisi palvella teologista tulkintaa. Watson näkee ongelmallisena modernin raamatuntutkimuksen taipumuksen pitää erillään raamatuntutkimus ja -tulkinta ja luoda vastakkainasetteluja yliopiston ja kirkon, eksegetiikan ja systemaattisen teologian sekä neutraalin ja teologisen tulkinnan välille. Kolmannessa luvussa tarkastellaan Watsonin kritiikkiä historiallis-kriittistä tutkimusta kohtaan ja hänen perustelujaan päätökselle käyttää raamatuntulkinnassa ensisijaisesti tekstien lopullista, kanonista muotoa. Watson tukeutuu perusteluissaan Brevard Childsin kanoniseen lukutapaan ja tekstien yhteisölliseen käyttöön. Havaitaan, että Watson kuitenkin kritisoi kanonista lukutapaa sekä formalismista että sen teologisista sidonnaisuuksista. Watson hakee tukea myös Hans Frein narratiivisesta lähestymistavasta, jota Watson samalla kritisoi totuuskysymyksen ohittamisesta. Lopuksi käsitellään Watsonin yritystä liittää tekstin maailma ja sen taustalla oleva sosio-poliittinen todellisuus toisiinsa. Neljännessä luvussa käsitellään Watsonin yritystä yhdistää historiallinen ja kirjallisuustieteellinen lähestymistapa Raamatun teksteihin. Havaitaan, että Watsonin mielestä historiallis-kriittinen tutkimus polkee paikallaan ja siksi tarvitaan kirjallinen lähestymistapa, joka painottaa tekstin lopullista muotoa. Luvussa osoitetaan, ettei Watson kuitenkaan halua korvata puhtaasti historiallista lähestymistapaa puhtaasti kirjallisuustieteellisellä lähestymistavalla, sillä hän näkee ongelmallisena myös narratiivisen kritiikin taipumuksen käsitellä raamatunkertomuksia fiktiivisinä narratiiveina. Watson pyrkii ratkaisemaan ongelman yhdistämällä historiallisen ja kirjallisuustieteellisen lähestymistavan toisiinsa käsittelemällä evankeliumeja kerrottuna historiana. Viidennessä luvussa selvitetään miten Watson suhtautuu postmodernismiin teologisessa hermeneutiikassaan. Siinä havaitaan, että Watson näkee postmodernismin tarjoavan hyödyllisiä näkökulmia useissa hermeneuttisissa kysymyksissä. Samalla Watson vastustaa postmodernismin näkemystä, ettei teksteillä ole yhtä määrättyä merkitystä ja postmodernin teologian taipumusta viedä Raamatun kertomukselta sen universaali merkitys. Luvussa kuitenkin osoitetaan, että Watsonin antama kuva George Lindbeckin ja Stanley Hauerwasin postmodernista teologiasta on yksipuolinen ja osittain virheellinen.

Cox-2, tenascin, CRP, and ingraft chimerism in a model of post-transplant obliterative bronchiolitis

Chronic rejection in the form of obliterative bronchiolitis (OB) is the major cause of death 5 years after lung transplantation. The exact mechanism of OB remains unclear. This study focused on the role of cyclo-oxygenase (COX) -2, tenascin, and C-reactive protein (CRP) expression, and the occurrence of ingraft chimerism (= cells from two genetically distinct individuals in a same individual) in post-transplant OB development. In our porcine model, OB developed invariably in allografts, while autografts stayed patent. The histological changes were similar to those seen in human OB. In order to delay or prevent obliteration, animals were medicated according to certain protocol. In the beginning of the bronchial allograft reaction, COX-2 induction occurred in airway epithelial cells prior to luminal obliteration. COX-2 expression in macrophages and fibroblasts paralleled the onset of inflammation and fibroblast proliferation. This study demonstrated for the first time, that COX-2 expression is associated with the early stage of post- transplant obliterative airway disease. Tenascin expression in the respiratory epithelium appeared to be predictive of histologic features observed in human OB, and influx of immune cells. Expression in the bronchial wall and in the early obliterative lesions coincided with the onset of onset of fibroblast and inflammatory cell proliferation in the early stage of OB and was predictive of further influx of inflammatory and immune cells. CRP expression in the bronchial wall coincided with the remodelling process. High grade of bronchial wall CRP staining intensity predicted inflammation, accelerated fibroproliferation, and luminal obliteration, which are all features of OB. In the early obliterative plaque, majority of cells expressed CRP, but in mature, collagen-rich plaque, expression declined. Local CRP expression might be a response to inflammation and it might promote the development of OB. Early appearance of chimeric (= recipient-derived) cells in the graft airway epithelium predicted epithelial cell injury and obliteration of the bronchial lumen, which both are features of OB. Chimeric cells appeared in the airway epithelium after repair following transplantation-induced ischemic injury. Ingraft chimerism might be a mechanism to repair alloimmune-mediated tissue injury and to protect allografts from rejection after transplantation. The results of this study indicate, that COX-2, tenascin, CRP, and ingraft chimerism have a role in OB development. These findings increase the understanding of the mechanisms of OB, which may be beneficial in further development of diagnostic options.

ESAT-6 induced COX-2 expression involves coordinated interplay between PI3K and MAPK signaling

Macrophages, as sentinels of robust host immunity, are key regulators of innate immune responses against invading mycobacteria; however, pathogenic mycobacteria survive in the infected host by subverting host innate immunity. Infection dependent expression of early secreted antigenic target protein 6 (ESAT-6) by Mycobacterium tuberculosis is strongly correlated with subversion of innate immune responses against invading mycobacteria. As a part of multifaceted immunity to mycobacterial infection, induced expression of cyclooxygenase-2 (COX-2) may act as an important influencing factor towards effective host immunity. In the current investigation, we demonstrate that ESAT-6 triggers COX-2 expression both in vitro and in vivo in a TLR2 dependent manner. Signaling perturbation data suggest that signaling dynamics of PI3K and p38 and JNK1/2 MAPK assume critical importance in ESAT-6 triggered expression of COX-2 in macrophages. Interestingly, ESAT-6 triggered PI3K-MAPK signaling axis holds the capacity to regulate coordinated activation of NF-kappa B and AP-1. Overall, current investigation provides mechanistic insights into ESAT-6 induced COX-2 expression and unravels TLR2 mediated interplay of PI3K and MAPK signaling axis as a rate-determining step during intricate host immune responses. These findings would serve as a paradigm to understand pathogenesis of mycobacterial infection and clearly pave a way towards development of novel therapeutics. (C) 2011 Elsevier Ltd. All rights reserved.