The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer

Prostacyclin synthase and thromboxane synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective synthases differ considerably with respect to the pathways described. While prostacyclin synthase is generally believed to be anti-tumor, a pro-carcinogenic role for thromboxane synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of thromboxane synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin synthase and thromboxane synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer. © 2010 Elsevier B.V. All rights reserved.

Factor Five : Transforming the Global Economy through 80% Improvements in Resource Productivity

The 21st century will see monumental change. Either the human race will use its knowledge and skills and change the way it interacts with the environment, or the environment will change the way it interacts with its inhabitants. In the first case, the focus of this book, we would see our sophisticated understanding in areas such as physics, chemistry, engineering, biology, planning, commerce, business and governance accumulated over the last 1,000 years brought to bear on the challenge of dramatically reducing our pressure on the environment. The second case however is the opposite scenario, involving the decline of the planet’s ecosystems until they reach thresholds where recovery is not possible, and following which we have no idea what happens. For instance, if we fail to respond to Sir Nicolas Stern’s call to meet appropriate stabilisation trajectories for greenhouse gas emissions, and we allow the average temperature of our planets surface to increase by 4-6 degrees Celsius, we will see staggering changes to our environment, including rapidly rising sea level, withering crops, diminishing water reserves, drought, cyclones, floods… allowing this to happen will be the failure of our species, and those that survive will have a deadly legacy. In this update to the 1997 International Best Seller, Factor Four, Ernst von Weizsäcker again leads a team to present a compelling case for sector wide advances that can deliver significant resource productivity improvements over the coming century. The purpose of this book is to inspire hope and to then inform meaningful action in the coming decades to respond to the greatest challenge our species has ever faced – that of living in harmony with our planet and its other inhabitants.

Energy productivity and decarbonization of the global economy: Factor five resource productivity

In the 21st Century much of the world will experience untold wealth and prosperity that could not even be conceived only some three centuries before. However as with most, if not all, of the human civilisations, increases in prosperity have accumulated significant environmental impacts that threaten to result in environmentally induced economic decline. A key part of the world’s response to this challenge is to rapidly decarbonise economies around the world, with options to achieve 60-80 per cent improvements (i.e. in the order of Factor 5) in energy and water productivity now available and proven in every sector. Drawing upon the 2009 publication “Factor 5”, in this paper we discuss how to realise such large-scale improvements, involving complexity beyond technical and process innovation. We begin by considering the concept of greenhouse gas stabilisation trajectories that include reducing current greenhouse gas emissions to achieve a ‘peaking’ of global emissions, and subsequent ‘tailing’ of emissions to the desired endpoint in ‘decarbonising’ the economy. Temporal priorities given to peaking and tailing have significant implications for the mix of decarbonising solutions and the need for government and market assistance in causing them to be implemented, requiring careful consideration upfront. Within this context we refer to a number of examples of Factor 5 style opportunities for energy productivity and decarbonisation, and then discuss the need for critical economic contributions to take such success from examples to central mechanisms in decarbonizing the global economy.

Factor five - Towards global sustainability through doing much more with much less

This is a revised text of the third lecture of the 2014 public lecture series, "The Path Toward a Global Civilzation" hosted by the Institute of Oriental Philosophy on October 2 in Tokyo. Dr Desha is a research principal of the Australian team at the Natural Edge Project which published Factor 5: Transforming the Global Economy through 80% Increase in Resource Productivity (2009) in collaboration with Dr Ernst Ulrich von Weizsacker.

HSPC117 deficiency in cloned embryos causes placental abnormality and fetal death

Somatic cell nuclear transfer (SCNT) has been successfully used in many species to produce live cloned offspring, albeit with low efficiency. The low frequency of successful development has usually been ascribed to incomplete or inappropriate reprogramming of the transferred nuclear genome. Elucidating the genetic differences between normal fertilized and cloned embryos is key to understand the low efficiency of SCNT. Here, we show that expression of HSPC117, which encodes a hypothetical protein of unknown function, was absent or very low in cloned mouse blastocysts. To investigate the role of HSPC117 in embryo development, we knocked-down this gene in normal fertilized embryos using RNA interference. We assessed the post-implantation survival of HSPC117 knock-down embryos at 3 stages: E9 (prior to placenta formation); E12 (after the placenta was fully functional) and E19 (post-natal). Our results show that, although siRNA-treated in vivo fertilized/produced (IVP) embryos could develop to the blastocyst stage and implanted without any difference from control embryos, the knock-down embryos showed substantial fetal death, accompanied by placental blood clotting, at E12. Furthermore, comparison of HSPC117 expression in placentas of nuclear transfer (NT), intracytoplasmic sperm injection (ICSI) and IVP embryos confirmed that HSPC117 deficiency correlates well with failures in embryo development: all NT embryos with a fetus, as well as IVP and ICSI embryos, had normal placental HSPC117 expression while those NT embryos showing reduced or no expression of HSPC117 failed to form a fetus. In conclusion, we show that HSPC117 is an important gene for post-implantation development of embryos, and that HSPC117 deficiency leads to fetal abnormalities after implantation, especially following placental formation. We suggest that defects in HSPC117 expression may be an important contributing factor to loss of cloned NT embryos in vivo. (C) 2010 Elsevier Inc. All rights reserved.

Characterisation of the role of canonical BMP-Smad 1/5/8 signalling in the development of ventral midbrain dopaminergic neurons

Ventral midbrain (VM) dopaminergic (DA) neurons, which project to the dorsal striatum via the nigrostriatal pathway, are progressively degenerated in Parkinson’s disease (PD). The identification of the instructive factors that regulate midbrain DA neuron development, and the subsequent elucidation of the molecular bases of their effects, is vital. Such an understanding would facilitate the generation of transplantable DA neurons from stem cells and the identification of developmentally-relevant neurotrophic factors, the two most promising therapeutic approaches for PD. Two related members of the bone morphogenetic protein (BMP) family, BMP2 and growth/differentiation factor (GDF) 5, which signal via a canonical Smad 1/5/8 signalling pathway, have been shown to have neurotrophic effects on midbrain DA neurons both in vitro and in vivo, and may function to regulate VM DA neuronal development. However, the molecular (signalling pathway(s)) and cellular (direct neuronal or indirect via glial cells) mechanisms of their effects remain to be elucidated. The present thesis hypothesised that canonical Smad signalling mediates the direct effects of BMP2 and GDF5 on the development of VM DA neurons. By activating, modulating and/or inhibiting various components of the BMP-Smad signalling pathway, this research demonstrated that GDF5- and BMP2-induced neurite outgrowth from midbrain DA neurons is dependent on BMP type I receptor activation of the Smad signalling pathway. The role of glial cell-line derived neurotrophic factor (GDNF)-signalling, dynamin-dependent endocytosis and Smad interacting protein-1 (Sip1) regulation, in the neurotrophic effects of BMP2 and GDF5 were determined. Finally, the in vitro development of VM neural stem cells (NSCs) was characterised, and the ability of GDF5 and BMP2 to induce these VM NSCs towards DA neuronal differentiation was investigated. Taken together, these experiments identify GDF5 and BMP2 as novel regulators of midbrain DA neuronal induction and differentiation, and demonstrate that their effects on DA neurons are mediated by canonical BMPR-Smad signalling.

Prevalence of the factor VR506Q mutation in two Irish control populations:use of a novel nested polymerase chain reaction approach

The prevalence of factor V (FV) Leiden among normal populations has primarily been determined using blood donors. This control group is carefully selected and therefore may not accurately reflect the true prevalence within the population. We assessed the prevalence of FV Leiden within the Irish population using Guthrie card samples randomly selected from all newborns. We compared this result with the prevalence of FV Leiden within blood donors. A novel nested polymerase chain reaction (PCR) method for FV Leiden was developed for analysis of the Guthrie card samples. There was no significant difference between the allele frequency within the Guthrie card samples and blood donors (2.07% vs. 2.35%, P = 0.66)

Effects of vitamin K deficiency and its mechanisms in vertebrate's early development: zebrafish as a model

Disertação de mestrado, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015

A five factor model of grief : a q-methodological study /

Q-methodology permitted 41 people to communicate their perspective of grief. In an attempt to clarify the research to date and to allow those who have experienced this human journey to direct the scientists, 80 statements were chosen to present to the participants based on the research from academic and counselling sources. Five different perspectives emerged from the Q-sorts and factor analysis. Each perspective was valuable for the understanding of different groups of mourners. They were interpreted using questionnaire data and interview information. They are as follows: Factor 1- Growth Optimism; Factor 2 - Schema Destruction and Negative Affect; Factor 3- Identification with the Deceased Person; Factor 4- Intact World view with High Clarity and High Social Support; Factor 5- Schema Destruction with High Preoccupation and Attention to Emotion. Some people grow in the face of grief, others hold on to essentially the same schemas and others are devastated by their loss. The different perspectives reported herein supply clues to the sources of these differing outcomes. From examination of Factor 1, it appears that a healthy living relationship helps substantially in the event of loss. An orientation toward emotions that encourages clarity, exemplified by Factor 4, without hyper-vigilance to emotion may be helpful as well. Strategies for maintaining schematic representations of the world with little alteration include: identification with the values of the deceased person, as in Factor 3 and reliance on social support and/or God as demonstrated by Factor 4. When the relationship had painful periods, social support may be accessed to benefit some mourners. When the person's frame of reference or higher order schemas are assaulted by the events of loss, the people most at risk for traumatic grief seem to be those with difficult relationships as indicated by Factor 5 individuals. When low social support, high attention to emotion with low clarity and little belief that feelings can be altered for the better are also attributes of the mourner devastating grief can result. In the end, there are groups of people who are forced to endure the entire process of schema destruction and devastation. Some appear to recover in part and others appear to stay in a form of purgatory for many years. The results of this study suggest that, those who experience devastating grief may be in the minority. In the future interventions could be more specifically addressed if these perspectives are replicated in a larger, more detailed study.

Vitamine K et fonctions cognitives chez la personne âgée en santé : une approche épidémiologique nutritionnelle

La vitamine K fait l’objet d’un intérêt croissant en regard du rôle qu’elle peut jouer dans la santé humaine hormis celui bien établi dans la coagulation sanguine. De plus en plus d’études expérimentales lui confèrent des fonctions dans le système nerveux central, particulièrement dans la synthèse des sphingolipides, l’activation de la protéine vitamine K-dépendante Gas6 et la protection contre les dommages oxydatifs. Toutefois, il demeure beaucoup moins bien établi si la perturbation de ces fonctions peut conduire à des déficits cognitifs. L’objectif principal de cette thèse est de vérifier l’hypothèse selon laquelle le statut vitaminique K des personnes âgées en santé est un déterminant de la performance cognitive. En vue de la réalisation de cet objectif, une meilleure compréhension des indicateurs du statut vitaminique K s’avérait nécessaire. Chacune des études présentées vise donc un objectif spécifique : 1) évaluer le nombre de rappels alimentaires de 24 heures non consécutifs nécessaire pour mesurer l’apport habituel de vitamine K des personnes âgées; 2) évaluer la valeur d’une seule mesure de la concentration sérique de vitamine K comme marqueur de l’exposition à long terme; et 3) examiner l’association entre le statut vitaminique K et la performance cognitive des personnes âgées en santé de la cohorte québécoise NuAge. Trois dimensions cognitives ont été évaluées soient la mémoire épisodique verbale et non-verbale, les fonctions exécutives et la vitesse de traitement de l’information. Cette thèse présente la première étude appuyant l’hypothèse d’un rôle de la vitamine K dans la cognition chez les personnes âgées. Spécifiquement, la concentration sérique de vitamine K a été associée positivement à la performance en mémoire épisodique verbale, et plus particulièrement au processus de consolidation de la trace mnésique. En accord avec les travaux chez l’animal et l’action de la protéine Gas6 dans l’hippocampe, un rôle spécifique de la vitamine K à l’étape de consolidation est biologiquement plausible. Aucune association significative n’a été observée avec les fonctions exécutives et la vitesse de traitement de l’information. Parallèlement, il a été démontré qu’une mesure unique de la concentration sérique de vitamine K constitue une mesure adéquate de l’exposition à long terme à la vitamine K. De même, il a été établi que six à 13 rappels alimentaires de 24 heures sont nécessaires pour estimer précisément l’apport de vitamine K des personnes âgées en santé. Collectivement, les résultats de ces deux études fournissent des informations précieuses aux chercheurs permettant une meilleure interprétation des études existantes et une meilleure planification des études futures. Les résultats de cette thèse constituent une avancée importante dans la compréhension du rôle potentiel de la vitamine K dans le système nerveux central et renforce la nécessité qu’elle soit considérée en tant que facteur nutritionnel du vieillissement cognitif, en particulier chez les personnes traitées par un antagoniste de la vitamine K.

GABA and 5-HT chitosan nanoparticles enhanced liver cell proliferation and neuronal survival in partially hepatectomised rats: GABAB and 5-HT2A receptors functional

Nanoparticulate drug delivery systems provide wide opportunities for solving problems associated with drug stability or disease states and create great expectations in the area of drug delivery (Bosselmann & Williams, 2012). Nanotechnology, in a simple way, explains the technology that deals with one billionth of a meter scale (Ochekpe, et al., 2009). Fewer side effects, poor bioavailability, absorption at intestine, solubility, specific delivery to site of action with good pharmacological efficiency, slow release, degradation of drug and effective therapeutic outcome, are the major challenges faced by most of the drug delivery systems. To a great extent, biopolymer coated drug delivery systems coupled with nanotechnology alleviate the major drawbacks of the common delivery methods. Chitosan, deacetylated chitin, is a copolymer of β-(1, 4) linked glucosamine (deacetylated unit) and N- acetyl glucosamine (acetylated unit) (Radhakumary et al., 2005). Chitosan is biodegradable, non-toxic and bio compatible. Owing to the removal of acetyl moieties that are present in the amine functional groups of chitin, chitosan is readily soluble in aqueous acidic solution. The solubilisation occurs through the protonation of amino groups on the C-2 position of D-glucosamine residues whereby polysaccharide is converted into polycation in acidic media. Chitosan interacts with many active compounds due to the presence of amine group in it. The presence of this active amine group in chitosan was exploited for the interaction with the active molecules in the present study. Nanoparticles of chitosan coupled drugs are utilized for drug delivery in eye, brain, liver, cancer tissues, treatment of spinal cord injury and infections (Sharma et al., 2007; Li, et a., 2009; Paolicelli et al., 2009; Cho et al., 2010). To deliver drugs directly to the intended site of action and to improve pharmacological efficiency by minimizing undesired side effects elsewhere in the body and decrease the long-term use of many drugs, polymeric drug delivery systems can be used (Thatte et al., 2005).

Trombosis asociada a cateter venoso central en pediatría de la Fundación Cardioinfantil julio 2013 a julio 2015

La trombosis relacionada al uso del catéter es un problema que cobra cada vez mayor importancia. Se han descrito factores de riesgo para su presentación en la población pediátrica pero aún no se han realizado estudios en nuestro medio. Objetivo: Determinar los factores de riesgo y la prevalencia de la trombosis asociada a catéter venoso central en los pacientes pediátricos de la Fundación Cardioinfantil hospitalizados durante el periodo comprendido entre Julio 2013 a Julio 2015. Metodología: Se realizó un estudio de corte transversal de asociación. Se incluyeron pacientes clasificados en 4 grupos: trombosis y catéter, trombosis sin catéter, catéter sin trombosis y sin trombosis ni catéter. Se estimaron OR como medidas de asociación utilizando el estadístico mantel haenszel. Resultados: En total se incluyeron 221 pacientes. La prevalencia de la trombosis y uso del catéter fue del 22%. La edad inferior a los 36 meses (OR 2,27 IC95% 1,16-4,44,p<0.001), profilaxis antitrombótica (OR 34,4 IC95% 4,18-282,92, p<0.01), hospitalización en la UCI (OR 3,82, IC95% 1,69-8,65, p<0.001) y el tiempo de hospitalización (OR 16,83 IC95% 7,8-36,27, p<0.001) están asociadas con un mayor riesgo de presentación de la trombosis. Conclusión: La edad, hospitalización en UCI, uso de profilaxis antitrombótica y el tiempo de hospitalización son factores de riesgo que estan relacionados con la presentación de la trombosis en pacientes con cateter.

Relationship between resistance factors and treatment efficacy when bromadiolone was used against anticoagulant-resistant Norway rats (Rattus norvegicus Berk.) in Wales

We investigated the relationship between the severity and incidence of resistance among Norway rats (Rattus norvegicus) on a farm in Wales and the subsequent outcome of a practical rodent control operation. Bromadiolone resistance factors were estimated for rats trapped on the farm using the blood clotting response test, and were found to be 2 to 3 for male rats and approximately 6 for females. The incidence of resistance in the rat population was high. Infestation size was estimated by census baiting and tracking, and was found to be substantial, with a maximum of 6.5 kg of bait being eaten on a single night. A proprietary rodenticide (Deadline (TM)), containing 0.005% bromadiolone, was used to control the infestation. The duration of baiting was 35 days and, according to the two methods of assessment used, treatment success was in the region of 87 and 93%. No evidence was observed of a significant impact of resistance on the rat control operation, and the remaining rats of this very heavy infestation would probably have been controlled if baiting had continued for longer.

A standardised BCR resistance test for all anticoagulant rodenticides

This paper presents a reappraisal of the blood clotting response (BCR) tests for anticoagulant rodenticides, and proposes a standardised methodology for identifying and quantifying physiological resistance in populations of rodent species. The standardisation is based on the International Normalised Ratio, which is standardised against a WHO international reference preparation of thromboplastin, and allows comparison of data obtained using different thromboplastin reagents. ne methodology is statistically sound, being based on the 50% response, and has been validated against the Norway rat (Rattus norvegicus) and the house mouse (Mus domesticus). Susceptibility baseline data are presented for warfarin, diphacinone, chlorophacinone and coumatetralyl against the Norway rat, and for bromadiolone, difenacoum, difethialone, flocoumafen and brodifacoum against the Norway rat and the house mouse. A 'test dose' of twice the ED50 can be used for initial identification of resistance, and will provide a similar level of information to previously published methods. Higher multiples of the ED50 can be used to assess the resistance factor, and to predict the likely impact on field control.

Resistance to the anticoagulant rodenticides – the deployment of the new molecular methodology to identify mutations of the VKORC1 ‘resistance gene’, and understanding their potential impact on treatment outcome

Anticoagulants rodenticides have already known for over half a century, as effective and safe method of rodent control. However, discovered in 1958 anticoagulant resistance has given us a very important problem for their future long-term use. Laboratory tests provide the main method for identification the different types of anticoagulant resistances, quantify the magnitude of their effect and help us to choose the best pest control strategy. The main important tests are lethal feeding period (LFP) and blood clotting response (BCR) tests. These tests can now be used to quantify the likely effect of the resistance on treatment outcome by providing an estimate of the ‘resistance factor’. In 2004 the gene responsible for anticoagulant resistance (VKORC1) was identified and sequenced. As a result, a new molecular resistance testing methodology has been developed, and a number of resistance mutations, particularly in Norway rats and house mice. Three mutations of the VKORC1 gene in Norway rats have been identified to date that confer a degree of resistance to bromadiolone and difenacoum, sufficient to affect treatment outcome in the field.