Investigating the effects of venom peptides on canine mammary cancer

Mammary Cancer is the most prevalent form of malignancy to occur in female dogs. With metastasised malignancies representing 50% of diagnosis, current treatments produce little efficacy towards survival and induce harsh adverse side effects, thus there is need for novel therapeutics. Venoms have been shown to exploit anti-cancer properties with specific selective effects towards many forms of human cancers, thus, the prospect of anti-cancer inhibition towards Canine Mammary Cancer is a feasible hypothesis. Utilising in-vitro cell viability assays, panels of venoms from snake, scorpions and spiders were profiled against canine mammary cancer cells lines, CMT28 and CMM26, and an immortalised normal canine kidney cell line, MDCK. Screening of these venom fractions identified selectivity towards the cancerous cells utilising venoms from the Naja genus by >70% inhibition. Mass spectrometry data of 5 fractions identified them as 3-finger toxins with 3 of the fractions identifying as novel cytotoxins and 2 matched to sequence in the database of the same species. Epidermal Growth factor receptor- 2 (HER2) is a key antigenic target in Human breast cancer and has been shown to be as a potential therapeutic target for Canine Mammary Cancer. Utilising computational modelling and molecular docking simulations, the identified cytotoxins obtained from mass spectrometry have been predicted to bind to the dimerisation loop of the extracellular domain of HER2, that is hypothesised to inhibit dimer formation. In practice Canine HER2 demonstrated to have a high binding affinity for proteins in whole snake venoms, signifying the potential of HER2 being a therapeutic target for the treatment of Canine Mammary Cancer

Avoiding chromosome pathology when replication forks collide

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2013 Macmillan Publishers Limited.Chromosome duplication normally initiates through the assembly of replication fork complexes at defined origins1, 2. DNA synthesis by any one fork is thought to cease when it meets another travelling in the opposite direction, at which stage the replication machinery may simply dissociate before the nascent strands are finally ligated. But what actually happens is not clear. Here we present evidence consistent with the idea that every fork collision has the potential to threaten genomic integrity. In Escherichia coli this threat is kept at bay by RecG DNA translocase3 and by single-strand DNA exonucleases. Without RecG, replication initiates where forks meet through a replisome assembly mechanism normally associated with fork repair, replication restart and recombination4, 5, establishing new forks with the potential to sustain cell growth and division without an active origin. This potential is realized when roadblocks to fork progression are reduced or eliminated. It relies on the chromosome being circular, reinforcing the idea that replication initiation is triggered repeatedly by fork collision. The results reported raise the question of whether replication fork collisions have pathogenic potential for organisms that exploit several origins to replicate each chromosome.THe MRC, the Leverhulme Trust, and the BBSRC

Different effects of oral and transdermal hormone replacement therapies on Factor IX, APC resistance, t-PA, PAI and C- reactive protein - a cross-sectional population survey

The effects of hormone replacement therapy (HRT) on thrombosis risk, thrombotic variables, and the inflammatory marker C- reactive protein (CRP) may vary by route of administration (oral versus transdermal). We studied the relationships of 14 thrombotic variables (previously related to cardiovascular risk) and CRP to menopausal status and to use of HRT subtypes in a cross-sectional study of 975 women aged 40-59 years. Our study confirmed previously-reported associations between thrombotic variables and menopausal status. Oral HRT use was associated with increased plasma levels of Factor IX, activated protein C (APC) resistance, and CRP; and with decreased levels of tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor (PAI) activity. Factor VII levels were higher in women taking unopposed oral oestrogen HRT. The foregoing associations were not observed in users of transdermal HRT; hence they may be consequences of the "first- pass" effect of oral oestrogens on hepatic protein synthesis. We conclude that different effects of oral and transdermal HRT on thrombotic and inflammatory variables may be relevant to their relative thrombotic risk; and suggest that this hypothesis should be tested in prospective, randomised studies

How accurately do adult sons and daughters report and perceive parental deaths from coronary disease?

<b>OBJECTIVES</b>: To describe how adult sons and daughters report and perceive parental deaths from heart disease <b>DESIGN</b>: Two generation family study. <b>SETTING</b>: West of Scotland. <b>SUBJECTS</b>: 1040 sons and 1298 daughters aged 30-59 from 1477 families, whose fathers and mothers were aged 45-64 in 1972-76 and have been followed up for mortality over 20 years. <b>OUTCOME</b> : Perception of a "family weakness" attributable to heart disease. RESULTS : 26% of sons and daughters had a parent who had died of coronary heart disease (CHD). The proportion was higher in older offspring (+18% per 10 year age difference) and in manual compared with non-manual groups (+37%). Eighty nine per cent of parental deaths from CHD were correctly reported by offspring. Only 23% of sons and 34% of daughters with at least one parent who had died of CHD considered that they had a family weakness attributable to heart disease. Perceptions of a family weakness were higher when one or both parents had died of CHD, when parental deaths occurred at a younger age, in daughters compared with sons and in offspring in non-manual compared with manual occupations. <b>CONCLUSIONS</b>: Only a minority of sons and daughters with experience of a parent having died from CHD perceive this in terms of a family weakness attributable to heart disease. Although men in manual occupations are most likely to develop CHD, they are least likely to interpret a parental death from CHD in terms of a family weakness. Health professionals giving advice to patients on their familial risks need to be aware of the difference between clinical definitions and lay perceptions of a family history of heart disease

AN APPLICATION OF SAFETY-FIRST PROBABILITY LIMITS IN A DISCRETE STOCHASTIC FARM MANAGEMENT PROGRAMMING MODEL

A sequential decision-making model was developed, and data from farm-raised catfish production were used to demonstrate its use. Outcomes of sequences of decisions which satisfied chance constraints on ending cash balances were traced through a specified time period. Discrete choice variables were specified due to the fixed nature of pond facilities. Recourse actions specified were sale of production in excess of endogenously determined transfer levels or purchase of inputs to supplement needs of the next production stage. Production activities cannot be changed during the planning period. Only yield variability was considered due to its impact on relative competitiveness among growth stages. Deviations were calculated from endogenously determined target levels based on goal and probability limits.Farm Management,

Pyrimido[1,2-a]-purin-10(3H)-one, M(1)G, is less prone to artifact than base oxidation

Pyrimido[1,2-a]-purin-10(3H)-one (M(1)G) is a secondary DNA damage product arising from primary reactive oxygen species (ROS) damage to membrane lipids or deoxyribose. The present study investigated conditions that might lead to artifactual formation or loss of M(1)G during DNA isolation. The addition of antioxidants, DNA isolation at low temperature or non-phenol extraction methods had no statistically significant effect on the number of M(1)G adducts measured in either control or positive control tissue samples. The number of M(1)G adducts in nuclear DNA isolated from brain, liver, kidney, pancreas, lung and heart of control male rats were 0.8, 1.1, 1.1, 1.1, 1.8 and 4.2 M(1)G/10(8) nt, respectively. In rat liver tissue, the mitochondrial DNA contained a 2-fold greater number of M(1)G adducts compared with nuclear DNA. Overall, the results from this study demonstrated that measuring M(1)G is a reliable way to assess oxidative DNA damage because the number of M(1)G adducts is significantly affected by the amount of ROS production, but not by DNA isolation procedures. In addition, this study confirmed that the background number of M(1)G adducts reported in genomic DNA could have been overestimated by one to three orders of magnitude in previous reports

Factors Influencing the Role of Women in Indonesian Fisheries Development

Gender consideration is an essential component of fishery development activities. The purpose of this thesis is to help guide planners and decision-makers who are concerned with understanding the role of women in fisheries development in general as well as in the Republic of Indonesia. Thus, it is partially based upon field research conducted in Indonesia among fishing communities which are representative of different types of fisheries. Justification for research concerning the role of women in the fisheries sector and the reasons why women should be included in development policy and planning are presented in Chapter I. The general research setting, the assumptions and delimitations of the study and operational definitions are also outlined in Chapter I. Methods and materials used to conduct research for this thesis are described in Chapter II. Women in Development (WID) literature and the body of literature focusing on women in fisheries worldwide are reviewed in Chapter III to provide a theoretical framework for the study of women in Indonesian fisheries. Chapter IV of the thesis describes the fisheries sector in Indonesia in general and then with more specific reference to the role of women in Indonesian fisheries development. Chapter V discusses research findings with a description of the sites which were visited and with an analysis of data gathered from a questionnaire. Chapter VI identifies factors influencing the role of women in Indonesian fisheries and outlines guidelines for incorporating gender considerations into fishery development activities. Strategies for enhancing the role of women in coastal communities are also presented