706 research outputs found

    Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate

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    A series of hydroxamates, which are not metalloprotease inhibitors, have been found to be selectively toxic to a range of transformed and human tumour cells without killing normal cells (fibroblasts, melanocytes) at the same concentrations. Within 24 h of treatment, drug action is characterized by morphological reversion of tumour cells to a more normal phenotype (dendritic morphology), and rapid and reversible acetylation of histone H4 in both tumour and normal cells. Two; hydroxamates inhibited growth of xenografts of human melanoma cells in nude mice; resistance did not develop in vivo or in vitro. A third hydroxamate, trichostatin A, was active in vitro but became inactivated and had no anti-tumour activity in vivo. Development of dendritic morphology was found to be dependent upon phosphatase activity, RNA and protein synthesis. Proliferating hybrid clones of sensitive and resistant cells remained sensitive to ABHA, indicating a dominant-negative mechanism of sensitivity. Histone H4 hyperacetylation suggests that these agents act at the chromatin level. This work may lead to new drugs that are potent, and selective anti-tumour agents with low toxicity to normal Cells

    Decomposition techniques with mixed integer programming and heuristics for home healthcare planning

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    We tackle home healthcare planning scenarios in the UK using decomposition methods that incorporate mixed integer programming solvers and heuristics. Home healthcare planning is a difficult problem that integrates aspects from scheduling and routing. Solving real-world size instances of these problems still presents a significant challenge to modern exact optimization solvers. Nevertheless, we propose decomposition techniques to harness the power of such solvers while still offering a practical approach to produce high-quality solutions to real-world problem instances. We first decompose the problem into several smaller sub-problems. Next, mixed integer programming and/or heuristics are used to tackle the sub-problems. Finally, the sub-problem solutions are combined into a single valid solution for the whole problem. The different decomposition methods differ in the way in which subproblems are generated and the way in which conflicting assignments are tackled (i.e. avoided or repaired). We present the results obtained by the proposed decomposition methods and compare them to solutions obtained with other methods. In addition, we conduct a study that reveals how the different steps in the proposed method contribute to those results. The main contribution of this paper is a better understanding of effective ways to combine mixed integer programming within effective decomposition methods to solve real-world instances of home healthcare planning problems in practical computation time

    Genetic and environmental influence on thyroid gland volume and thickness of thyroid isthmus: a twin study.

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    Objectives Decreased thyroid volume has been related to increased prevalence of thyroid cancer.Subjects and methods One hundred and fourteen Hungarian adult twin pairs (69 monozygotic, 45 dizygotic) with or without known thyroid disorders underwent thyroid ultrasound. Thickness of the thyroid isthmus was measured at the thickest portion of the gland in the midline using electronic calipers at the time of scanning. Volume of the thyroid lobe was computed according to the following formula: thyroid height*width*depth*correction factor (0.63).Results Age-, sex-, body mass index- and smoking-adjusted heritability of the thickness of thyroid isthmus was 50% (95% confidence interval [CI], 35 to 66%). Neither left nor right thyroid volume showed additive genetic effects, but shared environments were 68% (95% CI, 48 to 80%) and 79% (95% CI, 72 to 87%), respectively. Magnitudes of monozygotic and dizygotic co-twin correlations were not substantially impacted by the correction of covariates of body mass index and smoking. Unshared environmental effects showed a moderate influence on dependent parameters (24-50%).Conclusions Our analysis support that familial factors are important for thyroid measures in a general twin population. A larger sample size is needed to show whether this is because of common environmental (e.g. intrauterine effects, regional nutrition habits, iodine supply) or genetic effects

    The distal fascicle of the anterior inferior tibiofibular ligament as a cause of tibiotalar impingement syndrome: a current concepts review

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    Impingement syndromes of the ankle involve either osseous or soft tissue impingement and can be anterior, anterolateral, or posterior. Ankle impingement syndromes are painful conditions caused by the friction of joint tissues, which are both the cause and the effect of altered joint biomechanics. The distal fascicle of the anterior inferior tibiofibular ligament (AITFL) is possible cause of anterior impingement. The objective of this article was to review the literature concerning the anatomy, pathogenesis, symptoms and treatment of the AITFL impingement and finally to formulate treatment recommendations. The AITFL starts from the distal tibia, 5 mm in average above the articular surface, and descends obliquely between the adjacent margins of the tibia and fibula, anterior to the syndesmosis to the anterior aspect of the lateral malleolus. The incidence of the accessory fascicle differs very widely in the several studies. The presence of the distal fascicle of the AITFL and also the contact with the anterolateral talus is probably a normal finding. It may become pathological, due to anatomical variations and/or anterolateral instability of the ankle resulting from an anterior talofibular ligament injury. When observed during an ankle arthroscopy, the surgeon should look for the criteria described to decide whether it is pathological and considering resection of the distal fascicle. The presence of the AITFL and the contact with the talus is a normal finding. An impingement of the AITFL can result from an anatomical variant or anteroposterior instability of the ankle. The diagnosis of ligamentous impingement in the anterior aspect of the ankle should be considered in patients who have chronic ankle pain in the anterolateral aspect of the ankle after an inversion injury and have a stable ankle, normal plain radiographs, and isolated point tenderness on the anterolateral aspect of the talar dome and in the anteroinferior tibiofibular ligament. The impingement syndrome can be treated arthroscopically

    An efficient Foxtail mosaic virus vector system with reduced environmental risk

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    <p>Abstract</p> <p>Background</p> <p>Plant viral vectors offer high-yield expression of pharmaceutical and commercially important proteins with a minimum of cost and preparation time. The use of <it>Agrobacterium tumefaciens </it>has been introduced to deliver the viral vector as a transgene to each plant cell via a simple, nonsterile infiltration technique called "agroinoculation". With agroinoculation, a full length, systemically moving virus is no longer necessary for excellent protein yield, since the viral transgene is transcribed and replicates in every infiltrated cell. Viral genes may therefore be deleted to decrease the potential for accidental spread and persistence of the viral vector in the environment.</p> <p>Results</p> <p>In this study, both the coat protein (CP) and triple gene block (TGB) genetic segments were eliminated from <it>Foxtail mosaic virus </it>to create the "FECT" vector series, comprising a deletion of 29% of the genome. This viral vector is highly crippled and expresses little or no marker gene within the inoculated leaf. However, when co-agroinoculated with a silencing suppressor (p19 or HcPro), FECT expressed GFP at 40% total soluble protein in the tobacco host, <it>Nicotiana benthamiana</it>. The modified FoMV vector retained the full-length replicase ORF, the TGB1 subgenomic RNA leader sequence and either 0, 22 or 40 bases of TGB1 ORF (in vectors FECT0, FECT22 and FECT40, respectively). As well as <it>N. benthamiana</it>, infection of legumes was demonstrated. Despite many attempts, expression of GFP via syringe agroinoculation of various grass species was very low, reflecting the low <it>Agrobacterium</it>-mediated transformation rate of monocots.</p> <p>Conclusions</p> <p>The FECT/40 vector expresses foreign genes at a very high level, and yet has a greatly reduced biohazard potential. It can form no virions and can effectively replicate only in a plant with suppressed silencing.</p

    Limits on WWZ and WW\gamma couplings from p\bar{p}\to e\nu jj X events at \sqrt{s} = 1.8 TeV

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    We present limits on anomalous WWZ and WW-gamma couplings from a search for WW and WZ production in p-bar p collisions at sqrt(s)=1.8 TeV. We use p-bar p -> e-nu jjX events recorded with the D0 detector at the Fermilab Tevatron Collider during the 1992-1995 run. The data sample corresponds to an integrated luminosity of 96.0+-5.1 pb^(-1). Assuming identical WWZ and WW-gamma coupling parameters, the 95% CL limits on the CP-conserving couplings are -0.33<lambda<0.36 (Delta-kappa=0) and -0.43<Delta-kappa<0.59 (lambda=0), for a form factor scale Lambda = 2.0 TeV. Limits based on other assumptions are also presented.Comment: 11 pages, 2 figures, 2 table

    Search For Heavy Pointlike Dirac Monopoles

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    We have searched for central production of a pair of photons with high transverse energies in ppˉp\bar p collisions at s=1.8\sqrt{s} = 1.8 TeV using 70pb170 pb^{-1} of data collected with the D\O detector at the Fermilab Tevatron in 1994--1996. If they exist, virtual heavy pointlike Dirac monopoles could rescatter pairs of nearly real photons into this final state via a box diagram. We observe no excess of events above background, and set lower 95% C.L. limits of 610,870,or1580GeV/c2610, 870, or 1580 GeV/c^2 on the mass of a spin 0, 1/2, or 1 Dirac monopole.Comment: 12 pages, 4 figure

    Zgamma Production in pbarp Collisions at sqrt(s)=1.8 TeV and Limits on Anomalous ZZgamma and Zgammagamma Couplings

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    We present a study of Z +gamma + X production in p-bar p collisions at sqrt{S}=1.8 TeV from 97 (87) pb^{-1} of data collected in the eegamma (mumugamma) decay channel with the D0 detector at Fermilab. The event yield and kinematic characteristics are consistent with the Standard Model predictions. We obtain limits on anomalous ZZgamma and Zgammagamma couplings for form factor scales Lambda = 500 GeV and Lambda = 750 GeV. Combining this analysis with our previous results yields 95% CL limits |h{Z}_{30}| < 0.36, |h{Z}_{40}| < 0.05, |h{gamma}_{30}| < 0.37, and |h{gamma}_{40}| < 0.05 for a form factor scale Lambda=750 GeV.Comment: 17 Pages including 2 Figures. Submitted to PR
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