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Good Target (good + target)
Selected AbstractsFactor Xa or thrombin: is factor Xa a better target?JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2007J. ANSELL Summary., Existing vitamin K antagonists (VKAs) have drawbacks that limit their effectiveness, safety, and overall frequency of use. Oral anticoagulants in development with targeted action against individual coagulation factors, specifically direct factor (F) Xa and IIa inhibitors, appear to have pharmacokinetic and pharmacodynamic properties that overcome the limitations of the VKAs. Based on the theory of how coagulation factors interact, on the results of in vitro studies, and on clinical outcomes, there is accumulating evidence that FXa may represent a better target for inhibition than FIIa. This is based on an understanding of the amplified nature of coagulation factor interactions and fibrin formation, the need for smaller doses of an anticoagulant to block coagulation progression earlier in the sequence of reactions, the evidence for incomplete suppression of thrombin generation with direct thrombin inhibitors, evidence for rebound hypercoagulability with thrombin inhibitors, and clinical results with the indirect, parenteral, FXa inhibitor (fondaparinux), as well as early phase II results of new oral Xa and IIa inhibitors compared with enoxaparin. The latter studies, although not comparative, provide some evidence for the effectiveness and safety of Xa inhibitors at a range of doses not seen with the direct IIa inhibitors. [source] Travel Agents and the Prevention of Health Problems among Travelers in QuébecJOURNAL OF TRAVEL MEDICINE, Issue 1 2002Sylvie Provost Background: Among the factors influencing travelers to seek preventive health advice before departure, the travel agent's recommendation plays an important role. The objective of our study was to document the practices and needs of travel agents in Québec (Canada) in relation to the prevention of health problems among travelers. Methods: In June 2000, a cross-sectional descriptive survey was carried out among travel agents from all travel agencies in Québec. One agent per agency was asked to answer our questions. Data were collected using a 32-item telephone questionnaire. Results: Altogether, 708 travel agents from the 948 agencies contacted answered our questionnaire (participation rate: 75%). Most respondents (81%) believed that the travel agent has a role to play in the prevention of health problems among travelers, especially to recommend that travelers consult a travel clinic before departure. Although over 80% of the agents interviewed mentioned recommending a visit to a travel clinic before an organized tour to Thailand or a backpacking trip in Mexico, less than half said they make the same recommendation for a stay in a seaside resort in Mexico. The majority of respondents were acquainted with the services offered in travel health clinics, and these clinics were the source of travel health information most often mentioned by travel agents. However, nearly 60% of the agents questioned had never personally consulted a travel clinic. When asked about the best way to receive information about travelers' health, more than 40% of respondents favoured receiving information newsletters from public health departments regularly whereas 28% preferred the Internet. Conclusion: Despite the limits of this study, our results should help the public health network better target its interventions aimed to inform travel agents on prevention of health problems among travelers. [source] Regulation of transgene expressionACTA OPHTHALMOLOGICA, Issue 2009P KOCH Purpose Regulation of the transgene expression in the targeted cells is of course of major importance when using gene therapy. Actually, we have a huge range of possibilities to regulate gene expression. Methods There are two main classes of promoters: constitutive and inducible promoters. Amongst constitutive promoters, we have two sub-forms: non-tissue and tissue specific promoters. The lasts allows us to better target the tissue or cells in which we want to express our gene of interest. On the other hand, inducible promoters have been widely developed recently and allow us to obtain a regulated expression, depending on different factors. Very recently, disease specific inducible promoters emerged for a more precise regulation. Results We will together examine more precisely the different possibilities offered by gene regulation in Gene Therapy. Thereafter, we will more specifically describe usable promoters in ocular inflammation. Finally we will examine the effects of some inflammatory, disease specific, promoters. Conclusion Regulation of transgene expression is one of the fundaments of efficient gene transfer. Recent developments actually allow us to play within the targeted cell(s) to obtain an expression in specific conditions. [source] The First Chemical Synthesis of UDP[6- 3H]-,- D -galactofuranoseEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 14 2005Karina Mariño Abstract Galactofuranose metabolism is a good target for the development of novel chemotherapeutic agents for the treatment of some microbial infections. This is a valid objective because galactofuranose is absent in mammals. Two enzymes are involved in the biosynthesis of molecules containing galactofuranose: a mutase, which catalyzes the interconversion of UDP-Galp and UDP-Galf, and D -galactofuranosyltransferases. The mechanism of action of the mutase and its inhibition is currently being investigated, whereas studies on the galactofuranosyltransferases have been hampered by the lack of a labeled galactofuranose nucleotide. In the present work we describe the chemical synthesis of UDP-,- D -[6- 3H]Galf and we prove its effectiveness for incorporation of radioactive galactofuranose into a natural acceptor. This is the first report on the chemical synthesis of a labeled donor of galactofuranose with the potential for studying the galactofuranosyltransferases independently from the UDP-Galp mutase. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source] Human telomeric G-quadruplex: structures of DNA and RNA sequencesFEBS JOURNAL, Issue 5 2010Anh Tuân Phan Telomeres play an important role in cellular aging and cancer. Human telomeric DNA and RNA G-rich sequences are capable of forming a four-stranded structure, known as the G-quadruplex. Such a structure might be important for telomere biology and a good target for drug design. This minireview describes the structural diversity or conservation of DNA and RNA human telomeric G-quadruplexes, discusses structural views on targeting these G-quadruplexes and presents some future challenges for structural studies. [source] Effect of sequence polymorphism and drug resistance on two HIV-1 Gag processing sitesFEBS JOURNAL, Issue 16 2002Anita Fehér The HIV-1 proteinase (PR) has proved to be a good target for antiretroviral therapy of AIDS, and various PR inhibitors are now in clinical use. However, there is a rapid selection of viral variants bearing mutations in the proteinase that are resistant to clinical inhibitors. Drug resistance also involves mutations of the nucleocapsid/p1 and p1/p6 cleavage sites of Gag, both in vitro and in vivo. Cleavages at these sites have been shown to be rate limiting steps for polyprotein processing and viral maturation. Furthermore, these sites show significant sequence polymorphism, which also may have an impact on virion infectivity. We have studied the hydrolysis of oligopeptides representing these cleavage sites with representative mutations found as natural variations or that arise as resistant mutations. Wild-type and five drug resistant PRs with mutations within or outside the substrate binding site were tested. While the natural variations showed either increased or decreased susceptibility of peptides toward the proteinases, the resistant mutations always had a beneficial effect on catalytic efficiency. Comparison of the specificity changes obtained for the various substrates suggested that the maximization of the van der Waals contacts between substrate and PR is the major determinant of specificity: the same effect is crucial for inhibitor potency. The natural nucleocapsid/p1 and p1/p6 sites do not appear to be optimized for rapid hydrolysis. Hence, mutation of these rate limiting cleavage sites can partly compensate for the reduced catalytic activity of drug resistant mutant HIV-1 proteinases. [source] A new panel of NS1 antibodies for easy detection and titration of influenza A virus,JOURNAL OF MEDICAL VIROLOGY, Issue 3 2010Zhihao Tan Abstract The non-structural protein NS1 of the influenza A virus is a good target for the development of diagnostic assays. In this study, three NS1 monoclonal antibodies (mAbs) were generated by using recombinant NS1 protein of H5N1 virus and found to bind both the native and denatured forms of NS1. Two of the mAbs, 6A4 and 2H6, bind NS1 of three different strains of influenza A virus, namely H1N1, H3N2, and H5N1. Epitope mapping revealed that residues 42,53 of H5N1 NS1 are essential for the interaction with both mAbs. Between the three strains, there is only one amino acid difference in this domain, which is consistent with the observed cross-reactivities. On the other hand, mAb 1G1 binds to residues 206,215 of H5N1 NS1 and does not bind NS1 of H1N1 or H3N2. Furthermore, all three mAbs detected NS1 proteins expressed in virus infected MDCK cells and indirect immunofluorescence staining with mAbs 6A4 and 2H6 provided an alternative method for viral titer determination. Quantifying the numbers of fluorescent foci units yielded viral titers for three different isolates of H5N1 virus that are highly comparable to that obtained by observing cytopathic effect induced by virus infection. Importantly, this alternative method yields results at 1 day post-infection while the conventional method using cytopathic effect yields results at 3 days post-infection. The results showed that this new panel of NS1 antibodies can detect NS1 protein expressed during viral infection and can be used for fast and easy titration of influenza A virus. J. Med. Virol. 82:467,475, 2010. © 2010 Wiley-Liss, Inc. [source] Synthesis of Bicyclic N -Arylmethyl-Substituted Iminoribitol Derivatives as Selective Nucleoside Hydrolase InhibitorsCHEMMEDCHEM, Issue 2 2009Maya Berg Abstract A series of bicyclicN -arylmethyl-substituted iminoribitols were synthesised and evaluated in,vitro against T.,vivax nucleoside hydrolase. The importance of the N,Asp40 interaction was confirmed and depends on an optimal pKa value, which can be influenced by substituents. The compounds were active inhibitors of nucleoside hydrolase (IAG-NH) and are inactive against human purine nucleoside phosphorylase. The purine metabolism of Trypanosoma and Leishmania spp. provides a good target in the search for new selective drugs. Bicyclic N -arylmethyl-substituted iminoribitols were developed as inhibitors of T.,vivax nucleoside hydrolase, a key enzyme of the purine salvage pathway. The obtained results and structure,activity data confirmed our model for inhibitor binding with a hydrogen bond between a nitrogen atom of the nucleobase mimetic and the protonated Asp40 from the enzyme. This interaction depends on an optimal pKa value, which can be influenced by the electronic properties of the substituents. These compounds are potent, selective inhibitors of nucleoside hydrolase and are inactive toward human nucleoside phosphorylase. [source] Levels of cysteinyl leukotriene receptor mRNA in human peripheral leucocytes: significantly higher expression of cysteinyl leukotriene receptor 2 mRNA in eosinophilsCLINICAL & EXPERIMENTAL ALLERGY, Issue 11 2001H. Mita Background Cysteinyl leukotrienes (CysLTs) have been implicated as important contributors in the pathophysiology of asthma and their biological effects are mediated by at least two distinct G-protein-coupled receptors. cDNA sequences of cysteinyl leukotriene receptor 1 (CysLTR1) and cysteinyl leukotriene receptor 2 (CysLTR2) have recently been elucidated. Objectives Our aim is to explore gene expression and the comparative expression of CysLTR1 mRNA and CysLTR2 mRNA in human peripheral blood leucocytes. Methods Gene expression of CysLTR1 and CysLTR2 mRNAs in human peripheral blood eosinophils, neutrophils, monocytes and T lymphocytes has been measured by competitive reverse transcription-polymerase chain reactions using RNA or DNA competitors. Results(a) When cellular levels of CysLTR1 mRNA were normalized to those of G3PDH mRNA, the relative concentration of CysLTR1 mRNA in eosinophils (43.8 ± 37.2, n = 29) was significantly higher than that in neutrophils (18.7 ± 23.3, n = 11), monocytes (0.93 ± 1.1, n = 10) and T lymphocytes (3.4 ± 2.4, n = 11). (b) When measured using each DNA competitor, mRNAs for both types of CysLTR coexisted in each type of leucocyte. The ratio of CysLTR1 mRNA to CysLTR2 mRNA was significantly lower in eosinophils (0.65 ± 0.42, n = 12) than in neutrophils (6.9 ± 4.9, n = 12), monocytes (1.8 ± 0.9, n = 10) and T lymphocytes (4.5 ± 5.7, n = 10). (c) Human umbilical vein endothelial cells expressed CysLTR2 mRNA, but not CysLTR1 mRNA. Conclusion These studies reveal that CysLTR1 mRNA and, in particular, CysLTR2 mRNA are abundantly expressed at high levels in eosinophils, raising the possibility that CysLTR2 may have an important physiological role in eosinophils and a CysLTR2 antagonist may be a good target for preventing signal transduction by CysLTs in eosinophils. [source] Isolation and potential existence of side population cells in adult human kidneyINTERNATIONAL JOURNAL OF UROLOGY, Issue 3 2008Toshihiko Inowa Abstract: The existence of adult stem-like cells such as side population (SP) cells is reported in various kinds of animal tissues, and we recently reported that mice kidney SP cells differentiate into multilineage. However, there has thus far been no report about human kidney SP cells. In the present study, we examined the existence of SP cells in human kidney tissue by using Hoechst 33342 staining and fluorescence-activated cell sorting analysis. We used porcine kidney tissue to optimize the analysis conditions for human tissue, and found that the SP population in human kidney was 1.3%. The existence of SP cells in human kidney suggests that the cells could be good targets for clinical renal regenerative medicine. [source] | |||||||||||||