作者: Machado, Juliana Ferreira Fernandes ; Pinto, Charleston Ribeiro ; Franklin, Bryony Dean ; Assunção-Costa, Lindemberg ; Valli, Cleidenete Gomes ; de Souza, Luis Eugenio Portela Fernandes

IntroductionMedication errors are frequent and have high economic and social impacts; however, some medication errors are more likely to result in harm than others. Therefore, it is critical to determine their severity. Various tools exist to measure and classify the harm associated with medication errors; although, few have been validated internationally.MethodsWe validated an existing method for assessing the potential severity of medication administration errors (MAEs) in Brazil. Thirty healthcare professionals (doctors, nurses and pharmacists) from Brazil were invited to score 50 cases of MAEs as in the original UK study, regarding their potential harm to the patient, on a scale from 0 to 10. Sixteen cases with known harmful outcomes were included to assess the validity of the scoring. To assess test–retest reliability, 10 cases (of the 50) were scored twice. Potential sources of variability in scoring were evaluated, including the occasion on which the scores were given, the scorers, their profession and the interactions among these variables. Data were analysed using generalisability theory. A G coefficient of 0.8 or more was considered reliable, and a Bland-Altman analysis was used to assess test–retest reliability.ResultsTo obtain a generalisability coefficient of 0.8, a minimum of three judges would need to score each case with their mean score used as an indicator of severity. The method also appeared to be valid, as the judges’ assessments were largely in line with the outcomes of the 16 cases with known outcomes. The Bland-Altman analysis showed that the distribution was homogeneous above and below the mean difference for doctors, pharmacists and nurses.ConclusionThe results of this study demonstrate the reliability and validity of an existing method of scoring the severity of MAEs for use in the Brazilian health system.

2011-04-15·Cancer Research

Abstract 2323: Molecular modeling studies of the STAT3 homodimer:DNA complex

作者: Neidle, Stephen ; Haider, Shozeb M. ; Husby, Jarmila ; Thurston, David E. ; Zinzella, Giovanna

AbstractSignal Transducers and Activators of Transcription (STAT) are a group of latent cytoplasmic transcription factors in cytokine signaling, that transduce signals from the cell membrane to the nucleus, where they activate gene transcription. STAT activation by phosphorylation is mediated by growth factors or cytokines, inducing STAT:STAT dimer formation between two monomers via reciprocal phosphoTyr formation. A member of the STAT family, STAT3 (Figure 1), has been found to be expressed at elevated levels in a large number of diverse human cancers, thus STAT3 represents a validated target for anticancer drug design. Understanding the dynamics of the STAT3 dimer interface, accounting for both protein-DNA and protein-protein interactions, with respect to the dynamics of the latent, unphosphorylated STAT3 monomer, is important for designing potential small-molecule inhibitors of the activated dimer.The results of molecular dynamics (MD) simulations of the activated STAT3 homodimer:DNA complex, and latent unphosporylated STAT3 monomer in explicit water have been studied. Careful analysis of the data obtained from MD simulations over a 35 ns time-frame has revealed the dynamics of the macromolecular complex at the atomistic level; how the transcription factor interacts with the DNA, the nature of the conformational changes, and the way function may be affected. Further analysis of the dimer interface, with a main focus on the protein-DNA interaction, including the water molecules, has revealed the key residues contributing to the recognition events involved in STAT3 protein-DNA interactions. Moreover, locations of the majority of mutations in the DNA-binding domain are found at the protein-DNA interface. In particular, we have been able to map out these mutations in detail and relate them to specific protein-DNA contacts. Their structural stability and importance will be described, along with a discussion of how this model is being used to assist in the discovery of novel small-molecule inhibitors.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2323. doi:10.1158/1538-7445.AM2011-2323

2011-04-15·Cancer Research

Abstract 2310: Down-regulating BCL-2 gene expression in a resistant GIST cell line by a RNA G-quadruplex interacting small molecule ligand

作者: Neidle, Stephen ; Fletcher, Jonathan A. ; Collie, Gavin ; Todd, Alan R. ; Parkinson, Gary N. ; Reszka, Anthony P. ; Li, Xiong Wei ; Gunaratnam, Mekala

AbstractWe have previously shown that KIT protein expression in the gastrointestinal tumour (GIST) cell line GIST882 can be down-regulated using a small molecule approach that targets expression at the transcriptional level. The small-molecule naphthalene diimide derivative ND1 developed as a G-quadruplex telomere targeting agent can inhibit telomerase activity and can also reduce c-kit mRNA levels, consistent with a dual G-quadruplex mechanism of action in this cell line. An Imatinib (Gleevec) resistant patient-derived cell line GIST48 expresses high levels of the anti-apoptotic protein bcl-2. The compound ND1 down-regulates the expression of bcl-2 in this resistant cell line, while having no discernable effect on c-kit protein expression levels or telomerase activity, both associated with DNA quadruplex stabilization. Instead we observe that translation of the apoptosis-related protein is impeded, while mRNA levels remain unaffected. The identification of a G-rich quadruplex-forming sequence in the 5’-UTR region of the bcl-2 gene, upstream of the translation start site, lead us to the development of a dual luciferase reporter assay. Utilizing a psiCHECK-2 vector we inserted the G-rich 67 base pair bcl-2 5’-UTR gene sequence upstream of the Renilla luciferase start codon. In vitro experiments have shown that the G-rich sequence can form a stable RNA G-quadruplex and interfere with translation. Our in vivo transfection experiments with ND1 in a GIST cell line shows concentration-dependent inhibition of bcl-2 protein expression. RNA G-quadruplex formation and ligand stabilization may thus be a novel anti-cancer route for the down-regulation of the anti-apoptotic protein bcl-2 in chemo-resistant cancers.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2310. doi:10.1158/1538-7445.AM2011-2310

100 项与 The School of Pharmacy University of London 相关的药物交易

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100 项与 The School of Pharmacy University of London 相关的转化医学

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