| 1. |
- Gibney, A., et al.
(author)
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A Click Chemistry-Based Artificial Metallo-Nuclease
- 2023
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In: Angewandte Chemie-International Edition. - 1433-7851 .- 1521-3773. ; 62:38
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Journal article (peer-reviewed)abstract
- Artificial metallo-nucleases (AMNs) are promising DNA damaging drug candidates. Here, we demonstrate how the 1,2,3-triazole linker produced by the Cu-catalysed azide-alkyne cycloaddition (CuAAC) reaction can be directed to build Cu-binding AMN scaffolds. We selected biologically inert reaction partners tris(azidomethyl)mesitylene and ethynyl-thiophene to develop TC-Thio, a bioactive C-3-symmetric ligand in which three thiophene-triazole moieties are positioned around a central mesitylene core. The ligand was characterised by X-ray crystallography and forms multinuclear Cu-II and Cu-I complexes identified by mass spectrometry and rationalised by density functional theory (DFT). Upon Cu coordination, Cu-II-TC-Thio becomes a potent DNA binding and cleaving agent. Mechanistic studies reveal DNA recognition occurs exclusively at the minor groove with subsequent oxidative damage promoted through a superoxide- and peroxide-dependent pathway. Single molecule imaging of DNA isolated from peripheral blood mononuclear cells shows that the complex has comparable activity to the clinical drug temozolomide, causing DNA damage that is recognised by a combination of base excision repair (BER) enzymes.
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| 2. |
- Klassen, Anne F., et al.
(author)
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Psychometric findings and normative values for the CLEFT-Q based on 2434 children and young adult patients with cleft lip and/or palate from 12 countries
- 2018
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In: CMAJ. - : CMA Joule Inc.. - 0820-3946. ; 190:15, s. 455-462
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Journal article (peer-reviewed)abstract
- BACKGROUND: Patients with cleft lip and/or palate can undergo numerous procedures to improve appearance, speech, dentition and hearing. We developed a cleft-specific patientreported outcome instrument to facilitate rigorous international measurement and benchmarking. METHODS: Data were collected from patients aged 8-29 years with cleft lip and/or palate at 30 hospitals in 12 countries between October 2014 and November 2016. Rasch measurement theory analysis was used to refine the scales and to examine reliability and validity. Normative CLEFT-Q values were computed for age, sex and cleft type. RESULTS: Analysis led to the refinement of an eating and drinking checklist and 12 scales measuring appearance (of the face, nose, nostrils, teeth, lips, jaws and cleft lip scar), health-related quality of life (psychological, social, school, speech distress) and speech function. All scales met the requirements of the Rasch model. Analysis to explore differential item functioning by age, sex and country provided evidence to support the use of a common scoring algorithm for each scale for international use. Lower (worse) scores on CLEFT-Q scales were associated with having a speech problem, being unhappy with facial appearance, and needing future cleft-related treatments, providing evidence of construct validity. Normative values for age, sex and cleft type showed poorer outcomes associated with older age, female sex and having a visible cleft. INTERPRETATION: The CLEFT-Q represents a rigorously developed instrument that can be used internationally to collect and compare evidence-based outcomes data from patients aged 8-29 years of age with cleft lip and/or palate.
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