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1.
Analyst ; 146(3): 789-802, 2021 Feb 07.
Article in English | MEDLINE | ID: mdl-33393954

ABSTRACT

Stimulated Raman histopathology (SRH) utilises the intrinsic vibrational properties of lipids, proteins and nucleic acids to generate contrast providing rapid image acquisition that allows visualisation of histopathological features. It is currently being trialled in the intraoperative setting, where the ability to image unprocessed samples rapidly and with high resolution offers several potential advantages over the use of conventional haematoxylin and eosin stained images. Here we review recent advances in the field including new updates in instrumentation and computer aided diagnosis. We also discuss how other non-linear modalities can be used to provide additional diagnostic contrast which together pave the way for enhanced histopathology and open up possibilities for in vivo pathology.


Subject(s)
Nucleic Acids , Spectrum Analysis, Raman , Eosine Yellowish-(YS) , Hematoxylin , Vibration
2.
J Med Chem ; 63(5): 2028-2034, 2020 03 12.
Article in English | MEDLINE | ID: mdl-31829628

ABSTRACT

Stimulated Raman scattering (SRS) microscopy represents a powerful method for imaging label-free drug distribution with high resolution. SRS was applied to image label-free ponatinib with high sensitivity and specificity in live human chronic myeloid leukemia (CML) cell lines. This was achieved at biologically relevant, nanomolar concentrations, allowing determination of ponatinib uptake and sequestration into lysosomes during the development of acquired drug resistance and an improved understanding of target engagement.


Subject(s)
Antineoplastic Agents/metabolism , Imidazoles/metabolism , Intracellular Fluid/metabolism , Nonlinear Optical Microscopy/methods , Pyridazines/metabolism , Antineoplastic Agents/analysis , Cell Line, Tumor , Humans , Imidazoles/analysis , Pyridazines/analysis
3.
Chemistry ; 24(9): 2094-2097, 2018 Feb 09.
Article in English | MEDLINE | ID: mdl-29267987

ABSTRACT

Modified peptides, such as stapled peptides, which replicate the structure of α-helical protein segments, represent a potential therapeutic advance. However, the 3D solution structure of these stapled peptides is rarely explored beyond the acquisition of circular dichroism (CD) data to quantify bulk peptide helicity; the detailed backbone structure, which underlies this, is typically undefined. Diastereomeric stapled peptides based on helical sections of three proteins (αSyn, Cks1 and CK1α) were generated; their overall helicity was quantified by CD; and the most helical peptide from each series was selected for structural analysis. Solution-phase models for the optimised peptides were generated using NMR-derived restraints and a modified CHARMM22 force field. Comparing these models with PDB structures allowed deviation between the stapled peptides and critical helical regions to be evaluated. These studies demonstrate that CD alone is not sufficient to assess the structural fidelity of a stapled peptide.

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