Publications by authors named "Kiersten Thomas"

3 Publications

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Germinal center hypoxia in tumor-draining lymph nodes negatively regulates tumor-induced humoral immune responses in mouse models of breast cancer.

Oncoimmunology 2021 4;10(1):1959978. Epub 2021 Aug 4.

Integrative Oncology, BC Cancer, Vancouver, Canada.

Hypoxia develops in germinal centers (GCs) induced by model antigens; however, it is unknown whether tumor-reactive GCs are also hypoxic. We identified GC hypoxia in lymph nodes (LNs) draining murine mammary tumors and lethally irradiated tumor cells, and found that hypoxia is associated with the levels of antibody-secreting B cells. Hypoxic culture conditions impaired the proliferation of activated B cells, and inhibited class-switching to IgG1 and IgA immunoglobulin isotypes . To assess the role of the hypoxic response in tumor-reactive GCs , we deleted von Hippel-Lindau factor (VHL) in class-switched B cells and found decreased GC B cells in tumor-draining LNs, reduced class-switched and tumor-specific antibodies in the circulation, and modified phenotypes of tumor-infiltrating T cells and macrophages. We also detected the hypoxia marker carbonic anhydrase IX in the GCs of LNs from breast cancer patients, providing evidence that GC hypoxia develops in humans. We conclude that GC hypoxia develops in TDLNs, and that the hypoxic response negatively regulates tumor-induced humoral immune responses in preclinical models.
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August 2021

A Series of 2-((1-Phenyl-1H-imidazol-5-yl)methyl)-1H-indoles as Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

ChemMedChem 2021 Jul 26;16(14):2195-2205. Epub 2021 May 26.

Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC =0.16 μM, EC =0.3 μM). Structural-activity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.
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July 2021

Cost-effectiveness of magnetic resonance carotid plaque imaging for primary stroke prevention in Canada.

Br J Radiol 2018 01 21;91(1081):20170518. Epub 2017 Nov 21.

1 Department of Medical Imaging,University of Toronto , University of Toronto , Toronto, ON , Canada.

Objective: Magnetic resonance of the carotid arteries provides important insight into plaque composition and vulnerability in addition to the traditional measure of stenosis. The purpose of this study was to evaluate the cost-effectiveness of MR imaging as a first-line modality to assess carotid disease and guide management for high-risk patients with <50% stenosis.

Methods: Using TreeAge Pro, a cost-effectiveness simulation was conducted comparing two strategies: (a) standard of care first-line carotid duplex ultrasound (DUS) with regular follow-up, vs (b) first-line MR assessment of stenosis and intraplaque haemorrhage (MRIPH) in which patients with IPH received annual DUS surveillance and immediate carotid endarterectomy in case of plaque progression.

Results: For patients aged 70 years old, using a first-line MRIPH strategy resulted in a 16.8% relative risk reduction in strokes compared to DUS (0.080 vs 0.097 strokes per patient per lifetime), and an increased quality-adjusted-life years (12.23 vs 12.20) at an increased cost of $897.33 over a patient's lifetime ($5784.53 vs $4887.20 average total cost per patient per lifetime). The incremental cost-effectiveness ratio was $29,744 per quality-adjusted-life years. MRIPH remained cost-effective below a willingness-to-pay threshold of $50,000 for 91.8% of sensitivity analyses.

Conclusion: MRIPH was found to be a cost-effective first-line tool to identify asymptomatic patients at high risk for stroke requiring annual surveillance and prompt management. Advances in Knowledge: Using MR imaging as a fist-line method to detect the presence of IPH provides clinically useful and cost-effective information that allows for enhanced risk evaluation and primary stroke prevention.
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January 2018