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Probing amylin fibrillation at an early stage via a tetracysteine-recognising fluorophore.

ABSTRACT: Amyloid fibrillation is a nucleation-dependent process known be involved in the development of more than 20 progressive and chronic diseases. The detection of amyloid formation at the nucleation stage can greatly advance early diagnoses and treatment of diseases. In this work, we developed a new assay for the early detection of amylin fibrillation using the biarsenical dye 4,5-bis(1,3,2-dithiarsolan-2-yl)fluorescein (FlAsH), which could recognise tetracysteine motifs and transform from non-fluorescent form into strongly fluorescent complexes. Due to the close proximity of two cysteine residues within the hydrophilic domain of amylin, a non-contiguous tetracysteine motif can form upon amylin dimerisation or oligomerisation, which can be recognised by FlAsH and emit strong fluorescence. This enables us to report the nucleation-growth process of amylin without modification of the protein sequence. We showed that the use of this assay not only allowed the tracking of initial nucleation events, but also enabled imaging of amyloid fibrils and investigation of the effects of amyloid inhibitor/modulator toward amylin fibrillation.

SUBMITTER: Wang ST

PROVIDER: S-EPMC5516914 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Probing amylin fibrillation at an early stage via a tetracysteine-recognising fluorophore.

Wang Shih-Ting ST Lin Yiyang Y Lin Yiyang Y Hsu Chia-Chen CC Amdursky Nadav N Spicer Christopher D CD Stevens Molly M MM

Talanta 20170517

Amyloid fibrillation is a nucleation-dependent process known be involved in the development of more than 20 progressive and chronic diseases. The detection of amyloid formation at the nucleation stage can greatly advance early diagnoses and treatment of diseases. In this work, we developed a new assay for the early detection of amylin fibrillation using the biarsenical dye 4,5-bis(1,3,2-dithiarsolan-2-yl)fluorescein (FlAsH), which could recognise tetracysteine motifs and transform from non-fluor ...[more]

PMID: 28602190

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Project description:Importance:Several types of cancer have been linked to a higher risk of developing atrial fibrillation (AF). Fewer data exist regarding early-stage breast cancer (EBC), for which cardio-oncology concerns are more pertinent. Objective:To investigate the association of EBC and subsequent chemotherapy with the risk of developing AF. Design, Setting, and Participants:This was a population-based, retrospective, matched cohort study conducted in Toronto, Ontario, Canada, of 68 113 women diagnosed with EBC between April 2007 and December 2016 who were matched 1:3 to a cancer-free control group based on birth year and receipt of breast imaging. Prevalence of AF before the index date (date of EBC diagnosis) was compared between the cohorts using the McNemar test. Cumulative incidence function curves were used to describe the AF incidence. To study preexisting AF, participants were matched before exclusion for prior AF. For the remaining analyses, we excluded women with prior AF before matching. An analysis was conducted beginning 1 year after the index date (ie, excluding AF diagnoses in year 1), which we stratified by chemotherapy exposure. Multivariable cause-specific regression was used to determine the hazard ratio (HR) associated with EBC relative to the controls and the association of chemotherapy with AF in patients with EBC. Exposures:Breast cancer and chemotherapy. Main Outcomes and Measures:Incidence of AF. Results:A total of 68?113 women with EBC and 204?330 cancer-free controls were included in the study; both groups had a mean (SD) age of 60 (13) years. Of the women with EBC, 44.3% were diagnosed as having stage I breast cancer; 38.7%, stage II; and 13.4%, stage III; cancer stage information was missing for 3.6% of the patients. No difference was observed in preexisting AF prevalence (5.3% in the EBC cohort vs 5.2% in controls; P?=?.21). At 10 years after the index date, the AF incidence was 7.4% (95% CI, 7.1%-7.7%) for women with EBC and 6.8% (95% CI, 6.7%-7.0%) for the controls (P?<?.001). The adjusted cause-specific HR was significantly elevated at year 1 (HR, 2.16; 95% CI, 1.94-2.41) and after year 5 (HR, 1.20; 95% CI, 1.11-1.30) but not during years 2 through 5. Analyses beginning 1 year after diagnosis showed attenuated differences that remained statistically significant: the cumulative incidence of AF at 9-year follow-up was 7.0% (95% CI, 6.7%-7.3%) for patients with EBC and 6.5% (95% CI, 6.3%-6.7%) for the cancer-free controls. The rate of AF was higher in women who received chemotherapy (adjusted HR, 1.23; 95% CI, 1.13-1.35) but was not associated with exposure to anthracyclines or trastuzumab. Conclusions and Relevance:This study's findings suggest that patients with EBC may not have a higher prevalence of AF before cancer diagnosis. A higher rate of AF was observed in the first year and after 5 years following the EBC diagnosis. The rate of AF was higher in patients who received chemotherapy but appeared to not be associated with specific cardiotoxic agents. These findings suggest that the early and late periods of increased AF risk in EBC survivors warrant focused research to better understand the underlying causes and subsequent implications.

Dataset Information

Probing amylin fibrillation at an early stage via a tetracysteine-recognising fluorophore.

Publications

Probing amylin fibrillation at an early stage via a tetracysteine-recognising fluorophore.

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