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Fulltext Furo[3,2-c]coumarin-derived Fe3+ Selective Fluorescence Sensor: Synthesis, Fluorescence Study and Application to Water Analysis

Sarih NM, Ciupa A, Moss S, Myers P, Slater AG, Abdullah Z, et al.

Sci Rep, 2020 May 04;10(1):7421.
PMID: 32366859 DOI: 10.1038/s41598-020-63262-7

Furocoumarin (furo[3,2-c]coumarin) derivatives have been synthesized from single step, high yielding (82-92%) chemistry involving a 4-hydroxycoumarin 4 + 1 cycloaddition reaction. They are characterized by FTIR, 1H-NMR, and, for the first time, a comprehensive UV-Vis and fluorescence spectroscopy study has been carried out to determine if these compounds can serve as useful sensors. Based on the fluorescence data, the most promising furocoumarin derivative (2-(cyclohexylamino)-3-phenyl-4H-furo[3,2-c]chromen-4-one, FH), exhibits strong fluorescence (ФF = 0.48) with long fluorescence lifetime (5.6 ns) and large Stokes' shift, suggesting FH could be used as a novel fluorescent chemosensor. FH exhibits a highly selective, sensitive and instant turn-off fluorescence response to Fe3+ over other metal ions which was attributed to a charge transfer mechanism. Selectivity was demonstrated against 13 other competing metal ions (Na+, K+, Mg2+, Ca2+, Mn2+, Fe2+, Al3+, Ni2+, Cu2+, Zn2+, Co2+, Pb2+ and Ru3+) and aqueous compatibility was demonstrated in 10% MeOH-H2O solution. The FH sensor coordinates Fe3+ in a 1:2 stoichiometry with a binding constant, Ka = 5.25 × 103 M-1. This novel sensor has a limit of detection of 1.93 µM, below that of the US environmental protection agency guidelines (5.37 µM), with a linear dynamic range of ~28 (~2-30 µM) and an R2 value of 0.9975. As an exemplar application we demonstrate the potential of this sensor for the rapid measurement of Fe3+ in mineral and tap water samples demonstrating the real-world application of FH as a "turn off" fluorescence sensor.
Mammographic density assessed on paired raw and processed digital images and on paired screen-film and digital images across three mammography systems

Burton A, Byrnes G, Stone J, Tamimi RM, Heine J, Vachon C, et al.

Breast Cancer Res, 2016 12 19;18(1):130.
PMID: 27993168

BACKGROUND: Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types.
METHODS: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences.
RESULTS: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm2 respectively, mean √dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in √dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader-specific differences varied in magnitude and direction (p
Fulltext International Consortium on Mammographic Density: Methodology and population diversity captured across 22 countries

McCormack VA, Burton A, dos-Santos-Silva I, Hipwell JH, Dickens C, Salem D, et al.

Cancer Epidemiol, 2016 Feb;40:141-51.
PMID: 26724463 DOI: 10.1016/j.canep.2015.11.015

Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses.
Fulltext Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide

Burton A, Maskarinec G, Perez-Gomez B, Vachon C, Miao H, Lajous M, et al.

PLoS Med, 2017 Jun;14(6):e1002335.
PMID: 28666001 DOI: 10.1371/journal.pmed.1002335

BACKGROUND: Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known.
METHODS AND FINDINGS: We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35-85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (-0.46 cm [95% CI: -0.53, -0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was -0.24 cm (95% CI: -0.34, -0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (-0.38 cm [95% CI: -0.44, -0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature.
CONCLUSIONS: Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.
Fulltext Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Mikropoulos C, Selkirk CGH, Saya S, Bancroft E, Vertosick E, Dadaev T, et al.

Br J Cancer, 2018 Jan;118(2):266-276.
PMID: 29301143 DOI: 10.1038/bjc.2017.429

BACKGROUND: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort.
METHODS: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV.
RESULTS: 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml-l, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers.
CONCLUSIONS: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.
Fulltext Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study

Bancroft EK, Page EC, Castro E, Lilja H, Vickers A, Sjoberg D, et al.

Eur Urol, 2014 Sep;66(3):489-99.
PMID: 24484606 DOI: 10.1016/j.eururo.2014.01.003

BACKGROUND: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations.
OBJECTIVE: To report the first year's screening results for all men at enrollment in the study.
DESIGN, SETTING AND PARTICIPANTS: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng/ml were offered prostate biopsy.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types.
RESULTS AND LIMITATIONS: We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups.
CONCLUSIONS: The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease.
PATIENT SUMMARY: In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.