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  • 1
    Publication Date: 2018-06-02
    Description: Background: Despite age and sex differences in fecal hemoglobin (f-Hb) concentrations, most fecal immunochemical test (FIT) screening programs use population-average cut-points for test positivity. The impact of age/sex-specific threshold on FIT accuracy and colonoscopy demand for colorectal cancer screening are unknown. Methods: Using data from 723,113 participants enrolled in a Taiwanese population-based colorectal cancer screening with single FIT between 2004 and 2009, sensitivity and specificity were estimated for various f-Hb thresholds for test positivity. This included estimates based on a "universal" threshold, receiver-operating-characteristic curve–derived threshold, targeted sensitivity, targeted false-positive rate, and a colonoscopy-capacity-adjusted method integrating colonoscopy workload with and without age/sex adjustments. Results: Optimal age/sex-specific thresholds were found to be equal to or lower than the universal 20 μg Hb/g threshold. For older males, a higher threshold (24 μg Hb/g) was identified using a 5% false-positive rate. Importantly, a nonlinear relationship was observed between sensitivity and colonoscopy workload with workload rising disproportionately to sensitivity at 16 μg Hb/g. At this "colonoscopy-capacity-adjusted" threshold, the test positivity (colonoscopy workload) was 4.67% and sensitivity was 79.5%, compared with a lower 4.0% workload and a lower 78.7% sensitivity using 20 μg Hb/g. When constrained on capacity, age/sex-adjusted estimates were generally lower. However, optimizing age/-sex-adjusted thresholds increased colonoscopy demand across models by 17% or greater compared with a universal threshold. Conclusions: Age/sex-specific thresholds improve FIT accuracy with modest increases in colonoscopy demand. Impact: Colonoscopy-capacity-adjusted and age/sex-specific f-Hb thresholds may be useful in optimizing individual screening programs based on detection accuracy, population characteristics, and clinical capacity. Cancer Epidemiol Biomarkers Prev; 27(6); 704–9. ©2018 AACR .
    Print ISSN: 1055-9965
    Electronic ISSN: 1538-7755
    Topics: Medicine
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  • 2
    Publication Date: 2018-10-18
    Description: High-dimensional single-cell analyses have improved the ability to resolve complex mixtures of cells from human disease samples; however, identifying disease-associated cell types or cell states in patient samples remains challenging because of technical and interindividual variation. Here, we present mixed-effects modeling of associations of single cells (MASC), a reverse single-cell association strategy for testing whether case-control status influences the membership of single cells in any of multiple cellular subsets while accounting for technical confounders and biological variation. Applying MASC to mass cytometry analyses of CD4 + T cells from the blood of rheumatoid arthritis (RA) patients and controls revealed a significantly expanded population of CD4 + T cells, identified as CD27 – HLA-DR + effector memory cells, in RA patients (odds ratio, 1.7; P = 1.1 x 10 –3 ). The frequency of CD27 – HLA-DR + cells was similarly elevated in blood samples from a second RA patient cohort, and CD27 – HLA-DR + cell frequency decreased in RA patients who responded to immunosuppressive therapy. Mass cytometry and flow cytometry analyses indicated that CD27 – HLA-DR + cells were associated with RA (meta-analysis P = 2.3 x 10 –4 ). Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained about fivefold higher frequencies of CD27 – HLA-DR + cells, which comprised ~10% of synovial CD4 + T cells. CD27 – HLA-DR + cells expressed a distinctive effector memory transcriptomic program with T helper 1 (T H 1)– and cytotoxicity-associated features and produced abundant interferon- (IFN-) and granzyme A protein upon stimulation. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single-cell data.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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  • 3
    Publication Date: 2018-05-04
    Description: Objectives We aimed to determine the association between fasting insulin (FI) levels and metabolic syndrome (MetS) in non-diabetic middle-aged and elderly adults in a community in Taiwan. Design Cross-sectional observational study. Setting Community-based investigation in Guishan township of northern Taiwan. Participants Our study included adults aged 50 years and above during community health examinations between January and October 2014. People with diabetes mellitus were excluded. A total of 321 people were enrolled. Outcome measures We divided participants according to tertiles of FI as low, medium and high levels. Pearson correlation was assessed between insulin level and each of the diagnostic components of metabolic syndrome (MetS-DCs) with adjustment of age. The prevalence of MetS-DCs based on tertiles of FI were studied and analysed by Cochran–Armitage trend test. The risk for prevalence of MetS in the middle and high insulin group as compared with the low insulin group were assessed by multivariate logistic regression with adjustments for age, gender, smoking, body mass index (BMI), hypertension and hyperlipidaemia. Youden Index was performed for the optimised cut-off value. Results Our results showed positive correlation of FI level with systolic blood pressure, waist circumference, fasting plasma glucose and triglyceride levels, while negative correlation was shown with high-density lipoprotein (P〈0.001). The prevalence of each MetS-DCs increased as a trend while FI levels increased (P〈0.001). OR (95% CI) of MetS was 5.04 (2.15 to 11.81) for high insulin groups compared with the low insulin group after adjusting confounders (P〈0.001). Area under receiver operating characteristic curve (ROC) curve (AUC) was 0.78, and cut-off value 7.35 μU/mL for FI was obtained (sensitivity: 0.69; specificity: 0.77). Conclusions Middle-aged and elderly non-diabetic people with increased FI are associated with a higher prevalence of MetS in the community in Taiwan. Furthermore, FI is an independent risk factor of MetS in this study population.
    Keywords: Open access, General practice / Family practice
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 4
    Publication Date: 2018-03-06
    Description: Purpose: MPT0L145 has been developed as a FGFR inhibitor exhibiting significant anti-bladder cancer activity in vitro and in vivo via promoting autophagy-dependent cell death. Here, we aim to elucidate the underlying mechanisms. Experimental Design: Autophagy flux, morphology, and intracellular organelles were evaluated by Western blotting, transmission electron microscope, and fluorescence microscope. Molecular docking and surface plasmon resonance assay were performed to identify drug–protein interaction. Lentiviral delivery of cDNA or shRNA and CRISPR/Cas9-mediated genome editing was used to modulate gene expression. Mitochondrial oxygen consumption rate was measured by a Seahorse XFe24 extracellular flux analyzer, and ROS level was measured by flow cytometry. Results: MPT0L145 persistently increased incomplete autophagy and phase-lucent vacuoles at the perinuclear region, which were identified as enlarged and alkalinized late-endosomes. Screening of a panel of lipid kinases revealed that MPT0L145 strongly inhibits PIK3C3 with a K d value of 0.53 nmol/L. Ectopic expression of PIK3C3 reversed MPT0L145-increased cell death and incomplete autophagy. Four residues (Y670, F684, I760, D761) at the ATP-binding site of PIK3C3 are important for the binding of MPT0L145. In addition, MPT0L145 promotes mitochondrial dysfunction, ROS production, and DNA damage, which may in part, contribute to cell death. ATG5-knockout rescued MPT0L145-induced cell death, suggesting simultaneous induction of autophagy is crucial to its anticancer activity. Finally, our data demonstrated that MPT0L145 is able to overcome cisplatin resistance in bladder cancer cells. Conclusions: MPT0L145 is a first-in-class PIK3C3/FGFR inhibitor, providing an innovative strategy to design new compounds that increase autophagy, but simultaneously perturb its process to promote bladder cancer cell death. Clin Cancer Res; 24(5); 1176–89. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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