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  • Colon cancer, Screening (oncology), Epidemiology  (1)
  • Heart Failure  (1)
  • JCP Education  (1)
  • BMJ Publishing Group  (2)
  • American Heart Association (AHA)  (1)
Document type
Publisher
  • BMJ Publishing Group  (2)
  • American Heart Association (AHA)  (1)
Years
  • 1
    Publication Date: 2016-04-26
    Description: Background— The clinical use of doxorubicin is limited by cardiotoxicity. Histopathological changes include interstitial myocardial fibrosis and the appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. Methods and Results— Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity resulting from haploinsufficiency for Beclin 1 . Beclin 1 +/– mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals overexpressing Beclin 1 manifested an amplified cardiotoxic response. Conclusions— Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity.
    Keywords: Heart Failure
    Electronic ISSN: 1524-4539
    Topics: Medicine
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  • 2
    Publication Date: 2014-11-18
    Description: Background and aims Lynch syndrome (LS) patients have DNA mismatch repair deficiency and up to 80% lifetime risk of colorectal cancer (CRC). Screening of mutation carriers reduces CRC incidence and mortality. Selection for constitutional mutation testing relies on family history (Amsterdam and Bethesda Guidelines) and tumour-derived biomarkers. Initial biomarker analysis uses mismatch repair protein immunohistochemistry and microsatellite instability. Abnormalities in either identify mismatch repair deficiency but do not differentiate sporadic epigenetic defects, due to MLH1 promoter region methylation (13% of CRCs) from LS (4% of CRCs). A diagnostic biomarker capable of making this distinction would be valuable. This study compared two biomarkers in tumours with mismatch repair deficiency; quantification of methylation of the MLH1 promoter region using a novel assay and BRAF c.1799T〉A, p.(Val600Glu) mutation status in the identification of constitutional mutations. Methods Tumour DNA was extracted (formalin fixed, paraffin embedded, FFPE tissue) and pyrosequencing used to test for MLH1 promoter methylation and presence of the BRAF c.1799T〉A, p.(Val600Glu) mutation 71 CRCs from individuals with pathogenic MLH1 mutations and 73 CRCs with sporadic MLH1 loss. Specificity and sensitivity was compared. Findingss Unmethylated MLH1 promoter: sensitivity 94.4% (95% CI 86.2% to 98.4%), specificity 87.7% (95% CI 77.9% to 94.2%), Wild-type BRAF (codon 600): sensitivity 65.8% (95% CI 53.7% to 76.5%), specificity 98.6% (95% CI 92.4% to 100.0%) for the identification of those with pathogenic MLH1 mutations. Conclusions Quantitative MLH1 promoter region methylation using pyrosequencing is superior to BRAF codon 600 mutation status in identifying constitutional mutations in mismatch repair deficient tumours.
    Keywords: Colon cancer, Screening (oncology), Epidemiology
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 3
    Publication Date: 2014-07-18
    Description: Background In the USA, inpatient phlebotomy services are under constant operational pressure to optimise workflow, improve timeliness of blood draws, and decrease error in the context of increasing patient volume and complexity of work. To date, the principles of Lean continuous process improvement have been rarely applied to inpatient phlebotomy. Aims To optimise supply replenishment and cart standardisation, communication and workload management, blood draw process standardisation, and rounding schedules and assignments using Lean principles in inpatient phlebotomy services. Methods We conducted four Lean process improvement events and implemented a number of interventions in inpatient phlebotomy over a 9-month period. We then assessed their impact using three primary metrics: (1) percentage of phlebotomists drawing their first patient by 05:30 for 05:00 rounds, (2) percentage of phlebotomists completing 08:00 rounds by 09:30, and (3) number of errors per 1000 draws. Results We saw marked increases in the percentage of phlebotomists drawing their first patient by 05:30, and the percentage of phlebotomists completing rounds by 09:30 postprocess improvement. A decrease in the number of errors per 1000 draws was also observed. Conclusions This study illustrates how continuous process improvement through Lean can optimise workflow, improve timeliness, and decrease error in inpatient phlebotomy. We believe this manuscript adds to the field of clinical pathology as it can be used as a guide for other laboratories with similar goals of optimising workflow, improving timeliness, and decreasing error, providing examples of interventions and metrics that can be tailored to specific laboratories with particular services and resources.
    Keywords: JCP Education
    Print ISSN: 0021-9746
    Electronic ISSN: 1472-4146
    Topics: Medicine
    Published by BMJ Publishing Group
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