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Emmi Helle Aldo Córdova-Palomera Tiina Ojala Priyanka Saha Praneetha Potiny Stefan Gustafsson Erik Ingelsson Michael Bamshad Deborah Nickerson Jessica X. Chong University of Washington Center for Mendelian Genomics Euan Ashley James R. Priest 《Genetic epidemiology》2019,43(2):215-226
Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes. 相似文献
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The antiproliferative, cytotoxic and apoptogenic activities of Bufo melanostictus (Indian common toad) skin extract (TSE) on U937 and K562 leukemic cell line has been investigated. TSE significantly (P<0.001) reduced the time-dependent cell proliferation and decreased MTT values in U937 and K562 cells. TSE (IC50 doses) suppressed the proliferating cell nuclear antigen expression in both the cells. It was demonstrated that, TSE (IC50 doses) primarily arrested the U937 and K562 cells at G1 phase of the cell cycle. Confocal microscopy showed the altered fragmented nuclei and apoptotic bodies formation in TSE (IC50 doses) treated U937 and K562 cells. Membrane blebbing, cell surface shrinkage and perforation were observed through scanning electron microscope. TSE-induced DNA fragmentation in U937 and K562 cells was reflected in single-cell gel electrophoresis. TSE significantly (P<0.001) increase the length-width ratio of DNA mass as compared to control in comet assay. The flow cytometric analysis of annexin-V binding to the cancer cells further supported the apoptotogenic activity of TSE. The effect of TSE on normal human peripheral blood mononuclear cells viability and cytotoxicity was studied in culture and found to be less cytotoxic than on the U937 and K562 cells. The findings from the present study suggested that TSE might possess potent antineoplastic agent having antiproliferative, cytotoxic and apoptogenic activity against U937 and K562 myeloid leukemic cells. 相似文献
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A case of Ewing's tumour of rib presenting as chest mass is reported. The role of computed tomography and chest ultrasound in evaluating such patients is discussed along with a brief review of literature. 相似文献
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V Saha S Love T Eden P Micallef-Eynaud G MacKinlay 《Archives of disease in childhood》1993,68(6):771-774
The duration of symptoms before diagnosis (lag time) was defined for 184 of 236 children diagnosed as having a malignancy at the Royal Hospital for Sick Children, Edinburgh for the time period January 1982 until December 1990. The natural logarithm of the lag time was correlated with age, gender, diagnostic group, white cell count in acute leukaemia, clinical stage of disease in solid tumours, and event free survival. Age was significantly associated with lag time, older children presenting later. In the diagnostic groups, mean lag time ranged from 2.8 weeks in nephroblastoma to 13.3 weeks for brain tumours. Diagnostic group was predictive for lag time after adjustment for age, with for example, a significantly longer lag time for those with brain tumours. However lag time was not predictive of event free survival and it is likely that lag time has other major determinants. When compared with previous studies, there also appears to be a regional variation in lag time for diagnostic groups. It seems likely that this is a reflection of geographical difference in the structure of health systems and is therefore yet another important determinant. 相似文献
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The influence of food on the pharmacokinetics of ''biphasic'' nifedipine at steady state in normal subjects.
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G H Rimoy J R Idle N K Bhaskar P C Rubin 《British journal of clinical pharmacology》1989,28(5):612-615
Previous studies following single dose administration have suggested that the pharmacokinetics of various nifedipine formulations could be influenced by the timing of associated food consumption. In order more closely to reflect the clinical situation we have carried out a study at steady state using a 'biphasic' formulation comprising 'rapid' and 'retarded' drug release components. Fifteen normal subjects took 20 mg 'biphasic' nifedipine 12 hourly for 10 days. Studies were carried out on days 4, 7 and 10. On these days the nifedipine was taken 2 h or 1 h before or immediately following a light breakfast. A light breakfast influenced neither the rate nor the extent of nifedipine absorption nor the rate or extent of major metabolite appearance. We conclude that at steady state the timing of a light meal is unlikely to alter in any clinically important manner the pharmacokinetics of nifedipine released from 'biphasic' tablets. 相似文献
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