Performance of a cell-free DNA prenatal screening test, choice of prenatal procedure, and chromosome conditions identified during pregnancy after low-risk cell-free DNA screening.

OBJECTIVES: To evaluate the performance of cell-free DNA (cfDNA) screening for common fetal aneuploidies, choice of prenatal procedure, and chromosome conditions identified during pregnancy after low-risk cfDNA screening. METHOD: A single-center prenatal cfDNA screening test was employed to detect trisomies 21, 18, and 13 (T21, T18, T13) and sex chromosome aneuploidies (SCAs). Test performance, choice of prenatal procedure, and cytogenetic results in pregnancies with low-risk cfDNA screening were reviewed. RESULTS: CfDNA screening of 38,289 consecutive samples identified 720 (1.9%) pregnancies at increased risk for aneuploidy. Positive predictive values (PPVs) for high-risk singleton pregnancies were 98.5% (T21), 92.5% (T18) and 55.2% (T13). PPVs for SCAs ranged from 30.6% to 95.2%. Most women elected chorionic villus sampling for prenatal diagnosis of T21, T18 and T13; amniocentesis and/or postnatal testing were commonly chosen for SCAs. Cytogenetic tests from 616 screen-negative pregnancies identified 64 cases (12.7%) with chromosome conditions not detected by cfDNA screening, including triploidy (n = 30) and pathogenic and likely pathogenic copy number variants (n = 34). A further 15 (0.04%) false-negative common aneuploidy results were identified. CONCLUSIONS: CfDNA screening was highly accurate for detecting fetal aneuploidy in this general-risk obstetric population. Fetal ultrasound and prenatal diagnostic testing were important in identifying chromosome conditions in pregnancies screened as low-risk.

Cell biology, regulation and inhibition of beta-secretase (BACE-1).

Since the discovery of the beta-secretase responsible for initiating the Alzheimer's amyloid cascade as a novel membrane-bound aspartic proteinase, termed 'beta-site amyloid precursor protein cleaving enzyme', 'aspartyl protease-2' or 'membrane-anchored aspartic proteinase of the pepsin family-2', huge efforts have been devoted to an understanding of its biology and structure in the subsequent decade. This has paid off in many respects, as it has been cloned, its structure solved, novel physiological substrates of the enzyme discovered, and numerous inhibitors of its activity developed in a relatively short space of time. The inhibition of beta-secretase activity in vivo remains one of the most viable strategies for the treatment of Alzheimer's disease, although progress in getting inhibitors to the clinic has been slow, partly as a consequence of its aspartic proteinase character, which poses considerable problems for the production of potent, selective and brain-accessible compounds. This review reflects on the development of beta-secretase biology and chemistry to date, highlighting the diverse and innovative strategies applied to the modulation of its activity at the molecular and cellular levels.