Citations

Background.Noninvasive prenatal screening (NIPS) is revolutionizing prenatal screening as a result of its increased sensitivity, specificity. NIPS analyzes cell-free fetal DNA (cffDNA) circulating in maternal plasma to detect fetal chromosome abnormalities. However, cffDNA originates from apoptotic placental trophoblast; therefore cffDNA is not always representative of the fetus. Although the published data for NIPS testing states that the current technique ensures high sensitivity and specificity for aneuploidy detection, false positives are possible due to isolated placental mosaicism, vanishing twin or cotwin demise, and maternal chromosome abnormalities or malignancy.Results.We report a case of false negative cell-free DNA (cfDNA) screening due to fetoplacental mosaicism. An infant male with negative cfDNA screening result was born with multiple congenital abnormalities. Postnatal chromosome and FISH studies on a blood specimen revealed trisomy 13 in 20/20 metaphases and 100% interphase nuclei, respectively. FISH analysis on tissues collected after delivery revealed extraembryonic mosaicism.Conclusions.Extraembryonic tissue mosaicism is likely responsible for the false negative cfDNA screening result. This case illustrates that a negative result does not rule out the possibility of a fetus affected with a trisomy, as cffDNA is derived from the placenta and therefore may not accurately represent the fetal genetic information.

Animal models have played a critical role in validating human dilated cardiomyopathy (DCM) genes, particularly those that implicate novel mechanisms for heart failure. However, the disease phenotype may be delayed due to age-dependent penetrance. For this reason, we generated an adult zebrafish model, which is a simpler vertebrate model with higher throughput than rodents. Specifically, we studied the zebrafish homologue of GATAD1, a recently identified gene for adult-onset autosomal recessive DCM. We showed cardiac expression of gatad1 transcripts, by whole mount in situ hybridization in zebrafish embryos, and demonstrated nuclear and sarcomeric I-band subcellular localization of Gatad1 protein in cardiomyocytes, by injecting a Tol2 plasmid encoding fluorescently-tagged Gatad1. We next generated gatad1 knock-out fish lines by TALEN technology and a transgenic fish line that expresses the human DCM GATAD1-S102P mutation in cardiomyocytes. Under stress conditions, longitudinal studies uncovered heart failure (HF)-like phenotypes in stable KO mutants and a tendency toward HF phenotypes in transgenic lines. Based on these efforts of studying a gene-based inherited cardiomyopathy model, we discuss the strengths and bottlenecks of adult zebrafish as a new vertebrate model for assessing candidate cardiomyopathy genes.

In the United States alone, there are currently approximately 14.5 million cancer survivors, and this number is expected to increase to 20 million by 2020. Cancer therapies can cause significant injury to the vasculature, resulting in angina, acute coronary syndromes (ACS), stroke, critical limb ischemia, arrhythmias, and heart failure, independently from the direct myocardial or pericardial damage from the malignancy itself. Consequently, the need for invasive evaluation and management in the cardiac catheterization laboratory (CCL) for such patients has been increasing. In recognition of the need for a document on special considerations for cancer patients in the CCL, the Society for Cardiovascular Angiography and Interventions (SCAI) commissioned a consensus group to provide recommendations based on the published medical literature and on the expertise of operators with accumulated experience in the cardiac catheterization of cancer patients. © 2016 Wiley Periodicals, Inc.

Abstract Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). Methods: The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E−6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E−6; Pcorrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. Impact: This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446–54. ©2016 AACR.

Abstract BACKGROUND Revascularization of a stenotic renal artery improves kidney function only in select patients with renovascular hypertension (HT) secondary to atherosclerosis. However, the effects of reversal of renovascular HT (RRHT) on the nonstenotic kidney are unclear. We hypothesized that concurrent hypercholesterolemia (HC) attenuates nonstenotic kidney recovery. METHODS Female domestic pigs were randomized as Normal, renovascular HT, HT+RRHT, HTC (renovascular HT and HC), and HTC+RHT ( n = 7 each). RRHT or sham was performed after 6 weeks of HT. Nonstenotic renal blood flow, glomerular filtration rate, and injurious pathways were studied 4 weeks later. RESULTS Mean arterial pressure increased similarly in HT and HTC and decreased after RRHT. Oxidative stress increased in HT and HTC kidneys, and decreased in HT+RRHT, but remained elevated in HTC+RRHT. Renal interstitial fibrosis, glomerulosclerosis, and tubular injury were all attenuated in HT+RRHT, but not HTC+RRHT. Endothelin-1 signaling and PGF2α isoprostane levels were elevated in both HTC and HTC+RRHT pigs. CONCLUSIONS RRHT reverses nonstenotic kidney injury in experimental renovascular HT, but concurrent HC blunts regression of kidney injury, possibly due to predominant vasoconstrictors and oxidative stress. These findings reinforce the contribution of the nonstenotic kidney and of prevailing cardiovascular risk factors to irreversibility of kidney dysfunction after revascularization.

In the United States alone, there are currently approximately 14.5 million cancer survivors, and this number is expected to increase to 20 million by 2020. Cancer therapies can cause significant injury to the vasculature, resulting in angina, acute coronary syndromes (ACS), stroke, critical limb ischemia, arrhythmias, and heart failure, independently from the direct myocardial or pericardial damage from the malignancy itself. Consequently, the need for invasive evaluation and management in the cardiac catheterization laboratory (CCL) for such patients has been increasing. In recognition of the need for a document on special considerations for cancer patients in the CCL, the Society for Cardiovascular Angiography and Interventions (SCAI) commissioned a consensus group to provide recommendations based on the published medical literature and on the expertise of operators with accumulated experience in the cardiac catheterization of cancer patients. © 2015 Wiley Periodicals, Inc.