26 research outputs found
Frontiers in Precision Medicine II: Cancer, Big Data and the Public
Precision medicine is being developed within a complex landscape of public policy, science, economics, law, and regulation. In these and other policy areas, the goal of developing individually-tailored therapies poses novel challenges for health care research, delivery and policy. In this symposium, a range of experts in genetics, medicine, bioinformatics, intellectual property, health economics and bioethics identified and discussed many of the pressing questions raised by the development and practice of precision medicine. These and other issues will need to be taken into account as precision medicine moves ahead and becomes the standard of medical practice and care in the United States and around the world
Pan-cancer analysis reveals recurrent BCAR4 gene fusions across solid tumors
UNLABELLED: Chromosomal rearrangements often result in active regulatory regions juxtaposed upstream of an oncogene to generate an expressed gene fusion. Repeated activation of a common downstream partner-with differing upstream regions across a patient cohort-suggests a conserved oncogenic role. Analysis of 9,638 patients across 32 solid tumor types revealed an annotated long noncoding RNA (lncRNA), Breast Cancer Anti-Estrogen Resistance 4 (BCAR4), was the most prevalent, uncharacterized, downstream gene fusion partner occurring in 11 cancers. Its oncogenic role was confirmed using multiple cell lines with endogenous BCAR4 gene fusions. Furthermore, overexpressing clinically prevalent BCAR4 gene fusions in untransformed cell lines was sufficient to induce an oncogenic phenotype. We show that the minimum common region to all gene fusions harbors an open reading frame that is necessary to drive proliferation.
IMPLICATIONS: BCAR4 gene fusions represent an underappreciated class of gene fusions that may have biological and clinical implications across solid tumors
Germline Mutations in NFKB2 Implicate the Noncanonical NF-κB Pathway in the Pathogenesis of Common Variable Immunodeficiency
Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by antibody deficiency, poor humoral response to antigens, and recurrent infections. To investigate the molecular cause of CVID, we carried out exome sequence analysis of a family diagnosed with CVID and identified a heterozygous frameshift mutation, c.2564delA (p.Lys855Serfs∗7), in NFKB2 affecting the C terminus of NF-κB2 (also known as p100/p52 or p100/p49). Subsequent screening of NFKB2 in 33 unrelated CVID-affected individuals uncovered a second heterozygous nonsense mutation, c.2557C>T (p.Arg853∗), in one simplex case. Affected individuals in both families presented with an unusual combination of childhood-onset hypogammaglobulinemia with recurrent infections, autoimmune features, and adrenal insufficiency. NF-κB2 is the principal protein involved in the noncanonical NF-κB pathway, is evolutionarily conserved, and functions in peripheral lymphoid organ development, B cell development, and antibody production. In addition, Nfkb2 mouse models demonstrate a CVID-like phenotype with hypogammaglobulinemia and poor humoral response to antigens. Immunoblot analysis and immunofluorescence microscopy of transformed B cells from affected individuals show that the NFKB2 mutations affect phosphorylation and proteasomal processing of p100 and, ultimately, p52 nuclear translocation. These findings describe germline mutations in NFKB2 and establish the noncanonical NF-κB signaling pathway as a genetic etiology for this primary immunodeficiency syndrome
Performance of a proteomic preterm delivery predictor in a large independent prospective cohort
Background
Preterm birth remains a common and devastating complication of pregnancy. There remains a need for effective and accurate screening methods for preterm birth. Using a proteomic approach, we previously discovered and validated (Proteomic Assessment of Preterm Risk study, NCT01371019) a preterm birth predictor comprising a ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin.
Objective
To determine the performance of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin to predict both spontaneous and medically indicated very preterm births, in an independent cohort distinct from the one in which it was developed.
Study Design
This was a prospective observational study (Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor, NCT02787213) at 18 sites in the United States. Women had blood drawn at 170/7 to 216/7 weeks’ gestation. For confirmation, we planned to analyze a randomly selected subgroup of women having blood drawn between 191/7 and 206/7 weeks’ gestation, with the results of the remaining study participants blinded for future validation studies. Serum from participants was analyzed by mass spectrometry. Neonatal morbidity and mortality were analyzed using a composite score by a method from the PREGNANT trial (NCT00615550, Hassan et al). Scores of 0–3 reflect increasing numbers of morbidities or length of neonatal intensive care unit stay, and 4 represents perinatal mortality.
Results
A total of 5011 women were enrolled, with 847 included in this planned substudy analysis. There were 9 preterm birth cases at <320/7 weeks’ gestation and 838 noncases at ≥320/7 weeks’ gestation; 21 of 847 infants had neonatal composite morbidity and mortality index scores of ≥3, and 4 of 21 had a score of 4. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was substantially higher in both preterm births at <320/7 weeks’ gestation and there were more severe neonatal outcomes. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was significantly predictive of birth at <320/7 weeks’ gestation (area under the receiver operating characteristic curve, 0.71; 95% confidence interval, 0.55–0.87; P=.016). Stratification by body mass index, optimized in the previous validation study (22<body mass index≤37 kg/m2), resulted in an area under the receiver operating characteristic curve of 0.76 (95% confidence interval, 0.59–0.93; P=.023). The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio predicted neonatal outcomes with respective area under the receiver operating characteristic curve of 0.67 (95% confidence interval, 0.57–0.77; P=.005) and 0.78 (95% confidence interval, 0.63–0.93; P=.026) for neonatal composite morbidity and mortality scores of ≥3 or 4. In addition, the ratio of insulin-like growth factor-binding protein 4 to sex hormone binding globulin significantly stratified neonates with increased length of hospital stay (log rank P=.023).
Conclusion
We confirmed in an independent cohort the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio as a predictor of very preterm birth, with additional prediction of increased length of neonatal hospital stay and increased severity of adverse neonatal outcomes. Potential uses of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin predictor may be to risk stratify patients for implementation of preterm birth preventive strategies and direct patients to appropriate levels of care
PhD
dissertationMitochondrial morphology maintenance is a highly dynamic process regulated by multiple different pathways. The two main pathways that regulate dynamics are fission and fusion. In this thesis, I describe studies designed to further our understanding of both pathways. Fission requires the coordinated interaction of three proteins, Fis1p, Mdv1p, and Dnm1p. Fis1p is a tail-anchored, outer mitochondrial membrane protein. Mdv1p and Dnm1p are soluble, cytoplasmic proteins. The mechanism by which these three molecules assemble on the outer mitochondrial membrane to stimulate fission remains unclear even though multiple models have been proposed. In this thesis, I show that Fis1p and Mdv1p interact directly and it is this interaction that forms a platform for Dnm1p assembly into higher-ordered structures to stimulate fission. Related experiments also describe the molecular details of the Fis1p-Mdv1p interaction at an unprecedented resolution. In addition, I describe preliminary experiments required for future structural and biochemical studies to further define the interactions of the fission complex. Taken together, these studies have revised and refined existing models of mitochondrial fission. The mitochondrial fusion pathway also requires three proteins, Fzo1p, Mgm1p, and Ugo1p. Fzo1p and Mgm1p are both GTPases, with Fzo1p embedded in the outer mitochondrial membrane and Mgm1p found in the intermembrane space. Ugo1p is an integral, outer membrane protein with a large domain facing the cytoplasm and a slightly smaller domain localized to the intermembrane space. These three molecules form a complex, but at this point, little is known about the role that each protein plays in fusion. In this thesis I explore the role of Ugo1p in fusion. In addition to the transmembrane domain, the 502 amino acid Ugo1 protein contains only two recognizable motifs. These small motifs are characteristic of mitochondrial carrier domains found in mitochondrial carrier proteins. In this thesis, I test whether these putative carrier domains (PCDs) are required for Ugo1p function and find that while one of them is dispensable, the second one is required for efficient fusion. In addition, this thesis describes studies that begin to uncover the mechanism of Ugo1p targeting to the mitochondrial outer membrane. These studies show that the transmembrane domain of Ugo1p is not required for targeting, but that a 50 amino acid region at the C-terminus of the protein can be targeted efficiently to mitochondria
Frontiers in Precision Medicine II: Cancer, Big Data and the Public
Precision medicine is being developed within a complex landscape of public policy, science, economics, law, and regulation. In these and other policy areas, the goal of developing individually-tailored therapies poses novel challenges for health care research, delivery and policy. In this symposium, a range of experts in genetics, medicine, bioinformatics, intellectual property, health economics and bioethics identified and discussed many of the pressing questions raised by the development and practice of precision medicine. These and other issues will need to be taken into account as precision medicine moves ahead and becomes the standard of medical practice and care in the United States and around the world