Nancy Dower - Profile on Academia.edu (original) (raw)

Papers by Nancy Dower

BAY 81‐8973 safety and efficacy for prophylaxis and treatment of bleeds in previously treated children with severe haemophilia A: results of the LEOPOLD Kids Trial

Haemophilia, 2015

BAY 81‐8973, a full‐length, unmodified, recombinant factor VIII (FVIII) in development for treatm... more BAY 81‐8973, a full‐length, unmodified, recombinant factor VIII (FVIII) in development for treatment of haemophilia A, has the same primary amino acid sequence as Bayer's sucrose‐formulated recombinant FVIII but is produced with more advanced manufacturing technologies.

Pattern of Mucosal Tumor Necrosis Factor- Expression in Segmental Colitis Associated with Diverticula Suggests a Truly Autonomous Clinical Entity

1. Yoshida EM, Chaun H, Freeman HJ, et al. Immune thrombocytopenic purpura in three patients with... more 1. Yoshida EM, Chaun H, Freeman HJ, et al. Immune thrombocytopenic purpura in three patients with preexisting ulcerative colitis. Am J Gastroenterol. 1996;91:1232–1235. 2. Zlatanic J, Korelitz BI, Wisch N, et al. Inflammatory bowel disease and immune thrombocytopenic purpura: is there a correlation? Am J Gastroenterol. 1997;92:2285–2288. 3. HisadaT, Miyamae Y, Mizuide M, et al. Acute thrombocytopenia associated with preexisting ulcerative colitis successfully treated with colectomy. Intern Med. 2006;45:87–91. 4. Bauer W, Litchtin A, Lashner B. Can colectomy cure immune thrombocytopenic purpura in a patient with ulcerative colitis? Dig Dis Sci. 1999;44:2330–2333. 5. Higuchi L, Joffe S, Neufeld E, et al. Inflammatory bowel disease associated with immune thrombocytopenic purpura in children. J Pediatr Gastroenterol Nutr. 2001;33:582–587. 6. Brussel J. Autoimmune thrombocytopenic purpura. Hematol Oncol Clin North Am. 1990;4: 179–191. Pattern of Mucosal Tumor Necrosis FactorExpression in...

Liver Transplantation for Prothrombin Deficiency Causing Life-Threatening Bleeds

Blood

We report here the first case of living-related liver transplantation to correct a severe bleedin... more We report here the first case of living-related liver transplantation to correct a severe bleeding diathesis. A Caucasian infant was diagnosed at 11 weeks old with prothrombin deficiency after a spontaneous subdural hemorrhage. Even though he had a Factor II activity level of 0.08, he had severe clinical complications including umbilical bleeding, hemorrhagic shock after circumcision and bleeding per rectum. Prophylactic treatment with prothrombin complex concentrate prevented further bleeding episodes. Unfortunately, he developed clots of the superior vena cava and of the inferior vena cava in the context of central venous catheters. On-demand therapy via peripheral IV was followed for almost a year. He then had severe subdural and intraparenchymal hemorrhages. His clinical course did not correlate with measured Factor II activity. Investigations looking for other coagulation disorders were negative. He underwent a living-related liver transplant from his father in order to correct...

Outcome and Clinical Characteristics of Clonal and Malignant Myeloid Transformation in Inherited Bone Marrow Failure Syndromes

Blood

1266 Introduction: Inherited bone marrow failure syndromes (IBMFSs) are a group of rare, genetic ... more 1266 Introduction: Inherited bone marrow failure syndromes (IBMFSs) are a group of rare, genetic disorders with a risk of clonal and malignant myeloid transformation including clonal marrow cytogenetic abnormalities, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The clinical characteristics and outcome of IBMFS-related clonal and malignant myeloid transformation are unclear, particularly in cases of early transformation such as isolated clonal marrow cytogenetic abnormalities. Objectives: The aims of this study were to determine the risk and clinical outcome of IBMFS-related clonal and malignant myeloid transformation using data from the Canadian Inherited Marrow Failure Registry (CIMFR). Methods: The CIMFR is a multicenter collaborative study which is intended to enroll all patients with IBMFSs in Canada. The registry was approved by the Institutional Ethics Board of all the participating institutions, and includes 15 of 16 pediatric tertiary care centers across ...

RasGRP is essential for mouse thymocyte differentiation and TCR signaling

Nature Immunology

The Ras signaling pathway plays a critical role in thymopoiesis and T cell activation, but the me... more The Ras signaling pathway plays a critical role in thymopoiesis and T cell activation, but the mechanism of Ras regulation is controversial. At least one mode of Ras regulation in T cells involves the messenger diacylglycerol (DAG). RasGRP, a Ras activator with a DAG-binding C1 ...

Chi

Cold Spring Harbor Symposia on Quantitative Biology

Genetics

Chi, an element that stimulates recombination via the E. coli RecBC pathway, can arise by spontan... more Chi, an element that stimulates recombination via the E. coli RecBC pathway, can arise by spontaneous mutation in the transposon Tn5. When in phage A in one orientation, the mutant transposon confers Chi+ phenotype (large plaque and a high rate of exchange near the transposon). In the other orientation, however, the transposon does not confer Chi+ phenotype. The mobility of the transposon allosws us to show that the Chi+ orientation of the mutant Tn5 is the same at different locations in A. These include a site near gene J , one in gam at 69, one to the right of gum at 73 and several to the right of R between 95.7 and 99.5. To the right of R, the mutant transposon could be found in only one orientation, that which confers Chi+ phenotype. W e speculate that the other orientation of Tn5 in that locale is lethal to A. The orientationdependence of Chi+ phenotype also revealed that Tn5 flip-flops in 1. is a genetic elemefit that confers upon phage h a high rate of Rec-mediated C: change in its neighborhood (STAHL, CRASEMANN and STAHL 1975). Chi promotes recombination only via the RecBC pathway (GILLEN and CLARK 1974; STAHL and STAHL 1977), so that Chi has the most conspicuous effect on exchange when h is deficient for its own recombination pathway (Red) and for its RecBCinhibiting function, Gam (STAHL and STAHL 1977). When is Red-and Gamand growing in a rec+ cell, encapsidation is dependent upon Rec-mediated recombination (ENQUIST and SKALKA 1973; STAHL et al. 1972). Thus, the exchange-stimulating effect of Chi is manifested not only as a local increase in the recombination frequency, but also as an increase in burst (MALONE and CHAT-TORAJ 1975) and plaque size (HENDERSON and WEIL 1975). Chi elements arise by mutation at four (or more) places in the h chromosome and occur naturally in the Escherichia coli chromosome. When MALONE et al. (1978) examined EcoRI restriction fragments of E. coli DNA cloned in A, they found that about half of the fragments, of average length 7 kb, conferred a Chi+ phenotype upon h; i.e., when such phages were made Red-Gam-, they made

What Accounts for the Orientation Dependence and Directionality of Chi?

Mechanistic Studies of DNA Replication and Genetic Recombination, 1980

Neuroscience, 2002

Ras signal transduction pathways have been implicated as key regulators in neuroplasticity and sy... more Ras signal transduction pathways have been implicated as key regulators in neuroplasticity and synaptic transmission in the brain. These pathways can be modulated by Ras guanyl nucleotide exchange factors, (GEF) which activate Ras proteins by catalysing the exchange of GDP for GTP. Ras guanyl nucleotide-releasing protein (RasGRP), a recently discovered Ras GEF, that links diacylglycerol and probably calcium to Ras signaling pathways, is expressed in brain as well as in T-cells. Here, we have used a highly selective monoclonal antibody against RasGRP to localize this protein within the striatum and related forebrain structures of developing and adult rats. RasGRP immunolabeling was found to be widespread in the mature and developing rat forebrain. Most notably, it presented a prominent patchy distribution throughout the striatum at birth and at all postnatal ages examined. These patches were found to correspond with the striosomal compartment of the striatum, as identified by micro-o...

Neuroscience, 2001

Ras guanyl nucleotide-releasing protein (RasGRP) is a recently discovered Ras guanyl nucleotide e... more Ras guanyl nucleotide-releasing protein (RasGRP) is a recently discovered Ras guanyl nucleotide exchange factor that is expressed in selected regions of the rodent CNS, with high levels of expression in the hippocampus. Biochemical studies suggest that RasGRP can activate the Ras signal pathway in response to changes in diacylglycerol and possibly calcium. To investigate potential sites for RasGRP signaling, we have determined the cellular and subcellular localization of RasGRP protein in adult rat hippocampus, and have also examined the appearance of RasGRP mRNA and protein during hippocampal development. RasGRP immunoreactivity is predominately localized to those neurons participating in the direct cortico-hippocampo-cortical loop. In both hippocampal and entorhinal neurons, RasGRP protein appeared to be localized to both dendrites and somata, but not to axons. Electron microscopy of hippocampal pyramidal cells confirmed RasGRP immunoreactivity in neuronal cell bodies and dendrite...

Genetics, 1980

Genetics, 1986

The gol-1, gol-2, alb-1 and spa-1 mutations affect pigment pattern in the zebrafish. We show here... more The gol-1, gol-2, alb-1 and spa-1 mutations affect pigment pattern in the zebrafish. We show here that these loci are unlinked to each other. In addition, gene-centromere distances were determined for these loci by analysis of half-tetrads obtained by the inhibition of the second meiotic division. The fractions of tetratype (second-division segregation) tetrads range from 0.24 (spa-1) to 0.89 (gol-1). The observation of greater than 0.67 second-division segregation indicates that the zebrafish has high chiasma interference.

PloS one, 2013

T cell development is a highly dynamic process that is driven by interactions between developing ... more T cell development is a highly dynamic process that is driven by interactions between developing thymocytes and the thymic microenvironment. Upon entering the thymus, the earliest thymic progenitors, called CD4(-)CD8(-) 'double negative' (DN) thymocytes, pass through a checkpoint termed "β-selection" before maturing into CD4(+)CD8(+) 'double positive' (DP) thymocytes. β-selection is an important developmental checkpoint during thymopoiesis where developing DN thymocytes that successfully express the pre-T cell receptor (TCR) undergo extensive proliferation and differentiation towards the DP stage. Signals transduced through the pre-TCR, chemokine receptor CXCR4 and Notch are thought to drive β-selection. Additionally, it has long been known that ERK is activated during β-selection; however the pathways regulating ERK activation remain unknown. Here, we performed a detailed analysis of the β-selection events in mice lacking RasGRP1, RasGRP3 and RasGRP1 and 3...

Seminars in Thoracic and Cardiovascular Surgery: Pediatric Cardiac Surgery Annual, 2004

Unfractionated heparin (UFH) is immunogenic, and heparin-dependent antibodies can be demonstrated... more Unfractionated heparin (UFH) is immunogenic, and heparin-dependent antibodies can be demonstrated 5 to 10 days postoperatively in 25% to 50% of adult postcardiac surgery patients. In a minority of these cases (1% to 3% if UFH is continued longer than 1 week) these antibodies strongly activate platelets, causing thrombocytopenia and massive thrombin generation (HIT syndrome). HIT is an intensely procoagulant disorder, and in adult cardiac surgery patients carries both significant thrombotic morbidity (38% to 81%) and mortality (28%). Despite the ubiquitous use of UFH in pediatric intensive care units, and the repeated and sustained exposures to UFH in neonates and young children with congenital heart disease, HIT has been infrequently recognized and reported in this patient population. However, emerging experience at our institution and elsewhere suggests that HIT is significantly under-recognized in pediatric congenital heart disease patients, and may in fact have an incidence and associated thrombotic morbidity and mortality in this patient group comparable to that seen in adult cardiac surgery patients. This article will review HIT in pediatric patients with congenital heart disease and emphasize the special challenges posed in clinical recognition, laboratory diagnosis, and treatment of HIT in this patient group. We will also outline our experience with the off-label use of the direct thrombin inhibitor, argatroban, in pediatric patients with HIT.

Case Reports in Pediatrics, 2011

The recurrence of cerebral palsy in the same family is uncommon. We, however, report on two famil... more The recurrence of cerebral palsy in the same family is uncommon. We, however, report on two families with two or more affected siblings. In both families, numerous potential risk factors were identified including environmental, obstetric, and possible maternal effects. We hypothesize that multiple risk factors may lead to the increased risk of recurrence of cerebral palsy in families. Intrinsic and maternal risk factors should be investigated in all cases of cerebral palsy to properly counsel families on the risk of recurrence. Recent studies of genetic polymorphisms associated with cerebral palsy are considered with reference to our observations in these two families.

Somatic Cell and Molecular Genetics, 1986

MoML V-based retroviral vector capable of transmitting and expressing both the human hypoxanthine... more MoML V-based retroviral vector capable of transmitting and expressing both the human hypoxanthine phosphoribosyltransferase (hprt) coding sequence and the Herpes simplex type 1 thymidine kinase (tk) gene has been constructed. After infection of a rat cell line, cell clones were selected on the basis of expressing both markers. They were subsequently found to contain a single provirus of the expected topology. The ease with which loss of expression of the markers can be monitored has allowed us to make observations on the stability of proviral genes. In particular, we have found indirect evidence of strong position effects on proviral gene expression by comparing the characteristic frequency of marker loss in different clonal proviral lines. Effects of the selection protocol on the apparent frequency of variants have also been noted. Finally, a combination of molecular and genetic observations lead us to invoke chromosome loss as the major factor influencing marker stability in this system.

Proceedings of the National Academy of Sciences, 1981

X is a genetic element that stimulates phage A recombination by the Escherichia coi recBC pathway... more X is a genetic element that stimulates phage A recombination by the Escherichia coi recBC pathway during lytic infection Annu Rea Genet. 13, 7-241. Herein we show that X in A prophage influences exchange distribution in P1 phage-mediated transduction and in conjugation. This demonstration encourages the view that X may influence genetic ex- change in E. coi in the total absence of A. Generalized recombination promoted by the recBC pathway of Escherichia coli occurs more or less uniformly along bacte- riophage A chromosomes (1). Mutations ofA that create recom- bination hotspots have been isolated and called x (refs. 2-4; for review see ref. 5). These mutations, arising at four or more dif- ferent sites in A ( ), confer a growth advantage to red-gam- phage, which must use the host recombination system to make concatamers from which virion chromosomes can be packaged . Experiments on the effects of X in A lytic crosses have revealed the following: (i) x enhances recombination at and near its locale (2-4, 6). (ii) X can promote recombination when pres- ent in only one of the two participating chromosomes (3). (iii) X can stimulate recombination even when embedded in a stretch of DNA that has no homology with the other chromo- some. In this case, x-enhanced crossing-over occurs in homol- ogous DNA adjacent to the heterologous region (9, 10). (iv) X activity is dependent on products of the recA, recB, and recC genes, which define the recBC recombination pathway of E. coli. Neither A's red nor E. coli's recE or recF pathway utilizes X (11, 12). (v) X promotes recombination more to one side of itself than to the other (13). (vi) Complementary products of t- promoted exchange are recovered unequally (3, 13). In crosses between X0 and X+ phages, A°-containing recombinants are preferentially recovered from x-stimulated crossing-over. Circumstantial evidence suggests that X may play a role in E. coli recombination: (i) xcan utilize only E. coli's predominant (recBC) recombination pathway, and (ii) X exists in the DNA of E. coli at a frequency of 1 per 5 X 103 base pairs . The work presented here shows that X can act in transduction-and conjugation-associated recombination in the absence of A lytic functions. The X sites examined are in A prophage, and they are seen to alter the distribution ofexchanges in their neighborhood.

PLoS ONE, 2013

Ingenol-3-angelate (I3A) is a non-tumor promoting phorbol ester-like compound identified in the s... more Ingenol-3-angelate (I3A) is a non-tumor promoting phorbol ester-like compound identified in the sap of Euphoria peplus. Similar to tumor promoting phorbol esters, I3A is a diacylglycerol (DAG) analogue that binds with high affinity to the C1 domains of PKCs, recruits PKCs to cellular membranes and promotes enzyme activation. Numerous anti-cancer activities have been attributed to I3A and ascribed to I3A's effects on PKCs. We show here that I3A also binds to and activates members of the RasGRP family of Ras activators leading to robust elevation of Ras-GTP and engagement of the Raf-Mek-Erk kinase cascade. In response to I3A, recombinant proteins consisting of GFP fused separately to full-length RasGRP1 and RasGRP3 were rapidly recruited to cell membranes, consistent with direct binding of the compound to RasGRP's C1 domain. In the case of RasGRP3, IA3 treatment led to positive regulatory phosphorylation on T133 and activation of the candidate regulatory kinase PKCd. I3A treatment of select B non-Hodgkin's lymphoma cell lines resulted in quantitative and qualitative changes in Bcl-2 family member proteins and induction of apoptosis, as previously demonstrated with the DAG analogue bryostatin 1 and its synthetic analogue pico. Our results offer further insights into the anticancer properties of I3A, support the idea that RasGRPs represent potential cancer therapeutic targets along with PKC, and expand the known range of ligands for RasGRP regulation.

Cyclic Neutropenia: An Unusual Disorder of Granulopoiesis Effectively Treated with Recombinant Granulocyte Colony-Stimulating Factor

Pediatric Dermatology, 2001

Cyclic neutropenia (CN) is a rare hematologic disorder characterized by regular cycling of the ab... more Cyclic neutropenia (CN) is a rare hematologic disorder characterized by regular cycling of the absolute neutrophil count and a symptom complex presenting during the neutropenic nadirs. Despite the profound cyclic neutropenia, most patients have a benign course of recurrent fever, malaise, oral ulceration, and minor skin and upper respiratory tract infections. Recurrent infections, inflammation, and ulcers can lead to significant chronic morbidity. Severe dental disease is common, pregnancy complications are increased, and overwhelming infections, bowel necrosis, and mortality, although rare, are potential sequelae. We report a 10-year-old boy with a classical presentation of CN that had remained undiagnosed for 10 years. The difficulty in diagnosing this unusual disorder is highlighted. Treatment with daily recombinant granulocyte colony-stimulating factor (rG-CSF) resulted in a complete clearing of symptoms and a significant increase in quality of life. The excellent clinical response of CN to rG-CSF, in the absence of major adverse effects, is strongly demonstrated by this case and supports rG-CSF as a first-line therapy for CN. The physiologic and adverse effects of rG-CSF use in CN and other neutropenic disorders, including potential leukemic induction, are reviewed. The need for long-term follow-up to investigate the effects of chronic hematopoietic stimulation by rG-CSF is emphasized.

Experience with aggressive therapy in three children with unresectable malignant liver tumors

Medical and Pediatric Oncology, 2000

Children with malignant liver tumors often present with unresectable disease but need not be cons... more Children with malignant liver tumors often present with unresectable disease but need not be considered incurable. The advent of effective chemotherapy makes aggressive management feasible, as our experience with three such patients demonstrates. Procedure and Results One child with an unresectable undifferentiated sarcoma of the liver and two others with unresectable primary hepatoblastoma and lung metastases were treated with initial chemotherapy, followed by aggressive surgical management. Treatment with chemotherapy followed by hepatectomy and liver transplantation (cadaveric or live donor) in two children has resulted in disease-free survivals of 79 and 38 months. The third patient is alive and well 24 months following chemotherapy and aggressive resection of the primary and 12 metastatic lesions. Initial chemotherapy for unresectable liver tumors with or without metastases is supported by the review of the literature. Consideration of orthotopic liver transplantation (OLT) from cadaveric or living related donor is warranted when the malignancy is demonstrably chemosensitive, independent of initial staging. Aggressive resection of primary and metastatic disease may be called for in selected cases.

BAY 81‐8973 safety and efficacy for prophylaxis and treatment of bleeds in previously treated children with severe haemophilia A: results of the LEOPOLD Kids Trial

Haemophilia, 2015

Pattern of Mucosal Tumor Necrosis Factor- Expression in Segmental Colitis Associated with Diverticula Suggests a Truly Autonomous Clinical Entity

Liver Transplantation for Prothrombin Deficiency Causing Life-Threatening Bleeds

Blood

Outcome and Clinical Characteristics of Clonal and Malignant Myeloid Transformation in Inherited Bone Marrow Failure Syndromes

Blood

RasGRP is essential for mouse thymocyte differentiation and TCR signaling

Nature Immunology

Chi

Cold Spring Harbor Symposia on Quantitative Biology

Genetics

What Accounts for the Orientation Dependence and Directionality of Chi?

Mechanistic Studies of DNA Replication and Genetic Recombination, 1980

Neuroscience, 2002

Neuroscience, 2001

Genetics, 1980

Genetics, 1986

PloS one, 2013

Seminars in Thoracic and Cardiovascular Surgery: Pediatric Cardiac Surgery Annual, 2004

Case Reports in Pediatrics, 2011

Somatic Cell and Molecular Genetics, 1986

Proceedings of the National Academy of Sciences, 1981

PLoS ONE, 2013

Cyclic Neutropenia: An Unusual Disorder of Granulopoiesis Effectively Treated with Recombinant Granulocyte Colony-Stimulating Factor

Pediatric Dermatology, 2001

Experience with aggressive therapy in three children with unresectable malignant liver tumors

Medical and Pediatric Oncology, 2000