Publications by authors named "Janice M Staber"

13 Publications

  • Page 1 of 1

BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A.

N Engl J Med 2020 09;383(11):1018-1027

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Background: Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001.

Methods: In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed.

Results: No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments.

Conclusions: In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).
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http://dx.doi.org/10.1056/NEJMoa2002699DOI Listing
September 2020

Haemostatic efficacy of single-dose factor administration in neonates with severe haemophilia undergoing circumcision.

Haemophilia 2020 Sep 3;26(5):786-792. Epub 2020 Aug 3.

Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, USA.

Introduction: Perioperative management of children with haemophilia undergoing surgery is a complex and understudied topic. Circumcision is the most common procedure performed in the neonatal period, and guidelines to prevent bleeding complications from circumcision are lacking. Treatment protocols vary widely, and many centres treat patients with factor products for up to two weeks after circumcision. There is an unmet need for studies evaluating optimal factor replacement therapy around the time of circumcision in neonates with severe haemophilia.

Aim: To determine the efficacy of a single dose of factor replacement before circumcision to prevent bleeding complications in neonates with severe haemophilia.

Methods: We conducted a retrospective chart review of male infants born between January 2000 and June 2019. Male neonates with severe haemophilia diagnosed at the Iowa Hemophilia and Thrombosis Center (n = 22) and healthy newborn controls who underwent circumcision at the University of Iowa Hospitals were included. Data were collected from the electronic medical record. Neonates with severe haemophilia were separated into two groups-those pretreated with one dose of factor replacement before circumcision and those without pretreatment.

Results: We observed that neonates with severe haemophilia pretreated with a single dose of factor VIII or factor IX replacement had significantly reduced bleeding complications, shorter hospital stay and required less therapeutic intervention compared with untreated patients. Importantly, pretreated patients had outcomes similar to healthy controls.

Conclusions: Our results demonstrate that a single dose of factor replacement before circumcision is effective to prevent bleeding in neonates with severe haemophilia.
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http://dx.doi.org/10.1111/hae.14122DOI Listing
September 2020

Laboratory misdiagnosis of von Willebrand disease in post-menarchal females: A multi-center study.

Am J Hematol 2020 09 20;95(9):1022-1029. Epub 2020 Jun 20.

Department of Medicine, Division of Hematology/Oncology, Mary M. Gooley Hemophilia Center, Rochester, New York, USA.

Increased awareness of von Willebrand Disease (VWD) has led to more frequent diagnostic laboratory testing, which insurers often dictate be performed at a facility with off-site laboratory processing, instead of a coagulation facility with onsite processing. Off-site processing is more prone to preanalytical variables causing falsely low levels of von Willebrand Factor (VWF) due to the additional transport required. Our aim was to determine the percentage of discordance between off-site and onsite specimen processing for VWD in this multicenter, retrospective study. We enrolled females aged 12 to 50 years who had off-site specimen processing for VWF assays, and repeat testing performed at a consulting institution with onsite coagulation phlebotomy and processing. A total of 263 females from 17 institutions were included in the analysis. There were 251 subjects with both off-site and onsite VWF antigen (VWF:Ag) processing with 96 (38%) being low off-site and 56 (22%) low onsite; 223 subjects had VWF ristocetin co-factor (VWF:RCo), 122 (55%) were low off-site and 71 (32%) were low onsite. Similarly, 229 subjects had a Factor VIII (FVIII) assay, and 67 (29%) were low off-site with less than half, 29 (13%) confirmed low with onsite processing. Higher proportions of patients demonstrated low VWF:Ag, VWF:RCo, and/or FVIII with off-site processing compared to onsite (McNemar's test P-value <.0005, for all assays). These results emphasize the need to decrease delays from sample procurement to processing for VWF assays. The VWF assays should ideally be collected and processed at the same site under the guidance of a hematologist.
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http://dx.doi.org/10.1002/ajh.25869DOI Listing
September 2020

Mental health disorders in haemophilia: Systematic literature review and meta-analysis.

Haemophilia 2020 May 19;26(3):431-442. Epub 2020 Apr 19.

Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

Aim: Despite significant advances in morbidity and mortality outcomes, quality of life for people with haemophilia (PWH) remains compromised. Underrecognized and undertreated mental health disorders decrease quality of life; however, reports are inconsistent regarding the true prevalence of mental health disorders in PWH.

Methods: We conducted a systematic literature search of Ovid MEDLINE, EMBASE, Psychinfo and the Cochrane Library, and hand searched the journal Haemophilia to identify records and subsequently conducted a meta-analysis to determine the prevalence of depression, anxiety and attention deficit hyperactivity disorder (ADHD) in patients with congenital haemophilia.

Results: Our search strategy identified 2315 records, and 28 studies met eligibility criteria. Meta-analysis demonstrated that PWH are at increased risk of depression (odds ratio (OR) 2.45; 95% confidence interval (CI) 1.64-3.68), anxiety (OR 1.74, 95% CI 1.01-3.00), anxiety/depression (OR 2.60, 95% CI 2.35-2.87) and ADHD (OR 3.48, 95% CI 1.74-6.96). We found considerable heterogeneity among the studies likely due to differences in assessment tools, populations studied and year of publication. This suggests that standardized tools to diagnose mental health disorders in PWH are needed. Additionally, high-quality studies investigating mental health disorders in PWH are necessary to adequately document the prevalence of these disorders.

Conclusion: Overall, our meta-analysis suggests that the prevalence of depression, anxiety and ADHD across decades is significantly increased in PWH compared to the general population.
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http://dx.doi.org/10.1111/hae.13960DOI Listing
May 2020

Successful Management of Blue Rubber Bleb Nevus Syndrome (BRBNS) with Sirolimus.

Case Rep Pediatr 2018 8;2018:7654278. Epub 2018 Oct 8.

Division of Pediatric Hematology/Oncology, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Blue rubber bleb nevus syndrome (BRBNS) is a rare disease with vascular malformations in several systems of the body, most commonly the skin and gastrointestinal tract. Bleeding from the gastrointestinal (GI) tract is a major complication, which may lead to chronic iron deficiency anemia and the need for frequent blood transfusions due to ongoing gastrointestinal blood loss. In this case report, we describe a now 19-year-old female with BRBNS who required six blood transfusions per year and after starting sirolimus is symptom- and transfusion-free.
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http://dx.doi.org/10.1155/2018/7654278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196891PMC
October 2018

Endothelial Cell-Derived Von Willebrand Factor, But Not Platelet-Derived, Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice.

Arterioscler Thromb Vasc Biol 2018 03 18;38(3):520-528. Epub 2018 Jan 18.

From the Department of Internal Medicine (P.D., N.D., M.R.C., M.J., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (C.T., J.M.S.), University of Iowa, Iowa City.

Objective: VWF (von Willebrand factor) is synthesized by endothelial cells and megakaryocytes and is known to contribute to atherosclerosis. In vitro studies suggest that platelet-derived VWF (Plt-VWF) is biochemically and functionally different from endothelial cell-derived VWF (EC-VWF). We determined the role of different pools of VWF in the pathophysiology of atherosclerosis.

Approach And Results: Using bone marrow transplantation, we generated chimeric Plt-VWF, EC-VWF, and Plt-VWF mice lacking a disintegrin and metalloprotease with thrombospondin type I repeats-13 in platelets and plasma on apolipoprotein E-deficient () background. Controls were chimeric mice transplanted with bone marrow from mice (wild type) and mice transplanted with bone marrow from mice (VWF-knock out). Susceptibility to atherosclerosis was evaluated in whole aortae and cross-sections of the aortic sinus in female mice fed a high-fat Western diet for 14 weeks. VWF-knock out, Plt-VWF, and Plt-VWF mice lacking a disintegrin and metalloprotease with thrombospondin type I repeats-13 exhibited reduced plaque size characterized by smaller necrotic cores, reduced neutrophil and monocytes/macrophages content, decreased MMP9 (matrix metalloproteinase), MMP2, and CXCL1 (chemokine [C-X3-C motif] ligand 1)-positive area, and abundant interstitial collagen (<0.05 versus wild-type or EC-VWF mice). Atherosclerotic lesion size and composition were comparable between wild-type or EC-VWF mice. Together these findings suggest that EC-VWF, but not Plt-VWF, promotes atherosclerosis exacerbation. Furthermore, intravital microscopy experiments revealed that EC-VWF, but not Plt-VWF, contributes to platelet and leukocyte adhesion under inflammatory conditions at the arterial shear rate.

Conclusions: EC-VWF, but not Plt-VWF, contributes to VWF-dependent atherosclerosis by promoting platelet adhesion and vascular inflammation. Plt-VWF even in the absence of a disintegrin and metalloprotease with thrombospondin type I repeats-13, both in platelet and plasma, was not sufficient to promote atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.117.309918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823769PMC
March 2018

ADAMTS13 Retards Progression of Diabetic Nephropathy by Inhibiting Intrarenal Thrombosis in Mice.

Arterioscler Thromb Vasc Biol 2017 07 11;37(7):1332-1338. Epub 2017 May 11.

From the Department of Internal Medicine (N.D., P.D., M.R.C., M.K.N., S.R.L., A.K.C.) and Stead Family Department of Pediatrics (J.M.S.), University of Iowa; and Department of Molecular Pathogenesis, National Cardiovascular Centre Research Institute, Suita, Osaka, Japan (K.K.).

Objective: ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats-13) prevents microvascular thrombosis by cleaving prothrombogenic ultralarge von Willebrand factor (VWF) multimers. Clinical studies have found association between reduced ADAMTS13-specific activity, ultralarge VWF multimers, and thrombotic angiopathy in patients with diabetic nephropathy. It remains unknown, however, whether ADAMTS13 deficiency or ultralarge VWF multimers have a causative effect in diabetic nephropathy.

Approach And Results: The extent of renal injury was evaluated in wild-type (WT), 13 and 13 mice after 26 weeks of streptozotocin-induced diabetic nephropathy. We found that WT diabetic mice exhibited low plasma ADAMTS13-specific activity and increased VWF levels (<0.05 versus WT nondiabetic mice). 13 diabetic mice exhibited deterioration of kidney function (increased albuminuria, plasma creatinine, and urea; <0.05 versus WT diabetic mice), independent of hyperglycemia and hypertension. Deterioration of kidney function in 13 diabetic mice was concomitant with aggravated intrarenal thrombosis (assessed by plasminogen activator inhibitor, VWF, fibrin(ogen), and CD41-positive microthrombi), increased mesangial cell expansion, and extracellular matrix deposition (<0.05 versus WT diabetic mice). Genetic deletion of VWF in 13 diabetic mice improved kidney function, inhibited intrarenal thrombosis, and alleviated histological changes in glomeruli, suggesting that exacerbation of diabetic nephropathy in the setting of ADAMTS13 deficiency is VWF dependent.

Conclusions: ADAMTS13 retards progression of diabetic nephropathy, most likely by inhibiting VWF-dependent intrarenal thrombosis. Alteration in ADAMTS13-VWF balance may be one of the key pathophysiological mechanisms of thrombotic angiopathy in diabetes mellitus.
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http://dx.doi.org/10.1161/ATVBAHA.117.309539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501287PMC
July 2017

Endothelial Cell-Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor-Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo-Inflammation.

Arterioscler Thromb Vasc Biol 2016 09 21;36(9):1829-37. Epub 2016 Jul 21.

From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City.

Objective: von Willebrand factor (VWF), which is synthesized in endothelial cells and megakaryocytes, is known to worsen stroke outcome. In vitro studies suggest that platelet-derived VWF (Plt-VWF) is biochemically different from the endothelial cell-derived VWF (EC-VWF). However, little is known about relative contribution of different pools of VWF in stroke.

Approach And Results: Using bone marrow transplantation, we generated chimeric Plt-VWF mice, Plt-VWF mice that lack ADAMTS13 in platelets and plasma (Plt-VWF/Adamts13(-/-)), and EC-VWF mice to determine relative contribution of different pools of VWF in stroke. In brain ischemia/reperfusion injury model, we found that infarct size and postischemic intracerebral thrombo-inflammation (fibrin(ogen) deposition, neutrophil infiltration, interleukin-1β, and tumor necrosis factor-α levels) within lesions were comparable between EC-VWF and wild-type mice. Infarct size and postischemic thrombo-inflammation were comparable between Plt-VWF and Plt-VWF/Adamts13(-/-) mice, but decreased compared with EC-VWF and wild-type mice (P<0.05) and increased compared with Vwf(-/-) mice (P<0.05). Susceptibility to FeCl3 injury-induced carotid artery thrombosis was comparable between wild-type and EC-VWF mice, whereas Plt-VWF and Plt-VWF/Adamts13(-/-) mice exhibited defective thrombosis. Although most of the injured vessels did not occlude, slope over time showed that thrombus growth rate was increased in both Plt-VWF and Plt-VWF/Adamts13(-/-) mice compared with Vwf(-/-) mice (P<0.05), but decreased compared with wild-type or EC-VWF mice.

Conclusions: Plt-VWF, either in presence or absence of ADAMTS13, partially contributes to VWF-dependent injury and postischemic thrombo-inflammation after stroke. EC-VWF is the major determinant that mediates VWF-dependent ischemic stroke by promoting postischemic thrombo-inflammation.
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http://dx.doi.org/10.1161/ATVBAHA.116.307660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001895PMC
September 2016

Shortened Lifespan and Lethal Hemorrhage in a Hemophilia A Mouse Model.

PLoS One 2016 4;11(5):e0154857. Epub 2016 May 4.

Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, United States of America.

Background: Hemophilia A animal models have helped advance our understanding of factor VIII deficiency. Previously, factor VIII deficient mouse models were reported to have a normal life span without spontaneous bleeds. However, the bleeding frequency and survival in these animals has not been thoroughly evaluated.

Objective: To investigate the survival and lethal bleeding frequency in two strains of E-16 hemophilia A mice.

Methods: We prospectively studied factor VIII deficient hemizygous affected males (n = 83) and homozygous affected females (n = 55) for survival and bleeding frequency. Animals were evaluated for presence and location of bleeds as potential cause of death.

Results And Conclusions: Hemophilia A mice had a median survival of 254 days, which is significantly shortened compared to wild type controls (p < 0.0001). In addition, the hemophilia A mice experienced hemorrhage in several tissues. This previously-underappreciated shortened survival in the hemophilia A murine model provides new outcomes for investigation of therapeutics and also reflects the shortened lifespan of patients if left untreated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154857PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856382PMC
July 2017

piggyBac-mediated phenotypic correction of factor VIII deficiency.

Mol Ther Methods Clin Dev 2014 10;1:14042. Epub 2014 Sep 10.

Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases, Carver College of Medicine, University of Iowa , Iowa City, Iowa, USA ; Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa , Iowa City, Iowa, USA ; Interdisciplinary Graduate Program in Genetics, Carver College of Medicine, University of Iowa , Iowa City, Iowa, USA.

Hemophilia A, caused by a deficiency in factor VIII (FVIII), is the most severe inherited bleeding disorder. Hemophilia A is an attractive gene therapy candidate because even small increases in FVIII levels will positively alter the phenotype. While several vectors are under investigation, gene addition from an integrated transgene offers the possibility of long term expression. We engineered the DNA transposon-based vector, piggyBac (PB), to carry a codon-optimized B-domain deleted human FVIII cDNA. Evaluation of gene transfer efficiency in FVIII null mice demonstrated that PB containing the FVIII cDNA, delivered via hydrodynamic injection to immunocompetent hemophilia mice, conferred persistent gene expression, attaining mean FVIII activity of approximately 60% with 3/19 developing inhibitors. In addition to efficacious expression, a goal of gene transfer-based therapies is to develop vectors with low toxicity. To assess endoplasmic reticulum stress in hepatocytes stably expressing the transgene, we evaluated levels of ER stress markers via qPCR and found no evidence of cell stress. To evaluate phenotypic correction, a tail clip assay performed at the end of the study revealed reduced blood loss. These data demonstrate that PB can be used to achieve sustained FVIII expression and long-term therapeutic benefit in a mouse model.
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http://dx.doi.org/10.1038/mtm.2014.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362371PMC
May 2015

A Hyperactive Transposase Promotes Persistent Gene Transfer of a piggyBac DNA Transposon.

Mol Ther Nucleic Acids 2012 Oct 16;1:e50. Epub 2012 Oct 16.

1] Interdisciplinary Graduate Program in Genetics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA [2] Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA [3] Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.

Nonviral vector systems are used increasingly in gene targeting and gene transfer applications. The piggyBac transposon represents an alternative integrating vector for in vivo gene transfer. We hypothesized that this system could achieve persistent gene transfer to the liver when administered systemically. We report that a novel hyperactive transposase generated higher transposition efficiency than a codon-optimized transposase in a human liver cell line. Hyperactive transposase-mediated reporter gene expression persisted at levels twice that of codon-optimized transposase in the livers of mice for the 6-month study. Of note, expression persisted in mice following partial hepatectomy, consistent with expression from an integrated transgene. We also used the hyperactive transposase to deliver the human α(1)-antitrypsin gene and achieved stable expression in serum. To determine the integration pattern of insertions, we performed large-scale mapping in human cells and recovered 60,685 unique hyperactive transposase-mediated insertions. We found that a hyperactive piggyBac transposase conferred an altered pattern of integration from that of insect piggyBac transposase, with a decreased frequency of integration near transcription start sites than previously reported. Our results support that the piggyBac transposon combined with the hyperactive transposase is an efficient integrating vector system for in vitro and in vivo applications.Molecular Therapy - Nucleic Acids (2012) 1, e50; doi:10.1038/mtna.2012.12; published online 16 October 2012.
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http://dx.doi.org/10.1038/mtna.2012.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499692PMC
October 2012

Respiratory syncytial virus inhibits apoptosis and induces NF-kappa B activity through a phosphatidylinositol 3-kinase-dependent pathway.

J Biol Chem 2002 Jan 30;277(1):492-501. Epub 2001 Oct 30.

Department of Internal Medicine, University of Iowa College of Medicine and Veterans Administration Medical Center, Iowa City, Iowa 52242, USA.

Respiratory syncytial virus (RSV) infects airway epithelial cells, resulting in cell death and severe inflammation through the induction of NF-kappaB activity and inflammatory cytokine synthesis. Both NF-kappaB activity and apoptosis regulation have been linked to phosphatidylinositol 3-kinase (PI 3-K) and its downstream effector enzymes, AKT and GSK-3. This study evaluates the role of PI 3-K and its downstream mediators in apoptosis and inflammatory gene induction during RSV infection of airway epithelial cells. Whereas RSV infection alone did not produce significant cytotoxicity until 24-48 h following infection, simultaneous RSV infection and exposure to LY294002, a blocker of PI 3-K activity, resulted in cytotoxicity within 12 h. Furthermore, we found that RSV infection during PI 3-K blockade resulted in apoptosis by examining DNA fragmentation, DNA labeling by terminal dUTP nick-end labeling assay, and poly(ADP-ribose) polymerase cleavage by Western blotting. RSV infection produced an increase in the phosphorylation state of AKT, GSK-3, and the p85 regulatory subunit of PI 3-K. The activation of PI 3-K by RSV and its inhibition by LY294002 was confirmed in direct PI 3-K activity assays. Further evidence for the central role of a pathway involving PI 3-K and AKT in preserving cell viability during RSV infection was established by the observation that constitutively active AKT transfected into A549 cells prevented the cytotoxicity and apoptosis of combined RSV and LY294002 treatment. Finally, both PI 3-K inhibition by LY294002 and AKT inhibition by transfection of a dominant negative enzyme blocked RSV-induced NF-kappaB transcriptional activity. These data demonstrate that anti-apoptotic signaling and NF-kappaB activation by RSV are mediated through activation of PI 3-K-dependent pathways. Blockade of PI 3-K activation resulted in rapid, premature apoptosis and inhibition of RSV-stimulated NF-kappaB-dependent gene transcription.
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http://dx.doi.org/10.1074/jbc.M108107200DOI Listing
January 2002