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D L Browning, E M Everson, D J Leap, J D Hocum, H Wang, G Stamatoyannopoulos, G D Trobridge
Retroviral vector-mediated stem cell gene therapy is a promising approach for the treatment of hematopoietic disorders. However, genotoxic side effects from integrated vector proviruses are a significant concern for the use of retroviral vectors in the clinic. Insulated foamy viral (FV) vectors are potentially safer retroviral vectors for hematopoietic stem cell gene therapy. We evaluated two newly identified human insulators, A1 and A2, for use in FV vectors. These insulators had moderate insulating capacity and higher titers than previously developed insulated FV vectors...
March 2017: Gene Therapy
Cory Swingen, Laura Hocum Stone, Rosemary F Kelly
No abstract text is available yet for this article.
November 24, 2016: Journal of Thoracic and Cardiovascular Surgery
Laura L Hocum Stone, Cory Swingen, Christopher Holley, Christin Wright, Erin Chappuis, Herbert B Ward, Edward O McFalls, Rosemary F Kelly
OBJECTIVE: Clinical studies demonstrate delayed recovery of hibernating myocardium (HM) following coronary artery bypass graft (CABG) surgery. Cardiac magnetic resonance (CMR) imaging is effective in identifying HM in clinical settings. Our animal model of HM shows partial but incomplete functional recovery 1 month following CABG using echocardiography. This study uses CMR imaging to determine completeness of recovery 3 months post-CABG. METHODS: Swine (N = 12) underwent left anterior descending artery (LAD) 1...
March 2017: Journal of Thoracic and Cardiovascular Surgery
John L Carter, Ankura Patel, Gabriel Hocum, Brion Benninger
PURPOSE: In teaching anatomy, clinical imaging has been utilized to supplement the traditional dissection laboratory promoting education through visualization of spatial relationships of anatomical structures. Viewing the thyroid gland using 3D/4D ultrasound can be valuable to physicians as well as students learning anatomy. The objective of this study was to investigate the perceptions of first-year medical students regarding the integration of 3D/4D ultrasound visualization of spatial anatomy during anatomical education...
May 2017: Surgical and Radiologic Anatomy: SRA
Jonah D Hocum, Ian Linde, Dustin T Rae, Casey P Collins, Lindsay K Matern, Grant D Trobridge
Retroviral gene therapy offers immense potential to treat many genetic diseases and has already shown efficacy in clinical trials. However, retroviral vector mediated genotoxicity remains a major challenge and clinically relevant approaches to reduce integration near genes and proto-oncogenes are needed. Foamy retroviral vectors have several advantages over gammaretroviral and lentiviral vectors including a potentially safer integration profile and a lower propensity to activate nearby genes. Here we successfully retargeted foamy retroviral vectors away from genes and into satellite regions enriched for trimethylated histone H3 at lysine 9 by modifying the foamy virus Gag and Pol proteins...
November 4, 2016: Scientific Reports
Jennifer E Adair, Timothy Waters, Kevin G Haworth, Sara P Kubek, Grant D Trobridge, Jonah D Hocum, Shelly Heimfeld, Hans-Peter Kiem
Haematopoietic stem cell (HSC) gene therapy has demonstrated potential to treat many diseases. However, current state of the art requires sophisticated ex vivo gene transfer in a dedicated Good Manufacturing Practices facility, limiting availability. An automated process would improve the availability and standardized manufacture of HSC gene therapy. Here, we develop a novel program for semi-automated cell isolation and culture equipment to permit complete benchtop generation of gene-modified CD34(+) blood cell products for transplantation...
October 20, 2016: Nature Communications
Elizabeth M Everson, Miles E Olzsko, David J Leap, Jonah D Hocum, Grant D Trobridge
Hematopoietic stem cell (HSC) gene therapy using retroviral vectors has immense potential, but vector-mediated genotoxicity limits use in the clinic. Lentiviral vectors are less genotoxic than gammaretroviral vectors and have become the vector of choice in clinical trials. Foamy retroviral vectors have a promising integration profile and are less prone to read-through transcription than gammaretroviral or lentiviral vectors. Here, we directly compared the safety and efficacy of foamy vectors to lentiviral vectors in human CD34(+) repopulating cells in immunodeficient mice...
2016: Molecular Therapy. Methods & Clinical Development
Laura Hocum Stone, Tammy A Butterick, Cayla Duffy, Corey Swingen, Herbert B Ward, Rosemary F Kelly, Edward O McFalls
There is conflicting clinical evidence whether administration of coenzyme Q10 (CoQ10) improves function following coronary artery bypass graft surgery (CABG). Using a swine model of hibernating myocardium, we tested whether daily CoQ10 would improve contractile function by MRI at 4-week post-CABG. Twelve pigs underwent a thoracotomy and had a constrictor placed on the left anterior descending (LAD). At 12 weeks, they underwent off-pump bypass and received daily dietary supplements of either CoQ10 (10 mg/kg/day) or placebo...
August 2016: Journal of Cardiovascular Translational Research
Tammy A Butterick, Laura Hocum Stone, Cayla Duffy, Christopher Holley, Jesús A Cabrera, Melanie Crampton, Herbert B Ward, Rosemary F Kelly, Edward O McFalls
The peroxisome proliferator-activated receptor (PPAR)-γ drug pioglitazone (PIO) has been shown to protect tissue against oxidant stress. In a swine model of chronic myocardial ischemia, we tested whether PIO increases PGC1-α signaling and the expression of mitochondrial antioxidant peptides. Eighteen pigs underwent a thoracotomy with placement of a fixed constrictor around the LAD artery. At 8 weeks, diet was supplemented with either PIO (3 mg/kg) or placebo for 4 weeks. Regional myocardial function and blood flow were determined at the time of the terminal study...
May 2016: Basic Research in Cardiology
Robert C Albright, John J Dillon, Craig L Hocum, James R Stubbs, Pamela M Johnson, LaTonya J Hickson, Amy W Williams, David Dingli, James T McCarthy
BACKGROUND: Anemia management in chronic hemodialysis (HD) has been affected by the implementation of the prospective payment system (PPS) and changes in clinical guidelines. These factors could impact red blood cell (RBC) transfusion in HD patients. Our distinctive care system contains complete records for all RBC transfusions among our HD patients. AIMS: To determine RBC transfusions in patients with prevalent chronic HD, site of administration (inpatient or outpatient), and ordering physician specialty for inpatients; compare pre- and post-PPS RBC transfusions; and compare RBC transfusions during changes in desired outpatient hemoglobin (Hb) range for patients with chronic HD...
2016: Nephron
Laura L Hocum Stone, Feng Xiao, Jessica Rotschafer, Zhenhong Nan, Mario Juliano, Cyndy D Sanberg, Paul R Sanberg, Nicole Kuzmin-Nichols, Andrew Grande, Maxim C-J Cheeran, Walter C Low
Despite the high prevalence and devastating outcome, there remain a few options for treatment of ischemic stroke. Currently available treatments are limited by a short time window for treatment and marginal efficacy when used. We have tested a human umbilical cord blood-derived stem cell line that has been shown to result in a significant reduction in stroke infarct volume as well as improved functional recovery following stroke in the rat. In the present study we address the mechanism of action and compared the therapeutic efficacy of high- versus low-passage nonhematopoietic umbilical cord blood stem cells (nh-UCBSCs)...
2016: Cell Transplantation
Brian Thomas Hocum, John Raymond White, Jarrod W Heck, Ranjit K Thirumaran, Nicolas Moyer, Richard Newman, Kristine Ashcraft
PURPOSE: The results of a study of variant cytochrome P-450 (CYP) alleles and associated risks of drug-drug interactions (DDIs) and altered drug metabolism are reported. METHODS: The records of a pharmacogenetic testing laboratory were retrospectively analyzed to identify patients tested for polymorphisms of genes coding for five CYP isozymes important in drug metabolism (CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5) over a 16-month period. Based on the results of phenotyping, the patients were categorized by expected CYP isozyme activity (e...
January 15, 2016: American Journal of Health-system Pharmacy: AJHP
Diana L Browning, Casey P Collins, Jonah D Hocum, David J Leap, Dustin T Rae, Grant D Trobridge
Retroviral vector-mediated gene therapy is promising, but genotoxicity has limited its use in the clinic. Genotoxicity is highly dependent on the retroviral vector used, and foamy viral (FV) vectors appear relatively safe. However, internal promoters may still potentially activate nearby genes. We developed insulated FV vectors, using four previously described insulators: a version of the well-studied chicken hypersensitivity site 4 insulator (650cHS4), two synthetic CCCTC-binding factor (CTCF)-based insulators, and an insulator based on the CCAAT box-binding transcription factor/nuclear factor I (7xCTF/NF1)...
March 2016: Human Gene Therapy
Dustin T Rae, Jonah D Hocum, Victor Bii, H Joachim Deeg, Grant D Trobridge
Using a novel retroviral shuttle vector approach we identified genes that collaborate with a patient derived RUNX1 (AML1) mutant. RUNX1 mutations occurs in 40% of myelodysplastic syndromes (MDS). MDS are a group of hematopoietic stem cell disorders that are characterized by dysplasia that often progress to acute myeloid leukemia (AML). Our goal was to identify genes dysregulated by vector-mediated genotoxicity that may collaborate with the RUNX1 mutant (D171N). D171N expressing cells have a survival and engraftment disadvantage and require additional genetic lesions to survive and persist...
October 13, 2015: Oncotarget
Eric L Singman, Brian Hocum, Jithin Yohannan, Virginia Pearson
A 60-year-old woman reported horizontal "shimmering" movement while reading crossword puzzles when using fluvoxamine, bupropion, quetiapine, lithium, and levothyroxine. This visual disturbance, likely oscillopsia, started after the fluvoxamine was added and waned as the fluvoxamine was tapered, disappearing after the drug was discontinued. Genetic testing to explore how the patient metabolizes these medications combined with YouScript® interaction analysis suggest that she may have had abnormally high plasma concentrations of fluvoxamine during this time...
December 2015: Drug Metabolism and Personalized Therapy
Jonah D Hocum, Logan R Battrell, Ryan Maynard, Jennifer E Adair, Brian C Beard, David J Rawlings, Hans-Peter Kiem, Daniel G Miller, Grant D Trobridge
BACKGROUND: Analyzing the integration profile of retroviral vectors is a vital step in determining their potential genotoxic effects and developing safer vectors for therapeutic use. Identifying retroviral vector integration sites is also important for retroviral mutagenesis screens. RESULTS: We developed VISA, a vector integration site analysis server, to analyze next-generation sequencing data for retroviral vector integration sites. Sequence reads that contain a provirus are mapped to the human genome, sequence reads that cannot be localized to a unique location in the genome are filtered out, and then unique retroviral vector integration sites are determined based on the alignment scores of the remaining sequence reads...
2015: BMC Bioinformatics
Robert W Colbert, Christopher T Holley, Laura Hocum Stone, Melanie Crampton, Selcuk Adabag, Santiago Garcia, Paul A Iaizzo, Herbert B Ward, Rosemary F Kelly, Edward O McFalls
Clinicians often use the term "hibernating myocardium" in reference to patients with ischemic heart disease and decreased function within viable myocardial regions. Because the term is a descriptor of nature's process of torpor, we provide a comparison of the adaptations observed in both conditions. In nature, hearts from hibernating animals undergo a shift in substrate preference in favor of fatty acids, while preserving glucose uptake and glycogen. Expression of electron transport chain proteins in mitochondria is decreased while antioxidant proteins including uncoupling protein-2 are increased...
June 2015: Journal of Cardiovascular Translational Research
M E Olszko, J E Adair, I Linde, D T Rae, P Trobridge, J D Hocum, D J Rawlings, H-P Kiem, G D Trobridge
Foamy virus (FV) vectors are promising for hematopoietic stem cell (HSC) gene therapy but preclinical data on the clonal composition of FV vector-transduced human repopulating cells is needed. Human CD34(+) human cord blood cells were transduced with an FV vector encoding a methylguanine methyltransferase (MGMT)P140K transgene, transplanted into immunodeficient NOD/SCID IL2Rγ(null) mice, and selected in vivo for gene-modified cells. The retroviral insertion site profile of repopulating clones was examined using modified genomic sequencing PCR...
July 2015: Gene Therapy
Christopher T Holley, Eric K Long, Tammy A Butterick, Cayla M Duffy, Megan E Lindsey, Laura Hocum Stone, Edward O McFalls, Rosemary F Kelly
BACKGROUND: Hibernating myocardium is characterized by viable yet dysfunctional myocardium secondary to chronic ischemia, with studies demonstrating incomplete early recovery after coronary artery bypass graft (CABG). We tested whether mitochondrial fusion proteins, an indicator of mitochondrial biogenesis, are increased in hibernating myocardium post-CABG. METHODS: A constrictor was placed on the left anterior descending (LAD) artery of nine pigs. Four of these pigs additionally underwent CABG 12 wk later with a left internal mammary artery graft to the LAD distal to the constrictor...
May 1, 2015: Journal of Surgical Research
James T McCarthy, Craig L Hocum, Robert C Albright, James Rogers, Edward J Gallaher, David P Steensma, Stephen F Gudgell, Eric J Bergstralh, John C Dillon, LaTonya J Hickson, Amy W Williams, David Dingli
OBJECTIVE: To determine the value of a biomedical system dynamics (BMSD) approach for optimization of anemia management in long-term hemodialysis patients because elevated hemoglobin levels and high doses of erythropoiesis-stimulating agents (ESAs) may negatively affect survival in this population. PATIENTS AND METHODS: A model of erythropoiesis and its response to ESAs on the basis of a BMSD method (Mayo Clinic Anemia Management System [MCAMS]) was developed. Thereafter, an open-label, prospective, nonrandomized practice quality improvement project was performed with retrospective analysis in 8 community-based outpatient hemodialysis facilities...
January 2014: Mayo Clinic Proceedings
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