Publications by authors named "H Allison Bender"

611 Publications

ChAdOx1 nCoV-19 (AZD1222) vaccine candidate significantly reduces SARS-CoV-2 shedding in ferrets.

NPJ Vaccines 2021 May 10;6(1):67. Epub 2021 May 10.

CSIRO Australian Centre for Disease Preparedness, Geelong, VIC, Australia.

Vaccines against SARS-CoV-2 are likely to be critical in the management of the ongoing pandemic. A number of candidates are in Phase III human clinical trials, including ChAdOx1 nCoV-19 (AZD1222), a replication-deficient chimpanzee adenovirus-vectored vaccine candidate. In preclinical trials, the efficacy of ChAdOx1 nCoV-19 against SARS-CoV-2 challenge was evaluated in a ferret model of infection. Groups of ferrets received either prime-only or prime-boost administration of ChAdOx1 nCoV-19 via the intramuscular or intranasal route. All ChAdOx1 nCoV-19 administration combinations resulted in significant reductions in viral loads in nasal-wash and oral swab samples. No vaccine-associated adverse events were observed associated with the ChAdOx1 nCoV-19 candidate, with the data from this study suggesting it could be an effective and safe vaccine against COVID-19. Our study also indicates the potential for intranasal administration as a way to further improve the efficacy of this leading vaccine candidate.
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http://dx.doi.org/10.1038/s41541-021-00315-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110954PMC
May 2021

siRNA Therapeutics for Protein Misfolding Diseases of the Central Nervous System.

Methods Mol Biol 2021 ;2282:377-394

Prion Research Center, Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.

Nanoparticles have been used to deliver siRNA to tissues and cells to silence specific genes in diverse organisms. Research and clinical application of nanoparticles like liposomes for drug delivery requires targeting them to specific anatomic regions or cell types, while avoiding off-target effects or clearance by the liver, kidney, or the immune system. Delivery to the central nervous system (CNS) presents additional challenges to cross the blood-brain barrier (BBB) to specific cell types like neurons, astrocytes, or glia. Here, we describe the generation of three different liposomal siRNA delivery vehicles to the CNS using the thin film hydration method. Utilizing cationic or anionic liposomes protects the siRNA from serum nucleases and proteases en route. To deliver the siRNA specifically to the CNS, the liposomes are complexed to a peptide that acts as a neuronal address by binding to nicotinic acetylcholine receptors (nAchRs). When injected intravenously or instilled intranasally, these liposome-siRNA-peptide complexes (LSPCs) or peptide addressed liposome-encapsulated therapeutic siRNA (PALETS) resist serum degradation, effectively cross the BBB, and deliver siRNA to AchR-expressing cells to suppress protein expression in the CNS.
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http://dx.doi.org/10.1007/978-1-0716-1298-9_20DOI Listing
January 2021

Switching a baby from IV levomethadone to IV fentanyl.

J Opioid Manag 2021 Mar-Apr;17(2):181-183

Neonatology and Neonatal Intensive Care, Dr. von Hauner Children's Hospital, University of Munich Medical Center, Ludwig-Maximilians-University, Munich, Germany.

Methadone, or in Germany levomethadone, may be used for the treatment of iatrogenic opioid withdrawal syndrome in pediatric intensive care units. The limited literature on opioid rotation in children does not provide data for the switch from methadone to another opioid. We report switching a very ill preterm baby in an unstable condition from IV levomethadone to IV fentanyl identifying a possible conversion ratio of 6.0-4.5:1 emphasizing critical steps as equipotency appropriate for neonates and dose reduction for incomplete cross-tolerance. If clinical deterioration occurs in infants on opioid tapering with levomethadone, we hope that our observations may be helpful.
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http://dx.doi.org/10.5055/jom.2021.0627DOI Listing
April 2021

Neurotensin: A novel mediator of ovulation?

FASEB J 2021 Apr;35(4):e21481

Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USA.

The midcycle luteinizing hormone (LH) surge initiates a cascade of events within the ovarian follicle which culminates in ovulation. Only mural granulosa cells and theca cells express large numbers of LH receptors, and LH-stimulated paracrine mediators communicate the ovulatory signal within the follicle. Recent reports identified the neuropeptide neurotensin (NTS) as a product of granulosa cells. Here, we demonstrate that granulosa cells were the primary site of NTS expression in macaque ovulatory follicles. Granulosa cell NTS mRNA and protein increased after human chorionic gonadotropin (hCG) administration, which substitutes for the LH surge. To identify ovulatory actions of NTS, a NTS-neutralizing antibody was injected into preovulatory macaque follicles. hCG administration immediately followed, and ovaries were removed 48 hours later to evaluate ovulatory events. Follicles injected with control IgG ovulated normally. In contrast, 75% of NTS antibody-injected follicles failed to ovulate, containing oocytes trapped within unruptured, hemorrhagic follicles. Serum progesterone was unchanged. Of the three NTS receptors, SORT1 was highly expressed in follicular granulosa, theca, and endothelial cells; NTSR1 and NTSR2 were expressed at lower levels. Excessive blood cells in NTS antibody-injected follicles indicated vascular anomalies, so the response of monkey ovarian endothelial cells to NTS was evaluated in vitro. NTS stimulated endothelial cell migration and capillary sprout formation, consistent with a role for NTS in vascular remodeling associated with ovulation. In summary, we identified NTS as a possible paracrine mediator of ovulation. Further investigation of the NTS synthesis/response pathway may lead to improved treatments for infertility and novel targets for contraception.
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http://dx.doi.org/10.1096/fj.202002547RRDOI Listing
April 2021

Multi-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response.

Nat Commun 2021 03 2;12(1):1375. Epub 2021 Mar 2.

Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Cellular adaptation to hypoxia is a hallmark of cancer, but the relative contribution of hypoxia-inducible factors (HIFs) versus other oxygen sensors to tumorigenesis is unclear. We employ a multi-omics pipeline including measurements of nascent RNA to characterize transcriptional changes upon acute hypoxia. We identify an immediate early transcriptional response that is strongly dependent on HIF1A and the kinase activity of its cofactor CDK8, includes indirect repression of MYC targets, and is highly conserved across cancer types. HIF1A drives this acute response via conserved high-occupancy enhancers. Genetic screen data indicates that, in normoxia, HIF1A displays strong cell-autonomous tumor suppressive effects through a gene module mediating mTOR inhibition. Conversely, in advanced malignancies, expression of a module of HIF1A targets involved in collagen remodeling is associated with poor prognosis across diverse cancer types. In this work, we provide a valuable resource for investigating context-dependent roles of HIF1A and its targets in cancer biology.
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http://dx.doi.org/10.1038/s41467-021-21687-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925689PMC
March 2021