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1.
Am J Infect Control ; 49(10): 1215-1220, 2021 10.
Article de Anglais | MEDLINE | ID: mdl-34363872

RÉSUMÉ

INTRODUCTION: The COVID-19 pandemic placed unprecedented strain on the medical supply chain. Early in the pandemic, uncertainty regarding personal protective equipment (PPE) was high. Protecting health care workers from contracting illness is critical to preserve trust and workforce capacity. METHODS: We describe an initiative to design and manufacture a novel, re-usable, half-face respirator in case conventional medical supply chain failed to meet demand. It required new collaboration between the hospital, physicians, the medical school, and the school of engineering. We describe organizational priorities, constraints, and process of design, testing and approval as the health system engaged for the first time directly with the design and manufacturing process for PPE. RESULTS: An original mask design was developed, and the University Hospital had an initial batch of this novel mask manufactured during the first wave of the SARS-COV-2 pandemic. These masks, and the die necessary to produce more, are in reserve in case of depletion of stores of conventionally sourced PPE. CONCLUSIONS: The COVID-19 pandemic demonstrated fragility of medical supply chain. Organizations considering similar efforts should anticipate constraints on raw material supply chain and be flexible, adaptive, and fast. The incident command structure was vital to identifying priority areas needing alternative approaches, creating connections, and providing rapid approvals. We found organizational value in demonstrating commitment to assuring PPE supplies for health care worker safety.


Sujet(s)
COVID-19 , Pandémies , Personnel de santé , Hôpitaux universitaires , Humains , Masques , Équipement de protection individuelle , SARS-CoV-2
2.
Mol Genet Metab ; 117(2): 199-209, 2016 Feb.
Article de Anglais | MEDLINE | ID: mdl-26766614

RÉSUMÉ

New enzyme delivery technologies are required for treatment of lysosomal storage disorders with significant pathologies associated with the so-called "hard-to-treat" tissues and organs. Genetic deficiencies in the GLB1 gene encoding acid ß-galactosidase lead to GM1-gangliosidosis or Morquio B, lysosomal diseases with predominant disease manifestation associated with the central nervous system or skeletal system, respectively. Current lysosomal ERTs are delivered into cells based on receptor-mediated endocytosis and do not effectively address several hard-to-treat organs including those critical for GM1-gangliosidosis patients. Lectins provide alternative cell-uptake mechanisms based on adsorptive-mediated endocytosis and thus may provide unique biodistribution for lysosomal disease therapeutics. In the current study, genetic fusions of the plant galactose/galactosamine-binding lectin, RTB, and the human acid ß-galactosidase enzyme were produced using a plant-based bioproduction platform. ß-gal:RTB and RTB:ß-gal fusion products retained both lectin activity and ß-galactosidase activity. Purified proteins representing both fusion orientations were efficiently taken up into GM1 patient fibroblasts and mediated the reduction of GM1 ganglioside substrate with activities matching mammalian cell-derived ß-galactosidase. In contrast, plant-derived ß-gal alone was enzymatically active but did not mediate uptake or correction indicating the need for either lectin-based (plant product) or mannose-6-phosphate-based (mammalian product) delivery. Native ß-galactosidase undergoes catalytic activation (cleavage within the C-terminal region) in lysosomes and is stabilized by association with protective protein/cathepsin A. Enzymatic activity and lysosomal protein processing of the RTB fusions were assessed following internalization into GM1 fibroblasts. Within 1-4h, both ß-gal:RTB and RTB:ß-gal were processed to the ~64kDa "activated" ß-gal form; the RTB lectin was cleaved and rapidly degraded. The activated ß-gal was still detected at 48h suggesting interactions with protective protein/cathepsin A. Uptake-saturation analyses indicated that the RTB adsorptive-mediated mechanisms of ß-gal:RTB supported significantly greater accumulation of ß-galactose activity in fibroblasts compared to the receptor-mediated mechanisms of the mammalian cell-derived ß-gal. These data demonstrate that plant-made ß-gal:RTB functions as an effective replacement enzyme for GM1-gangliosidosis - delivering enzyme into cells, enabling essential lysosomal processing, and mediating disease substrate clearance at the cellular level. RTB provides novel uptake behaviors and thus may provide new receptor-independent strategies that could broadly impact lysosomal disease treatments.


Sujet(s)
Gangliosidose à GM1/traitement médicamenteux , Protéines de fusion recombinantes/métabolisme , beta-Galactosidase/métabolisme , Cellules cultivées , Thérapie enzymatique substitutive , Fibroblastes/enzymologie , Humains , Cinétique , Lysosomes/métabolisme , Lectines végétales/composition chimique , Lectines végétales/génétique , Lectines végétales/métabolisme , Protéines de fusion recombinantes/composition chimique , Protéines de fusion recombinantes/génétique , Nicotiana , beta-Galactosidase/composition chimique , beta-Galactosidase/génétique
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