34 results on '"Stoudemire J"'
Search Results
2. Developing therapeutic microRNAs for cancer
- Author
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Bader, A G, Brown, D, Stoudemire, J, and Lammers, P
- Published
- 2011
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3. 4LBA A phase 1 study of first-in-class microRNA-34 mimic, MRX34, in patients with hepatocellular carcinoma or advanced cancer with liver metastasis
- Author
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Beg, M., primary, Brenner, A., additional, Sachdev, J., additional, Borad, M., additional, Cortes, J., additional, Tibes, R., additional, Kang, Y., additional, Bader, A., additional, Stoudemire, J., additional, Smith, S., additional, Kim, S., additional, and Hong, D., additional
- Published
- 2014
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4. Recombinant human interleukin-11 stimulates megakaryocytopoiesis and increases peripheral platelets in normal and splenectomized mice
- Author
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Neben, TY, primary, Loebelenz, J, additional, Hayes, L, additional, McCarthy, K, additional, Stoudemire, J, additional, Schaub, R, additional, and Goldman, SJ, additional
- Published
- 1993
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5. The importance of N- and O-linked oligosaccharides for the biosynthesis and in vitro and in vivo biologic activities of erythropoietin
- Author
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Wasley, LC, primary, Timony, G, additional, Murtha, P, additional, Stoudemire, J, additional, Dorner, AJ, additional, Caro, J, additional, Krieger, M, additional, and Kaufman, RJ, additional
- Published
- 1991
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6. Replacement of finger and growth factor domains of tissue plasminogen activator with plasminogen kringle 1. Biochemical and pharmacological characterization of a novel chimera containing a high affinity fibrin-binding domain linked to a heterologous protein
- Author
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Langer-Safer, P R, primary, Ahern, T J, additional, Angus, L B, additional, Barone, K M, additional, Brenner, M J, additional, Horgan, P G, additional, Morris, G E, additional, Stoudemire, J B, additional, Timony, G A, additional, and Larsen, G R, additional
- Published
- 1991
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7. Site-directed mutagenesis in human tissue-plasminogen activator. Distinguishing sites in the amino-terminal region required for full fibrinolytic activity and rapid clearance from the circulation.
- Author
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Ahern, T J, primary, Morris, G E, additional, Barone, K M, additional, Horgan, P G, additional, Timony, G A, additional, Angus, L B, additional, Henson, K S, additional, Stoudemire, J B, additional, Langer-Safer, P R, additional, and Larsen, G R, additional
- Published
- 1990
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8. Improved Immune-Specificity in Monoclonal Radioimmunoimaging Using Dual Radionuclide Color Functional Maps
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Villanueva J, Scannon P, Robert S. Hattner, D. Faulkner, Lynn E. Spitler, Barry L. Engelstad, Stoudemire J, E C Ramos, and O'Connell Jw
- Subjects
medicine.drug_class ,Melanoma, Experimental ,Mice, Nude ,Gallium Radioisotopes ,Monoclonal antibody ,Scintigraphy ,Indium ,Mice ,Immune system ,Antigen ,Antibody Specificity ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Radionuclide Imaging ,Hue ,Radioisotopes ,Pixel ,biology ,medicine.diagnostic_test ,Chemistry ,business.industry ,Antibodies, Monoclonal ,General Medicine ,Image Enhancement ,Monoclonal ,biology.protein ,Antibody ,Nuclear medicine ,business ,Biomedical engineering - Abstract
Diagnostic radioimmunoimaging is potentially limited by tissue localization of radiolabeled antibody products through mechanisms other than antigen binding. Comparing the distributions of reactive and nonreactive products can distinguish tracer in targeted and nontargeted tissues. To achieve this in a single imaging procedure, dual photopeak scintigraphy was performed using /sup 111/In and 67Ga products. Melanoma-bearing athymic mice were coadministered intravenously subtype-matched /sup 111/In melanoma-reactive and 67Ga melanoma-nonreactive murine monoclonal antibodies. Paired images from 245 and 93 keV windows were processed with a unique dual parameter color display program. The display algorithm expresses pixel counts from paired photo-peak images in polar coordinates and color-encodes angle as hue and magnitude as intensity. The color functional maps permitted ready distinction of immune from nonimmune uptake. Compared with single tracer imaging methods, this technique better depicts antigen distribution.
- Published
- 1986
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9. Metabolism of lipoproteins containing apolipoprotein B-100 in blood plasma of rabbits: heterogeneity related to the presence of apolipoprotein E.
- Author
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Yamada, N, Shames, D M, Stoudemire, J B, and Havel, R J
- Abstract
Apolipoprotein B-100 is a constant component of very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL) in mammalian blood plasma. We have found that each of these classes of lipoproteins includes particles that contain apolipoprotein E (B,E particles) as well as particles that lack this protein (B particles). These two species can be separated by immunosorption on columns of anti-apolipoprotein E bound to Sepharose. We have injected radioiodinated VLDL, IDL, and LDL intravenously into recipient rabbits and have determined the concentration of radioiodine in apolipoprotein B-100 in B,E and B particles in whole-blood plasma obtained at intervals for 24 hr. We have developed a multicompartmental model that is consistent with this new information and with current concepts of lipoprotein metabolism. The model indicates that all apolipoprotein B-100 enters the blood as VLDL, of which about 90% is in B,E particles. Most VLDL B,E particles are removed rapidly from the blood, and only a small fraction is converted to IDL and eventually to LDL (overall conversion is approximately 2%). By contrast, a much smaller fraction of VLDL B particles is removed directly, and approximately 27% is converted to LDL. In addition, some B,E particles are converted to B particles as VLDL are converted to LDL, so that most LDL particles lack apolipoprotein E. Fractional rates of irreversible removal of B,E and B particles in IDL and LDL are similar. Our results indicate that the presence of apolipoprotein E is a major determinant of the metabolic fate of VLDL particles and support the hypothesis that polyvalent binding of particles containing several molecules of apolipoprotein E promotes receptor-dependent endocytosis of hepatogenous lipoproteins and limits their conversion to lipoproteins of higher density.
- Published
- 1986
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10. RECOMBINANT HUMAN MACROPHAGE COLONY STIMULATING FACTOR (RH-MCSF) LOWERS LDL AND RAISES HDL IN WHHL RABBITS
- Author
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Parker, T. S., Levine, D. M., Thomas Donnelly, Stoudemire, J. B., and Garnick, M. B.
11. Effect of Cyclophosphamide on the Immunogenicity of Monoclonal Antimelanoma Antibody-Ricin A Chain Immunotoxin in Rats
- Author
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HARKONEN, S., primary, MISCHAK, R., additional, LOPEZ, H., additional, and STOUDEMIRE, J., additional
- Published
- 1987
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12. Impaired receptor-mediated catabolism of low density lipoproteins in fasted rabbits.
- Author
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Stoudemire, J B, primary, Renaud, G, additional, Shames, D M, additional, and Havel, R J, additional
- Published
- 1984
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13. Effects of microgravity on human iPSC-derived neural organoids on the International Space Station.
- Author
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Marotta D, Ijaz L, Barbar L, Nijsure M, Stein J, Pirjanian N, Kruglikov I, Clements T, Stoudemire J, Grisanti P, Noggle SA, Loring JF, and Fossati V
- Subjects
- Humans, Cell Differentiation, Space Flight, Parkinson Disease therapy, Parkinson Disease metabolism, Organoids metabolism, Organoids cytology, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells metabolism, Weightlessness
- Abstract
Research conducted on the International Space Station (ISS) in low-Earth orbit (LEO) has shown the effects of microgravity on multiple organs. To investigate the effects of microgravity on the central nervous system, we developed a unique organoid strategy for modeling specific regions of the brain that are affected by neurodegenerative diseases. We generated 3-dimensional human neural organoids from induced pluripotent stem cells (iPSCs) derived from individuals affected by primary progressive multiple sclerosis (PPMS) or Parkinson's disease (PD) and non-symptomatic controls, by differentiating them toward cortical and dopaminergic fates, respectively, and combined them with isogenic microglia. The organoids were cultured for a month using a novel sealed cryovial culture method on the International Space Station (ISS) and a parallel set that remained on Earth. Live samples were returned to Earth for analysis by RNA expression and histology and were attached to culture dishes to enable neurite outgrowth. Our results show that both cortical and dopaminergic organoids cultured in LEO had lower levels of genes associated with cell proliferation and higher levels of maturation-associated genes, suggesting that the cells matured more quickly in LEO. This study is continuing with several more missions in order to understand the mechanisms underlying accelerated maturation and to investigate other neurological diseases. Our goal is to make use of the opportunity to study neural cells in LEO to better understand and treat neurodegenerative disease on Earth and to help ameliorate potentially adverse neurological effects of space travel., (© The Author(s) 2024. Published by Oxford University Press.)
- Published
- 2024
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14. Cosmic-Ray Radiation Effects on Ibuprofen Tablet Formulation Inside and Outside of the International Space Station.
- Author
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Tran QD, Spooner N, Geoghehan S, Thavarajah SR, Rahman S, Tran NN, Williams PM, Jarquin SM, Kim DH, Davey K, Buell J, Shumbera M, Gittleman M, Clements T, Stoudemire J, Fisk I, and Hessel V
- Abstract
In extreme environments people will have different needs for medicine(s), making it crucial to understand how such environments affect drug efficacy. Ibuprofen, commonly used in tablet formulation on Earth, could fail in space despite standard pharmaceutical packaging. We introduce the concept of 'space medicines', where solid-dosage forms protect the pharmaceutical from accelerated degradation in spaceflight. We simulate dose(s) in International Space Station (ISS) through radionuclide and photon experiments, and establish the impact of alpha, beta and gamma rays. We demonstrate that tablet formulation protects from impact of alpha and beta rays; however, gamma rays decompose ibuprofen even when 'masked'. We systematically analyse 19 tablet compositions inside and outside the ISS to determine the effect of compositional changes in the tablet matrix. We confirm that the iron oxide-shielded tablets show minimal degradation (〈10%) inside the ISS, compared to moderate reductions (〉10%) for other formulations, with one exception. The tablets exhibited significantly greater ibuprofen degradation (〉 30-50%) outside ISS, due to harsh conditions. Significantly, we found that flavour have shielding potential by scavenging free radicals. We conclude that ibuprofen efficacy is adversely affected in space, and these effects are expected to worsen on missions to deeper space destinations., (© 2024 Wiley‐VCH GmbH.)
- Published
- 2024
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15. Surface tension enables induced pluripotent stem cell culture in commercially available hardware during spaceflight.
- Author
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Mozneb M, Arzt M, Mesci P, Martin DMN, Pohlman S, Lawless G, Doraisingam S, Al Neyadi S, Barnawi R, Al Qarni A, Whitson PA, Shoffner J, Stoudemire J, Countryman S, Svendsen CN, and Sharma A
- Abstract
Low Earth Orbit (LEO) has emerged as a unique environment for evaluating altered stem cell properties in microgravity. LEO has become increasingly accessible for research and development due to progress in private spaceflight. Axiom Mission 2 (Ax-2) was launched as the second all-private astronaut mission to the International Space Station (ISS). Frozen human induced pluripotent stem cells (hiPSCs) expressing green fluorescent protein (GFP) under the SOX2 promoter, as well as fibroblasts differentiated from SOX2-GFP hiPSCs, were sent to the ISS. Astronauts then thawed and seeded both cell types into commercially available 96-well plates, which provided surface tension that reduced fluid movement out of individual wells and showed that hiPSCs or hiPSC-derived fibroblasts could survive either in suspension or attached to a Matrigel substrate. Furthermore, both cell types could be transfected with red fluorescent protein (RFP)-expressing plasmid. We demonstrate that hiPSCs and hiPSC-fibroblasts can be thawed in microgravity in off-the-shelf, commercially-available cell culture hardware, can associate into 3D spheroids or grow adherently in Matrigel, and can be transfected with DNA. This lays the groundwork for future biomanufacturing experiments in space., (© 2024. The Author(s).)
- Published
- 2024
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16. Establishing Neural Organoid Cultures for Investigating the Effects of Microgravity in Low-Earth Orbit (LEO).
- Author
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Pirjanian NA, Kalpana K, Kruglikov I, Mesci P, Stoudemire J, Grisanti P, Noggle SA, Loring JF, and Fossati V
- Abstract
Recent findings from studies involving astronauts and animal models indicate that microgravity increases immune cell activity and potentially alters the white and gray matter of the central nervous system (CNS). To further investigate the impact of microgravity on CNS cells, we established cultures of three-dimensional neural organoids containing isogenic microglia, the brain's resident immune cells, and sent them onboard the International Space Station. When using induced pluripotent stem cell (iPSC) lines from individuals affected by neuroinflammatory and neurodegenerative diseases such as multiple sclerosis (MS) and Parkinson's disease (PD), these cultures can provide novel insights into pathogenic pathways that may be exacerbated by microgravity. We have devised a cryovial culture strategy that enables organoids to be maintained through space travel and onboard the International Space Station (ISS) without the need for medium or carbon dioxide exchange. Here, we provide a comprehensive description of all the steps involved: generating various types of neural organoids, establishing long-term cultures, arranging plans for shipment to the Kennedy Space Center (KSC), and ultimately preparing organoids for launch into low-Earth orbit (LEO) and return to Earth for post-flight analyses., (© 2024. Springer Science+Business Media, LLC.)
- Published
- 2024
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17. In-Space Fabrication of Janus Base Nano-Matrix for Improved Assembly and Bioactivities.
- Author
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Yau A, Landolina M, Snow MA, Mesci P, Williams B, Hoying J, Duflo D, Wu H, Stoudemire J, Hernandez R, and Chen Y
- Abstract
In-space manufacturing of nanomaterials is a promising concept while having limited successful examples. DNA-inspired Janus base nanomaterials (JBNs), used for therapeutics delivery and tissue regeneration, are fabricated via a controlled self-assembly process in water at ambient temperature, making them highly suitable for in-space manufacturing. For the first time, we designed and accomplished the production of JBNs on orbit during the Axiom-2 (Ax-2) mission demonstrating great promising and benefits of in-space manufacturing of nanomaterials.
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- 2024
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18. Freezing Biological Time: A Modern Perspective on Organ Preservation.
- Author
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Criswell T, Swart C, Stoudemire J, Brockbank KGM, Powell-Palm M, Stilwell R, and Floren M
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- Humans, Freezing, Temperature, Organ Preservation, Cryopreservation
- Abstract
Transporting tissues and organs from the site of donation to the patient in need, while maintaining viability, is a limiting factor in transplantation medicine. One way in which the supply chain of organs for transplantation can be improved is to discover novel approaches and technologies that preserve the health of organs outside of the body. The dominant technologies that are currently in use in the supply chain for biological materials maintain tissue temperatures ranging from a controlled room temperature (+25 °C to +15 °C) to cryogenic (-120 °C to -196 °C) temperatures (reviewed in Criswell et al. Stem Cells Transl Med. 2022). However, there are many cells and tissues, as well as all major organs, that respond less robustly to preservation attempts, particularly when there is a need for transport over long distances that require more time. In this perspective article, we will highlight the current challenges and advances in biopreservation aimed at "freezing biological time," and discuss the future directions and requirements needed in the field., (© The Author(s) 2022. Published by Oxford University Press.)
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- 2023
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19. Leveraging Spaceflight to Advance Cardiovascular Research on Earth.
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Scott JM, Stoudemire J, Dolan L, and Downs M
- Subjects
- Astronauts, Humans, United States, United States National Aeronautics and Space Administration, Induced Pluripotent Stem Cells, Space Flight, Weightlessness adverse effects
- Abstract
The direct (eg, radiation, microgravity) and indirect (eg, lifestyle perturbations) effects of spaceflight extend across multiple systems resulting in whole-organism cardiovascular deconditioning. For over 50 years, National Aeronautics and Space Administration has continually enhanced a countermeasures program designed to characterize and offset the adverse cardiovascular consequences of spaceflight. In this review, we provide a historical overview of research evaluating the effects of spaceflight on cardiovascular health in astronauts and outline mechanisms underpinning spaceflight-related cardiovascular alterations. We also discuss how spaceflight could be leveraged for aging, industry, and model systems such as human induced pluripotent stem cell-derived cardiomyocytes, organoid, and organ-on-a-chip technologies. Finally, we outline the increasing opportunities for scientists and clinicians to engage in cardiovascular research in space and on Earth.
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- 2022
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20. Shipping and Logistics Considerations for Regenerative Medicine Therapies.
- Author
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Criswell T, Swart C, Stoudemire J, Brockbank K, Floren M, Eaker S, and Hunsberger J
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- Cell- and Tissue-Based Therapy, Humans, Pandemics, Tissue Engineering methods, COVID-19, Regenerative Medicine methods
- Abstract
Advances in regenerative medicine manufacturing continue to be a priority for achieving the full commercial potential of important breakthrough therapies. Equally important will be the establishment of distribution chains that support the transport of live cells and engineered tissues and organs resulting from these advanced biomanufacturing processes. The importance of a well-managed distribution chain for products requiring specialized handling procedures was highlighted during the COVID-19 pandemic and serves as a reminder of the critical role of logistics and distribution in the success of breakthrough therapies. This perspective article will provide insight into current practices and future considerations for creating global distribution chains that facilitate the successful deployment of regenerative medicine therapies to the vast number of patients that would benefit from them worldwide., (© The Author(s) 2022. Published by Oxford University Press.)
- Published
- 2022
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21. Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.
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Hong DS, Kang YK, Borad M, Sachdev J, Ejadi S, Lim HY, Brenner AJ, Park K, Lee JL, Kim TY, Shin S, Becerra CR, Falchook G, Stoudemire J, Martin D, Kelnar K, Peltier H, Bonato V, Bader AG, Smith S, Kim S, O'Neill V, and Beg MS
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents pharmacokinetics, Female, Humans, Liposomes adverse effects, Liposomes pharmacokinetics, Male, Maximum Tolerated Dose, MicroRNAs pharmacokinetics, Middle Aged, Nanoparticles administration & dosage, Nanoparticles adverse effects, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, MicroRNAs administration & dosage, MicroRNAs adverse effects, Neoplasms drug therapy
- Abstract
Background: In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours., Methods: Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles., Results: Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m
2 for hepatocellular carcinoma (HCC) and 93 mg/m2 for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11-55)., Conclusion: MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy., Clinical Trial Registration: NCT01829971.- Published
- 2020
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22. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors.
- Author
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Beg MS, Brenner AJ, Sachdev J, Borad M, Kang YK, Stoudemire J, Smith S, Bader AG, Kim S, and Hong DS
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Drug Administration Schedule, Female, Humans, Liposomes, Male, Maximum Tolerated Dose, MicroRNAs adverse effects, MicroRNAs pharmacokinetics, MicroRNAs therapeutic use, Middle Aged, Nanoparticles administration & dosage, Nanoparticles adverse effects, Neoplasms metabolism, Treatment Outcome, Antineoplastic Agents administration & dosage, MicroRNAs administration & dosage, Neoplasms drug therapy
- Abstract
Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles. Results Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC; n = 14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1-12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3%: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3%/G4%: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m
2 , with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m2 . The half-life was >24 h, and Cmax and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles. Conclusion MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m2 for non-HCC and 93 mg/m2 for HCC patients. Additional dose schedules of MRX34 have been explored to improve tolerability.- Published
- 2017
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23. Quantification of therapeutic miRNA mimics in whole blood from nonhuman primates.
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Kelnar K, Peltier HJ, Leatherbury N, Stoudemire J, and Bader AG
- Subjects
- Animals, Biomimetic Materials pharmacokinetics, Biomimetic Materials therapeutic use, Calibration, Drug Stability, Drug Storage, Freezing, Limit of Detection, MicroRNAs therapeutic use, Biomimetic Materials analysis, Macaca fascicularis blood, MicroRNAs blood
- Abstract
MRX34, a microRNA (miRNA)-based therapy for cancer, has recently entered clinical trials as the first clinical candidate in its class. It is a liposomal nanoparticle loaded with a synthetic mimic of the tumor suppressor miRNA miR-34a as the active pharmaceutical ingredient. To understand the pharmacokinetic properties of the drug and to rationalize an optimal dosing regimen in the clinic, a method is needed to quantitatively detect the miRNA mimic. Here, we report the development and qualification of a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay in support of pharmacokinetic and toxicokinetic assessments in the nonhuman primate. Detection and quantification were performed on total ribonucleic acid (RNA) isolated from whole blood. The qualified range of the standard curve spans 6 orders of magnitude from 2.5 × 10(-7) to 2.5 × 10(-1) ng per reverse transcription (RT) reaction, corresponding to an estimated blood concentration from 6.2 × 10(-5) to 6.2 × 10(1) ng/mL. Our results demonstrate that endogenous as well as the exogenous miR-34a can be accurately and precisely quantified. The assay was used to establish the pharmacokinetic profile of MRX34, showing a favorable residence time and exposure of the miRNA mimic in whole blood from nonhuman primates.
- Published
- 2014
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24. The effect of aerosolized recombinant human granulocyte macrophage colony-stimulating factor on lung leukocytes in nonhuman primates.
- Author
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Rose RM, Kobzik L, Dushay K, Wolfthal S, Hondalus M, Metzger M, Stoudemire J, Brain JD, Garnick M, and O'Donnell C
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- Administration, Inhalation, Aerosols, Animals, Bronchoalveolar Lavage Fluid cytology, Disease Models, Animal, Drug Evaluation, Preclinical, Granulocyte-Macrophage Colony-Stimulating Factor administration & dosage, Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use, Infusions, Intravenous, Leukocyte Count, Leukocytes physiology, Macaca fascicularis, Male, Phagocytosis drug effects, Respiratory Burst drug effects, Respiratory Distress Syndrome chemically induced, Respiratory Distress Syndrome diagnosis, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Leukocytes drug effects, Lung cytology
- Abstract
The number and function of myeloid cells in the lungs are critical determinants of health and disease. To examine whether these cells can be modulated in vivo by a colony-stimulating factor (CSF), recombinant human granulocyte macrophage-CSF (GM-CSF) was given to cynomolgus monkeys by either continuous intravenous infusion (7,200 U/kg/day) for 2 wk or by aerosol exposure to 10(7) U on 1 or 2 consecutive days. At intervals after the initiation of GM-CSF administration, animals underwent bronchoalveolar lavage (BAL) and had peripheral blood sampled to characterize changes in lung and circulating phagocytic cells. Compared with animals exposed to bovine serum albumin, there was an increase in the total number of BAL cells retrieved. This increase was greatest in animals receiving aerosolized GM-CSF, and it was the result of more macrophages and neutrophils. Both lung macrophages and blood neutrophils from animals exposed to aerosolized GM-CSF exhibited an augmented respiratory burst in response to phorbol myristate acetate. Lung macrophages from GM-CSF-exposed animals exhibited increased capacity to bind and/or ingest opsonized and unopsonized Staphylococcus aureus. Despite functional activation of lung phagocytic cells, biochemical analyses of BAL fluid for markers of lung injury revealed an increase in only some parameters in the GM-CSF group. Intravenous administration of GM-CSF had the expected effect on augmenting the number of myeloid cells in the bloodstream. Aerosolized GM-CSF produced a transient effect on circulating myeloid cell number between 3 and 5 days after exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1992
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25. Modulation of macrophage colony stimulating factor in cultured human retinal pigment epithelial cells.
- Author
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Jaffe GJ, Peters WP, Roberts W, Kurtzberg J, Stuart A, Wang AM, and Stoudemire JB
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- Cells, Cultured, DNA biosynthesis, Dose-Response Relationship, Drug, Humans, Interleukin-1 pharmacology, RNA, Messenger biosynthesis, Time Factors, Tumor Necrosis Factor-alpha pharmacology, Macrophage Colony-Stimulating Factor biosynthesis, Pigment Epithelium of Eye metabolism
- Abstract
Steady-state mRNA expression and protein production of macrophage colony stimulating factor were measured in visually confluent monolayers of unstimulated cultured human retinal pigment epithelial cells and after cells were stimulated with recombinant cytokines. Using reverse transcription polymerase chain reaction, macrophage colony stimulating factor mRNA expression was detected in unstimulated cells obtained from each of four separate donors. In these cells, mRNA expression was accompanied by secretion of macrophage colony stimulating factor protein into cell-conditioned medium; 48 hr after cells were switched to fresh medium, the mean (+/- S.D.) quantity of macrophage colony stimulating factor, measured by enzyme-linked immunoassay, was 5.1 +/- 2.3 ng 10(-6) cells. There was a dose- and time-dependent induction of macrophage colony stimulating factor mRNA after cells were exposed to recombinant human interleukin-1 and tumor necrosis factor alpha. Maximal mRNA induction was observed in cells exposed for 4 hr to interleukin-1 beta (5 U ml-1) or for 4-8 hr to tumor necrosis factor alpha; under these conditions, macrophage colony stimulating factor mRNA was induced up to 23- and 46-fold after exposure to interleukin-1 beta and tumor necrosis factor alpha, respectively. Similarly, macrophage colony stimulating factor protein production was enhanced after cells were exposed to recombinant cytokines. Protein secretion increased 1.3-2.5-fold (P less than 0.001) after exposure to interleukin-1 beta (5 U ml-1), and 1.2-1.6-fold after exposure to tumor necrosis factor alpha (P less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1992
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26. Improved pharmacokinetics and tumor localization of immunotoxins constructed with the Mr 30,000 form of ricin A chain.
- Author
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Trown PW, Reardan DT, Carroll SF, Stoudemire JB, and Kawahata RT
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- Animals, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal therapeutic use, Cell Line, Cell Survival drug effects, Colorectal Neoplasms drug therapy, Colorectal Neoplasms metabolism, Female, Humans, Immunotoxins chemical synthesis, Immunotoxins pharmacology, Immunotoxins therapeutic use, Leukemia, T-Cell, Mice, Mice, Nude, Molecular Weight, Neoplasm Transplantation, Osteosarcoma metabolism, Ricin pharmacology, Ricin therapeutic use, Sarcoma, Experimental metabolism, Tissue Distribution, Transplantation, Heterologous, Immunotoxins pharmacokinetics, Osteosarcoma drug therapy, Ricin pharmacokinetics, Sarcoma, Experimental drug therapy
- Abstract
The two naturally occurring forms of ricin A chain, Mr 33,000 and Mr 30,000 (RTA33 and RTA30) have been purified, and their chemical compositions, toxicities, and tissue distributions have been determined. As reported previously, the in vitro and in vivo toxicities of RTA30 and RTA33 are similar. However, RTA30, which contains less carbohydrate with a lower mannose content than RTA33, accumulated less in the liver than did RTA33. Monoconjugate immunotoxins (i.e., containing one RTA per monoclonal antibody molecule) were constructed between RTA30 or RTA33 and the antitumor monoclonal antibody 791T/36, which recognizes a Mr 72,000 antigen on osteosarcoma and colon carcinoma cells. The two immunotoxins had similar cytoxicities in vitro but differed substantially in their pharmacokinetics and tissue distributions in vivo in nude mice bearing C170 human colorectal carcinoma xenografts. The immunotoxin derived from RTA30 (IT30) accumulated less in the liver than the immunotoxin derived from RTA33 (IT33) and cleared more slowly from the blood; the alpha and beta half-lives for IT30 and IT33 were 0.50 and 20.5 versus 0.17 and 14.6 h, respectively. As a probable consequence, IT30 accumulated to approximately 3-fold higher levels in the C170 xenografts than IT33. The reduced clearance of IT30 by the reticuloendothelial system thus resulted in prolonged survival in the blood and enhanced tumor localization relative to IT33.
- Published
- 1991
27. Protein engineering of novel plasminogen activators with increased thrombolytic potency in rabbits relative to activase.
- Author
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Larsen GR, Timony GA, Horgan PG, Barone KM, Henson KS, Angus LB, and Stoudemire JB
- Subjects
- Animals, Cell Line, Cricetinae, Fibrinogen metabolism, Fibrinolysin metabolism, Hemostasis, Injections, Intravenous, Metabolic Clearance Rate, Plasminogen Activators genetics, Plasminogen Activators pharmacokinetics, Protein Engineering, Rabbits, alpha-Macroglobulins metabolism, Fibrinolytic Agents pharmacokinetics, Plasminogen Activators pharmacology, Tissue Plasminogen Activator pharmacology
- Abstract
Human tissue-type plasminogen activator (t-PA) is a glycoprotein used currently in thrombolytic therapy for patients with acute myocardial infarction. Due to its rapid rate of clearance from the circulation, continuous intravenous administration of approximately 100 mg over 3 h is recommended. We have previously characterized novel thrombolytic variant forms of t-PA which offer the potential of administration by bolus injection and reduced dosage due to their slower rates of clearance, relative to t-PA. This study was undertaken to quantitatively compare the pharmacokinetics, thrombolytic activity, and hemostatic effects of two of these variant forms, called delta FE1X and delta FE3X plasminogen activator (PA), with commercially available recombinant t-PA (Activase). These evaluations were performed in rabbits after bolus intravenous injection of the proteins. Following injection of 0.25 mg of protein/kg of body weight, the rates of clearance for delta FE3X and delta FE1X PA antigen were decreased approximately 9- and 18-fold, respectively, relative to Activase. Plasma plasminogen activator activity was also measured and the rates of clearance of delta FE3X and delta FE1X PA activity were similarly decreased by approximately 9- and 22-fold, respectively, relative to Activase. To quantitate thrombolytic activity we used the rabbit jugular vein thrombosis model and demonstrated that approximately 50% thrombolysis was achieved with delta FE1X and delta FE3X PA at approximately an 8.6- and 3-fold lower dose than Activase, respectively. No major differences in fibrinogen and alpha 2-antiplasmin depletion were observed among the agents at doses required to produce 50% thrombolysis, indicating similarities in fibrin specificities among these agents. These results demonstrate a reciprocal relationship between thrombolysis and rate of clearance for these thrombolytic proteins. The 8.6-fold increase in potency of delta FE1X PA relative to Activase supports the future clinical testing of this novel engineered protein as a thrombolytic agent.
- Published
- 1991
28. Effects of recombinant human macrophage colony-stimulating factor on plasma cholesterol levels.
- Author
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Stoudemire JB and Garnick MB
- Subjects
- Animals, Cholesterol, HDL blood, Cholesterol, LDL blood, Female, Homeostasis, Hyperlipidemias blood, Hyperlipidemias pathology, Leukocyte Count, Liver pathology, Macaca fascicularis, Macrophage Colony-Stimulating Factor administration & dosage, Macrophage Colony-Stimulating Factor adverse effects, Macrophages pathology, Male, Rabbits, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects, Recombinant Proteins pharmacology, Spleen pathology, Cholesterol blood, Macrophage Colony-Stimulating Factor pharmacology
- Abstract
Recombinant human macrophage colony-stimulating factor (rhM-CSF) is a hematopoietic growth factor that stimulates the growth, differentiation, proliferation, and activation of cells of the monocyte/macrophage lineage. rhM-CSF was administered to rabbits and nonhuman primates to evaluate effects on cholesterol homeostasis. Decreases in plasma cholesterol concentrations were observed during rhM-CSF administration. The observed mean (+/- SD) decreases over a range of doses in nonhuman primates receiving rhM-CSF by continuous intravenous infusion (CIVI) or intravenous bolus (IVB) injection were approximately 16% +/- 8% and 43% +/- 10%, respectively. Low-density lipoprotein (LDL) cholesterol levels decreased 55% +/- 9% from pretreatment baseline values in the animals receiving rhM-CSF by IVB. Normocholesterolemic New Zealand white rabbits receiving rhM-CSF over a range of doses by CIVI showed a decrease from baseline in total cholesterol of approximately 28% +/- 17%, with LDL cholesterol levels decreasing by approximately 72% +/- 33%, while high-density lipoprotein levels showed variable changes, including increased values. A decrease of 36% +/- 26% in total plasma cholesterol was observed in Watanabe Heritable Hyperlipidemic rabbits receiving rhM-CSF by CIVI for 7 days. This decrease was attributable almost entirely to decreases in LDL cholesterol, which fell approximately 34% +/- 24% from baseline. Although the mechanism of this cholesterol-lowering effect is unknown, these results strongly suggest that rhM-CSF may provide a novel treatment for hypercholesterolemia and may be useful in investigations into the mechanisms of cholesterol homeostasis and atherogenesis.
- Published
- 1991
29. The effects of cyclophosphamide on the toxicity and immunogenicity of ricin A chain immunotoxin in rats.
- Author
-
Stoudemire JB, Mischak R, Foxall C, Harkonen WS, Del Rio M, and Spitler LE
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal immunology, Antibody Formation drug effects, Cyclophosphamide administration & dosage, Drug Interactions, Female, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents pharmacology, Immunotoxins administration & dosage, Immunotoxins immunology, Rats, Rats, Inbred Strains, Ricin administration & dosage, Ricin immunology, Cyclophosphamide pharmacology, Immunotoxins toxicity, Ricin toxicity
- Abstract
We conducted a study to determine if treatment with cyclophosphamide (CY) could suppress the formation of anti-murine and anti-ricin A chain antibodies in rats treated with a murine monoclonal antibody-ricin A chain immunotoxin (IT). Female Sprague-Dawley rats received intravenous doses of IT at a dose of 5 mg/kg body weight alone or in combination with CY at a dose level of either 10 or 20 mg/kg body weight. The IT was given as one or two courses consisting of five consecutive daily intravenous injections (days 0 to 4, or days 0 to 4 and days 21 to 25 of the study). Cyclophosphamide was given on days 2, 4, 6, 13, and 17 of the study to the group receiving a single course of IT; additional doses of CY were administered on days 23, 25, and 27 to the group receiving two courses of IT. On days 4, 14, 21, 28, and 35, animals from each group were evaluated for antibodies to murine IgG and ricin A chain, and for clinical laboratory parameters and histopathology. Animals receiving IT alone developed significant titers of both anti-murine and anti-ricin A chain antibodies. Compared with the response in the animals receiving single-course IT, the response to both of the components of the IT was significantly increased on days 28 and 35 in the animals receiving a second course of IT. The groups receiving a combination of either one or two courses of CY and IT demonstrated a significantly decreased antibody response to both the murine IgG and the ricin A chain compared with the group receiving IT alone.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1990
30. Preclinical and clinical evaluation of recombinant human macrophage colony-stimulating factor (rhM-CSF).
- Author
-
Garnick MB and Stoudemire JB
- Subjects
- Animals, Humans, In Vitro Techniques, Macrophage Colony-Stimulating Factor, Macrophages drug effects, Recombinant Proteins therapeutic use, Colony-Stimulating Factors therapeutic use
- Abstract
The promise of hematopoietic growth factors is now being realized as clinical trials become more mature. The uses of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor are now becoming more established in therapeutic applications of disease states. A variety of new hematopoietic growth factors is on the horizon, including recombinant human macrophage colony-stimulating factor (rhM-CSF), which has recently entered clinical trials after extensive preclinical testing. The diverse biological actions of rhM-CSF will provide novel ways of approaching various medical problems across the disciplines of hematology, oncology, infectious disease and cardiology.
- Published
- 1990
- Full Text
- View/download PDF
31. Properties of serum high-density lipoproteins in the crab, Cancer antennarius Stimpson.
- Author
-
Spaziani E, Havel RJ, Hamilton RL, Hardman DA, Stoudemire JB, and Watson RD
- Subjects
- Animals, Cholesterol Esters analysis, Fatty Acids analysis, Female, Glycerides analysis, Hemolymph analysis, Macromolecular Substances, Microscopy, Electron, Molecular Weight, Phospholipids analysis, Solubility, Brachyura metabolism, Lipoproteins, HDL isolation & purification
- Abstract
Two classes of high-density lipoprotein (HDL) comprise virtually all the lipoprotein mass in female hemolymph. These lipoproteins have hydrated densities of 1.187 g/ml (HDL3) and 1.112 g/ml (HDL2). A third species (HDL1, density 1.080 g/ml) appeared in ovigerous crabs. The mean annual HDL protein concentration was 109 mg/dl of which 67% was HDL3. HDL proteins of both HDL2 and HDL3 were mostly insoluble in tetramethylurea. Three major components with apparent mol. wts of 185,000, 100,000 and 84,000 daltons were identified by gel electrophoresis in SDS. Amino acid compositions are reported. Electron microscopy indicated that the HDL are polymorphic and discoidal. Similarities in shape and differences in size of HDL3 and HDL2 particles were consistent with their lipid and protein composition. Phospholipids, mostly phosphatidylcholine, were the dominant lipid class (74%); no cholesteryl esters were detected. Palmitic and oleic acids were the major fatty acid components of esterified lipids.
- Published
- 1986
- Full Text
- View/download PDF
32. Improved immune-specificity in monoclonal radioimmunoimaging using dual radionuclide color functional maps.
- Author
-
Engelstad BL, Ramos EC, Stoudemire J, O'Connell JW, Villanueva J, Faulkner DB, Hattner RS, Spitler LE, and Scannon P
- Subjects
- Animals, Gallium Radioisotopes metabolism, Image Enhancement, Mice, Mice, Nude, Radionuclide Imaging, Antibodies, Monoclonal metabolism, Antibody Specificity, Indium immunology, Melanoma, Experimental diagnostic imaging, Radioisotopes immunology
- Abstract
Diagnostic radioimmunoimaging is potentially limited by tissue localization of radiolabeled antibody products through mechanisms other than antigen binding. Comparing the distributions of reactive and nonreactive products can distinguish tracer in targeted and nontargeted tissues. To achieve this in a single imaging procedure, dual photopeak scintigraphy was performed using 111In and 67Ga products. Melanoma-bearing athymic mice were coadministered intravenously subtype-matched 111In melanoma-reactive and 67Ga melanoma-nonreactive murine monoclonal antibodies. Paired images from 245 and 93 keV windows were processed with a unique dual parameter color display program. The display algorithm expresses pixel counts from paired photo-peak images in polar coordinates and color-encodes angle as hue and magnitude as intensity. The color functional maps permitted ready distinction of immune from nonimmune uptake. Compared with single tracer imaging methods, this technique better depicts antigen distribution.
- Published
- 1986
- Full Text
- View/download PDF
33. Defect in cholesterol transport in patients receiving maintenance hemodialysis.
- Author
-
Hsia SL, Perez GO, Mendez AJ, Schiffman J, Fletcher S, and Stoudemire JB
- Subjects
- Adult, Aged, Chromatography, Gas, Female, Humans, Lipids blood, Lipoproteins, HDL analysis, Lipoproteins, HDL metabolism, Lipoproteins, LDL analysis, Lipoproteins, LDL metabolism, Lipoproteins, VLDL analysis, Lipoproteins, VLDL metabolism, Male, Middle Aged, Renal Dialysis, Cholesterol metabolism, Uremia metabolism
- Abstract
A defect in cholesterol transport was detected in patients with uremia who were receiving long-term hemodialysis when the rate of cholesterol transfer (RCT) from high-density lipoprotein (HDL) to very low-density (VLDL) and low-density lipoproteins (LDL) was compared with that in controls. The RCT (mean +/- SD) in 29 men with uremia (1.85 +/- 1.29 mg/hr/100 ml) and 11 women with uremia (1.84 +/- 1.00 mg/hr/100 ml) was significantly lower (P less than 0.001) than values in 55 healthy men (4.50 +/- 2.61 mg/hr/100 ml) and 23 healthy women (3.72 +/- 1.92 mg/hr/100 ml), respectively. Six patients, but none of the controls, totally lacked the ability for cholesterol transfer. The decreased RCT of the patients could not be completely accounted for by their decreased HDL cholesterol levels, because patients matched with controls for HDL cholesterol within 1 mg/100 ml also had lower RCT (P less than 0.0025). Recombination and crossover of serum fractions of patients and controls separated by ultracentrifugation revealed that the defect in cholesterol transfer of the patients was in the d greater than 1.063 gm/ml fraction (containing HDL and other serum proteins), which not only contained less HDL cholesterol, but was also qualitatively inferior as donor for cholesterol transfer. In one of four patients studied, the d less than 1.063 gm/ml fraction (VLDL and LDL) also had deficient ability to accept cholesteryl esters in the transfer. These in vitro data indicate a defect in cholesterol transport in the patients who are undergoing hemodialysis. Whether this defect exists in vivo and creates the risk of accelerated atherosclerosis warrants further study.
- Published
- 1985
34. Toxicity and immunogenicity of monoclonal antimelanoma antibody-ricin A chain immunotoxin in rats.
- Author
-
Harkonen S, Stoudemire J, Mischak R, Spitler LE, Lopez H, and Scannon P
- Subjects
- Animals, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal immunology, Female, Immunotoxins immunology, Leukocyte Count, Liver pathology, Muscles pathology, Myocardium pathology, Rats, Rats, Inbred Strains, Ricin immunology, Serum Albumin analysis, Immunotoxins adverse effects, Melanoma immunology, Ricin toxicity
- Abstract
This study was performed to assess the subacute toxicity and immunogenicity in rats of XOMAZYME-MEL, an antimelanoma monoclonal antibody-ricin A chain immunotoxin. Female Sprague-Dawley rats received 14 consecutive daily i.v. injections of XOMAZYME-MEL at doses of 5 mg/kg/day, 1 mg/kg/day, or normal saline. Animals from each dose group were sacrificed on days 8, 15, and 22. The low dose of immunotoxin was well tolerated and produced only minimal signs of toxicity. Side effects in animals receiving the high dose of immunotoxin consisted of transient weight loss, peripheral edema, leukocytosis, hypoalbuminemia, and mildly elevated liver function tests. Histological findings in these animals included cytoplasmic vacuolization of hepatocytes, focal myocardial and skeletal muscle degeneration, and renal deposits of proteinaceous casts. The administration of immunotoxin resulted in the appearance of anti-mouse and antiricin A chain immunoglobulin binding activity in the sera of treated animals. This study documents the systemic effect of the multiple-dose administration of a ricin A chain immunotoxin in rats.
- Published
- 1987
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