16 research outputs found
Comorbidity Burden in Trial-Aligned Patients with Established Gout in Germany, UK, US, and France: a Retrospective Analysis
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1024. Dual Targeted Vector for Multiple Myeloma Tumors and its Associated Angiogenesis
We have engineered an attenuated measles virus derived from the vaccine Edmonton strain to display the venom peptide echistatin with M28L mutation for targeting multiple myeloma tumors and associated angiogenesis. Echistatin binds irreversibly to integrin αVβ3 that has been shown by others to be expressed on activated endothelial cells and also on multiple myeloma tumor cells. We have chemically synthesized the echistatin gene and cloned it into p(+)MVGFP, a plasmid used to rescue measles virus, at the C-terminus of the gene coding for the viral attachment protein, H. Incorporation of the echistatin gene was confirmed by RT-PCR and the successful display of the protein as a C-terminal extension of H was demonstrated in replicating viruses by immunoblotting. Specific targeting of the virus was confirmed by infection of B10 cells (transformed Chinese Hamster Ovary cells) expressing the cognate receptor αVβ3. The recombinant measles virus displaying echistatin produced characteristic green syncytial rings, thereby, the vector was named emerald ring virus (ERV). Soluble echistatin peptide competitively inhibited ERV infection of B10 cells in a dose dependent manner. The growth kinetics of ERV showed similar characteristics to the wild type virus MV-Edm, but the titer was consistently about one log lower. In vitro, ERV infected primary cow pulmonary endothelial (CPAE) cells plated on matrigel more efficiently than the control virus, MV-Edm. Both MV-Edm and ERV infected human umbilical vein endothelial cells (HUVEC) in monolayer cultures, but when HUVEC formed capillary-like structures on matrigel, ERV infected the tubules more efficiently than MV-Edm. Although echistatin constitutes a toxin in snake venom, no toxicity was observed in ERV treated mice. ERV was injected intravenously or subcutaneously into SCID mice without any apparent toxicity. Chick chorioallantoic membrane (CAM) assay showed that ERV can infect bFGF-stimulated blood vessels. In an in vivo pilot study, ERV showed significant oncolytic activity against MM1 myeloma xenografts which are completely resistant to therapy with unmodified MV-Edm. In conclusion, we have explored the possibility of using a ligand derived from snake venom to display on measles virus. The ligand, echistatin, targets both activated endothelial cells and multiple myeloma cells
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Targeted measles virus vector displaying echistatin infects endothelial cells via αvβ3 and leads to tumor regression
In Vivo Persistence and Function of Adaptive NK Cell Infusions (FATE-NK100) from CMV Seropositive Haploidentical Related Donors
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Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial.
ObjectiveTo investigate the efficacy and safety of lesinurad in combination with febuxostat in a 12-month phase III trial in patients with tophaceous gout.MethodsPatients with serum urate (UA) ≥8.0 mg/dl (≥6.0 mg/dl with urate-lowering therapy) and ≥1 measurable target tophus were given febuxostat 80 mg/day for 3 weeks before randomization to receive lesinurad (200 or 400 mg daily) or placebo in addition to the febuxostat. The primary end point was the proportion of patients achieving a serum UA level of <5.0 mg/dl (month 6). The key secondary end point was the proportion of patients with complete resolution of ≥1 target tophus (month 12). Other end points included the percentage change in total target tophi area. Safety assessments included adverse events and laboratory data.ResultsPatients (n = 324) were predominantly male, with a mean age of 54.1 years. Significantly more patients achieved the serum UA target by month 6 with the addition of lesinurad 400 mg (76.1%; P < 0.0001), but not 200 mg (56.6%; P = 0.13), to the febuxostat therapy as compared with febuxostat alone (46.8%). At all other time points, significantly more patients in the lesinurad 200 mg group achieved the serum UA target. The number of patients with complete tophus resolution was not different between groups. Treatment with lesinurad (200 mg and 400 mg) plus febuxostat reduced the total target tophi area as compared with febuxostat alone (50.1% and 52.9% versus 28.3%, respectively; P < 0.05). Safety was generally comparable with that of febuxostat alone, except for higher rates of predominantly reversible elevations in the serum creatinine level, particularly with lesinurad 400 mg.ConclusionTreatment with lesinurad in combination with febuxostat demonstrated superior lowering of serum UA levels as compared with febuxostat alone, with clinically relevant added effects on tophi and an acceptable safety profile with lesinurad 200 mg in patients with tophaceous gout warranting additional therapy