6 research outputs found
The Impact of GLP-1 Receptor Agonists on Patients with Diabetes on Insulin Therapy
Objective: The clinical benefit of adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) to basal-bolus or very high dose insulin regimens is unclear. This study investigated the impact of adding a GLP-1RA to a spectrum of insulin regimens (basal, basal-bolus, and U-500) to determine the impact on hemoglobin A1c (HbA1c), weight loss, and total daily insulin dose (TDD) over the course of 12 months. Methods: A retrospective chart review was conducted on 113 participants with type 2 diabetes mellitus using insulin therapy. Each participant\u27s HbA1c, body weight, and TDD were recorded prior to initiation of GLP-1RA therapy and at the 3, 6, and 12-month time points while on combination therapy. Results: Across all participants, the HbA1c values decreased significantly from a baseline of 8.9 (74 mmol/mol) ± 0.14% to 8.2 (66 mmol/mol) ± 0.14% (P\u3c.01) in the first 3 months, 8.0 (64 mmol/mol) ± 0.12% (P\u3c.01) at 6 months, to 8.3 (67 mmol/mol) ± 0.14% (P\u3c.01) at 12 months. There was no significant decrease in weight or TDD with the addition of a GLP-1RA overall or in different insulin groups. However, there was a clinically significant decrease in weight over the study duration. Conclusion: The results of this study suggest that adding a GLP-1RA to various insulin regimens may help to achieve glycemic goals while avoiding the less desirable side effects of weight gain and increasing insulin regimens. However, the expected weight loss and decrease in TDD may not be as sizable in the clinical setting. Abbreviations: DCOE = Diabetes Center of Excellence; DM = diabetes mellitus; GLP-1RA = glucagon-like peptide-1 receptor agonist; HbA1c = hemoglobin A1c; RCT = randomized controlled trial; TDD = total daily dose
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Lineage of origin in rhabdomyosarcoma informs pharmacological response
Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.Stem Cell and Regenerative Biolog
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Intravenous Cobinamide Versus Hydroxocobalamin for Acute Treatment of Severe Cyanide Poisoning in a Swine (Sus scrofa) Model
Study objectiveHydroxocobalamin is a Food and Drug Administration-approved antidote for cyanide poisoning. Cobinamide is a potential antidote that contains 2 cyanide-binding sites. To our knowledge, no study has directly compared hydroxocobalamin with cobinamide in a severe, cyanide-toxic large-animal model. Our objective is to compare the time to return of spontaneous breathing in swine with acute cyanide-induced apnea treated with intravenous hydroxocobalamin, intravenous cobinamide, or saline solution (control).MethodsThirty-three swine (45 to 55 kg) were intubated, anesthetized, and instrumented (continuous mean arterial pressure and cardiac output monitoring). Anesthesia was adjusted to allow spontaneous breathing with FiO2 of 21% during the experiment. Cyanide was continuously infused intravenously until apnea occurred and lasted for 1 minute (time zero). Animals were then randomly assigned to receive intravenous hydroxocobalamin (65 mg/kg), cobinamide (12.5 mg/kg), or saline solution and monitored for 60 minutes. A sample size of 11 animals per group was selected according to obtaining a power of 80%, an α of .05, and an SD of 0.17 in mean time to detect a 20% difference in time to spontaneous breathing. We assessed differences in time to death among groups, using Kaplan-Meier estimation methods, and compared serum lactate, blood pH, cardiac output, mean arterial pressure, respiratory rate, and minute ventilation time curves with repeated-measures ANOVA.ResultsBaseline weights and vital signs were similar among groups. The time to apnea and cyanide dose required to achieve apnea were similar. At time zero, mean cyanide blood and lactate concentrations and reduction in mean arterial pressure from baseline were similar. In the saline solution group, 2 of 11 animals survived compared with 10 of 11 in the hydroxocobalamin and cobinamide groups (P<.001 between the 2 treated groups and the saline solution group). Time to return of spontaneous breathing after antidote was similar between hydroxocobalamin and cobinamide (1 minute 48 seconds versus 1 minute 49 seconds, respectively). Blood cyanide concentrations became undetectable at the end of the study in both antidote-treated groups, and no statistically significant differences were detected between the 2 groups for mean arterial pressure, cardiac output, respiratory rate, lactate, or pH.ConclusionBoth hydroxocobalamin and cobinamide rescued severely cyanide-poisoned swine from apnea in the absence of assisted ventilation. The dose of cobinamide was one fifth that of hydroxocobalamin