Cost-effectiveness analysis of CYP3A5 genotype-guided tacrolimus dosing in solid organ transplantation using real-world data
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Correction to: A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform
Introduction Although rs776746 T > C (also known as CYP3A5*3), which is a nonfunctioning allele of the CYP3A5 gene, is associated with decreased tacrolimus metabolism4, the role…
Gut microbiota modulation in cardiac cell therapy with immunosuppression in a nonhuman primate ischemia/reperfusion model
Gut microbiota affect transplantation outcomes; however, the influence of immunosuppression and cell therapy on the gut microbiota in cardiovascular care remains unexplored. We investigated gut microbiota dynamics in a nonhuman primate (NHP) cardiac ischemia/reperfusion model while under immunosuppression and receiving cell therapy with human induced pluripotent stem cell (hiPSC)-derived endothelial cells (EC) and cardiomyocytes (CM). Both immunosuppression and EC/CM co-treatment increased gut microbiota alpha diversity. Immunosuppression promoted anaerobes, such as Faecalibacterium, Streptococcus, Anaerovibrio and Dialister, and altered amino acid metabolism and nucleosides/nucleotides biosynthesis in host plasma. EC + CM cotreatment favors Phascolarctobacterium, Fusicatenibacter, Erysipelotrichaceae UCG-006, Veillonella and Mailhella. Remarkably, gut microbiota of the EC/CM co-treatment group resembled that of the pre-injury group, and the NHPs exhibited a metabolic shift towards amino acid and fatty acid/lipid biosynthesis in plasma following cell therapy. The interplay between shift in microbial community and host homeostasis during treatment suggests gut microbiome modulation could improve cell therapy outcomes.
Dominant HPAIV H5N1 genotypes of Germany 2021/2022 are linked to high virulence in Pekin ducklings
Highly pathogenic avian influenza viruses (HPAIV) of H5 clade 2.3.4.4b pose an ongoing threat worldwide. It remains unclear whether this panzootic situation would favor low virulent phenotypes expected by the ‘avirulence hypothesis’ of viral evolution. Assessing virulence in Pekin ducklings in an intramuscular infection model revealed that the two genotypes that dominated the epidemiological situation in Germany during the period 2021 and 2022 (EU-RL:CH and EU-RL:AB) were of high virulence. In contrast, rare genotypes were of intermediate virulence. The genetic constellation of these reassortants pointed to an important role of the viral polymerase complex (RdRP), particularly the PB1 genome segment, in shaping virulence in ducklings. Occulo-nasal infection of ducklings confirmed the phenotypes for two representative viruses and indicated a more efficient replication for the high virulence strain. These observations would be in line with the ‘virulence-transmission trade-off’ model for describing HPAIV epidemiology in wild birds in Germany.
Plasma concentrations of venetoclax and Pharmacogenetics correlated with drug efficacy in treatment naive leukemia patients: a retrospective study
Venetoclax (VEN) was the only Bcl-2 inhibitor approved yet and showed large differences in clinical efficacy. The aim of the study was to explore the relationships between the plasma concentration and efficacy of VEN, and identify potential influencing factors. A retrospective cohort study was conducted and a total of 76 trough (C0h) and 91 6 h post-dose plasma concentration (C6h) blood concentrations of VEN were collected in 54 patients. C6h/D concentration of VEN was found to be significantly correlated with treatment efficacy (p = 0.006) in leukemia patients with good or intermediate prognosis stratification. A ROC curve was then established and the cut-off value was calculated as 0.2868 μg/ml (AUC = 0.7097, p = 0.1081). Besides, patients co-administered with triazoles or carrying CYP3A5 rs776746 AA/AG genotypes were prone to induce higher VEN plasma concentration regardless of whether VEN dosage was reduced or not. Through LASSO-logistic regression and nomogram analysis, chemotherapy regimens and neutrophil percentages were identified as the critical elements that may predict drug response. Above all, in addition to identify prognostic stratification, AML patients taken with VEN were suggested to test plasma concentration routinely so as to achieve desired efficacy, especially when co-administered with triazoles or carried with CYP3A5 rs776746 AA/AG.
Donor MHC-specific thymus vaccination allows for immunocompatible allotransplantation
Organ transplantation is the last-resort option to treat organ failure. However, less than 10% of patients benefit from this only option due to lack of major histocompatibility complex (MHC)-matched donor organs and 25%–80% of donated organs could not find MHC-matched recipients. T cell allorecognition is the principal mechanism for allogeneic graft rejection. We herein present a “donor MHC-specific thymus vaccination” (DMTV) strategy to induce T cell tolerance to both autologous and allogeneic donor MHC. Allogeneic MHC molecules were expressed in the recipient thymus through adeno-associated virus-mediated delivery, which led to stable expression of allogeneic MHC together with the autologous MHC in the engineered thymus. During local T cell education, those T cells recognizing either autologous MHC or allogeneic MHC were equally depleted. We constructed C57BL/6-MHC and BALB/c-MHC dual immunocompatible mice via thymus vaccination of C57BL/6-MHC into the BALB/c thymus and observed long-term graft tolerance after transplantation of C57BL/6 skin and C57BL/6 mouse embryonic stem cells into the vaccinated BALB/c mice. We also validated our DMTV strategy in a bone marrow, liver, thymus (BLT)-humanized mouse model for immunocompatible allotransplantation of human embryonic stem cells. Our study suggests that the DMTV strategy is a potent avenue to introduce a donor compatible immune system in recipients, which overcomes the clinical dilemma of the extreme shortage of MHC-matched donor organs for treating patients with end-stage organ failure.
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