Epstein-Barr virus and malaria upregulate AID and APOBEC3 enzymes, but only AID seems to play a major mutagenic role in Burkitt lymphoma.

Endemic Burkitt lymphoma (eBL) is characterized by an oncogenic IGH/c-MYC translocation and Epstein-Barr virus (EBV) positivity, and is epidemiologically linked to Plasmodium falciparum malaria. Both EBV and malaria are thought to contribute to eBL by inducing the expression of activation-induced cytidine deaminase (AID), an enzyme involved in the IGH/c-MYC translocation. AID/apolipoprotein B mRNA editing catalytic polypeptide-like (AID/APOBEC) family enzymes have recently emerged as potent mutagenic sources in a variety of cancers, but apart from AID, their involvement in eBL and their regulation by EBV and P. falciparum is unknown. Here, we show that upon inoculation with EBV, human B cells strongly upregulate the expression of enzymatically active APOBEC3B and APOBEC3G. In addition, we found significantly increased levels of APOBEC3A in B cells of malaria patients, which correlated with parasite load. Interestingly, despite the fact that APOBEC3A, APOBEC3B, and APOBEC3G caused c-MYC mutations when overexpressed in HEK293T cells, a mutational enrichment in eBL tumors was only detected in AID motifs. This suggests that even though the EBV- and P. falciparum-directed immune response triggers the expression and activity of several AID/APOBEC members, only the upregulation of AID has oncogenic consequences, while the induction of the APOBEC3 subfamily may primarily have immunoprotective functions.

SwissPKcdw - A clinical data warehouse for the optimization of pediatric dosing regimens.

Clinical trials have been performed mainly in adults and accordingly the necessary information is lacking for pediatric patients, especially regarding dosage recommendation for approved drugs. This gap in information could be filled with results from pharmacokinetic (PK) modeling, based on data collected in daily clinical routine. In order to make this data accessible and usable for research, the Swiss Pharmacokinetics Clinical Data Warehouse (SwissPKcdw ) project has been set up, including a clinical data warehouse (CDW) and the regulatory framework for data transfer and use within. Embedded into the secure BioMedIT network, the CDW can connect to various data providers and researchers in order to collaborate on the data securely. Due to its modularity, partially containerized deployment and open-source software, each of the components can be extended, modified, and re-used for similar projects that require integrated data management, data analysis, and web tools in a secure scientific data and information technology (IT) environment. Here, we describe a collaborative and interprofessional effort to implement the aforementioned infrastructure between several partners from medical health care and academia. Furthermore, we describe a real-world use case where blood samples from pediatric patients were analyzed for the presence of genetic polymorphisms and the results were aggregated and further analyzed together with the health-related patient data in the SwissPKcdw .

Gentamicin Population Pharmacokinetics in Pediatric Patients-A Prospective Study with Data Analysis Using the saemix Package in R.

The aminoglycoside gentamicin is used for the empirical treatment of pediatric infections. It has a narrow therapeutic window. In this prospective study at University Children's Hospital Zurich, Switzerland, we aimed to characterize the pharmacokinetics of gentamicin in pediatric patients and predict plasma concentrations at typical recommended doses. We recruited 109 patients aged from 1 day to 14 years, receiving gentamicin (7.5 mg/kg at age ≥ 7 d or 5 mg/kg). Plasma levels were determined 30 min, 4 h and 24 h after the infusion was stopped and then transferred, together with patient data, to the secure BioMedIT node Leonhard Med. Population pharmacokinetic modeling was performed with the open-source R package saemix on the SwissPKcdw platform in Leonhard Med. Data followed a two-compartment model. Bodyweight, plasma creatinine and urea were identified as covariates for clearance, with bodyweight as a covariate for central and peripheral volumes of distribution. Simulations with 7.5 mg/kg revealed a 95% CI of 13.0-21.2 mg/L plasma concentration at 30 min after the stopping of a 30-min infusion. At 24 h, 95% of simulated plasma levels were <1.8 mg/L. Our study revealed that the recommended dosing is appropriate. It showed that population pharmacokinetic modeling using R provides high flexibility in a secure environment.