The Transcriptome Response to Azole Compounds in Aspergillus fumigatus Shows Differential Gene Expression across Pathways Essential for Azole Resistance and Cell Survival.

The opportunistic pathogen Aspergillus fumigatus is found on all continents and thrives in soil and agricultural environments. Its ability to readily adapt to novel environments and to produce billions of spores led to the spread of azole-resistant A. fumigatus across the globe, posing a threat to many immunocompromised patients, including critically ill patients with severe influenza or COVID-19. In our study, we sought to compare the adaptational response to azoles from A. fumigatus isolates that differ in azole susceptibility and genetic background. To gain more insight into how short-term adaptation to stressful azole compounds is managed through gene expression, we conducted an RNA-sequencing study on the response of A. fumigatus to itraconazole and the newest clinically approved azole, isavuconazole. We observed many similarities in ergosterol biosynthesis up-regulation across isolates, with the exception of the pan-azole-resistant isolate, which showed very little differential regulation in comparison to other isolates. Additionally, we found differential regulation of membrane efflux transporters, secondary metabolites, iron metabolism, and various stress response and cell signaling mechanisms.

Proteinuria and Exposure to Eculizumab in Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Eculizumab is a monoclonal antibody for the treatment of atypical hemolytic uremic syndrome (aHUS). Kidney damage, a common condition in patients with aHUS, may result in proteinuria. Because proteinuria may affect the pharmacokinetics of therapeutic proteins such as eculizumab, the aim of our study was to investigate the effect of proteinuria on eculizumab pharmacokinetics. METHODS: This study was an ancillary study of a previously performed pharmacokinetic-pharmacodynamic study of eculizumab in aHUS. Proteinuria, measured as urinary protein-creatinine ratios (UPCR), was investigated as covariate for eculizumab clearance. Thereafter, we evaluated the effect of proteinuria on the exposure to eculizumab in a simulation study for the initial phase and for a 2-weekly and 3-weekly interval in the maintenance phase. RESULTS: The addition of UPCR as a linear covariate on clearance to our base model resulted in a statistically improved fit ( P < 0.001) and reduction of unexplained variability in clearance. From our data, we predicted that in the initial phase, 16% of the adult patients with severe proteinuria (UPCR >3.1 g/g) will have inadequate complement inhibition (classical pathway activity >10%) on day 7 of treatment, compared with 3% of the adult patients without proteinuria. None of the pediatric patients will have inadequate complement inhibition at day 7 of treatment. For the 2- and 3-weekly dosing intervals, we predicted that, respectively, 18% and 49% of the adult patients and, respectively, 19% and 57% of the pediatric patients with persistent severe proteinuria will have inadequate complement inhibition, compared with, respectively, 2% and 13% of the adult patients and, respectively, 4% and 22% of the pediatric patients without proteinuria. CONCLUSIONS: Severe proteinuria is associated with a higher risk of underexposure to eculizumab. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: CUREiHUS, Dutch Trial Register, NTR5988/NL5833.

To be or not to be pink(1): contradictory findings in an animal model for Parkinson's disease.

The PTEN-induced putative kinase 1 knockout rat (Pink1-/-) is marketed as an established model for Parkinson's disease, characterized by development of motor deficits and progressive degeneration of half the dopaminergic neurons in the substantia nigra pars compacta by 8 months of age. In this study, we address our concerns about the reproducibility of the Pink1-/- rat model. We evaluated behavioural function, number of substantia nigra dopaminergic neurons and extracellular striatal dopamine concentrations by in vivo microdialysis. Strikingly, we and others failed to observe any loss of dopaminergic neurons in 8-month-old male Pink1-/- rats. To understand this variability, we compared key experimental parameters from the different studies and provide explanations for contradictory findings. Although Pink1-/- rats developed behavioural deficits, these could not be attributed to nigrostriatal degeneration as there was no loss of dopaminergic neurons in the substantia nigra and no changes in neurotransmitter levels in the striatum. To maximize the benefit of Parkinson's disease research and limit the unnecessary use of laboratory animals, it is essential that the research community is aware of the limits of this animal model. Additional research is needed to identify reasons for inconsistency between Pink1-/- rat colonies and why degeneration in the substantia nigra is not consistent.