Cisplatin-induced DNA crosslinks trigger neurotoxicity in C. elegans.

The anticancer drug cisplatin (CisPt) injures post-mitotic neuronal cells, leading to neuropathy. Furthermore, CisPt triggers cell death in replicating cells. Here, we aim to unravel the relevance of different types of CisPt-induced DNA lesions for evoking neurotoxicity. To this end, we comparatively analyzed wild-type and loss of function mutants of C. elegans lacking key players of specific DNA repair pathways. Deficiency in ercc-1, which is essential for nucleotide excision repair (NER) and interstrand crosslink (ICL) repair, revealed the most pronounced enhancement in CisPt-induced neurotoxicity with respect to the functionality of post-mitotic chemosensory AWA neurons, without inducing neuronal cell death. Potentiation of CisPt-triggered neurotoxicity in ercc-1 mutants was accompanied by complex alterations in both basal and CisPt-stimulated mRNA expression of genes involved in the regulation of neurotransmission, including cat-4, tph-1, mod-1, glr-1, unc-30 and eat-18. Moreover, xpf-1, csb-1, csb-1;xpc-1 and msh-6 mutants were significantly more sensitive to CisPt-induced neurotoxicity than the wild-type, whereas xpc-1, msh-2, brc-1 and dog-1 mutants did not distinguish from the wild-type. The majority of DNA repair mutants also revealed increased basal germline apoptosis, which was analyzed for control. Yet, only xpc-1, xpc-1;csb-1 and dog-1 mutants showed elevated apoptosis in the germline following CisPt treatment. To conclude, we provide evidence that neurotoxicity, including sensory neurotoxicity, is triggered by CisPt-induced DNA intra- and interstrand crosslinks that are subject of repair by NER and ICL repair. We hypothesize that especially ERCC1/XPF, CSB and MSH6-related DNA repair protects from chemotherapy-induced neuropathy in the context of CisPt-based anticancer therapy.

The Rhinobiome of Exacerbated Wheezers and Asthmatics: Insights From a German Pediatric Exacerbation Network.

Although the nose, as a gateway for organism-environment interactions, may have a key role in asthmatic exacerbation, the rhinobiome of exacerbated children with asthma was widely neglected to date. The aim of this study is to understand the microbiome, the microbial immunology, and the proteome of exacerbated children and adolescents with wheeze and asthma. Considering that a certain proportion of wheezers may show a progression to asthma, the comparison of both groups provides important information regarding clinical and phenotype stratification. Thus, deep nasopharyngeal swab specimens, nasal epithelial spheroid (NAEsp) cultures, and blood samples of acute exacerbated wheezers (WH), asthmatics (AB), and healthy controls (HC) were used for culture (n = 146), 16 S-rRNA gene amplicon sequencing (n = 64), and proteomic and cytokine analyses. Interestingly, Proteobacteria were over-represented in WH, whereas Firmicutes and Bacteroidetes were associated with AB. In contrast, Actinobacteria commonly colonized HCs. Moreover, Staphylococcaceae, Enterobacteriaceae, Burkholderiaceae, Xanthobacteraceae, and Sphingomonadaceae were significantly more abundant in AB compared to WH and HC. The α-diversity analyses demonstrated an increase of bacterial abundance levels in atopic AB and a decrease in WH samples. Microbiome profiles of atopic WH differed significantly from atopic AB, whereby atopic samples of WH were more homogeneous than those of non-atopic subjects. The NAEsp bacterial exposure experiments provided a disrupted epithelial cell integrity, a cytokine release, and cohort-specific proteomic differences especially for Moraxella catarrhalis cultures. This comprehensive dataset contributes to a deeper insight into the poorly understood plasticity of the nasal microbiota, and, in particular, may enforce our understanding in the pathogenesis of asthma exacerbation in childhood.