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Biology subjects

Christie, A. L.

Publications and source records attributed to Christie, A. L..

2 recordsLinked to original sources
bioRxiv2022

Bacterial growth-promoting properties of pooled urine and individual urines from post-menopausal women with or without a urinary tract infection can vary substantially

Urinary tract infections (UTIs), mostly caused by uropathogenic E. coli (UPEC), are common bacterial infections that affect a majority of women and often recur. Genomic and transcriptomic analyses have not identified a common set of virulence genes which has suggested conserved virulence functions instead of virulence genes, multiple virulence mechanisms, and complex host-pathogen interactions. One aspect of the host-pathogen interaction is rapid UPEC growth in urine in vivo. When bacteria are grown in pooled urine, an averaged urine is assumed to diminish individual variation. We grew a non-pathogenic and pathogenic E. coli strains in urine from individuals who never had a UTI, had a UTI history but no current infection, and had a UTI history with a current infection. Bacterial growth showed large variations in individual urines and pooled urine supported significantly more growth than predicted for never and history groups but not the current group. UPEC strains, but not the non-pathogenic strain, were resistant to urinary inhibitory factors e.g., antimicrobial peptides based on an indirect inoculation-density effect assay. Total nutrient content tended to be higher in current group urine than never and history group urine. We propose that pooling optimizes a nutrient mixture in never and history group urines, which are often studied, whereas urine from current group individuals appear to have a more optimal nutrient mixture. We conclude that pooled urine is not "an average urine", and that the best comparisons of results between labs using pooled urine would also include results with a standardized synthetic urine.

microbiology↗
bioRxiv2022

Targeting TRIP13 in Wilms Tumor with Nuclear Export Inhibitors

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies in a systematic manner remains challenging in part due to the lack of faithful preclinical in vitro models. We established ten short-term patient-derived WT cell lines and characterized these models using low-coverage whole genome sequencing, whole exome sequencing and RNA-sequencing, which demonstrated that these ex-vivo models faithfully recapitulate WT biology. We then performed targeted RNAi and CRISPR-Cas9 loss-of-function screens and identified the nuclear export genes (XPO1 and KPNB1) as strong vulnerabilities. We observed that these models are sensitive to nuclear export inhibition using the FDA approved therapeutic agent, selinexor (KPT-330). Selinexor treatment of FHWT suppressed TRIP13 expression, which was required for survival. We further identified in vitro and in vivo synergy between selinexor and doxorubicin, a chemotherapy used in high risk FHWT. Taken together, we identified XPO1 inhibition with selinexor as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

cancer biology↗