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Stiver, I.

Publications and source records attributed to Stiver, I..

2 recordsLinked to original sources

Environment and host infection history jointly predict disease risk in a multi-pathogen system

Forecasting disease epidemics may require considering both abiotic and biotic conditions. Abiotic conditions can influence pathogen dispersal, survival, and infection, while prior infection by one pathogen species can alter host susceptibility to subsequent pathogens, creating historical contingencies. Yet, the relative importance of environmental conditions, within-host pathogen interactions, and their interplay in predicting seasonal disease dynamics remains underexplored. We analyzed approximately 30,000 plant-level observations of three foliar fungal diseases on the grass species tall fescue in a North Carolina old field, and meteorological data, from 2017-2024. Using such datasets to make ecological predictions that are accurate and interpretable may require multiple modeling approaches. Temporally explicit random forest models predicted future disease with over 80% accuracy for two of the three diseases and revealed environmental thresholds for disease prediction in environmental variables including temperature and humidity. Survival analyses showed that pathogen-pathogen interactions rivaled environmental conditions in predicting risk of crown rust, which was strongly facilitated by prior anthracnose infection. Across all pathogens, Bayesian hierarchical models recovered evidence that facilitative interactions between coinfecting pathogens were modulated by effects of environmental conditions, particularly temperature. Together, these complementary approaches show that a host's current disease state can matter as much as its environment in predicting disease, identify key environmental factors associated with disease risk, and show that modulation of environmental drivers by pathogen coinfections can improve predictions of seasonal disease epidemics. Other disease forecasts may be improved by accounting not just for environmental drivers, but also how those drivers propagate through pathogen species interactions.

ecology↗

Enzalutamide-induced PTH1R-mediated TGFBR2 decrease in osteoblasts contributes to resistance in bone-metastatic prostate cancer

Over 80% of prostate cancer (PCa) patients in the United States die with bone metastases. Second-line hormonal therapies, such as enzalutamide, improve overall survival in about 50% of patients with bone metastases, but almost all responsive patients eventually develop enzalutamide resistance. Our study showed that although enzalutamide significantly inhibited the tumor growth of subcutaneously or orthotopically grafted PCa C4-2B cells, it had no effect on the bone lesion development when C4-2B tumors were grafted in the bone, suggesting a crucial role of the microenvironment in enzalutamide resistance in PCa bone metastasis. We found that enzalutamide significantly decreased the amount of the TGFBR2 (TGF-{beta} type II receptor) in osteoblasts, both in vitro and in patient samples. The osteoblast-specific knockout of Tgfbr2 significantly induced bone metastasis. We showed that the enzalutamide-induced TGFBR2 decrease in osteoblasts was mediated by increased PTH1R (parathyroid hormone/parathyroid hormone-related peptide receptor), which resulted in TGFBR2 degradation, and that blocking PTH1R rescued the TGFBR2 decrease. Furthermore, we found that PTH1R up-regulation by enzalutamide was correlated with increased Pth1r promoter occupancy by transcription factor NR2F1. Our findings highlight a potential enzalutamide-resistance mechanism through TGFBR2 decrease in osteoblasts, thus suggesting future PTH1R-blocking approaches to overcome enzalutamide resistance in PCa bone metastasis.

cancer biology↗