Provider-based initiation and management of pharmacologic therapy for gestational diabetes mellitus.

OBJECTIVE: After failure of diet and exercise prescribed for gestational diabetes mellitus (GDM), pharmacotherapy initiation is recommended. The objective of this study was to examine the association between provider type and timing of pharmacotherapy initiation. METHODS: This was a retrospective cohort study of women with a singleton pregnancy and diagnosis of A2GDM (GDM requiring pharmacotherapy) delivering in a tertiary care center between 2009 and 2019. Variables including maternal demographics, GDM characteristics, and provider type (general obstetrician/gynecologists (OBGYN), maternal-fetal medicine (MFM), or endocrinology) were assessed. The percent of abnormal glucose values at pharmacotherapy initiation was compared among provider types via univariable and multivariable analyses. RESULTS: A total of 428 women were included in the analysis. Eighteen percent were managed by MFM, 54% by general OBGYN, and 28% by endocrinology. Insulin was prescribed in 45.8% of women. In univariable analysis, the percent of abnormal glucose values was higher in women managed by MFMs, compared with general OBGYN and endocrinology (58.0%±25.1, 50.0%±23.1, and 50.3%±26.8, respectively, p = .041). Women started on insulin as first-line pharmacotherapy were more likely to be managed by endocrinology (p < .001). After adjusting for confounding variables, provider type was not significantly associated with percent of abnormal glucose values at pharmacotherapy initiation, but endocrinology was more likely to initiate insulin (aOR = 9.33, 95% CI 4.27-20.39). CONCLUSIONS: Provider type was not associated with percent of elevated glucose values at the time of pharmacotherapy initiation for A2GDM, but it was associated with insulin usage as first-line pharmacotherapy.

Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer.

Eukaryotic translation initiation factor 4E (eIF4E) selectively promotes translation of mRNAs with atypically long and structured 5'-UTRs and has been implicated in drug resistance. Through genome-wide transcriptome and translatome analysis we revealed eIF4E overexpression could promote cellular activities mediated by ERα and FOXM1 signalling pathways. Whilst eIF4E overexpression could enhance the translation of both ERα and FOXM1, it also led to enhanced transcription of FOXM1. Polysome fractionation experiments confirmed eIF4E could modulate the translation of ERα and FOXM1 mRNA. The enhancement of FOXM1 transcription was contingent upon the presence of ERα, and it was the high levels of FOXM1 that conferred Tamoxifen resistance. Furthermore, tamoxifen resistance was conferred by phosphorylation independent eIF4E overexpression. Immunohistochemistry on 134 estrogen receptor (ER+) primary breast cancer samples confirmed that high eIF4E expression was significantly associated with increased ERα and FOXM1, and significantly associated with tamoxifen resistance. Our study uncovers a novel mechanism whereby phosphorylation independent eIF4E translational reprogramming in governing the protein synthesis of ERα and FOXM1 contributes to anti-estrogen insensitivity in ER+ breast cancer. In eIF4E overexpressing breast cancer, the increased ERα protein expression in turn enhances FOXM1 transcription, which together with its increased translation regulated by eIF4E, contributes to tamoxifen resistance. Coupled with eIF4E translational regulation, our study highlights an important mechanism conferring tamoxifen resistance via both ERα dependent and independent pathways.