Summary Background Due to the critical role of folates in neurodevelopment, it is important to understand potential interactions between anti-HIV drugs used during pregnancy, and folate delivery pathways in the placenta. This study investigates the effect of dolutegravir (DTG) exposure on the functional expression of the reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor-α (FRα) in the placenta. Methods Human placental cell lines, human placental explants, and a pregnant mouse model treated with clinically relevant concentrations of DTG were used. Gene and protein expression were assessed by qPCR, immunoblot and immunohistochemical assays. Folate transport function was measured by applying radioisotope-based transport assays. Findings In placental cells, clinically relevant DTG exposure for 3h or 6h was associated with a modest but significant reduction in the expression of RFC and PCFT both at the mRNA and protein levels, as well as decreased uptake of RFC and PCFT substrates [ 3 H]-methotrexate and [ 3 H]-folic acid, respectively. In pregnant mice, DTG administration was associated with an increase in both placental RFC and PCFT mRNA expression, accompanied by a decrease in placental FRα mRNA under folate-deficient dietary conditions. Interpretation These findings demonstrate a potential interaction between DTG and folate transport pathways in the placenta, particularly in vivo, under folate deficient conditions, potentially impacting folate delivery to the foetus in the context of DTG-based ART during pregnancy. Funding Funded by Ontario HIV Treatment Network, grant #506657; and Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, award #R01HD104553.

BackgroundOvarian cancer (OC) is the most lethal gynecologic malignancy, yet the clinical results for OC patients are still variable. Therefore, we examined how elafin expression affects the patients’ prognoses and immunotherapy responses in OC, which may facilitate treatment selection and improve prognosis.MethodsThe elafin mRNA expression profile was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus. Elafin’s prognostic potential and its relationship with clinical variables were investigated using Kaplan–Meier survival curves, time-dependent receiver operating characteristic curves as well as univariate and multivariate Cox regression models. As validation, protein expression in the tumor and adjacent tissues of OC patients was investigated by using immunohistochemistry (IHC). Comprehensive analyses were then conducted to explore the correlation between immune infiltration and elafin expression.ResultsA higher mRNA expression of elafin was associated with an unfavorable prognosis in TCGA cohort and was validated in GSE31245 and IHC. Moreover, elafin was indicated as an independent risk factor for OC. A significantly higher protein expression of elafin was detected in the adjacent tissues of OC patients with shorter overall survival (OS). The immune-related pathways were mainly enriched in the high-elafin-mRNA-expression group. However, the mRNA expression of elafin was favorably correlated with indicators of the immune filtration and immunotherapy response, which also proved better immunotherapy outcomes.ConclusionThe high elafin expression was associated with an unfavorable OS, while it also indicated better immunotherapy responses. Thus, the detection of elafin is beneficial to diagnosis and treatment selection.

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BACKGROUND Recent studies in our laboratory demonstrated downregulation of breast cancer resistance protein (BCRP/ABCG2) in placenta obtained from women with preeclampsia (PE). Pregnant women with PE are often prescribed medications to manage disease progression and prevent adverse outcomes. Many of these drugs, as well as other clinically relevant therapeutics are substrates for BCRP. BCRP is highly expressed in placenta and plays an important role in preventing xenobiotics from crossing the placenta and entering the fetal compartment. Thus, the impact of PE and BCRP downregulation on fetal drug exposure needs to be examined. As studies in pregnant women are often not feasible, use of preclinical models is an important approach. Thus, our objective was to characterize transporter changes in an endotoxin rat model of PE to determine its utility and predictive value for future drug disposition studies. This frequently utilized PE model is associated with maternal immune activation and induction of PE‐like symptoms including high blood pressure, proteinuria and pathology which are characteristic of human disease. METHODS Pregnant rats were injected intraperitoneally with 10 μg/kg of bacterial endotoxin (LPS) on GD13, followed by 40 μg/kg LPS daily until GD 16. Controls were injected with sterile saline. Urine was collected daily. Dams were sacrificed on GD17 or GD18 for collection of maternal plasma, placentas, and fetuses (n=7‐8/group/day). Plasma levels of TNF‐α and IL‐6 were quantified by ELISA Kit. Tissues were analyzed for the expression of transporters by using qPCR and western blot. Urine was analyzed using creatinine colorimetric and protein assays. RESULTS Consistent with previous reports, the urinary ratio of protein/creatinine was significantly elevated in PE dams on GDs 16‐18, demonstrating proteinuria. As compared to controls, maternal plasma concentrations and placental mRNA levels of the pro‐inflammatory cytokines, TNF‐α and IL‐6, were significantly higher in the PE group on GD17 and GD18. The mRNA levels of BCRP was significantly decreased by 40‐60 % in placenta of PE dams on GD17 and GD18 along with a corresponding decrease in protein expression on GD18. Significantly lower mRNA levels of Abcb1a, Abcb1b and Slco2b1 were observed in the PE group. PE was also associated with significantly decreased transcript levels of Bcrp, Abcb1a and Abc1b in fetal brains. CONCLUSION Our data demonstrates that the endotoxin PE rat model exhibits proteinuria and immune activation consistent with human disease. Importantly, our observations of decreased placenta expression of BCRP in this PE model is consistent with findings in humans. This indicates that this preclinical model may serve as a useful translational tool to examine the impact of PE on the disposition and fetal exposure of BCRP drug substrates.