吉澤 ひかり

INTRODUCTION: Alternative RNA splicing adds diverse variations to gene function, and its abnormalities are occasionally associated with the etiology of disease. We examined this possibility in pre-eclampsia. METHODS: We performed transcriptome analysis of placentas from pre-eclamptic and normotensive pregnancies and screened for disease-specific aberrant splicing. RESULTS: We identified aberrant splicing at exon 14 in the ZC3H4 gene. This in-frame exon is generally skipped in placentas from normal pregnancies but often observed in those from pre-eclampsia patients. The level of exon inclusion did not correlate with disease severity, such as blood pressure or fetal weight, but showed an association with the decrease in placental weight. Significantly, placental blood flow resistance measured by Doppler ultrasound correlated with the level of ZC3H4 exon 14 inclusion, suggesting that this retention leads to the onset and/or symptoms of pre-eclampsia. ZC3H4 is known to act on transcriptional regulation via suppression of lncRNA expression. Moreover, the SOD1 gene, encoding superoxide dismutase that eliminates toxic free superoxide radicals, was identified in the downstream gene group for ZC3H4. Indeed, the expression of SOD1 was found in this current study to be decreased in the pre-eclamptic placenta in correlation with the levels of ZC3H4 exon 14 retention. DISCUSSION: Aberrant splicing of ZC3H4 gene may induce excessive oxidative stress in the placenta via the downregulation of downstream SOD1 expression thereby leading to the onset and development of pre-eclampsia.

BACKGROUND: When using assisted reproductive technology, there are cases where, despite the transfer of a good embryo, sometimes pregnancy may not be the case. Thus, during hormone replacement cycle implantation, it is important to synchronize the number of days of progesterone administration with the degree of embryo maturity. This study aimed to compare the outcomes of the administration of oral dydrogesterone for the duration of progestin use during the hormone replacement cycle for frozen-thawed blastocyst transfer. MATERIAL AND METHODS: The primary outcome of this study was the clinical pregnancy rate. We performed a retrospective cohort study of patients who underwent frozen-thawed blastocyst transfers between January 2017 and December 2024. According to our standard protocol, a vitrified-warmed blastocyst transfer was performed using dydrogesterone, which was administered orally at our center. A total of 554 cases were included in the study. Using the Gardner classification to evaluate the quality of blastocysts, grade AA was classified as the best quality, the AB/BA group as good quality, and the BB group as fair quality. We classified the 554 cases into 317 AA, 163 AB/BA, and 74 BB cases using the Gardner classification. Based on the duration of progestin administration, patients were divided into four groups: 120 hours (120 h), 132 hours (132 h), 144 hours (144 h), and 156 hours (156 h). We used the Shapiro-Wilk method and the Steel-Dwass test to determine whether there were differences in patients' background age and BMI among the four groups (120 h, 132 h, 144 h, and 156 h). We used Fisher's exact test and the Bonferroni method to determine whether there were differences in the final outcome of pregnancy rate between the four groups of 120 h, 132 h, 144 h, and 156 h. RESULTS: In the analysis of all embryos, the pregnancy rate at each timepoint of the primary evaluation was significantly higher in the 144-h group than in the 132-h group. Next, on analyzing the results by embryo grade, there was no difference in the pregnancy rate at each timepoint in the AA group. In the AB/BA group, the pregnancy rate was higher in the 144-h group than in the 132-h group. In the BB group, the pregnancy rate was higher in the 144-h group than in the 132-h group. CONCLUSION: This study clarified two aspects. First, the pregnancy rate in the 144-h group was significantly higher than that in the 132-h group in the analysis of all embryos. Second, the window of implantation may be more important for poor-quality embryos. This study showed that the oral administration of dydrogesterone requires a window of implantation of at least 144 hours.

OBJECTIVES: Nectin-4 is a cell adhesion molecule with vital functions at adherens and tight junctions. Cumulative evidence now indicates that the NECTIN4 gene is overexpressed in a variety of cancers, and that the nectin-4 protein is both a disease marker and therapeutic target in a subset of these cancers. We previously demonstrated that NECTIN4 is overexpressed in placenta during pre-eclamptic pregnancy, which is one of the most serious obstetric disorders. METHODS: Nectin-4 protein levels were measured in maternal sera from pregnant women with pre-eclampsia and its related disorder, unexplained fetal growth retardation. RESULTS: Maternal serum concentrations of nectin-4 were significantly elevated in pre-eclamptic women compared with those with an uncomplicated normotensive pregnancy. However, no increase was observed in pregnancies with unexplained fetal growth retardation. Serum nectin-4 levels were higher in cases with early-onset pre-eclampsia that generally showed more severe clinical symptoms, but levels were not correlated to other clinical indicators of disease severity. CONCLUSIONS: Nectin-4 is a potential new diagnostic and predictive biomarker for severe pre-eclampsia.