The effects of unexpected follicular growth and ovulation in artificial cycles: a retrospective cohort study of frozen, single-blastocyst transfer.

OBJECTIVE: To study the effects of unexpected follicular development and ovulation in artificial cycles (ACs) on pregnancy outcomes. DESIGN: A retrospective cohort study. SETTING: A university-affiliated fertility center. PATIENT(S): A total of 1,427 patients who underwent a single, frozen-thawed blastocyst transfer with AC regimens from January 2014 to December 2020 at a university-affiliated fertility center were included. INTERVENTION(S): Unexpected follicular development and ovulation in ACs. MAIN OUTCOME MEASURE(S): Live birth rate (LBR), biochemical pregnancy rate, clinical pregnancy rate, and ongoing pregnancy rate. RESULT(S): A total of 161 patients with unexpected follicular development and ovulation in ACs (ovulation group) and 1,266 patients without growing follicles in ACs (control group) were enrolled. The patients in the ovulation group were older and had higher levels of serum follicle-stimulating hormone and lower levels of serum antimüllerian hormone. After propensity score matching, the baseline characteristics between the 2 groups were comparable and no significant difference was observed in the LBR (ovulation group, 39.0% vs. control group, 39.0%), biochemical pregnancy rate (ovulation group, 60.3% vs. control group, 58.2%), clinical pregnancy rate (ovulation group, 53.4% vs. control group, 50.7%), or ongoing pregnancy rate (ovulation group, 42.5% vs. control group, 40.4%). Moreover, the patients in the ovulation group showed a lower risk of hypertensive disorders of pregnancy (HDP) (1.6% vs. 15.3%). A subgroup analysis of women who delivered singleton live-born babies also demonstrated that unexpected follicular development and ovulation in ACs was associated with a decreased risk of HDP (adjusted odds ratio, 0.070; 95% confidence interval, 0.007-0.712) and an increased risk of large-for-gestational-age infants (adjusted odds ratio, 4.046; 95% confidence interval, 1.319-12.414). CONCLUSION(S): Women with unexpected follicular development and ovulation during single frozen-thawed blastocyst transfer with AC regimens had a similar LBR and a reduced risk of HDP compared with those with routine AC regimens, and singleton neonates had an increased risk of being large for gestational age.

Association between first-trimester subchorionic hematoma detected at 6-8 weeks of gestation and pregnancy outcomes after fresh embryo transfers: a propensity score-matching cohort study.

PURPOSE: This study aimed to investigate the association between first-trimester subchorionic hematoma (SCH) detected at 6-8 weeks of gestation after fresh embryo transfers and adverse pregnancy outcomes. METHODS: We performed a retrospective cohort involving 3074 patients. All of them acquired singleton pregnancies after fresh embryo transfers in the first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. According to first-trimester ultrasound examinations at 6-8 weeks of gestation, we divided patients into SCH and non-SCH groups and compared their perinatal outcomes. Symptomatic patients with vaginal bleeding and asymptomatic patients were analyzed separately, and propensity score matching (PSM) and multivariable regression were adopted to control potential confounding factors. RESULTS: The incidence of SCH was 17.1% in 3074 women, and vaginal bleeding occurred in 92 SCH patients and 215 control patients. In the asymptomatic cohort, 415 women with SCH and 807 women without SCH were finally included after PSM. No significant differences were observed in livebirth rate (91.3% vs 92.9%, P = 0.314), miscarriage rate (8.4% vs 6.7%, P = 0.267), and preterm birth rate (4.8% vs 5.7%, P = 0.519) between two groups. Secondary outcomes including gestational hypertension or preeclampsia, gestational diabetes mellitus (GDM), gestational age (GA) at delivery, mode of delivery, sex of newborns and birthweight of newborns were comparable. For symptomatic patients, both univariable and multivariable regression analysis showed no significant association between SCH and pregnancy outcomes. A subgroup analysis including patients with SCH illustrated the symptom of vaginal bleeding rather than hematoma size was associated with livebirth. CONCLUSION: First-trimester SCH detected at 6-8 weeks of gestation was not associated with adverse pregnancy outcomes in singleton pregnancies after fresh embryo transfers. Vaginal bleeding was the risk factor of pregnancy loss for patients with SCH.

SHARPIN regulates the development of clear cell renal cell carcinoma by promoting von Hippel-Lindau protein ubiquitination and degradation.

SHANK-associated RH domain interacting protein (SHARPIN) plays an important role in carcinogenesis, as well as inflammation and immunity. Our study explored the effects and underlying mechanisms of SHARPIN in clear cell renal cell carcinoma (ccRCC). By analyzing The Cancer Genome Atlas database, we found that upregulated SHARPIN in patients with ccRCC led to a poor prognosis. Semiquantitative immunohistochemical analysis of clinical samples was carried out and the results suggested the positive association between SHARPIN and hypoxia-induced factor-2α (HIF-2α). Von Hippel-Lindau protein (pVHL) is a tumor suppressor that contributes to degrading HIF-2α. Mechanically, SHARPIN promoted the ubiquitination and proteasomal degradation of pVHL, resulting in the sustained activation of HIF-2α. The α and ß domains of pVHL and ubiquitin-like domain of SHARPIN are required for the interaction. The knockdown of SHARPIN effectively inhibited acquired sorafenib resistance in ccRCC cell lines and tumor growth in xenograft models. In conclusion, our work reveals a novel posttranslational regulation of SHARPIN on pVHL, indicating that SHARPIN could be a potential target for ccRCC treatment.

Switching of the substrate specificity of protein tyrosine phosphatase N12 by cyclin-dependent kinase 2 phosphorylation orchestrating 2 oncogenic pathways.

The protein tyrosine phosphatase nonreceptor type 12 (PTPN12) is a multifunctional protein and has elicited much research attention because its decreased protein level has been associated with poor prognosis of several types of cancers. Recently, we have solved the crystal structure of the phosphatase domain of PTPN12, which disclosed a specific PTPN12-insert-loop harboring a cyclin-dependent kinase 2 (CDK2) phosphorylation site. However, the functional significance of this phosphorylation is undefined. In the present study, we found that S19 site phosphorylation of PTPN12 by CDK2 discharged its antitumor activity by down-regulation of its inhibitory role in cell migration, but not affecting its other regulatory functions. Phosphorylation of PTPN12 at the S19 site changed its substrate interface, and by doing so, selectively decreased its activity toward the human epidermal growth factor receptor 2 (HER2)- pY1196 site, but not other HER2 phosphorylation sites or other known PTPN12 substrates. A further in-depth mechanism study revealed that the phosphorylation of PTPN12 by CDK2 impaired recruitment of the serine/threonine-protein kinase 1 (PAK1) to HER2, resulted in the blockade of the HER2-pY1196-PAK1-T423 signaling pathway, thus increased tumor cell motility. Taken together, our results identified a new phosphorylation-based substrate recognition mechanism of PTPN12 by CDK2, which orchestrated signaling crosstalk between the oncogenic CDK2 and HER2 pathways. The newly identified governing mechanism of the substrate selectivity of a particular phosphatase was previously unappreciated and exemplifies how a phospho-network is precisely controlled in different cellular contexts.-Li, H., Yang, D., Ning, S., Xu, Y., Yang, F., Yin, R., Feng, T., Han, S., Guo, L., Zhang, P., Qu, W., Guo, R., Song, C., Xiao, P., Zhou, C., Xu, Z., Sun, J.-P., Yu, X. Switching of the substrate specificity of protein tyrosine phosphatase N12 by cyclin-dependent kinase 2 phosphorylation orchestrating 2 oncogenic pathways.