Gene therapy in preeclampsia: the dawn of a new era.

Preeclampsia is a severe complication of pregnancy, affecting an estimated 4 million women annually. It is one of the leading causes of maternal and fetal mortality worldwide, and it has life-long consequences. The maternal multisystemic symptoms are driven by poor placentation, which causes syncytiotrophoblastic stress and the release of factors into the maternal bloodstream. Amongst them, the soluble fms-like tyrosine kinase-1 (sFLT-1) triggers extensive endothelial dysfunction by acting as a decoy receptor for the vascular endothelial growth factor (VEGF) and the placental growth factor (PGF). Current interventions aim to mitigate hypertension and seizures, but the only definite treatment remains induced delivery. Thus, there is a pressing need for novel therapies to remedy this situation. Notably, CBP-4888, a siRNA drug delivered subcutaneously to knock down sFLT1 expression in the placenta, has recently obtained Fast Track approval from the Food and Drug Administration (FDA) and is undergoing a phase 1 clinical trial. Such advance highlights a growing interest and significant potential in gene therapy to manage preeclampsia. This review summarizes the advances and prospects of gene therapy in treating placental dysfunction and illustrates crucial challenges and considerations for these emerging treatments.

Impact of thyroid autoimmunity on pregnancy outcomes in euthyroid patients with recurrent implantation failure.

RESEARCH QUESTION: Does thyroid autoimmunity (TAI) adversely affect pregnancy outcomes after IVF/intracytoplasmic sperm injection (ICSI) in euthyroid patients with recurrent implantation failure (RIF)? DESIGN: This retrospective cohort study was conducted at the Reproductive Hospital Affiliated with Shandong University from November 2016 to September 2021. A total of 1031 euthyroid patients diagnosed with RIF were enrolled. Based on serum thyroid autoantibody concentrations, the participants were divided into two groups: the TAI-positive group (219 women with RIF) and the TAI-negative group (812 women with RIF). The parameters were compared between the two groups. Additionally, logistic regression was used to adjust related confounders for primary outcomes, and subgroup and stratified analyses were performed according to different thyroid autoantibody types and TSH concentrations. RESULTS: There was no significant difference in ovarian reserve, ovarian response, embryo quality, pregnancy outcome or neonatal outcome between the two groups (P > 0.05). After adjustments for age, body mass index, thyroid-stimulating hormone and free thyroxine, the biochemical pregnancy rate in the TAI-positive group was significantly lower than that in the TAI-negative group (odds ratio 1.394, 95% CI 1.023-1.901, adjusted P = 0.036). Regarding the implantation rate, clinical pregnancy rate, pregnancy loss rate, stillbirth rate and live birth rate, no significant differences were observed even with subgroup and stratified analyses (P > 0.05). CONCLUSIONS: TAI had no impact on pregnancy outcomes in euthyroid RIF patients who underwent IVF/ICSI. In clinical practice, interventions targeting thyroid autoantibodies in these patients should be implemented with caution and additional evidence is needed.

Activin A promotes human trophoblast invasion by upregulating integrin ß3 via ALK4-SMAD4 signaling.

INTRODUCTION: Activin A has been widely regarded as an important promoter of trophoblast invasion during the first trimester of pregnancy. However, whether integrin ß3 is involved in activin A-upregulated trophoblast invasion and the underlying molecular mechanisms remain largely unknown. METHODS: We utilized immortalized (HTR8/SVneo) and primary human extravillous trophoblast (EVT) cells, as well as first-trimester chorionic villous explants as study models to investigate the function and underlying molecular mechanisms of integrin ß3 in activin A-promoted human trophoblast invasion. RESULTS: We found that activin A increased integrin ß3 mRNA and protein levels in both HTR8/SVneo and primary EVT cells, and knockdown of integrin ß3 significantly decreased basal and activin A-upregulated trophoblast invasion. Moreover, SB431542 (a specific inhibitor of TGF-ß type Ι receptor kinase) abolished activin A-upregulated integrin ß3 expression and SMAD2/3 phosphorylation. In addition, siRNA-mediated knockdown of ALK4 or SMAD4 both abolished activin A-upregulated integrin ß3 expression in HTR8/SVneo cells, while knockdown of ALK4 or SMAD4 attenuated activin A-upregulated integrin ß3 expression in primary EVTs. DISCUSSION: Our findings reveal the mediation role of integrin ß3 in activin A-upregulated human trophoblast invasion and that activin An upregulates integrin ß3 expression in an ALK4-SMAD4 signaling-dependent manner.

Imaging-Based Body Fat Distribution in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Background: Women with polycystic ovary syndrome (PCOS) are generally considered to be central obese and at higher risks of metabolic disturbances. Imaging methods are the golden standards for detecting body fat distribution. However, evidence based on magnetic resonance imaging (MRI) and computed tomography (CT) is conflicting. This study systematically reviewed the imaging-based body fat distribution in PCOS patients and quantitatively evaluated the difference in body fat distribution between PCOS and BMI-matched controls. Methods: PUBMED, EMBASE, and Web of Science were searched up to December 2019, and studies quantitatively compared body fat distribution by MRI, CT, ultrasound, or X-ray absorptiometry (DXA) between women with PCOS and their BMI-matched controls were included. Two researchers independently reviewed the articles, extract data and evaluated the study quality based on Newcastle-Ottawa Scale (NOS). Results: 47 studies were included in systematic review and 39 were eligible for meta-analysis. Compared to BMI-matched controls, higher accumulations of visceral fat (SMD 0.41; 95%CI: 0.23-0.59), abdominal subcutaneous fat (SMD 0.31; 95%CI: 0.20-0.41), total body fat (SMD 0.19; 95% CI: 0.06-0.32), trunk fat (SMD 0.47; 95% CI: 0.17-0.77), and android fat (SMD 0. 36; 95% CI: 0.06-0.66) were identified in PCOS group. However, no significant difference was identified in all the above outcomes in subgroups only including studies using golden standards MRI or CT to evaluate body fat distribution (SMD 0.19; 95%CI: -0.04-0.41 for visceral fat; SMD 0.15; 95%CI: -0.01-0.31 for abdominal subcutaneous fat). Moreover, meta-regression and subgroup analyses showed that young and non-obese patients were more likely to accumulate android fat. Conclusions: PCOS women seem to have abdominal fat accumulation when compared with BMI-matched controls. However, MRI- and CT- assessed fat distribution was similar between PCOS and controls, suggesting central obesity may be independent of PCOS. These findings will help us reappraise the relationship between PCOS and abnormal fat deposition and develop specialized lifestyle interventions for PCOS patients. Systematic Review Registration: PROSPERO, identifier CRD42018102983.