Effects of atosiban on clinical outcome in frozen-thawed embryo transfer: a propensity score matching study.

PURPOSE: To evaluate the effects of atosiban on clinical outcomes in patients undergoing frozen-thawed embryo transfer. METHODS: The clinical data of 1093 infertile patients who underwent frozen-thawed embryo transfer in our center from January 2019 to December 2020 were retrospectively analyzed (control, 418; atosiban, 675). Propensity score matching (PSM) analysis identified 400 matched pairs of patients. The implantation rate, clinical pregnancy rate, live birth rate, biochemical pregnancy rate, abortion rate, multiple pregnancy rate, and ectopic pregnancy rate between the two groups were compared. RESULTS: Before PSM, patients differed by infertility factors, number of transferred embryos, and endometrial preparation protocol (P < 0.05). After PSM, characteristics were similar in corresponding patients of the atosiban and control groups. After propensity score matching, we found that there was no significant difference in the implantation rate, clinical pregnancy rate, live birth rate, biochemical pregnancy rate, abortion rate, multiple pregnancy rate, and ectopic pregnancy rate in atosiban and control group (P > 0.05). CONCLUSION: Atosiban did not improve the clinical outcomes of infertile patients with frozen-thawed embryo transfer.

Differential expression of tsRNAs and miRNAs in embryo culture medium: potential impact on embryo implantation.

PURPOSE: Can small RNA derived from embryos in conditioned embryo culture medium (ECM) influence embryo implantation? METHODS: We employed small RNA sequencing to investigate the expression profiles of transfer RNA-derived small RNA (tsRNA) and microRNA (miRNA) in ECM from high-quality and low-quality embryos. Quantitative real-time PCR was employed to validate the findings of small RNA sequencing. Additionally, we conducted bioinformatics analysis to predict the potential functions of these small RNAs in embryo implantation. To establish the role of tiRNA-1:35-Leu-TAG-2 in embryonic trophoblast cell adhesion, we utilized co-culture systems involving JAR and Ishikawa cells. RESULTS: Our analysis revealed upregulation of nine tsRNAs and four miRNAs in ECM derived from high-quality embryos, whereas 37 tsRNAs and 12 miRNAs exhibited upregulation in ECM from low-quality embryos. The bioinformatics analysis of tsRNA, miRNA, and mRNA pathways indicated that their respective target genes may play pivotal roles in both embryo development and endometrial receptivity. Utilizing tiRNA mimics, we demonstrated that the prominently expressed tiRNA-1:35-Leu-TAG-2 in the low-quality ECM group can be internalized by Ishikawa cells. Notably, transfection of tiRNA-1:35-Leu-TAG-2 into Ishikawa cells reduced the attachment rate of JAR spheroids. CONCLUSION: Our investigation uncovers significant variation in the expression profiles of tsRNAs and miRNAs between ECM derived from high- and low-quality embryos. Intriguingly, the release of tiRNA-1:35-Leu-TAG-2 by low-quality embryos detrimentally affects embryo implantation and endometrial receptivity. These findings provide fresh insights into understanding the molecular foundations of embryo-endometrial communication.

MELTF Might Regulate Ferroptosis, Pyroptosis, and Autophagy in Platelet-Rich Plasma-Mediated Endometrial Epithelium Regeneration.

The endometrial basal layer is essential for endometrial regeneration, whose disruption leads to thin endometrium or intrauterine adhesion (IUA) with an unsatisfactory prognosis. Emerging data indicate that platelet-rich plasma (PRP) can promote endometrial proliferation, but the mechanism by which PRP regulates endometrial regeneration remains unclear. Herein, we investigated the therapeutic effects and possible mechanisms of PRP on endometrial regeneration. IUA animal model was generated by sham, mechanically damaging endometrium with or without PRP for 10 days. The uterine section in the model group showed degenerative changes with a narrow endometrial lumen, atrophic columnar epithelium, decreased number of endometrial glands, decreased endometrial thickness, and increased collagen deposition. The above disruption could be ameliorated by the PRP. Transcriptome sequencing analysis displayed that the retinol metabolism pathway and extracellular matrix (ECM) receptor interaction pathway were up-regulated and enriched in differential expression genes (DEGs). Melanotransferrin (MELTF) was the key up-regulated gene in PRP-induced endometrial regeneration, which was verified in vivo and in vitro. Ferroptosis, autophagy, and pyroptosis were down-regulated in PRP-treated Ishikawa cells. Conclusively, PRP promotes endometrium regeneration by up-regulating the retinol metabolism and ECM receptor interaction pathway with MELTF. Meanwhile, PRP could also inhibit endometrial epithelial cell death by regulating ferroptosis, autophagy, and pyroptosis.

The effect of a single escalating dose of long-acting recombinant human follicle-stimulating hormone Fc fusion protein (KN015) on healthy, pituitary-suppressed women: first-in-human and randomized study on its pharmacokinetics, pharmacodynamics, and tolerability.

OBJECTIVE: KN015 is a long-acting, recombinant human follicle-stimulating hormone Fc fusion protein that induces follicle development. This first-in-human study evaluated the effect of KN015 on healthy, pituitary-suppressed women and examined its pharmacokinetics, pharmacodynamics, and tolerability. METHODS: This phase I study was a double-blind, randomized, and placebo-controlled design with a single ascending dose (20, 40, and 60 µg, respectively). RESULTS: After subcutaneous administration of a single dose, the maximum serum KN015 concentrations reached 1.57, 2.78, and 3.62 ng/mL, respectively, after baseline adjustment. Over this dose range, the median Tmax occurred at 240-312 h, and the half-life (t½) was 752-1160 h. Dose proportionality was shown across the studied dose range. In most subjects, follicular growth was observed, and the number and diameter of the follicles increased with an increasing dose. In the 40-µg and 60-µg groups, the mean numbers of follicles with a diameter of ≥17 mm were 3 and 4, respectively. There was no significant difference in adverse events between the KN015 and placebo groups. KN015 antibody was not detected in any of the dosage groups. CONCLUSION: The administration of a single ascending dose of KN015 was tolerated and able to induce follicular growth. TRIAL REGISTRATION: This trial is registered at the Chinese Clinical Trials website (http://www.chinadrugtrials.org.cn/index.html # CTR20160741) and ClinicalTrials.gov (https://clinicaltrials.gov/ # NCT03192527).

[Analysis of a pedigree affected with HSAS syndrome due to a noval variant of L1CAM gene].

OBJECTIVE: To explore the genetic basis for a fetus with hydrocephalus. METHODS: The fetus was found to have hydrocephalus upon ultrasonography duringthe second trimester. Following induced abortion, fetal tissue was collected for the extraction of DNA and whole exome sequencing.Sanger sequencing was used to verify the suspected variants in the family. RESULTS: The fetus was found to harbor a hemizygous c.620A>G (p.Tyr207Cys) variant of the L1CAM gene (OMIM 308840),for which his mother and sister were heterozygous carriers. The same variant was not found in his father, uncle and grandparents.Based on the standards and guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic (PM1+PM2+PP3+PP4). CONCLUSION: The hemizygous c.620A>G (p.Tyr207Cys) variant of the L1CAM gene probably underlay the hydrocephalus in this fetus.

Safety and pharmacokinetics of a biosimilar of denosumab (KN012): Phase 1 and bioequivalence study in healthy Chinese subjects.

BACKGROUND: KN012 is a proposed biosimilar candidate for the reference drug denosumab, with the brand name Prolia®. This study explored the tolerance, variability, and pharmacokinetics (PK) of denosumab and its biosimilar in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: A randomized, double-blind, parallel, two-arm study was performed to analyze the bioequivalence of denosumab biosimilar (60 mg) compared with denosumab. RESULTS: The PK properties of denosumab biosimilar were similar to those of denosumab. When denosumab biosimilar was compared to denosumab, the geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ were 98.74%, 102.54%, and 102.18%, respectively, and the 90% confidence interval was observed to be within 80-125%. The inter-subject variability ranged from 31.4% to 34.6%. Five subjects in the denosumab biosimilar group and one subject in the denosumab group were positive for anti-drug antibodies (ADAs) and negative for neutralizing antibodies (NAbs). Adverse reactions were observed in 100% (52 subjects) and 94.0% (47 subjects) of the subjects in the denosumab biosimilar and denosumab groups, respectively. Reductions in the blood calcium and phosphate levels were the most common adverse reactions. CONCLUSION: The PK characteristics were comparable for the denosumab biosimilar and denosumab groups. Their safety profiles were also similar. TRIAL REGISTRATION: : The trial is registered at the Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html #CTR20181231).

Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients.

In the past several months, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated infection (coronavirus disease 2019 [COVID-19]) developed rapidly and has turned into a global pandemic. Although SARS-CoV-2 mainly attacks respiratory systems, manifestations of multiple organs have been observed. A great concern was raised about whether COVID-19 may affect male reproductive functions. In this study, we collected semen specimens from 12 male COVID-19 patients for virus detection and semen characteristics analysis. No SARS-CoV-2 was found in semen specimens. Eight out of 12 patients had normal semen quality. We also compared the sex-related hormone levels between 119 reproductive-aged men with SARS-CoV-2 infection and 273 age-matched control men. A higher serum luteinizing hormone (LH) and a lower ratio of testosterone (T) to LH were observed in the COVID-19 group. Multiple regression analysis indicated that serum T: LH ratio was negatively associated with white blood cell counts and C-reactive protein levels in COVID-19 patients. It's the first report about semen assessment and sex-hormone evaluation in reproductive-aged male COVID-19 patients. Although further study is needed to clarify the reasons and underlying mechanisms, our study presents an abnormal sex hormone secretion among COVID-19 patients, suggesting that attention should be paid to reproductive function evaluation in the follow-up.

Bisphenol A Exposure Enhances Endometrial Stromal Cell Invasion and Has a Positive Association with Peritoneal Endometriosis.

Results of previous epidemiology studies on BPA exposure and endometriosis (EMs) risk were inconsistent, and were limited by inappropriate control selection, incorrect BPA detection method, and the generalization of different subtypes of EMs. Upregulated matrix metalloproteinase (MMP) 2 and MMP9 are involved in the development of EMs. We conducted a case-control study among 120 EMs patients and 100 healthy women to evaluate the relationships between BPA exposure and MMP2, MMP9 expressions, and the risk of EMs subtypes. Besides, we used human endometrial stromal cell lines (HESCs) to investigate the underlying mechanisms. Creatinine-adjusted urinary BPA concentrations were positively correlated with serum MMP2, MMP9 levels, and the risk of peritoneal EMs (third vs lowest quartile: OR 4.92, 95% CI 1.47, 16.50; fourth versus lowest quartile: OR 3.70, 95% CI 1.07, 12.74, Ptrend = 0.030). The risk of peritoneal EMs increased approximately tenfold when creatinine-adjusted urinary BPA concentration was 2 µg/g. In vitro study found that BPA exposure increased MMP2, MMP9 expressions in a dose-dependent manner. The effects of BPA on HESCs could be blocked by G protein-coupled estrogen receptor (GPER) inhibitor or mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) inhibitor. This study provides evidence that BPA exposure promotes peritoneal EMs, and raises a concern about the potential toxicity of BPA on the female reproductive system.

The Solidification of Lead-Zinc Smelting Slag through Bentonite Supported Alkali-Activated Slag Cementitious Material.

The proper disposal of Lead-Zinc Smelting Slag (LZSS) having toxic metals is a great challenge for a sustainable environment. In the present study, this challenge was overcome by its solidification/stabilization through alkali-activated cementitious material i.e., Blast Furnace Slag (BFS). The different parameters (water glass modulus, liquid-solid ratio and curing temperature) regarding strength development were optimized through single factor and orthogonal experiments. The LZSS was solidified in samples that had the highest compressive strength (after factor optimization) synthesized with (AASB) and without (AAS) bentonite as an adsorbent material. The results indicated that the highest compressive strength (AAS = 92.89MPa and AASB = 94.57MPa) was observed in samples which were prepared by using a water glass modulus of 1.4, liquid-solid ratio of 0.26 and a curing temperature of 25 °C. The leaching concentrations of Pb and Zn in both methods (sulfuric and nitric acid, and TCLP) had not exceeded the toxicity limits up to 70% addition of LZSS due to a higher compressive strength (>60 MPa) of AAS and AASB samples. While, leaching concentrations in AASB samples were lower than AAS. Conclusively, it was found that the solidification effect depends upon the composition of binder material, type of leaching extractant, nature and concentration of heavy metals in waste. The XRD, FTIR and SEM analyses confirmed that the solidification mechanism was carried out by both physical encapsulation and chemical fixation (dissolved into a crystal structure). Additionally, bentonite as an auxiliary additive significantly improved the solidification/stabilization of LZSS in AASB by enhancing the chemical adsorption capacity of heavy metals.