Elucidating the role of liver enzymes as markers and regulators in ovarian cancer: a synergistic approach using Mendelian randomization, single-cell analysis, and clinical evidence.

OBJECTIVE: To investigate the association between liver enzymes and ovarian cancer (OC), and to validate their potential as biomarkers and their mechanisms in OC. Methods Genome-wide association studies for OC and levels of enzymes such as Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase, and gamma-glutamyltransferase were analyzed. Univariate and multivariate Mendelian randomization (MR), complemented by the Steiger test, identified enzymes with a potential causal relationship to OC. Single-cell transcriptomics from the GSE130000 dataset pinpointed pivotal cellular clusters, enabling further examination of enzyme-encoding gene expression. Transcription factors (TFs) governing these genes were predicted to construct TF-mRNA networks. Additionally, liver enzyme levels were retrospectively analyzed in healthy individuals and OC patients, alongside the evaluation of correlations with cancer antigen 125 (CA125) and Human Epididymis Protein 4 (HE4). RESULTS: A total of 283 single nucleotide polymorphisms (SNPs) and 209 SNPs related to ALP and AST, respectively. Using the inverse-variance weighted method, univariate MR (UVMR) analysis revealed that ALP (P = 0.050, OR = 0.938) and AST (P = 0.017, OR = 0.906) were inversely associated with OC risk, suggesting their roles as protective factors. Multivariate MR (MVMR) confirmed the causal effect of ALP (P = 0.005, OR = 0.938) on OC without reverse causality. Key cellular clusters including T cells, ovarian cells, endothelial cells, macrophages, cancer-associated fibroblasts (CAFs), and epithelial cells were identified, with epithelial cells showing high expression of genes encoding AST and ALP. Notably, TFs such as TCE4 were implicated in the regulation of GOT2 and ALPL genes. OC patient samples exhibited decreased ALP levels in both blood and tumor tissues, with a negative correlation between ALP and CA125 levels observed. CONCLUSION: This study has established a causal link between AST and ALP with OC, identifying them as protective factors. The increased expression of the genes encoding these enzymes in epithelial cells provides a theoretical basis for developing novel disease markers and targeted therapies for OC.

Diagnostic value of the combination of circulating serum miRNAs and CA125 in endometriosis.

Circulating microRNAs (miRNAs) can serve as noninvasive biomarkers for endometriosis, but their diagnostic and prognostic values require investigation. This study evaluated the potential of 6 miRNAs in diagnosing endometriosis and predicting fertility. The study included patients with endometriosis (stages I-IV) and controls admitted to Sun Yat-Sen Memorial Hospital between May 2013 and March 2014. The serum expression levels of 6 miRNAs (miR-199a, miR-145*, miR-122, miR-9*, miR-141*, and miR-542-3p) were determined using qRT-PCR. Receiver operating characteristics curves were used to determine the diagnostic accuracy. The study included 155 patients with endometriosis and 77 controls. The model combining miR-199a, miR-122, miR-145*, and miR-141* with the carbohydrate antigen 125 (CA125) exhibited 81.8% sensitivity and 92.6% specificity and an area under the curve of 0.939 for diagnosing endometriosis. When combining miR-199a, miR-122, miR-145*, miR-542-3p, and CA125, the receiver operating characteristics curve showed an area under the curve of 0.759 and 79.6% sensitivity and 73.5% specificity for stage I/II versus III/IV endometriosis. Circulating miRNA levels were associated with pelvic adhesions (miR-199a, P < .05), lesion distribution (miR-9*, miR-145*, and miR-141*; all P < .05), and the presence of deep infiltrating endometriosis (miR-199a and miR-122; both P < .001). The expression levels of miR-199a, miR-122, and miR-542-3p decreased with an increasing endometriosis fertility index. The model combining circulating miRNAs (miR-199a, miR-122, miR-145*, and miR-141*) and CA125 is promising for diagnosing endometriosis and its severity. miR-199a, miR-122, and miR-542-3p were associated with the endometriosis fertility index and might be used to predict fertility preoperatively, but these results require confirmation.

Ensemble effects in Cu/Au ultrasmall nanoparticles control the branching point for C1 selectivity during CO2 electroreduction.

Bimetallic catalysts provide opportunities to overcome scaling laws governing selectivity of CO2 reduction (CO2R). Cu/Au nanoparticles show promise for CO2R, but Au surface segregation on particles with sizes ≥7 nm prevent investigation of surface atom ensembles. Here we employ ultrasmall (2 nm) Cu/Au nanoparticles as catalysts for CO2R. The high surface to volume ratio of ultrasmall particles inhibits formation of a Au shell, enabling the study of ensemble effects in Cu/Au nanoparticles with controllable composition and uniform size and shape. Electrokinetics show a nonmonotonic dependence of C1 selectivity between CO and HCOOH, with the 3Au:1Cu composition showing the highest HCOOH selectivity. Density functional theory identifies Cu2/Au(211) ensembles as unique in their ability to synthesize HCOOH by stabilizing CHOO* while preventing H2 evolution, making C1 product selectivity a sensitive function of Cu/Au surface ensemble distribution, consistent with experimental findings. These results yield important insights into C1 branching pathways and demonstrate how ultrasmall nanoparticles can circumvent traditional scaling laws to improve the selectivity of CO2R.

Effect of surface ligands on gold nanocatalysts for CO2 reduction.

Nanoparticle catalysts display optimal mass activity due to their high surface to volume ratio and tunable size and structure. However, control of nanoparticle size requires the presence of surface ligands, which significantly influence catalytic performance. In this work, we investigate the effect of dodecanethiol on the activity, selectivity, and stability of Au nanoparticles for electrochemical carbon dioxide reduction (CO2R). Results show that dodecanethiol on Au nanoparticles significantly enhances selectivity and stability with minimal loss in activity by acting as a CO2-permeable membrane, which blocks the deposition of metal ions that are otherwise responsible for rapid deactivation. Although dodecanethiol occupies 90% or more of the electrochemical active surface area, it has a negligible effect on the partial current density to CO, indicating that it specifically does not block the active sites responsible for CO2R. Further, by preventing trace ion deposition, dodecanethiol stabilizes CO production on Au nanoparticles under conditions where CO2R selectivity on polycrystalline Au rapidly decays to zero. Comparison with other surface ligands and nanoparticles shows that this effect is specific to both the chemical identity and the surface structure of the dodecanethiol monolayer. To demonstrate the potential of this catalyst, CO2R was performed in electrolyte prepared from ambient river water, and dodecanethiol-capped Au nanoparticles produce more than 100 times higher CO yield compared to clean polycrystalline Au at identical potential and similar current.

Comparison of Combined Bipolar Radiofrequency Impedance-Controlled Endometrial Ablation with Levonorgestrel Intrauterine System versus Bipolar Radiofrequency Endometrial Ablation Alone in Women with Abnormal Uterine Bleeding.

STUDY OBJECTIVE: This study aims to evaluate the efficacy of the combination of bipolar radiofrequency impedance-controlled endometrial ablation (NovaSure; Hologic Inc., Bedford, MA) and levonorgestrel intrauterine system (LNG-IUS; Mirena; Schering AG, Berlin, Germany) placement in comparison with NovaSure endometrial ablation alone in patients with abnormal uterine bleeding (AUB). DESIGN: A propensity score matching study. SETTING: Beijing Tiantan Hospital, Capital Medical University, Beijing, China. PATIENTS: A retrospective study was conducted on 246 patients with AUB who underwent NovaSure endometrial ablation with (NovaSure+LNG-IUS group) or without (NovaSure group) LNG-IUS between January 2013 and August 2016. To overcome selection bias, propensity score matching was used to establish a 1:1 match between these 2 groups. Accordingly, 41 patients were included in each group. INTERVENTION: NovaSure endometrial ablation, immediately followed by LNG-IUS insertion in the NovaSure+LNG-IUS group, and NovaSure endometrial ablation alone in the control group. MEASUREMENTS AND MAIN RESULTS: Follow-up assessments performed at postablation months 6, 12, and 24 revealed the following: The rate of amenorrhea (78.05% vs 46.34%, 85.37% vs 53.65%, and 87.80% vs 58.54%, respectively; p <.005) and the rate of dysmenorrhea remission (100% vs 70.59%, 100% vs 64.70%, and 100% vs 64.70% [p <.05, p <.01, and p <.01], respectively) were significantly higher in the NovaSure+LNG-IUS group than in the NovaSure group. The rate of reinterventions was similar for both groups at postablation month 6. However, at postablation months 12 and 24, these rates were significantly lower in the NovaSure+LNG-IUS group than in the NovaSure group (0 vs 14.63% and 2.44% vs 21.95% [p <.05 and p <.01], respectively). CONCLUSION: For women with AUB, the combination of NovaSure endometrial ablation and LNG-IUS is more effective than NovaSure alone in achieving amenorrhea, alleviating dysmenorrhea and reducing reinterventions.

Estrogen therapy before hysteroscopic adhesiolysis improves the fertility outcome in patients with intrauterine adhesions.

PURPOSES: To describe the fertility outcomes after hysteroscopic adhesiolysis combined with preoperative hormone treatment in women with intrauterine adhesion (IUA). METHODS: This study is a retrospective cohort study. A total of 230 patients with IUA underwent hysteroscopic adhesiolysis combined with hormone treatment from Jan 2012 to Jun 2018. 148 patients who received preoperative estrogen treatment were enrolled into group A and 82 patients without preoperative estrogen treatment were enrolled into group B. All the patients underwent hysteroscopic adhesiolysis and received postoperative estrogen therapy, intrauterine indwelling device. Second or third look was performed after 2-3 months. RESULTS: 90.87% (209/230) patients complete the study. The AFS scores at baseline were higher in the group A than group B. After the preoperative E2 treatment, group A achieved the comparable AFS score to group B before the surgery. The cumulative fertility rate in group A was comparable in group B, both in the ITT analysis (49.32% vs. 52.44%, p = 0.651) and the PP analysis (54.07% vs.58.10%, p = 0.575).The mean conception time was also similar in group A and group B (8.30 ± 6.47 vs. 8.54 ± 5.68 months, p = 0.837). Besides, the surgery times in group A were less than group B. There was no difference in the rate of adverse events between two groups. CONCLUSIONS: Hysteroscopic adhesiolysis combined with preoperative oestrogen could reduce the preoperative AFS scores and the times of surgery which yield a similar conception rate in women with less severe intrauterine adhesions.

A systematic RNA interference screen reveals a cell migration gene network in C. elegans.

Cell migration is essential during embryonic development and tissue morphogenesis. During gonadogenesis in the nematode Caenorhabditis elegans, migration of the distal tip cells forms two U-shaped gonad arms. Malformation results if the distal tip cells stop prematurely or follow an aberrant path, and abnormalities are easily visualized in living nematodes. Here we describe the first comprehensive in vivo RNA interference screen for genes required for cell migration. In this non-biased screen, we systematically analyzed 16,758 RNA-interference depletion experiments by light microscopy and identified 99 genes required for distal tip cell migration. Genetic and physical interaction data connect 59 of these genes to form a cell migration gene network that defines distal tip cell migration in vivo.