Few-shot learning to identify atypical endometrial hyperplasia and endometrial cancer based on transvaginal ultrasonic images.

Objective: It is challenging to accurately distinguish atypical endometrial hyperplasia (AEH) and endometrial cancer (EC) under routine transvaginal ultrasonic (TVU) detection. Our research aims to use the few-shot learning (FSL) method to identify non-atypical endometrial hyperplasia (NAEH), AEH, and EC based on limited TVU images. Methods: The TVU images of pathologically confirmed NAEH, AEH, and EC patients (n = 33 per class) were split into the support set (SS, n = 3 per class) and the query set (QS, n = 30 per class). Next, we used dual pretrained ResNet50 V2 which pretrained on ImageNet first and then on extra collected TVU images to extract 1*64 eigenvectors from the TVU images in SS and QS. Then, the Euclidean distances were calculated between each TVU image in QS and nine TVU images of SS. Finally, the k-nearest neighbor (KNN) algorithm was used to diagnose the TVU images in QS. Results: The overall accuracy and macro precision of the proposed FSL model in QS were 0.878 and 0.882 respectively, superior to the automated machine learning models, traditional ResNet50 V2 model, junior sonographer, and senior sonographer. When identifying EC, the proposed FSL model achieved the highest precision of 0.964, the highest recall of 0.900, and the highest F1-score of 0.931. Conclusions: The proposed FSL model combining dual pretrained ResNet50 V2 eigenvectors extractor and KNN classifier presented well in identifying NAEH, AEH, and EC patients with limited TVU images, showing potential in the application of computer-aided disease diagnosis.

Temporal context modulates cross-modality time discrimination: Electrophysiological evidence for supramodal temporal representation.

Although the peripheral nervous system lacks a dedicated receptor, the brain processes temporal information through different sensory channels. A critical question is whether temporal information from different sensory modalities at different times forms modality-specific representations or is integrated into a common representation in a supramodal manner. Behavioral studies on temporal memory mixing and the central tendency effect have provided evidence for supramodal temporal representations. We aimed to provide electrophysiological evidence for this proposal by employing a cross-modality time discrimination task combined with electroencephalogram (EEG) recordings. The task maintained a fixed auditory standard duration, whereas the visual comparison duration was randomly selected from the short and long ranges, creating two different audio-visual temporal contexts. The behavioral results showed that the point of subjective equality (PSE) in the short context was significantly lower than that in the long context. The EEG results revealed that the amplitude of the contingent negative variation (CNV) in the short context was significantly higher (more negative) than in the long context in the early stage, while it was lower (more positive) in the later stage. These results suggest that the audiovisual temporal context is integrated with the auditory standard duration to generate a subjective time criterion. Compared with the long context, the subjective time criterion in the short context was shorter, resulting in earlier decision-making and a preceding decrease in CNV. Our study provides electrophysiological evidence that temporal information from different modalities inputted into the brain at different times can form a supramodal temporal representation.

Analysis of the current situation and demand for perinatal education in pregnant women in general grade A tertiary hospitals in China: a cross-sectional survey.

OBJECTIVES: This study aimed to assess the factors influencing pregnant women's participation in perinatal education and their demand for educational courses. DESIGN: A cross-sectional study. SETTING: Tertiary hospital in Suzhou, China, July-September 2022. PARTICIPANTS: Pregnant women from a general grade A tertiary hospital in Suzhou were recruited via online survey invitations during the specified period. MEASURES: A self-designed scale was used to evaluate pregnant women's demand for perinatal education. Multiple response sets were employed for the assessment of multiple-choice items and analyses included frequency and cross-tabulation. Logistic regression analysis was conducted to assess the factors influencing pregnant women's participation in perinatal education. OUTCOME: The primary outcome measured was the demand for perinatal education among pregnant women. RESULTS: A majority (53.8%) of pregnant women expressed a preference for a mixed teaching mode combining online and offline formats. Logistic regression analysis showed that education level significantly influenced pregnant women's participation in online learning. Specifically, women with higher education levels were more likely to participate actively in online courses. Additionally, compared with those with first-born children, pregnant women with second-born children participated less actively in online learning. Pregnant women in their second and third trimesters showed greater engagement in online learning compared with those in their first trimester. CONCLUSIONS: These findings indicate that Chinese pregnant women's preferences for perinatal education are influenced by their educational background, pregnancy history and the mode of teaching employed. The variability in educational needs underscores the importance of regularly updating course content based on participant feedback.

Exosomal lncRNA USP30-AS1 activates the Wnt/ß-catenin signaling pathway to promote cervical cancer progression via stabilization of ß-catenin by USP30.

Cervical cancer (CC) remains a major cause of cancer-related mortality among women globally. Long noncoding RNAs (lncRNAs) play crucial regulatory roles in various cancers, including CC. This study investigates the function of a novel lncRNA, USP30 antisense RNA 1 (USP30-AS1), in CC tumorigenesis. We analyzed USP30-AS1 expression using RT-qPCR and conducted in vitro loss-of-function assays, as well as in vivo assays, to evaluate the effects of USP30-AS1 silencing on CC cell growth and migration. Additional mechanistic experiments, including RNA pull-down, RNA immunoprecipitation (RIP), and co-immunoprecipitation (Co-IP) assays, were performed to elucidate the regulatory mechanisms influenced by USP30-AS1. We discovered that USP30-AS1 is overexpressed in CC tissues and cells. Silencing USP30-AS1 significantly reduced cell proliferation, migration, invasion, and tumor growth. Moreover, USP30-AS1 was found to modulate the expression of ubiquitin-specific peptidase 30 (USP30) by sponging microRNA-2467-3p (miR-2467-3p) and recruiting the FUS RNA binding protein (FUS), thereby stabilizing ß-catenin and activating the Wnt/ß-catenin signaling pathway. These findings suggest that USP30-AS1 enhances CC cell growth and migration through the miR-2467-3p/FUS/USP30 axis, highlighting its potential as a biomarker for CC.

Exosomal miR-4516 derived from ovarian cancer stem cells enhanced cisplatin tolerance in ovarian cancer by inhibiting GAS7.

Ovarian cancer (OC) is a devastating disease for women, with chemotherapy resistance taking the lead. Cisplatin has been the first-line therapy for OC for a long time. However, the resistance of OC to cisplatin is an important impediment to its efficacy. Mounting studies showed that ovarian cancer stem cells (OCSCs) affected chemotherapy resistance by secreting exosomes. MicroRNAs (miRNAs) play important roles in exosomes secreted by OCSCs. Here, through the analysis of GEO database (GSE107155) combined with RT-qPCR of OC-related cells/clinical tissues, it was found that hsa-miR-4516 (miR-4516) was significantly up-regulated in OCSCs. Then, OCSCs-derived exosomes were isolated and identified, and it was observed the influence of exosomes on the chemoresistance in SKOV3/cisplatin (SKOV3/DDP) cells. These results manifested that OCSCs-mediated exosomes facilitated the chemoresistance of SKOV3/DDP cells by delivering miR-4516 into them. Growth arrest-specific 7 (GAS7), a downstream target of miR-4516, was determined by bioinformatics prediction combined with molecular biological detection. Next, we up-regulated GAS7 expression and discovered that the promotion of chemoresistance in SKOV3/DDP cells by OCSCs-derived exosomes was significantly impaired. Finally, the mice tumor model of SKOV3/DDP cells was built to estimate the effect of GAS7 over-expression on OC growth. The results showed that GAS7 inhibited the chemoresistance of OC in vivo. In conclusion, our experiments suggested that OCSCs-derived exosomes enhanced OC cisplatin resistance by suppressing GAS7 through the delivery of miR-4516. This study provides a possible target for the treatment of OC DDP resistance.

NAP1L1 Promotes Endometrial Cancer Progression via EP300-Mediated DDX5 Promoter Acetylation.

Endometrial cancer (EC) is one of the predominant tumors of the female reproductive system. In this current study, we investigated the functions and related mechanisms of NAP1L1/DDX5 in EC. This retrospective study analyzed the medical records of EC patients, collected tissue samples for NAP1L1 and DDX5 staining, and conducted survival analysis using the Kaplan-Meier method. To evaluate the impact of NAP1L1 and/or DDX5 on cellular processes in EC cells, several techniques were employed. These included CCK-8 assay, wound healing assay, Transwell assay, as well as overexpression or knockdown of target gene expression. Additionally, ChIP, dual luciferase reporter gene, Co-IP assay were utilized to confirm the interaction between NAP1L1, EP300 and DDX5. Furthermore, qRT-PCR, western blot and Co-IP assay were performed to analyze the modulation of NAP1L1/DDX5 in Wnt/ß-catenin. NAP1L1 and DDX5 expression were upregulated in EC tissues, and correlated with poor prognosis. NAP1L1/DDX5 promoted EC cell proliferation, migration and invasion. NAP1L1 promotes acetylation and transcription by recruiting EP300 to the DDX5 promoter. DDX5 could activate Wnt/ß-catenin signal by binding to ß-catenin. In animal models, knockdown of NAP1L1 inhibits EC tumor growth and lung metastasis. To sum up, our study demonstrated that NAP1L1 promoted the malignant phenotypes of EC cells via recruiting EP300 to promote DDX5 acetylation, thus activating the Wnt/ß-catenin signaling pathway. Implications: Our research findings indicate that targeting the NAP1L1/EP300/DX5 axis might be a new potential treatment option for endometrial cancer.

M6A-mediated hsa_circ_0061179 inhibits DNA damage in ovarian cancer cells via miR-143-3p/TIMELESS.

Ovarian cancer (OC) is among the most common and deadly solid malignancies in women. Despite many advances in OC research, the incidence of OC continues to rise, and its pathogenesis remains largely unknown. Herein, we elucidated the function of hsa_circ_0061179 in OC. The levels of hsa_circ_0061179, miR-143-3p, TIMELESS, and DNA damage repair-related proteins in OC or normal ovarian tissues and cells were measured using real-time quantitative polymerase chain reaction and immunoblotting. The biological effects of hsa_circ_0061179 and miR-143-3p on proliferation, clone formation, DNA damage, and apoptosis of OC cells were detected by the cell counting kit-8 assay, 5-methylethyl-2'-deoxyuridine, flow cytometry, the comet assay, and immunofluorescence staining combined with the confocal microscopy. The interaction among hsa_circ_0061179, miR-143-3p, and TIMELESS was validated by the luciferase reporter assay. Mice tumor xenograft models were used to evaluate the influence of hsa_circ_0061179 on OC growth in vivo. We found that human OC biospecimens expressed higher levels of hsa_circ_0061179 and lower levels of miR-143-3p. Hsa_circ_0061179 was found to bind with miR-143-3p, which directly targets TIMELESS. Hsa_circ_0061179 knockdown or miR-143-3p overexpression suppressed the proliferation and clone formation of OC cells and increased DNA damage and apoptosis of OC cells via the miR-143-3p/TIMELESS axis. Furthermore, we demonstrated that METTL3 could direct the formation of has_circ_0061179 through a specific m6A modification site. YTHDC1 facilitated the cytoplasmic transfer of has_circ_0061179 by directly binding to the modified m6A site. Our findings suggest that hsa_circ_0061179 acts as the sponge of miR-143-3p to activate TIMELESS signaling and inhibits DNA damage and apoptosis in OC cells.

Current data and future perspectives on DNA methylation in ovarian cancer (Review).

Ovarian cancer (OC) represents the most prevalent malignancy of the female reproductive system. Its distinguishing features include a high aggressiveness, substantial morbidity and mortality, and a lack of apparent symptoms, which collectively pose significant challenges for early detection. Given that aberrant DNA methylation events leading to altered gene expression are characteristic of numerous tumor types, there has been extensive research into epigenetic mechanisms, particularly DNA methylation, in human cancers. In the context of OC, DNA methylation is often associated with the regulation of critical genes, such as BRCA1/2 and Ras­association domain family 1A. Methylation modifications within the promoter regions of these genes not only contribute to the pathogenesis of OC, but also induce medication resistance and influence the prognosis of patients with OC. As such, a more in­depth understanding of DNA methylation underpinning carcinogenesis could potentially facilitate the development of more effective therapeutic approaches for this intricate disease. The present review focuses on classical tumor suppressor genes, oncogenes, signaling pathways and associated microRNAs in an aim to elucidate the influence of DNA methylation on the development and progression of OC. The advantages and limitations of employing DNA methylation in the diagnosis, treatment and prevention of OC are also discussed. On the whole, the present literature review indicates that the DNA methylation of specific genes could potentially serve as a prognostic biomarker for OC and a therapeutic target for personalized treatment strategies. Further investigations in this field may yield more efficacious diagnostic and therapeutic alternatives for patients with OC.

Research Advances in the Roles of N6-Methyladenosine Modification in Ovarian Cancer.

Ovarian cancer (OC) is the most lethal gynecological tumor, characterized by its insidious and frequently recurring metastatic progression. Owing to limited early screening methods, over 70% of OC cases are diagnosed at advanced stages, typically stage III or IV. Recently, N6-methyladenosine (m6A) modification has emerged as a hotspot of epigenetic research, representing a significant endogenous RNA modification in higher eukaryotes. Numerous studies have reported that m6A-related regulatory factors play pivotal roles in tumor development through diverse mechanisms. Moreover, recent studies have indicated the aberrant expression of multiple regulatory factors in OC. Therefore, this paper comprehensively reviews research advancements concerning m6A in OC, aiming to elucidate the regulatory mechanism of m6A-associated regulators on pivotal aspects, such as proliferation, invasion, metastasis, and drug resistance, in OC. Furthermore, it discusses the potential of m6A-associated regulators as early diagnostic markers and therapeutic targets, thus contributing to the diagnosis and treatment of OC.

Ovarian cancer (OC) presents a formidable challenge in the medical field, often detected at advanced stages, necessitating urgent exploration of diagnostic and therapeutic avenues. This review delves into the intricate role of N6-methyladenosine (m6A) RNA modification in OC, a dynamic epigenetic process increasingly recognized for its regulatory role in cancer biology. Highlighting recent advancements, the review sheds light on how m6A-related factors influence crucial aspects of OC progression, including tumor growth, metastasis, and resistance to treatment. Specifically, m6A methyltransferases, binding proteins, and demethylases exert multifaceted effects on OC progression, influencing the expression of pivotal oncogenes and tumor suppressors. While promising, translating these insights into effective therapies requires further investigation. By comprehensively understanding the influence of m6A on OC, there lies hope for developing improved diagnostic techniques and novel treatment strategies to combat this complex disease.

Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .

MATN2 overexpression suppresses tumor growth in ovarian cancer via PTEN/PI3K/AKT pathway.

The incidence rate of developing ovarian cancer decreases over the years; however, mortality ranks top among malignancies of women, mainly metastasis through local invasion. Matrilin-2 (MATN2) is a member of the matrilin family that plays an important role in many cancers. However, its relationship with ovarian cancer remains unknown. Our study aimed to explore the function and possible mechanism of MATN2 in ovarian cancer. Human ovarian cancer tissue microarrays were used to detect the MATN2 expression in different types of ovarian cancer using immunohistochemistry (IHC). CCK-8, wound scratch healing assay, transwell assay, and flow cytometry were used to detect cell mobility. Gene and protein expression were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. MATN2 interacts with phosphatase, and the tensin homolog (PTEN) deleted on chromosome 10 was analyzed using TCGA database and co-immunoprecipitation (Co-IP). In vivo experiments were conducted using BALB/c nude mice, and tumor volume and weight were recorded. Tumor growth was determined using hematoxylin and eosin (H&E) and IHC staining. MATN2 was significantly downregulated in ovarian cancer cells. The SKOV3 and A2780 cell mobility was significantly inhibited by MATN2 overexpression, while the cell apoptosis rate was significantly increased. MATN2 overexpression decreased transplanted tumor size in vivo. These results were reversed by inhibiting MATN2. Furthermore, we found that PTEN closely interacted with MATN2 using bioinformatics and Co-IP. MATN2 overexpression significantly inhibited the PI3K/AKT pathway, however, PTEN suppression reversed this effect of MATN2 overexpression. These results indicated that MATN2 may play a critical role in ovarian cancer development by inhibiting cells proliferation and migration. The mechanism was related to interacting with PTEN, thus inhibiting downstream effectors in the PI3K/AKT pathway, which may be a novel target for treating ovarian cancer.

A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer.

PURPOSE: Ovarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer. METHODS: The SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, AKT-pS473 and MYLK-pS343. SIC-19 emerged as the most promising drug candidate and was further evaluated using multiple assays. RESULTS: SIC-19 exhibited selective and potent inhibition of SIK2, leading to its degradation through the ubiquitination pathway. The IC50 of SIC-19 correlated inversely with endogenous SIK2 expression in ovarian cancer cell lines. Treatment with SIC-19 significantly inhibited cancer cell growth and sensitized cells to PARP inhibitors in vitro, as well as in ovarian cancer organoids and xenograft models. Mechanistically, SIK2 knockdown and SIC-19 treatment reduced RAD50 phosphorylation at Ser635, prevented nuclear translocation of RAD50, disrupted nuclear filament assembly, and impaired DNA homologous recombination repair, ultimately inducing apoptosis. These findings highlight the crucial role of SIK2 in the DNA HR repair pathway and demonstrate the significant PARP inhibitor sensitization achieved by SIC-19 in ovarian cancer. CONCLUSIONS: SIC-19, a novel SIK2 inhibitor, effectively inhibits tumor cell growth in ovarian cancer by interfering with RAD50-mediated DNA HR repair. Furthermore, SIC-19 enhances the efficacy of PARP inhibitors, providing a promising therapeutic strategy to improve outcomes for ovarian cancer patients.

TPD52 as a Potential Prognostic Biomarker and its Correlation with Immune Infiltrates in Uterine Corpus Endometrial Carcinoma: Bioinformatic Analysis and Experimental Verification.

BACKGROUND: Aberrant expression of tumor protein D52 (TPD52) is associated with some tumors. The role of TPD52 in uterine corpus endometrial carcinoma (UCEC) remains uncertain. OBJECTIVE: We aimed to investigate the involvement of TPD52 in the pathogenesis of UCEC. METHODS: We employed bioinformatics analysis and experimental validation in our study. RESULTS: Our findings indicated that elevated TPD52 expression in UCEC was significantly associated with various clinical factors, including clinical stage, race, weight, body mass index (BMI), histological type, histological grade, surgical approach, and age (p < 0.01). Furthermore, high TPD52 expression was a predictor of poorer overall survival (OS), progress-free survival (PFS), and disease-specific survival (DSS) (p = 0.011, p = 0.006, and p = 0.003, respectively). TPD52 exhibited a significant correlation with DSS (HR: 2.500; 95% CI: 1.153-5.419; p = 0.02). TPD52 was involved in GPCR ligand binding and formation of the cornified envelope in UCEC. Moreover, TPD52 expression was found to be associated with immune infiltration, immune checkpoints, tumor mutation burden (TMB)/ microsatellite instability (MSI), and mRNA stemness indices (mRNAsi). The somatic mutation rate of TPD52 in UCEC was 1.9%. A ceRNA network of AC011447.7/miR-1-3p/TPD52 was constructed. There was excessive TPD52 protein expression. The upregulation of TPD52 expression in UCEC cell lines was found to be statistically significant. CONCLUSION: TPD52 is upregulated in UCEC and may be a useful patent for prognostic biomarkers of UCEC, which may have important value for clinical treatment and supervision of UCEC patients.

LOC644656 promotes cisplatin resistance in cervical cancer by recruiting ZNF143 and activating the transcription of E6-AP.

Cisplatin resistance remains a persistent challenge in cervical cancer (CC) treatment. Molecular biomarkers have garnered attention for their association with cisplatin resistance in various diseases. Long non-coding RNAs (lncRNAs) exert significant influence on CC development. This study explores the role of LOC644656 in regulating cisplatin resistance in CC. Parental and cisplatin-resistant CC cells underwent cisplatin treatment. Functional assays assessed cell proliferation and apoptosis under different conditions. RNA pull-down with mass spectrometry, along with literature review, elucidated the interaction between LOC644656, ZNF143, and E6-AP. Mechanistic assays analyzed the relationship between different factors. RT-qPCR and western blot quantified RNA and protein levels, respectively. In vivo models validated E6-AP's function. Results revealed LOC644656 overexpression in cisplatin-resistant CC cells, exacerbating cell growth. LOC644656 recruited ZNF143 to activate E6-AP transcription, promoting cisplatin resistance in CC. In conclusion, LOC644656 positively modulates E6-AP expression via ZNF143-mediated transcriptional activation, contributing to cisplatin resistance in CC.

Maternal intrapartum fever during epidural labour analgesia: Incidence and influencing factors.

BACKGROUND: The management and nursing care of women's temperature during delivery is an important part of clinical obstetrics. We aimed to evaluate maternal intrapartum fever during epidural labour analgesia to provide evidence for the management and care of women in labour. METHODS: This study was conducted and reported according to the STROBE statement. Women in labour undergoing epidural labour analgesia in our hospital from 1 January 2021 to 31 August 2022 were retrospectively selected. The characteristics of women in labour with and without intrapartum fever were compared. Pearson correlation and logistic regression analysis were used to analyse the influencing factors of postpartum fever. RESULTS: A total of 196 women in labour were included, the incidence of maternal intrapartum fever in women in labour undergoing epidural analgesia was 27.5%. Pearson correlation analyses showed that BMI, oxytocin use, labour duration, number of vaginal examinations, time from rupture of the foetal membranes to the end of labour and duration of epidural analgesia were all correlated with the occurrence of intrapartum fever (all P < 0.05). Logistic regression analyses indicated that body mass index ≥28 kg/m2 (OR = 1.825), oxytocin use (OR = 2.082), labour duration ≥9.2 h (OR = 2.613), number of vaginal examinations ≥8 (OR = 2.044-3.115), the time from rupture of the foetal membranes to the end of labour ≥250 min (OR = 2.766) and duration of epidural analgesia ≥300 min (OR = 3.106) were risk factors for intrapartum fever in women in labour undergoing epidural analgesia (all P < 0.05). CONCLUSIONS: Maternal intrapartum fever in women in labour undergoing epidural analgesia is common and influenced by many factors. Nurses should take early preventive care measures according to these factors during epidural analgesia in labour.

Estrogen Regulates Scribble Localization in Endometrial Epithelial Cells Through Acyl Protein Thioesterase (APT)-Mediated S-Palmitoylation in Adenomyosis.

Despite its prevalence and the severity of symptoms, little is known about the pathogenesis and etiology of adenomyosis. In our previous study, Scribble localization has been found to be partially translocated to cytoplasm; however, its regulatory mechanism is known. In consideration of the important role of supraphysiologic estrogen production in the endometrium in the development of adenomyosis, we analyzed the effect and mechanism of estrogen on Scribble localization in vivo and in vitro. Firstly, we found Scribble translocation from the basolateral membrane to the cytoplasm was easily to be seen in women and mice with adenomyosis (68% vs 27%, 60% vs 10% separately). After treatment with the S-palmitoylation inhibitor 2-bromopalmitate for 48H, cytoplasmic enrichment of Scribble and the reduced level of palm-Scribble was observed by immunofluorescence, Western blot, and acyl-biotin exchange palmitoylation assay. High estrogen exposure could not only induce partially cytoplasmic translocation of Scribble but also decrease the expression level of palm-Scribble, which can be recovered by estrogen receptor inhibitor ICI182,780. Based on following experiments, we found that estrogen regulated Scribble localization by APT through S-palmitoylation of Scribble protein. At last, IHC was performed to verify the expression of APT1 and APT2 in human clinical tissue specimens and found that they were all increased dramatically. Furthermore, positive correlations were found between APT1 or APT2 and aromatase P450. Therefore, our research may provide a new understanding of the pathogenesis of adenomyosis.

Research Progress of Immuno-Inhibitory Receptors in Gynecological Cervical Cancer.

The mortality rate of cervical cancer is the highest among female malignant tumors and seriously threatens women's lives and health. Persistent high-risk human papillomavirus (HPV) infection is the leading cause of cervical cancer, which provides the basis for immunotherapy. In recent years, owing to progress in targeted therapy and immunotherapy, the survival time of patients with cervical cancer has been significantly extended. However, effective treatments for advanced, recurrent, and metastatic cancers are lacking. "Tumor immunotherapy" has been described as a viable option for tumor therapy but the efficacy of immunotherapy for cervical cancer has only been demonstrated in phase I or II clinical trials. Immune checkpoint inhibitors (ICIs) have shown promising clinical results particularly for treating recurrent and advanced cervical cancer, however, they remain inadequate in some patients. Immune checkpoint is the target of immunotherapy. Therefore, the identification of novel therapeutic targets is essential. In this paper, the structure, expression, function, biological effect of immune inhibitory receptors (IRs) and related clinical studies were reviewed, in order to further explore the application potential of these immune checkpoints and apply them to the future clinical treatment of cervical cancer.

Clinical Significance of Soluble LAG-3 (sLAG-3) in Patients With Cervical Cancer Determined via Enzyme-Linked Immunosorbent Assay With Monoclonal Antibodies.

Background: The tumor microenvironment and tumor immunity have become the focus of research on tumor diagnosis and treatment. Lymphocyte activation gene-3 (LAG-3, CD223) is a newly discovered immunosuppressive receptor that is abnormally expressed in various tumor microenvironments and plays an important role as an immune checkpoint in the tumor immune response. Objective: We developed a novel enzyme-linked immunosorbent assay kit, examined the levels of soluble LAG-3 (sLAG-3) in the serum of patients with cervical cancer, and identified new biomarkers for cervical cancer development. Methods: To investigate the potential biological function of sLAG-3, we generated and characterized 2 novel anti-LAG-3 monoclonal antibodies, namely 4F4 and 4E12. We performed western blotting, immunofluorescence, and immunohistochemistry using hybridoma technology and an enzyme-linked immunosorbent assay kit for detecting human sLAG-3 based on an improved double-antibody sandwich enzyme-linked immunosorbent assay method. The stability and sensitivity of these kits were also assessed. Results: We screened and characterized 2 novel monoclonal antibodies against human LAG-3. The enzyme-linked immunosorbent assay kit also includes a wide range of tests. Using this enzyme-linked immunosorbent assay system, we found that the expression level of sLAG-3 in the peripheral blood of patients with cervical cancer significantly decreased as the disease progressed (P < .0001). Multivariate logistic regression analysis revealed that low sLAG-3 expression was an independent predictor of cervical cancer and related diseases (P < .05). Furthermore, receiver operating characteristic curve analysis showed that sLAG-3 had diagnostic value for cervical cancer metastasis (P < .0001). Conclusion: These data suggest that sLAG-3 is a potential biomarker for cervical cancer development. Therefore, this kit has a certain application value in the diagnosis of cervical cancer.

Long-term Efficacy of Fibroid Devascularization with Ultrasound-Guided High-Intensity Focused Ultrasound.

RATIONALE AND OBJECTIVES: High-intensity focused ultrasound (HIFU) has been increasingly used for treatment of uterine leiomyoma. The superiority of HIFU therapy targeting uterine leiomyoma blood vessels, however, still needs to be further explored. This study aims to evaluate the long-term efficacy of fibroid devascularization with ultrasound-guided HIFU (USgHIFU) and the effects of treatment on the ovarian reserve and endometrial injury. MATERIALS AND METHODS: Fibroid devascularization was assessed with the Adler grade obtained by color Doppler flow imaging and power Doppler imaging (PDI). The targeted vessels were covered and then sonicated by HIFU focal spots. The patients were followed up at 1 month, 3 months, 6 months, 1 year, 2 years and 3 years after treatment. Adverse effects and complications were recorded. The non-perfusion volume rate (NPVR), fibroid volume shrinkage rate (FVSR), Adler Grade, symptom severity score (SSS) and uterine fibroid symptom and quality of life (UFS-QOL) were evaluated. Adverse events (AEs) were recorded. In Center 1, the enrolled patients completed the anti-Müllerian hormone (AMH) test before and at 6 months after treatment. RESULTS: A total of 117 eligible patients were consecutively enrolled to receive interventions and follow-up evaluations of the three centers from January 2019 to May 2023. The 1-month and 6-month NPVRs were 66.60% ± 33.14% and 51.12% ± 39.84%, respectively. The mean FVSRs at 1 month and 6 months after treatment were 38.20% and 43.89%, respectively. No significant difference was observed in AMH levels before and after treatment (p > 0.05). No irreversible endometrial injury was observed in MR images after HIFU treatment. No significant difference was observed in both 1-month and 6-month FVSRs among Center 1, 2 and 3 (p > 0.05). No severe AEs occurred. For long-term outcomes, significant differences were observed in Adler grade, FV, FVSR, SSS, reduction in SSS and UFS-QOL before and after treatment (p < 0.001) whereas no significant difference was observed in Adler grade among 3 months, 1 year, 2 years and 3 years after treatment (p > 0.05). The SSSs were reduced by 33.42% at 1 year, 42.32% at 2 years and 52.46% at 3 years after treatment. CONCLUSION: For patients with uterine fibroids, USgHIFU-induced devascularization is a safe and effective treatment option. It has little effect on ovarian function and the endometrial injury is reversible, which could be attractive for patients who plan to become pregnant.