ARTICLE | doi:10.20944/preprints202107.0073.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: second primary cancers (SPCs); endometrial cancer (EC); risk prediction.
Online: 2 July 2021 (15:54:58 CEST)
Due to the high effectiveness of cancer screening and therapies, the diagnosis of second primary cancers (SPCs) has increased in women with endometrial cancer (EC). However, there’s no previous literature mentioned about adequate evidence to support screening for SPCs in endometrial cancer. This study was aimed to develop effective risk prediction models of second primary endometrial cancer in women with obesity (Body-mass index; BMI > 25) and this study includes datasets of the incidence of SPCs and the other risks of SPCs in 4480 primary cancer survivors by a hospital-based cancer registry database. In our study, we found the obesity played a key role in SPCs. There’re 10 independent variables used as predicting variables, which corelated to obesity should be monitored for the early detection of SPCs in endometrial cancer. In conclusion, it is a promising SPCs prediction. The proposed scheme can support the important influence of obesity and clinical data representations in all cases after primary treatments. Our results suggested that obesity is still a crucial risk factor to SPCs in endometrial cancer.
ARTICLE | doi:10.20944/preprints202310.1012.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: Minimally invasive surgery, Type II endometrial cancer, overall survival
Online: 18 October 2023 (03:05:50 CEST)
Objective: To compare the overall survival (OS) and surgical outcomes between open and minimally invasive surgery (MIS) in a large cohort of women with Type II endometrial cancer. Methods: Using the National Cancer Database, we identified a cohort of women who underwent hysterectomy for type II endometrial cancer (serous, clear cell, carcinosarcoma) between January 2010 and December 2014. Primary outcome was the comparison of OS between MIS and the open approach. Secondary outcomes included the length of hospital stay, readmission rate, 30- and 90-day mortality. Multivariable logistic regression and inverse propensity weighting analyses were performed. Results: A total of 12,905 patients with Type II, Stage I-III endometrial cancer who underwent hysterectomy were identified. Among these patients, 7,123 (55.2%) underwent MIS. The utilization of MIS increased from 39% to 64% over the four-year period. In propensity-score-weighted analysis, MIS was associated with superior OS (101.7 vs. 86.7 months, p=0.0003 by the log-rank test), with a hazard ratio of 0.9 (CI 0.857-0.954, p=0.0002). MIS was also associated with improved perioperative outcomes, including a shorter length of stay (1 vs. 4 days, p<0.001), lower 30-day readmission rate (2.5% vs. 5%), and lower 30- and 90-day postoperative mortality (0.5% vs. 1.3% and 1.5% vs. 3.6%, respectively; p<0.001). The time interval between surgery and initiation of chemotherapy was shorter in the MIS group (38 vs. 41 days, p<0.001).The increase in MIS adoption correlated with a decrease in 90-day postoperative mortality (2.8% to 2.2%, r=-0.89; p=0.003) and 12-month overall mortality (51% to 38%, r=-0.95, p=0.006). Conclusions: In an epidemiologic study, MIS is associated with improved overall survival and superior perioperative outcomes compared to open surgery in women with Type II endometrial cancer.
ARTICLE | doi:10.20944/preprints202307.2092.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Endometrial Cancer (EC); Multigene-NGS panel; POLE; TP53
Online: 31 July 2023 (10:25:29 CEST)
Endometrial cancer (EC) is the most frequent gynaecological malignancy. The ESGO/ESTRO/ESP 2020 guidelines identify prognostic groups based on morpho-molecular characteristics. This study aims to evaluate the clinical applicability of NGS analysis to define an appropriate risk class and application for a better diagnostic and prognostic stratification of ECs. Cases of serous carcinoma (OHEC), high (HGEC) and low (LGEC) grade endometrioid carcinoma diagnosed with the morphological and immunohistochemical (IHC) protocols were considered. After a standardized pre-analytical phase, the tumor DNA was semi-automatically extracted and analyzed by NGS with a panel of 14 genes. A total of 63 cases were considered. NGS analysis was successful in 60 cases; all of these were classified according to the new diagnostic algorithm. The molecular risk classification showed a good correlation with the morphological (k=0.8). The study showed that the protocols of the pre-analytical and analytical phases used are robust and can lead to molecular results that fall within the standards required for use in clinical practice for a more precise diagnostic-therapeutic management of patients. The implementation of the classification is particularly relevant for better prognostic stratification of HGECs. In addition, the identification of a suspicious VUS in POLE questions the classification of truncating variants.
ARTICLE | doi:10.20944/preprints202308.0237.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: SPRR2A; Endometrial cancer; TCGA; Bioinformatics analysis
Online: 2 August 2023 (14:37:19 CEST)
Objective: To verify SPRR2A is a hub gene for endometrial cancer (EC). Methods: Bioinformatics analysis was performed on the high-throughput sequencing dataset of 587 EC cases in TCGA. RT-qPCR verified the differential expression of the SPRR2A gene in EC cell lines. Results: Enrichment of differentially expressed genes in comparison with normal tissues has been found in several biological process pathways, including keratinization and epidermal growth. The signalling pathways of differentially expressed genes were mainly focused on the receptor-ligand pathway and passive transmembrane transport pathway. High SPRR2A expression was a poor prognostic indicator for EC, according to a one-way Cox analysis of TCGA EC data. Compared with normal tissues, EC tissues had considerably elevated SPRR2A expression according to the differential expressed genetic analysis of TCGA-UCEC data (P < 0.05). RT-qPCR was used to experimentally confirm that the Ishikawa EC cell line expressed SPRR2A mRNA at a greater level than the human endometrial epithelial cell line and that this difference was statistically obvious (P < 0.01). Conclusion: SPRR2A has been identified as hub gene for EC and potentially become a new marker for early diagnosis, precise treatment and prognosis predictor of EC.
ARTICLE | doi:10.20944/preprints202109.0105.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: endometrial cancer; tumor microenvironment; Wnt/β-catenin pathway; SATB1; SATB2
Online: 6 September 2021 (14:29:35 CEST)
Wnt/β-catenin signaling pathway plays an established role in various diseases and is considered a hallmark of endometrial cancer (EC). Special AT-rich sequence-binding protein 1 and 2 (SATB1 and SATB2) are nuclear matrix-associated proteins involved in chromatin remodeling and regulation of gene expression. SATB1 promotes the progression of numerous types of cancers, whereas SATB2 acts as a tumor suppressor. Despite a recent progress in our knowledge about EC, the exact mechanisms that control their proliferation and metastatic potential still remain unknown. The aim of our study was to investigate the association between Wnt3A, β-catenin, SATB1 and SATB2 protein level and the clinicopathological features of EC patients. 92 EC patients, aged 37-84, were enrolled to our study. The immunoexpression of WNT3A was found in specimens from all EC patients, β-catenin was expressed in 97% of the cases, SATB1 in 87%. The significant association between Wnt3a expression and tumor grade was found; moreover mean IRS for Wnt3a turned out to be significantly lower in high-grade tumors than in low-grade malignancies (p=0.038). In turn, immunoexpression of β-catenin varied significantly across FIGO stages and was associated with the presence of lymph node metastases. Mean IRS for β-catenin in patients with lymph node metastases was significantly lower than in those without (p = 0.028). The Kaplan-Meier analyses demonstrated a stepwise impairment of cancer overall survival with increasing SATB1 expression. In conclusion, both Wnt/β-catenin signaling pathway and SATB1 contribute to progression of EC. Downregulation of β-catenin may predispose to lymphatic spread of EC. In turn, downregulation of Wnt3a seems to be characteristic for high-grade tumors, but probably does not play a role in formation of lymph node metastases. The important role of SATB1 as a predictor of poor survival and could be helpful in establishing a more accurate prognosis in endometrial cancer patients.
ARTICLE | doi:10.20944/preprints202308.0879.v1
Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: early-stage endometrial cancer; molecular classification; L1CAM; risk stratification; prognosis
Online: 11 August 2023 (08:38:07 CEST)
Aim: To improve risk stratification in early-stage endometrial cancer (EC), we performed mo-lecular classification, and L1CAM immunohistochemistry (IHC) for additional risk assessment. Method: We analyzed archival tumor tissue from 247 early-stage EC patients. POLE mutations were detected using a Droplet digital polymerase chain reaction assay and Sanger sequencing, while the mismatch repair (MMR) status was determined by MMR protein IHC and MSI test. Additionally, we conducted IHC of p53 and L1CAM. Results: The 247 ECs were categorized into four subgroups: POLE-mutated (13.0%), MMR-deficient (27.9%), p53-abnormal (8.5%), and non-specific molecular profile (NSMP, 50.6%). We further subcategorized NSMP subgroup into NSMP-L1CAMneg (44.9%) and NSMP-L1CAMpos (5.7%), which we refer to as the molecu-lar-L1CAM classification. The molecular-L1CAM classification was an independent prognostic factor for recurrence-free survival (RFS) and overall survival (OS) (p <0.001, each). Similarly, the simplified L1CAM-p53 categorization, for practical use, remained an independent prognostic factor for RFS and OS (p <0.001, p =0.003, respectively). Conclusion: Integrating the molecu-lar-L1CAM classification or the simplified L1CAM/p53 categorization can enhance risk stratifi-cation in early-stage EC, providing valuable prognostic information to guide treatment deci-sions and improve patient outcomes.
ARTICLE | doi:10.20944/preprints201808.0146.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: histone deacetylase inhibitor, MHY2256, p53, apoptosis, autophagy, Ishikawa, endometrial cancer
Online: 7 August 2018 (14:37:46 CEST)
We previously found a novel a new sirtuin (SIRT) inhibitor MHY2256 that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. Here, we investigated the anticancer activity of MHY2256 against hormone-related cancer, which is an endometrial cancer with poor prognosis. We found that MHY2256 markedly reduced cellular proliferation at low concentrations against Ishikawa endometrial cancer cells. The IC50 values of MHY2256 were much lower than that of salermide. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3 with similar effects as salermide, a well-known SIRT inhibitor. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. Detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers.
ARTICLE | doi:10.20944/preprints202310.0810.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: early-onset endometrial cancer; prognostic nomogram; overall survival; cancer-specific survival; SEER
Online: 13 October 2023 (03:02:06 CEST)
Background. This study aimed to establish a prognostic nomogram for predicting overall survival (OS) and cancer-specific survival (CSS) of patients with early-onset endometrial cancer (EOEC). Methods. Patients diagnosed with EOEC during 2004-2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression analyses were performed to ascertain the independent factors impacting the prognosis of EOEC patients, while a prognostic nomogram was established. Its performance was verified by the receiver operating characteristic (ROC) curves, and calibration plots. The prediction accuracy and clinical net benefit between the model, TNM stage and SEER stage were further compared by the concordance index (C-index) and decision curve analysis (DCA). Results. A total of 4415 eligible patients with EOEC were identified and enrolled in this study. Independent prognostic factors for OS and CSS were confirmed by multivariate Cox regression, which were further incorporated to constructed a nomogram. ROC curves and calibration curves indicated an optimal accuracy of the nomogram. Meanwhile, the C-index and DCA showed the predictive capability and the clinical applicability of the nomogram was superior over the TNM stage and SEER stage. Conclusions. Nomogram based on risk factors was developed as an individualized tool to predict OS and CSS for EOEC patients. The novel tool will assist in patient counseling and selection of appropriate therapeutic regimens.
ARTICLE | doi:10.20944/preprints202306.0937.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Endometrial cancer; microsatellite instability; mismatch repair deficiency; platinum-based chemotherapy
Online: 13 June 2023 (12:27:39 CEST)
Background: There is poor evidence about sensitivity to chemotherapy according to microsatellite instability (MSI)/mismatch repair (MMR) status in endometrial cancer (EC). Methodology: The RAME study is a retrospective analysis aiming to assess response to chemotherapy in MSI-high (h) /deficient (d) MMR and MSI- low (l)/proficient (p)MMR EC patients. Primary endpoints were recurrence-free survival (RFS) for patients with localized disease and progression-free survival (PFS) and overall survival (OS) in patients with advanced/recurrent disease. Results: 312 patients treated between 2010-2022 in 4 high volume Multicenter Italian Trial in Ovarian cancer and gynecological malignancies (MITO) centers were selected. 239 patients had endometrioid EC (76.6%), 151 had FIGO stage I at diagnosis (48.9%) and 71 were MSI-h/dMMR (22.8%). Median age was 65 (range 31–91) years. Among patients with localized disease, median RFS was 100.0 months (95%CI 59.4–140.7) for MSI-l/pMMR and 120.9 months (60.0-181.8) for MSI-h/dMMR (p=0.39). Seventy-seven patients received first-line chemotherapy for advanced/recurrent disease. Patients with MSI-h/dMMR ECs had a significantly worse OS (p=0.039). In patients receiving platinum-based chemotherapy, no statistically significant difference in PFS (p=0.21) and OS (p=0.057) were detected, although PFS and OS were numerically longer in the MSI-l/pMMR population. Conclusion: Patients with metastatic MSI-h/dMMR EC receiving first-line chemotherapy had a significantly worse OS.
ARTICLE | doi:10.20944/preprints201810.0451.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: CTCF; tumour suppressor gene; haploinsufficiency; zinc finger; CRISPR/Cas9; cancer; endometrial cancer; gene editing
Online: 19 October 2018 (11:29:01 CEST)
CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in CTCF, which we have shown, functions as a tumour suppressor gene. While CTCF is essential for embryonic development, little is known of its absolute requirement in somatic cells and the consequences of CTCF haploinsufficiency. We examined the consequences of CTCF depletion in immortalised human and mouse cells using shRNA knockdown and CRISPR/Cas9 genome editing and examined the growth and development of heterozygous Ctcf (Ctcf+/-) mice. We also analysed the impact of CTCF haploinsufficiency by examining gene expression changes in CTCF-altered endometrial carcinoma. Knockdown and CRISPR/Cas9-mediated editing of CTCF reduced the cellular growth and colony-forming ability of K562 cells. CTCF knockdown also induced cell cycle arrest and a pro-survival response to apoptotic insult. However, in p53 shRNA-immortalised Ctcf+/- MEFs we observed the opposite: increased cellular proliferation, colony formation, cell cycle progression and decreased survival after apoptotic insult compared to wild type MEFs. CRISPR/Cas9-mediated targeting in Ctcf+/- MEFs revealed a predominance of in-frame microdeletions in Ctcf in surviving clones, however protein expression could not be ablated. Examination of CTCF mutations in endometrial cancers showed locus-specific alterations in gene expression due to CTCF haploinsufficiency, in concert with downregulation of tumour suppressor genes and upregulation of estrogen-responsive genes. Depletion of CTCF expression imparts a dramatic negative effect on normal cell function. However, CTCF haploinsufficiency can have growth-promoting effects consistent with known cancer hallmarks in the presence of additional genetic hits. Our results confirm the absolute requirement for CTCF expression in somatic cells and provide definitive evidence of CTCF’s role as a haploinsufficient tumour suppressor gene. CTCF genetic alterations in endometrial cancer indicate that gene dysregulation is a likely consequence of CTCF loss, contributing to, but not solely driving cancer growth.
ARTICLE | doi:10.20944/preprints202111.0506.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: endometrial cancer; fertility-sparing management; molecular classification; reproductive age; pregnancy
Online: 26 November 2021 (12:42:15 CET)
Conclusions: Molecular classification could provide reliable supplementary information for evaluating prognostic and contribute to treatment option decision-making in EEC patients. Fertility-sparing treatment is not recommended for EEC patients with CNH and MSI-H. Furthermore, fertility-sparing treatment can be attempted in EEC patients with CHL, but regular follow-up should be carried out to early detection of EC relapse and prevention of disease progression.
ARTICLE | doi:10.20944/preprints202208.0147.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: endometrial cancer; ultrasound; lymph nodes; staging; metastases; biomarkers; model; COVID-19
Online: 8 August 2022 (10:24:17 CEST)
Background: Myometrial invasion (MI) is a parameter currently used in transvaginal ultrasound (TVS) in endometrial cancer (EC) to determine local staging, however, without molecular diagnostics, it is insufficient for selection of high-risk cases, i.e., those with a high risk of lymph node metastases (LNM). Methods: One hundred sixteen consecutive EC patients, who had received 2D transvaginal ultrasound examinations in their preoperative workup and final histopathology results as a reference standard, were included in this prospective study. Univariate and multivariate logistic models of analyzed TVS biomarkers (tumor [T] size, T area [AREA], T volume [SPE-VOL], MI, T-free distance to serosa [TFD], endo-myometrial irregularity, [EMIR], cervical stromal involvement, CSI) were evaluated to assess the relative accuracy of the possible LNM predictors. To avoid a potential bias in assuming linear relations between LNM and continuous predictors, spline functions were applied. Calculations were made in R with the use of libraries splines, glmulti, and pROC. Results: LNM was found in 20 out of 116 (17%) patients. In univariate analysis, only uMI, EMIR, uCSI and uTFD were significant predictors of LNM. Accuracy was 0.707 (AUC 0.684, 95% CI 0.568-0.801) for uMI (p<0.01), 0.672 (AUC 0.664, 95% CI 0.547-0.781) for EMIR (p<0.01), 0.776 (AUC 0.647, 95% CI 0.529-0.765) for uCSI (p<0.01), and 0.638 (AUC 0.683, 95% CI 0.563-0.803) for uTFD (p<0.05). The cut-off value for uTFD was 5.2 mm. However, AREA and VOL revealed significant relation by non-linear analysis as well. Among all possible multivariate models, the one comprising interactions of splines of uTFD with uMI and splines of SPE-VOL with uCSI showed most usefulness. Accuracy was 0.802 (AUC 0.791, 95% CI 0.673-0.91) Conclusions: A combination of uTFD for patients with uMI>50%, and SPE-VOL for patients with uCSI, allows for the most accurate prediction of LNM in EC, rather than uMI alone.
ARTICLE | doi:10.20944/preprints202103.0354.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: Endometrial Mesenchymal Stromal Cells; Good Manufacturing Practice (GMP); infertility; Asherman’s syndrome, endometrial thickness; Human platelet lysate (HPL); endometrial sampling
Online: 12 March 2021 (20:51:55 CET)
The cyclic regeneration of human endometrium is guaranteed by the proliferative capacity of Endometrial Mesenchymal Stromal Cells (E-MSCs). Due to this, the autologous infusion of E-MSCs has been proposed to support endometrial growth in a wide range of gynecological diseases. We aimed to compare two different endometrial sampling methods, the surgical curettage and the Vacuum Aspiration Biopsy Random Assay, and to validate a novel xeno-free method to culture human E-MSCs. Six E-MSCs cell lines were isolated after a mechanical tissue homogenization and cultured using human platelet lysate. E-MSCs were characterized for the colony formation capacity, proliferative potential and multilineage differentiation. The expression of mesenchymal and stemness markers was tested by FACS analysis and Real-Time PCR, respectively. Chromosomal alterations were evaluated by karyotype analysis, whereas tumorigenic capacity and invasiveness were tested by soft agar assay. Both endometrial sampling techniques allowed to efficiently isolate and expand E-MSCs using a xeno-free method preserving their mesenchymal and stemness phenotype, proliferative potential and multi-lineage differentiation ability during the culture. No chromosomal alterations and invasive/tumorigenic capacity were observed. Herein we report the first evidence of efficient E-MSCs isolation and culture in Good Manufacturing Practice compliance conditions, suggesting Vabra endometrial sampling as alternative to surgical curettage.
ARTICLE | doi:10.20944/preprints202307.0096.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: Endometrial neoplasms; molecular classification; Neural cell adhesion molecule L1 (L1CAM); Prognosis; Recurrence; Survival
Online: 4 July 2023 (03:52:30 CEST)
(1) Background: This study aimed to identify the recurrence and survival rates according to the mismatch repair (MMR), p53, and L1 cell adhesion molecule (L1CAM) states in patients with advanced and recurrent endometrial cancer receiving systemic chemotherapy.; (2) Methods: This single-center retrospective cohort study included chemotherapy-naïve patients (n=156) with advanced-stage (III/IV) or recurrent endometrial cancer who were administered chemotherapy as adjuvant therapy (n=112) or first-line palliative treatment (n=44) between January 2015 and June 2022. MMR and p53 states were assessed using PCR, and L1CAM was tested using immunohistochemistry in the no specific molecular profile (NSMP) group. The primary outcomes were progression-free survival (PFS) and overall survival (OS).; (3) Results: Of the 156 patients, 62 (39.7%), 53 (34.0%), and 41 (26.3%) had NSMP, abnormal p53 (p53abn), and an MMR deficiency (MMR-D), respectively. PFS and OS were longest in MMR-D, followed by NSMP, and were the least in p53abn tumors (PFS: p=0.0006, OS: p=0.0013). After NSMP was classified according to positive or negative L1CAM status, the L1CAM-negative group exhibited significantly lower survival rates than the L1CAM-positive group (PFS: p=0.0001, OS: p=0.0027); p53abn tumors were independent prognostic factors for poor PFS (p=0.039 on the multivariable analysis).; (4) Conclusions: In chemotherapy-naïve patients with advanced and recurrent endometrial cancer, the best prognosis after chemotherapy was obtained using MMR-D, followed by NSMP and p53abn tumors. The L1CAM status is a useful new marker for stratifying NSMP in advanced and recurrent patients.
ARTICLE | doi:10.20944/preprints202107.0676.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: ultrasound; endometrial cancer; lymph nodes metastasis; myometrial invasion; tumor-free distance
Online: 30 July 2021 (09:06:16 CEST)
Background: Ultrasonography’s usefulness in endometrial cancer (EC) diagnosis consists of its staging and predictive roles. Ultrasound-measured tumor-free distance from the tumor to the uterine serosa (uTFD) is a promising marker for this variable. The aim of the study was to determine the usefulness of this biomarker in locoregional staging, and thus in the prediction of lymph node metastasis (LNM). Methods: We conducted a single-institutional, prospective study on 116 consecutive patients with EC who underwent 2D transvaginal ultrasound examination. The uTFD marker was compared with the depth of ultrasound-measured myometrial invasion (uMI). Univariate and multivariate logit models were evaluated to assess the predictive power of the uTFD and uMI in regard to LNM. The reference standard was a final histopathology result. Survival was assessed by the Kaplan-Meyer method. Results: LNM was found in 17% of the patients (20/116). In the univariate analysis, uMI and uTFD were significant predictors of LNM. Accuracy was 70.7%, and NPV was 92.68% (OR 4.746, 95% CI 1.710-13.174) for uMI (p = 0.002), and 63.8%, and 89.02% (OR 0.842, 95% CI 0.736 – 0.963), respectively, for uTFD (p = 0.01). The cut-off value for uTFD in the prediction of LNM was 5.2 mm. The absence of LNM was associated more with biomarker values uMI <1/2 and uTFD >=5.2 mm than with the presence of metastases with uMI >1/2 and uTFD values <5.2 mm. In the multivariate analysis, the accuracy of the uMI-uTFD model was 74%, and NPV was 90.24% (p = NS). Neither uMI nor uTFD are surrogates for overall and recurrence-free survivals in endometrial cancer. Conclusions: Both uMI and uTFD, either alone or in combination, are valuable tools for gaining additional preoperative information on expected lymph node status. Negative lymph nodes status is better described by ultrasound biomarkers than a positive status. It is easier to use uTFD measurement as a biomarker of EC invasion than uMI, and the former still maintains a similar predictive value for lymph node metastases to the latter at diagnosis.
REVIEW | doi:10.20944/preprints202007.0448.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: C-reactive protein; hs-CRP; albumins; Glasgow Prognostic Score; Endometrial Cancer; CRP to albumin ratio; CRP; Cancer; Inflammation
Online: 19 July 2020 (21:13:19 CEST)
Endometrial Cancer (EC) is the sixth most commonly occurring cancer in women with 380 000 cases in 2018. Sadly, EC morbidity and mortality are continuously increasing, therefore the medical society have a substantial need for an accurate and inexpensive diagnostic test for EC early detection and a prognostic tool for treatment planning and evaluation. Considering experience with different types of cancers C-reactive protein (CRP) appears to be a promising diagnostic and prognostic factor. Aiming to investigate its potential and in view of EC authors, this paper reviewed the following databases for metanalysis, randomized controlled trials and review articles published up to June 2020: Pubmed, Scopus, Google scholar and ClinicalKey. Studies indicate CRP >3.33 mg/l correlate with EC incidence with HR = 2.29 (p<0.05). Moreover, High-sensitivity CRP assay allows to detect CRP in very low concentrations and distinguish patients with endometriosis, soft tissue sarcomas and possibly EC. Preoperational and postoperational CRP, as well as its dynamic change are independent prognostic factors for EC and are more reliable if analyzed together. However, CRP-to-albumin ratio as well as Glasgow Prognostic Scale have greater prognostic value that CRP alone. Additionally, CRP is possibly a mediator of carcinogenesis and cancer progression through activation of inter alia FcgRs/MAPK/ERK, FcgRs/IL-6/AKT/STAT3 and FcgRs/NF-κB/NLRP3 pathways.
ARTICLE | doi:10.20944/preprints202107.0369.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Endometrial cancer; sentinel lymph node; micrometastases; ultrastaging; one-step nucleic acid amplification; OSNA; cytokeratin 19
Online: 16 July 2021 (11:57:14 CEST)
The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study. 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1-mm portion of each lymph node was subjected to semi-serial sectioning at 200-μm intervals and examined by hematoxylin-eosin and immunohistochemistry with CK19; the remaining tissue was analysed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/μl), the sensitivity of the OSNA assay was 92%; specificity was 82%; diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis.
REVIEW | doi:10.20944/preprints202306.0468.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Endometrial cancer (EC); assisted reproduction techniques (ART); miR-based; molecular evaluation; ethical and legal/regulatory implications
Online: 6 June 2023 (14:54:47 CEST)
This review article is aimed at exploring the possibility of developing an integrated approach in the management of the different needs of endometrial cancer (EC) patients seeking to become pregnant. Life preservation of the woman, health preservation of the baby, a precocious and – as much as possible – minimally invasive characterization of the health and fertility parameters of the patient, together with the concerns regarding the obstetric, neonatal, and adult health risks of the children conceived via assisted reproduction techniques (ART) are all essential aspects of the problem to be taken into consideration, yet the possibility to harmonize such needs through a concerted integrated approach is still highly challenging. This article aims to illustrate the main features of EC and how it affects the normal physiology of pre-menopausal women. Then, we focus on the prospect for a miR-based, molecular evaluation of patient health status, including both EC early diagnosis and staging and, similarly, the receptivity of the woman, discussing the possible evaluation of both aspects using a single specific panel of circulating miR in the patient, thus allowing a relatively fast, non-invasive way to perform such testing with a significantly reduced margin of error. Finally, the ethical and legal/regulatory complexities arising from such innovative techniques require not only a risk-benefit analysis; respect for patient autonomy and equitable health care access allocation are fundamental issues as well.
ARTICLE | doi:10.20944/preprints202307.1756.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: endometrial stromal cells; senescence; oncogenes; cancer; HRASG12V
Online: 26 July 2023 (10:39:31 CEST)
Being the major cellular component of highly dynamic tissue endometrial stromal cells (EnSC) are exposed to cycles of proliferation upon hormonal stimulation what might pose risks for mutations accumulation and malignization. However, endometrial stromal tumors are rare and unusual types of tumor. The present study aimed to uncover defense mechanisms that might underlie resistance of EnSC against oncogenic transformation. All experiments were performed in vitro using the following methods: FACS, WB, RT-PCR, IF, molecular cloning, lentiviral transduction, and CRISPR/Cas9 genome editing. We revealed that expression of the mutant HRASG12V results in senescence of EnSC. We experimentally confirmed inability of HRASG12V-expressing EnSC to bypass senescence and resume proliferation even upon oestrogen stimulation. At the molecular level, induction of oncogene-induced senescence (OIS) was accompanied by the activation of MEK/ERK, PI3K/AKT, p53/p21WAF/CIP/Rb and p38/p16INK4a/Rb pathways, however inhibiting either pathway did not prevent cell cycle arrest. PTEN loss was established as the additional feature of HRASG12V-induced senescence of EnSC. By using CRISPR-Cas9 mediated PTEN knockout, we distinguished PTEN loss-induced senescence as a reserve molecular mechanism to prevent transformation of HRASG12V-expressing EnSC. The present study highlights oncogene-induced senescence as an antitumor defense mechanism of EnSC controlled by multiple backup molecular pathways.
REVIEW | doi:10.20944/preprints201810.0117.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: decidualisation; oestradiol; aromatase; testosterone; DHEA; endometriosis; endometrial cancer; sulfatase
Online: 7 October 2018 (10:03:09 CEST)
Peripheral tissue metabolism of steroids (intracrinology) is now accepted as a key way in which tissues, such as the endometrium, can utilize inactive steroids present in the blood to respond to local physiological demands and ‘fine-tune’ the activation or inhibition of steroid hormone receptor-dependent processes. Expression of enzymes that play a critical role in activation and inactivation of bioactive oestrogens (E1, E2) and androgens (A4, T, DHT), as well as expression of steroid hormone receptors, has been detected in endometrial tissues and cells recovered during the menstrual cycle. There is robust evidence that increased expression of aromatase is important for creating a local microenvironment that can support a pregnancy. Measurement of intra-tissue concentrations of steroids using liquid chromatography–tandem mass spectrometry has been important in advancing our understanding of a role for androgens in the endometrium acting both as active ligands for the androgen receptor and as substrates for oestrogen biosynthesis. The emergence of intracrinology, associated with disordered expression of key enzymes such as aromatase, in the aetiology of common women’s health disorders such as endometriosis and endometrial cancer has prompted renewed interest in development of drugs targeting these pathways opening up new opportunities for targeted therapies and precision medicine.
ARTICLE | doi:10.20944/preprints202310.0307.v1
Subject: Biology And Life Sciences, Virology Keywords: Bovine herpesvirus type 4; bovine endometrial primary culture cells; apoptosis
Online: 6 October 2023 (05:11:25 CEST)
The prevalent pathogens associated with bovine uterine infections are bacteria that appear to increase the host's susceptibility to secondary infections with other bacteria or viruses, among which BoHV-4 is the most frequently found. In this work, the study of the pathways of apoptosis induction was carried out on an experimental model of primary culture of endometrial cells, in order to know the implication of BoHV-4 and the presence of bacterial LPS in the pathogenesis of the bovine reproductive tract. For this, different staining techniques and molecular analysis by RT-PCR were used. The results obtained allowed us to conclude that the level of cell death observed in the proposed primary culture is directly related to the time of viral infection and the presence of LPS in BoHV-4 infection. The apoptosis indices in cells infected with BoHV-4, BoHV-4 + LPS presented a maximum that correlates with the appearance of the cytopathic effect, and the maximum viral titers in the model studied. However, morphological, biochemical and molecular changes were evident during both early and late stages of apoptosis. These findings provide information on the factors that may influence the pathogenesis of BoHV-4 and help to better understand the mechanisms involved in virus infection.
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: circulating endometrial cells; endometriosis; rare cells; menstrual cycle; liquid biopsy
Online: 18 August 2019 (16:36:07 CEST)
The focus of the presented work was to isolate and characterize circulating endometrial cells (CECs) enriched from peripheral blood (PB) of patients with diagnosed endometriosis to support endometriosis diagnosis and treatment. Material and Methods Blood samples (n=423) were tested for CECs presence. Subsequently, gene expression analysis (GEA) was carried out for CECs. In parallel, the presence and character of CECs was tested during phases of menstrual cycle (MC) (n= 11). CECs were isolated by size-based separation from 2x 8ml PB. Results CECs were detected in 78.4% of blood samples. In line with the revised American Fertility Society (rAFS) classification CECs presence was confirmed in all the acknowledged endometriosis stages: minimal, mild, moderate and severe. Surprisingly, the highest CEC negativity rate was reported for severe disease (21.1%). The highest CEC numbers were detected in the mid-secretory periods of MC, which corresponds with uterine lining decidualization. The cytomorphology of CECs captured during MC is changing between the epithelial, stromal and stem cell-like. CECs captured in mid-secretory period expressed KRT18, NANOG and VIM in higher amounts when compared to the genes in the proliferative phase of MC when KRT19 and ESR1 were mostly observed. GEA of the super-positive CECs samples (1000 CECs/8mL PB) revealed high expression of KRT18, VIM, NANOG and FLT1. The expression of these genes was elevated in the endometriosis tissue samples and endometrioma, too. Conclusion The panel of the identified CECs - genes could be tested in a prospective manner to confirm the predictive value of CECs in endometriosis diagnostics.
REVIEW | doi:10.20944/preprints202307.0891.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: endometrial microbiota; microbiome; fertility; chronic endometritis; uterus; reproductive outcomes; endometriosis, oncology
Online: 13 July 2023 (09:25:34 CEST)
Contrary to popular belief, we have known for many years that the endometrium is not a sterile environment and is considered to be a low-biomass milieu compared to the vagina. Numerous trials and studies have attempted to establish a valid sampling method and assess its physiological composition, but no consensus has been reached. Many factors such as ethnicity, age and inflammation, can influence the microbiome. Moreover, it possesses a higher alpha-diversity and therefore contains more diverse bacteria than the vagina. For instance, Lactobacillus has been shown to be a predominant genus in the vaginal microbiome of healthy women. Consequently, even if a majority of scientists postulate that a predominance of Lactobacillus inside the uterus improves reproductive outcomes, vaginal contamination by these bacteria during sampling cannot be ruled out. Certain pathologies, such as chronic endometritis, have been identified as inflammation perpetrators that hinder the embryo implantation process. This pro-inflammatory climate created by dysbiosis of the endometrial microbiota could induce secondary inflammatory mediators via Toll-like receptors, creating an environment conducive to the development of endometriosis and even promoting carcinogenesis. However, studies to this day have focused on small populations. In addition, there is no clearly defined healthy uterine composition yet. At most, only a few taxa have been identified as pathogenic. As sampling and analysis methods become increasingly precise, we can expect the endometrial microbiota to be incorporated into future diagnostic tools and treatments for women’s health.
ARTICLE | doi:10.20944/preprints202101.0510.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Frozen-Thawed Embryo Transfer; Birthweight; Endometrial Preparation; Ovulatory Cycle; Artificial Cycle
Online: 25 January 2021 (15:06:40 CET)
Background: It is unknown whether prolonged artificial hormonal environment during early fetal development affects the birthweight of singletons born after frozen-thawed embryo transfer (FET). Methods: A retrospective observational study included singleton births>22 weeks of gestation obtained after FET between 2013-2019 after endometrial preparation with ovulatory cycle (OC) or artificial cycle (AC). Our primary objective was to compare birthweight of singletons after FET between endometrial preparation by OC or AC. Secondary objectives included prolonged pregnancies, high birthweight, low birthweight, SGA and LGA rates. Multivariate analyses were performed considering potential confounding factors. Results: Among 198 singleton live births after FET, 112 were obtained with OC and 86 with AC. Prolonged pregnancies rate was higher in AC (25.6% vs. 7.1%, respectively, p=0.001). Mean birthweight was higher (+219g) in AC (3386g vs. 3167g, p=0.01; adjusted-p=0.052), as well as the rate of babies exceeding 4000g (16.3% vs. 2.7%, p=0.03, adjusted-p=0.015). The rate of babies <2500g was lower in AC (3.5% vs. 11.6%, respectively, p=0.050, adjusted-p=0.049). Conclusions: Since OC does not strain the chances of pregnancy and in the incomplete knowledge of the consequences of neonatal overweight on the future health of children, OC preparation could be advocated as first-line endometrial preparation in FET.
ARTICLE | doi:10.20944/preprints201805.0088.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: p53; proteasome inhibitor; endometrial cancer; ovarian cancer; gain-of-function mutation
Online: 4 May 2018 (09:03:27 CEST)
Mutations in the “guardian of the genome” TP53 predominate in solid tumors. In addition to loss of tumor suppressor activity, a specific subset of missense mutations confers additional oncogenic properties. These “gain-of-function” (GOF) mutations portend poor prognosis across cancer types regardless of treatment. Our objective in this study was to identify novel therapeutic opportunities to overcome the deleterious effects of GOF TP53 mutants. Using gynecologic cancer cell lines with known TP53 mutational status, we established that treatment with a proteasome inhibitor induced cell death in cells with two recurrent GOF TP53 mutations (R175H and R248Q), and addition of a histone deacetylase inhibitor (HDACi) enhanced this effect. By contrast, p53-null cancer cells were relatively resistant to the combination. Towards understanding the mechanism, we found that proteasome inhibition promotes apoptosis of cells with TP53 GOF mutations, potentially through induction of the unfolded protein response. In line with the reported hyperstabilization of GOF p53 protein, cells treated with HDACi exhibited reduced levels of p53 protein. Together, these data form the basis for future clinical studies examining therapeutic efficacy in a preselected patient population with GOF TP53 mutations.
ARTICLE | doi:10.20944/preprints201610.0122.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: isoflavones; menopause management; endometrial thickness; mammary density; liver function; plant extracts
Online: 27 October 2016 (12:21:59 CEST)
Long-term safety of a nutraceutical combination based on agnus castus and magnolia extracts combined with soy isoflavones (SI) and lactobacilli, and effectiveness on vasomotor symptoms and sleep disorders in postmenopausal women, were assessed. A controlled study was carried-out in menopausal women comparing this nutraceutical combination (ESP group) with formulation containing isoflavones alone (C group), at the dosage recommended. Kuppermann index, PSQI, and SF-36 were determined at baseline, 3, 6 and 12 months. Endometrial thickness, mammary density and liver function were evaluated at baseline and after 12 months. 180 women (100 in ESP group and 80 in C group, mean age 55.5 years, in menopause for about 36 months) were enrolled in the study. At the treatment end, mammary density, endometrial thickness, and hepatic function did not show substantial differences between groups. Kuppermann index, and particularly hot flushes, were progressively and significantly decreased in frequency and severity during ESP versus C treatment. No adverse events were observed. Agnus castus and magnolia, combined with SI + lactobacilli, can effectively and safely be used in symptomatic postmenopausal women, mainly when quality of sleep is the most disturbing complaint. Endometrium, mammary glands and liver function, were unaffected after 12 months treatment.
REVIEW | doi:10.20944/preprints202202.0052.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: cervical cancer; endometrial cancer; ovarian cancer; 2021 update; novel targeted therapies; immunotherapy
Online: 3 February 2022 (13:02:11 CET)
This review of the meaningful data from 2021 on cervical, endometrial, and ovarian cancers aims to provide an update of the most clinically relevant studies presented at important oncologic congresses during the year [the American Society of Clinical Oncology (ASCO) Annual Meeting, the European Society for Medical Oncology (ESMO) Congress and the Society of Gynecologic Oncology (SGO) Annual Meeting]. Despite the underlying existence of the COVID-19 pandemic, the last year has been notable in terms of research, with significant and promising advances in gynecologic malignancies. Several major studies reporting the effects of innovative therapies for patients with cervical, endometrial, and ovarian cancers might change the medical practice in the future.
REVIEW | doi:10.20944/preprints201806.0001.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: endocannabinoid system; gynaecological cancers; endometrial cancer; cervical cancer; ovarian cancer, CB1R; CB2R; FAAH;
Online: 1 June 2018 (05:45:19 CEST)
Background: The endocannabinoid system (ECS) is a very heterogeneous array consisting of many proteins like ligands, enzymes and receptors synthetized in various tissues and immunity cells. The main endogenous ligands are unsaturated fatty acid derivatives like anandamide(AEA), 2-arachidonoylglycerol(2-AG), but many others are under study. Endocannabinoids are involved in both physiological and pathological conditions. ECS plays an important role in the regulation of main processes which lead to cancer and also in sex steroid hormone-related cancers. Methods: With focus on gynaecological cancers, main papers and review articles, up to April 2018, on the role of the ECS, were acquired by PubMed searches using the search terms: ‘cancer’, ‘cannabinoid’, ‘endocannabinoid’, ‘gynaecology’ and ‘malignancy’. Results: The review of recent literature data showed the involvement of the endocannabinoid system in numerous physiological and pathological conditions of the female genital tract up to the development of gynaecological malignancy as cervical, endometrial and ovarian cancer. Conclusions: The endocannabinoid system has an important role in antitumor actions involving different signalling receptor and receptor-independent pathways. It represents an exciting challenge to researchers for its potential use in diagnosis and treatment of all gynaecological malignancies
ARTICLE | doi:10.20944/preprints202010.0185.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: Trueperella pyogenes; bovine endometrial epithelial cells; inflammasome; tight junction; apoptosis; Lactobacillus rhamnosus GR-1
Online: 8 October 2020 (22:07:15 CEST)
Trueperella pyogenes is a common opportunistic pathogen which is one of the main causes of postpartum endometritis in dairy cows. As a substitute for antibiotics, the probiotic Lactobacillus rhamnosus GR-1 has been used in a wide range of clinical treatments. Our experiments were designed to establish a model of anti-damage which LGR-1 was used to protect bovine endometrial epithelial cells (BEECs) from inflammatory damage and cell destruction caused by T. pyogenes. Increased expression of NLRP3 inflammasomes and cytokines was observed following T. pyogenes challenge, but this increase was relieved by LGR-1 pretreatment. Immunofluorescence and Western blot analyses revealed that T. pyogenes infection also results in the damage of tight junction proteins in BEECs. The expression levels of Claudin-1, Occludin, and ZO-1 were decreased in cells only infected with T. pyogenes but not in cells pretreated with LGR-1. Moreover, the detection of the anti-apoptotic protein Bcl-2 and apoptotic proteins BAX, cytochrome c, as well as the activating effector caspase-3 revealed that T. pyogenes induced apoptosis of BEECs, which was also confirmed by DAPI staining to observe the morphological changes of the nuclei of cell apoptosis and by TUNEL staining to locate the cells undergoing apoptosis. Our data indicate that LGR-1 ameliorates the T. pyogenes–induced barrier dysfunction of BEECs and pre-application of LGR-1 could be an effective strategy for controlling T. pyogenes infection.
ARTICLE | doi:10.20944/preprints202305.1397.v1
Subject: Public Health And Healthcare, Public Health And Health Services Keywords: high dose rate brachytherapy; vaginal cuff brachytherapy; single channel cylinder; multiple channel cylinder, endometrial cancer.
Online: 19 May 2023 (07:42:29 CEST)
Purpose: The purpose of this study was to evaluate the dosimetric impact of multiple channels compared to a single channel in high dose rate (HDR) vaginal cuff brachytherapy (VCBT). Methods and materials: Sample plans of HDR VCBT from both single and multiple channel cylinders at 2.5, 3.0 and 3.5 cm in diameter were created and analyzed. The doses were prescribed either at the 0.5 cm depth with 5.5 Gy for 4 fractions or at the cylinder surface with 8.8 Gy for 4 frac¬tions, in various treatment lengths ranging from 3 to 8 cm. A 0.5 cm ring target volume called PTV_Eval was contoured for each plan and served as the target volume for dosimetric evaluation. Mean doses and the doses covering 90% (D90), 10% (D10), and 5% (D5) of PTV_Eval were calculated and compared. The same treatment lengths, same prescription regimens, same target volume contouring and same plan evaluation methods were repeated for the similar size single channel and multiple channel cylinders. Results: The mean doses of both regimens with the multi-channel cases (6.3 to 7.1 Gy) were comparable to single channel ones (6.4 and 7.5 Gy). The ranges of D90, D10 and D5 were from 3.654 to 5.04 Gy, 8.44 to 10.08 Gy and 8.84 to 10.86 Gy in the multi-channel cases, but from 5.36 to 5.76 Gy, 7.40 to 9.97 Gy and 8.16 to 11.93 Gy in the single channel cases, respectively. Conclusion: The single channel and multiple-channel cylinder deliver a similar mean dose, but with marked heterogeneity in D90, D5 and D10 for the same prescription dose and target volume. Multi-channel cylinders adequately cover the target volume, but given the heterogeneity, increased treatment time and cost are best suited for asymmetric target volumes.
REVIEW | doi:10.20944/preprints202009.0649.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Infertile women; Hysteroscopy; Clinical pregnancy rate; Live birth rate; No Intrauterine pathology; endometrial stimulation; Systematic review
Online: 26 September 2020 (16:39:39 CEST)
(1) Background: The aim of this work was to systematically review existing studies on whether hysteroscopy improves the reproductive outcomes of women with infertility even in the absence of intrauterine pathologies when compared to women who did not receive a hysteroscopy. (2) Methods: We established the Participant-Intervention-Comparison-Outcome strategy and used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement to conduct a systematic review of 11 studies which were retrieved from 3 electronic databases: Ovid-Medline, Ovid-Embase, and the Cochrane Library. Two independent investigators extracted the data from the included studies and used the Cochrane risk-of-bias tool to assess their quality. (3) Results: The primary outcome measures were the clinical pregnancy rates (CPRs) and live birth rates (LBRs) in the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Hysteroscopy in infertile women without intrauterine pathologies showed higher CPRs and LBRs than those in the same population who did not receive hysteroscopy in cases of recurrent implantation failure and IVF (odds ratio: 1.79 and 1.46, 95% confidence interval: 1.46-2.30 and 1.08-1.97 for CPR and LBR, respectively); however, the degree of significance was not as high for LBR. (4) Conclusions: Hysteroscopy before IVF/ICSI in infertile women without intrauterine pathologies may potentially be effective in improving the CPRs and LBRs in patients with RIF. Robust and high-quality randomized trials are warranted to confirm this finding.
ARTICLE | doi:10.20944/preprints202007.0399.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: microRNA; miR-142-3p; endometriosis; cytoskeleton; integrin; collagen; WASL; ITGAV; endometrial stroma cells; in vitro study
Online: 17 July 2020 (16:08:42 CEST)
Downregulated microRNA-142-3p signaling contributes to the pathogenesis of endometriosis  , an invasive disease where the lining of the uterus grows at ectopic locations, by yet incompletely understood mechanisms. Using bioinformatics and in vitro assays, this study identifies cytoskeletal regulation and integrin signaling as two relevant categories of miR-142-3p targets. qPCR revealed that miR-142-3p upregulation in St-T1b cells downregulates ROCK2, CFL2, RAC1, WASL and ITGAV. qPCR and Western-blotting showed miR-142-3p effect on WASL and ITGAV was significant also in primary endometriotic stroma cells. Luciferase reporter assays in ST-T1b cells then confirmed direct regulation of ITGAV and WASL. On the functional side, miR-142-3p upregulation significantly reduced ST-T1b cell size, the size of vinculin plaques, migration through fibronectin-coated transwell filters and the ability of ST-T1b and primary endometriotic stroma cells to contract collagen I gels. These results suggest that miR-142-3p has a strong mechanoregulatory effect on endometrial stroma cells and its external administration reduces the invasive endometrial phenotype. Within the limits of an in vitro investigation, our study provides new mechanistic insights into the pathogenesis of endometriosis and provides a perspective for the development of miR-142-3p based drugs for inhibiting invasive growth of endometriotic cells.
REVIEW | doi:10.20944/preprints202311.1526.v1
Subject: Medicine And Pharmacology, Reproductive Medicine Keywords: copper; gynecological diseases; Cu chelators; Cu ionophores; ovarian cancer; polycystic ovarian syndrome; cervical cancer; endometrial cancer; endometriosis
Online: 23 November 2023 (11:17:31 CET)
Copper (Cu) is an essential micronutrient for the correct development of eukaryotic organisms. This metal plays a key role in many cellular and physiological activities, including enzymatic activity, oxygen transport, and cell signaling. Although the redox activity of Cu is crucial for enzymatic reactions, this property also makes it potentially toxic when found at high levels. Due to this dual action of Cu, highly regulated mechanisms are necessary to prevent both the deficiency and the accumulation of this metal since its dyshomeostasis may favor the development of multiple diseases, such as Menkes’ and Wilson’s diseases, neurodegenerative diseases, diabetes mellitus, and cancer. As the relationship between Cu and cancer has been the most studied, we analyze how this metal can affect three fundamental processes for tumor progression: cell proliferation, angiogenesis, and metastasis. Gynecological diseases are characterized by high prevalence, morbidity, and mortality, depending on the case, and mainly include benign and malignant tumors. The cellular processes that promote their progression are affected by Cu, and the mechanisms that occur may be similar. We analyze the crosstalk between Cu deregulation and gynecological diseases, focusing on therapeutic strategies derived from this metal.