ANGPTL4 regulates ovarian cancer progression by activating the ERK1/2 pathway.

BACKGROUND: Ovarian cancer (OC) has the highest mortality rate among all gynecological malignancies. A hypoxic microenvironment is a common feature of solid tumors, including ovarian cancer, and an important driving factor of tumor cell survival and chemo- and radiotherapy resistance. Previous research identified the hypoxia-associated gene angiopoietin-like 4 (ANGPTL4) as both a pro-angiogenic and pro-metastatic factor in tumors. Hence, this work aimed to further elucidate the contribution of ANGPTL4 to OC progression. METHODS: The expression of hypoxia-associated ANGPTL4 in human ovarian cancer was examined by bioinformatics analysis of TCGA and GEO datasets. The CIBERSORT tool was used to analyze the distribution of tumor-infiltrating immune cells in ovarian cancer cases in TCGA. The effect of ANGPTL4 silencing and overexpression on the proliferation and migration of OVCAR3 and A2780 OC cells was studied in vitro, using CCK-8, colony formation, and Transwell assays, and in vivo, through subcutaneous tumorigenesis assays in nude mice. GO enrichment analysis and WGCNA were performed to explore biological processes and genetic networks associated with ANGPTL4. The results obtained were corroborated in OC cells in vitro by western blotting. RESULTS: Screening of hypoxia-associated genes in OC-related TCGA and GEO datasets revealed a significant negative association between ANGPTL4 expression and patient survival. Based on CIBERSORT analysis, differential representation of 14 distinct tumor-infiltrating immune cell types was detected between low- and high-risk patient groups. Silencing of ANGPTL4 inhibited OVCAR3 and A2780 cell proliferation and migration in vitro and reduced the growth rate of xenografted OVCAR3 cells in vivo. Based on results from WGCNA and previous studies, western blot assays in cultured OC cells demonstrated that ANGPTL4 activates the Extracellular signal-related kinases 1 and 2 (ERK1/2) pathway and this results in upregulation of c-Myc, Cyclin D1, and MMP2 expression. Suggesting that the above mechanism mediates the pro-oncogenic actions of ANGPTL4T in OC, the pro-survival effects of ANGPTL4 were largely abolished upon inhibition of ERK1/2 signaling with PD98059. CONCLUSIONS: Our work suggests that the hypoxia-associated gene ANGPTL4 stimulates OC progression through activation of the ERK1/2 pathway. These findings may offer a new prospect for targeted therapies for the treatment of OC.

Associating Peritoneal Metastasis With T2-Weighted MRI Images in Epithelial Ovarian Cancer Using Deep Learning and Radiomics: A Multicenter Study.

BACKGROUND: The preoperative diagnosis of peritoneal metastasis (PM) in epithelial ovarian cancer (EOC) is challenging and can impact clinical decision-making. PURPOSE: To investigate the performance of T2 -weighted (T2W) MRI-based deep learning (DL) and radiomics methods for PM evaluation in EOC patients. STUDY TYPE: Retrospective. POPULATION: Four hundred seventy-nine patients from five centers, including one training set (N = 297 [mean, 54.87 years]), one internal validation set (N = 75 [mean, 56.67 years]), and two external validation sets (N = 53 [mean, 55.58 years] and N = 54 [mean, 58.22 years]). FIELD STRENGTH/SEQUENCE: 1.5 or 3 T/fat-suppression T2W fast or turbo spin-echo sequence. ASSESSMENT: ResNet-50 was used as the architecture of DL. The largest orthogonal slices of the tumor area, radiomics features, and clinical characteristics were used to construct the DL, radiomics, and clinical models, respectively. The three models were combined using decision-level fusion to create an ensemble model. Diagnostic performances of radiologists and radiology residents with and without model assistance were evaluated. STATISTICAL TESTS: Receiver operating characteristic analysis was used to assess the performances of models. The McNemar test was used to compare sensitivity and specificity. A two-tailed P < 0.05 was considered significant. RESULTS: The ensemble model had the best AUCs, outperforming the DL model (0.844 vs. 0.743, internal validation set; 0.859 vs. 0.737, external validation set I) and clinical model (0.872 vs. 0.730, external validation set II). After model assistance, all readers had significantly improved sensitivity, especially for those with less experience (junior radiologist1, from 0.639 to 0.820; junior radiologist2, from 0.689 to 0.803; resident1, from 0.623 to 0.803; resident2, from 0.541 to 0.738). One resident also had significantly improved specificity (from 0.633 to 0.789). DATA CONCLUSIONS: T2W MRI-based DL and radiomics approaches have the potential to preoperatively predict PM in EOC patients and assist in clinical decision-making. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Intra- and Interimage Reliability of Inter-Rectus Distance Measurements Determined via Ultrasound Imaging by the Same or Different Testers in Women in the Early Postpartum Period.

OBJECTIVES: No consensus regarding the optimal position and location for the measurement of the inter-rectus distance (IRD) via ultrasound (US) has been reached. By investigating the intra- and interimage reliability of IRD measurements taken in different positions and at different locations within and between testers, this study provides a theoretical basis for the current situation. METHODS: The IRD was measured via US in 46 women at 42-60 days after delivery at the superior margin of the umbilicus and 3 cm above, 5 cm above and 3 cm below the umbilicus while the women were in the supine, crunch and standing positions. In the interimage test, every participant was tested 2 times by Physician X and 1 time by Physician Y; in the intraimage test, the images collected by Physician X during the first test were saved in the machines, and two measurements were performed by Physician X and one measurement was performed by Physician Y. Paired t tests and intraclass correlation coefficients (ICCs) were calculated. RESULTS: Only the first IRD measurements by tester X and tester Y at 3 cm below the umbilicus in the crunch position were significantly different (9.56 ± 6.00 versus 11.00 ± 5.55) (P < .05). All the ICCs were greater than .75, and the intratester ICCs were greater than or equal to the corresponding intertester ICCs. The ICCs at 3 cm below the umbilicus were the smallest in the supine and crunch positions and the largest in the standing position due to the increased frequency of IRD values of 0. The ICCs for the crunch position were greatest according to the intraimage test but smallest according to the interimage test. The interimage ICCs between the two testers in the supine position at the superior margin, 3 cm above, 5 cm above, and 3 cm below the umbilicus were .972, .974, .975, and .956, respectively. CONCLUSIONS: Ultrasound imaging (USI) is a reliable method for measuring the IRD in women in the early postpartum period. The dynamic measurement of the IRD at or above the umbilicus in the supine position by different testers in real time showed the highest reliability.

Novel predictors for identifying cervical minimal deviation adenocarcinoma patients with poor prognosis: a long-term observational study in a tertiary centre.

PURPOSE: To elucidate the clinicopathological features and prognostic factors of minimal deviation adenocarcinoma (MDA) of the uterine cervix, a clinically rare but highly invasive disease. METHODS: This was a retrospective, observational, real-world study of 43 patients with pathologically confirmed MDA at the Obstetrics and Gynaecology Hospital of Fudan University between November 2010 and November 2021. Baseline clinicopathological data were collected and reviewed. Prognostic factors for progression-free survival (PFS) and overall survival (OS) were investigated by univariate and multivariate Cox proportional hazards analyses. RESULTS: Chief complaints included irregular vaginal discharge and/or bleeding (74.4%). Preoperative diagnosis was difficult, the detection rate was low (36.8%), all cases showed endophytic lesions, and 88.4% had deep stromal invasion, with biologically aggressive characteristics. The ovarian metastasis rate was high (16.3%, 7/43). The median maximum diameter of the tumour (MDOT) was 4.3 cm (range, 0.5-8.0 cm). MDOT was significantly associated with OS (P = 0.009), and the optimal cut-off value to define bulky MDA was 5.5 cm (P < 0.0001, χ= 21.161) using X-tile software. Independent prognostic factors included MDOT (HR = 10.095, P = 0.001) and ovarian metastasis (HR = 5.888, P = 0.008) for OS and MDOT (HR = 3.944, P = 0.028), ovarian metastasis (HR = 9.285, P = 0.001), and deep infiltration (HR = 3.627, P = 0.048) for PFS. CONCLUSION: Endophytic lesion development and ovarian metastasis are likely in MDA. A bulky tumour and ovarian metastasis indicate a worse prognosis. Given the special biological features of MDA, it is more appropriate to use 5.5 cm as the threshold for defining a bulky tumour than it is to use 4 cm. Ovary removal should be given higher priority to improve prognosis.

E3 ligase FBXO22 is not significant for spermatogenesis and male fertility in mice.

BACKGROUND: F-box-only protein 22 (FBXO22), an important substrate receptor of the SKP1-Cullin-F-box (SCF) ubiquitin ligases, has been reported to be involved in many biological processes, including tumorigenesis, neurological disorders, cellular senescence, and DNA damage. However, the specific role of FBXO22 during spermatogenesis is poorly understood. METHODS: We produced Fbxo22 conditional knockout (cKO) and global knockout (KO) mice and assessed their sperm masurements using a computer-assisted sperm analysis (CASA) system. Additionally, we conducted histologic staining and immunostaining to examine the impact of Fbxo22 loss on spermatogenesis. RESULTS: Our results revealed that there were no notable differences in semen quality, fertility test results, or histologic findings in Fbxo22-KO and Fbxo22-cKO mice compared to the control group. CONCLUSIONS: Our study demonstrated that Fbxo22 is not significant for spermatogenesis or male fertility in mice. These findings will help researchers avoid redundant efforts and serve as a foundational resource for genetic studies on human fertility.

TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation.

BACKGROUND: Ovarian cancer is a common gynecological tumor with high malignant potential and poor prognosis. TRIM8, is involved in the development of various tumors, but its precise regulatory role in ovarian cancer is still unknown. AIMS: The aim of this study was to explore the specific mechanism by which TRIM8 regulates ovarian cancer. MATERIALS AND METHODS: We used bioinformatics analysis to screen for high expression of TRIM8 in ovarian cancer. The expression of TRIM8 in healthy and cancerous ovarian tissues was assessed by immunofluorescence. TRIM8 was silenced or overexpressed in ovarian cancer cell lines, with cell proliferation and migration evaluated by CCK8, transwell and clonal formation assays. The effect of TRIM8 on ovarian cancer cells in vivo was assessed by subcutaneous tumor formation experiments in nude mice. The potential interacting protein VDAC2 was identified by mass spectrometry. The mechanism underlying TRIM8 regulation of VDAC2 was evaluated by co-immunoprecipitation and western blotting. RESULTS: TRIM8 was overexpressed in ovarian cancer. TRIM8 promoted the proliferation and migration of ovarian cancer cells in vitro and the growth of subcutaneous tumors in mice in vivo. TRIM8 interacted with VDAC2, weakened the stability of the protein, and promoted its polyubiquitination and subsequent degradation. Knockdown of VDAC2 increased the resistance of ovarian cancer cells to iron death, whereas overexpression of VDAC2 attenuated ovarian cancer progression induced by TRIM8 overexpression. DISCUSSION: TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation, these finding may provide new targets for the treatment of ovarian cancer. CONCLUSION: TRIM8 degraded VDAC2 through the ubiquitination pathway, increased the resistance of ovarian cancer cells to iron death, and promoted the proliferation and migration of ovarian cancer.

The distribution pattern of pelvic lymph nodal metastases in cervical cancer.

PURPOSE: Depiction of pelvic lymph node metastasis (LNM) sites among patients with cervical cancer facilitates accurate determination of the extent of dissection and radiotherapy regimens. METHODS: A retrospective study of 1182 cervical cancer patients who underwent radical hysterectomy and pelvic lymph node dissection between 2008 and 2018 was performed. The number of removed pelvic lymph nodes and metastasis status in different anatomical regions was analyzed. The prognostic difference of patients with lymph node involvement stratified by various factors was analyzed by Kaplan-Meier method. RESULTS: The median number of pelvic lymph nodes detected was 22, mainly from obturator (29.54%) and inguinal (21.14%) sites. Metastatic pelvic lymph nodes were found in 192 patients, with obturator accounting for the highest percentage (42.86%). The patients with lymph node involvement in single site had better prognosis that those in multiple sites. The overall- (P = 0.021) (OS) and progression-free (P < 0.001) survival (PFS) curves of patients with inguinal lymph node metastases were worse compared to those with obturator site. There was no difference in the OS and PFS among patients with 2 and more than 2 lymph nodes involvement. CONCLUSION: An explicit map of LNM in patients with cervical cancer was presented in this study. Obturator lymph nodes tended to be involved. The prognosis of patients with inguinal lymph node involvement was poor in contrast to that with obturator LNM. In patients with inguinal lymph node metastases, clinical staging needs to be reconsidered and extended radiotherapy to the inguinal region needs to be strengthened.

Deep Learning Radiomics Nomogram Based on Magnetic Resonance Imaging for Differentiating Type I/II Epithelial Ovarian Cancer.

RATIONALE AND OBJECTIVES: To develop and validate a T2-weighted magnetic resonance imaging (MRI)-based deep learning radiomics nomogram (DLRN) to differentiate between type I and type II epithelial ovarian cancer (EOC). MATERIALS AND METHODS: This multicenter study incorporated 437 patients from five centers, divided into training (n = 271), internal validation (n = 68), and external validation (n = 98) sets. The deep learning (DL) model was constructed using the largest orthogonal slices of the tumor area. The extracted radiomics features were employed in building the radiomics model. The clinical model was developed based on clinical characteristics. A DLRN was built by integrating the DL signature, radiomics signature, and independent clinical predictors. Model performances were evaluated through receiver operating characteristic (ROC) analysis, Brier score, calibration curve, and decision curve analysis (DCA). The areas under the ROC curve (AUCs) were compared using the DeLong test. A two-tailed P < 0.05 was considered significantly different. RESULTS: The DLRN exhibited satisfactory discrimination between type I and type II EOC with the AUC of 0.888 (95% confidence interval [CI] 0.810, 0.966) and 0.866 (95% CI 0.786, 0.946) in the internal and external validation sets, respectively. These AUCs significantly exceeded those of the clinical model (P = 0.013 and 0.043, in the internal and external validation sets, respectively). The DLRN demonstrated optimal classification accuracy and clinical application value, according to Brier scores, calibration curves, and DCA. CONCLUSION: A T2-weighted MRI-based DLRN showed promising potential in differentiating between type I and type II EOC, which could offer assistance in clinical decision-making.

GANT61 elevates chemosensitivity to cisplatin through regulating the Hedgehog, AMPK and cAMP pathways in ovarian cancer.

Background: This study aimed to explore the effect of GANT61 on ovarian cancer (OC) chemosensitivity. Materials & methods: OC cells (Caov-3 and SKOV-3) were treated by GANT61 alone or combined with cisplatin/taxol. The mRNA sequencing was conducted, followed by rescue experiments. Results: GANT61 reduced OC cell viability in a dose-dependent manner and enhanced chemosensitivity to cisplatin but not to taxol. In total, 545 dysregulated genes were identified after the addition of GANT61 to cisplatin-treated OC cells, which were enriched in the AMPK, Hedgehog and cAMP pathways, then further validated by western blot. Furthermore, rescue experiments observed that AMPK pathway inhibitor and cAMP pathway inhibitor attenuated GANT61's chemosensitivity to cisplatin. Conclusion: GANT61 enforces OC chemosensitivity to cisplatin by regulating the Hedgehog, AMPK and cAMP pathways.