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.

Long non-coding RNA NRSN2-AS1 promotes ovarian cancer progression through targeting PTK2/ß-catenin pathway.

As a common malignant tumor among women, ovarian cancer poses a serious threat to their health. This study demonstrates that long non-coding RNA NRSN2-AS1 is over-expressed in ovarian cancer tissues using patient sample and tissue microarrays. In addition, NRSN2-AS1 is shown to promote ovarian cancer cell proliferation and metastasis both in vitro and in vivo. Mechanistically, NRSN2-AS1 stabilizes protein tyrosine kinase 2 (PTK2) to activate the ß-catenin pathway via repressing MG-53-mediated ubiquitinated degradation of PTK2, thereby facilitating ovarian cancer progression. Rescue experiments verify the function of the NRSN2-AS1/PTK2/ß-catenin axis and the effects of MG53 on this axis in ovarian cancer cells. In conclusion, this study demonstrates the key role of the NRSN2-AS1/PTK2/ß-catenin axis for the first time and explores its potential clinical applications in ovarian cancer.

Changes in retinal and choroidal blood flow after one or two horizontal rectus muscle surgeries by optical coherence tomography angiography.

PURPOSE: To evaluate the retinal and choroidal microvasculature after one or two horizontal rectus muscle surgeries in strabismus patients using swept-source optical coherence tomography angiography (SS-OCTA). METHODS: 30 eyes of 26 patients who underwent horizontal rectus muscle surgery were included in this study. Group A, A' and Group B , B' respectively consisted preoperative and postoperative measurements of patients who underwent one or two horizontal rectus muscle surgeries. We analyzed the vessel density (VD) of the superficial vascular complex (SVC), the deep vascular complex (DVC), the choriocapillary layer (CC), choroidal vascular index (CVI), choroidal thickness (T-Ch) and retinal nerve fiber layer thickness (T-RNFL) preoperatively, and one week postoperatively. RESULTS: Only in the nasal sector of the perifoveal zone, the VD in SVC demonstrated a significant increase in Group A' (p = 0.027). There was a statistically significant difference in the VD changes of SVC between Group A and Group B (p = 0.043). The VD in DVC did not change significantly in the whole macular compared with the preoperative. Moreover, in both Group A' and Group B', the VD in CC showed a reduction in a single sector of the parafoveal area (p < 0.05). Group A' have increased CVI in the nasal sector of the perifoveal region (p = 0.008). In addition, the T-Ch increase in the perifoveal region was more significant in Group B' than in Group A' (p < 0.05). Group A' showed statistically significant decreases in T-RNFL in the foveal and parafoveal regions (p < 0.05). CONCLUSION: This study revealed that the increase in choroidal thickness was more significant after two rectus muscle surgery. In addition, there were microvascular changes in sectional macular regions after strabismus surgery. OCTA is an excellent way to study the impact of strabismus surgery on the macular structure and blood flow.

We used SS-OCTA, which provided more objective and accurate measurements, to assess macular vessel density and thickness of retinal and choroid after one or two horizontal rectus muscle surgeries.

Identification of a ferroptosis- and oxidative stress-associated gene signature for prognostic stratification of ovarian cancer.

BACKGROUND: Studies have shown that ferroptosis- and oxidative stress-related genes (FORGs) perform crosstalk in ovarian cancer (OC). The specific role of FORGs in OC, however, remains unclear. We aimed to develop a molecular subtype and prognostic model associated with FORGs that could predict OC prognosis and evaluate the infiltration of tumor-associated immune cells. METHODS: Gene expression samples were collected from the GEO (GSE53963) and Cancer Genome Atlas (TCGA) databases. Kaplan-Meier analysis was used to evaluate prognostic efficacy. Unsupervised clustering was applied to identify molecular subtypes, which was followed by tumor immune cell infiltration and functional enrichment analyses. Subtype-related differentially expressed genes (DEGs) were identified and used to establish prognostic models. Associations between the model and immune checkpoint expression, stromal scores, and chemotherapy were investigated. RESULTS: OC patients were categorized into two FORG subtypes based on the expression characteristics of 19 FORGs. Molecular subtypes associated with patient prognosis, immune activity, and energy metabolism pathways were identified. Subsequently, DEGs in the two FORG subtypes were identified and used in prognostic models. We identified six signature genes (MEGF8, ECE1, SASH1, ARHGEF16, PLXNA1, and FCGBP) with LASSO analysis to assess the risk of OC. Patients in the high-risk group had poor prognoses and immunosuppression, while the risk scores were significantly associated with immune checkpoint expression, stromal scores, and chemotherapy sensitivity. CONCLUSIONS: Our novel clustering algorithm was used to create distinct clusters of OC patients and a prognostic model was developed that accurately predicted patient outcomes and chemotherapy responses. This approach offers effective precision medicine for OC patients.

CDC20 is a novel biomarker for improved clinical predictions in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC), a common tumor of the female reproductive system, ranks first in fatalities among gynecological malignancies. Most patients find tumors at late stage and have extremely poor prognoses, which necessitates improvements in early detection. This study applied bioinformatic methods to identify potential biomarkers of EOC. First, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on differentially expressed genes (DEGs) and hub genes, and a protein-protein interaction (PPI) network was constructed. The network of hub genes was analyzed using GeneMANIA, and an analysis of biological processes was constructed with BINGO. Lastly, hub genes were analyzed for EOC-related oncology using the Oncomine and TCGA databases, and the cBioPortal online platform. Overall, cell division cycle 20 (CDC20) was identified as a key gene in EOC. Short hairpin RNA (shRNA) was used to silence CDC20 to explore its effects on EOC cell proliferation, apoptosis and SRY-related HMG-box 2 (SOX2) expression. DEGs were enriched in pathways related to cell cycle signaling, cancer, progesterone-mediated oocyte maturation, Wnt signaling and P53 signaling. Analysis revealed high expression of CDC20 in EOC tissues and a correlation with histology and tumor grade. CDC20 levels are highest in serous adenocarcinoma, when compared to ovarian clear cell carcinoma, ovarian endometrioid carcinoma and mucinous adenocarcinoma. High CDC20 expression within the tumor is associated with poor EOC prognosis. After silencing CDC20, EOC cell proliferation and migration decreased, apoptosis increased, and SOX2 expression decreased. In conclusion, CDC20 is likely a key biomarker of EOC and may act as an upstream regulator of SOX2 to mediate the SOX2 signaling in the progression of EOC. Future application of CDC20 analysis to early detection may improve prognosis, and it has the potential to be a therapeutic target.

Triclosan activates c-Jun/miR-218-1-3p/SLC35C1 signaling to regulate cell viability, migration, invasion and inflammatory response of trophoblast cells in vitro.

BACKGROUND: Spontaneous abortion is considered as the commonest complication of pregnancy. Triclosan (TCS) is an antimicrobial agent, which participates in the process of multiple human diseases, including spontaneous abortion. Our study aimed to evaluate the effect of TCS on spontaneous abortion and disclose the possible regulatory mechanism in vitro. RESULTS: RT-qPCR analyzed that miR-218-1-3p derived from abortion-associated factor slit guidance ligand 2 (SLIT2) was up-regulated in trophoblast cells under TCS treatment. Supported by western blot analysis, functional experiments demonstrated that miR-218-1-3p overexpression impeded the proliferation, migration and invasion while exacerbating the inflammatory response of trophoblast cells. Moreover, mechanism assays revealed that TCS modulated c-Jun production to promote MIR218-1 transcription and enhance miR-218-1-3p expression. Moreover, solute carrier family 35 member C1 (SLC35C1) was validated as a target gene of miR-218-1-3p, and miR-218-1-3p was sustained to negatively modulate SLC35C1 expression in trophoblast cells. Rescue assays validated the role of TCS/miR-218-1-3p/SLC35C1 axis in regulating the viability, migration, invasion and inflammatory response of trophoblast cells. CONCLUSIONS: TCS regulated miR-218-1-3p/SLC35C1 axis to modulate the proliferation, migration, invasion and inflammatory response of trophoblast cells in vitro, which might provide novel insights for spontaneous abortion prevention.

Enhanced Visualization of Retinal Microvasculature via Deep Learning on OCTA Image Quality.

PURPOSE: To investigate the impact of denoising on the qualitative and quantitative parameters of optical coherence tomography angiography (OCTA) images of the optic nerve and macular area. METHODS: OCTA images of the optic nerve and macular area were obtained using a Canon-HS100 OCT device for 48 participants (48 eyes). Multiple image averaging (MIA) and denoising techniques were used to improve the quality of the OCTA images. The peak signal-to-noise ratio (PSNR) as an image quality parameter and vessel density (VD) as a quantitative parameter were obtained from single-scan, MIA, and denoised OCTA images. The parameters were compared, and the correlation was analyzed between different imaging protocols. RESULTS: In the optic nerve area, there were significant differences in the PSNR and VD in all measured regions between the three groups (P < 0.0001). The PSNR of the denoised group was significantly higher than that of the other two groups (P < 0.0001). The VD in the denoised group was significantly lower than that in the single-scan group in all measured regions (P < 0.0001). In the macular area, there were significant differences in the PSNR and VD in all measured regions among the three groups. The PSNR of the denoised group was significantly higher than that of the other two groups (P < 0.0001). The VD in the denoised group was significantly lower than that in the single-scan group in all measured regions. The VD around the optic nerve in the denoised group was correlated with that in the single-scan group (R = 0.9403, P < 0.0001), but the VD in the MIA group was not correlated with that in the single-scan group (R = 0.2505, P = 0.2076). The VD around the fovea in the denoised and MIA images was correlated with that in the single-scan group (R = 0.7377, P < 0.0001; R = 0.7005, P = 0.0004, respectively). CONCLUSION: Denoising could provide an easy and quick way to improve image quality parameters, such as PSNR. It shows great potential in improving the sensitivity of OCTA images as retinal disease markers.

The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta-analysis of efficacy and safety.

The use of immune checkpoint inhibitors (ICIs) in combination therapy is an emerging trend in tumor immunology. However, the value of combination immunotherapy remains controversial, because of the toxic effects induced by combination. The added benefit of each additional drug has not been assessed against the added toxicity. We searched for clinical trials that evaluated ICI monotherapies and combination therapies in lung cancer and melanoma patients. The overall response rate (ORR), grade 3/4 treatment-related adverse event rate, overall survival (OS), and progression-free survival (PFS) were extracted from the most recently published studies to determine the relative risk (RR), hazard ratios (HRs), and 95% confidence intervals (CIs). Seven randomized controlled trials and one open-label study were identified (n = 3,097). Treatments included combinations of several ICIs, a combination of an ICI and dacarbazine, two combinations of an ICI, paclitaxel and carboplatin, and a combination of an ICI and gp100 vaccine. Higher ORR (RR: 1.51, 95% CI: 1.03-2.20, p = 0.034), OS (HR: 0.86, 95% CI: 0.78-0.95, p = 0.000), and PFS (HR: 0.93, 95% CI: 0.72-1.14, p = 0.000) values were observed in combination therapy than in monotherapy. In addition, the toxicity of combination ICI immunotherapy was higher (RR: 1.50, 95% CI: 1.03-2.19, p = 0.036) than that of monotherapy. This meta-analysis showed that the addition of nivolumab to ipilimumab better benefits PFS and ORR. Adding sargramostim was associated with better OS and safety. The efficacy and safety of a nivolumab-ipilimumab-sargramostim combination should be investigated further.

Research progress of stem cell-derived RPE cell transplantation therapy for retinal degenerative diseases / 国际眼科杂志(Guoji Yanke Zazhi)

·Age - related macular degeneration ( ARMD ) and Stargardt's macular dystrophy ( SMD ) are two kinds of degenerative retinal diseases that respectively lead to irreversible vision loss of the elderly and juvenile population. However, the severe visual impairment in dry ARMD and SMD remains untreatable. In recent years, with the advancement of stem cell technology, stem cell-derived RPE cell transplantation therapy of retinal degeneration has become new research hotspot and direction. This article reviewed the progress of stem cell based approaches for treating retinal degenerative diseases and discussed the prospect and challenges in this field.