BBOX1 mediates metabolic reprogramming driven by hypoxia and participates in the malignant progress of high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is the most aggressive type of ovarian cancer that causes great threats to women's health. Therefore, we performed RNA-sequencing technology in clinical samples to explore the molecular mechanisms underlying the progression of HGSOC. We then noticed BBOX1, a kind of 2-oxoglutarate-dependent enzyme that is highly expressed in HGSOC tumor tissues. Functional studies showed that BBOX1 promotes cell survival and growth of HGSOC cells in vitro and in vivo. Overexpression of the wild-type BBOX1 promoted cell proliferation, but the Asn191 and Asn292 mutation (key amino acid for the enzymatic activity of BBOX1) counteracted this effect (P < 0.05), which indicated that the promotion effect of BBOX1 on HGSOC cell proliferation was related to its catalytic activity. Downregulation of BBOX1 reduced the activity of the mTORC1 pathway, and decreased protein expression of IP3R3 and phosphorylation level of S6KThr389. Metabolomics analysis revealed that BBOX1 is implicated in the glucose metabolism, amino acid metabolism, and nucleotide metabolism of HGSOC cells. In addition, inhibition of BBOX1 suppressed HGSOC cell glycolysis and decreased glucose consumption, lactate production, and the expression of key factors in glycolysis. Finally, we found hypoxia induced the expression of BBOX1 in HGSOC cells and confirmed that BBOX1 could be transcriptionally activated by hypoxia-inducible factor-1α, which could directly bind to the BBOX1 promoter. In summary, BBOX1 mediated the metabolic reprogramming driven by hypoxia, and affected cell metabolism through the mTORC1 pathway, thus acting as an oncogene during HGSOC development.

ALDH1A3 contributes to tumorigenesis in high-grade serous ovarian cancer by epigenetic modification.

High-grade serous ovarian cancer (HGSOC) is the most lethal histotype of ovarian cancer due to its unspecific symptoms in part. ALDH1A3 (aldehyde dehydrogenase 1 family member A3) is a key enzyme for acetyl-CoA production involving aggressive behaviors of cancers. However, ALDH1A3's effects and molecular mechanisms in HGSOC remain to be clarified. Using RNA-seq and publicly available datasets, ALDH1A3 was found to be highly expressed in HGSOC, and associated with poor survival. Knockdown of ALDH1A3 prevented HGSOC tumorigenesis and enhanced cell sensitivity to paclitaxel or cisplatin. ALDH1A3 expression in HGSOC cells was found to be increased by hypoxia, but decreased by HIF-1α inhibitor KC7F2. The dual-luciferase reporter assay showed that the increased transcriptional activity of ALDH1A3 induced by HIF-1α overexpression was reduced by KC7F2. In addition, PITX1 (paired like homeodomain 1) was identified to be inhibited by ALDH1A3 knockdown, and PITX1 depletion inhibited cell proliferation. The mechanistic studies showed that ALDH1A3 knockdown reduced the acetylation of histone 3 lysine 27 (H3K27ac). Treatment of exogenous acetate with NaOAc or inhibition of histone deacetylase with Pracinostat increased H3K27ac and PITX1 levels. CHIP assay demonstrated a significant enrichment of H3K27ac at the PITX1 promoter, and ALDH1A3 knockdown reduced the binding between H3K27ac and PITX1. Taken together, our data suggest that ALDH1A3, transcriptional activated by HIF-1α, promotes tumorigenesis and decreases chemosensitivity by increasing H3K27ac of PITX1 promoter in HGSOC.

ANXA3, associated with YAP1 regulation, participates in the proliferation and chemoresistance of cervical cancer cells.

BACKGROUND: Cervical cancer, as one of the most common cancers in women, remains a major health threat worldwide. Annexin A3 (ANXA3), a component of the annexin family, is upregulated in numerous cancers, with no explicit role in cervical cancer. OBJECTIVE: This study aims to investigate the function of ANXA3 in cervical cancer. METHODS: Differential expression genes between the cervical cancer tissues of patients and the controls were analyzed in The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) database. Using transfection approaches to either upregulate or downregulate ANXA3, its role in cell proliferation and chemosensitivity of human cervical cancer cell lines (HeLa and C33A) was evaluated. Furthermore, the binding activity between YAP1 and ANXA3 was also explored. RESULTS: Genomics analysis indicated that differential genes were mostly associated with cell cycle progression and DNA replication. ANXA3 was highly expressed in the cervical cancer tissues and closely linked to malignancy degree. Knockdown of ANXA3 in cervical cancer cells inhibited cell cycle progression. A similar result was observed in the reduction of cyclin D, CDK4, cyclin E, and CDK2 in cervical cancer cells with ANXA3 silencing. Cervical cancer cells obtained high sensitivity to cisplatin (DDP) when ANXA3 was downregulated. Conversely, these capabilities were the opposite in cervical cancer cells overexpressing ANXA3. Furthermore, the expression levels of ANXA3 and YAP1 were positively correlated. YAP1 upregulation was positively connected with malignant behaviors, which were reversed by ANXA3 downregulation. CONCLUSION: In light of our findings, targeting ANXA3 expressed in cervical cancer might contribute to more potential therapeutic strategies.

Choriocarcinoma masquerading as lumbar spinal tumor: Case report and literature review.

RATIONALE: Choriocarcinoma is a highly invasive gestational trophoblastic neoplasm, usually metastasis to lung and brain, but occurrence of choriocarcinoma following spontaneous abortion presenting as a vertebral tumor is extremely rare, to the best of our knowledge. Because of the poor diagnosis and high malignancy, the low progression-free survival follows up. PATIENT CONCERNS: We here are reporting a case of choriocarcinoma that presented with vertebral tumor induced paralysis of limbs and incontinence of urine. DIAGNOSIS: Combined with the childbearing history, high ß-human chorionic gonadotrophinin levels, and imaging examination, a clinical diagnosis was made exactly. Till the pathological results after the operation of lumbar spinal canal tumorectomy, the diagnosis was exactly clear. INTERVENTIONS: After performing the laminectomy, the fierce bleeding follows up, just did the temporary limited decompression. Because of the vertebral artery embolization, lumbar spinal canal tumorectomy, spinal canal and root canal decompression, subdural decompression and hematoma removal were performed. OUTCOMES: After performing the operation and chemotherapy timely and positively, the patient lost consciousness and died due to the pulmonary embolism at last. LESSONS: This is the first case report describing choriocarcinoma with metastases to the spine amongst Chinese population as well. Early metastasis is one of the marked tendencies of choriocarcinoma, but spine metastasis and the related spinal oppressional symptoms were found instead of vaginal bleeding in this case, which is indeed rare.

Comparison of machine learning and logistic regression as predictive models for adverse maternal and neonatal outcomes of preeclampsia: A retrospective study.

Introduction: Preeclampsia, one of the leading causes of maternal and fetal morbidity and mortality, demands accurate predictive models for the lack of effective treatment. Predictive models based on machine learning algorithms demonstrate promising potential, while there is a controversial discussion about whether machine learning methods should be recommended preferably, compared to traditional statistical models. Methods: We employed both logistic regression and six machine learning methods as binary predictive models for a dataset containing 733 women diagnosed with preeclampsia. Participants were grouped by four different pregnancy outcomes. After the imputation of missing values, statistical description and comparison were conducted preliminarily to explore the characteristics of documented 73 variables. Sequentially, correlation analysis and feature selection were performed as preprocessing steps to filter contributing variables for developing models. The models were evaluated by multiple criteria. Results: We first figured out that the influential variables screened by preprocessing steps did not overlap with those determined by statistical differences. Secondly, the most accurate imputation method is K-Nearest Neighbor, and the imputation process did not affect the performance of the developed models much. Finally, the performance of models was investigated. The random forest classifier, multi-layer perceptron, and support vector machine demonstrated better discriminative power for prediction evaluated by the area under the receiver operating characteristic curve, while the decision tree classifier, random forest, and logistic regression yielded better calibration ability verified, as by the calibration curve. Conclusion: Machine learning algorithms can accomplish prediction modeling and demonstrate superior discrimination, while Logistic Regression can be calibrated well. Statistical analysis and machine learning are two scientific domains sharing similar themes. The predictive abilities of such developed models vary according to the characteristics of datasets, which still need larger sample sizes and more influential predictors to accumulate evidence.

A bibliometric analysis of the research on preeclampsia in the first two decades of the twenty-first century.

BACKGROUND: Preeclampsia still remains one of the leading causes of maternal and perinatal mortality worldwide. Despite the concerted efforts of researchers, only a little improvement has been seen. Clinical decision-making is based on the published literatures. With the explosive growth of medical documents in recent decades, a bibliometric method is essential for assessing the intellectual contributions, major components and potential trends. METHODS: Web of Science Core Collections was selected as the original database and datasets were retrieved consisting of literatures published from 2000 to 2020. Different bibliometric software were employed to visualize the co-authorship network, citation analysis and research theme detection. RESULTS: A total of 25497 articles and 3668 reviews were obtained. Despite the number of publications increased annually, the quantity of high-quality contributions did not elevate accordingly. Clinical practitioners should be alerted to the false bloom of achievements and the yield of improvement in future research. Nicolaides Kypros H was found to be the most productive and influential researcher. University of Pittsburgh was the most productive institution whereas Harvard University showed its leading academic status. America located at the central point in global collaboration and scholarship network. Reference citation analysis revealed the top landmark articles. Moreover, keywords co-occurrence analysis and burst detection certificated the lack of novel themes in this field, which needs further efforts. CONCLUSION: This study provides the overall landscape of science mapping in recent two decades in the field of preeclampsia, with the aim of identifying evolution of research topics and promoting potential concentration or collaboration in the future.

The effects of raloxifene on endothelial function and Inflammation in Postmenopausal women: A Meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Raloxifene treatment has been reported to be associated with cardiovascular benefits if prescribed to women during the postmenopausal period. However, a final conclusion regarding this hypothesis has not yet been achieved. We conducted a systematic review and meta-analysis to evaluate the effect of raloxifene on the endothelial function and inflammation in postmenopausal women. METHODS: We systematically searched the following 4 databases from inception to 23 January 2021 without any language restrictions: Web of Science, PubMed/Medline, Embase and Scopus. The eligible randomized controlled trials (RCTs) reporting the effects of raloxifene on the flow-mediated dilatation (FMD), C-reactive protein (CRP), carotid intima-media thickness (CIMT), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin levels, were included in the final meta-analysis. RESULTS: A total of 16 RCTs were included in the final analysis. Raloxifene administration had no significant effect on ICAM-1 and E-selectin levels. However, we observed a decrease of the CIMT (WMD: -0.071 mm, 95% CI: -0.09 to -0.04, P = 0.000), CRP (WMD: -0.342 mg/L, 95% CI: -0.591, -0.094, p = 0.007), and VCAM-1 (WMD: -197.90 mg/L, 95% CI: -269.58 to -126.23, P = 0.000) levels in the intervention versus control groups following the prescription of this pharmacological agent. Moreover, raloxifene treatment resulted in a significant elevation of the FMD (WMD: 1.64%, 95% CI: 0.46 to 2.81, P = 0.006), particularly if the intervention was equal to or exceeded 12 weeks. CONCLUSION: Raloxifene might emerge as a potential therapeutic option in the management of endothelial dysfunction and inflammation in postmenopausal women.