Identification of ubiquitin markers for survival and prognosis of ovarian cancer.

Ovarian cancer (OC) is one of the most common malignancies and a leading cause of death among women worldwide. The ubiquitin pathway plays an important role in OC development. Using the single nucleotide polymorphism data obtained using the prevalence and dominance strategies, four ubiquitin marker genes were identified according to their expression levels: BARD1, BRCA2, FANCA, and BRCA1. Based on these four genes, a consensus clustering of OC expression data was performed. The significant differences in the survival analysis, ESTIMATE, and CIBERSORT results among the clusters indicated the pivotal role of these four genes in OC development. Of the ubiquitin-representative genes in each cluster, two ubiquitin genes, TOP2A and MYLIP, were identified in the survival risk model after univariate survival, Least Absolute Shrinkage and Selection Operator regression, and multivariate survival analyses. The reliability and robustness of both the training and validation data were confirmed by comparing the significant survival difference between high- and low-risk patients. We further explored the association between our risk model and clinical outcomes as well as predicted potentially interacting drugs. The co-expression network showed clear interactions among the four marker genes and two model genes and between high- and low-risk differentially expressed genes. Significantly enriched genes were found in pathways associated with ion channels, channel activity, and neuroactive ligand-receptor interactions. Therefore, suggesting the involvement of ubiquitin genes in the survival and development of OC through neurohumoral regulation. Our results will provide valuable reference or supplementary information for studies investigating OC diagnosis and therapies.

Treatment With Niraparib Maintenance Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer: A Phase 3 Randomized Clinical Trial.

Importance: The efficacy of niraparib maintenance therapy with an individualized starting dose (ISD) warrants further investigation in a broad population with newly diagnosed advanced ovarian cancer (aOC), including patients without postoperative residual disease. Objective: To evaluate the efficacy and safety of niraparib with an ISD in a broad population with newly diagnosed aOC (R0 resection permitted). Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled, phase 3 study was conducted in China and enrolled 384 patients with newly diagnosed aOC who received primary or interval debulking surgery and responded to treatment with first-line platinum-based chemotherapy. By data cutoff (September 30, 2021), median follow-up for progression-free survival (PFS) was 27.5 (IQR, 24.7-30.4) months. Interventions: Patients were randomized 2:1 to receive niraparib or placebo with ISD (200 mg/d for those with a body weight of <77 kg and/or platelet count of <150 ×103/µL [to convert to ×109/µL, multiply by 1] at baseline; 300 mg/d otherwise) stratified by germline BRCA variant status, tumor homologous recombination deficiency status, neoadjuvant chemotherapy, and response to first-line platinum-based chemotherapy. Main Outcomes and Measurements: The primary end point was blinded, independent central review-assessed PFS in the intention-to-treat population. Results: A total of 384 patients were randomized (255 niraparib [66.4%]; median [range] age, 53 [32-77] years; 129 placebo [33.6%]; median [range] age, 54 [33-77] years), and 375 (247 niraparib [65.9%], 128 placebo [34.1%]) received treatment at a dose of 200 mg per day. Median PFS with niraparib vs placebo was 24.8 vs 8.3 months (hazard ratio [HR], 0.45; 95% CI, 0.34-0.60; P < .001) in the intention-to-treat population; not reached vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68) and 19.3 vs 8.3 months (HR, 0.48; 95% CI, 0.34-0.67) in patients with and without germline BRCA variants, respectively; not reached vs 11.0 months (HR, 0.48; 95% CI, 0.34-0.68) and 16.6 vs 5.5 months (HR, 0.41; 95% CI, 0.22-0.75) in homologous recombination deficient and proficient patients, respectively; and 24.8 vs 8.3 months (HR, 0.44; 95% CI, 0.32-0.61) and 16.5 vs 8.3 months (HR, 0.27; 95% CI, 0.10-0.72) in those with optimal and suboptimal debulking, respectively. Similar proportions of niraparib-treated and placebo-treated patients (6.7% vs 5.4%) discontinued treatment due to treatment-emergent adverse events. Conclusion and Relevance: This randomized clinical trial found that niraparib maintenance therapy prolonged PFS in patients with newly diagnosed aOC regardless of postoperative residual disease or biomarker status. The ISD was effective and safe in the first-line maintenance setting. Trial Registration: ClinicalTrials.gov Identifier: NCT03709316.

Identification of exosomal and non­exosomal microRNAs associated with the drug resistance of ovarian cancer.

MicroRNAs (miRNAs) serve important roles in drug­resistance; however, exosomal miRNAs associated with drug­resistance in ovarian cancer (OC) have not been reported to date. The current study aimed to analyze the drug resistance­associated exosomal miRNAs in original OC cells and their derived exosomes using microarray data downloaded from the Gene Expression Omnibus database (series GSE76449). The chemosensitive OC cell lines SKOV3_ip1, A2780_PAR and HEYA8, as well as the chemoresistant cell lines SKOV3_TR, A2780_CP20 and HEYA8_MDR, were investigated. Differentially expressed miRNAs (DE­miRNAs) were identified using the limma method, and their mRNA targets were predicted using the miRWalk and LinkedOmics database. Functions of target genes were analyzed with DAVID tool, while TCGA data were used to explore the survival association of identified miRNAs. According to the results, 28 DE­miRNAs were found to be common in exosomal and original samples of A2780_CP20 cells, among which the functions of 5 miRNAs were predicted (including miR­146b­5p, miR­509­5p, miR­574­3p, miR­574­5p and miR­760). In addition, 16 and 35 DE­miRNAs were detected for HEYA8_MDR and SKOV3_TR, respectively, with the functions of 4 of these miRNAs predicted for each cell line (HEYA8_MDR: miR­30a­3p, miR­30a­5p, miR­612 and miR­617; SKOV3_TR: miR­193a­5p, miR­423­3p, miR­769­5p and miR­922). It was also reported that miR­183­5p was the only one common miRNA among the three cell lines. Furthermore, miR­574­3p, miR­30a­5p and miR­922 may regulate CUL2 to mediate HIF­1 cancer signaling pathway, while miR­183­5p may modulate MECP2, similar to miR­760, miR­30a­5p and miR­922, to influence cell proliferation. Finally, the downregulated miR­612 may promote the expression of TEAD3 via the Hippo signaling pathway, and this miRNA was associated with poor prognosis. In conclusion, the findings of the present study suggested several underlying miRNA targets for improving the chemotherapy sensitivity of OC.

Downregulation of miR-145-5p in cancer cells and their derived exosomes may contribute to the development of ovarian cancer by targeting CT.

The present study aimed to identify shared microRNAs (miRNAs) in ovarian cancer (OC) cells and their exosomes using microarray data (accession number GSE103708) available from the Gene Expression Omnibus database, including exosomal samples from 13 OC cell lines and 3 normal ovarian surface epithelial cell lines, and their original cell samples. Differentially expressed miRNAs (DE­miRNAs) were identified using the Linear Models for Microarray data method, and mRNA targets of DE­miRNAs were predicted using the miRWalk2 database. The potential functions of target genes were analyzed using Database for Annotation, Visualization and Integrated Discovery and intersected with known OC­associated pathways downloaded from the Comparative Toxicogenomics Database. The associations between crucial miRNAs and target genes, and their clinical associations, were validated using data from The Cancer Genome Atlas. As a result, 16 upregulated and 6 downregulated DE­miRNAs were shared in OC cell lines and their exosomes compared with normal controls. The target genes of 11 common DE­miRNAs were predicted. Among these DE­miRNAs, a low expression of homo sapiens (hsa)­miR­145­5p was significantly correlated with a poor prognosis and higher stages. Although 91 target genes were predicted for hsa­miR­145­5p, only 4 genes [connective tissue growth factor (CTGF), myotubularin­related protein 14, protein phosphatase 3 catalytic subunit alpha and suppressor of cytokine signaling 7] were suggested as risk factors for prognosis. The subsequent Pearson's correlation analysis validated a significant negative correlation between hsa­miR­145­5p and CTGF (r=­0.1126, P=0.02188). According to the results of the functional analysis, CTGF is involved in the Hippo signaling pathway (hsa04390). In conclusion, decreased expression of hsa­miR­145 in OC and OC­derived exosomes may be a crucial biomarker for the diagnosis and treatment of OC.

Preliminary report on a sonographic method to determine the location of the intimal breach in Stanford type B aortic dissection.

Using a defined angle T, which can be measured noninvasively using Doppler ultrasound, we aim to determine the location of the intimal breach in Stanford type B aortic dissection (AD) and estimate the risk of AD using that measurement. Our subjects included 86 healthy volunteers, 60 hypertensive patients, and 42 patients with Stanford type B AD. We used dual functional color Doppler ultrasound to locate the central point of the high-speed flow zone within the descending aorta, and then calculated the angle T, using the law of cosines. In addition, we measured the degree of distortion within the descending aorta using Line BD, defined as the distance from the lateral edge of the left subclavian artery (LSA) to the center of the breach in the intima in AD. The value of T was approximately 24° ± 3° and was constant across all 3 groups. In addition, the increase in BD distance corresponded to increased distortion in the descending aorta between the LSA and the region of aortic artery ligament (RAALE). We found that when the preoperative BD was less than 2.6 cm, the aortic arch could be straightened, using a stent-graft, to approximate the normal aorta. When the preoperative BD is less than 2.6 cm, the aortic arch can be corrected using a stent. In addition, since the T angle is constant, we speculate that it can be used to predict the risk of intimal breach and estimate its location using digital subtraction angiography (DSA) to guide surgery.

Emergency endovascular repair of complicated Stanford type B aortic dissections within 24 hours of symptom onset in 30 cases.

OBJECTIVE: To investigate the results of emergency endovascular repair of complicated Stanford type B aortic dissections within 24 hours of symptom onset. METHODS: A retrospective analysis of the clinical data of 30 patients with complicated Stanford type B aortic dissections who underwent emergency endovascular repair between June 2007 and October 2008. Endovascular repairs were performed within 24 hours of symptom onset. Stent-grafts were deployed at the first entry tear through the femoral artery under fluoroscopic guidance. Follow-up computed tomography scans were performed at 1, 3, 6, 12, and 18 months after treatment. RESULTS: The mean patient age was 64 years (range, 43-83 years). There were 3 cases associated with rupture, 6 cases associated with refractory hypertension, 15 cases associated with persistent pain, 2 cases associated with retrograde dissection, and 4 cases associated with malperfusion. The technical success rate was 100%, and the incidence of immediate postoperative endoleaks was 13.4%. One patient died of dissection rupture within 30 days. The mean follow-up period was 12 ± 8 months. A small, persistent endoleak (<10%) occurred in 1 patient, and 1 patient died of acute liver failure 2 months after the operation. No stent dislocation, false lumen expansion, or paraplegia occurred. The false lumen was completely thrombosed in 6 patients and partially thrombosed in 19 patients. The mortality rate was 6.67%. CONCLUSIONS: Our results suggest that emergency endovascular repair of complicated Stanford type B aortic dissections within 24 hours of symptom onset is associated with good outcomes and can decrease mortality.