Prognosis and adjuvant chemotherapy for patients with malignant peritoneal cytology in early-stage non-endometrioid endometrial cancer.

OBJECTIVE: To investigate the influence of malignant peritoneal cytology (MPC) on the prognosis of early-stage patients with endometrial clear cell carcinoma(CCC) and serous carcinoma(SC), and the value of chemotherapy in their treatment. METHODS: A retrospective observational cohort study was conducted by querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2010 to 2019. Women with early-stage CCC and SC with available peritoneal cytology results were enrolled. Propensity score matching(PSM) and propensity score inverse probability of treatment weighting (IPTW) was used to balance the measured covariates in each sub-cohort. RESULTS: A total of 3,616 eligible patients were included, and 368 patients had MPC (10.2%). Women with MPC were more likely to receive postoperative chemotherapy (OR 2.033; 95%CI 1.589-2.602). In PSM model, MPC had worse overall survival(OS) and cancer-specific survival (CSS) (All,p < 0.001). The 5-year OS rates were 56.5% for women with MPC and 74.4% for those with negative peritoneal cytology, and the 5-year CSS rates were 60.8% versus 80.0%(All, p < 0.0001). In the subgroup analyses, MPC was associated with decreased OS and CSS in serous, clear cell histology group, and stage IA cases(All,p < 0.001), but not for stage IB or stage II disease. In multivariate analysis, chemotherapy improved the prognosis of patients with MPC(OS:p = 0.005; CSS:p = 0.010). Additionally, in stage IA subgroup, chemotherapy improved survival outcomes in patients with MPC(OS:P = 0.025; CSS:P = 0.038), in NPC patients, however, chemotherapy was a good prognostic factor for OS (P = 0.001) but not for CSS(P = 0.300). CONCLUSION: MPC was a prognostic factor for decreased survival in early-stage endometrial CCC and SC, and those with MPC could further benefit from chemotherapy.

The role of TCGA molecular classification in clear cell endometrial carcinoma.

Clear cell endometrial carcinoma (CCEC) represents a relatively rare and heterogeneous entity. Based on The Cancer Genome Atlas (TCGA) molecular classification, the risk stratification and management of endometrial cancer (EC) have been improved. Although the relationship of CCEC with the TCGA classification is less well understood, data has emerged to suggest that molecular classification plays an important role in the prognosis and management of CCEC. Most of patients with CCEC are characterized by p53abn or NSMP type and the prognosis of these patients is poor, whereas those with MMRd or POLEmut seem to have a favorable prognosis. Adjuvant therapy is recommended in CCEC with p53abn and NSMP. Advanced/recurrent CCEC with MMRd benefit much more from immune checkpoint inhibitors after the failure of platinum-based chemotherapy. In addition, bevacizumab plus chemotherapy upfront seems to improve outcomes of advanced/recurrent patients whose tumors harbored mutated TP53, including CCECs with p53abn. Further studies which exclusively recruit CCEC are urgently needed to better understand the role of molecular classification in CCEC. This review will provide an overview of our current understanding of TCGA classification in CCEC.

Extracellular Vesicles Derived from Mesenchymal Stem Cells as Cell-Free Therapy for Intrauterine Adhesion.

Intrauterine adhesion (IUA) can occur after trauma to the basal layer of the endometrium, contributing to severe complications in females, such as infertility and amenorrhea. To date, the proposed therapeutic strategies are targeted to relieve IUA, such as hysteroscopic adhesiolysis, Foley catheter balloon, and hyaluronic acid injection have been applied in the clinic. However, these approaches showed limited effects in alleviating endometrial fibrosis and thin endometrium. Mesenchymal stem cells (MSCs) can offer the potential for endometrium regeneration owing to reduce inflammation and release growth factors. On this basis, MSCs have been proposed as promising methods to treat intrauterine adhesion. However, due to the drawbacks of cell therapy, the possible therapeutic use of extracellular vesicles released by stem cells is raising increasing interest. The paracrine effect, mediated by MSCs derived extracellular vehicles (MSC-EVs), has recently been suggested as a mechanism for their therapeutic properties. Here, we summarizes the main pathological mechanisms involved in intrauterine adhesion, the biogenesis and characteristics of extracellular vesicles, explaining how these vesicles could provide new opportunities for MSCs.

A thinner endometrium is associated with lower newborn birth weight during in vitro fertilization-frozen-embryo transfer: a cohort study.

PURPOSE: This study explores the effects of endometrial thickness (EMT) before embryo transfer on newborn birth weight after in vitro fertilization-frozen embryo transfer (IVF-FET). METHODS: We collected the medical records related to singleton live births after IVF-FET from June 2015 to February 2019. Pregnant women were aged ≤ 42 years at delivery. Afterward, analyses were performed on outcomes related to newborns (birth weight, gestational age, delivery mode, percentage of newborns with low birth weight, and incidence of macrosomia) and pregnant women (pregnancy-induced hypertension, gestational diabetes mellitus, premature rupture of membranes, and placenta previa). RESULTS: The birth weight was higher in singleton newborns delivered by patients with EMT > 12 mm before embryo transfer than those delivered by patients with a thinner endometrium. The mean birth weight was 85.107 g higher in the EMT ≥ 12 mm group and 25.942 g higher in the 8-12 mm EMT group than in the EMT < 8 mm group. Independent predictors of newborn birth weight included pregnancy-induced hypertension, premature rupture of membranes, placenta previa, newborn sex, gestational age, delivery mode, number of implanted embryos, follicle-stimulating hormone levels, estradiol levels, and pre-pregnancy body mass index. CONCLUSION: The weight of newborn singletons is associated with EMT before embryo transfer in patients undergoing the first FET cycle. Specifically, the birth weight is lower for newborns delivered by patients with a thinner endometrium. Accordingly, it is warranted to increase EMT before embryo transfer for improving neonatal outcomes after fertility treatment.

Inhibition of TMUB1 blocks apoptosis and NF-κB pathway-mediated inflammation in recurrent spontaneous abortion.

INTRODUCTION: Approximately 50% of cases with recurrent spontaneous abortion (RSA) have unexplained etiology. Aberrant expression of transmembrane and ubiquitin-like domain containing 1 (TMUB1) is closely related to a series of diseases, including RSA. However, the function and underlying mechanism of TMUB1 in the occurrence of RSA has not been described. METHODS: TMUB1 expression was detected in the placental villous tissues of 30 women with normal miscarriages and 12 women with RSA. The pregnant mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce abortion. Human chorionic trophoblast cells were treated with LPS. Pathological analysis of placental tissues was performed by hematoxylin and eosin staining. RESULTS: TMUB1 was highly expressed in the placental villous tissues of RSA patients compared to the patients who underwent induced abortions. After LPS administration, the mice exhibited high embryo absorption and pathological alterations, as well as presented an increase in inflammation and apoptosis (the etiology of RSA induction) in placental tissues. Moreover, the upregulated expression of TMUB1 was also found in placental tissues of LPS-induced mice, and further investigation showed that TMUB1 deficiency blocked embryo loss as well as inhibited apoptotic rate and inflammation after LPS activation. Furthermore, we found that the loss of TMUB1 suppressed the phosphorylation of IkappaB kinase (IKK) α/ß and attenuated cytoplasmic-nuclear translocation of nuclear factor-κB (NF-κB) p65 in LPS-induced cells. CONCLUSION: Our results indicate that TMUB1 may involve in the modulation of apoptosis and NF-κB pathway-mediated inflammation in RSA. Therefore, TMUB1 may develop as a potential biomarker for RSA treatment.

PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma.

The prognosis of renal cell carcinoma (RCC) remains poor due to metastases and resistance to chemotherapy. Salinomycin (Sal) exhibits the potential of antitumor, while the underlying mechanism is not completely clear. Here, we found that Sal induced ferroptosis in RCCs and identified Protein Disulfide Isomerase Family A Member 4 (PDIA4) as a mediator of Sal's effect on ferroptosis. Sal suppressed PDIA4 by increasing its autophagic degradation. Downregulation of PDIA4 increased the sensitivity to ferroptosis, while ectopic overexpression of PDIA4 conferred ferroptosis resistance to RCCs. Our data showed that downregulation of PDIA4 suppressed activating transcription factor 4 (ATF4) and its downstream protein SLC7A11 (solute carrier family 7 member 11), thereby aggravating ferroptosis. In vivo, the administration of Sal promoted ferroptosis and suppressed tumor progress in the xenograft mouse model of RCC. Bioinformatical analyses based on clinical tumor samples and database indicated a positive correlation exists between PDIA4 and PERK/ATF4/SLC7A11 signaling pathway, as well as the malignant prognosis of RCCs. Together, our findings reveal that PDIA4 promotes ferroptosis resistance in RCCs. Treatment of Sal sensitizes RCC to ferroptosis via suppressing PDIA4, suggesting the potential therapeutical application in RCCs.

Immunomodulatory hybrid micro-nanofiber scaffolds enhance vascular regeneration.

The inertness of synthetic polymer materials and the insufficient mechanical strength of reprocessed decellularized extracellular matrix (dECM) limited their promotive efforts on tissue regeneration. Here, we prepared a hybrid scaffold composed of PCL microfibers and human placental extracellular matrix (pECM) nanofibers by co-electrospinning, which was grafted with heparin and further absorbed with IL-4. The hybrid scaffold with improved hemocompatibility firstly switched macrophages to anti-inflammatory phenotype (increased by 18.1%) and then promoted migration, NO production, tube formation of endothelial cells (ECs), and migration and maturation of vascular smooth muscle cells (VSMCs), and ECM deposition in vitro and in vivo. ECs coverage rate increased by 8.6% and the thickness of the smooth muscle layer was 1.8 times more than PCL grafts at 12 wks. Our study realized the complementary advantages of synthetic polymer materials and dECM materials, and opened intriguing perspectives for the design and construction of small-diameter vascular grafts (SDVGs) and immune-regulated materials for other tissue regeneration.

Clinical manifestations and prognosis of unexpected uterine sarcoma of uterine fibroids in Tianjin China.

BACKGROUND: Uterine sarcoma is a rare malignancy of women and fewer uterine sarcomas are detected preoperatively. The reported incidence of preoperatively diagnosed uterine sarcoma (PDUS) was 0.07%. This study aims to identify the prevalence of unexpected uterine sarcoma (UUS) after operation for presumed leiomyoma and compare clinical outcomes after primary therapy. METHODS: A retrospective study was performed evaluating all uterine sarcoma diagnosed in Tianjin Central Hospital of Gynecology and Obstetrics between May 2011 and July 2016.We used the χ2 and T tests to assess the incidence and clinical features of patients. The Kaplan-Meier method was used to calculate disease-related survival. RESULTS: The study retrospectively analyzed 6625 patients with uterine fibroids and found 45 UUS patients and 21 patients of PDUS. The incidence of UUS is (45/6625) 0.67%. The incidence of UUS in patients undergoing total hysterectomy was higher undergoing tumor resection (P < 0.001); the age of UUS is younger than PDUS (P = 0.046); the differences in menopausal status and primary complaints between the two groups are not statistically significant. The PDUS group had more patients with Stage II and III sarcomas than the UUS group (P < 0.001); the duration of symptoms in the PDUS group was longer than in the UUS group (P = 0.033). The 5-year overall survival (OS) rate of the UUS group (77.7%) is higher than the PDUS group (46.3%) (P < 0.001). CONCLUSIONS: The incidence of UUS is low. UUS has a younger age of onset, shorter history of the disease, earlier clinical stage, and better prognosis.

NINJ1 triggers extravillous trophoblast cell dysfunction through blocking the STAT3 signaling pathway.

BACKGROUND: Trophoblasts are the most important parts of the placenta in early pregnancy. Trophoblast cell dysfunction can induce embryo implantation insufficiency, thereby resulting in multiple diseases, including recurrent spontaneous abortion (RSA). A previous study indicates higher nerve injury-induced protein 1 (NINJ1) RNA levels in the villi tissues of RSA patients. OBJECTIVE: This study aimed to investigate the effect of NINJ1 on trophoblast behaviors and pregnancy loss. METHODS: Fresh villi tissues were obtained from with RSA patients and patients with artificial selective abortion for personal reasons, and NINJ1 expression in these tissues was detected. Extravillous trophoblast cell line HTR-8/SVneo was transfected with small-interfering RNA targeting NINJ1 or NINJ1 overexpression vector to perform loss-/gain-of-function experiments. Spontaneous abortion (SA) was induced by mating CBA/J females with DBA/2 males and the pregnant females were intraperitoneally injected with adenovirus vector carrying NINJ1 short hairpin RNA. RESULTS: NINJ1 mRNA and protein levels were higher in the villi tissues of RSA patients than those of artificial selective abortion patients. NINJ1 knockdown promoted trophoblast cell proliferation, migration and invasion but inhibited cell apoptosis. Moreover, conditioned medium from NINJ1-depleted trophoblasts promoted the angiogenesis of human umbilical vein endothelial cells. NINJ1 knockdown also promoted activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway in trophoblasts, and STAT3 inhibitor reversed NINJ1 knockdown-induced effects on trophoblast behaviors. Furthermore, pregnancy loss was attenuated by NINJ1 inhibition. CONCLUSION: NINJ1 contributes to the development of SA and triggers trophoblast cell dysfunction through inhibiting the STAT3 pathway.

Circ_0039569 contributes to the paclitaxel resistance of endometrial cancer via targeting miR-1271-5p/PHF6 pathway.

Circular RNA (circRNA) has been confirmed to be involved in the chemoresistance process of cancers. However, whether circ_0039569 mediates the chemoresistance of endometrial cancer (EC) remains unclear. Quantitative real-time PCR was performed to analyze circ_0039569, microRNA (miR)-1271-5p and PHD finger protein 6 (PHF6) expression. Cell counting kit-8 assay was used to assess the paclitaxel (PTX) resistance of cells. Cell proliferation, apoptosis and invasion were determined using EdU assay, colony formation assay, flow cytometry and transwell assay. Protein expression was examined by western blot analysis. RNA interaction was verified by dual-luciferase reporter assay and RNA pull-down assay. Xenograft tumor models were constructed to explore the effect of circ_0039569 knockdown on the PTX sensitivity of EC tumors. Circ_0039569 was upregulated in PTX-resistant EC tissues and cells. Knockdown of circ_0039569 enhanced the PTX sensitivity of EC cells by inhibiting cell growth and invasion. MiR-1271-5p could be sponged by circ_0039569, and its inhibitor abolished the regulation of circ_0039569 knockdown on the PTX sensitivity of EC cells. PHF6 was targeted by miR-1271-5p, and its overexpression eliminated the promotion effect of miR-1271-5p on the PTX sensitivity of EC cells. Also, interference of circ_0036569 enhanced the PTX sensitivity of EC tumors by regulating the miR-1271-5p/PHF6 pathway. Collectively, circ_0039569 might contribute to the PTX resistance of EC through the regulation of the miR-1271-5p/PHF6 axis.

A novel ultrasound probe calibration method for multimodal image guidance of needle placement in cervical cancer brachytherapy.

PURPOSE: Interstitial needles placement is a critical component of combined intracavitary/interstitial (IC/IS) brachytherapy (BT). To ensure precise placement of interstitial needles, we proposed a novel ultrasonic (US) probe calibration method to accurately register the US image in the magnetic resonance imaging (MRI) image and provide multimodal image guidance for needle placement. METHODS: A wire-based calibration phantom combined with the stylus was developed for the calibration of US probe. The calibration phantom helps to quickly align the imaging plane of the US probe with the fiducial points to obtain US images of these points. The coordinates of fiducial points in US images were located automatically by feature extraction algorithms and were further corrected by the proposed correction method. Ingenious structures were designed on both sides of the calibration phantom to accurately obtain the coordinates of the fiducial points relative to the tracking device. Marker validation and pelvic phantom study were performed to evaluate the accuracy of the proposed calibration method. RESULTS: In the marker validation, the US probe calibration method with corrected transformation achieves a registration accuracy of 0.694 ± 0.014 mm, and the uncorrected one is 0.746 ± 0.018 mm. In the pelvic phantom study, the needle tip difference was 1.096 ± 0.225 mm and trajectory difference was 1.416 ± 0.284 degrees. CONCLUSION: The proposed US probe calibration method is helpful to achieve more accurate multimodality image guidance for needle placement.

Fuzuloparib Maintenance Therapy in Patients With Platinum-Sensitive, Recurrent Ovarian Carcinoma (FZOCUS-2): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial.

PURPOSE: This phase III trial aimed to explore the efficacy and safety of fuzuloparib (formerly fluzoparib) versus placebo as a maintenance treatment after response to second- or later-line platinum-based chemotherapy in patients with high-grade, platinum-sensitive, recurrent ovarian cancer. PATIENTS AND METHODS: Patients with platinum-sensitive, recurrent ovarian cancer previously treated with at least two platinum-based regimens were assigned (2:1) to receive fuzuloparib (150 mg, twice daily) or matching placebo for 28-day cycles. The primary end points were progression-free survival (PFS) assessed by blinded independent review committee (BIRC) in the overall population and PFS by BIRC in the subpopulation with germline BRCA 1/2 mutation. RESULTS: Between April 30, 2019, and January 10, 2020, 252 patients were randomly assigned to the fuzuloparib (n = 167) or placebo (n = 85). As of July 1, 2020, the median PFS per BIRC assessment in the overall population was significantly improved with fuzuloparib treatment (hazard ratio [HR], 0.25; 95% CI, 0.17 to 0.36; one-sided P < .0001) compared with that with placebo. The HR derived from a prespecified subgroup analysis showed a consistent trend of benefit in patients with germline BRCA 1/2 mutations (HR, 0.14; 95% CI, 0.07 to 0.28) or in those without mutations (HR, 0.46; 95% CI, 0.29 to 0.74). The most common grade ≥ 3 treatment-emergent adverse events reported in the fuzuloparib group were anemia (25.1%), decreased platelet count (16.8%), and decreased neutrophil count (12.6%). Only one patient (0.6%) discontinued fuzuloparib because of treatment-related toxicity (concurrent decreased white blood cell count and neutrophil count). CONCLUSION: Fuzuloparib as maintenance therapy achieved a statistically significant and clinically meaningful improvement in PFS for patients with platinum-sensitive, recurrent ovarian cancer versus placebo, regardless of germline BRCA 1/2 mutation, and showed a manageable safety profile.

Clinical outcome of FIGO 2018 stage IB3/IIA2 cervical cancer treated by neoadjuvant chemotherapy followed by radical surgery due to lack of radiotherapy equipment: A retrospective comparison with concurrent chemoradiotherapy.

This study aimed to assess neoadjuvant chemotherapy's clinical outcomes such as efficacy, toxicity, and survival outcomes followed by radical hysterectomy ((NACT-RS) among women with cervical cancer stage IB3 and IIA2, by comparing concurrent chemoradiotherapy (CCRT) and NACT-RS. The study retrospectively reviewed patients with (2018 FIGO) stage IB3 and IIA2 cervical cancer who received preoperative neoadjuvant chemotherapy followed by NACT-RS or concurrent chemoradiotherapy (CCRT). The outcome measures were the 5-year survival and complication rates between the two groups. The median follow-up was 75 months. In total, 218 patients had stage IIA2, 136 patients had stage IB3, 201 patients received CCRT, and 153 patients received preoperative NACT-RS. In the CCRT group, the incidence of early complications (myelosuppression, gastrointestinal and urinary) was higher compared with that in the NACT-RS group (76.1 vs. 26.1%; p < 0.001, respectively). There was no significant difference between the two study groups concerning late complications. Five-year PFS was 79.9% and 85.5% in the NACT-RS and CCRT groups, respectively (p = 0.093). Five-year OS was 86.9% and 85.5% in the NACT-RS and CCRT groups, respectively (p = 0.97). In the multivariate clinicopathologic characteristics analysis for OS, initial tumor size > 4.3 cm (HR 5.11; p < 0.001), AC/ASC (HR 1.89; p = 0.02), histologic grade 2-3 (HR 2.25; p = 0.04), and 2018 FIGO stage IIA2 (HR 8.67; p < 0.001) were independent risk factors. The survival of patients with stage IB3 and IIA2 cervical cancer treated with NACT-RS was similar to that of patients treated with CCRT without increasing side effects.

Molecular mechanisms and differences in lynch syndrome developing into colorectal cancer and endometrial cancer based on gene expression, methylation, and mutation analysis.

PURPOSE: The aim of this study was to screen biomarkers specific to Lynch syndrome (LS) with colorectal cancer (CRC) or endometrial cancer (EC) to explore the mechanisms by which LS develops into CRC and EC and their differences. METHODS: Differentially expressed or differentially methylated genes and differential mutations were identified in 10 LS, 50 CRC, and 50 EC patients from TCGA, and genes overlapping between LS and CRC or EC (named SGs-LCs and SGs-LEs, respectively) were identified. Afterward, we annotated the enriched GO terms and pathways and constructed a protein-protein interaction (PPI) network. Finally, samples from 10 clinical cases with MSI-H/MSS CRC and EC were collected to verify the mutations and their correlations with five LS pathogenic genes in the SGs-LCs and SGs-LEs. RESULTS: A total of 494 SGs-LCs and 104 SGs-LEs were identified and enriched in 106 and 14 GO terms, respectively. There were great differences in the gene count and enriched terms between SGs-LCs and SGs-LEs. In the PPI network, SST, GCG, SNAP25, and NPY had the highest degree of connection among the SGs-LCs, and KIF20A and NUF2 had the highest degree of connection among the SGs-LE. In the SGs-LCs and SGs-LEs, the genes whose expression levels affected the survival of LS, CRC or EC patients were quite different. CONCLUSIONS: COL11A1 was found to be mutated in MSS CRC patients, similar to the mutations of MSH6. SST, GCG, SNAP25, and NPY may be biomarkers for the development of LS into CRC, and KIF20A and NUF2 may be markers of LS developing into EC.

Protein tyrosine phosphatase receptor type Z1 inhibits the cisplatin resistance of ovarian cancer by regulating PI3K/AKT/mTOR signal pathway.

Most patients with ovarian cancer (OC) get remission after undergoing cytoreductive surgery and platinum-based standard chemotherapy, but more than 50% of patients with advanced OC relapse within the first 5 years after treatment and develop resistance to standard chemotherapy. The production of medicinal properties is the main reason for the poor prognosis and high mortality of OC patients. Cisplatin (DDP) resistance is a major cause for poor prognosis of OC patients. PTPRZ1 can regulate the growth and apoptosis of ovarian cancer cells, while the molecular mechanism remains unknown. This study was designed to investigate the roles of PTPRZ1 in DDP-resistant OC cells and possible mechanism. PTPRZ1 expression in OC tissues and normal tissues was analyzed by GEPIA database and verified by Real-time Quantitative Reverse Transcription PCR (RT-PCR) assay. PTPRZ1 expression in normal ovarian cancer cells and DDP-resistant OC cells was also analyzed. Subsequently, RT-PCR, Western blot, MTT experiment and flow cytometry were used to assess the effects of PTPRZ1-PI3K/AKT/mTOR regulating axis on DDP resistance of OC. PTPRZ1 expression was abnormally low in OC tissues, and notably reduced in DDP-resistant OC cells. MTT experiment and flow cytometer indicated that overexpression of PTPRZ1 enhanced the DDP sensitivity of OC cells and promoted the cell apoptosis. Moreover, the results of our research showed that PTPRZ1 might exert its biological effects through blocking PI3K/AKT/mTOR pathway. PTPRZ1 overexpression inhibitied OC tumor growth and resistance to DDP in vivo. Overall, PTPRZ1 might suppress the DDP resistance of OC and induce the cytotoxicity by blocking PI3K/AKT/mTOR pathway.

Deep reinforcement learning for treatment planning in high-dose-rate cervical brachytherapy.

PURPOSE: High-dose-rate (HDR) brachytherapy (BT) is an effective cancer treatment method in which the radiation source is placed within the body. Treatment planning is a critical component for a successful outcome. Almost all currently proposed treatment planning methods are built on stochastic heuristic algorithms, which limits the generation of higher quality plans. This study proposed a novel treatment planning method to adjust dwell times in a human-like fashion to improve the quality of the plan. METHODS: We built an intelligent treatment planner network (ITPN) based on deep reinforcement learning (DRL). The network architecture of ITPN is Dueling Double-Deep Q Network. The state is the dwell time of each dwell position and the action is which dwell time to adjust and how to adjust it. A hybrid equivalent uniform dose objective function was established and assigned corresponding rewards according to its changes. Experience replay was performed with the epsilon greedy algorithm and SumTree data structure. RESULTS: In the evaluation of ITPN using 20 patient cases, D90, D100 and V100 showed no significant difference compared with inverse planning simulated annealing (IPSA) optimization. However, D2cc of bladder, rectum and sigmoid, V150 and V200 were significant reduced, and homogeneity index and conformity index were significantly increased. CONCLUSION: The proposed ITPN was able to generate higher quality plans based on the learned dwell time adjustment policy than IPSA. This is the first artificial intelligence system that can directly determine the dwell times of HDR BT, which demonstrated the potential feasibility of solving optimization problems via DRL.

Identification of keygenes, miRNAs and miRNA-mRNA regulatory pathways for chemotherapy resistance in ovarian cancer.

BACKGROUND: Chemotherapy resistance, especially platinum resistance, is the main cause of poor prognosis of ovarian cancer. It is of great urgency to find molecular markers and mechanism related to platinum resistance in ovarian cancer. METHODS: One mRNA dataset (GSE28739) and one miRNA dataset (GSE25202) were acquired from Gene Expression Omnibus (GEO) database. The GEO2R tool was used to screen out differentially expressed genes (DEGs) and differentially expressed miRNAs (DE-miRNAs) between platinum-resistant and platinum-sensitive ovarian cancer patients. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs were performed using the DAVID to present the most visibly enriched pathways. Protein-protein interaction (PPI) of these DEGs was constructed based on the information of the STRING database. Hub genes related to platinum resistance were visualized by Cytoscape software. Then, we chose seven interested hub genes to further validate using qRT-PCR in A2780 ovarian cancer cell lines. And, at last, the TF-miRNA-target genes regulatory network was predicted and constructed using miRNet software. RESULTS: A total of 63 upregulated DEGs, 124 downregulated DEGs, four upregulated miRNAs and six downregulated miRNAs were identified. From the PPI network, the top 10 hub genes were identified, which were associated with platinum resistance. Our further qRT-PCR showed that seven hub genes (BUB1, KIF2C, NUP43, NDC80, NUF2, CCNB2 and CENPN) were differentially expressed in platinum-resistant ovarian cancer cells. Furthermore, the upstream transcription factors (TF) for upregulated DE-miRNAs were SMAD4, NFKB1, SMAD3, TP53 and HNF4A. Three overlapping downstream target genes (KIF2C, STAT3 and BUB1) were identified by miRNet, which was regulated by hsa-miR-494. CONCLUSIONS: The TF-miRNA-mRNA regulatory pairs, that is TF (SMAD4, NFKB1 and SMAD3)-miR-494-target genes (KIF2C, STAT3 and BUB1), were established. In conclusion, the present study is of great significance to find the key genes of platinum resistance in ovarian cancer. Further study is needed to identify the mechanism of these genes in ovarian cancer.

Exploration of Potential Diagnostic Value of Protein Content in Serum Small Extracellular Vesicles for Early-Stage Epithelial Ovarian Carcinoma.

Epithelial ovarian carcinoma (EOC) is one of the most common gynecologic malignancies with a high mortality rate. Serum biomarkers and imaging approaches are insufficient in identifying EOC patients at an early stage. This study is to set up a combination of proteins from serum small extracellular vesicles (sEVs) for the diagnosis of early-stage EOC and to determine its performance. A biomarker for early-stage ovarian cancer (BESOC) cohort was used as a Chinese multi-center population-based biomarker study and registered as a Chinese Clinical Trial ChiCTR2000040136. The sEV protein levels of CA125, HE4, and C5a were measured in 299 subjects. Logistic regression was exploited to calculate the odds ratio and to create the sEV protein model for the predicted probability and subsequently receiver-operating characteristic (ROC) analysis. The combined sEV marker panel of CA125, HE4, and C5a as a sEV model obtained an area under curve (AUC) of 0.912, which was greater than the serum model (0.809), by ROC analysis to identify EOC patients from the whole cohort. With the cutoff of 0.370, the sensitivity and specificity of the sEV model were 0.80 and 0.89, which were much better performance than the serum markers (sensitivity: 0.55~0.66; specificity: 0.59~0.68) and the risk of ovarian malignancy algorithm (ROMA) index approved by the U.S. Food and Drug Administration (sensitivity: 0.65; specificity: 0.61), to identify EOC patients from patients with benign ovarian diseases or other controls. The sEV levels of CA125 significantly differed among early-stage and late-stage EOC (p < 0.001). Moreover, the AUC of ROC to identify early-stage EOC patients was 0.888. Further investigation revealed that the sEV levels of these 3 proteins significantly decreased after cytoreductive surgery (CA125, p = 0.008; HE4, p = 0.025; C5a, p = 0.044). In summary, our study showed that CA125, HE4, and C5a levels in serum sEVs can identify EOC patients at the early stage, elucidating the possibility of using a sEV model for the diagnosis of early-stage EOC.

Evaluating pentraxin-3 and hypersensitivity CRP expression in obese pregnancies.

OBJECTIVE: This study was designed to evaluate the correlation between serum pentraxin-3 (PTX3)/hypersensitivity CRP (hs-CRP) expression and obesity during pregnancy and their application as inflammatory biomarkers in obese pregnant women. MATERIALS AND METHODS: Pregnant women scheduled to experience a single-birth at our hospital between 2016 and 2017 were selected for this nested case-control study. These patients were evaluated for age and gestational age in the first trimester (11-14 weeks), had their body mass index (BMI) calculated and were subjected to an OGTT between Week 24 and 28 of pregnancy. Obese patients with normal OGTT and a BMI of ≥30 kg/m2 in the second trimester were selected as the obese group (OBE, n = 80), and non-obese pregnant women with normal OGTT with a BMI of <30 kg/m2 were selected as the control group (CON, n = 80). ELISA was used to detect the expression of PTX3 and hs-CRP. RESULTS: The expression of both PTX3 and hs-CRP increased in both groups, with increasing gestational age (P < 0.05). However, hs-CRP level in Group OBE was increased, compared to that in the healthy control (P < 0.01), during the second trimester. PTX3 expression was also significantly higher in OBE samples than in the control (P < 0.05), during the third trimester; correlation analysis demonstrated that PTX3 was positively correlated with hs-CRP, BMI, fasting plasma glucose and HOMA-IR. CONCLUSIONS: The expression levels of both PTX3 and hs-CRP increased with increasing gestational age, and PTX3 expression was related to BMI, which serves to confirm the inflammatory response in these patients.

The High Expression of RRM2 Can Predict the Malignant Transformation of Endometriosis.

INTRODUCTION: A large number of epidemiological studies have revealed that women with endometriosis (EMS) have a higher risk of developing endometriosis-associated ovarian cancer (EAOC). At present, there are few studies on predicting the malignant transformation of ovarian endometriosis (OE). The purpose of this study is to identify and verify the molecules that may be able to predict the malignant transformation of OE. METHODS: The gene expression profiles of ovarian cancer and OE were downloaded from Gene Expression Omnibus (GEO), and a common hub gene ribonucleotide reductase M2 (RRM2) was identified. A total of 44 patients with EAOC and 44 with OE were enrolled in this study. Immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect the expression of RRM2, while the relationship between RRM2 and Ki-67 was analyzed by IHC co-localization. RESULTS: Bioinformatics analysis showed that the expression of RRM2 was low in EMS and high in ovarian cancer. RRM2 was obviously positively expressed in eutopic endometrium (EU), ectopic endometrium (EC), and cancer tissues of EAOC patients. The IHC signal and mRNA levels of RRM2 were higher in the EC of EAOC patients compared with OE patients (P < 0.01). In addition, there was a correlation between the expression of RRM2 and Ki-67 in EC of EAOC patients (P < 0.01). CONCLUSION: The upregulated expression of RRM2 in the EC of OE patients may indicate malignant transformation. High expression of RRM2 promotes abnormal proliferation of histiocytes. RRM2 can be used as a potential marker of malignant transformation of OE.