Engineering Magnetic Extracellular Vesicles Mimetics for Enhanced Targeting Chemodynamic Therapy to Overcome Ovary Cancer.

Chemodynamic therapy (CDT), employing metal ions to transform endogenous H2O2 into lethal hydroxyl radicals (•OH), has emerged as an effective approach for tumor treatment. Yet, its efficacy is diminished by glutathione (GSH), commonly overexpressed in tumors. Herein, a breakthrough strategy involving extracellular vesicle (EV) mimetic nanovesicles (NVs) encapsulating iron oxide nanoparticles (IONPs) and ß-Lapachone (Lapa) was developed to amplify intracellular oxidative stress. The combination, NV-IONP-Lapa, created through a serial extrusion from ovarian epithelial cells showed excellent biocompatibility and leveraged magnetic guidance to enhance endocytosis in ovarian cancer cells, resulting in selective H2O2 generation through Lapa catalysis by NADPH quinone oxidoreductase 1 (NQO1). Meanwhile, the iron released from IONPs ionization under acidic conditions triggered the conversion of H2O2 into •OH by the Fenton reaction. Additionally, the catalysis process of Lapa eliminated GSH in tumor, further amplifying oxidative stress. The designed NV-IONP-Lapa demonstrated exceptional tumor targeting, facilitating MR imaging, and enhanced tumor suppression without significant side effects. This study presents a promising NV-based drug delivery system for exploiting CDT against NQO1-overexpressing tumors by augmenting intratumoral oxidative stress.

Function of homocysteine and HE4 in endometrial carcinoma: verified by prospective experiment.

Background: Timely diagnosis is the key factor to improve the prognosis of endometrial carcinoma (EC). To date, no particularly good markers could significantly improve the detection rate of EC. This study aimed to assess the utility of serum markers homocysteine (Hcy), human epididymal protein 4 (HE4), cancer antigen 199 (CA199), cancer antigen 125 (CA125), fibrinogen (Fib), and D-dimer (D-D) for EC diagnosis, especially Hcy of which its role in EC has not been noticed. Methods: Pre-test and verification tests were performed. In Pre-test, the diagnostic value of the included markers was evaluated and the right marker was chosen to establish an efficient new risk index for screening EC. In verification tests, the applicability of the new risk index was tested. Several evaluation indices including receiver operating characteristic (ROC) curve, Youden Index, sensitivity (SN), and specificity (SP), were adopted to assess the diagnostic value of the included markers for EC. Results: Hcy may be useful in the diagnosis of EC. Its diagnostic value was not significantly lower than that of HE4. Based on the diagnostic value of Hcy and HE4, a new risk index was established, which demonstrated high value in EC diagnosis (ROC, 0.801), especially among young female patients (age ≤50 years, ROC, 0.871). Furthermore, the level of Hcy, but not HE4, was notably different in normal or benign endometrial lesions, atypical endometrial hyperplasia (AEH), and EC. Conclusions: The change of Hcy levels could be used to diagnose EC and when taken into consideration together with the detection of HE4, the diagnostic accuracy of EC is further improved.

Engineering extracellular vesicles mimetics for targeted chemotherapy of drug-resistant ovary cancer.

Aim: To develop nanocarriers for targeting the delivery of chemotherapeutics to overcome multidrug-resistant ovarian cancer. Materials & methods: Doxorubicin-loaded nanovesicles were obtained through serial extrusion, followed by loading of P-glycoprotein siRNA and folic acid. The targeting ability and anticancer efficacy of the nanovesicles were evaluated. Results: The doxorubicin-loaded nanovesicles showed a high production yield. The presence of P-glycoprotein siRNA and folic acid resulted in reversed drug resistance and tumor targeting. This nanoplatform tremendously inhibited the viability of multidrug-resistant ovarian cancer cells, which was able to target tumor tissue and suppress tumor growth without adverse effects. Conclusion: These bioengineered nanovesicles could serve as novel extracellular vesicles mimetics for chemotherapeutics delivery to overcome multidrug resistance.

When treating cancer affecting the ovaries, which is an organ in the female reproductive system, two challenges that arise are the inefficient delivery of chemotherapeutic drugs and the development of drug resistance inside the tumor. In this study, very small nano-scale particles called nanovesicles, which contain a chemotherapeutic drug called doxorubicin, were developed in an attempt to overcome both of these concerns. These nanovesicles were secreted by a healthy cell from an ovary, isolated and loaded with doxorubicin. These nanovesicles were also loaded with siRNA, which, in this case, prevents the synthesis of a protein in ovarian tumor cells called P-glycoprotein. This protein is responsible for pumping chemotherapy drugs back out of tumor cells, so preventing its synthesis was intended to counter chemotherapeutic resistance. The targeting ability of the nanovesicle was also enhanced with folic acid, as folic acid receptors are present on the surface of these tumor cells in higher numbers. These nanovesicles were readily and specifically taken up by ovarian tumor cells in mice with induced ovarian cancer. This reversed drug resistance and enhanced the toxic effects of doxorubicin on the tumor cells, which, in turn, increased tumor cell death and prevented tumor cell migration. No obvious adverse effect was found in mice treated with the nanovesicle system compared with the free chemotherapy drug with critical systematic toxicity. This research provides new avenues for ovarian cancer treatment, with combined therapies of siRNAs and chemotherapeutic drugs, targeted to tumor cells specifically, within nanovesicles.

New use of preoperative fibrinogen in ovarian cancer management.

Background: Ovarian cancer (OC) is often diagnosed at an advanced stage due to the absence of specific symptoms in its early stages. And the prognosis greatly depends on when the disease is diagnosed. Thus, we conducted to evaluate the value of preoperative fibrinogen (Fib) levels for the diagnosis of OC in the hope of improving its diagnostic efficiency. Methods: A total of 126 ovarian tumor patients were retrospectively included in this study. Four candidate OC markers, including cancer antigen 125 (CA125), Fib, platelet (PLT) and homocysteine (Hcy) were employed to establish a diagnosis model for OC. The diagnostic performance of the model was evaluated using the area under the receiver operating characteristic curve (AUC) and Youden index. Results: All included markers could be used for the diagnosis of OC. The AUCs of CA125, Fib, PLT and Hcy were 0.881, 0.825, 0.676 and 0.647, respectively. The new diagnosis model combining CA125 and Fib (CA125-Fib) had a higher AUC (0.924), Youden index (0.730), and best sensitivity (SN) (74.6%) and specificity (SP) (98.41%). CA125-Fib also had a high value in the diagnosis of stage I-II OC (AUC, Youden index, SN and SP: 0.853, 0.624, 81.48% and 80.95%). Conclusions: Fib could be used for OC diagnosis. In particular, the combination of Fib and CA125 could further improve the diagnostic efficiency. And the diagnostic value of PLT and Hcy was found to be poor.

LncRNA IDH1-AS1 sponges miR-518c-5p to suppress proliferation of epithelial ovarian cancer cell by targeting RMB47.

Long noncoding RNA (lncRNA) IDH1 antisense RNA 1 ( IDH1-AS1) is involved in the progression of multiple cancers, but its role in epithelial ovarian cancer (EOC) is unknown. Therefore, we investigated the expression levels of IDH1-AS1 in EOC cells and normal ovarian epithelial cells by quantitative real-time PCR (qPCR). We first evaluated the effects of IDH1-AS1 on the proliferation, migration, and invasion of EOC cells through cell counting kit-8, colony formation, EdU, transwell, wound-healing, and xenograft assays. We then explored the downstream targets of IDH1-AS1 and verified the results by a dual-luciferase reporter, qPCR, rescue experiments, and Western blotting. We found that the expression levels of IDH1-AS1 were lower in EOC cells than in normal ovarian epithelial cells. High IDH1-AS1 expression of EOC patients from the Gene Expression Profiling Interactive Analysis database indicated a favorable prognosis, because IDH1-AS1 inhibited cell proliferation and xenograft tumor growth of EOC. IDH1-AS1 sponged miR-518c-5p whose overexpression promoted EOC cell proliferation. The miR-518c-5p mimic also reversed the proliferation-inhibiting effect induced by IDH1-AS1 overexpression. Furthermore, we found that RNA binding motif protein 47 (RBM47) was the downstream target of miR-518c-5p, that upregulation of RBM47 inhibited EOC cell proliferation, and that RBM47 overexpressing plasmid counteracted the proliferation-promoting effect caused by the IDH1-AS1 knockdown. Taken together, IDH1-AS1 may suppress EOC cell proliferation and tumor growth via the miR-518c-5p/RBM47 axis.

Plasma circRNA microarray profiling identifies novel circRNA biomarkers for the diagnosis of ovarian cancer.

BACKGROUND: Circular RNA (circRNA), a class of RNA with a covalent closed circular structure that widely existed in serum and plasma, has been considered an ideal liquid biopsy marker in many diseases. In this study, we employed microarray and qRT-PCR to evaluate the potential circulating circRNAs with diagnostic efficacy in ovarian cancer. METHODS: We used microarray to explore the circRNA expression profile in ovarian cancer patients' plasma and quantitative real-time (qRT)-PCR approach to assessing the candidate circRNA's expression. Then the receiver operating characteristic (ROC) curve was employed to analyze the diagnostic values of candidate circRNAs. The diagnostic model circCOMBO was a combination of hsa_circ_0003972 and hsa_circ_0007288 built by binary logistic regression. Then bioinformatic tools were used to predict their potential mechanisms. RESULTS: Hsa_circ_0003972 and hsa_circ_0007288 were downregulated in ovarian cancer patients' plasma, tissues, and cell lines, comparing with the controls. Hsa_circ_0003972 and hsa_circ_0007288 exhibited diagnostic values with the Area Under Curve (AUC) of 0.724 and 0.790, respectively. circCOMBO showed a better diagnostic utility (AUC: 0.781), while the combination of circCOMBO and carbohydrate antigen 125 (CA125) showed the highest diagnostic value (AUC: 0.923). Furthermore, the higher expression level of hsa_circ_0007288 in both plasma and ovarian cancer tissues was associated with lower lymph node metastasis potential in ovarian cancer. CONCLUSIONS: Our results revealed that hsa_circ_0003972 and hsa_circ_0007288 may serve as novel circulating biomarkers for ovarian cancer diagnosis.

Distribution characteristics of soil microbial communities and their responses to environmental factors in the sea buckthorn forest in the water-wind erosion crisscross region.

Soil microorganisms are an important part of forest ecosystems, and their community structure and ecological adaptations are important for explaining soil material cycles in the fragile ecological areas. We used high-throughput sequencing technology to examine the species composition and diversity of soil bacterial and fungal communities in sea buckthorn forests at five sites in the water-wind erosion crisscross in northern Shaanxi (about 400 km long). The results are described as follows: (1) The soil bacterial community of the sea buckthorn forest in the study region was mainly dominated by Actinobacteria, Proteobacteria, and Acidobacteria, and the fungi community was mainly dominated by Ascomycota. (2) The coefficient of variation of alpha diversity of microbial communities was higher in the 0-10 cm soil layer than in the 10-20 cm soil layer. (3) Soil electrical conductivity (36.1%), available phosphorous (AP) (21.0%), available potassium (16.2%), total nitrogen (12.7%), and the meteorological factors average annual maximum temperature (33.3%) and average annual temperature (27.1%) were identified as the main drivers of structural changes in the bacterial community. Available potassium (39.4%), soil organic carbon (21.4%), available nitrogen (AN) (13.8%), and the meteorological factors average annual maximum wind speed (38.0%) and average annual temperature (26.8%) were identified as the main drivers of structural changes in the fungal community. The explanation rate of soil factors on changes in bacterial and fungal communities was 26.6 and 12.0%, respectively, whereas that of meteorological factors on changes in bacterial and fungal communities was 1.22 and 1.17%, respectively. The combined explanation rate of environmental factors (soil and meteorological factors) on bacterial and fungal communities was 72.2 and 86.6%, respectively. The results of the study offer valuable insights into the diversity of soil microbial communities in the water-wind erosion crisscross region and the mechanisms underlying their interaction with environmental factors.

LBX2-AS1 promotes ovarian cancer progression by facilitating E2F2 gene expression via miR-455-5p and miR-491-5p sponging.

LBX2-AS1 is a long non-coding RNA that facilitates the development of gastrointestinal cancers and lung cancer, but its participation in ovarian cancer development remained uninvestigated. Clinical data retrieved from TCGA ovarian cancer database and the clinography of 60 ovarian cancer patients who received anti-cancer treatment in our facility were analysed. The overall cell growth, colony formation, migration, invasion, apoptosis and tumour formation on nude mice of ovarian cancer cells were evaluated before and after lentiviral-based LBX2-AS1 knockdown. ENCORI platform was used to explore LBX2-AS1-interacting microRNAs and target genes of the candidate microRNAs. Luciferase reporter gene assay and RNA pulldown assay were used to verify the putative miRNA-RNA interactions. Ovarian cancer tissue specimens showed significant higher LBX2-AS1 expression levels that non-cancerous counterparts. High expression level of LBX2-AS1 was significantly associated with reduced overall survival of patients. LBX2-AS1 knockdown significantly down-regulated the cell growth, colony formation, migration, invasion and tumour formation capacity of ovarian cancer cells and increased their apoptosis in vitro. LBX2-AS1 interacts with and thus inhibits the function of miR-455-5p and miR-491-5p, both of which restrained the expression of E2F2 gene in ovarian cancer cells via mRNA targeting. Transfection of miRNA inhibitors of these two miRNAs or forced expression of E2F2 counteracted the effect of LBX2-AS1 knockdown on ovarian cancer cells. LBX2-AS1 was a novel cancer-promoting lncRNA in ovarian cancer. This lncRNA increased the cell growth, survival, migration, invasion and tumour formation of ovarian cancer cells by inhibiting miR-455-5p and miR-491-5p, thus liberating the expression of E2F2 cancer-promoting gene.

Long noncoding RNA ZEB1-AS1 affects paclitaxel and cisplatin resistance by regulating MMP19 in epithelial ovarian cancer cells.

PURPOSE: The long noncoding RNA (lncRNA) ZEB1-AS1 is reported overexpressed in sensitive ovarian cancer cells A2780 compared with paclitaxel (PTX)-and cisplatin (DDP)- resistant. However, the function and mechanism of ZEB1-AS1 in EOC cells still unknown. METHODS: We used quantitative real-time PCR (qPCR) to detect ZEB1-AS1 expression in A2780 and A2780/R cells. A combination of siRNA, plasmids, CCK8 and flow cytometry was used to detect the effect of ZEB1-AS1 on ovarian cancer cell A2780 PTX and DDP resistance. Transcriptome sequencing, qPCR, and western blot were used for further mechanistic studies. RESULTS: ZEB1-AS1 depletion using siRNA in chemosensitive A2780 cells significantly increased PTX and DDP resistance. In contrast, ZEB1-AS1 overexpression in PTX- and DDP-resistant A2780/resistant (A2780/R) cells reversed the observed drug resistance. Thus, ZEB1-AS1 plays an important role in PTX and DDP resistance in EOC cells. However, quantitative real-time PCR (qPCR) and western blot results suggested that ZEB1-AS1 did not regulate chemoresistance through regulation of ZEB1 protein. We used sequencing to detect mRNA expression changes in A2780 cells after ZEB1-AS1 silencing. The results indicated that MMP19 was the likely downstream factor of ZEB1-AS1. We further examined whether ZEB1-AS1 played an important role in chemoresistance by silencing MMP19 in ZEB1-AS1-overexpressing cells. CCK8 assay results suggested that MMP19 knockdown promoted ZEB1-AS1-induced chemoresistance to PTX and DDP in A2780 cells. CONCLUSION: This study is the first to reveal that ZEB1-AS1 plays a pivotal role in cancer chemoresistance.

Peptidome characterization of ovarian cancer serum and the identification of tumor suppressive peptide ZYX36-58.

BACKGROUND: Several serum biomarkers, including miRNA, mRNA, protein and peptides in cancer patients are also important mediators of cancer progression. METHODS: The differentially expressed peptides between the serum of ovarian cancer patients and healthy controls were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The function of the peptides was analyzed by CCK8, transwell, wound healing, and flow cytometry analysis. And the mechanism of the peptides was analyzed by peptide pull down, and high-throughput RNA-sequencing. RESULTS: A total of 7 and 46 peptides were significantly up-regulated and down-regulated in the serum of ovarian cancer patients, respectively. The precursor proteins of the differentially expressed peptides mainly involved in the complement and coagulation cascades, platelet activation, phagosome and focal adhesion pathways. Interestingly, focal adhesion, platelet activation, platelet-cancer cell interaction, complement activation, coagulation cascades and phagosome formation are all critical factors for cancer initiation or progression, which indicated that the peptides may play a crucial role in cancer development. And we identified one peptide, ZYX36-58, which was down-regulated in the serum of ovarian cancer patients, significantly inhibited invasion and migration and promoted the apoptosis of ovarian cancer cells. Mechanistic study indicated that ZYX36-58 interacted with and increased the protein level of the antiangiogenic protein thrombospondin-1 (TSP1), which has a tumor suppressive effect on ovarian cancer. CONCLUSIONS: ZYX36-58, which was significantly down-regulated in the serum of ovarian cancer patients can significantly inhibit cell invasion, migration and promote apoptosis of ovarian cancer cells by binding and up-regulating TSP1 protein expression.

A New Risk Index Combining d-Dimer, Fibrinogen, HE4, and CA199 Differentiates Suspecting Endometrial Cancer From Patients With Abnormal Vaginal Bleeding or Discharge.

PURPOSE: To establish an efficient new risk index for screening patients with endometrial cancer from patients with abnormal vaginal bleeding or discharge. METHOD: A total of 254 patients with abnormal vaginal bleeding or discharge were included in this study. Several candidate markers, including HE4, CA125, CA199, CA153, AFP, CEA, d-dimer, and fibrinogen, were employed. A new risk index for endometrial cancer screening was established by binary logistic regression. The diagnostic value of the candidate markers and the new risk index were assessed by a receiver operating characteristic curve, sensitivity, and specificity. RESULTS: The most valuable diagnostic indicator for endometrial cancer was HE4, followed by d-dimer and then fibrinogen (area under the receiver operating characteristic curve: HE4 = 0.794, d-dimer = 0.717, fibrinogen = 0.690). The new risk index was superior to a single application of markers and a widely used combination (HE4 and CA125). At the ideal cutoff level, the sensitivity and specificity were 91.34% and 70.08%, respectively. In addition, only patients without organic disease served as controls, which further increase its performance (area under the receiver operating characteristic curve = 0.932, sensitivity = 94.49%, and specificity = 77.42%). CONCLUSIONS: The new risk index combining HE4, d-dimer, fibrinogen, and CA199 was the ideal combination for the screening of endometrial cancer. As a simple, rapid, nondestructive detection method, the new risk index is worth promotion in clinical practice, especially in primary medical institutions.

LncRNA KB-1471A8.2 Overexpression Suppresses Cell Proliferation and Migration and Antagonizes the Paclitaxel Resistance of Ovarian Cancer Cells.

Objective: The aim was to investigate the lncRNA KB-1471A8.2 function in ovarian cancer progression and paclitaxel resistance. Methods: The expression and distribution of KB-1471A8.2 was detected by qRT-PCR. The cell proliferation, apoptosis, invasion, migration and chemoresistance were analyzed by CCK8 assay, flow cytometry and transwell assay. The expression of DEPTOR, whose sequence is reverse overlapped with KB-1471A8.2 was analyzed by qRT-PCR, western blot and immunofluorescence. The cell cycle and the cell cycle related gene expression were analyzed by flow cytometry and qRT-PCR, respectively. Results: KB-1471A8.2 was significantly downregulated in both ovarian cancer tissues and chemoresistant ovarian cancer cells. Overexpression of KB-1471A8.2 significantly inhibited the proliferation, invasion, migration, and paclitaxel resistance, and increased the apoptosis of ovarian cancer cells. KB-1471A8.2 was mainly distributed in the nucleus of ovarian cancer cells. KB-1471A8.2 overexpression significantly decreased the S phase cell ratio, increased the G0/G1 phase cell ratio, but not affected the expression and distribution of DEPTOR. However, cyclin-dependent kinase 4 (CDK4), which is an important regulator of G1/S transition, was significantly decreased in KB-1471A8.2-overexpressed ovarian cancer cells. Conclusion: KB-1471A8.2 could significantly inhibit the development and paclitaxel resistance of ovarian cancer cells, at least partly, by suppressing CDK4 expression.

Knockdown of JARID2 inhibits the proliferation and invasion of ovarian cancer through the PI3K/Akt signaling pathway.

Protein Jumonji (JARID2), a member of the family of JmjC domain-containing proteins, has been reported to serve an important role in tumor growth and metastasis. However, the expression pattern and role of JARID2 in ovarian cancer remains unclear. Therefore, in the present study, the role of JARID2 in ovarian cancer was investigated, as well as the underlying mechanisms. The results of the present study demonstrated that the expression of JARID2 is upregulated in human ovarian cancer cell lines. Furthermore, downregulation of JARID2 significantly suppressed proliferation, migration, invasion and epithelial­mesenchymal transition in human ovarian cancer cells. Mechanistically, downregulation of JARID2 decreased the protein expression levels of phosphorylated phosphoinositide 3­kinase (PI3K) and protein kinase B (Akt) in ovarian cancer cells. In conclusion the observations suggested that knockdown of JARID2 inhibited proliferation, migration and invasion in vitro through the inactivation of the PI3K/Akt signaling pathway. Therefore, JARID2 may represent a potential therapeutic target for the treatment of ovarian cancer.

Clinical significance of plasma D-dimer in ovarian cancer: A meta-analysis.

BACKGROUND: D-dimer has been widely used for the diagnosis and prognosis of ovarian cancer, but there is still controversy on its prediction value of ovarian cancer. OBJECTIVES: To explore the clinical significance of plasma D-dimer level on ovarian cancer systematically. METHODS: Using PubMed, Cochrane Library, and Web of Science libraries, all the relevant studies for the diagnostic and prognostic value of plasma D-dimer for ovarian cancer and the relationship between elevated D-dimer level and venous thromboembolism (VTE) risk of ovarian cancer were searched till May 30, 2016. Standardized mean difference (SMD), odds ratio (OR), hazard ratio (HR), and 95% confidence interval (CI) were appropriately pooled. RESULTS: A total of 15 eligible studies involving a total of 1437 cancer patients were included. No significant association was found between high D-dimer level and overall survival of patients with ovarian cancer (HR 1.32, 95% CI: 0.90-1.95, P  =  .044). However, subgroup analysis indicated that the sample sizes could explain the heterogeneity between studies. And elevated D-dimer could predict increased risk of mortality when the sample sizes were >100 (HR 1.800, 95% CI: 1.283-2.523, P  =  .845). Besides, plasma D-dimer level was significantly higher in malignant ovarian cancer patients compared with benign controls (SMD 0.774, 95% CI: 0.597-0.951, P  =  .39), higher in advanced ovarian cancer patients (International Federation of Gynecology and Obstetrics [FIGO] classification III and IV) than in early stage ovarian cancer patients (FIGO classification I and II, SMD 0.611, 95% CI: 0.373-0.849, P  =  .442). And high D-dimer level indicated high VTE risk (OR 4.068, 95% CI: 2.423-6.829, P  =  .629) of ovarian cancer patients. CONCLUSION: The plasma D-dimer level in ovarian cancer patients can predict the changes that correlated with disease progression and the VTE risk. But its predictive value for the prognosis of ovarian cancer was significantly dependent on the sample sizes. More well-designed studies with large sample sizes are needed to validate and update the findings of present study.

Comparison of three treatment strategies for cesarean scar pregnancy.

PURPOSE: To explore the optimal treatment for cesarean scar pregnancy. METHOD: In total, 86 women diagnosed with a cesarean scar pregnancy were divided into three groups according to treatment. The human chorionic gonadotrophin (hCG) decline percentage, intraoperative blood loss and success rate were analyzed in Group A [combination of uterine arterial embolization (UAE), local methotrexate (MTX) injection and dilation & curettage (D&C)], Group B (combination of UAE and local MTX injection) and Group C (D&C). Then, the best treatment was carefully analyzed, and recommendations were provided. RESULTS: The success rate was highest in Group A (97.5%) compared with Group B (76%) and Group C (63.15%). The reduction in hCG was greatest in Group A (86.62%, 44.0-99.97%) compared with group B (67.83%, 18.0-98.03%) and Group C (68.21%, 27.0-93.24%). The intraoperative blood loss was lowest in Group A (44.881, 5-200 ml) compared with Group C (224.737, 10-1000 ml). Additionally, we found that the best time to perform D&C in group A depended on the hCG reduction percentage, and a 35% reduction after UAE and local MTX injection could be used as the indicator to perform D&C. CONCLUSIONS: The combination of UAE, local MTX injection and D&C for CSP patients is the optimal treatment strategy. A 35% reduction in hCG after UAE and local MTX injection can be recommended as the indicator to perform D&C.

Prognostic and Clinicopathological Significance of ARID1A in Endometrium-Related Gynecological Cancers: A Meta-Analysis.

The tumor suppressor gene, AT Rich Interactive Domain 1A (ARID1A) mutation has been reported in a variety of cancers, especially the endometrium-related gynecological cancers, including the ovarian clear cell carcinoma, ovarian endometrioid carcinoma, and uterine endometrioid carcinoma. However, the prognostic value of ARID1A in endometrium-related gynecological cancers is still inconclusive. Therefore, we performed this meta-analysis to evaluate the clinical significance of ARID1A in endometrium-related gynecological cancers. By systematically searching all the relevant studies from Pubmed, Cochrane Library, and Web of Science up to September 2016, 11 studies with 1,432 patients were included. All the study characteristics and the prognostic data were extracted. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled using the fixed-effect or random-effect model. Our results indicated that negative ARID1A expression predicted shorter Progression free survival (PFS, HR, 1.84; 95%CI, 1.32-2.57, P = 0.000) of patients with endometrium related gynecological cancers, especially the patiently with OCCC and the patients in Japan. Besides, a marginal trend towards the same direction was found in the Overall analysis (OS, HR, 1.34; 95%CI, 0.93-1.93, P = 0.112). Furthermore, the significant correlation was achieved between the negative ARID1A expression and the FIGO stage of endometrium-related gynecological cancers, but not the other characteristics. J. Cell. Biochem. 118: 4517-4525, 2017. © 2017 Wiley Periodicals, Inc.

Genetic variants in PTPRD and risk of gestational diabetes mellitus.

Genome-wide association studies (GWASs) showed that two single nucleotide polymorphisms (SNPs) (rs17584499 and rs649891) in the protein tyrosine phosphatase receptor type D (PTPRD) were associated with type 2 diabetes (T2D). We sought to determine the influence of the PTPRD variants on the gestational diabetes mellitus (GDM) risk. In this research, two SNPs in PTPRD reported in T2D GWASs and six PTPRD expression-related SNPs were genotyped in 964 GDM cases and 1,021 controls using the Sequenom platform. Logistic regression analyses in additive models showed consistently significant associations of PTPRD rs10511544 A>C, rs10756026 T>A and rs10809070 C>G with a decreased risk of GDM [adjusted OR (95% CI) = 0.83 (0.72-0.97) for rs10511544; adjusted OR (95% CI) = 0.81 (0.70-0.94) for rs10756026; adjusted OR (95% CI) = 0.78 (0.65-0.92) for rs10809070]. Furthermore, the risk of GDM was significantly decreased with an increasing number of variant alleles of the three SNPs in a dose-dependent manner (Ptrend = 0.008). Moreover, the haplotype containing variant alleles of the three SNPs were significantly associated with a decreased risk of GDM [adjusted OR (95% CI) = 0.77 (0.64-0.92), P = 0.005], when compared with the most frequent haplotype. However, there were no significant associations for the SNPs reported in the T2D GWASs. Altogether, these findings indicate that the variants of rs10511544, rs10756026 and rs10809070 in PTPRD may contribute to a decreased susceptibility to GDM. Further validation in different ethnic backgrounds and biological function analyses are needed.

Genetic variants in vitamin D signaling pathways and risk of gestational diabetes mellitus.

Vitamin D (VD) deficiency during pregnancy has been repeatedly linked to an increased gestational diabetes mellitus (GDM) risk. We sought to determine the influences of genetic variants in vitamin D signaling pathways on the risk of GDM. In this study, we genotyped 15 single nucleotide polymorphisms (SNPs) within 8 representative genes (CYP27A1, CYP27B1, CYP24A1, VDR, RXRA, RXRB, RXRG and GC) of the vitamin D signaling pathways in a case-control study with 964 GDM cases and 1,021 controls using the Sequenom MassARRAY iPLEX platform. Logistic regression analyses in additive model showed that GC rs16847024 C>T, RXRG rs17429130 G>C and RXRA rs4917356 T>C were significantly associated with the increased risk of GDM (adjusted OR = 1.31, 95% CI = 1.10-1.58 for rs16847024; adjusted OR = 1.28, 95% CI = 1.04-1.57 for rs17429130; adjusted OR = 1.28, 95% CI = 1.06-1.54 for rs4917356). And GDM risk significantly increased with the increasing number of variant alleles of the three SNPs in a dose-dependent manner (P for trend < 0.001). Moreover, the combined effect of the three SNPs on GDM occurrence was more prominent in older women (age > 30). Further interactive analyses also detected a significantly multiplicative interaction between the combined variant alleles and age on GDM risk (P = 0.035). Together, these findings indicate that GC rs16847024, RXRG rs17429130 and RXRA rs4917356 were candidate susceptibility markers for GDM in Chinese females. Further validation studies with different ethnic background and biological function analyses were needed.

The reversal effects of 3-bromopyruvate on multidrug resistance in vitro and in vivo derived from human breast MCF-7/ADR cells.

PURPOSE: P-glycoprotein mediated efflux is one of the main mechanisms for multidrug resistance in cancers, and 3-Bromopyruvate acts as a promising multidrug resistance reversal compound in our study. To test the ability of 3-Bromopyruvate to overcome P-glycoprotein-mediated multidrug resistance and to explore its mechanisms of multidrug resistance reversal in MCF-7/ADR cells, we evaluate the in vitro and in vivo modulatory activity of this compound. METHODS: The in vitro and in vivo activity was determined using the MTT assay and human breast cancer xenograft models. The gene and protein expression of P-glycoprotein were determined using real-time polymerase chain reaction and the Western blotting technique, respectively. ABCB-1 bioactivity was tested by fluorescence microscopy, multi-mode microplate reader, and flow cytometry. The intracellular levels of ATP, HK-II, and ATPase activity were based on an assay kit according to the manufacturer's instructions. RESULTS: 3-Bromopyruvate treatment led to marked decreases in the IC50 values of selected chemotherapeutic drugs [e.g., doxorubicin (283 folds), paclitaxel (85 folds), daunorubicin (201 folds), and epirubicin (171 folds)] in MCF-7/ADR cells. 3-Bromopyruvate was found also to potentiate significantly the antitumor activity of epirubicin against MCF-7/ADR xenografts. The intracellular level of ATP decreased 44%, 46% in the presence of 12.5.25 µM 3-Bromopyruvate, whereas the accumulation of rhodamine 123 and epirubicin (two typical P-glycoprotein substrates) in cells was significantly increased. Furthermore, we found that the mRNA and the total protein level of P-glycoprotein were slightly altered by 3-Bromopyruvate. Moreover, the ATPase activity was significantly inhibited when 3-Bromopyruvate was applied. CONCLUSION: We demonstrated that 3-Bromopyruvate can reverse P-glycoprotein-mediated efflux in MCF-7/ADR cells. Multidrug resistance reversal by 3-Bromopyruvate occurred through at least three approaches, namely, a decrease in the intracellular level of ATP and HK-II bioactivity, the inhibition of ATPase activity, and the slight decrease in P-glycoprotein expression in MCF-7/ADR cells.

Screening and identification of functional Lactobacillus specific for vegetable fermentation.

In this study, functional lactic acid bacteria (LAB) specific for vegetable fermentation were screened from Chinese sauerkraut brine by designing purpose media. The selected LAB strains showed excellent tolerance to high concentrations of bile salt and acids. They can also survive passage through the simulated gastric fluid and may be able to reach to the intestine. Through the performance measurements of vegetable fermentation, one of these strains, NCU116 was found to have the best fermentation ability, and further subjected to a series of analyses including identification of physiological and biochemical characteristics, 16S rDNA and pheS sequencing. Taken together, the strain NCU116 was identified as Lactobacillus plantarum subsp. plantarum. These results laid a good foundation for the fermentation research in the future.