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Objective: To investigate the feasibility to restore functional endometrium using bone marrow mesenchymal stem cells (BMSCs) in the Sprague Dawley (SD["SD" has been defined as both "Sprague Dawley" and "standard deviation." Please clarify which one is to be followed.]) rat model for Asherman syndrome (AS). Design: Basic research on treatment of AS utilizing an optimized rat model. Setting: University research laboratories. Animal(s): Sprague Dawley rat model in which AS was induced in accordance to an optimized protocol. Intervention(s): Bone marrow mesenchymal stem cells were harvested from the rat's bone marrow and labeled with green fluorescent protein (GFP) in the second passage of BMSCs. The fifth passage of GFP-labeled BMSCs was injected systemically through the tail vein in the optimized AS rat model. Main Outcome Measure(s): We examined the reproliferation of the endometrial lining and the expression of markers for endometrium and endometrial receptivity. The localization of engrafted GFPlabeled BMSCs was determined by a laser scanning confocal microscope and a fluorescence microscope. The number of pregnant rats and implanted embryos in each uterus was recorded to evaluate the function of endometrium. Result(s): We had demonstrated that in the in vivo experiments on our rat model for AS, the group which received BMSC injection had significantly improved reproductive outcomes-70% of these rats conceived, whereas none of the rats in the control group got pregnant (P < .01, w 2 test). The mean number of embryos undergoing implantation was 14 + 1.24 in the sham group and 7 + 5.70 in the BMSC group (Levene test, P ¼ .001). There was no significant difference between the groups from the time of coitus to conception. To further determine how BMSC injection could have resulted in the improved reproductive outcomes in rats with AS, we employed immunohistochemical techniques to examine the endometrium of these treated rats. On hematoxylin-eosin staining, we noted the reproliferation of all layers of the endometrium and with Masson staining, we noted significant reduction in fibrosis in the damaged endometrium of rats treated with BMSCs. Counterstaining for GFP and cytokeratin-positive cells was noted in the endometrial lining of treated rats, which might suggest the action of BMSCs in regenerating the damaged endometrial lining. The expression of the endometrial receptivity marker, Leukemia inhibitory factor (LIF), in this regenerated endometrial lining could have resulted in the improved reproductive outcomes observed in the AS rat model treated with BMSCs. Conclusion: Bone marrow mesenchymal stem cells were likely to play an important role in the reconstruction of the injured endometrium and improvement of reproductive outcomes in the optimized AS rat model.

BackgroundPrevious studies have demonstrated that serum amyloid A (SAA) levels are correlated with the clinical outcomes of solid tumors. However, the available data have not been systematically evaluated. The objective of the present meta-analysis was to explore the prognostic value of SAA levels in solid tumors.MethodsEligible studies were identified from the PubMed, EMBASE and Science Citation Index electronic databases. The clinical characteristics, disease/progression-free survival (DFS/PFS) and overall survival (OS) were extracted from the eligible studies. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Stata 12.0 software. We also performed subgroup, meta-regression and sensitivity analyses.ResultsIn total, 12 eligible studies including 2749 patients were enrolled in the present meta-analysis. The pooled HRs with 95% CIs showed that elevated levels of SAA were significantly associated with poor OS (HR = 3.01, 95% CI 1.96–4.63) and DFS/PFS (HR = 1.67, 95% CI 1.31–2.12) in patients with solid tumors. Although publication bias was seem found in the studies with regard to OS, a further trim and fill analysis revealed that the adjusted HR was 3.02 (95% CI 1.96–4.63), which was close to the original HR. Subgroup analysis confirmed an elevated level of SAA as a strong prognostic marker in patients with solid tumors, regardless of tumor type, detection method, cut-off value, sample size, area and variance analyses.ConclusionOur meta-analysis indicated that elevated levels of SAA might be an unfavorable prognostic marker for OS in patients with solid tumors.

Emerging evidence indicates that β-galactoside-α2,3-sialyltransferase III (ST3Gal3) involves in development, inflammation, neoplastic transformation, and metastasis. However, the role of ST3Gal3 in regulating cancer chemoresistance remains elusive. Herein, we investigated the functional effects of ST3Gal3 in cisplatin-resistant ovarian cancer cells. We found that the levels of ST3Gal3 mRNA differed significantly among ovarian cancer cell lines. HO8910PM cells that have high invasive and metastatic capacity express elevated ST3Gal3 mRNA and are resistant to cisplatin, comparing to SKOV3 cells that have a lower level of ST3Gal3 expression and are more chemosensitive to cisplatin. We found that the expression of ST3Gal3 has reverse correlation with the dosage of cisplatin used in both SKOV3 and HO8910PM cells, and high dose of cisplatin could down-regulate ST3Gal3 expression. We then examined the functional effects of ST3Gal3 knockdown in cancer cell lines using FACS analysis. The number of apoptotic cells was much higher in cells if ST3Gal3 expression was knocked down by siRNA and/or by treating cells with higher dosage of cisplatin in comparison to control cells. Interestingly, in HO8910PM cells with ST3Gal3 knockdown, the levels of caspase 8 and caspase 3 proteins increased, which was more obvious in cells treated with both ST3Gal3 knockdown and cisplatin, suggesting that ST3Gal3 knockdown synergistically enhanced cisplatin-induced apoptosis in ovarian cancer cells. Taken together, these results uncover an alternative mechanism of cisplatin-resistance through ST3Gal3 and open a window for effective prevention of chemoresistance and relapse of ovarian cancer by targeting ST3Gal3.

Background: Gene therapy is considered a novel way to treat osteosarcoma, and microRNAs are potential therapeutic targets for osteosarcoma. miR-214 has been found to promote osteosarcoma aggression and metastasis. Graphene oxide (GO) is widely used for gene delivery for the distinct physiochemical properties and minimal cytotoxicity. Methods: Polyethyleneimine (PEI)-functionalized GO complex was well-prepared and loaded with miR-214 inhibitor at different concentrations. The load efficacy was tested by gel retardation assay and the cy3-labeled fluorescence of cellular uptake. The experiments of wound healing, immunofluorescence staining, Western blot, qRT-PCR and immunohistochemical staining were performed to measure the inhibitory effect of the miR-214 inhibitor systematically released from the complexes against MG63, U2OS cells and xenograft tumors. Results: The systematic mechanistic elucidation of the efficient delivery of the miR-214 inhibitor by GO-PEI indicated that the inhibition of cellular miR-214 caused a decrease in osteosarcoma cell invasion and migration and an increase in apoptosis by targeting phosphatase and tensin homolog (PTEN). The synergistic combination of the GO-PEI-miR-214 inhibitor and CDDP chemotherapy showed significant cell death. In a xenograft mouse model, the GO-PEI-miR-214 inhibitor significantly inhibited tumor volume growth. Conclusion: This study indicates the potential of functionalized GO-PEI as a vehicle for miRNA inhibitor delivery to treat osteosarcoma with low toxicity and miR-214 can be a good target for osteosarcoma therapy.

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Osteosarcoma (OS) is the most common primary cancer in the skeletal system, characterized by a high incidence of lung metastasis, local recurrence and death. Systemic treatment of this aggressive cancer has not improved significantly since the introduction of chemotherapy regimens, underscoring a critical need for new treatment strategies. TRAIL receptors have long been proposed to be therapeutic targets for cancer treatment, but their role in osteosarcoma remains unclear. In this study, we investigated the expression profile of four TRAIL receptors in human OS cells using total RNA-seq and single-cell RNA-seq (scRNA-seq). The results revealed that TNFRSF10B and TNFRSF10D but not TNFRSF10A and TNFRSF10C are differentially expressed in human OS cells as compared to normal cells. At the single cell level by scRNA-seq analyses, TNFRSF10B, TNFRSF10D, TNFRSF10A and TNFRSF10C are most abundantly expressed in endothelial cells of OS tissues among nine distinct cell clusters. Notably, in osteoblastic OS cells, TNFRSF10B is most abundantly expressed, followed by TNFRSF10D, TNFRSF10A and TNFRSF10C. Similarly, in an OS cell line U2-OS using RNA-seq, TNFRSF10B is most abundantly expressed, followed by TNFRSF10D, TNFRSF10A and TNFRSF10C. According to the TARGET online database, poor patient outcomes were associated with low expression of TNFRSF10C. These results could provide a new perspective to design novel therapeutic targets of TRAIL receptors for the diagnosis, prognosis and treatment of OS and other cancers.