OSI-906 restores the sensitivity of ovarian clear cell carcinoma to cisplatin by targeting the IGF1R/AKT pathway.

Among the various histologic subtypes of ovarian cancers (OCs), ovarian clear cell carcinoma (OCCC) represents a great challenge due to its disease aggressiveness and resistance to chemotherapy. IGF1 is overexpressed in epithelial ovarian cancer (EOC), and IGF1 pathway activation is related to the chemoresistance of various cancers. In this study, we found that the expression level of IGF1 was higher in OCCC than in the most common type of OC, high-grade serous adenocarcinoma (HGSC). Then, we investigated the role of IGF1 pathway activation in the progression of OCCC, observing that activation of the IGF1 pathway using IGF1 promoted the proliferation and migration of ES2 cells, while inactivation of the IGF1 pathway using the selective IGF1R inhibitor OSI-906 reversed the alteration mediated by IGF1. Based on the role of the IGF1 pathway in cancer chemoresistance, we proposed that OSI-906 may restore the sensitivity of OCCC to cisplatin. We first validated that IGF1 increased the IC50 value of cisplatin in ES2 cells, while OSI-906 decreased it. Then we confirmed that IGF1 decreased the apoptosis rate of ES2 cells induced by cisplatin, while OSI-906 increased it. Finally, we conducted animal experiments to investigate whether OSI-906 helps cisplatin control the growth of OCCC. As expected, OSI-906 increased the effect of cisplatin in attenuating the growth of OCCC in vivo. Therefore, we conclude that using OSI-906 may be an effective method to restore the sensitivity of OCCC to cisplatin by targeting the IGF1R/AKT pathway.

Construction of novel antimicrobial peptide-modified extracellular matrix biologic scaffold material.

In the field of implantable medical devices, the antibacterial extracellular matrix (ECM) biologic scaffold, which is constructed by modifying biomaterials with antibacterial peptides, has excellent potential. An antibacterial peptide-modified ECM scaffold was formed with chitosan (CS), antimicrobial peptide (AMP), and ECM scaffold. Chitosan has a firm positive-charge surface and can combine with the ECM scaffold material to form a positive-charge layer on the surface. The surface potential was characterized using a surface potential map. Infrared spectroscopy and scanning electron microscopy (SEM) were used to observe the scaffold surface characteristics and cell morphology. Fluorescence staining and MTS assay kit were used to assess cytotoxicity and biocompatibility. To evaluate the antibacterial and repairing effects on the infected wounds in vivo, a subcutaneous antibacterial test of rabbit back was conducted. The antibacterial peptide-modified ECM scaffold was successfully formed and presented an excellent three-dimensional micro-surface porous structure. The antibacterial peptide-modified ECM scaffold could be effectively-prepared by surface modification and activation. Fluorescence staining tests showed good cell adhesion, proliferation ability, and cell affinity. The in vivo experiment indicated that the antibacterial ECM scaffold had antibacterial and healing-promotion abilities.

Classification of serous ovarian carcinoma based on immunogenomic profiling.

Treatment of serous ovarian cancer (SOC) remains a clinical challenge. Classification of SOC based on immunogenomic profiling is important for establishing immunotherapy strategies. We extracted RNA-seq data of SOC from TCGA-OV. The samples were ultimately classified into high immune (Immunity_H) group and low immune (Immunity_L) group based on the immunogenomic profiling of 29 immune signatures by using unsupervised machine learning methods and modified by multifaceted characterization of immune response. High immune group showed the lower tumor purity and higher anti-tumor immune activity, and the higher expressions of PDCD1, CD274 and CTLA4. Furthermore, the overall survival time and the progression-free interval were significantly longer in high-immun group. The differentially expressed genes were mainly enriched in some immune response related functional terms and PI3K-AKT signaling pathway. According to ImmuCellAI, the abundance of various T cell subtypes in high immune group were significantly higher than those in low immune group. This novel immunotyping shows promise for prognostic and immunotherapeutic stratification in SOC patients.

Improved the biocompatibility of cancellous bone with compound physicochemical decellularization process.

Due to the unique microstructures and components of extracellular matrix (ECM), decellularized scaffolds had been used widely in clinical. The reaction of the host toward decellularized scaffolds depends on their biocompatibility, which should be satisfied before applied in clinical. The aim of this study is to develop a decellularized xenograft material with good biocompatibility for further bone repair, in an effective and gentle method. The existing chemical and physical decellularization techniques including ethylene diamine tetraacetic acid (EDTA), sodium dodecyl sulfate (SDS) and supercritical carbon dioxide (SC-CO2) were combined and modified to decellularize bovine cancellous bone (CB). After decellularization, almost 100% of ɑ-Gal epitopes were removed, the combination of collagen, calcium and phosphate was reserved. The direct and indirect contact with macrophages was used to evaluate the cytotoxicity and immunological response of the materials. Mesenchymal stem cells (MSCs) were used in the in vitro cells' proliferation assay. The decellularized CB was proved has no cytotoxicity (grade 1) and no immunological response (NO, IL-2, IL-6 and TNF-α secretion inhibited), and could support MSCs proliferated continuedly. These results were similar to that of commercial decellularized human bone. This study suggests the potential of using this kind of combine decellularization process to fabricate heterogeneous ECM scaffolds for clinical application.

A novel antibacterial biomaterial mesh coated by chitosan and tigecycline for pelvic floor repair and its biological performance.

The biomaterials composed of mammalian extracellular matrix (ECM) have a great potential in pelvic floor tissue repair and functional reconstruction. However, bacterial infection does cause great damage to the repair function of biomaterials which is the major problem in clinical utilization. Therefore, the development of biological materials with antimicrobial effect is of great clinical significance for pelvic floor repair. Chitosan/tigecycline (CS/TGC) antibacterial biofilm was prepared by coating CS/TGC nanoparticles on mammalian-derived ECM. Infrared spectroscopy, scanning electron microscopy, bacteriostasis circle assay and static dialysis methods were used to characterize the membrane. MTS assay kit and DAPI fluorescence staining were used to evaluate cytotoxicity and cell adhesion. The biocompatibility was assessed by subabdominal implantation model in goats. Subcutaneous antimicrobial test in rabbit back was used to evaluate the antimicrobial and repairing effects on the infected wounds in vivo. Infrared spectroscopy showed that the composite coating had been successfully modified. The antibacterial membrane retained the main structure of ECM multilayer fibers. In vitro release of biomaterials showed sustained release and stability. In vivo studies showed that the antibacterial biological membrane had low cytotoxicity, fast degradation, good compatibility, anti-infection and excellent repair ability.

Tissue Resident Memory γδT Cells in Murine Uterus Expressed High Levels of IL-17 Promoting the Invasion of Trophocytes.

γδT cells are non-conventional T cells and serve as the bridge for connecting the innate and adaptive immune systems. γδT cells form a substantial population at barrier sites and play an important role in the development of physiology, inflammation, autoimmune diseases and tumors. γδT cells not only distribute in the maternal-fetal interface during pregnancy but also in non-pregnant uterus. However, the phenotypes and functions of γδT cells in uterus were not clear. In the current study, we found that the percentages of γδT cells were significantly higher in uterus than peripheral blood and most of γδT cells in uterus were distributed in endometrium. Further studies indicated that the majority of γδT cells in uterus were memory cells with higher expression of CD44 and CD27 but lower expression of CD62L and CCR7 compared to those in blood. In addition, we found that γδT cells in uterus were tissue resident memory γδT cells expressing CD69, expressed high levels of CCR6, GranzymeB and CD107a. Moreover, γδT cells in uterus were activated and fully expressed transcription factor RORγt. After short time of activation, γδT cells in uterus significantly expressed high levels of IL-17 but not IFN-γ, which promotes the invasion of murine trophocytes. Taken together, our study will lay the foundation for future research on uterine γδT cells in pregnancy and autoimmune disease.

MicroRNA-433 inhibits cervical cancer progression by directly targeting metadherin to regulate the AKT and ß-catenin signalling pathways.

Cervical cancer is one of the most common female malignancies worldwide. Emerging data have shown that microRNAs (miRNAs) play significant roles in various human cancers, including cervical cancer. Aberrantly expressed miRNAs in cervical cancer contribute to tumour occurrence and development as either tumour suppressors or promoters. Research suggests that miRNA-433 (miR-433) possibly plays an important role in the development of various cancer types. However, no study has explored the expression patterns, roles and underlying mechanisms of miR-433 in cervical cancer. In the present study, we demonstrated significant downregulation of miR-433 in cervical cancer tissues and cell lines. Low miR-433 expression was found to significantly correlate with patient characteristics including tumour size, International Federation of Gynecology and Obstetrics stage, lymph node and distant metastases. Functional studies showed that restoration of miR-433 inhibited cell proliferation and invasion and increased apoptosis in cervical cancer cells. Metadherin (MTDH) was also validated as a direct target gene of miR-433. MTDH mRNA expression was upregulated in cervical cancer tissues and was inversely correlated with miR-433 expression. MTDH knockdown showed similar tumour-suppressive roles as miR-433 overexpression in regards to cervical cancer cell proliferation, invasion and apoptosis. Rescue experiments revealed that MTDH overexpression markedly reversed the effects of miR-433 overexpression in regards to proliferation, invasion and apoptosis of cervical cancer cells. Further investigations revealed that miR-433 inactivated AKT and ß-catenin pathways in cervical cancer. Collectively, these findings indicate the essential roles of miR-433 in suppressing cervical cancer progression and suggest its potential as a therapeutic target for the treatment of cervical cancer.

The association of pretreatment thrombocytosis with prognosis and clinicopathological significance in cervical cancer: a systematic review and meta-analysis.

Previous studies reported inconsistent findings about the relationship between pretreatment thrombocytosis and survival in patients with cervical cancer. This study aimed to evaluate the prognostic significance of thrombocytosis in cervical cancer. We searched databases to identify relevant articles. Pooled hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Fourteen studies including 3,394 patients were eligible for the meta-analysis. Overall, an elevated platelet count was significantly associated with inferior overall survival (OS, hazard ratio [HR]: 1.66, 95% confidence interval [CI]: 1.42-1.95, P < 0.001) and recurrence-free survival (RFS, HR: 1.67, 95% CI: 1.15-2.42, P = 0.007) but not progression-free survival (PFS, HR: 1.21, 95% CI: 0.89-1.64; P = 0.235). The results were similar for low stage patients treated with surgery alone. Moreover, a pretreatment thrombocytosis status was significantly associated with higher clinical stage (odd ratio [OR]: 2.39, 95% CI: 1.68-3.38, P < 0.001), positive pelvic node status (OR: 1.58, 95% CI: 1.01- 2.45, P = 0.044) and larger tumor size (OR: 2.32, 95% CI: 1.39-3.87, P = 0.001). Pretreatment thrombocytosis is an independent prognosis predictor in cervical cancer patients. It may be used as a readily available biomarker to refine clinical outcome prediction for cervical cancer patients.

Improved therapeutic effect of folate-decorated PLGA-PEG nanoparticles for endometrial carcinoma.

Folate (FOL) mediated poly-lactide-co-glycolide-polyethylene glycol nanoparticles (FOL-PEG-PLGA NPs) bearing paclitaxel (PTX) were prepared for the effective delivery of drug to endometrial carcinoma. The average size, zeta potential and encapsulation efficiency of FOL-targeted NPs were found to be around 220 nm, -30.43 mV and 95.6%. Cellular uptake was observed. The accumulation of FOL-targeted NPs depends on dual effects of passive and active targeting. The FOL-targeted PTX NPs showed a greater cytotoxicity against HEC-1A cancer cells in vitro and in vivo, which might be induced by apoptosis. H&E staining did not showed apparent tissue damage to liver and kidney of the mice after injecting NPs intravenously. These results suggest that the novel FOL-PEG-PLGA NPs could be a potential delivery system with excellent therapeutic efficacy for targeting the drugs to cancer cells.

Down-regulation of IGF-1R expression inhibits growth and enhances chemosensitivity of endometrial carcinoma in vitro.

The type-1 insulin-like growth factor receptor (IGF-1R) is over-expressed by endometrial carcinoma, level of IGF-1R has been correlated with tumor progression, and high IGF-1R expression has been found to be an important prognostic factor. In the study, we used lentivirus-mediated shRNA targeting IGF-1R to silence its expression, then assessed the effect of down-regulation of this receptor on cell growth and chemosensitivity to cisplatin. Lentivirus-mediate shRNA was designed and transfected to the endometrial carcinoma HEC-1B cell. The IGF-1R mRNA and related protein expression, cell proliferation ability, cell apoptosis, and cell cycle change were detected. Cell proliferation inhibition rates, cell apoptosis, and level of cleaved caspase-9 were measured in various concentrations of cisplatin. The mRNA and protein level of IGF-1R, and the phosphorylated protein p-Akt, p-Erk were all suppressed after transfection. Cell proliferation was inhibited in successive five days after transfection, the highest inhibition rate was 43.28 ± 3.55% on day 5. After transfection, 24.96 ± 1.05% cells were in G(2)/M phase, and cell apoptotic rate increased from 10.66 ± 0.08 to 19.92 ± 1.34%. In various concentrations of cisplatin, transfected cells proliferation was significantly inhibited which made the IC50 value drop from 21.85 uM to 10.58 uM. Incubation with different concentrations of cisplatin for 48 h, cells apoptotic rate increased to 41.92 ± 2.5, 31.13 ± 2.76, 22.21 ± 4.63%, respectively, which was accompanied with increased cleaved caspase-9 expression. Lentivirus-mediated shRNA targeting IGF-1R has the potential to develop as a clinical treatment method in advanced and chemoresistant endometrial carcinoma.

Inhibitory effect of siRNA targeting IGF-1R on endometrial carcinoma.

The type-1 insulin-like growth factor receptor (IGF-1R) is one member of tyrosine protein kinase receptor family. It is a causal factor for tumor initiation, development and frequently overactivated in a variety of human malignancies, including endometrial carcinoma. To investigate its possibility as a therapeutic target for endometrial carcinoma, we adopted RNA interference technology to down-regulate IGF-1R expression in endometrial carcinoma and analyzed its apoptosis inductive effect and tumorigenicity in vivo. Results showed that RNAi mediated down-regulation of IGF-1R expression in endometrial carcinoma significantly induced apoptosis, reduced downstream protein phosphorylation and decreased tumorigenicity in vivo accompanied with lower proliferation index in tumor tissue, Which implied the therapeutic potential of RNAi in the treatment of endometrial carcinoma by targeting IGF-1R and IGF-1R may be a potential therapeutic target for human endometrial carcinoma.