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Jiao Song,* Huixia Ye,* Senwei Jiang, Yuebo Yang, Xiaomao Li Gynaecology Department, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuebo Yang; Xiaomao Li, Gynaecology Department, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, People’s Republic of China, Tel/Fax +86 20-85252259 ; +86 20-85253289, Email yangyueb@mail.sysu.edu.cn; Lixmao@mail.sysu.edu.cnIntroduction: Complete resection of all visible disease (R0 resection) is critical for the treatment of ovarian cancer patients, and accurate real-time guidance provided by intraoperative near-infrared (NIR) fluorescence images is beneficial for achieving complete resection of all visible disease.Methods: Based on the optical properties of IR780 and the characteristics of the acidic tumor microenvironment, we develop a new smart nanoparticle (eg, FA-IR780&PFOB-SNPs) by using the pH response nano framework (FA-PEG-PLGA-PEOz) and adjusting the amount of IR780. The FA-IR780&PFOB-SNPs was characterized for morphology, microstructure, particle size, pH-response, drug-loading efficiency and biological safety. The ultraclear fluorescence Navigation Endoscopy System was applied to evaluate the tumor recognition of FA-IR780&PFOB-SNPs in vivo.Results: The structure of FA-IR780&PFOB-SNPs was stable in a neutral environment, and the near-infrared (NIR) fluorescence was turned off, while the structure of FA-IR780&PFOB-SNPs was degraded in the acidic tumour microenvironment, and the NIR fluorescence was turned on. Through the ovarian subcutaneous xenograft tumour and ovarian intraperitoneal xenograft tumour models, it was confirmed that FA-IR780&PFOB-SNPs could clearly display the boundaries of abdominal micron-sized tumours through near-infrared fluorescence imaging, with a TBR greater than 5.Conclusion: The FA-IR780&PFOB-SNPs have the potential to provide to ovarian cancer intraoperative near infrared fluorescence navigation during precision tumour resection to achieve R0 and improve the prognosis of ovarian cancer patients.Keywords: near-infrared fluorescence imaging, IR780 iodide, epithelial ovarian cancer, tumour-activatable nanoparticles

This phase 3, randomized, open-label, active-controlled, multicenter study investigated the efficacy of triptorelin pamoate prolonged-release (PR) 3-month in Chinese patients with endometriosis by demonstrating the noninferiority of the 3-month formulation to the standard of care, triptorelin acetate PR 1-month.The trial was conducted in 24 clinical centers in China, and included 300 Chinese women (18-45 years) with endometriosis and regular menstrual cycles who required treatment with a gonadotropin-releasing hormone agonist for 6 months. One group of patients (n = 150) was treated with triptorelin pamoate PR 3-month (15 mg per injection, once every 12 weeks), and the other (n = 150) with triptorelin acetate PR 1-month (3.75 mg per injection, once every 4 weeks). The primary outcome measure was the proportion of patients with estradiol (E2) concentrations suppressed to castration levels (≤ 184 pmol/L, or 50 pg/mL) after 12 weeks of treatment.Triptorelin pamoate PR 3-month was noninferior to triptorelin acetate PR 1-month for the treatment of endometriosis: over 98% of patients in both groups were chemically castrated at week 12. Both formulations were also equally efficacious in reducing endometriosis-associated pelvic pain, and reducing serum concentrations of E2, luteinizing hormone, and follicle-stimulating hormone over time. No new safety concerns were identified.Triptorelin pamoate PR 3-month is a valid alternative to triptorelin acetate PR 1-month for the treatment of Chinese women with endometriosis, with fewer injections and a potentially lower burden of care.NCT03232281.

Historically, immunotherapies have only resulted in a partial response from patients with advanced ovarian cancer, resulting in poor clinical efficacy. A full understanding of immune-related gene expression and immunocyte infiltration in ovarian cancer would be instrumental for the improved implementation of immunotherapy. The Capping Actin Protein, Gelsolin-Like (

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.

The study was conducted to evaluate the application of human umbilical cord mesenchymal stem cells (hUCMSCs) in the treatment of tubal factor infertility (TFI) caused by Chlamydia trachomatis, and investigate their effect on fertility in animal models of chronic salpingitis. In this study, we investigated the therapy effects of the transplantation of hUCMSCs in tubal factor infertility using a chronic salpingitis murine model which induced Chlamydia trachomatis. Twenty rats were divided into two groups: control group (n = 10) and treatment group (n = 10). hUCMSCs were given to mice after exposure to C. trachomatis for 4 weeks. After treatment for 4 weeks, five mice were randomly selected from each of the two groups to sacrifice and we examined the organ morphology and pathology, inflammatory cytokines, proliferation, and apoptosis in fallopian tube (FT).The remaining five mice from each group were caged 2:1 with male mice for another 4 weeks, the numbers of pregnant mice and the mean number of pups in the different groups were enumerated and calculated. Intravaginal inoculation of hUCMSCs alleviated hydrosalpinx of the oviduct. EdU-labeled hUCMSCs are located at the interstitial site of the fallopian tube. Macrophage (F4/80) infiltration was significantly reduced in the treatment group compared with the control group and expression levels of the anti-inflammatory cytokine IL10 were increased after hUCMSCs treatment. Furthermore, mRNA and protein expression levels of PCNA and Caspase-3 were increased and decreased, respectively, in the hUCMSCs’ treatment group compared with the control. Moreover, hUCMSCs’ transplantation improved murine fertility. Anti-inflammatory and anti-apoptotic effects of hUCMSCs may play an important role in TFI. Our data suggest that hUCMSCs’ transplantation contributed to the repair of tubal injury and improvement of fertility, providing a basis for assessing the contribution of stem cells in the oviduct for direct repair of the tube to assist reproduction.

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.

Objective. To study the clinical characteristics and surgical outcomes of anti-NMDAR encephalitis and the immunopathology of associated teratomas. Methods. Twenty-one patients were enrolled in this retrospective study, who were diagnosed with anti-NMDAR encephalitis with ovarian teratoma and admitted to two tertiary hospitals in South China from July 2014 to December 2019. The clinical data of patients were reviewed. Comparisons were made between the patients with different outcomes after surgery. Immunohistochemical analyses of associated ovarian teratomas were performed. Results. The mean age of the patients was 24.33 ± 5.12 years. The peak seasons of disease onset were autumn and winter (30.61% and 32.65%). The symptoms could be divided into 8 categories, including psychiatric abnormalities, seizures, movement dysfunction, consciousness disorders, autonomic dysregulation, speech disturbance, central hypoventilation, and memory deficits. All patients developed four or more categories of symptoms within the first four weeks. Twelve patients (57.1%) had a maximum mRS of 5, and 11 patients (52.4%) were admitted to ICU. Twenty patients received surgery, and only 3 patients were diagnosed pathologically with immature ovarian teratomas, while the other 17 patients had mature ovarian teratomas. After surgery, 17 patients (85.0%) got clinical improvement. The central hypoventilation symptom and mature ovarian teratomas were associated with surgical outcome. Immunohistochemical analysis revealed that there were NMDAR-positive neural tissues in all 8 teratomas and in which 3 cases also contained large numbers of NMDAR-positive sebaceous glands and squamous epithelial tissues. Conclusion. The disease is of high prevalence in autumn and winter. The central hypoventilation symptom and mature ovarian teratomas were associated with surgical outcome. NMDAR-positive neural tissue is not the only etiological factor of encephalitis. We speculate that encephalitis development in some patients may result from NMDAR expression in sebaceous glands and squamous epithelial tissues.

BACKGROUND Uterine leiomyosarcoma (uLMS) is a rare female malignancy with poor survival rates. The objective of this study was to construct prognostic nomograms for predicting the prognosis of women with uLMS. MATERIAL AND METHODS Patients with uLMS diagnosed between 2004 and 2015 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. The essential clinical predictors were identified via univariate and multivariate Cox analysis models. Nomograms were constructed to predict the 3- and 5-year cancer-specific survival (CSS) and overall survival (OS) rates. Concordance index (C-index) and calibration plots were constructed to validate the predictive performance of nomograms. RESULTS We enrolled 1448 patients with uLMS from the SEER database, with 1016 categorized into a training set and 432 categorized into a validation set. In multivariate analysis of the training set, predictors including age, disease stage, histological grade, tumor size, and surgery type were found to be associated with OS and CSS. Race and chemotherapy were only associated with OS. Construction of nomograms based on these predictors was performed to evaluate the prognosis of uLMS patients. The C-index and calibration curves also showed the satisfactory performance of these nomograms for prediction of prognosis. CONCLUSIONS The developed nomograms are useful tools for precisely analyzing the prognosis of uLMS patients, which could help clinicians in making personalized survival predictions and assessing individualized clinical options.

Ovarian cancer (OvCa) is an intractable gynecological malignancy due to the high recurrence rate. Several molecular biomarkers have been previously screened for early identifying patients with a high recurrence risk and poor prognosis. However, all the known studies focused on a single type of RNAs, not integrating various types. This study was to construct a new multi-RNA-based model to predict the recurrence and prognosis for OvCa patients by using the messenger RNA (mRNA, including long noncoding RNA (lncRNA)) and microRNA (miRNA) sequencing data of The Cancer Genome Atlas database. After univariate Cox regression and least absolute shrinkage and selection operator analyses, a multi-RNA-based signature (2 miRNAs: hsa-miR-508, hsa-miR-506; 1 lncRNA: TM4SF1-AS1; 11 mRNAs: MAGI3, SLAMF7, GLI2, PDK1, ARID3A, PLEKHG4B, TNFAIP8L3, C1QTNF3, NDUFAF1, CH25H, TMEM129) was generated and used to establish a risk score model. The high- and low-risk patients classified by the median risk score exhibited significantly different recurrence risks (89% versus 61%, p<0.001) and survival time (the area under the receiver operating characteristic curve (AUC) = 0.901 for 5-year disease-free survival (DFS)). This risk model was independent of other clinical features and superior to pathologic staging for DFS prediction (AUC, 0.906 versus 0.524; C-index, 0.633 versus 0.510). Furthermore, some new interaction axes were revealed to explain the possible functions of these RNAs (competing endogenous RNA: TM4SF1-AS1-miR-186-STEAP2, LINC00536-miR-508-STEAP2, LINC00475-miR-506-TMEM129; coexpression: LINC00598-PLEKHG4B). In conclusion, this multi-RNA-based risk model may be clinically useful to stratify OvCa patients with different recurrence risks and survival outcomes and included RNAs may be potential therapeutic targets.

Background. This study was to compare the efficacy and safety between neoadjuvant chemotherapy followed by radical surgery (NACT+RS) and radiotherapy only (RT) or concurrent chemoradiotherapy (CCRT) for treatment of patients with stage IB2, IIA, or IIB cervical cancer. Method. The electronic databases of PubMed, Embase, and the Cochrane Library were searched to screen relevant studies from their inception to October 2018. Clinical data including overall survival (OS), disease-free survival (DFS), and adverse events were extracted. Egger’s test was used to evaluate the publication bias, and sensitivity analysis was conducted to estimate the robustness of results. Results. Finally, three randomized controlled trials (RCTs) and two case-control studies consisting of 1,275 patients with stage IB2, IIA, or IIB cervical cancer were included in the current study. Overall, pooled results showed no significant differences in OS ((hazard ratio HR=0.603, 95%CI=0.350−1.038) and DFS (HR=0.678, 95%CI=0.242−1.904) for patients treated with NACT+RS compared with RT only or CCRT, but the subgroup analysis showed that the OS and DFS were significantly longer in the NACT+RS groups than the RT or CCRT group (OS: HR=0.431, 95%CI=0.238−0.781, p=0.006; DFS: HR=0.300, 95%CI=0.187−0.482, p<0.001) for the population with median follow-up time of more than 60 months. For adverse events, the incidence of thrombocytopenia in the NACT+RS group was significantly higher than that in the RT only or CCRT group (relative risk RR=3.240, 95% CI 1.575-6.662), while the incidence of diarrhea was significantly lower than that in the RT only or CCRT group (RR=0.452, 95% CI =0.230-0.890). Conclusion. These findings suggest that the short-term therapeutic effects of the two treatments may be possibly equal for patients with stage IB2-IIB cervical cancer, but the long-term effects for improving OS and DFS may be better using NACT+RS compared with the RT only or CCRT.

(1) Background: Endometrial cancer is the most prevalent cause of gynecological malignant tumor worldwide. The prognosis of endometrial carcinoma patients with distant metastasis is poor. (2) Method: The RNA-Seq expression profile and corresponding clinical data were downloaded from the Cancer Genome Atlas database and the Gene Expression Omnibus databases. To predict patients’ overall survival, a 9 EMT-related genes prognosis risk model was built by machine learning algorithm and multivariate Cox regression. Expressions of nine genes were verified by RT-qPCR. Responses to immune checkpoint blockades therapy and drug sensitivity were separately evaluated in different group of patients with the risk model. (3) Endometrial carcinoma patients were assigned to the high- and low-risk groups according to the signature, and poorer overall survival and disease-free survival were showed in the high-risk group. This EMT-related gene signature was also significantly correlated with tumor purity and immune cell infiltration. In addition, eight chemical compounds, which may benefit the high-risk group, were screened out. (4) Conclusions: We identified a novel EMT-related gene signature for predicting the prognosis of EC patients. Our findings provide potential therapeutic targets and compounds for personalized treatment. This may facilitate decision making during endometrial carcinoma treatment.

BACKGROUND This study aimed to investigate the expression profile of the phosphatase and tensin homolog (PTEN) gene, the cadherin genes, CDH1 and CDH2, and the cell membrane glycoprotein, CD133, in the Ishikawa human endometrial adenocarcinoma cell line. MATERIAL AND METHODS The Ishikawa endometrial carcinoma cell groups included cells transfected with the pLVX-puro lentiviral expression vector (the Ishikawa-puro group) and cells transfected with the pLVX-puro-PTEN lentiviral expression vector (the Ishikawa-PTEN group). The mRNA expression of the cadherin genes, CDH1 and CDH2, was detected by quantitative reverse transcription-polymerase chain reaction (RT-qPCR). The expression levels of the transmembrane glycoprotein CD133, a cancer stem cell marker, was detected by flow cytometry. RESULTS The expression of CDH1 and CDH2 mRNA in the Ishikawa-PTEN cells was lower than in the control cells. CD133 expression was lower in the Ishikawa-PTEN cells compared with the control cells. CONCLUSIONS This in vitro study showed that in Ishikawa endometrial carcinoma cells, downregulation of PTEN was associated with the expression of the CDH1 and CDH2 genes and upregulated expression of the cell membrane glycoprotein, CD133, which are associated with epithelial-mesenchymal transition (EMT) in malignancy. These findings support the need for further studies to investigate the potential role of PTEN in invasion and metastasis in endometrial carcinoma.

Endometrial cancer (EC) is one of the most common gynecologic malignancies. To identify potential prognostic biomarkers for EC, we analyzed the relationship between the EC tumor microenvironment and gene expression profiles. Using the ESTIMATE R tool, we found that immune and stromal scores correlated with clinical data and the prognosis of EC patients. Based on the immune and stromal scores, 387 intersection differentially expressed genes were identified. Eight immune-related genes were then identified using two machine learning algorithms. Functional enrichment analysis revealed that these genes were mainly associated with T cell activation and response. Kaplan-Meier survival analysis showed that expression of TMEM150B, CACNA2D2, TRPM5, NOL4, CTSW, and SIGLEC1 significantly correlated with overall survival times of EC patients. In addition, using the TIMER algorithm, we found that expression of TMEM150B, SIGLEC1, and CTSW correlated positively with the tumor infiltration levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, and dendritic cells. These findings indicate that the composition of the tumor microenvironment affects the clinical outcomes of EC patients, and suggests that it may provide a basis for development of novel prognostic biomarkers and immunotherapies for EC patients.

OBJECTIVE To investigate the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG), measured by preoperative ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT), in risk stratification of patients with endometrial carcinoma (EC). METHODS The patients with pathological diagnosis of EC who underwent preoperative ¹⁸F-FDG PET/CT imaging were retrospectively selected for analysis of the prognostic values of PET parameters in risk classification and lymph node metastases (LNMs). Receiver-operating-characteristic analysis was used to analyze the correlation of PET parameters cutoff values with deep myometrial invasion (MI), lymphovascular space involvement and LNM for prognostic values in risk stratification. RESULTS The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for detection of LNM are 83.3%, 99.7%, 90.9%, 99.5% and 99.2%, respectively. The MTV and TLG of primary lesion of EC in the patients with LNM are notably higher than those in patients without LNM, p

Endometrial carcinoma (EC) is the fourth most common cancer in women. Some long non-coding RNAs (lncRNAs) are regarded as potential prognostic biomarkers or targets for treatment of many types of cancers. We aim to screen prognostic-related lncRNAs and build a possible lncRNA signature which can effectively predict the survival of patients with EC. We obtained lncRNA expression profiling from the TCGA database. The patients were classified into training set and verification set. By performing Univariate Cox regression model, Robust likelihood-based survival analysis, and Cox proportional hazards model, we developed a risk score with the Cox co-efficient of individual lncRNAs in the training set. The optimum cut-off point was selected by ROC analysis. Patients were effectively divided into high-risk group and low-risk group according to the risk score. The OS of the low-risk patients was significantly prolonged compared with that of the high-risk group. At last, we validated this 11-lncRNA signature in the verification set and the complete set. We identified an 11-lncRNA expression signature with high stability and feasibility, which can predict the survival of patients with EC. These findings provide new potential biomarkers to improve the accuracy of prognosis prediction of EC.

Studies have showed that diabetes is one of the high risk factors of endometrial cancer; however, no reports describe the anti- or pro-cancer effect of a new kind of anti-diabetes drug, glucagon-like peptide-1 receptor agonist exenatide (exendin-4), on endometrial cancer. To investigate whether exenatide promotes or inhibits the growth of endometrial cancer, we used the subcutaneous human endometrial cancer cell Ishikawa xenografts in nude mouse model, and divided them into control group and exenatide-treated group. The tumor growth rate in exenatide group was slower than that in control group, and the apoptosis rate of exenatide group was higher than that in control group. In vitro, exendin-4 also attenuated Ishikawa cell viability and clone formation rate, but promoted cell apoptosis. There was an increase of phosphorylated-AMPK protein, a decrease of phosphorylated-mTOR protein both in vivo and in vitro after exenatide or exendin-4 treatment. Moreover, when treated with exendin-4 plus AICAR, an AMPK activator, cell apoptosis increased with higher ratio of phosphorylayed-AMPK/AMPK, lower ratio of phosphorylated-mTOR/mTOR and higher expression of cleaved caspase-3 than those in exendin-4 alone group, and the results were the opposite when treated with exendin-4 plus compound C, an AMPK inhibitor. Our results suggest that exenatide could attenuate the growth of endometrial cancer Ishikawa xenografts in nude mice, and AMPK may be the target of the mechanism.

Autophagy has been shown to be involved in cancer cell resistance to chemotherapy. Paclitaxel, a widely used chemotherapeutic drug, was demonstrated to induce autophagy in various cancer cells. Therefore, we sought to evaluate the role of autophagy on the paclitaxel-induced cell death in endometrial carcinoma. In this study, we found that paclitaxel induced autophagy in paclitaxel-insensitive HEC-1A and JEC cells, exhibiting an increased microtubule associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, a decrease in p62/SQSTM1 abundance, the upregulation of Beclin 1 expression and punctate dots of yellow fluorescent protein (YFP)-LC3 in the cytosol. Paclitaxel-mediated cell death was further potentiated by pretreatment with autophagy inhibitor chloroquine (CQ) or shRNA against the autophagic gene beclin 1. Moreover, paclitaxel stimulated reactive oxygen species (ROS) generation, and inhibition of the ROS by antioxidant N-acetyl-cysteine (NAC) blocked paclitaxel-induced autophagy, indicating that paclitaxel-induced autophagy in endometrial carcinoma cells is mediated by ROS. These findings suggest that paclitaxel-elicited autophagic response plays a protective role that impedes the eventual death of endometrial carcinoma cell, and that autophagy-inhibitor therapy could be an effective and potent strategy to improve paclitaxel treatment outcomes in the treatment of endometrial carcinoma.

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 β-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.

article i nfo Objective: To investigate maternal and perinatal outcomes in cases of fulminant viral hepatitis in late preg- nancy (FVHILP). Methods: A multicenter retrospective study was conducted. The records of 40 patients with FVHILP were retrieved from 3 hospitals in China. To analyze the influence of mode of delivery on mater- nal and perinatal outcomes, women were allocated to the cesarean delivery group or the spontaneous vaginal delivery (SVD) group. To study the relationship between maternal outcome and perinatal outcome, patients were allocated to the maternal survival group or the non-survival group. Results: There were no significant differences between the cesarean group and the SVD group in clinical manifestations or laboratory indices before delivery, or in fatality rate (P>0.05 for all), whereas there were significant differences in newborn weight, 1-minute Apgar score, and incidence of severe perinatal asphyxia between the maternal survival group and the non-survival group (Pb0.05 for all). Conclusion: Maternal and perinatal outcomes in cases of FVHILP were not influenced by mode of delivery, whereas perinatal outcome significantly correlated with maternal outcome.

Objective: Impairment of a cell cycle checkpoint is often associated with sensitivity to chemotherapeutic drugs. Here, we studied the correlations between the checkpoint with forkhead-associated and ring finger (CHFR) gene expression and responses to paclitaxel in endometrial cancer cells. Methods: We cultured 6 endometrial cancer cell lines exposed to paclitaxel, studied the cell cytotoxicity, cell cycle distribution, CHFR expression, and methylation status before and after a demethylation agent (5-aza) treatment. CHFR was silenced by small interfering RNA (siRNA). Then we examined tumor growth and CHFR expression with paclitaxel alone or combined with 5-aza pretreatment in vivo. Results: We found that HEC-1B, RL-952, and AN3CA cells were sensitive to paclitaxel. Moreover, CHFR was weakly expressed in these cells, whereas paclitaxel-resistant cells (ISH, HEC-1A, and KLE) had high CHFR expression. Then we found that restored expression of CHFR by demethylation decreased the sensitivity to paclitaxel in AN3CA cells. In addition, cells with CHFR demethylation resulted in G2/M phase arrest that induced to paclitaxel resistance. These results were confirmed again in small interfering RNA-transfected HEC-1A cells. Furthermore, in nude mice model, restored expression of CHFR by demethylation inhibited tumor growth and decreased sensitivity to paclitaxel. Conclusion: Our data suggest that CHFR suppression regulated by hypermethylation may sensitize endometrial cancer cells to paclitaxel, and CHFR may be a promising marker to predict the response of endometrial cancer to paclitaxel.

Objective To analyze factors contributing to the prognosis of patients with fulminant viral hepatitis in pregnancy (FVHP). Methods A retrospective study was conducted among 90 patients with FVHP who were admitted between January 1994 and August 2008 in 9 Chinese hospitals with expertise in the treatment of FVHP. Results Different clinical types of FVHP presented with different fatality rates; the acute type showed the highest fatality rate and the chronic type showed the lowest fatality rate. Serum albumin (Alb), total cholesterol (Tch), total bilirubin (Tbil), prothrombin activity (PTA), creatinine (Scr), white blood cell count (WBC), the phenomenon of “bilirubin-transaminase separation”, and intractable complications correlated with the prognosis of FVHP. The fatality rate increased with decreasing Tch and PTA, increasing WBC, the appearance of “bilirubin-transaminase separation”, and complications such as hepatic encephalopathy, hepatorenal syndrome, hemorrhage, and infection. The above indices were all significantly different between survivor and non-survivor groups. Conclusion The clinical type of fulminant hepatitis, Alb, Tch, PTA, TBIL, Scr WBC, phenomenon of “bilirubin-transaminase separation”, and intractable complications are important factors associated with prognosis of patients with FVHP. Dynamic monitoring of these indicators and active treatment of complications are key to the improvement of outcomes in patients with FVHP.

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.

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.

Bao-An Chen1, Nan Jin1, Jun Wang1, Jiahua Ding1, Chong Gao1, Jian Cheng1, Guohua Xia1, Feng Gao1, Yin Zhou1, Yue Chen1, Guina Zhou1, Xiaomao Li2, Yu Zhang3, Men Tang3, Xuemei Wang31Department of Hematology, Zhongda Hospital, Clinical Medical School, Southeast University, Nanjing, People’s Republic of China; 2Department of Physics, University of Saarland, D-266041 Saarbruechen, Germany; 3National Key Laboratory of Bioelectronics (Chien-Shiung Wu Laboratory), Southeast University, Nanjing, People’s Republic of ChinaAbstract: We investigated the effect of magnetic nanoparticles of Fe3O4 (Fe3O4-MNPs) on the mice immune system. Imprinting control region (ICR) mice were assigned randomly into four groups and treated with normal saline or low, medium, or high doses of Fe3O4-MNPs, respectively. After intravenous administration of Fe3O4-MNPs for 72 hours, the peripheral T cells and the induction of primary immune responses in mice were investigated by flow cytometry and determined using enzyme-linked immunosorbent assay, respectively. The results showed that the ratio of spleen to body weight was not different between the experimental groups and control group (P > 0.05). The lymphocyte transformation rates in the suspension of spleen were higher in low-dose group than those in the control group (P < 0.05), while the proliferation of splenocytes was low in the medium and high groups when compared to the control group (P < 0.05). In peripheral blood, both the proportions of subset CD4+ and CD8+ T lymphocytes in the low-dose group were higher than those in the control group, whereas there was no difference in the number of CD4+ T cells between the medium- and low-dose groups. Interestingly, the Fe3O4-MNPs enhanced the production of interleukin-2 (IL-2), interferon-γ, and IL-10 but did not affect the production of IL-4 in peripheral blood. It is concluded that Fe3O4-MNPs could influence immune functions of normal ICR mice in a dose-dependent manner.Keywords: magnetic nanoparticle of Fe3O4, immune function, splenocyte proliferation, cytokine

Aim: This paper is a report of a study conducted to describe the experience of postpartum depression among first-time mothers in mainland China. Background: Postpartum depression affects approximately 10-20% of women across many different cultural settings; however, most theories of this condition have been developed in Western societies. Transcultural studies may enhance the understanding of the sociocultural factors associated with postpartum depression. Method: A phenomenological approach was used. Data were collected through in-depth interviews from January to June 2008. A purposive sample was recruited from a postnatal clinic at a regional hospital in mainland China. Fifteen first-time mothers who scored 13 or above on the Edinburgh Postnatal Depression Scale at 6 weeks after childbirth were interviewed. Findings: Three themes were identified: feeling drained, perceiving oneself to be a failure and dissonance. Women felt physically and emotionally exhausted. They perceived themselves to be incompetent and imperfect mothers, and thus, failures. They experienced dissonance between tradition and modernity and between expectations and reality. The practice of 'doing the month', daughter-in-law/mother-in-law relationship, gender of the baby and one-child policy contributed to their depression. Conclusion: Cultural values need to be taken into account in order better to understand the causes, prevention, and diagnosis of postpartum depression, and care provision for women with this condition. Perinatal education could aim at improving a woman's resilience by enhancing her problem-solving ability and cognitive restructuring skills. Further studies could be carried out in other parts of China or other Asian countries to determine the transferability of the findings.

To evaluated the value of hysteroscopy and dilatation and curettage (DC) in diagnosis of endometrial cancer.This retrospective analysis included clinical pathologic data of 3 676 patients with endometrial cancer from Jan. 1, 2000 to Dec. 31, 2010 in hospitals of endometrial cancer prevention projects in Guangdong Province.A total of 3 676 patients with endometrial cancer were divided into DC group (3 211 patients) and hysteroscopy group (465 patients). Compared to the results of pathological diagnosis, the accuracy rate between DC group and in hysteroscopy group were no statistically difference was 91.00% (2 922/3 211) vs 90.75% (422/465; χ² = 0.030, P = 0.862). The accuracy rate, sensitivity, specificity, positive predictive value and negative predictive value of cervical involvement between DC group and hysteroscopy group were 81.28% vs 86.45% (P0.01), 24.78% vs 23.68% (P0.05), 93.76% vs 98.71% (P0.01), 46.75% vs 78.26% (P0.01) and 84.95% vs 86.88% (P0.05), respectively. Rate of positive peritoneal cytology in DC group was 4.76% (153/3 211), and the rate was 3.23% (15/465) in hysteroscopy group, which were no statistically difference (χ² = 2.206, P = 0.137). There were no statistically difference in 5-year overall survival (91.02% vs 92.03%; χ² = 0.033, P = 0.856) and 5-year progression-free survival (89.81% vs 91.83%; χ² = 1.508, P = 0.219) between DC group and hysteroscopy group.Hysteroscopy and dilatation and curettage is an effective method in diagnosis of endometrial cancer, especially hysteroscopy is better in diagnosis of cervical involvement. Hysteroscopy don't improve risks of positive peritoneal cytology and don't affect the prognosis of patients with endometrial cancer.

Assess the efficacy and safety of etoricoxib 120 mg compared with ibuprofen 600 mg qid in the treatment of moderate to severe primary dysmenorrhea in Chinese women.This multicenter, double-blind, two-period, cross-over study randomized healthy, Chinese women ≥18 years of age to etoricoxib 120 mg qd or ibuprofen up to 2400 mg (600 mg qid) upon onset of moderate or severe primary dysmenorrhea symptoms during two menstrual cycles. The primary efficacy endpoint was Total Pain Relief score over the first 6 hours (TOPAR6). Secondary endpoints included Sum of Pain Intensity Difference scores over the first 6 hours (SPID6) and Patient's Global Evaluation (GLOBAL) of pain at 6 and 24 hours post initial dose. The primary hypothesis was that etoricoxib would be non-inferior to ibuprofen. Adverse experiences (AE) were monitored and evaluated.A total of 139 patients were included in this study. Difference in least squares (LS) mean (95% CI) TOPAR6 score for etoricoxib vs. ibuprofen was 0.89 (0.03, 1.76) (p = 0.043). LS mean (95% CI) difference for etoricoxib vs. ibuprofen SPID6, GLOBAL6, and GLOBAL24 were 0.20 (-1.16, 1.57) (p = 0.768), 0.26 (0.07, 0.45) (p = 0.007), and 0.36 (0.17, 0.54) (p 0.001), respectively. AEs were rare, with the following AEs determined to be drug-related: hypomenorrhea (two patients on etoricoxib) and allergic dermatitis (one patient on ibuprofen). Limitations of the study design include a sample size that is not adequate for evaluation of rare adverse effects, an evaluation period that was limited to 24 hours, and inconsistent frequency of active treatment doses between etoricoxib (once daily) and ibuprofen (up to four times daily).The primary objective of the study was met, demonstrating that etoricoxib 120 mg qd was non-inferior to ibuprofen 600 mg qid; further, etoricoxib was statistically superior to ibuprofen 600 mg qid according to the primary endpoint (TOPAR6) and patient global assessments of study medication. Etoricoxib and ibuprofen were generally well tolerated.

Mother-to-child transmission (MTCT) of HBV is responsible for approximately half of the HBV transmission routes and continues to be a challenging problem worldwide. Even after the development of effective vaccines and clear World Health Organization guidelines toward HBV several decades ago, 1-9% newborns of HBV-carrying mothers still acquire HBV in early life as a result of in utero infection. The prevention of MTCT is of high importance, because chronically infected individuals function as a reserve for sustained HBV transmission, and 25% of them can develop asymptomatic liver cirrhosis and hepatocellular carcinoma. In this article, we review the canonical and novel HBV infection routes/mechanisms, influencing factors, diagnostic criteria, and interruption strategies for HBV MTCT. The preventative strategy of HBV MTCT has evolved from routine postpartum HB immune globulin (HBIG) plus HB vaccine schedules to administration of HBIG or nucleoside analogs during pregnancy and minimizing the exposure of maternal body fluids to the newborn during delivery.

The activation of mammalian target of rapamycin (mTOR) signaling pathway in endometrial carcinoma cells Ishikawa and HEC-1A was investigated. The expression of mTOR was detected by confocal fluorescence microscopy in Ishikawa and HEC-1A cells. The mRNA levels of PTEN and mTOR, the downstream substrate S6K1 and 4E-BP1 protein were assayed by RT-PCR and Western blot, respectively. The expression of PTEN in Ishikawa cells was deficient, but intact in HEC-1A cells respectively (P

This study was conducted to evaluate and compare molecular and cellular effects of paclitaxel in combination with epidermoid growth factor receptor (EGFR) or/and mammalian target of rapamycin( mTOR) inhibitors with two endometrial cancer lines HEC-1A and Ishikawa. Treatment was with the EGFR inhibitor RG14620, the mTOR inhibitor rapamycin, and the conventional cytotoxic drug paclitaxel, alone or in combination. The 50% inhibitory concentration (IC50) and cell viability were determined by the MTT assay. Multiple drug effect/ combination indexes (CI) analysis was applied to assess interactions between paclitaxel and the two inhibitors. Apoptosis and cell cycling were evaluated by flow cytometry analysis. Western blotting was performed to evaluate the related protein alteration in PI3K/AKT signaling pathway. RG14620, rapamycin and paclitaxel showed obvious dose-dependent growth inhibition with time. The IC50 of paclitaxel at 24 hours decreased significantly when pretreated with low doses of RG14620 and Rapamycin alone or in combination. Moreover, combination index (CI) of paclitaxel with each inhibitor was larger than 1, indicating a synergistic effect between pairs of drugs in these two cell lines. FACS analysis showed the cell apoptosis rate increased with a synergistic effect. On Western blotting, activation of PI3K/AKT pathway was detected in both two cell lines in the control case. When paclitaxel was used as a single-agent or in combinations, the protein expression of PI3K/AKT pathway totally abated, especially in HEC-1A cells, suggesting a role in chemoresistance. The combination of three drugs induced the greatest over-expression of caspase-3. Combining targeted inhibitors with cytotoxic chemotherapy appears to be a promising strategy for the effective treatment of endometrial cancer which merits further clinical investigation.

In recent years, it has been reported that CHFR may be a useful biomarker for chemotherapeutic response to microtubule inhibitors in some tumor cells. The purpose of the present study was to test the hypothesis and to elucidate the underlying mechanism in endometrial cancer cells. First, we effectively inhibited CHFR expression at both the mRNA and protein levels using siRNA targeting the CHFR gene in Ishikawa and Hec-1a cells. We found that inhibition of CHFR expression significantly enhanced the cytotoxicity of taxol to both cell types, which was confirmed again by colony formation assays. Moreover, suppression of CHFR induced a significant increase of the mitotic index and much lower numbers of cells at the G2/M phase in both cells treated with taxol, indicating mitotic checkpoint impairment. On the other hand, the number of apoptotic cells significantly increased in Ishikawa and Hec-1a cells transfected with CHFR siRNA after treatment with taxol, which was associated with cyclin B1 nuclear localization. Our data indicate that RNA interference targeting CHFR can sensitize endometrial cancer cells to taxol and CHFR may be a promising molecular target to enhance the therapeutic effect of taxol for endometrial cancer.

Objective To perform a systematic review of prospective studies to confirm the role of breastfeeding in mother-to-child transmission (MTCT) of hepatitis B virus (HBV). Data Sources A database was constructed from MEDLINE, EMBASE, Cochrane Library, National Science Digital Library, and China Biological Medicine Database and through contact with experts in this field from January 1, 1990, to August 31, 2010. Study Selection All studies were peer reviewed and met the preset inclusion standards. Main Exposure Breastfeeding. Main Outcome Measures Data regarding HBV intrauterine infection, MTCT, maternal blood and breast milk infectiousness, infant immunoprophylaxis methods and response, and adverse events. The Mantel-Haenszel fixed-effects model was used for all analyses using odds ratios and 95% confidence intervals. Results Ten qualified studies were included. All were clinical controlled trials, involving 751 infants in the breastfeeding group and 873 infants in the nonbreastfeeding group. As indicated by infant peripheral blood hepatitis B surface antigen or HBV DNA positivity at age 6 to 12 months, the odds ratio of MTCT of HBV in the breastfeeding group compared with that in the nonbreastfeeding group was 0.86 (95% confidence interval, 0.51-1.45) (from 8 clinical controlled trials, P = .56; I 2 = 0%, P = .99). As indicated by infant peripheral blood hepatitis B surface antibody positivity at age 6 to 12 months, the odds ratio of development of hepatitis B surface antibodies in the breastfeeding group compared with that in the nonbreastfeeding group was 0.98 (95% confidence interval, 0.69-1.40) (from 8 clinical controlled trials, P = .93; I 2 = 0%, P = .99). No adverse events or complications during breastfeeding were observed. Conclusion Breastfeeding after proper immunoprophylaxis did not contribute to MTCT transmission of HBV.

Jun Wang1, Baoan Chen1, Nan Jin1, Guohua Xia2, Yue Chen1, Ying Zhou1, Xiaohui Cai1,2, Jiahua Ding1, Xiaomao Li3, Xuemei Wang41Department of Hematology, Zhongda Hospital, 2Department of Medical Laboratory, Medical School, Southeast University, Nanjing, People's Republic of China; 3Department of Physics, University of Saarland, Saarbruecken, Germany; 4National Key Laboratory of Bioelectronics (Chien-Shiung Wu Laboratory), Southeast University, Nanjing, People’s Republic of ChinaAbstract: The aim of this article is to study the changes inhibited T lymphocytes and cytokines related to the cellular immunity in ICR (imprinting control region) mice fed with Fe3O4 magnetic nanoparticles (Fe3O4-MNPs). The Fe3O4-MNPs were synthesized, and their characteristics such as particle size, zeta potential, and X-ray diffraction patterns were measured and determined. All ICR mice were sacrificed after being exposed to 0, 300, 600, and 1200 mg/kg of Fe3O4-MNPs by single gastric administration for 14 days. Splenocytes proliferation was indicated with stimulate index by MTT assay; release of cytokines in the serum of ICR mice was detected by enzyme-linked immunosorbent assay, and the phenotypic analyses of T-lymphocyte subsets were performed using flow cytometry. Our results indicated that there were no significant differences in splenocyte proliferation and release of cytokines between exposed and control groups. Furthermore, there was no significant difference in the proportions of T-lymphocyte subsets in the low-dose Fe3O4-MNPs group when compared to the control group, but the proportions of CD3+CD4+ and CD3+CD8+ T-lymphocyte subsets both in the medium- and high-dose Fe3O4-MNPs groups were higher than those in the control group. It is concluded that a high dose of Fe3O4-MNPs, to some extent, could influence in vivo immune function of normal ICR mice.Keywords: Fe3O4, magnetic nanoparticles, splenocyte proliferation, release of cytokines, T-lymphocyte subsets, ICR mice

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.

Objective The purpose of this study was to investigate changes of the antigen-presenting function of tumor infiltrating dendritic cells (TIDCs) in human endometrioid adenocarcinoma. Study design The TIDCs from 45 cases of endometrioid adenocarcinoma were compared with 20 cases of normal human endometrial tissue, using transmission electron microscopic examination, and the expression of CD80, CD86, and CD40 was analyzed by flow cytometry. Results In comparison with the control group, the ultrastructure of TIDCs in human endometrioid adenocarcinoma showed the following differences: numerous TIDCs were small in volume and round in shape but some were oval and multi-angular. The cytoplasmic processes were obviously decreased in number and stubbed. Round primary lysosomes with high electron-dense granules, and secondary lysosomes with high or low electron-dense granules were seen frequently in the cytoplasm. TIDCs contained much rough endoplasmic reticulum (RER). Vacuoles with flocculent electron-dense granules were rare. High electron-dense contents in the granules were near one side and the other side was bright. The nucleus became markedly small in volume, nephroid or hoofed in shape. The nucleus had little euchromatin and lots of heterochromatin under the nuclear membrane. The levels of expression of CD80, CD86 and CD40 on TIDCs were low or even nonexistent. The expression levels of CD80, CD86 and CD40 on DCs in human normal endometrium were significantly higher than those on TIDCs in endometrioid adenocarcinoma. Conclusion It is suggested that morphological differences and low expression of co-stimulatory molecules on TIDCs in endometrioid adenocarcinoma reflected the functional changes of the TIDCs in uptake, processing and presenting antigen, which may lead to the occurrence of tumor immune escape.

BACKGROUND AND OBJECTIVE Resistance to cisplatin (DDP) remains a major obstacle for the successful treatment of ovarian cancer. This study was to determine the reversal effect of Fe3O4-magnetic nanoparticles (MNPs) on DDP-resistance of ovarian carcinoma cell line SKOV3/DDP, and to explore its correlation with apoptosis-associated genes. METHODS SKOV3/DDP cells were divided into the DDP group, the Fe3O4-MNPs group, the combination (DDP plus Fe3O4-MNPs) group, and the control group. Cell proliferation was determined by MTT assay. Cell apoptosis was analyzed by flow cytometry (FCM). Intracellular DDP level was detected by inductively coupled plasma atomic emission spectrometry (ICP-AES). The expressions of apoptosis-associated genes, bcl-2, and survivin were detected by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS Fe3O4-MNPs reversed DDP-resistance of SKOV3/DDP cells by 2.259 folds. The cell apotosis rate and the intracellular DDP level were significantly higher in the combination group than in the DDP group (P

Bao-an Chen1, Bin-bin Lai1, Jian Cheng1, Guo-hua Xia1, Feng Gao1, Wen-lin Xu2, Jia-hua Ding1, Chong Gao1, Xin-chen Sun3, Cui-rong Xu1, Wen-ji Chen1, Ning-na Chen1, Li-jie Liu4, Xiao-mao Li5, Xue-mei Wang61Department of Hematology, 3Department of Oncology, the Affiliated Zhongda Hospital, Clinical Medical School, Southeast University, Nanjing, People’s Republic of China; 2Department of Hematology, the Affiliated People’s Hospital, Jiangsu University, Zhenjiang, People’s Republic of China; 4Institution of Physiology, 6State Key Lab of Bioelectronics (Chien-shiung Wu Laboratory), Southeast University, Nanjing, People’s Republic of China; 5Department of Physics, University of Saarland, Saarbruechen, GermanyAbstract: Multidrug resistance (MDR) is a major obstacle to cancer chemotherapy. We evaluated the effect of daunorubicin (DNR)-loaded magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) on K562-n/VCR cells in vivo. K562-n and its MDR counterpart K562-n/VCR cell were inoculated into nude mice subcutaneously. The mice were randomly divided into four groups: group A received normal saline, group B received DNR, group C received MNPs-Fe3O4, and group D received DNR-loaded MNPs-Fe3O4. For K562-n/VCR tumor, the weight was markedly lower in group D than that in groups A, B, and C. The transcriptions of Mdr-1 and Bcl-2 gene were significantly lower in group D than those in groups A, B, and C. The expression of Bcl-2 was lower in group D than those in groups A, B, and C, but there was no difference in the expression of P-glycoprotein. The transcriptions and expressions of Bax and caspase-3 in group D were increased significantly when compared with groups A, B, and C. In conclusion, DNR-loaded MNPs-Fe3O4 can overcome MDR in vivo.Keywords: multidrug-resistance reversal, leukemia, magnetic nanoparticles of Fe3O4, in vivo

Prior studies in different tumor models have shown that, under conditions of PTEN deficiency, the mitogen-activated protein kinase (MAPK) signaling pathway appear to play a major role in the tumor cell’s proliferative and survival pathway, and that pharmacological inhibition of this pathway results in tumor growth inhibition. This study aimed to explore whether sensitivity to p38MAPK inhibitors are specifically due to status of PTEN in endometrial cancer cells. We developed a series of endometrial cancer cell lines with different PTEN expressions (Ishikawa, RL-952, HEC-1B and HEC-1A cells) or introduced the wild-type PTEN and PTEN-siRNA in four endometrial cancer cells to change its PTEN expression with a p38MAPK inhibitor, SB203580 for 2 days. Cell proliferation, cell apoptosis, and cell cycle distribution were studied, and activation of AKT, ATF-2, and p38MAPK was examined by Western blotting. In cultivated PTEN-deficient endometrial cancer cells, in addition to an activation of AKT, a phosphorylation of p38MAPK and ATF-2 was evident, while PTEN-positive endometrial cancer cells lacked AKT activation but revealed a reduced expression of p-p38MAPK and p-ATF-2. These PTEN-deficient endometrial cancer cells demonstrated an increased sensitivity to the anti-proliferative effects induced by SB203580 compared with the PTEN-positive endometrial cancer cells, which corresponded to alterations in cell cycle response and cell apoptosis. PTEN-deficient endometrial cancer cells exhibit higher p38MAPK activity, and genetic studies demonstrate that p38MAPK functions dependently of AKT. Furthermore, PTEN loss sensitizes cells to p38MAPK inhibition in endometrial carcinoma cells. These findings indicate that inhibitors of p38MAPK have the potential to be effective in the treatment of endometrial cancer patients with PTEN-deficient tumors and should be evaluated in this setting.

Zhi Jiang1,6, Bao-An Chen1,6, Guo-Hua Xia1, Qiang Wu2, Yu Zhang1, Tie-Yan Hong1, Wei Zhang1, Jian Cheng1, Feng Gao1, Li-Jie Liu3, Xiao-Mao Li4, Xue-Mei Wang51Department of Hematology, the Affiliated Zhongda Hospital of Southeast University, Nanjing, China; 2The Jiangsu Province Cancer Hospital, Nanjing, China; 3Institutions of Physiology, Southeast University, Nanjing, China; 4Department of Physics, University of Saarland, Saarbruechen, Germany; 5National Key Lab of Bioelectronics (Chien-Shiung Wu Laboratory), Southeast University, Nanjing, China; 6These authors have contributed equally to this workAbstract: To explore whether the magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) loaded with cisplatin can reverse the diaminedichloro platinum (DDP) resistance to multidrug resistance of ovarian carcinoma cells and to investigate its mechanisms. The SKOV3/DDP cells were divided into DDP treatment (DDP group), MNPs-Fe3O4 treatment (MNPs-Fe3O4 group), DDP + MNPs-Fe3O4 treatment (DDP + MNPs-Fe3O4 group), and control group. After incubation with those conjugates for 48 h, the cytotoxic effects were measured by MTT assay. Apoptosis and the intracellular DDP concentration were investigated by flow cytometry and inductively coupled plasma atomic emission spectroscopy, respectively. The expression of apoptosis associated gene Bcl-2 mRNA was detected by reverse transcription polymerase chain reaction and the expressions of MDR1, lung resistance-related protein (LRP), and P-glycoprotein (P-gp) genes were studied by Western blot. Our results indicated that the 50% inhibition concentration (IC50) of the MNPs-Fe3O4 loaded with DDP was 17.4 µmol/ l, while the IC50 was 39.31 µmol/l in DDP groups (p< 0.05); Apoptosis rates of SKOV3/DDP cells increased more than those of DDP groups. Accumulation of intracellular cisplatin in DDP + MNPs-Fe3O4 groups was higher than those in DDP groups (p< 0.05). Moreover, the expression of Bcl-2 mRNA and the protein expressions of MDR1, LRP, and P-gp were decreased when compared with those of DDP groups, respectively. Our results suggest that MNPs-Fe3O4 can reverse the DDP resistance to the ovarian carcinoma cell. The effects may be associated with over-expression of MDR1, LRP, P-gp, and Bcl-2, which can increase the intracellular platinum accumulation and induce the cell apoptosis.Keywords: magnetic nanoparticles of Fe3O4 , multidrug resistance reversal, SKOV3/DDP, MDR1, LRP, P-gp, Bcl-2

SummaryObjectivesTo evaluate the efficacy and safety of using hepatitis B immunoglobulin (HBIG) during pregnancy to prevent hepatitis B virus (HBV) mother-to-child transmission (MTCT).MethodsWe systematically reviewed the effect of HBIG in decreasing HBV MTCT from randomized controlled trials (RCTs) carried out between January 1990 and December 2008, in English and Chinese languages. Multiple databases were searched, and experts in this field were contacted. The methodological quality of each RCT was assessed by the Jadad score. We abstracted data on HBV intrauterine infection, MTCT, treatment methods, newborn immune prophylaxis methods, and adverse effects. A Mantel–Haenszel random-effects model was employed for all analyses using odds ratios (OR) and 95% confidence intervals (95% CI).ResultsFive thousand nine hundred newborns of asymptomatic hepatitis B surface antigen (HBsAg)-seropositive mothers from 37 qualified RCTs were included. Compared with the control group, newborns in the HBIG group had a lower intrauterine infection rate (indicated by HBsAg as OR 0.22, 95% CI [0.17, 0.29], from 32 RCTs; indicated by HBV DNA as OR 0.15, 95% CI [0.07, 0.30], from 13 RCTs; p

AIM: To investigate the clinical characteristics of fulminant hepatitis in pregnancy. METHODS: We compared and analyzed the etiology, clinical characteristics, and laboratory examinations of 25 cases of fulminant hepatitis in pregnancy and 30 cases of fulminant hepatitis not in pregnancy. RESULTS: HBV infection and chronic fulminant hepatitis were most common both in the pregnant and in the non-pregnant groups. Jaundice, digestive tract symptoms, increase of bilirubin and thrombinogen activity were the main manifestations. The incidence of hepatic encephalopathy (HE) and hepato-renal syndrome (HRS) was significantly different between the two groups. The incidence of preterm labor, dead fetus and neonatal asphyxia was high. CONCLUSION: Fulminant hepatitis is likely to occur in late pregnancy with more severe complications, which significantly influences maternity, perinatal fetus, and newborn.

Results on the effect of ritodrine in the treatment of preterm labour are different all over the world. Therefore, a concrete conclusion cannot be drawn from a single randomized control trial (RCT). In this study, we selected a large number of RCTs worldwide on the treatment of preterm labour comparing ritodrine and placebo or magnesium sulfate and by applying meta-analysis, evaluated the effect of ritodrine in the treatment of preterm labour.We searched and identified 20 RCTs about ritodrine versus placebo, and ritodrine versus magnesium sulphate in the main medical data resources (MEDLINE, PubMed, CBMdisc, Cochrane Library and EMBASE) from January 1970 to December 2001 published in English and Chinese literature. We abstracted data about delay of gestation, gestational age at delivery, birth weight, severe neonatal respiratory system diseases, perinatal deaths, and administration to contraction-ceased interval, etc.The odds ratio (OR) of 1 day (d) delay in 10 RCTs on ritodrine in preterm labour versus placebo was 2.95 (95%CI 2.15, 4.04), and OR of 2d delay was 1.91 (95%CI 1.49, 2.45), both differences were statistically significant. There were no significant difference on the OR of birthor =37 wk, birth weightor =2500 g, severe respiratory morbidity and perinatal mortality. The OR of 2d delay of four RCTs from abroad on ritodrine versus magnesium sulphate was 1.56 (95%CI 0.62, 3.94), and OR of 7d delay was 1.45 (95%CI 0.80, 2.62), both without significant difference. But the combined estimated rate difference (CERD) of side effects interruption rate was 12 per cent with significant difference. There were six Chinese RCTs on ritodrine and magnesium sulphate. The OR of 1d delay was 3.95 (95%CI 1.98, 7.88), and OR of neonatal death was 0.45 (95%CI 0.22, 0.93), both with significant difference. The average administration to contractionceased interval were 2.5 and 6.3 h, respectively, with CERD being -4.2 h.In treating preterm labour, ritodrine can significantly prolong a short interval more quickly but with relatively more side effects than magnesium sulphate. Stratified RCTs for different gestational ages and different labour stages should be designed for further study.

AIM: To evaluate the efficacy of hepatitis B immunoglobulin (HBIG) in interrupting hepatitis B virus (HBV) intrauterine infection during late pregnancy. METHODS: We allocated 112 HBsAg positive pregnant women into 2 groups randomly. Fifty seven cases in the HBIG group received 200 IU (unit) HBIG intramuscularly every 4 wk from the 28 wk of gestation to the time of delivery, while 55 cases in the control group received no special treatment. HBsAg, HBeAg, HBcAb, HBeAb, HBsAb and HBV DNA levels were tested in the peripheral blood specimens from all of the mothers at 28 wk of gestation, just before delivery, and in blood from their newborns within 24 h before administration of immune prophylaxis. RESULTS: The intrauterine infection rate in HBIG group and control group were 10.5% and 27.3%, respectively, with significant difference (P < 0.05). It showed ascendant trend as HBV DNA levels in the peripheral blood increased before delivery. CONCLUSION: HBIG is potent to cut down HBV intrauterine infection rate significantly when administered to pregnant women regularly during late pregnancy. The possibility of HBV intrauterine infection increases if maternal blood HBV DNA ≥ 108 copies/mL.

To report the experience in successfully treating pregnant women with severe hepatitis.Comprehensive medical treatments were performed under strict monitoring.Pregnant woman with severe hepatitis was successfully rescued.Vital measures taken in the treatment of pregnant women with severe hepatitis include termination of the pregnancy at a proper time and control of various complications, such as disseminated intravascular coagulation (DIC), hepatorenal syndrome, hepatic encephalopathy and infection.

To investigate the effect of hepatitis B virus (HBV) specific immunoglobin (HBIG) and lamivudine on HBV intrauterine transmission in HBsAg positive pregnant women.Each subject in the HBIG group (56 cases) was given 200 IU HBIG intramuscularly (im.) every 4 weeks from 28-week (wk) of gestation, while each subject in the lamivudine group (43 cases) received 100 mg lamivudine orally (po.) every day from 28-wk of gestation until the 30(th) day after labor. Subjects in the control group (52 cases) received no specific treatment. Blood specimens were tested for HBsAg, HBeAg, and HBV-DNA in all maternities at 28-wk of gestation, before delivery, and in their newborns 24 hours before the administration of immune prophylaxis.Reductions of HBV DNA in both treatments were significant (P0.05). The rate of neonatal intrauterine HBV infection was significantly lower in HBIG group (16.1 %) and lamivudine group (16.3 %) compared with control group (32.7 %) (P0.05), but there was no significant difference between HBIG group and lamivudine group (P0.05). No side effects were found in all the pregnant women or their newborns.The risk of HBV intrauterine infection can be effectively reduced by administration of HBIG or Lamivudine in the 3(rd) trimester of HBsAg positive pregnant women.

Pancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100beta. pSC-autoreactive T- and B-cell responses arise in 3- to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable beta-cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) -positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100beta prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8+ T-cell receptor(gp) double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and beta-cell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8+/8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes.