A first-in-class POLRMT specific inhibitor IMT1 suppresses endometrial carcinoma cell growth.

Exploring novel molecularly-targeted therapies for endometrial carcinoma is important. The current study explored the potential anti-endometrial carcinoma activity by a first-in-class POLRMT (RNA polymerase mitochondrial) inhibitor IMT1. In patient-derived primary human endometrial carcinoma cells and established lines, treatment with IMT1 potently inhibited cell viability, proliferation, cell-cycle progression and motility, while inducing robust caspase-apoptosis activation. Treatment with the PLORMT inhibitor impaired mitochondrial functions, leading to mtDNA (mitochondrial DNA) transcription inhibition, mitochondrial membrane potential decline, reactive oxygen species formation, oxidative stress and ATP loss in the endometrial carcinoma cells. Similarly, POLRMT depletion, through shRNA-induced silencing or CRISPR/Cas9-caused knockout (KO), inhibited primary endometrial carcinoma cell proliferation and motility, and induced mitochondrial dysfunction and apoptosis. Importantly, IMT1 failed to induce further cytotoxicity in POLRMT-KO endometrial carcinoma cells. Contrarily, ectopic overexpression of POLRMT further augmented proliferation and motility of primary endometrial carcinoma cells. In vivo, oral administration of a single dose of IMT1 substantially inhibited endometrial carcinoma xenograft growth in the nude mice. mtDNA transcription inhibition, oxidative stress, ATP loss and apoptosis were detected in IMT1-treated endometrial carcinoma xenograft tissues. Together, targeting PLORMT by IMT1 inhibited endometrial carcinoma cell growth in vitro and in vivo.

Retrospective validation of ultrasound characteristics at 19-24 weeks as predictive tools for selective intrauterine growth restriction in monochorionic diamniotic twin pregnancies: a diagnostic study.

Background: Seeking an optimal time point for ultrasound examination is important for the diagnosis of late selective intrauterine growth restriction (sIUGR) at birth in monochorionic diamniotic (MCDA) twin pregnancies. We aimed to assess the role of ultrasound characteristics at 19-24 weeks as predictive tools for late sIUGR at birth in MCDA twin pregnancies. Methods: We retrospectively recruited 32 sIUGR and 56 normal patients with MCDA twin pregnancies. Ultrasound indexes of these included subjects at 19-24 weeks, including the middle cerebral artery peak systolic velocity (MCA-PSV), umbilical artery pulsatility index (UA-PI), middle cerebral artery pulsatility index (MCA-PI), and cerebroplacental ratio (CPR) were assessed. Receiver operating characteristic (ROC) curves were used to ascertain the predictive value of ultrasound characteristics discrepancy for such complications, and the relationship between the ultrasound characteristics and sIUGR was assessed by a logistic regression analysis. Results: Differences were found in the MCA-PI, UA-PI, and CPR discordances between the normal MCDA and sIUGR subjects. CPR discordance was the most effective characteristic for predicting sIUGR [area under the ROC curve (AUC) =0.883; 95% CI: 0.795-0.948], followed by UA-PI discordance (AUC =0.772; 95% CI: 0.685-0.829), and MCA-PI discordance (AUC =0.746; 95% CI: 0.681-0.823), respectively. Additionally, the optimal cutoff value of CPR discordance was 21.65, and the corresponding sensitivity and specificity were 0.750 and 0.929, respectively. The correlation analysis revealed that gestational age (GA) at ultrasound scan but not at delivery was significantly correlated with the MCA-PSV (r=0.55, P<0.01), UA-PI (r=0.55, P<0.01), MCA-PI (r=0.49, P<0.01), and CPR (r=0.55, P<0.01) in sIUGR, while GA at both ultrasound scan and birth was significantly correlated with MCA-PSV (r=0.65, P<0.01), UA-PI (r=0.49, P<0.01), MCA-PI (r=0.48, P<0.01), and CPR (r=0.63, P<0.01) in normal MCDA. Conclusions: Increased MCA-PI, UA-PI, and CPR discordances were found in fetuses with sIUGR. CPR discordance could serve as a predictive index for sIUGR. An early ultrasound examination may be more accurate than biochemical modality for sIUGR prediction.

Hyperthermia enhances the efficacy of chemotherapeutic drugs in heat-sensitive cells through interfering with DNA damage repair.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be clinically effective, but the mechanisms by which hyperthermia enhances the sensitivity of cells to chemotherapeutic drugs has not yet been elucidated. Methods: To identify the key molecules involved in thermochemotherapy, this study used mass spectrometry (MS)-based quantitative proteomics technology to analyze the effects of thermochemotherapy on the heat-sensitive ovarian cancer cell line A2780. We divided the A2780 cell line into four groups, one group served as blank control, and the other three groups were stimulated by oxaliplatin, stimulated by hyperthermia at 42 ℃, and stimulated by hyperthermia combined with oxaliplatin. Samples were then collected for tandem mass tag (TMT) labeling, high-performance liquid chromatography fractionation, and MS-based quantitative proteomics for analysis The differentially expressed proteins were quantitatively compared and identified, and Gene Ontology (GO) assessment and cluster analyses were performed. Finally, the above MS results were verified again by Western blotting experiments. Results: A total of 349 differentially expressed proteins were identified between cells treated with chemotherapy alone (group B) and cells treated with a combination of chemotherapy and hyperthermia (group D). There were 145 upregulated proteins and 204 downregulated proteins. Among the top 20 proteins with significantly different expression levels, nearly two-thirds were involved in DNA damage repair. These proteins were subsequently verified by Western blot analysis. Indeed, consistent with MS data, the expression of the RBL1 protein was significantly upregulated in cells treated with thermochemotherapy (group D) compared to cells treated with chemotherapy alone (group B). Conclusions: In heat-sensitive ovarian cancer cells, the damage repair of tumor cell DNA is disturbed by hyperthermia, making it unable to fully repair when damaged by chemotherapeutic drugs. As a result, hyperthermia enhances the efficacy of chemotherapeutic drugs. RBL1, as a tumor suppressor gene, may be associated with the repair of DNA damage, and thus it may be a key target for hyperthermia to enhance the sensitivity of thermosensitive cells to chemotherapeutic drugs.

Retrospective validation of 11-13 weeks' gestation ultrasound characteristics as predictive tools for twin-twin transfusion syndrome and selective intrauterine growth restriction in monochorionic diamniotic twin pregnancies.

BACKGROUND: Twin to twin transfusion syndrome (TTTS) is a serious syndrome that can affect twin pregnancies involving a single placenta, impacts some of twin gestations with monochorionic diamniotic (MCDA) placentas. We validated the ultrasound characteristics of 11-13 weeks' gestation to predict TTTS and selective intrauterine growth restriction (sIUGR) in MCDA pregnancies. METHODS: We retrospectively included all of the MCDA twin pregnancies with ultrasound characteristics, including the crown-rump length (CRL), ductus venosus pulsatility index for veins (DV PIV), and nuchal translucency (NT) thickness, at 11-13 weeks' gestation, followed by mean difference and discordance comparison. Receiver operating characteristic (ROC) curves were constructed for the comparison of values of these predictive markers for identification of MCDA pregnancies with high-risk of adverse outcomes. RESULTS: A total of 98 MCDA pregnancies were included in this study. Among the 98, 34 (34.7%) developed sIUGR, whereas 10 (10.2%) expressed TTTS. Significant differences in NT discordance were found among the normal, sIUGR, and TTTS groups; moreover, a significant difference was found between pregnancies with normal outcomes and sIUGR (P<0.001), normal and TTTS (P<0.001), and sIUGR and TTTS (P<0.001). Difference in NT was determined to be the best predictive marker for sIUGR [area under the curve (AUC) =0.769; 95% confidence interval (CI): 0.591 to 0.992], and NT discordance was considered the best predictive marker for TTTS (AUC =0.802; 95% CI: 0.485 to 0.936). CONCLUSIONS: Significant differences in NT discordance were found between the normal, sIUGR, and TTTS groups, while NT difference and NT discordance were identified as predictive markers for sIUGR and TTTS, respectively.

miR­302c­3p and miR­520a­3p suppress the proliferation of cervical carcinoma cells by targeting CXCL8.

The aim of the present study was to identify the differentially expressed microRNAs (miRs) in cervical carcinoma (CC) tissues and cells and to explore the function of miR­302c­3p and miR­520a­3p in the proliferation of CC cells. Potential dysregulated miRNAs in CC tissues and tumour­adjacent tissues were detected. Reverse transcription­quantitative PCR (RT­qPCR) was performed to determine the expression of miR­302c­3p, miR­520a­3p and CXCL8 in CC tissues and cell lines. The target genes of the miRNAs were predicted using miRTarBase and verified by luciferase reporter assays. RT­qPCR and western blotting were performed to measure the expression of C­X­C motif ligand (CXCL)8 after transfection. The effect on proliferation was verified by Cell Counting Kit assay and ethynyl­2­deoxyuridine staining. Flow cytometry was utilised to assess the effect on apoptosis. In the present study, miR­302c­3p and miR­520a­3p were markedly downregulated in CC cell lines compared to the normal cervical cell line H8. Functionally, overexpression of miR­302c­3p and/or miR­520a­3p inhibited proliferation and promoted the apoptosis of CC cell lines in vitro, while the knockdown of miR­302c­3p and/or miR­520a­3p had the opposite effect. Furthermore, miR­302c­3p and miR­520a­3p could both bind to CXCL8. Inhibition of CXCL8 in combination with miR­302c­3p and/or miR­520a­3p overexpression exerted proliferation­suppressive and apoptosis­stimulating effects on CC cells, whereas restoring CXCL8 attenuated the miR­302c­3p­ and miR­520a­3p­induced anti­proliferative and pro­apoptotic effects. miR­302c­3p and miR­520a­3p suppress the proliferation of CC cells by downregulating the expression of CXCL8, which may provide a novel target for the treatment of CC.

CircATRNL1 activates Smad4 signaling to inhibit angiogenesis and ovarian cancer metastasis via miR-378.

Ovarian cancer is one of the most frequent carcinomas in females, and the occurrence rate is still rising despite many advances made. The pathogenesis of ovarian cancer remains greatly unclear. Here, we investigated the mechanisms of ovarian cancer, with the focus on circATRNL1. Human ovarian cancer tissues and cell lines were used to examine levels of circATRNL1, miR-378, Smad4, AKT, and other proliferation-related and migration-related proteins. Cellular assays were used to determine cancer cell proliferation, invasion, migration, apoptosis, and angiogenesis. We validated the interactions of circATRNL1/miR-378 and miR-378/Smad4, and a mouse tumor xenograft model was employed to assess the effect of circATRNL1 on tumor growth and metastasis in vivo. We found that circATRNL1 was decreased while miR-378 was increased in human ovarian cancer tissues and cells. circATRNL1 bound to miR-378 while miR-378 directly targeted Smad4. Overexpression of circATRNL1 or knockdown of miR-378 suppressed angiogenesis and ovarian cancer cell proliferation, invasion, and migration via decreasing proliferation- and migration-related proteins via miR-378 or Smad4, respectively. Overexpression of circATRNL1 restrained ovarian cancer growth and abdominal metastasis in vivo. Our findings indicate that circATRNL1 acts as a miR-378 sponge to active Smad4 signaling and suppresses angiogenesis and ovarian cancer metastasis.

Prognostic value of preoperative serum bilirubin levels in ovarian cancer.

Bilirubin is a promising prognostic factor for non-liver disease-related deaths in various cancers. We investigated the association between preoperative serum bilirubin levels and oncological outcomes in patients with ovarian cancer. We retrospectively analyzed the clinical data of 282 patients with epithelial ovarian carcinoma (EOC), and grouped them according to optimal threshold values of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBL) measured by receiver operating characteristic curve analysis. Univariate and multivariate Cox proportional hazards regression analyses were used to evaluate various parameters that might affect overall survival (OS) and progression-free survival (PFS) in patients with EOC. The optimal cutoff values for TBIL, DBIL, and IBIL levels were 9.65 µmol/L, 2.95 µmol/L, and 6.75 µmol/L, respectively. Increased TBIL, DBIL, and IBIL levels correlated with the serum carbohydrate antigen (CA)-125 levels, International Federation of Gynecology and Obstetrics stage, and pathological differentiation (all P<0.05). Univariate analysis revealed longer OS and PFS in patients with high TBIL (≥9.65 µmol/L) and IBIL (≥6.75 µmol/L) levels (P<0.05). Multivariate analysis showed that patients with high IBIL levels (≥6.75 µmol/L) had significantly longer OS and PFS than those with low IBIL levels (<6.75 µmol/L) [hazard ratio (HR) = 0.333, 95% confidence interval (CI): 0.123~0.904, P<0.05; HR = 1.814, 95% CI: 1.169~2.816, P<0.05]. Therefore, IBIL is a potential independent prognostic factor for OS and PFS in patients with EOC. The higher the IBL level, the better the prognosis of patients with EOC.

microRNA-1203 targets and silences cyclophilin D to protect human endometrial cells from oxygen and glucose deprivation-re-oxygenation.

Oxygen and glucose deprivation (OGD)-re-oxygenation (OGDR) stimulation to the human endometrial cells mimics ischemia-reperfusion injury. Cyclophilin D (CypD)-dependent programmed necrosis pathway mediates OGDR-induced cytotoxicity to human endometrial cells. We here identified a novel CypD-targeting miRNA, microRNA-1203 (miR-1203). In T-HESC and primary human endometrial cells, ectopic overexpression of miR-1203, using a lentiviral construct, potently downregulated the CypD 3'-untranslated region (3'-UTR) activity and its expression. Both were however upregulated in endometrial cells with forced miR-1203 inhibition by its anti-sense sequence. Functional studies demonstrated that ectopic miR-1203 overexpression in endometrial cells alleviated OGDR-induced programmed necrosis, inhibiting mitochondrial CypD-p53-adenine nucleotide translocator 1 association, mitochondrial depolarization, reactive oxygen species production, and medium lactate dehydrogenase release. Contrarily OGDR-induced programmed necrosis and cytotoxicity were intensified with forced miR-1203 inhibition in endometrial cells. Significantly, ectopic miR-1203 overexpression or inhibition failed to change OGDR-induced cytotoxicity in CypD-knockout T-HESC cells. Furthermore, ectopic miR-1203 overexpression was unable to protect T-HESC endometrial cells from OGDR when CypD was restored by an UTR-depleted CypD construct. Collectively, these results show that miR-1203 targets and silences CypD to protect human endometrial cells from OGDR.

Expression of the lncRNA ZFAS1 in cervical cancer and its correlation with prognosis and chemosensitivity.

OBJECTIVE: To investigate the expression of the lncRNA ZFAS1 in cervical cancer and its relationship with patient prognosis and cervical cancer cell chemosensitivity. METHODS: The expression of ZFAS1 in cervical cancer tissues and cell lines was detected by qRT-PCR. The cervical cancer CaSki and the HeLa cell lines were transfected to be divided into Blank, siR-Control, and siR-ZFAS1 groups. MTT, wound-healing, and transwell assays were used to evaluate cell biological function. Cisplatin with different concentrations was used to treat cells in different transfection groups, and MTT assays were used to detect the cell growth inhibition rate and the half-inhibitory concentration (IC50) of cisplatin was measured. Cell apoptosis was determined by flow cytometry. A xenograft mouse model was used to investigate the effects of siR-ZFAS1 on the chemosensitivity to cisplatin. RESULTS: ZFAS1 was significantly upregulated in cervical cancer tissues and cell lines, and increased ZFAS1 levels led to poor prognoses in patients. In addition, cells in the siR-ZFAS1 group showed remarkably reduced ZFAS1 expression as well as cell proliferation, invasion and migration. After being treated with cisplatin at different concentrations, cells in the siR-ZFAS1 group had dramatically increased cell growth inhibition and apoptosis but lower cisplatin IC50s. In addition, siR-ZFAS1 reduced the volumes and weights of tumors in nude mice treated with cisplatin and enhanced the chemosensitivity of cervical cancer cells to cisplatin. CONCLUSION: The lncRNA ZFAS1 was upregulated in cervical cancer tissues, and its high expression indicated a poor prognosis. Silencing ZFAS1 may inhibit cell proliferation, migration and invasion and enhance cisplatin chemosensitivity.

Matrix Metallopeptidase 14 Plays an Important Role in Regulating Tumorigenic Gene Expression and Invasion Ability of HeLa Cells.

OBJECTIVES: The objectives of this study were to investigate the functional effect of matrix metallopeptidase 14 (MMP14) on cell invasion in cervical cancer cells (HeLa line) and to study the underlying molecular mechanisms. METHODS: Expression vector of short hairpin RNA targeting MMP14 was treated in HeLa cells, and then, transfection efficiency was verified by a florescence microscope. Transwell assay was used to investigate cell invasion ability in HeLa cells. Quantitative polymerase chain reaction and Western blotting analysis were used to detect the expression of MMP14 and relative factors in messenger RNA and protein levels, respectively. RESULTS: Matrix metallopeptidase 14 short hairpin RNA expression vector transfection obviously decreased MMP14 expression in messenger RNA and protein levels. Down-regulation of MMP14 suppressed invasion ability of HeLa cells and reduced transforming growth factor ß1 and vascular endothelial growth factor B expressions. Furthermore, MMP14 knockdown decreased bone sialoprotein and enhanced forkhead box protein L2 expression in both RNA and protein levels. CONCLUSION: Matrix metallopeptidase 14 plays an important role in regulating invasion of HeLa cells. Matrix metallopeptidase 14 knockdown contributes to attenuating the malignant phenotype of cervical cancer cell.

Expression Levels of Myostatin and Matrix Metalloproteinase 14 mRNAs in Uterine Leiomyoma are Correlated With Dysmenorrhea.

Uterine leiomyoma is the most common benign neoplasm of female reproductive system, found in about 50% of women in reproductive age. The mechanisms of leiomyoma growth include cell proliferation, which is modulated by growth factors, and deposition of extracellular matrix (ECM). Activin A and myostatin are growth factors that play a role in proliferation of leiomyoma cells. Matrix metalloproteinases (MMPs) are known for their ability to remodel the ECM in different biological systems. The aim of this study was to evaluate the expression levels of activin ßA-subunit, myostatin, and MMP14 messenger RNAs (mRNAs) in uterine leiomyomas and the possible correlation of these factors with clinical features of the disease. Matrix metalloproteinase 14 was highly expressed in uterine leiomyoma and correlated with myostatin and activin A mRNA expression. Moreover, MMP14 and myostatin mRNA expression correlated significantly and directly with the intensity of dysmenorrhea. Overall, the present findings showed that MMP14 mRNA is highly expressed in uterine leiomyoma, where it correlates with the molecular expression of growth factors and is further increased in cases of intense dysmenorrhea.

Increased progesterone receptor expression in uterine leiomyoma: correlation with age, number of leiomyomas, and clinical symptoms.

OBJECTIVE: To investigate the possible correlation between progesterone receptor (PR) expression in uterine leiomyoma or adjacent myometrium and patient's age, size/number of leiomyomas, or clinical symptoms such as dysmenorrhea, acyclic pelvic pain, or menstrual and intermenstrual uterine bleeding. DESIGN: Cross-sectional study. SETTING: Referral center. PATIENT(S): Sixty-two Chinese women undergoing elective hysterectomy for uterine leiomyomata. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Evaluation of PR-total and PR-B mRNA with real-time polymerase chain reaction; PR-A and PR-B proteins quantified by Western blot in leiomyoma tissue and myometrium; symptoms rated by the patients using visual analog scores. RESULT(S): The PR-B mRNA and PR-A and PR-B proteins were more concentrated in leiomyomas than in matched myometrium. A direct correlation between PR-B mRNA levels in leiomyoma and age (r = 0.347) and number of tumors (r = 0.295) was found. Conversely, there was an inverse correlation between PR-B mRNA levels in leiomyoma and dysmenorrhea (r = -0.260) and intermenstrual bleeding (r = -0.266). Multiple regression analysis indicated that age (ß = 0.363) and the number of myomas (ß = 0.296) were independently associated with PR-B mRNA levels in leiomyoma tissue. CONCLUSION(S): The levels of PR-B mRNA in leiomyoma tissue are directly associated with the number of tumors and inversely correlated with the intensity of intermenstrual bleeding and dysmenorrhea, suggesting that PR signaling may favor leiomyoma growth while attenuating clinical symptoms. This duality should be taken into account in the clinical management of patients with symptomatic uterine leiomyoma.

MicroRNA-370 suppresses proliferation and promotes endometrioid ovarian cancer chemosensitivity to cDDP by negatively regulating ENG.

MicroRNAs (miRNAs) are a class of non-coding RNAs that post-transcriptionally inhibit gene expression. In this study, we discovered that microRNA-370 (miR-370) was down-regulated in endometrioid ovarian cancer cells. In IGROV1 and TOV112D endometrioid ovarian cancer cells, miR-370 suppressed cellular viability and colony formation. miR-370 also enhanced endometrioid ovarian cancer cell chemosensitivity to cDDP. Endoglin (ENG) was directly and negatively regulated by miR-370. In addition, hypermethylation was a potential mechanism of miR-370 epigenetic silencing. We conclude that miR-370 acts as a tumor suppressor in endometrioid ovarian cancer via ENG regulation.

Analysis of HGF, MACC1, C-met and apoptosis-related genes in cervical carcinoma mice.

To understand the underlying pharmacological basis and the molecular mechanism of Taxol in therapy of cervical carcinoma (CC) disease, we need to explore the effect of Taxol on CC-related genes and pro-apoptosis and anti-apoptosis genes expression. Immunohistochemistry, western blot and reverse transcription-polymerase chain reaction were applied to examine postive expression levels of Bcl-2, Bax and Caspase-3, HGF, MACC1, Caspase-3 and C-met proteins and MACC1 mRNA expression in tumour of CC mice. Results showed that treatment of Taxol could increase the inhibition rate of tumour growth, positive expression levels of Caspase-3, Bax and decrease positive expression levels of Bcl-2 and Bcl-2/Bax, expression levels of HGF, MACC1 and C-met proteins and MACC1 mRNA in tumour tissue of CC mice. It can be concluded that inhibitory activity of Taxol against tumour growth in CC mice is closely associated with its modulating positive expression of Bcl-2, Bax, Caspase-3, expression of HGF, MACC1, Caspase-3 and C-met proteins and MACC1 mRNA in tumour of CC mice. In conclusion, HGF, MACC1 and C-met genes involve into malignant cervical tumors occurrence, development and prognosis, and might become potential molecular target therapy site of cervical cancer. Taxol intervention may serve as a multi-targeted CC therapeutic capable of inducing selective cancer cell death.

Factors associated with maternal near-miss morbidity and mortality in Kowloon Hospital, Suzhou, China.

OBJECTIVE: To investigate factors associated with acute maternal morbidity and mortality in Kowloon Hospital, Suzhou, China. METHODS: Data from cases of near-miss and maternal death between January 2008 and December 2012 were reviewed retrospectively. Maternal characteristics and related factors were identified, and multiple regression analysis was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: During the study period, there were 18 104 deliveries, 69 near-miss cases, and 3 maternal deaths. Women who had no health insurance (aOR, 4.55; 95% CI, 0.87-21.8), had fewer than 6 prenatal consultations (aOR, 6.76; 95% CI, 0.76-45.8), were part of a migrant population (aOR, 2.34; 95% CI, 0.45-24.9), or delayed seeking healthcare (aOR, 4.76; 95% CI, 0.89-13.6) had a greater risk of near-miss morbidity or death. Admission to intensive care (aOR, 6.75; 95% CI, 0.89-34.6) and blood transfusion within 30 min (aOR, 3.79; 95% CI, 0.65-8.67) were protective factors in disease progression. CONCLUSION: The factors associated with maternal near-miss morbidity and mortality were closely related to health insurance and socioeconomic status, suggesting that the government should take an active role in the community in preventing morbidity and mortality in pregnancy.

Health-related quality of life among breast cancer patients and its influencing factor in a Chinese population.

AIM: The aim of this study was to investigate the quality of life (QOL) of breast cancer patients by using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaires. METHODS: A total of 522 adult patients who were admitted to our hospital with breast cancer were collected during the period of Jun. 2007 to Dec. 2009. RESULTS: Our FACT-B questionnaire study suggested that women below 50 years old, employed, higher education and annual income, lower TNM stage and receiving modified radical mastectomy manifested significantly better QOL using the assessment tool of the FACT-B subscale. Moreover, regression analysis indicated patients with young age, low stage cancer, high education and income were more likely to have high score of QOL, with ORs (95% CI) of 2.8 (1.52-4.56), 2.1 (1.15-3.95), 3.1 (1.45-5.12) and 3.54 (1.54-5.43), respectively. CONCLUSION: Our study showed younger age, lower stage of cancer, higher education and income could influence the QOL of breast cancer patients in our Chinese population. Further large sample studies are still needed for confirmation.

CD40 is overexpressed by HPV16/18-E6 positive cervical carcinoma and correlated with clinical parameters and vascular density.

CD40 is expressed in many tumor cells, however, its role in tumor biology is yet to be demonstrated. In the present study, we investigated the role of CD40 in cervical carcinoma. In vivo, we evaluated CD40 expression in 56 cervical carcinoma tissues, 43 cervicitis and 38 normal cervix, and investigated the relationship between CD40 and HPV antigen, histopathological parameters, vascular density, and vascular endothelial growth factor (VEGF) expressions. The results clearly demonstrated that CD40 expression, including membranous and cytoplasmic staining, was significantly higher in cervical carcinoma than in the cervicitis and normal cervix. The expression of CD40 was significantly correlated with HPV and VEGF expressions and microvessel density (MVD). These observations provide evidence that CD40 may be involved in neovascularization of cervical carcinoma, they also suggest that CD40 and VEGF may be useful biomarkers for evaluating the risk of developing cervical carcinoma, and may also be used as a target for therapy.

Sensitization of SiHa cell to gemcitabine by CD40 activation and its overexpression in cervical carcinoma.

CD40, a member of the tumor necrosis factor receptor superfamily, is widely expressed on various cell types. Some studies show that CD40 expression is related to several carcinomas, where its function remains largely unknown. This study investigated the expression of CD40 on cervical carcinoma and evaluated the effect of agnostic anti-CD40 mAb (5C11) on tumor cell line (SiHa). CD40 expression on the primary cervical carcinoma samples was detected by immunohistochemistry. Results showed that CD40 is commonly expressed in human cervical carcinoma, which is higher than that of normal cervix, cervical precancerous tissue and chronic cervicitis. Treatment of the SiHa cell with the agonistic anti-CD40 monoclonal antibody or Gemcitabine alone did not inhibit the proliferation of the SiHa cell in vitro, but the activation of CD40 on SiHa could enhance its sensitivity to Gemcitabine. Furthermore, CD40 activation blocked SiHa in the S phase, stimulated proapoptotic Bax and inhibited antiapoptotic Bcl-XL mRNA synthesis in the SiHa cell. Apoptosis in SiHa was associated with an increasing ratio of Bax to Bcl-XL in mRNA levels. It is concluded that use of the anti-CD40 mAb 5C11 in combination with chemotherapy may have significant therapeutic potential.

[Differences in the expression of inhibin receptors and activin receptors in normal human ovaries and their significance].

OBJECTIVE: To explore the differences in the expression of inhibin (INH) receptors and activin (ACT) receptors in the follicular/luteinic phase in normal human ovaries and their relationship with female endocrine hormone levels. METHODS: Real time PCR and immunohistochemistry were used to determine the expression of inhibin receptors (INHR) genes, activin receptors (ACTR) genes. Serum estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), INHB, ACTA levels were determined by a solid quantitative sandwich enzyme immunoassay technique (Sandwich ELISA) in 21 women during follicular phase and another 21 women during luteinic phase, the correlations between each gene and each hormone were analyzed. RESULTS: (1) ACT type I and II receptors genes (ACTR I A, ACTR I B, ACTR II A, ACTR II B) and INH receptor beta-glycan genes were expressed higher in the follicular phase than in the luteinic phase: ACTR I A (0.50 +/- 0.17 vs 0.36 +/- 0.18; P < 0.05), ACTR I B (0.050 +/- 0.019 vs 0.036 +/- 0.020; P < 0.05), ACTR II A (0.10 +/- 0.04 vs 0.07 +/- 0.04; P < 0.05), ACTR II B (0.28 +/- 0.10 vs 0.19 +/- 0.11; P < 0.05), beta-glycan (0.26 +/- 0.10 vs 0.17 +/- 0.09; P < 0.01). (2) The intensities of ACTR I A, ACTR II A, beta-glycan immunostaining in human normal ovaries in the follicular phase were significantly stronger compared to those in luteinic phase. In the follicular phase beta-glycan expression was positively correlated with serum E2, FSH, LH, INHB levels. The correlation coefficient was 0.53 (P < 0.05), 0.74 (P < 0.01), 0.85 (P < 0.01) and 0.76 (P < 0.01) respectively. CONCLUSION: In normal human ovary in the follicular phase INH and ACT bind their receptors and down-regulate or up-regulate FSH, thus influencing the follicular development.