Construction of artificial neural network (ANN) based on predictive value of prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) in patients with cervical squamous cell carcinoma.

To explore the analytical worth of prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) in patients with cervical squamous cell carcinoma. The clinical data of 539 patients with cervical cancer in the Affiliated Tumor Hospital of Nantong University from December 2007 to October 2016 were analyzed retrospectively. The ROC is used to select the best cutoff values of PNI and NLR, which are 48.95 and 2.4046. Cox regression analysis was used for univariate and multivariate analysis. Survival differences were assessed by Kaplan-Meier (KM) survival method. Finally, a 3-layer artificial neural network (ANN) model is established. In cervical squamous cell carcinoma, the KM survival curve showed that the overall survival (OS) rate of high-level PNI group was significantly higher than that of low-level PNI group (P < .001), while the OS rate of low-level NLR group was significantly higher than that of high-level NLR group (P = .002). In non-squamous cell carcinoma, there was no significant difference in OS between the 2 groups (P > .005). According to Cox multivariate analysis, preliminary diagnosed PNI and NLR were independent prognostic factors of cervical squamous cell carcinoma (P < .001, P = .008), and pathological type and International Federation of Gynecology and Obstetrics (FIGO) stage also had a certain impact on tumor progression (P = .042, P = .048). The increase of PNI and the decrease of NLR will help patients with cervical squamous cell carcinoma live longer. ANN showed that PNI and NLR were of great importance in predicting survival. Preoperative PNI and NLR are independent predictors of cervical squamous cell carcinoma patients related to clinicopathological features, and have particular value in judging prognosis.

Clusters of Body Fat and Nutritional Parameters are Strongly Associated with Diabetic Kidney Disease in Adults with Type 2 Diabetes.

INTRODUCTION: Diabetic kidney disease (DKD) has become the leading cause of chronic kidney disease and end-stage renal failure in most developed and many developing countries. Strategies aimed at identifying potential modifiable risk factors for DKD are urgently needed. Here, we investigated the association between clusters of body fat and nutritional parameters with DKD in adults with type 2 diabetes mellitus (T2DM). METHODS: This was a cross-sectional study of 184 participants with T2DM. Biochemical parameters including fasting blood glucose, hemoglobin A1c, hemoglobin, albumin, creatinine, and urinary albumin-to-creatinine ratio (UACR) were measured. The data for percentage of body fat mass (PBF), visceral fat area (VFA), phase angle at 50 kHz (PA50), and body cell mass (BCM) were obtained by bioelectrical impedance analysis (BIA). DKD was diagnosed by UACR and estimated glomerular filtration rate. Factor analysis was used for dimensionality reduction clustering among variables. The association of clusters with the presence of DKD was assessed using binary logistic regression analysis. RESULTS: Factor analysis identified two clusters which were interpreted as a body fat cluster with positive loadings of VFA, body mass index, waist circumstance, and PBF and a nutritional parameters cluster with positive loadings of PA50, hemoglobin, BCM, and albumin. Participants were divided into the four groups based on the sex-specific cutoff value (median) of each cluster score calculated using the cluster weights and the original variable values. Only participants with high body fat and poor nutritional parameters (OR 3.43, 95% CI 1.25-9.42) were associated with increased odds of having DKD. CONCLUSION: Body fat and nutritional parameters were strongly associated with and considerably contributed to the presence of DKD, suggesting that body fat and nutrition might be promising markers representing metabolic state in pathogenesis of DKD and clinical utility of BIA might provide valuable recommendations to patients with T2DM.

Efficacy and Safety of Niraparib as First-Line Maintenance Treatment for Patients with Advanced Ovarian Cancer: Real-World Data from a Multicenter Study in China.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors are a new maintenance therapy option for patients with ovarian cancer (OC). OBJECTIVE: To evaluate the efficacy and influencing factors of the novel PARP inhibitor niraparib for maintenance treatment of Chinese patients with advanced OC. PATIENTS AND METHODS: In this retrospective multicenter real-world study patients with advanced OC from 15 hospitals throughout China were enrolled. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included the time to treatment discontinuation and safety. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to identify possible risk factors for PFS, after which a prediction model was established to evaluate the likelihood of achieving an 18-month PFS. The relationship between the dose of niraparib and PFS was also evaluated. RESULTS: The PFS rates of 199 patients at 6, 12, 18, 24, and 30 months were 87.4%, 75.9%, 63.6%, 56.1%, and 51.8%, respectively. LASSO regression model revealed that only age < 65 years (P = 0.011), BRCA mutations (P < 0.001), and R0 status after cytoreductive surgery (P = 0.01) were significant factors associated with prolonged PFS times. Based on the LASSO logistic regression analysis, a clinical prediction formula was developed: - 2.412 + 1.396Age≥65yr + 2.374BRCAwt + 1.387R1 + 0.793Interval≥12w + 0.178BMI>24kg/m2 which yielded a cut-off value of 0.091, an area under the curve (AUC) of 0.839 (0.763-0.916), a sensitivity of 94.3%, and an accuracy of 78.5%. A nomogram was then built to visualize the results. The major treatment-emergent adverse events of ≥ grade 3 included a platelet count decrease (19.1%), white blood cell count decrease (15.1%), neutrophil count decrease (13.1%), and anemia (18.6%). The 18-month PFS rates in patients treated with 200 mg niraparib were somewhat higher than in patients treated with 100 mg after 3-months of therapy. CONCLUSIONS: For Chinese OC patients, niraparib, particularly at a 200 mg individual starting dose, was an effective therapy with easily manageable safety.

Maintenance therapy with poly (ADP-ribose) polymerase inhibitors is a new option for patients with ovarian cancer (OC) after they have received platinum-based chemotherapy to reduce the recurrence or relapse rates, but it remains unclear whether there are any changes in efficacy and safety when different starting doses of niraparib are administrated to Chinese patients, who typically have a bodyweight < 77 kg. We found that niraparib exhibited satisfactory efficacy with tolerable safety during maintenance therapy for advanced OC whether administered at 100 mg or 200 mg doses. We believe these regimens can serve as a valuable addition to the previous results of randomized controlled trials.

Efficacy and Safety of Anlotinib in Overall and Disease-Specific Advanced Gynecological Cancer: A Real-World Study.

Purpose: Anlotinib is a novel oral small-molecule multi-target tyrosine kinase inhibitor that has been approved for treating non-small cell lung cancer. However, its efficacy and safety among patients with advanced gynecological cancer have not been comprehensively evaluated. We conducted this study to address this issue in the real-world setting. Patients and Methods: Data from patients treated with Anlotinib for persistent, recurrent or metastatic gynecological cancer were collected from 17 centers from August 2018. The database lock-time was on March 2022. Anlotinib was administered orally on days 1-14 every 3 weeks until disease progression, severe toxicity occurred, or death. In this study, disease-specific advanced gynecological cancer was mainly referred to cervical, endometrial, and ovarian cancer. The outcomes included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: A total of 249 patients were analyzed, with a median follow-up of 14.5 months. The overall ORR and DCR were 28.1% [95% confidence interval (CI) 22.6% to 34.1%] and 80.7% (95% CI 75.3% to 85.4%), respectively. Specifically, the ORR varied from 19.7% to 34.4% and the DCR differed from 81.7% to 90.0% in disease-specific advanced gynecological cancer. The median PFS was 6.1 months and ranged from 5.6 to 10.0 months in the overall and disease-specific advanced gynecological cancer, respectively. Larger cumulative dosage of Anlotinib (>700 mg) was in general associated with longer PFS in the overall and disease-specific advanced gynecological cancer. The most common adverse event related to Anlotinib treatment was pain/arthralgia (18.3%). Conclusion: In conclusion, Anlotinib holds promise in treating patients with advanced gynecological cancer including its disease-specific types, with reasonable efficacy and tolerable safety.

CRTC2 promotes paclitaxel resistance by inducing autophagy in ovarian cancer in part via the PI3K-AKT signaling axis.

Background: Ovarian cancer is the most malignant gynecological disease, which seriously threatens female physical and mental health. Paclitaxel is a first-line chemotherapy drug in the clinical treatment of ovarian cancer, but drug resistance has become an important factor affecting the survival of ovarian cancer patients. However, the main mechanism of chemotherapy resistance in ovarian cancer remains unclear. In this study, we analyzed the Integrated Gene Expression Database (GEO) dataset using comprehensive bioinformatics tools to provide new therapeutic strategies and search for prognostic targets for ovarian cancer. Methods: Ovarian cancer related genes were extracted from GSE18520 by bioinformatics method. Differentially expressed genes (DEGs) were obtained by differential analysis, and related genes and functions were elucidated. The key gene CRTC2 was identified by prognostic analysis. Immunohistochemistry was used to detect the expression of CRTC2 in chemotherapy-resistant and chemotherapy-sensitive ovarian cancer tissues. Functional analysis (cell assay) confirmed the role of CRTC2 in paclitaxel resistance. Autophagy related proteins were detected by Western blot. Autophagy flux analysis was performed using the GFP/RFP-LC3 adenovirus reporter. Results: A total of 3,852 DEGs were identified in the GEO microarray dataset. Key genes were screened by prognostic analysis. We found that CRTC2 was highly expressed in chemoresistant tissues of ovarian cancer. In 110 patients with ovarian cancer, high expression of CRTC2 was associated with poorer prognostic factors and shorter survival. At the same time, we found that CRTC2 can promote the proliferation and invasion ability of ovarian cancer cells. In addition, CRTC2 can affect the expression of PI3K, AKT, autophagic flux and sensitivity to paclitaxel chemotherapy in ovarian cancer. Conclusion: CRTC2 can affect autophagy partially through PI3K-AKT signaling pathway, and then affect the sensitivity of ovarian cancer to paclitaxel chemotherapy. CRTC2 may be a potential predictor or target for ovarian cancer therapy.

Urinary metabolites associate with the presence of diabetic kidney disease in type 2 diabetes and mediate the effect of inflammation on kidney complication.

AIMS: Diabetic kidney disease (DKD) is the one of the leading causes of end-stage kidney disease. Unraveling novel biomarker signatures capable to identify patients with DKD is favorable for tackle the burden. Here, we investigated the possible association between urinary metabolites and the presence of DKD in type 2 diabetes (T2D), and further, whether the associated metabolites improve discrimination of DKD and mediate the effect of inflammation on kidney involvement was evaluated. METHODS: Two independent cohorts comprising 192 individuals (92 DKD) were analyzed. Urinary metabolites were analyzed by targeted metabolome profiling  and inflammatory cytokine IL-18 were measured by ELISA. Differentially expressed metabolites were selected and mediation analysis was carried out. RESULTS: Seven potential metabolite biomarkers (i.e., S-Adenosyl-L-homocysteine, propionic acid, oxoadipic acid, leucine, isovaleric acid, isobutyric acid, and indole-3-carboxylic acid) were identified using the discovery and validation design. In the pooled analysis, propionic acid, oxoadipic acid, leucine, isovaleric acid, isobutyric acid, and indole-3-carboxylic acid were markedly and independently associated with DKD. The composite index of 7 potential metabolite biomarkers (CMI) mediated 32.99% of the significant association between the inflammatory IL-18 and DKD. Adding the metabolite biomarkers improved the discrimination of DKD. CONCLUSIONS: In T2D, several associated urinary metabolites were identified to improve the prediction of DKD. Whether interventions aimed at reducing CMI also reduce the risk of DKD especially in patients with high IL-18 needs further investigations.

Long noncoding RNA FTX promotes epithelial-mesenchymal transition of epithelial ovarian cancer through modulating miR-7515/TPD52 and activating Met/Akt/mTOR.

Overexpressed long noncoding RNA FTX is associated with low survival rate of epithelial ovarian cancer (EOC) patients, and enhances tumor infiltration. Thus, we aim to illuminate the undefined underlying mechanisms. Real-time quantitative polymerase chain reaction was applied to detect the expressions of FTX, miR-7515, miR-342-3p, miR-940, miR-150-5p, miR-205-5p and tumor protein D52 (TPD52). Cell counting kit-8 and transwell assays were utilized to explore the cell viability, migration or invasion of EOC cells. Western blot was conducted to measure the expressions of E-cadherin, N-cadherin, Met, phosphorylated (p)-Met, Akt, p-Akt, mTOR and p-mTOR. LncBase and TargetScan predicted the binding of miR-7515 with FTX, and the binding of TPD52 with miR-7515, respectively. The two bindings were further validated by dual luciferase reporter assay. As a result, FTX sponged miR-7515 and miR-7515 targeted to TPD52. FTX was overexpressed in four EOC cell lines. Overexpressed FTX enhanced the cell viability, migration or invasion of EOC cells, elevated N-cadherin and TPD52 expressions, phosphorylated Met/Akt/mTOR, and inhibited E-cadherin expression. All these influences were subsequently reversed by miR-7515 mimic. Collectively, FTX regulates miR-7515/TPD52 to facilitate the migration, invasion or epithelial-mesenchymal transition of EOC through activating Met/Akt/mTOR signaling pathway.

Gab2 plays a carcinogenic role in ovarian cancer by regulating CrkII.

OBJECTIVE: To detect the expression of Growth factor binding protein 2 associated binding protein 2 (Gab2) and CT10 regulator of kinase II (CrkII) in ovarian cancer and analyze their clinical significance. To explore the effects of Gab2 and CrkII on the biological behavior of ovarian cancer cells. To analyze the possible molecular mechanism of Gab2 in the development of ovarian cancer. METHODS: Immunohistochemistry was used to detect the expression of Gab2 and CrkII in ovarian cancer. Chi square test was used to analyze the correlation between Gab2, CrkII and clinical parameters. Using Cox regression model to evaluate the risk factors affecting the prognosis. To analyze the correlation between Gab2, CrkII and survival rate by Kaplan-Meier. Cell experiments were preformed to explore the effects of Gab2 and CrkII on the biological behavior of cells. The interaction between Gab2 and CrkII was explored by immunoprecipitation. RESULTS: Immunohistochemistry revealed that high expression of Gab2 and CrkII in ovarian cancer. Patients with high expression of Gab2 or CrkII had higher International Federation of Gynecology and Obstetrics (FIGO) stage, grade and platinum-resistance recurrence. Multivariate analysis showed that Gab2 and CrkII were independent prognostic factors. Kaplan-Meier curve showed that the higher Gab2 and CrkII were, the poor prognosis the patients had. We observed that the overexpression of Gab2 and CrkII promoted the proliferation, metastasis and reduced chemosensitivity of cells. Conversely, the knockdown of Gab2 and CrkII resulted in the opposite results. In CrkII-knockdown cells, we found that Gab2 mediates biological behavior through CrkII. CONCLUSIONS: The expression of Gab2 and CrkII increase in ovarian cancer. The higher expression of Gab2 and CrkII predict the poor prognosis of patients. Gab2 and CrkII promote the proliferation and migration and reduce the chemosensitivity of cells. Gab2 regulates the biological behaviors of ovarian cancer cells through CrkII.

Identification and validation of novel biomarker TRIM8 related to cervical cancer.

Background: Cervical cancer, as a common gynecological disease, endangers female health. Give the lack of effective biomarkers for the diagnosis and treatment of cervical cancer, this paper aims to analyze the Gene Expression Omnibus (GEO) data sets using comprehensive bioinformatics tools, and to identify biomarkers associated with the cancer in patient samples. Methods: The bioinformatics methods were used to extract genes related to cervical cancer from GSE39001, while the GEO2R online tool to elaborate on differentially expressed genes (DEGs) in normal and cancer samples, and to clarify related genes and functions. The results were verified by IHC, WB, CCK-8, clone formation and flow cytometry experiments. Results: A total of 2,859 DEGs were identified in the GEO microarray dataset. We extracted genes associated with both ubiquitination and autophagy from the key modules of weighted gene co-expression network analysis (WGCNA), and the analysis showed that TRIM8 was of great significance for the diagnosis and prognosis of cervical cancer. Besides, experimental validation showed the high TRIM8 expression in cervical cancer, as well as its involvement in the proliferation of cervical cancer cells. Conclusion: We identified a biomarker (TRIM8) that may be related to cervical cancer through a series of analyses on the GEO dataset. Experimental verification confirmed the inhibition of cervical cancer cells proliferation by lowering TRIM8 expression. Therefore, TRIM8 can be adopted as a new biomarker of cervical cancer to develop new therapeutic targets.

Urinary IL-18 is associated with arterial stiffness in patients with type 2 diabetes.

Objective: Diabetic kidney disease (DKD) has been shown to be associated with an excess risk of cardiovascular death. Inflammation has been considered central to type 2 diabetes (T2D) pathophysiology, and inflammation markers have been linked to cardiovascular disease. The serum and urinary IL-18 levels were significantly elevated in patients with T2D; however, whether interleukin 18 (IL-18) are associated with the severity of arterial stiffness remains to be determined. This study examined the relationship of IL-18 levels with pulse wave velocity (PWV) as a reflector for arterial stiffness in patients with T2D. Methods: A total of 180 participants with T2D who had undergone PWV examination were enrolled. Serum and urinary IL-18 levels were measured using sandwich enzyme linked immunosorbent assay (ELISA) kits. Arterial stiffness was determined by carotid-femoral PWV (cf-PWV) and carotid-radial PWV (cr-PWV). Results: The urinary IL-18 levels correlated positively with cf-PWV in patients with T2D with DKD (r = 0.418, p < 0.001); however, we found no significant correlation between urinary IL-18 and cf-PWV in diabetic subjects without DKD. In addition, we found no significant correlation between urinary IL-18 and cr-PWV in participants with T2D with or without DKD. Moreover, the association remained significant when controlling for arterial stiffness risk factors, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. cf-PWV was greater in the higher group of urinary IL-18 than in the lower group. Nevertheless, we found no significant correlation between serum IL-18 and cf-PWV in participants with T2D. Conclusion: The urinary IL-18 levels appear to be associated with greater cf-PWV, suggesting the link between urinary IL-18 and arterial stiffness in patients with T2D.

High expression of PYK2 is associated with poor prognosis and cancer progression in early-stage cervical carcinoma.

Proline-rich tyrosine kinase-2 (PYK2), also known as calcium dependent tyrosine kinase, regulates different signal transduction cascades that control cell proliferation, migration, and invasion. However, the role of PYK2 in cervical cancer remains to be elucidated. The current study retrospectively included 134 patients with cervical cancer from December 2007 to September 2014. PYK2 expression was detected in tissue microarray and cervical cancer cell lines. Statistical analysis was performed to evaluate its clinicopathological significance. Small interfering RNA (siRNA) was employed to suppress endogenous PYK2 expression in cervical cancer cells to observe the biological function. PYK2 expression was up-regulated in cervical cancer specimens compared with paired adjacent normal cervical tissue samples. Statistical analyses indicated that PYK2 expression might be an independent prognostic indicator for patients with early-stage cervical cancer. A nomogram model was constructed based on PYK2 expression and other clinicopathological risk factors, and it performed well in predicting patients survival. In cellular studies, down-regulation of PYK2 remarkably inhibited cellular proliferation, migration and invasion. PYK2 expression possessed the potential to serve as a novel prognostic marker in cervical cancer patients.

Low FOXJ2 expression is associated with unfavorable postoperative prognosis of patients with epithelial ovarian cancer.

ABSTRACT: The forkhead box (FOX) family is a large and diverse group of transcription factors. Forkhead box J2 (FOXJ2) is a member of the FOX family that is aberrantly expressed in a variety of cancers. However, its role in epithelial ovarian cancer (EOC) remains elusive. The purpose of this study was to evaluate the prognostic value of FOXJ2 expression in patients with epithelial ovarian cancer.The current study retrospectively included 151 patients with EOC from January 2013 to September 2016. FOXJ2 expression was analyzed by immunohistochemistry based on tissue microarrays. Then, the prognostic value of FOXJ2 expression and clinical outcomes were evaluated by Kaplan-Meier and cox regression analysis.Low FOXJ2 expression was associated with high International Federation of Gynecology and Obstetrics (FIGO) stage. Kaplan-Meier curves showed that high FOXJ2 expression was associated with improved median overall survival (OS, 57.9 vs 31.9 months; P = .037) and longer median progression-free survival (PFS, 31.8 vs 18.1 months; P = .012). Univariate analysis demonstrated that FOXJ2 expression was significantly correlated with OS and PFS in patients with epithelial ovarian cancer. Multivariate analysis revealed FOXJ2 expression as an independent prognostic factor of progression-free survival of epithelial ovarian cancer patients.Low FOXJ2 expression is a novel adverse prognostic factor of clinical outcome in epithelial ovarian cancer.

Detection and analysis of multiple biomarkers in ovarian cancer: clinical significance in diagnosis, treatment, and prognosis evaluation.

BACKGROUND: The purpose of this study was to explore the clinical significance of CA125, CK7, CK20, ER, PR, C-erbb2, and P-gp in ovarian cancer. METHODS: Ovarian cancer patients were recruited from Nantong Cancer Hospital between March 2006 and July 2011. The expressions of CA125, CK7, CK20, ER, PR, C-erbb2, and P-gp were determined by immunohistochemistry (IHC).The chi-square test (χ2) was used to analyze the correlation between each index and the clinical characteristics of the patients. The patients were followed up to record the cancer recurrence time. The Kaplan-Meier method was used to map the cumulative recurrence-free survival (RFS) rate, and COX regression analysis was established for multivariate analysis. RESULTS: The results of IHC showed that the positive expression rates of CA125, CK7, ER, C-erbb2, and P-gp in malignant ovarian cancer tissues were significantly higher than those in benign ovarian cancer tissues. CA125 expression in malignant ovarian cancer was significantly correlated with the age of patients and the Federation of International Gynecology and Obstetrics (FIGO) stage. CK7 expression in malignant ovarian cancer was significantly correlated with the age, tissue differentiation, and number of residual lesions. CK20 expression in malignant ovarian cancer was significantly correlated with the age and tissue differentiation of the patients. ER expression in malignant ovarian cancer was significantly correlated with the age of patients and FIGO stage. PR expression in malignant ovarian cancer was significantly correlated with the age of the patients. C-erbb2 expression in malignant ovarian cancer was significantly correlated with the age of the patients. P-gp expression in malignant ovarian cancer was significantly correlated with the patient age, pathological type, and tissue differentiation. The expression of CA125, CK7, CK20, C-erbb2, and P-gp had significant effects on the prognosis of patients with ovarian cancer. The COX regression analysis showed that P-gp was an independent risk factor for ovarian cancer. CONCLUSIONS: In malignant ovarian cancer tissues, CA125, CK7, CK20, ER, PR, C-erbb2, and P-gp are over-expressed. The expression of P-gp is an independent risk factor for ovarian cancer, and it can be an important target for the treatment of malignant ovarian cancer.

Prognostic significance of the controlling nutritional status (CONUT) score in epithelial ovarian cancer.

PURPOSE: The controlling nutritional status (CONUT) score is a nutritional indicator that serves as a prognostic factor for many malignancies. This study aimed to investigate the prognostic significance of pre-treatment CONUT scores in patients with epithelial ovarian cancer. METHODS: We evaluated newly diagnosed patients with epithelial ovarian cancer who were treated at the Nantong Tumor Hospital, between January 2013 and April 2016. Pre-treatment CONUT scores were calculated using serum albumin levels, total lymphocyte counts, and cholesterol levels. The optimal CONUT score cut-off was determined via receiver operating characteristic curve and Youden's index. The difference in survival rates between the high-CONUT score group and the low-CONUT score group was analyzed using Kaplan-Meier curves and the log-rank test. Univariate and multivariate Cox proportional hazard regression models were used to identify prognostic factors influencing survival in these patients. RESULTS: In total, 206 patients were included. The optimal cut-off value for the CONUT score was 3. The high-CONUT score group (score ≥3) had higher International Federation of Gynecology and Obstetrics (FIGO) stages, medium-large amounts of ascitic fluid, higher CA125 levels, and more chemoresistance than those with a low-CONUT score (score <3). The low-CONUT score group had longer median overall survival (64.8 vs 32.3 months, respectively; p<0.001) and longer median progression-free survival (32.3 vs 18.8 months, respectively; p=0.002) than those in the high-CONUT score group. Multivariate analysis showed that the CONUT score was an independent prognostic factor for overall survival. CONCLUSIONS: The CONUT score predicts the prognosis of epithelial ovarian cancer and is thus helpful for individualizing treatment and improving survival in these patients.

The Prognostic Significance Of Pretreatment Albumin/alkaline Phosphatase Ratio In Patients With Stage IB-IIA Cervical Cancer.

BACKGROUND: Pretreatment albumin/alkaline phosphatase ratio (AAPR) has been discussed about its prognostic value in several malignancies, whereas its role in cervical cancer remains unclear. In this study, we attempt to explore the prognostic significance of the AAPR in stage IB-IIA cervical cancer patients who underwent a radical hysterectomy. PATIENTS AND METHODS: A total of 230 cervical cancer patients were enrolled in this retrospective study. The threshold value of AAPR was determined by receiver operating characteristic (ROC) curve. Kaplan-Meier survival analysis and multivariate analysis were performed to identify independent prognostic predictors of disease-free survival (DFS) and overall survival (OS). RESULTS: The optimal cut-off value of the preoperative AAPR was 0.68. Patients with AAPR<0.68 showed obviously inferior OS and DFS than those with AAPR>0.68 according to Kaplan-Meier curves (DFS: P = 0.011; OS: P = 0.017). In multivariate analysis, the preoperative AAPR showed to be an independent predictive factor for disease-free survival (DFS: P = 0.015) and overall survival (OS: P = 0.019). Moreover, subgroup analysis revealed that the lower AAPR was correlated with worse prognosis in patients with histologic grade I-II; but in those with histologic grade III, there was no significant difference between the two groups. CONCLUSION: Preoperative AAPR was a potentially valuable prognostic index in stage IB-IIA cervical cancer patients. Further prospective studies are required to validate its prognostic value.

Eukaryotic elongation factors 2 promotes tumor cell proliferation and correlates with poor prognosis in ovarian cancer.

Eukaryotic elongation factors 2 (eEF2) plays an essential role in the GTP-dependent translocation of the ribosome along mRNA. Previous studies have shown that eEF2 is overexpressed in various tumors. However, little is known about the role of eEF2 in ovarian cancer. The aim of the present study is to examine the effect of eEF2 on ovarian cancer proliferation. We first measured eEF2 protein expression by western blot using six fresh ovarian cancer tissues from G1 to G3. The results showed that eEF2 expression gradually increased from G1 to G3. Additionally, eEF2 expression correlated significantly with grade (P = 0.045), FIGO stage (P = 0.035) and Ki67 (P < 0.05). Additionally, there was a significant positive association between eEF2 expression and Ki67 (r = 0.855). Cox's proportional hazards model also showed that eEF2 (P = 0.004) and Ki67 (P < 0.001) were an independent prognostic factor of overall survival in ovarian cancer patients. In vitro, after the release of ovarian cancer cell line (HO8910) from serum starvation, the expression of eEF2, cyclinD1 and PCNA was up-regulated. Moreover, silencing eEF2 in HO8910 cells decreased cell proliferation. Finally, we hypothesize that eEF2 may be activated in a positive feedback cycle through inactivation of eEF2K via the PI3K/Akt/mTOR pathway. These data provide novel insights into developing experimental therapies for ovarian cancer.

CD200Fc reduces LPS-induced IL-1ß activation in human cervical cancer cells by modulating TLR4-NF-κB and NLRP3 inflammasome pathway.

Chronic inflammation plays an important role in tumorigenesis of cervical cancer. CD200Fc, a CD200R1 agonist, has been found to have anti-inflammatory effects in autoimmune diseases and neuro-degeneration. However, the anti-inflammatory effect of CD200Fc on cervical cancer has not yet to be completely understood. This study investigated the anti-inflammatory effects and mechanisms of CD200Fc in LPS-induced human SiHa cells and Caski cells. SiHa cells and Caski cells were stimulated with 40 µg/ml LPS under different concentrations of CD200Fc for 90 min or 12 hours. The mRNA and protein levels of pro-IL-1ß, cleaved-IL-1ß and NLRP3, as well as the protein level of cleaved caspase-1, were significantly increased in LPS-induced SiHa cells and Caski cells. LPS stimulation did not change ASC and pro-caspase-1 expression. CD200Fc down-regulated protein expression of cleaved caspase-1 and mRNA and protein expression of pro-IL-1ß, cleaved-IL-1ß and NLRP3. In addition, the protein levels of TLR4, p-P65 and p-IκB, as well as the translocation of P65 to nucleus, were significantly increased in LPS-induced SiHa cells and Caski cells. LPS stimulation did not change t-P65 and t-IκB on protein levels, which were components of TLR-NF-κB pathway. CD200Fc down-regulated protein expression of TLR4, p-P65 and p-IκB and inhibited the translocation of P65 to nucleus in LPS-induced SiHa cells and Caski cells. These results indicated that CD200Fc appeared to suppress the inflammatory activity of TLR4-NF-κB and NLRP3 inflammasome pathway in LPS-induced SiHa cells and Caski cells. It provided novel mechanistic insights into the potential therapeutic uses of CD200Fc for cervical cancer.

The rs767649 polymorphism in the promoter of miR-155 contributes to the decreased risk for cervical cancer in a Chinese population.

Genetic variants in miRNAs have attracted more and more attention these years because they are capable of altering miRNA function and/or expression, consequently affecting downstream biological pathways and disease risk. The rs767649 polymorphism, locating in the promoter of miR-155, was recently reported to be able to alter transcriptional activity of miR-155 and relate to lung cancer risk. In this study, we aimed to assess the relationship between rs767649 and cervical cancer (CC) risk. We investigated the association of rs767649 with CC risk in a two-stage case-control study with 1157 cases and 1280 controls. Genotyping was determined with TaqMan allelic discrimination method. The results showed that the rs767649 TT genotype was associated with a significantly reduced risk of CC in both test (549 cases and 603 controls), validation (608 cases and 677 controls) and combined sets [adjusted odds ratio (OR)=0.67, 95% confidence interval (CI)=0.51-0.87 for the combined set] compared with the AA/AT genotypes. Moreover, the association was more prominent among patients of age>49years and postmenopausal status (OR=0.56, 95% CI=0.38-0.83, and 0.60, 0.40-0.89, respectively) and patients with clinical stage I and II CC (OR=0.67, 95% CI=0.50-0.91, and 0.60, 0.40-0.92, respectively). Further analyses showed that miR-155 was overexpressed in the CC tissues as compared with normal tissues, suggesting an oncogenic role in CC. Luciferase assay indicated that the transition of A to T allele might lead to miR-155 downregulation at the transcriptional level. In conclusion, rs767649 might be a causal variant for CC susceptibility.

TLR4-MyD88-TRAF6-TAK1 Complex-Mediated NF-κB Activation Contribute to the Anti-Inflammatory Effect of V8 in LPS-Induced Human Cervical Cancer SiHa Cells.

The synthetic compound 7-4-[Bis-(2-hydroxyethyl)-amino]-butoxy-5-hydroxy-8-methoxy-2-phenylchromen-4-one (V8) is a novel flavonoid-derived compound. In this study, we investigated the effects of V8 on Toll-like receptor 4 (TLR4)-mediated inflammatory reaction in human cervical cancer SiHa cells and lipopolysaccharide (LPS)-induced TLR4 activity in cervical cancer SiHa (HPV16+) cells, but not in HeLa (HPV18+) and C33A (HPV-) cells. In addition, V8 inhibited LPS-induced expression of TLR4, MyD88, TRAF6 and phosphorylation of TAK1, and their interaction with TLR4 in SiHa cells, resulting in an inhibition of TLR4-MyD88-TRAF6-TAK1 complex. Moreover, V8 blocked LPS-induced phosphorylation of IκB and IKK, resulting in inhibition of the nuclear translocation of P65-NF-κB in SiHa cells. We also found that V8 reduced the expression of NF-κB target genes, such as those for COX-2, iNOS, IL-6, IL-8, CCL-2, and TNF-α in LPS-stimulated SiHa cells. These results suggested that V8 exerted an anti-inflammatory effect on SiHa cells by inhibiting the TLR4-MyD88-TRAF6-TAK1 complex-mediated NF-κB activation.