M5C regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in lung adenocarcinoma.

BACKGROUND: In recent years, immunotherapy has made great progress, and the regulatory role of epigenetics has been verified. However, the role of 5-methylcytosine (m5C) in the tumor microenvironment (TME) and immunotherapy response remains unclear. METHODS: Based on 11 m5C regulators, we evaluated the m5C modification patterns of 572 lung adenocarcinoma (LUAD) patients. The m5C score was constructed by principal component analysis (PCA) algorithms in order to quantify the m5C modification pattern of individual LUAD patients. RESULTS: Two m5C methylation modification patterns were identified according to 11 m5C regulators. The two patterns had a remarkably distinct TME immune cell infiltration characterization. Next, 226 differentially expressed genes (DEGs) related to the m5C phenotype were screened. Patients were divided into three different gene cluster subtypes based on these genes, which had different TME immune cell infiltration and prognosis characteristics. The m5C score was constructed to quantify the m5C modification pattern of individual LUAD patients. We found that the high m5C score group had a better prognosis. The role of the m5C score in predicting prognosis was also verified in the dataset GSE31210. CONCLUSIONS: Our study revealed that m5C modification played a significant role in TME regulation of LUAD. Investigation of the m5C regulation mode may have some implications for tumor immunotherapy in the future.

Proteomic Analysis of Desiccation Tolerance and Its Re-Establishment in Different Embryo Axis Tissues of Germinated Pea Seeds.

The model of loss and re-establishment of desiccation tolerance (DT) in germinated seeds has been well developed to explore the mechanisms associated with DT, but little attention has been paid to the tissue variation in this model. Herein, we investigated DT in different embryo axis tissues of germinated pea seeds and its re-establishment by poly(ethylene glycol) (PEG) treatment and then employed an iTRAQ-based proteomic method to explore the underlying mechanisms. DT varied among the four embryo axis parts of germinated seeds: epicotyl > hypocotyl-E (hypocotyl part attached to the epicotyl) > hypocotyl-R (hypocotyl part attached to the radicle) > radicle. Meanwhile, PEG treatment of germinated seeds resulted in a differential extent of DT re-establishment in these tissues. Proteins involved in detoxification and stress response were enriched in desiccation-tolerant hypocotyls-E and epicotyls of germinated seeds, respectively. Upon rehydration, proteome change during dehydration was recovered in the hypocotyls-E but not in the radicles. PEG treatment of germinated seeds led to numerous changes in proteins, in abundance in desiccation-sensitive radicles and hypocotyls-R, of which many accumulated in the hypocotyls-E and epicotyls before the treatment. We hypothesized that accumulation of groups 1 and 5 LEA proteins and proteins related to detoxification, ABA, ethylene, and calcium signaling contributed mainly to the variation of DT in different tissues and its re-establishment.

Fibrinogen alpha chain promotes the migration and invasion of human endometrial stromal cells in endometriosis through focal adhesion kinase/protein kinase B/matrix metallopeptidase 2 pathway†.

Fibrinogen alpha chain (FGA), a cell adhesion molecule, contains two arginyl-glycyl-aspartic acid (RGD) cell adhesion sequences. Our previous study demonstrated that FGA, as an up-regulated protein in endometriosis (EM), was closely related to disease severity and involved in the development of EM. However, the biological functions and underlying mechanism of FGA in EM have not been fully understood. To explore the roles of FGA in EM, we analyzed the effects of FGA on the biological behaviors of human primary eutopic endometrial stromal cells (EuESC). The results indicated FGA knockdown suppressed the migration and invasion ability of EuESC, which also altered the distribution of cytoskeletal filamentous and cell morphology. Western blot analysis demonstrated that knockdown of FGA attenuated the migration-related protein levels of vimentin and matrix metallopeptidase 2 (MMP-2), but not integrin subunit alpha V (ITGAV) and integrin subunit beta 3 (ITGB3). Meanwhile, integrin-linked transduction pathways were detected. We found FGA knockdown significantly suppressed the expression of focal adhesion kinase (FAK) level and protein kinase B (AKT) phosphorylation, without extracellular-signal-regulated kinase (ERK) dependent pathways. Treatment with the AKT inhibitor MK2206 or RGD antagonist highly decreased the effects of FGA on the migration and invasion of EuESC. RGD antagonist treatment strongly inhibited FAK- and AKT-dependent pathways, but not ERK pathways. Our data indicated that FGA may enhance the migration and invasion of EuESC through RGD sequences binding integrin and activating the FAK/AKT/MMP-2 signaling pathway. This novel finding suggests that FGA may provide a novel potential approach to the treatment of EM, which provides a new way to understand the pathogenesis of EM.

Age and menopausal status are important factors influencing the serum human epididymis secretory protein 4 level: a prospective cross-sectional study in healthy Chinese people.

BACKGROUND: Human epididymis secretory protein 4 (HE4) is a new ovarian cancer biomarker. The factors influencing HE4 levels are not clear, and the reference data in China are limited. Here, we aim to evaluate the effects of menopause and age on HE4 levels and to provide a possible reference value for HE4 in healthy Chinese people. METHODS: A total of 2493 healthy females aged 40 years or older were recruited from March 2013 to March 2017 with the cooperation of four medical institutions across Beijing, China. The serum levels of HE4 and cancer antigen 125 (CA125) were measured by enzyme-linked immunosorbent assay. The Wilcoxon rank-sum test of variance and a stratified analysis were used to analyze the relationships among age, menopausal status, and levels of HE4 or CA125. Confidence intervals (5%-95%) were determined for reference ranges in different populations. RESULTS: There was a statistically significant difference in median HE4 levels between the post-menopausal (n = 2168) and pre-menopausal groups (n = 325) (36.46 vs. 24.04 pmol/L, Z = -14.41, P < 0.001). HE4 increased significantly with age in the post-menopausal groups (H = 408.18, P < 0.001) but not in the pre-menopausal subjects (Z = -0.43, P = 0.67). The upper 95th percentile of HE4 levels were 44.63 pmol/L for pre-menopausal women, 78.17 pmol/L for post-menopausal women, and 73.3 pmol/L for all women. In the post-menopausal population, the HE4 reference ranges were 13.15 to 47.31, 14.31 to 58.04, 17.06 to 73.51, 24.50 to 115.25, and 35.71 to 212.37 pmol/L for different age groups from forty divided by decade. The CA125 level was affected mainly by menopausal status and not age. CONCLUSIONS: Menopausal status and age were both important factors influencing the level of HE4, and age affected HE4 levels mainly in post-menopausal women. The HE4 level was higher in the post-menopausal population than in the pre-menopausal population and increased with age.

Fibrinogen alpha chain is up-regulated and affects the pathogenesis of endometriosis.

RESEARCH QUESTION: In the group's previous study, fibrinogen alpha chain (FGA) was identified as an up-regulated differential protein that was highly expressed in women with endometriosis. The current study investigated the expression and effects of FGA in endometriosis. It also evaluated the effects of FGA on human endometrial stromal cells and studied the possible mechanism. DESIGN: This was a cross-sectional analysis of FGA expression in plasma and endometrial tissue of matched eutopic and ectopic samples from women with endometriosis undergoing laparoscopic surgery and samples from women without endometriosis. Forty-four patients with endometriosis and 32 healthy control subjects who donated plasma for FGA analysis, including 26 matched cases of eutopic and ectopic endometria from endometriosis patients and 22 endometria from healthy control subjects, were analysed. The effects of FGA were studied in a human endometrial stromal cell line after transfection with FGA short interfering RNA (siRNA). RESULTS: FGA concentrations in serum and expression in eutopic and ectopic endometrial tissue were significantly higher in women with endometriosis than controls (P < 0.05 and P < 0.01 respectively), whereas FGA expression was not significantly different in eutopic compared with ectopic endometrial tissues from the same patients. High FGA concentrations in serum were related to disease stage and ovarian involvement, but were not affected by age and menstrual cycle. The knockdown of FGA expression by FGA siRNA inhibited hEM15A cellular adhesion, migration and invasion, and attenuated matrix metalloproteinase-2 (MMP-2) expression. CONCLUSIONS: High FGA expression in endometriosis was closely related to disease severity and affected cell adhesion, migration and invasion, which might play an important role in the pathogenesis of endometriosis.

Diagnostic value of HE4+ circulating tumor cells in patients with suspicious ovarian cancer.

Lacking a satisfactory screening test, ovarian cancer is frequently diagnosed at a late stage, leading to poor patient outcomes. This study investigated the diagnostic value of circulating tumor cells (CTCs) in peripheral blood from patients with suspected ovarian tumors. Sixty-one women suspected of having an ovarian mass were prospectively enrolled in this study. CTCs were identified and counted using microfluidic isolation and immunofluorescent staining of CD45, HE4, and epithelial and mesenchymal (E&M) markers (epithelial cell adhesion molecule, cytokeratins, and vimentin). Thirty (49%) of the patients were diagnosed with ovarian cancer. DAPI+/E&M+/CD45-/HE4+ CTC counts were higher in these patients than in patients with benign tumors (p = 0.016). The receiver operating characteristic (ROC) curve showed that the sensitivity of CTCs was 73.3%, which was superior to that of CA125 (56.7%). In patients with elevated CA125 levels (≥35 U/ml), CTC counts still showed good specificity (86.7%). Our findings suggest the DAPI+/E&M+/CD45-/HE4+ CTC count is a useful diagnostic indicator in patients with suspected ovarian cancer.

Overexpression of GPNMB predicts an unfavorable outcome of epithelial ovarian cancer.

OBJECTIVE: Glycoprotein non-metastatic protein B (GPNMB) is a transmembrane glycoprotein that is expressed at higher levels in several malignant human tissues than those in matched normal tissues. Thus, GPNMB may serve as an attractive therapeutic target of cancer treatment. In this study, the prognostic value of GPNMB expression was examined in tumors derived from a cohort of patients with epithelial ovarian cancer (EOC). METHODS: GPNMB expression in matched formalin-fixed and paraffin-embedded tissue samples was evaluated by immunohistochemistry (IHC), whereas GPNMB mRNA expression in fresh-frozen biopsy tissues was detected using real-time quantitative PCR (qPCR). Meanwhile, the correlations of GPNMB expression with the clinical characteristics of EOC were assessed. Besides, survival data were analysed using Kaplan-Meier and Cox regression analyses, respectively. RESULTS: GPNMB expression was remarkably upregulated in EOC tissues compared with that in normal ovarian controls at both mRNA and protein levels. In addition, abundant GPNMB expression in EOC was correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.001), residual tumor (P = 0.036), and lymph node metastasis (P = 0.004). Furthermore, results of univariate and multivariate analyses indicated that GPNMB expression level was an independent prognostic factor of the progression-free survival (PFS) and overall survival (OS) (P < 0.001 and P < 0.001, respectively) for EOC patients. CONCLUSION: Upregulated GPNMB levels in EOC patients are associated with dismal prognosis. Moreover, findings in the current study indicate that GPNMB is a potentially useful prognostic predictor of the therapeutic approaches for EOC.

Evaluation of Circulating Endometrial Cells as a Biomarker for Endometriosis.

BACKGROUND: Circulating endometrial cells (CECs) have been reported to be present in the peripheral blood of women with endometriosis (EM), providing clear and specific evidence of the presence of ectopic lesions. In this study, we established a method with a high detection rate of CECs, assessed the diagnostic value of CECs for EM and compared with serum CA125, and proposed a hypothesis for the pathogenesis of EM from the new perspective of CECs. METHODS: The participants were enrolled prospectively from October 2015 to July 2016. The peripheral blood samples were collected from 59 participants, and the blood cells were isolated for immunofluorescence staining via microfluidic chips. The cells that were positive for vimentin/cytokeratin and estrogen/progesterone receptor and negative for CD45 were identified as CECs. The serum CA125 level was tested with electrochemiluminescence immunoassay. RESULTS: The detection rate of CECs reached 89.5% (17/19) in the EM group, which was significantly higher than that of the control group (15.0% [6/40], P < 0.001) and was independent of menstrual cycle phases. Furthermore, a positive CEC assay detected 4/5 cases of Stage I-II EM. In contrast, a positive CA125 test had limited value in detecting EM (13/19, 68.4%) and detected only one case of Stage I-II EM. CONCLUSION: CECs are promising biomarkers for EM with great potential for a noninvasive diagnostic assay.

Impact of PET/CT on radiation treatment in patients with esophageal cancer: A systematic review.

PURPOSE: With the advances in radiotracers, positron emission tomography/computed tomography (PET/CT) is recognized as a useful adjunct to anatomic imaging with CT, MRI and endoscopic ultrasonography (EUS). The objective of this review was to comprehensively analyze the roles of PET/CT for the radiotherapy of esophageal cancer. METHODS: In this review, we focused on issues concerning the application of PET/CT in TNM staging, target volume delineation and response to therapy, both for the primary tumor and regional lymph nodes. Furthermore, the following questions were addressed: how does PET/CT guide appropriate treatment protocols, how does it allow accurate tumor delineation and how does it guide prognosis and future treatment decisions. RESULTS AND CONCLUSION: For the staging of esophageal cancer, PET/CT played a crucial role in exploring distant malignant lymph nodes and metastasis with high sensitivity, specificity and accuracy. PET/CT using different radiotracer provided a serial of thresholding methods based on standardized uptake value (SUV) to assist in auto-contouring the gross tumor volume (GTV). The change in SUV may offer a potential paradigm of personalized treatment to definitive chemoradiotherapy (CRT). In total, PET/CT has sought to further optimize radiotherapy treatment planning for patients with esophageal cancer.

Dose-Dependent Associations between Wine Drinking and Breast Cancer Risk - Meta-Analysis Findings.

PURPOSE: To investigate any potential association between wine and breast cancer risk. MATERIALS AND METHODS: We quantitatively assessed associations by conducting a meta-analysis based on evidence from observational studies. In May 2014, we performed electronic searches in PubMed, EmBase and the Cochrane Library to identify studies examining the effect of wine drinking on breast cancer incidence. The relative risk (RR) or odds ratio (OR) were used to measure any such association. RESULTS: The analysis was further stratified by confounding factors that could influence the results. A total of twenty-six studies (eight case-control and eighteen cohort studies) involving 21,149 cases were included in our meta-analysis. Our study demonstrated that wine drinking was associated with breast cancer risk. A 36% increase in breast cancer risk was observed across overall studies based on the highest versus lowest model, with a combined RR of 1.0059 (95%CI 0.97-1.05) in dose-response analysis. However, 5 g/d ethanol from wine seemed to have protective value from our non-linear model. CONCLUSIONS: Our findings indicate that wine drinking is associated with breast cancer risk in a dose-dependent manner. High consumption of wine contributes to breast cancer risk with protection exerted by low doses. Further investigations are needed for clarification.

Small Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma in Cirrhotic Livers May Share Similar Enhancement Patterns at Multiphase Dynamic MR Imaging.

Purpose To assess the accuracy of magnetic resonance (MR) imaging-based differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in a cohort of patients with focal liver lesions and cirrhosis. Materials and Methods This study was institutional review board approved, and the requirement for informed consent was waived. Between January 2009 and December 2014, a cohort of cirrhotic patients, including 71 with ICC and 612 with HCC, underwent unenhanced T1- and T2-weighted MR imaging, gadolinium-based contrast material-enhanced dynamic phase imaging, and partial hepatectomy. Results of pathologic examinations were obtained for all patients. Clinical, radiologic, and pathologic results in these patients were analyzed and compared comprehensively. Differences in signal intensity on baseline and contrast material-enhanced images and dynamic enhancement patterns were evaluated and compared by using the χ(2) test or the Fisher exact test. Results The preoperative diagnoses of 517 of 683 lesions were confirmed pathologically. Five ICCs and 481 HCCs displayed contrast material washout in delayed phases (P < .001). Thirty-six ICCs and 23 HCCs displayed a progressive enhancement pattern (P < .001). Twenty-six ICCs and 63 HCCs displayed a stable enhancement pattern (P < .001). ICCs displayed significantly different enhancement patterns according to size (P = .022). Conclusion The accurate discrimination of small ICCs from HCCs in the setting of cirrhosis at MR imaging is difficult, as substantial proportions of ICCs and HCCs have similar enhancement patterns. Absence of contrast material washout at MR imaging is not a factor that prevents the misdiagnosis of HCC. (©) RSNA, 2016 Online supplemental material is available for this article.

The role of three-dimensional imaging in optimizing diagnosis, classification and surgical treatment of hepatocellular carcinoma with portal vein tumor thrombus.

BACKGROUND: Accurate assessment of characteristics of tumor and portal vein tumor thrombus is crucial in the management of hepatocellular carcinoma. AIMS: Comparison of the three-dimensional imaging with multiple-slice computed tomography in the diagnosis and treatment of hepatocellular carcinoma with portal vein tumor thrombus. METHOD: Patients eligible for surgical resection were divided into the three-dimensional imaging group or the multiple-slice computed tomography group according to the type of preoperative assessment. The clinical data were collected and compared. RESULTS: 74 patients were enrolled into this study. The weighted κ values for comparison between the thrombus type based on preoperative evaluation and intraoperative findings were 0.87 for the three-dimensional reconstruction group (n = 31) and 0.78 for the control group (n = 43). Three-dimensional reconstruction was significantly associated with a higher rate of en-bloc resection of tumor and thrombus (P = 0.025). Using three-dimensional reconstruction, significant correlation existed between the predicted and actual volumes of the resected specimens (r = 0.82, P < 0.01), as well as the predicted and actual resection margins (r = 0.97, P < 0.01). Preoperative three-dimensional reconstruction significantly decreased tumor recurrence and tumor-related death, with hazard ratios of 0.49 (95% confidential interval, 0.27-0.90) and 0.41 (95% confidential interval, 0.21-0.78), respectively. CONCLUSION: For hepatocellular carcinoma with portal vein tumor thrombus, three-dimensional imaging was efficient in facilitating surgical treatment and benefiting postoperative survivals.

Adjuvant Radiotherapy after Breast Conserving Treatment for Breast Cancer: A Dosimetric Comparison between Volumetric Modulated Arc Therapy and Intensity Modulated Radiotherapy.

BACKGROUND: Radiotherapy is an important treatment of choice for breast cancer patients after breast- conserving surgery, and we compare the feasibility of using dual arc volumetric modulated arc therapy (VMAT2), single arc volumetric modulated arc therapy (VMAT1) and Multi-beam Intensity Modulated Radiotherapy (M-IMRT) on patients after breast-conserving surgery. MATERIALS AND METHODS: Thirty patients with breast cancer (half right-sided and half left-sided) treated by conservative lumpectomy and requiring whole breast radiotherapy with tumor bed boost were planned with three different radiotherapy techniques: 1) VMAT1; 2) VMAT2; 3) M-IMRT. The distributions for the planning target volume (PTV) and organs at risk (OARs) were compared. Dosimetries for all the techniques were compared. RESULTS: All three techniques satisfied the dose constraint well. VMAT2 showed no obvious difference in the homogeneity index (HI) and conformity index (CI) of the PTV with respect to M-IMRT and VMAT1. VMAT2 clearly improved the treatment efficiency and can also decrease the mean dose and V5Gy of the contralateral lung. The mean dose and maximum dose of the spinal cord and contralateral breast were lower for VMAT2 than the other two techniques. The very low dose distribution (V1Gy) of the contralateral breast also showed great reduction in VMAT2 compared with the other two techniques. For the ipsilateral lung of right-sided breast cancer, the mean dose was decreased significantly in VMAT2 compared with VMAT1 and M-IMRT. The V20Gy and V30Gy of the ipsilateral lung of the left- sided breast cancer for VMAT2 showed obvious reduction compared with the other two techniques. The heart statistics of VMAT2 also decreased considerably compared to VMAT1 and M-IMRT. CONCLUSIONS: Compared to the other two techniques, the dual arc volumetric modulated arc therapy technique reduced radiation dose exposure to the organs at risk and maintained a reasonable target dose distribution.

Low programmed cell death 5 expression is a prognostic factor in ovarian cancer.

BACKGROUND: Ovarian cancer is a leading gynecological malignancy. We investigated the prognostic value of programmed cell death 5 (PDCD5) in patients with ovarian cancer. METHODS: Expression levels of PDCD5 mRNA and protein were examined in six ovarian cancer cell lines (SKOV3, CAOV3, ES2, OV1, 3AO, and HOC1A) and one normal ovarian epithelial cell line (T29) using reverse transcription polymerase chain reaction, Western blotting, and flow cytometry. After inducing PDCD5 induction in SKOV3 cells or treating this cell line with taxol or doxorubicin (either alone or combined), apoptosis was measured by Annexin V-FITC/propidium iodide staining. Correlations between PDCD5 protein expression and pathological features, histological grade, FIGO stage, effective cytoreductive surgery, and serum cancer antigen-125 values were evaluated in patients with ovarian cancer. RESULTS: PDCD5 mRNA and protein expression were downregulated in ovarian cancer cells. Recombinant human PDCD5 increased doxorubicin-induced apoptosis in SKOV3 cells (15.96 ± 2.07%, vs. 3.17 ± 1.45% in controls). In patients with ovarian cancer, PDCD5 expression was inversely correlated with FIGO stage, pathological grade, and patient survival (P < 0.05, R = 0.7139 for survival). CONCLUSIONS: PDCD5 expression is negatively correlated with disease progression and stage in ovarian cancer. Therefore, measuring PDCD5 expression may be a good method of determining the prognosis of ovarian cancer patients.

Computed tomography manifestations of histologic subtypes of retroperitoneal liposarcoma.

OBJECTIVE: Liposarcoma (LPS) is the most common soft tissue sarcoma and accounts for approximately 20% of all mesenchymal malignancies, often occurring in deep soft tissue of retroperitoneal space. Accurate preoperative diagnosis is therefore necessary. We explored whether computed tomography (CT) could be used to differentiate between the various types of retroperitoneal liposarcoma (RPLS). METHOD: Forty-seven cases of RPLS, diagnosed surgically and histologically, were analyzed retrospectively. CT features were correlated with postoperative pathological appearance. RESULTS: The study radiologist identified 29, 11, 2, 2 and 3 RPLS as atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL), dedifferentiated liposarcoma (DDL), myxoid/round cell liposarcoma (ML/RCL), pleomorphic liposarcoma (PL) and mixed-type liposarcoma. Analysis of CT scans revealed the following typical findings of the different subtypes of RPLS: ALT/WDL was mainly visible as a well-delineated fatty hypodense tumor with uniform density and integrity margin; DDL was marked by the combination of focal nodular density and hypervascularity. ML/RCL, PL and mixed liposarcoma showed malignant biological behaviour and CT findings need further studies. CONCLUSIONS: CT scanning can reveal important details including internal components, margins and surrounding tissues. Based on CT findings, tumor type can be roughly evaluated and biopsy location and therapeutic scheme guided.

AT-406, an IAP inhibitor, activates apoptosis and induces radiosensitization of normoxic and hypoxic cervical cancer cells.

IAP antagonists increased the antitumor efficacy of X-irradiation in some types of cancers, but their effects on hypoxic cancer cells remain unclarified. We aims to investigate the radiosensitizing effect of an IAP inhibitor AT-406 on cervical cancer cell lines under both normoxia and hypoxia conditions. Hela and Siha cells were treated to investigate the effects of drug administration on cell proliferation, apoptosis, and radiosensitivity. Western blot analysis was used to determine the role of AT-406 in inhibition of IAPs. The pathway of apoptosis was characterized by caspases activity assay. AT-406 potently sensitized Hela cells but not Siha cells to radiation under normoxia. Notably, the radiosensitizing effect of AT-406 on hypoxic cells was more evident than on normoxic cells in both cell lines. Further mechanism studies by western blot showed that under normoxia AT-406 decreased the level of cIAP1 in Hela cells in a dose-dependent manner; while additional downregulation of XIAP expression was induced by AT-406 treatment under hypoxia in both cell lines. Finally, AT-406 works on both extrinsic death receptor and intrinsic mitochondrial apoptosis pathways to activate apoptosis. Totally, AT-406 acts as a strong radiosensitizer in human cervical cancer cells, especially in hypoxic condition.

Fenofibrate increases radiosensitivity in head and neck squamous cell carcinoma via inducing G2/M arrest and apoptosis.

Radiation therapy is an important treatment for head and neck squamous cell carcinoma (HNSCC). However, how to promote radiation sensitivity in HNSCC remains a challenge. This study aimed to investigate the radiosensitizing effects of fenofibrate on HNSCC and explore the underlying mechanisms. HNSCC cell lines CNE-2 and KB were subjected to ionizing radiation (IR), in the presence or absence of fenofibrate treatment. Cell growth and survival, apoptosis and cell cycle were evaluated. In addition, CNE-2 cells were xenografted into nude mice and subjected to IR and/ or fenofibrate treatment. The expression of cyclinB and CDK1 was detected by Western blotting. Our results showed that fenofibrate efficiently radiosensitized HNSCC cells and xenografts in mice, and induced apoptosis and G2/M arrest via reducing the activity of the CDK1/cyclinB1 kinase complex. These data suggest that fenofibrate could be a promising radiosensitizer for HNSCC radiotherapy.

[Expression and significance of tumor necrosis factor receptor associated protein 1 in epithelial ovarian cancer].

OBJECTIVE: To explore the levels of TRAP1 and its roles in patients with ovarian tumor, and investigate the correlation between the expressions of TRAP1 in ovarian tumor tissues and related clinicopathological characteristics. METHODS: 38 health women, 50 cases of benign ovarian tumors and 114 cases of epithelial ovarian cancers were examined by real-time RT-PCR and immunohistochemical staining. RESULTS: The immunohistochemical analysis demonstrated that TRAP1 protein was mainly located in the cytoplasm, the protein and mRNA expression of TRAP1 in ovarian cancer were significantly increased compared with those of normal control and benign tumor (P < 0.05). The protein and mRNA expression of TRAP1 was related to histological grade and pathologic types (P < 0.05), but not age, clinical stages, lymphnode metastasis or omental metastasis, and the amount of ascites (P > 0.05). CONCLUSION: The high expression of TRAP1 may play potential role in epithelial ovarian cancer occurrence and progress.

Resveratrol inhibits oesophageal adenocarcinoma cell proliferation via AMP-activated protein kinase signaling.

Resveratrol has been examined in several model systems for potential effects against cancer. Adenosine monophosphate-activated protein kinase (AMPK) is reported to suppress proliferation in most eukaryocyte cells. Whether resveratrol via AMPK inhibits proliferation of oesophageal adenocarcinoma cells (OAC) is unknown. The aim of this study was to determine the roles of AMPK in the protective effects of resveratrol in OAC proliferation and to elucidate the underlying mechanisms. Treatment of cultured OAC derived from human subjects or cell lines with resveratrol resulted in decreased cell proliferation. Further, inhibition of AMPK by pharmacological reagent or genetical approach abolished resveratrol-suppressed OAC proliferation, reduced the level of p27Kip1, a cyclin-dependent kinase inhibitor, and increased the levels of S-phase kinase-associated protein 2 (Skp2) of p27Kip1-E3 ubiquitin ligase and 26S proteasome activity reduced by resveratrol. Furthermore, gene silencing of p27Kip1 reversed resveratrol-suppressed OAC proliferation. In conclusion, these findings indicate that resveratrol inhibits Skp2-mediated ubiquitylation and 26S proteasome-dependent degradation of p27Kip1 via AMPK activation to suppress OAC proliferation.

Association of four polymorphisms in the death receptor 4 gene with cancer risk: an updated meta-analysis.

To date, no scientific consensus about the associations of DR4 C626G, A683C, A1322G, and G422A polymorphisms with cancer risk has been reached. Therefore, we conducted a meta-analysis to assess the associations. This meta-analysis involved 16 studies, of which 15 (4,261 cases and 4,598 controls) described C626G genotypes, 8 (2,898 cases and 3,135 controls) described A683C genotypes, 6 (1,564 cases and 1,673 controls) described A1322G genotypes, and 5 (584 cases and 607 controls) described A683C genotypes. We associated all the four polymorphisms with cancer risk. The C626G polymorphism was associated with slightly elevated cancer risk in recession model comparison [odds ratio (OR)=1.12, 95 % confidence interval (CI)=1.00-1.26, P heterogeneity=0.425]. In the subgroup analysis by cancer type, significantly elevated cancer risks were found among groups with lung cancer for heterozygote comparison (OR=1.76, 95 % CI=1.00-3.09, P heterogeneity=0.863). The A1322G polymorphism was associated with significantly elevated cancer risk in the different models (heterozygote comparison: OR=1.21, 95 % CI=1.00-1.46, P heterogeneity=0.347; dominant model: OR=1.21, 95 % CI=1.01-1.46, P heterogeneity=0.189; allele model comparison for G allele vs. A allele: OR=1.17, 95 % CI=1.02-1.35, P heterogeneity=0.173). The A683C and G422A polymorphisms were not associated with cancer risk in all genetic models. The C626G and A1322G polymorphisms are associated with increased cancer risk, but the A683C polymorphism is rarely associated with cancer risk.