Current Issue : April - June Volume : 2015 Issue Number : 2 Articles : 5 Articles
Background: Over the past few years, the concurrent use of cisplatin-based chemotherapy and radiation therapy\nhas dramatically improved the local response and increased overall survival in early-stage cervical cancer. However,\nfor the advanced stages of the disease this standard treatment has proved insufficient. We investigated the capacity\nof Mifepristone and ICI 182,780, which are anti-progestin and anti-estrogen drugs, respectively, to act as chemoradiosensitizing\nagents in cervical cancer cells and cervix xenografts.\nMethods: The effect of chemo-radiation alone or combined with Mifepristone or ICI 182,780 was evaluated in HeLa\ncells and with tumor growth in cervix xenografts. After concomitant chemo-radiotherapy, the effect of each of these\nantihormonal agents on apoptosis (determined by Annexing V assay) and the cell cycle phases were determined by\nflow cytometry. The expression of angiogenic factor VEGF in tumor samples was determined using quantitative\nRT-PCR analysis of VEGF gene expression.\nResults: Compared to radiation alone or radiation/cisplatin therapy, there was significantly higher cytotoxicity and a\ngreater antitumoral effect with the combined application of radiation/cisplatin and Mifepristone or ICI 182,780.\nAnalyses of the apoptosis and cell cycle demonstrated changes only with ICI, not with Mifepristone, when was\napplied in combination with radiation/cisplatin. The analysis of VEGF mRNA expression levels in tumors at the end\nof the study demonstrated a significant inhibition, compared to radiation only or the radiation/cisplatin treatment,\nafter concurrent chemo-radiotherapy and each one of the antihormonal drugs.\nConclusion: Mifepristone and ICI 182,780 may be potentially promising chemo-radiosensitizing compounds to be\nused in combination with ionizing irradiation and cisplatin in the treatment of patients with advanced cervical cancer....
Background: EphA5 is a member of the Eph/ephrin family and plays a critical role in the regulation of carcinogenesis.\nA significant reduction of EphA5 transcripts in high-grade prostate cancer tissue was shown using a transcriptomic\nanalysis, compared to the low-grade prostate cancer tissue. As less is known about the mechanism of EphA5\ndownregulation and the function of EphA5, here we investigated the expression and an epigenetic change of EphA5\nin prostate cancer and determined if these findings were correlated with clinicopathologic characteristics of prostate\ncancer.\nMethods: Seven prostate cell lines (RWPE-1, LNCap, LNCap-LN3, CWR22rv-1, PC-3, PC-3M-LN4, and DU145), thirty-nine\nBPH, twenty-two primary prostate carcinomas, twenty-three paired noncancerous and cancerous prostate tissues were\nexamined via qRT-PCR, methylation-specific PCR, bisulfite sequencing, immunohistochemistry and western blotting. The\nrole of EphA5 in prostate cancer cell migration and invasion was examined by wound healing and transwell assay.\nResults: Downregulation or loss of EphA5 mRNA or protein expression was detected in 28 of 45 (62.2%) prostate\ncarcinomas, 2 of 39 (5.1%) hyperplasias, and all 6 prostate cancer cell lines. Methylation of the EphA5 promoter region\nwas present in 32 of 45 (71.1%) carcinoma samples, 3 of 39 (7.7%) hyperplasias, and the 6 prostate cancer cell lines.\nAmong 23 paired prostate carcinoma tissues, 16 tumor samples exhibited the hypermethylation of EphA5, and 15 of\nthese 16 specimens (93.8%) shown the downregulation of EphA5 expression than that of their respectively matched\nnoncancerous samples. Immunostaining analysis demonstrated that the EphA5 protein was absent or down-regulated\nin 10 of 13 (76.9%) available carcinoma samples, and 8 of these 10 samples (80.0%) exhibited hypermethylation. The\nfrequency of EphA5 methylation was higher in cancer patients with an elevated Gleason score or T3-T4 staging.\nFollowing the treatment of 6 prostate cancer cell lines with 5-aza-2?-deoxycytidine, the levels of EphA5 mRNA were\nsignificantly increased. Prostate cancer cells invasion and migration were significantly suppressed by ectopic expression\nof EphA5 in vitro.\nConclusion: Our study provides evidence that EphA5 is a potential target for epigenetic silencing in primary prostate\ncancer and is a potentially valuable prognosis predictor and thereapeutic marker for prostate cancer....
Background: Metastatic dissemination can exist before a pathologically and clinically detectable manifestation. The\nstructural heterogeneity of colon cancer (CC) in histological sections with respect to the morphology of tumor\naggressiveness and composition of the tumor microenvironment raises the question of whether the microscopical\ntumor architecture enables a discrimination of groups with different metastatic potential. This would result in an\nassessment of the prognosis and provision of an ancillary tool for the therapeutic management after surgery,\nbeside the estimation of the local tumor extent.\nMethods: In order to identify predictive biomarkers for metastasis of locally advanced CC, which can easily be\nintegrated into the pathologist�s daily routine diagnostic activity, we determined tumor budding, peritumoral\ninflammation, extent of desmoplasia and necrosis, density of macro- and microvascular blood vessels and functional\nstate of lymphatics in the tumor center, invasive margin and tumor-free surrounding tissue in 86 non-metastatic,\nlymphogenous-metastatic and haematogenous-metastatic, subserosa-invasive CC.\nResults: Features influencing nodal metastasis in the univariate analysis included high tumor budding (p = 0.004),\nhigh large vessel density in the subserosa (p = 0.043), abundant desmoplasia (p = 0.049), non-finger-like desmoplastic\npattern (p = 0.051) and absent lymphocellular intratumoral inflammation (p = 0.084). In the multivariate analysis,\nwith the exception of large vessel density, these pathomorphological features were independent risk factors for\nlymphogenous metastasis (p = 0.023, p = 0.017, p = 0.037, p = 0.012, respectively) with a good discrimination ability\n(AUC of 0.853). Features associated with distant metastasis in the univariate analysis included high tumor budding\n(p = 0.002), low intratumoral small vessel density (p = 0.013), absent lymphocellular intratumoral inflammation\n(p = 0.048) and abundant necrosis (p = 0.073). In the multivariate analysis only tumor budding was an independent\npredictor for haematogenous metastasis (p = 0.007) with a good discrimination ability (AUC of 0.829).\nConclusions: Thus, mainly tumor budding but also the described structural characteristics of the peritumoral\ntissue appears to reflect the metastatic potential of locally advanced CC and therefore should be stated in\npathological reports....
Background: DNAX accessory molecule-1 (DNAM-1) is an activating receptor constitutively expressed by macrophages/\ndendritic cells and by T lymphocytes and Natural Killer (NK) cells, having an important role in anticancer responses; in\nthis regard, combination therapies able to enhance the expression of DNAM-1 ligands on tumor cells are of therapeutic\ninterest. In this study, we investigated the effect of different nitric oxide (NO) donors on the expression of the DNAM-1\nligand Poliovirus Receptor/CD155 (PVR/CD155) in multiple myeloma (MM) cells.\nMethods: Six MM cell lines, SKO-007(J3), U266, OPM-2, RPMI-8226, ARK and LP1 were used to investigate the activity of\ndifferent nitric oxide donors [DETA-NO and the NO-releasing prodrugs NCX4040 (NO-aspirin) and JS-K] on the expression\nof PVR/CD155, using Flow Cytometry and Real-Time PCR. Western-blot and specific inhibitors were employed\nto investigate the role of soluble guanylyl cyclase/cGMP and activation of the DNA damage response (DDR).\nResults: Our results indicate that increased levels of nitric oxide can upregulate PVR/CD155 cell surface and\nmRNA expression in MM cells; in addition, exposure to nitric oxide donors renders myeloma cells more\nefficient to activate NK cell degranulation and enhances their ability to trigger NK cell-mediated cytotoxicity.\nWe found that activation of the soluble guanylyl cyclase and increased cGMP concentrations by nitric oxide is\nnot involved in the up-regulation of ligand expression. On the contrary, treatment of MM cells with nitric oxide\ndonors correlated with the activation of a DNA damage response pathway and inhibition of the ATM /ATR/Chk1/2\nkinase activities by specific inhibitors significantly abrogates up-regulation.\nConclusions: The present study provides evidence that regulation of the PVR/CD155 DNAM-1 ligand expression\nby nitric oxide may represent an additional immune-mediated mechanism and supports the anti-myeloma activity\nof nitric oxide donors....
Background: SBA is a rare tumour which carries a poor prognosis. Very few data on prognostic factors and\ntreatment outcomes are available. We conducted a retrospective analysis of patients treated for SBA at our\ninstitution.\nMethods: Clinico-pathological characteristics, treatments and outcomes of all the SBA patients treated consecutively\nfrom 1996 to 2011 were retrospectively collected. The prognostic value of baseline factors was assessed using the Cox\nregression model. The Kaplan-Meier method was used to estimate the survival outcomes.\nResults: Eighty-four patients with SBA were treated during the study period. Of these, 48 presented with early stage\nSBA, while 36 had unresectable disease. All early stage SBA patients (58.3% males; median age, 59 years) underwent\nresection (R0 in 44/48) and 27 (56%) received adjuvant chemotherapy. Median relapse-free survival and overall survival\n(OS) were 31.1 months (95% CI: 8.0-54.3) and 42.9 (95% CI: 0ââ?¬â??94.9), respectively. In univariate analyses, poor histological\ndifferentiation (p = 0.025) and lymphovascular invasion (p = 0.003) were prognostic for OS. In the group of patients with\nrelapsed, unresectable or metastatic disease (n = 59), systemic chemotherapy was administered in 46 cases (78%). The\nresponse rate to first line chemotherapy was 50%. Median progression-free survival and OS were 8.8 (95% CI: 5.5-12.3)\nand 12.8 months (95% CI: 8.4-17.2), respectively. In univariate analyses, low albumin (p = 0.041) and high platelet count\n(p = 0.007) were prognostic for OS....
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