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Background and Aims: MicroRNAs (miRNA) can act as oncogenes or tumor suppressors. Polymorphisms present in pri-, pre- and mature miRNAs can potentially modulate the expression of hundreds of genes, broadly affecting miRNA function. Notably, the rs11614913 SNP in miR-196a2 has been implicated in carcinogenesis, but its association with colorectal cancer (CRC) remains unexplored. We performed a case−control study to investigate the genetic association between this functional SNP and CRC susceptibility and progression. Methods: We genotyped the rs11614913 SNP in 252 CRC patients and 543 healthy controls by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). In addition, we examined miR-196a expression level in colorectal cancer tissues (n = 50) obtained from the studied CRC patients. Results: Frequency of the CC genotype was higher in CRC patients than controls, implying that the subjects with the CC genotype or C allele containing genotypes (CT and CC) have a higher risk of CRC. However, no significant association between this polymorphism and CRC progression was observed. Expression analysis revealed that rs11614913 CC or carrying at least one C allele was associated with a significantly increased level of mature miR-196a (p = 0.010 or = 0.022). Conclusions: The present study provides the first evidence that miR-196a2 polymorphism may contribute to CRC susceptibility in a Chinese population through modulating mature miR-196a expression. [ABSTRACT FROM AUTHOR]

Purpose: To determine the impact of prolonged fraction delivery times (FDTs) simulating intensity-modulated radiotherapy (IMRT) on cultured nasopharyngeal carcinoma (NPC) cell killing. Methods and Material: Cultured NPC cell lines CNE1 and CNE2 were used in this study. The biological effectiveness of fractionated irradiation protocols simulating conventional external beam radiotherapy and IMRT (FDT of 15, 36, and 50 minutes) was estimated with standard colony assay, and the differences in cell surviving fractions after irradiation with different protocols were tested by use of the paired t test. The impact degree of prolonged FDTs (from 8 to 50 minutes) on cell killing was also assessed by the dose-modifying factors, which were estimated by comparing the effectiveness of intermittently delivered 2 Gy with that of continuously delivered 1.5 to 2 Gy. Results: The cell surviving fractions of both CNE1 and CNE2 after fractionated irradiation simulating IMRT were higher than those simulating conventional external beam radiotherapy (p < 0.05). The dose-modifying factors for a fraction dose of 2 Gy increased from 1.05 to 1.18 for CNE1 and from 1.05 to 1.11 for CNE2 with the FDT being prolonged from 15 to 50 minutes. Conclusions: This study showed that the prolonged FDTs simulating IMRT significantly decreased the cell killing in both CNE1 and CNE2 cell lines, and these negative effects increased with the FDT being prolonged from 15 to 50 minutes. These effects, if confirmed by in vivo and clinical studies, need to be considered in designing IMRT treatments for NPC. [ABSTRACT FROM AUTHOR]

Purpose: To test the radiosensitising effects of a tumour-suppressor gene, phosphatase and tensin homologue deleted from chromosome 10 (PTEN), in hepatocellular carcinoma cells (HCC). Materials and methods: Radiation-induced wild-type PTEN or mutant PTEN was transfected into the SMMC-7721 human hepatocellular carcinoma cells. The expressions of PTEN and serine/threonine protein kinase (Akt) were detected by Western blot analysis. 3-(4,5)-dimethylthiahiazo-(-z-y1)- 3,5-di-phenytetrazoliumromide (MTT) absorbance and clonogenic survival assays were used to determine cell viability, proliferation and radiosensitivity. By performing cell-cycle analysis, terminal deoxynucleotidyltransferase (TdT)-mediated dUTP biotin nick end labelling (TUNEL) assays and gamma-histone H2A (γ-H2AX) formation assays, we were able to explore the mechanism of PTEN enhancement of radiosensitivity. Results: Restoration of wild-type PTEN induced growth suppression and sensitised the cells to ionising radiation specifically by its lipid phosphatase activity through the PTEN-phosphatidylinositol 3-kinase (PI3K)-Akt signalling pathway. Restoring PTEN function correlated with G2/M arrest, apoptosis and the retardation of repair of radiation-induced double strand breaks (DSB). Conclusions: Our study suggests that strategies designed to restore the expression of PTEN may represent promising new therapies for sensitising HCC cells to ionising radiation. [ABSTRACT FROM AUTHOR]

Purpose: Assuming F-18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET)/computed tomography (CT) to be more accurate in representing the true disease extent than CT alone, we prospectively designed this study to evaluate how the addition of FDG-PET influences CT-based radiotherapy planning for locally recurrent nasopharyngeal carcinoma. Patients and Methods: All patients underwent FDG-PET/CT simulation scans. For each patient, the gross tumor volume (GTV) was separately delineated with or without the addition of PET information and defined as GTVPET/CT and GTVCT, respectively. Corresponding planning target volumes (PTV) were generated for the GTVCT (PTVCT) and GTVPET/CT (PTVPET/CT). Three-dimensional conformal radiotherapy plans were separately created for PTVCT and PTVPET/CT. To assess the potential geographic miss of the PET/CT-based disease in CT-based treatment planning, the size and location of the GTVPET/CT, PTVPET/CT, and PTVCT were analyzed, and the three-dimensional conformal radiotherapy plans created using the PTVCT were evaluated with the GTVPET/CT and PTVPET/CT information. Results: A total of 43 patients were enrolled in this study. Distant metastasis was found in 4 patients with the addition of the PET information. The 39 patients without distant metastasis proceeded to three-dimensional conformal radiotherapy planning. Inadequate coverage of the GTVPET/CT and PTVPET/CT by the PTVCT occurred in 7 (18%) and 20 (51%) patients, respectively. This resulted in <95% of the GTVPET/CT and PTVPET/CT receiving ≥95% of the prescribed dose in 4 (10%) and 13 (33%) patients, respectively. Conclusions: The addition of FDG-PET information might influence CT-based radiotherapy planning for locally recurrent nasopharyngeal carcinoma by altering the definition of the target volume, with the potential to avoid a geographic miss of true disease. [Copyright &y& Elsevier]

Purpose: The purpose of this study was to evaluate the role of [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) in influencing salvage treatment decision making for locally persistent nasopharyngeal carcinoma (NPC). Methods and Materials: A total of 33 NPC patients with histologic persistence at nasopharynx 1 to 6 weeks after a full course of radiotherapy underwent both computed tomography (CT) and FDG-PET/CT simulation at the same treatment position. The salvage treatment decisions, with regard to the decision to offer salvage treatment and the definition of gross tumor volume (GTV), were made before knowledge of the FDG-PET findings. Subsequently the salvage treatment decisions were made again based on the FDG-PET findings and compared with the pre-FDG-PET decisions. Results: All 33 patients were referred for salvage treatment in the pre-FDG-PET decision. After knowledge of the FDG-PET results, the decision to offer salvage treatment was withdrawn in 4 of 33 patients (12.1%), as no abnormal uptake of FDG was found at nasopharynx. Spontaneous remission was observed in repeat biopsies and no local recurrence was found in these 4 cases. For the remaining 29 patients, GTV based on FDG-PET was smaller than GTV based on CT in 24 (82.8%) cases and was greater in 5 (17.2%) cases, respectively. The target volume had to be significantly modified in 9 of 29 patients (31%), as GTV based on FDG-PET images failed to be enclosed by the treated volume in the salvage treatment plan performed based on GTV based on CT simulation images. Conclusion: Use of FDG-PET was found to influence the salvage treatment decision making for locally persistent NPC by identifying patients who were not likely to benefit from additional treatment and by improving accuracy of GTV definition in salvage treatment planning. [ABSTRACT FROM AUTHOR]

Purpose: To compare the outcomes of three-dimensional conformal radiotherapy (3D-CRT) and intracavitary brachytherapy (ICBT) as salvage treatment for locally persistent nasopharyngeal carcinoma.Methods and materials: Between March 1994 and November 2001, a total of 117 patients with locally persistent nasopharyngeal carcinoma received salvage treatment for 2–8 weeks (median, 4 weeks) after a full course of conventional external beam RT. Of the 117 patients, 54 were salvaged with 3D-CRT (3D group) and 63 with ICBT (BT group). No statistically significant differences were found in the patient characteristics between the two groups (p >0.05). In the 3D group, the planning target volume for 3D-CRT was defined as the persistent disease plus a 5-mm margin; three to seven static conformal coplanar or noncoplanar portals were delivered for each fraction. The median salvage dose was 24 Gy (range, 18–38 Gy), with fraction size of 2.0 Gy/d. In the BT group, a median salvage dose of 20 Gy (range, 15–30 Gy) was delivered with a 192Ir source, at 5 Gy/fraction, twice weekly. The brachytherapy dose was prescribed at a distance of 1 cm from the center of the surface as defined by the sources, irrespective of the extent of persistent disease. The actuarial rates of survival were estimated using the Kaplan-Meier method. Potential differences in the actuarial outcomes between groups were evaluated using the Mantel log–rank test. Multivariate analyses were performed with the Cox regression proportional hazards model.Results: The 5-year actuarial rates of overall survival, disease-specific survival, and local failure-free survival for the 3D group and BT group were 64.50% vs. 55.78% (p = 0.33), 70.03% vs. 59.56% (p = 0.11), and 88.93% vs. 76.28% (p = 0.07), respectively. Subgroup analysis showed that the 5-year actuarial local failure-free survival rate of patients with initially diagnosed T3-T4 disease for the 3D group and BT group was 84.01% vs. 60.50% (p = 0.03). The incidence of Grade 3-4 late complications was comparable between the two groups. Multivariate analyses performed in the whole group showed that T stage at initial diagnosis and the salvage technique (3D-CRT or ICBT) were the statistically significant, independent prognostic factors for local failure-free survival (p = 0.00 and p = 0.02, respectively).Conclusion: 3D-CRT seemed to provide better local control than ICBT as a salvage treatment for locally persistent nasopharyngeal carcinoma, especially in patients with initially diagnosed T3-T4 disease. CT/MRI evaluation of the extent of persistent disease is recommended for technique selection of salvage RT. Patients should be cautioned about the potentially increased complications. The optional time for salvage treatment remains controversial. [Copyright &y& Elsevier]

The aim of this study was to ascertain the diagnostic value of serum squamous cell carcinoma antigen (SCCA) and SCCA-IgM for hepatocellular carcinoma (HCC). After a comprehensive search of PubMed and Web of Science databases, we identified eligible studies on the diagnostic value serum SCCAs for HCC. The quality of the eligible studies was assessed using the revised Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2) tool. The overall diagnostic value of SCCAs for HCC was pooled using a bivariate model. Twelve studies were included in this systematic review and meta-analysis. The pooled sensitivities for SCCA and SCCA-IgM were 0.61 (95% confidence interval [CI], 0.37–0.81) and 0.70 (95% CI, 0.55–0.82), respectively. The corresponding specificities were 0.80 (95% CI, 0.52–0.94) and 0.62 (95% CI, 0.51–0.72), respectively. The areas under summary receiver operating characteristic (sROC) curves for SCCA and SCCA-IgM were 0.76 (95% CI, 0.72–0.80) and 0.70 (95% CI, 0.66–0.74), respectively. Major design deficiencies of the included studies were two-gate design and partial verification bias. Therefore, we concluded that both serum SCCA and SCCA-IgM have a fair diagnostic value for HCC. [ABSTRACT FROM PUBLISHER]

Background: Caner-initiating cells (CICs or cancer stem cells) have been shown both experimentally and clinically to be resistant to radiation. The mechanism underlying radioresistance remains unclear. Methods: In the present study, we screened 51 genes which are potentially important in mediating radioresistance of breast CICs. Results: The expression of AKT1 and AKT2 at protein and mRNA levels was dramatically increased among the screened genes by 8 Gy radiation treatment in MCF-7 mammosphere cells (predominantly CD24/CD44 CICs), but not in the bulk population of MCF-7 cells (predominantly CD24/CD44). Using apoptosis and clonogenic survival assays, we found pharmacological inhibition of AKT with selective inhibitors of AKT sensitized MCF-7 mammosphere cells, but not MCF-7 monolayer cells to radiation. Conclusion: The present findings suggest that treatment with AKT inhibitors prior to ionizing radiation treatment may be a potential benefit to patients with breast cancer, in particular to eradiate breast CICs. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To assess the dosimetric and clinical results of three-dimensional conformal radiotherapy (3D CRT) for locally recurrent nasopharyngeal carcinoma (NPC). Methods: A total of 86 patients with locally recurrent NPC were retreated with 3D CRT. The median prescribed dose was 68Gy with 2Gy per fractionation. Dosimetric quality was evaluated with dose distribution in planning target volume (PTV) and specified organs at risk (OAR), dose conformity index (CI) and dose homogeneity index (HI). The actuarial rate of local failure-free (LFF), overall survival (OS) and major late toxicities (MLT) were estimated with Kaplan–Meier method. Multivariate analysis for prognosis was performed using the Cox regression proportional hazards model. Results: The mean dose to PTV averaged 66.8Gy, and the dose to specified OAR was acceptable. The average value of CI and HI was 0.59 and 9.1%. The 5-year actuarial rate of LFF and OS was 71 and 40%, respectively. The 5-year actuarial incidence of MLT≥Grade 3 and ≥Grade 4 were 100 and 49%, respectively. The major prognostic factors were T stage and the size of gross tumor volume (GTV). Advanced T stage and large GTV volume were associated with poor LFF and OS and high risk of MLT. Conclusion: The dosimetric quality of 3D CRT for locally recurrent NPC is generally excellent. A relatively high local control was achieved with this technique. However, the incidence of late toxicities were not found to decrease as originally expected. Early diagnosis of the recurrence and reasonable definition of the target volume are crucial to achieve a better outcome. [Copyright &y& Elsevier]

Upregulation of histone methyltransferase SET domain bifurcated 1 (SETDB1) is associated with poor prognosis in cancer patients. However, the mechanism of oncogenicity of SETDB1 in cancer is hitherto unknown. Here, we show that SETDB1 is upregulated in human colorectal cancer (CRC) where its level correlates with poor clinical outcome. Ectopic SETDB1 promotes CRC cell proliferation, whereas SETDB1 attenuation inhibits this process. Flow cytometry reveals that SETDB1 promotes proliferation by driving the CRC cell cycle from G0/G1 phase to S phase. Mechanistically, SETDB1 binds directly to the STAT1 promoter region resulting in increased STAT1 expression. Functional characterization reveals that STAT1-CCND1/CDK6 axis is a downstream effector of SETDB1 -mediated CRC cell proliferation. Furthermore, SETDB1 upregulation is sufficient to accelerate in vivo proliferation in xenograft animal model. Taken together, our results provide insight into the upregulation of SETDB1 within CRC and can lead to novel treatment strategies targeting this cell proliferation-promoting gene. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is a type of cancer that is characterized by increased invasiveness, metastatic potential and tumor recurrence. Camptothecin has been demonstrated to exhibit anticancer activity. However, the potential underlying molecular mechanisms mediated by camptothecin in NPC cells remain elusive. In the present study, the efficacy of camptothecin for NPC was investigated in vitro and in vivo. Additionally, the potential signaling pathway mediated by camptothecin in NPC cells was also examined. The results indicated that the viability and aggressiveness of NPC cells were suppressed by camptothecin treatment in a dose-dependent manner. Camptothecin administration downregulated the expression levels of cell-cycle-associated proteins including cyclin 1, cyclin-dependent kinase (CDK)1 and CDK2 in NPC cells. Expression levels of migration-associated proteins including vimentin, fibronectin and epithelial cadherin were regulated by camptothecin treatment in NPC cells. Additionally, camptothecin inhibited the expression of transforming growth factor-β (TGF-β), phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), whereas TGF-β overexpression abrogated camptothecin-mediated inhibition of PI3K and AKT expression and camptothecin-mediated inhibition of the viability and aggressiveness of NPC cells. Camptothecin significantly inhibited tumor growth and increased survival times in a mouse model of cancer. In conclusion, these results indicate that camptothecin treatment may inhibit the viability of NPC cells and aggressiveness by regulating the TGF-β-induced PI3K/AKT signaling pathways, which in turn may be a potential molecular target for the treatment of NPC. [ABSTRACT FROM AUTHOR]

The expression of microRNA (miR-433) is altered in various types of human cancer. The present study analyzed the prognostic and biological value of miR-433 expression in colorectal cancer using reverse transcription-quantitative polymerase chain reaction in 125 colorectal tissue specimens (including a test cohort of 40 cases of paired colorectal cancer and adjacent normal mucosae and a confirmation cohort of 85 cases of stage I-III colorectal cancer). In vitro and nude mouse xenograft experiments were subsequently used to assess the effects of miR-433 expression on the regulation of colorectal cancer cell proliferation, adhesion, migration, and invasion. The data indicated that miR-433 expression was significantly downregulated in colorectal cancer tissues in the test and confirmation patient cohorts and that low miR-433 expression was associated with advanced tumor stage and early relapse. Furthermore, the restoration of miR-433 expression was able to significantly inhibit the proliferation of tumor cells by inducing G1-S cell cycle arrest, suppressing cyclinD1 and CDK4 expression, and markedly inhibited the migratory and invasive capacities of tumor cells in vitro. The restoration of miR-433 expression or liposome-based delivery of miR-433 mimics suppressed the growth of colorectal cancer cell xenografts in nude mice. In conclusion, miR-433 may be a putative tumor suppressor in colorectal cancer, and the detection of low miR-433 expression will be investigated in further studies as a putative biomarker for the detection of early relapse in patients with colorectal cancer. [ABSTRACT FROM AUTHOR]