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.

Outcomes and Prognostic Factors of Salvage Radiation for Postoperative Lymph Node Recurrence of Esophageal Squamous Cell Carcinoma.

Purpose: Recurrence of esophageal squamous cell carcinoma (ESCC) in regional lymph nodes (LNs) after surgical section can be treated with salvage resection, radiotherapy (RT) or chemoradiotherapy (CRT). RT or CRT is more widely used in clinic. This paper investigates the effects, toxicities and prognostic risk factors of salvage RT or CRT on patients with LN recurrence. Methods: We retrospectively analyzed the clinical outcomes of 103 patients receiving salvage RT or CRT for LN recurrence after ESCC resection. In total, 39 patients received RT alone and 64 received concurrent CRT. All the patients received intensity modulated radiation therapy (IMRT), administered with a median dose of 62 Gy (range, 50-70 Gy). Results: The median follow-up time was 44.5 months, and median survival was 22.5 months (5.5-99.5 months). One-, 3-, and 5-year overall survival (OS) were 80.6, 37.0, and 25.8%, respectively. One- and 2-year progression free survival (PFS) were 57.3 and 34.0%, respectively. Grade 3 or above toxicity was low (16.5%) and no treatment-related deaths occurred. In univariate analysis of OS, pN0 (p = 0.039), smaller LN volume (≤25 cm3, p = 0.019), combined chemotherapy (p = 0.041) and single LN recurrence (p = 0.001) were associated with prolonged OS. And pT1-2 (p = 0.044), pN0 (p = 0.042), irradiation dose (>60 Gy, p = 0.044), combined chemotherapy (p = 0.019) and single LN recurrence (p = 0.002) were associated with prolonged PFS. In multivariate analysis, the patients with only one recurrent node had a significant better OS (HR = 0.556, 95% CI 0.324-0.956, p = 0.034) and PFS (HR = 0.528, 95% CI 0.339-0.847, p = 0.008). Conclusions: Salvage RT or CRT for regional LN recurrence is effective and acceptable. Fewer recurrent nodes may indicate a better long-term survival.

Prognostic Factors for Patients with Esophageal Cancer Receiving Definitive Radiotherapy Alone: A Retrospective Analysis.

PURPOSE: Intensity-modulated radiotherapy (IMRT) can improve the prognosis of patients with esophageal cancer. This study aimed to evaluate clinical factors relevant to the prognosis of patients with esophageal cancer who received intensity-modulated radiotherapy (IMRT) alone. PATIENT AND METHODS: Data of 103 patients with pathologically confirmed esophageal cancer who were admitted to our hospital between October 2011 and November 2017 were retrospectively reviewed. All patients had squamous cell carcinoma. All patients received IMRT. Patients with stage I-IVA tumors were included to represent the real-world clinical practice. We performed univariate and multivariate analyses to identify prognostic factors for overall survival (OS) and progression-free survival (PFS). In univariate analyses, the Kaplan-Meier method was used to estimate OS and PFS for various subgroups. In multivariate analyses, hazard ratios were calculated. RESULTS: Single-factor analysis revealed that T stage (P=0.019), N stage (P =0.047), and lesion length (P =0.000) were associated with the prognosis of esophageal cancer patients who received IMRT. Cox regression analysis revealed that T stage (odds ratio [OR] = 4.68; P < 0.05), N stage (OR = 0.28; P < 0.05), and lesion length (OR = 0.09; P < 0.05) were independent factors relevant to prognosis. CONCLUSION: T stage, N stage, and lesion length influenced the long-term curative effects of IMRT for esophageal cancer and were prognostic factors for patients with esophageal cancer receiving definitive radiotherapy alone. The higher the stage and the longer the tumor, the lower the survival rate.

Synthesis and Preliminary Evaluation of a Novel 18F-Labeled 2-Nitroimidazole Derivative for Hypoxia Imaging.

OBJECTIVE: Hypoxia is prevalent in tumors and plays a pivotal role in resistance to chemoradiotherapy. 18F-MISO (18F-labeled fluoromisonidazole) is currently the preferred choice of PET hypoxia tracers in clinical practice, but has severe disadvantages involving complex labeling methods and low efficient imaging due to lipophilicity. We aimed to design a novel nitroimidazole derivative labeled by 18F via a chelation technique to detect hypoxic regions and provide a basis for planning radiotherapy. MATERIALS AND METHODS: First, we synthesized a 2-nitroimidazole precursor, 2-[4-(carboxymethyl)-7-[2-(2-(2-nitro-1H-imidazol-1-yl)acetamido)ethyl]-1,4,7-triazanonan-1-yl]acetic acid (NOTA-NI). For 18F-labeling, a 18F solution was reacted with a mixture of AlCl3 and NOTA-NI at pH 3.5 and 100°C for 20 min, and the radiochemical purity and stability were evaluated. Biological behaviors of Al18F-NOTA-NI were analyzed by an uptake study in ECA109 normoxic and hypoxic cells, and a biodistribution study and microPET imaging in ECA109 xenografted mice. RESULTS: Al18F-NOTA-NI required a straightforward and efficient labeling procedure compared with 18F-MISO. The uptake values were distinctly higher in hypoxic tumor cells. Animal studies revealed that the imaging agent was principally excreted via the kidneys. Due to hydrophilicity, the radioactivities in blood and muscle were decreased, and we could clearly distinguish xenografted tumors from para-carcinoma tissue by PET imaging. CONCLUSIONS: The nitroimidazole tracer Al18F-NOTA-NI steadily accumulated in hypoxic areas in tumors and was rapidly eliminated from normal tissue. It appears to be a promising candidate for hypoxia imaging with high sensitivity and resolution.

Concurrent liposomal paclitaxel and cisplatin chemotherapy improved outcomes for locally advanced esophageal squamous cell carcinoma treated with intensity-modulated radiotherapy.

BACKGROUND: To ascertain whether concurrent chemotherapy using liposomal paclitaxel and cisplatin could improve the outcomes of patients with locally advanced esophageal squamous cell carcinoma receiving intensity-modulated radiotherapy (IMRT). METHODS: A total of 72 patients with locally advanced esophageal squamous cell carcinoma, which were admitted to our hospital from October 2011 to December 2013, were retrospectively analyzed in this study. RESULTS: Thirty-six patients (50%) were treated with IMRT alone, while the other 36 patients (50%) were treated by IMRT combined with chemotherapy containing liposomal paclitaxel and cisplatin. Patients treated with chemoradiotherapy showed significantly superior overall survival (OS) and progression-free survival (PFS) compared to patients treated with IMRT alone (median OS: respectively, 29.7 vs. 12.9 months, P=0.0287; median PFS: respectively, 14.0 vs. 6.5 months, P=0.0186). Multivariate Cox analysis confirmed the inclusion of chemotherapy as an independent predictor of favorable OS and PFS. Both chemoradiotherapy and IMRT were well-tolerated in our cohort. CONCLUSIONS: Chemotherapy improved the prognosis of locally advanced esophageal squamous cell carcinoma treated with IMRT. Large prospective studies are needed to confirm the therapeutic value of IMRT combined with chemotherapy in locally advanced esophageal squamous cell carcinoma.

Raltitrexed increases radiation sensitivity of esophageal squamous carcinoma cells.

BACKGROUND: Radiation therapy remains an important therapeutic modality, especially for those patients who are not candidates for radical resection. Many strategies have been developed to increase the radiosensitivity of esophageal cancer, with some success. METHODS: This study was conducted to determine whether raltitrexed can enhance radiosensitivity of esophageal squamous cell carcinoma (ESCC). ESCC cell lines 24 h were incubated with raltitrexed or DMSO with or without subsequent irradiation. Cell Counting Kit assay-8 assay and clonogenic survival assay were used to measure the cell proliferation and radiosensitization, respectively. Flow cytometry was utilized to examine cell apoptosis and cell cycle distribution in different groups. Immunofluorescence analysis was performed to detect deoxyribonucleic acid (DNA) double-strand breaks. In addition, the expression levels of proteins that are involved in radiation induced signal transduction including Bax, Cyclin B1, Cdc2/pCdc2, and Cdc25C/pCdc25C were examined by western blot analysis. RESULTS: The results indicated that raltitrexed enhanced radiosensitivity of ESCC cells with increased DNA double-strand breaks, the G2/M arrest, and the apoptosis of ESCC cells induced by radiation. The sensitization enhancement ratio of 1.23-2.10 was detected for ESCC cells with raltitrexed treatment in TE-13 cell line. In vitro, raltitrexed also increased the therapeutic effect of radiation in nude mice. CONCLUSION: Raltitrexed increases the radiosensitivity of ESCC. This antimetabolite drug is promising for future clinical trials with concurrent radiation in esophageal cancer.

What is the optimal radiation dose for non-operable esophageal cancer? Dissecting the evidence in a meta-analysis.

The standard radiation dose 50.4 Gy with concurrent chemotherapy for localized inoperable esophageal cancer as supported by INT-0123 trail is now being challenged since a radiation dose above 50 Gy has been successfully administered with an observable dose-response relationship and insignificant untoward effects. Therefore, to ascertain the treatment benefits of different radiation doses, we performed a meta-analysis with 18 relative publications. According to our findings, a dose between 50 and 70 Gy appears optimal and patients who received ≥ 60 Gy radiation had a significantly better prognosis (pooled HR = 0.78, P = 0.004) as compared with < 60 Gy, especially in Asian countries (pooled HR = 0.75, P = 0.003). However, contradictory results of treatment benefit for ≥ 60 Gy were observed in two studies from Western countries, and the pooled treatment benefit of ≥ 60 Gy radiation was inconclusive (pooled HR = 0.86, P = 0.64). There was a marginal benefit in locoregional control in those treated with high dose (> 50.4/51 Gy) radiation when compared with those treated with low dose (≤ 50.4/51 Gy) radiation (pooled OR = 0.71, P = 0.06). Patients that received ≥ 60 Gy radiation had better locoregional control (OR = 0.29, P = 0.001), and for distant metastasis control, neither the > 50.4 Gy nor the ≥ 60 Gy treated group had any treatment benefit as compared to the groups that received ≤ 50.4 Gy and < 60 Gy group respectively. Taken together, a dose range of 50 to 70 Gy radiation with CCRT is recommended for non-operable EC patients. A dose of ≥ 60 Gy appears to be better in improving overall survival and locoregional control, especially in Asian countries, while the benefit of ≥ 60 Gy radiation in Western countries still remains controversial.

Foretinib Enhances the Radiosensitivity in Esophageal Squamous Cell Carcinoma by Inhibiting Phosphorylation of c-Met.

As a crucial event involved in the metastasis and relapse of esophageal cancer, c-Met overexpression has been considered as one of the culprits responsible for the failure in patients who received radiochemotherapy. Since c-Met has been confirmed to be pivotal for cell survival, proliferation and migration, little is known about its impact on the regulation of radiosensitivity in esophageal cancer. The present study investigated the radiosensitization effects of c-Met inhibitor foretinib in ECA-109 and TE-13 cell lines. Foretinib inhibited c-Met signaling in a dose-dependent manner resulting in decreases in the cell viability of ECA-109 and TE-13. Pretreatment with foretinib synergistically prompted cell apoptosis and G2/M arrest induced by irradiation. Moreover, decreases ability of DNA damage repair was also observed. In vivo studies confirmed that the combinatorial use of foretinib with irradiation significantly diminishes tumor burden compared to either treatment alone. The present findings implied a crucial role of c-Met in the modulation of radiosensitization in esophageal cancer, and foretinib increased the radiosensitivity in ECA-109 and TE-13 cells mainly via c-Met signaling, highlighting a novel profile of foretinib as a potential radiosensitizer for the treatment of esophageal cancer.

The mechanisms of radioresistance in esophageal squamous cell carcinoma and current strategies in radiosensitivity.

Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer-related death worldwide. Surgery is the primary form of treatment, but the survival is poor, especially for patients with locally advanced esophageal cancer. Radiotherapy has been a critical treatment option that may be combined with chemotherapy in patients with unresectable esophageal cancer. However, resistance to chemoradiotherapy might result in treatment failures and cancer relapse. This review will mainly focus on the possible cellular mechanisms and tumor-associated microenvironmental (TAM) factors that result in radioresistance in patients with esophageal cancer. In addition, current strategies to increase radiosensitivity, including targeted therapy and the use of radiosensitive biomarkers in clinical treatment, are discussed in this review.

TCN, an AKT inhibitor, exhibits potent antitumor activity and enhances radiosensitivity in hypoxic esophageal squamous cell carcinoma in vitro and in vivo.

The aim of the present study was to investigate the radiosensitization effect of triciribine (TCN) on human esophageal squamous cell carcinoma (ESCC) in normoxia or hypoxia and its mechanism. The cytotoxicity and radiosensitization mechanism of TCN were investigated by Cell Counting Kit 8, clonogenic assay, flow cytometry, western blotting (WB) and immunofluorescence staining of phospho-histone H2A.X, Ser139 (γ-H2AX) in ESCC in vitro, while the protein expression levels of AKT, phosphorylated (p)-AKT, hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were evaluated by WB in vivo. The cytotoxicity of TCN was dose dependent. Upon exposure to TCN, ESCC cells in hypoxia treated with 4-Gy radiotherapy exhibited an evidently higher apoptotic rate than cells subjected to other treatments. TCN could significantly inhibit the protein expression of p-AKT, HIF-1α and VEGF in vitro and in vivo. The present results suggested that TCN can effectively inhibit AKT, p-AKT, HIF-1α and VEGF, thus conferring radiosensitivity to ESCC in vitro and vivo. TCN is considered as an adjuvant in radiotherapy of ESCC in clinical application.

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.

Transdermal granisetron for the prevention of nausea and vomiting following moderately or highly emetogenic chemotherapy in Chinese patients: a randomized, double-blind, phase III study.

BACKGROUND: The granisetron transdermal delivery system (GTDS) has been demonstrated effectiveness in the control of chemotherapy-induced nausea and vomiting (CINV) in previous studies. This is the first phase III study to evaluate the efficacy and tolerability of GTDS in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in China. METHODS: A total of 313 patients were randomized into the GTDS group (one transdermal granisetron patch, 7 days) or the oral granisetron group (granisetron oral 2 mg/day, ≥2 days). The primary endpoint was the percentage of patients achieving complete control (CC) from chemotherapy initiation until 24 h after final administration (PEEP). Chi-square test and Fisher's exact test were used for statistical analysis. RESULTS: Two hundred eighty-one patients were included in the per protocol analysis. During PEEP, CC was achieved by 67 (47.52%) patients in the GTDS group and 83 (59.29%) patients in the oral granisetron group. There was no statistical significance between the groups (P=0.0559). However, the difference of the CC percentage mainly occurred on the first day of chemotherapy between the groups. The CC was 70.13% on day 1 in the GTDS group, which was significantly lower than that of 91.03% in the oral granisetron group in the full analysis set. In the following days of chemotherapy, the CC was similar between the groups. In terms of cisplatin-contained regimen and female, there was statistical significance between the groups. Both treatments were well tolerated and safe. The most common adverse event was constipation. CONCLUSIONS: GTDS provided effective and well-tolerated control of CINV in Chinese patients, especially to non-cisplatin-contained regimen.

Improved sensitization effect of sunitinib in cancer cells of the esophagus under hypoxic microenviroment.

Radiotherapy is widely used in esophageal squamous cell carcinoma (ESCC) treatment. Promoting the radiation sensitivity of cancer cells is required. Recent studies have shown that sunitinib can inhibit the growth of several cancer lines. However, few studies on the radiosensitive effect of sunitinib on ESCC cells under hypoxic conditions have been conducted. In the present study, the radiosensitive effects of sunitinib on human ESCC cells were assessed, and the underlying mechanisms were explored. ESCC cells were exposed to hypoxia and treated with sunitinib at different concentrations prior to irradiation. Sunitinib potently inhibited ESCC cell proliferation in an MTT assay. In a clonogenic survival assay, sunitinib sensitized hypoxic ESCC cells to radiation, with sensitizing enhancement ratios of 1.31-1.59. In addition, sunitinib promoted the apoptosis of ESCC cells, but did not alter their cell cycle distribution. Radiosensitization was accompanied by inhibition of the radiation-induced upregulation of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) expression. Thus, sunitinib confers radiosensitivity to esophageal cancer cells, which is associated with the downregulation of HIF-1α and VEGF expression. Sunitinib can be a promising radiosensitizer for esophageal cancer radiotherapy.

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.

IGF-I CA19 repeat polymorphisms and cancer risk: a meta-analysis.

IGF-I CA repeat polymorphisms, especially the allele containing CA19 repeats, have been reported to be associated with the risk for various types of cancers. However, the results still remain controversial and ambiguous. This meta-analysis was performed to evaluate the association between IGF-I CA19 repeat polymorphisms and the risk of cancer. Total 18 studies with IGF-I CA19 repeat genotyping on 9,873 patients and 15,607 controls were analyzed. We used random-effects model with a pooled OR of 0.69 (95% CI = 0.60-0.79) for the recessive genetic model, 0.97 (95% CI = 0.86-1.10) for the dominant genetic model, 0.99 (95% CI = 0.86-1.14) for the homozygote comparison and 1.06 (95% CI = 0.91-1.23) for the heterozygote comparison. In the subgroup analysis of recessive model, OR (95% CI) was 0.65 (0.52-0.80) in breast cancer, 0.68 (0.53-0.86) in prostate cancer, and 0.71 (0.52-0.96) in Caucasian. In conclusion, IGF-1 CA19 repeat polymorphisms are unlikely to be a major determinant of susceptibility to cancer. However, the subgroup analysis of recessive model indicates that IGF-I CA19 repeat polymorphisms may reduce the risk of certain types of cancer or in a specific population.

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.

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.