Berberine Radiosensitizes Human Esophageal Cancer Cells by Downregulating Homologous Recombination Repair Protein RAD51

Esophageal squamous cell carcinomas (ESCC) have poor prognosis. While combined modality of chemotherapy and radiotherapy increases survival, most patients die within five years. Development of agents that confer cancer cell-specific chemo- and radiosensitivity may improve the therapy of ESCC. We here reported the discovery of berberine as a potent radiosensitizing agent on ESCC cells. by RNA interference similarly radiosensitized the cancer cells, and, conversely, introduction of exogenous RAD51 was able to significantly counteract the radiosensitizing effect of berberine, thus establishing RAD51 as a key determinant in radiation sensitivity. We also observed that RAD51 was commonly overexpressed in human ESCC tissues, suggesting that it is necessary to downregulate RAD51 to achieve high radio- or chemotherapeutic efficacy of ESCC in clinic, because overexpression of RAD51 is known to confer radio- and chemoresistance.Berberine can effectively downregulate RAD51 in conferring radiosensitivity on esophageal cancer cells. Its clinical application as an adjuvant in chemotherapy and radiotherapy of esophageal cancers should be explored

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin

BACKGROUND: Although pemetrexed, a potent thymidylate synthase (TS) inhibitor, enhances the cytoytoxic effect of platinum compounds against malignant pleural mesothelioma (MPM), novel combinations with effective targeted therapies are warranted. To this end, the current study evaluates new targeted agents and their pharmacological interaction with carboplatin-pemetrexed in human MPM cell lines. METHODS: We treated H2052, H2452, H28 and MSTO-211H cells with carboplatin, pemetrexed and targeted compounds (gefitinib, erlotinib, sorafenib, vandetanib, enzastaurin and ZM447439) and evaluated the modulation of pivotal pathways in drug activity and cancer cell proliferation. RESULTS: Vandetanib emerged as the compound with the most potent cytotoxic activity, which interacted synergistically with carboplatin and pemetrexed. Drug combinations blocked Akt phosphorylation and increased apoptosis. Vandetanib significantly downregulated epidermal growth factor receptor (EGFR)/Erk/Akt phosphorylation as well as E2F-1 mRNA and TS mRNA/protein levels. Moreover, pemetrexed decreased Akt phosphorylation and expression of DNA repair genes. Finally, most MPM samples displayed detectable levels of EGFR and TS, the variability of which could be used for patients' stratification in future trials with vandetanib-pemetrexed-carboplatin combination. CONCLUSION: Vandetanib markedly enhances pemetrexed-carboplatin activity against human MPM cells. Induction of apoptosis, modulation of EGFR/Akt/Erk phosphorylation and expression of key determinants for pemetrexed and carboplatin activity contribute to this synergistic interaction, and, together with the expression of these determinants in MPM samples, warrant further clinical investigation

The promoter of IL-18 binding protein: Activation by an IFN-γ-induced complex of IFN regulatory factor 1 and CCAAT/enhancer binding protein β

The IL-18 binding protein (IL-18BP) is a circulating inhibitor of the proinflammatory cytokine IL-18. It is constitutively expressed in mononuclear cells, and elevated expression is induced by IFN-γ. In this study, we characterized the IL-18BP promoter. We first showed that induction is at the transcriptional level and requires de novo protein synthesis. The IL-18BP promoter resides within 1.6 kb DNA upstream of the first exon and includes at least six regulatory elements. We identified in the basal promoter a gamma-activated sequence (GAS) proximal to the transcription start site (base 1), followed by an IFN regulatory factor 1 response element (IRF-E) and two CCAAT/enhancer binding protein β (C/EBPβ) sites, all of which are essential for basal promoter activity. Furthermore, GAS and IRF-E were essential for IFN-γ-induced transcription. Indeed, sera of IRF-1-deficient mice lacked basal and IFN-γ-induced IL-18BP. We found that after induction of IRF-1 by IFN-γ, it formed a complex with C/EBPβ, which bound to the IRF-E and GAS-containing proximal DNA. In contrast, the IFN-γ-induced signal transducer and activator of transcription 1 dimer did not associate with this GAS. In addition, we identified a silencer element and a distal enhancer at bases −1081 to −1272, which was also physically associated with IRF-1. The IRF-1–C/EBPβ complex described here probably plays a fundamental role in regulating additional IFN-γ-responsive genes

The Impact of Interlayer Electronic Coupling on Charge Transport in Organic Semiconductors: A Case Study on Titanylphthalocyanine Single Crystals

Traditionally, it is believed that three-dimensional transport networks are preferable to those of lower dimensions. We demonstrate that inter-layer electronic couplings may result in a drastic decrease of charge mobilities by utilizing field-effect transistors (FET) based on two phases of titanyl phthalocyanine (TiOPc) crystals. The -phase crystals with electronic couplings along two dimensions show a maximum mobility up to 26.8cm(2)V(-1)s(-1). In sharp contrast, the -phase crystals with extra significant inter-layer electronic couplings show a maximum mobility of only 0.1cm(2)V(-1)s(-1). Theoretical calculations on the bulk crystals and model slabs reveal that the inter-layer electronic couplings for the -phase devices will diminish remarkably the device charge transport abilities owing to the coupling direction perpendicular to the current direction. This work provides new insights into the impact of the dimensionality and directionality of the packing arrangements on charge transport in organic semiconductors

Platform of quality evaluation system for multimedia video communication based NS2

The obtained video sequence scores are statistically averaged as the final quality assessment, and the resulting quality assessment results are less accurate. Therefore, a multimedia video communication quality assessment system platform based NS2 is designed. On the basis of compressed sensing theory, image/video signal is the main research object, aiming at the requirements of quality assessment methods in video transmission systems and the determination of observations in transmission, a video signal recovery quality based on redundant observations is proposed. The purpose of the evaluation method is to solve the problem of quality estimation after video recovery for non-structural dimensionality reduction signals in the transmission of video observations. According to the obtained video quality information, an adaptive adjustment scheme of quality information feedback observation rate suitable for video transmission system is designed to solve the problem of determining the observing rate of unknown sparse signal and improve the quality of video recovery. Under the scheme of observation rate adaptive adjustment, the quality assessment model is given considering the requirements of compressive sensing video features and the subjective perceived quality characteristics in the video system. Meanwhile, a video transmission quality evaluation platform is built based on the evaluation model. The experimental results show that the minimum root mean square error of the proposed method is 0.08. The mean square error of traditional methods are much higher than the proposed method, indicating that the proposed method can better simulate the subjective feelings of the human eye, and the obtained quality assessment results are more accurate