bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular Proteins PML and Daxx Mediate an Innate Antiviral Defense Antagonized by the Adenovirus E4 ORF3 Protein
Authors: Ullman Amanda J. , Hearing Patrick 
Published: May 2008

ABSTRACT
The adenovirus (Ad) E4 ORF3 protein is both necessary and sufficient to reorganize a nuclear subdomain, the PML nuclear body (PML-NB), from punctate structures into elongated nuclear tracks. PML-NB disruption is recapitulated by a variety of DNA viruses that encode proteins responsible for compromising PML-NB integrity through different mechanisms. PML-NB disruption has been correlated with the antagonism of both innate and intrinsic immune responses. The E4 ORF3 protein is required for adenoviral DNA replication in the interferon (IFN)-induced antiviral state. This may reflect the fact that PML itself, in addition to several other PML-NB proteins, is encoded by an interferon-stimulated gene. Here, we demonstrate that reorganization of the PML-NB by E4 ORF3 antagonizes an innate antiviral response mediated by both PML and Daxx. Reduction of either of these proteins is sufficient to restore the replicative capacity of virus with the E4 ORF3 protein deleted in the IFN-induced antiviral state. Further, we provide evidence that both the HSV1 ICP0 and HCMV IE1 proteins, which disrupt PML-NBs by mechanistically distinct strategies, behave in a manner functionally analogous to E4 ORF3 with respect to antagonizing the IFN-induced antiviral state. In addition, we assert that this innate antiviral strategy mediated by PML and Daxx does not involve transcriptional repression. While early gene transcription is modestly diminished in the absence of E4 ORF3 protein expression, this reduction does not affect early protein function. We propose that, in addition to its ability to repress gene expression, the PML-NB participates in additional innate immune activities.
Transcription Factor YY1 and Its Associated Acetyltransferases CBP and p300 Interact with Hepatitis Delta Antigens and Modulate Hepatitis Delta Virus RNA Replication
Authors: Huang Wen-Hung , Mai Ru-Tsun , Wu Lee Yan-Hwa 
Published: May 2008

ABSTRACT
Hepatitis delta virus (HDV) is a pathogenic RNA virus with a plant viroid-like genome structure. HDV encodes two isoforms of delta antigen (HDAg), the small and large forms of HDAg (SHDAg and LHDAg), which are essential for HDV RNA replication and virion assembly, respectively. Replication of HDV RNA depends on host cellular transcription machinery, and the exact molecular mechanism for HDV RNA replication is still unclear. In this study, we demonstrated that both isoforms of HDAg interact with transcription factor YY1 (Yin Yang 1) in vivo and in vitro. Their interaction domains were identified as the middle region encompassing the RNA binding domain of HDAg and the middle GA/GK-rich region and the C-terminal zinc-finger region of YY1. Results of sucrose gradient centrifugation analysis indicated the cosedimentation of the majority of SHDAg and a portion of the LHDAg with YY1 and its associated acetyltransferases CBP (CREB-binding protein) and p300 as a large nuclear complex in vivo. Furthermore, exogenous expression of YY1 or CBP/p300 in HDV RNA replication system showed an enhancement of HDV RNA replication. Interestingly, the acetyltransferase activity of p300 is important for this enhancement. Moreover, SHDAg could be acetylated in vivo, and treatment with cellular deacetylase inhibitor elevated the replication of HDV RNA and acetylation of SHDAg. All together, our results reveal that HDAg interacts with cellular transcription factor YY1 and its associated acetyltransferases CBP and p300 in a large nuclear complex, which in turn modulates the replication of HDV RNA.
Distributed musical performances
Authors: Zimmermann Roger , Chew Elaine , Ay Sakire Arslan , Pawar Moses 
Published: May 2008

An increasing number of novel applications produce a rich set of different data types that need to be managed efficiently and coherently. In this article we present our experience with designing and implementing a data management infrastructure for a distributed immersive performance (DIP) application. The DIP project investigates a versatile framework for the capture, recording, and replay of video, audio, and MIDI (Musical Instrument Digital Interface) streams in an interactive environment for collaborative music performance. We are focusing on two classes of data streams that are generated within this environment. The first category consists of high-resolution isochronous media streams, namely audio and video. The second class comprises MIDI data produced by electronic instruments. MIDI event sequences are alphanumeric in nature and fall into the category of the data streams that have been of interest to data management researchers in recent years.
We present our data management architecture, which provides a repository for all DIP data. Streams of both categories need to be acquired, transmitted, stored, and replayed in real time. Data items are correlated across different streams with temporal indices. The audio and video streams are managed in our own High-performance Data Recording Architecture (HYDRA), which integrates multistream recording and retrieval in a consistent manner. This paper reports on the practical issues and challenges that we encountered during the design, implementation and experimental phases of our prototype. We also present some analysis results and discuss future extensions for the architecture.
Prospects of 4H-SiC Double Drift Region IMPATT Device as a Photo-Sensitive High-Power Source at 0.7 Terahertz Frequency Regime
Authors: Mukherjee Moumita , Mazumder Nilratan , Roy Sitesh Kumar 
Published: May 2008

The dynamic performance of wide-bandgap 4H-SiC based double drift region (p++ p n n++) IMPATT diode is simulated for the first time at terahertz frequency (0.7 Terahertz) region. The simulation experiment establishes the potential of SiC based IMPATT diode as a high power (2.5×1011 Wm−2) terahertz source. The parasitic series resistance in the device is found to reduce the RF power output by 10.7%. The effects of external radiation on the simulated diode are also studied. It is found that (i) the negative conductance and (ii) the negative resistance of the diode decrease, while, the frequency of operation and the quality factor shift upward under photoillumination. Holes in 4H-SiC based IMPATT are found to dominate the modulation activities. The inequality in the magnitude of electron and hole ionization rates in the semiconductors may be correlated with these findings.
Phosphorylation Regulates Transcriptional Activity of PAX3/FKHR and Reveals Novel Therapeutic Possibilities
Authors: Amstutz Ralf , Wachtel Marco , Troxler Heinz , Kleinert Peter , Ebauer Margret , Haneke Torsten , Oehler-Jänne Christoph , Fabbro Doriano , Niggli Felix K. , Schäfer Beat W. 
Published: May 2008

Abstract
Inhibition of constitutive active signaling pathways, which are a characteristic phenomenon for many tumors, can be an effective therapeutic strategy. In contrast, oncogenic transcription factors, often activated by mutational events, are in general less amenable to small-molecule inhibition despite their obvious importance as therapeutic targets. One example of this is alveolar rhabdomyosarcoma (aRMS), in which specific translocations lead to the formation of the chimeric transcription factor PAX3/FKHR. Here, we found unexpectedly that the transcriptional activity of PAX3/FKHR can be inhibited by the kinase inhibitor PKC412. This occurs via specific phosphorylation sites in the PAX3 domain, phosphorylation of which is required for efficient DNA-binding and subsequent transcriptional activity. Consequently, we show that PKC412 exerts a potent antitumorigenic potential for aRMS treatment both in vitro and in vivo. Our study suggests that posttranscriptional modifications of oncogenic transcription factors can be explored as a promising avenue for targeted cancer therapy. [Cancer Res 2008;68(10):3767–76]
Antagonistic Roles of CD4+ and CD8+ T-Cells in 7,12-Dimethylbenz(a)anthracene Cutaneous Carcinogenesis
Authors: Yusuf Nabiha , Nasti Tahseen H. , Katiyar Santosh K. , Jacobs Michael K. , Seibert Megan D. , Ginsburg Alexis C. , Timares Laura , Xu Hui , Elmets Craig A. 
Published: May 2008

AbstractThe role that cell-mediated immune responses play during cutaneous carcinogenesis has received little attention. In this study, we evaluated the contribution of CD4+ and CD8+ T cells in C3H/HeN mice that were subjected to a two-stage 7,12-dimethylbenz(a)anthracene (DMBA) initiation, 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion skin carcinogenesis protocol. In CD8 knockout (CD8−/−) mice, allergic contact hypersensitivity to DMBA was reduced compared with wild-type (WT) C3H/HeN mice. On the other hand, CD4 knockout (CD4−/−) mice developed an exaggerated contact hypersensitivity response. CD4+ T cells from DMBA contact–sensitized mice preferentially produced interleukin 4 (IL-4), IL-10, and IL-17; CD8+ T cells, on the other hand, secreted IFN-γ. When CD4−/−, CD8−/−, and WT mice were subjected to a standard two-stage DMBA/TPA cutaneous carcinogenesis protocol, the percentage of mice with tumors was much greater (P &lt; 0.001) in CD8−/− mice than in WT mice. In contrast, the percentage of tumors was significantly less (P &lt; 0.001) in CD4−/− mice than in WT mice. Similar results were obtained when the data were evaluated as the number of tumors per mouse. These findings indicate that (a) CD8+ T cells are the predominant effector cells in allergic contact hypersensitivity to DMBA and that CD4+ T cells have an inhibitory role and (b) the development of CD8+ T cells plays a protective role in skin tumor development whereas CD4+ T cells have the opposite effect. Manipulation of T-cell subpopulations that are induced by carcinogenic chemicals, like DMBA, could be a means of preventing skin cancers caused by these agents. [Cancer Res 2008;68(10):3924–30]
Inactivation of gadd45a Sensitizes Epithelial Cancer Cells to Ionizing Radiation In vivo Resulting in Prolonged Survival
Authors: Lu Xiangdong , Yang Chunyu , Hill Reginald , Yin Chaoyin , Hollander M. Christine , Fornace Albert J. , Van Dyke Terry 
Published: May 2008

Abstract
Ionizing radiation (IR) therapy is one of the most commonly used treatments for cancer patients. The responses of tumor cells to IR are often tissue specific and depend on pathway aberrations present in the tumor. Identifying molecules and mechanisms that sensitize tumor cells to IR provides new potential therapeutic strategies for cancer treatment. In this study, we used two genetically engineered mouse carcinoma models, brain choroid plexus carcinoma (CPC) and prostate, to test the effect of inactivating gadd45a, a DNA damage response p53 target gene, on tumor responses to IR. We show that gadd45a deficiency significantly increases tumor cell death after radiation. Effect on survival was assessed in the CPC model and was extended in IR-treated mice with gadd45a deficiency compared with those expressing wild-type gadd45a. These studies show a significant effect of gadd45a inactivation in sensitizing tumor cells to IR, implicating gadd45a as a potential drug target in radiotherapy management. [Cancer Res 2008;68(10):3579–83]
Attenuation of Melanoma Invasion by a Secreted Variant of Activated Leukocyte Cell Adhesion Molecule
Authors: van Kilsdonk Jeroen W.J. , Wilting Roel H. , Bergers Mieke , van Muijen Goos N.P. , Schalkwijk Joost , van Kempen Léon C.L.T. , Swart Guido W.M. 
Published: May 2008

Abstract
Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD), a marker of various cancers and mesenchymal stem cells, is involved in melanoma metastasis. We have exploited a secreted NH2-terminal fragment, sALCAM, to test the hypothesis that ALCAM coordinates tissue growth and cell migration. Overexpression of sALCAM in metastatic melanoma cells disturbed clustering of endogenous ALCAM and inhibited activation of matrix metalloproteinase-2 (MMP-2). Exposure of HT1080 fibrosarcoma cells to sALCAM similarly inhibited MMP-2, suggesting a broader effect on ALCAM-positive tumor cells. In contrast to the previously reported, promotive effects of an NH2-terminally truncated, transmembrane variant (ΔN-ALCAM), sALCAM impaired the migratory capacity of transfected cells in vitro, reduced basement membrane penetration in reconstituted human skin equivalents, and diminished metastatic capacity in nude mice. Remarkably, L1 neuronal cell adhesion molecule (L1CAM/CD171), another progression marker of several cancers including melanoma, was suppressed upon sALCAM overexpression but was up-regulated by ΔN-ALCAM. The partially overlapping and opposite effects induced by alternative strategies targeting ALCAM functions collectively attribute an integrative role to ALCAM in orchestrating cell adhesion, growth, invasion, and proteolysis in the tumor tissue microenvironment and disclose a therapeutic potential for sALCAM. [Cancer Res 2008;68(10):3671–9]
Functions of Anti-MAGE T-Cells Induced in Melanoma Patients under Different Vaccination Modalities
Authors: Connerotte Thierry , Van Pel Aline , Godelaine Danièle , Tartour Eric , Schuler-Thurner Beatrice , Lucas Sophie , Thielemans Kris , Schuler Gerold , Coulie Pierre G. 
Published: May 2008

AbstractTumor regressions have been observed in a small proportion of melanoma patients vaccinated with a MAGE-A3 peptide presented by HLA-A1, administered as peptide, ALVAC canarypox virus containing a MAGE-A3 minigene, or peptide-pulsed dendritic cells (DC). There was a correlation between tumor regression and the detection of anti–MAGE-3.A1 CTL responses. These responses were monoclonal and often of a very low magnitude after vaccination with peptide or ALVAC, and usually polyclonal and of a higher magnitude after DC vaccination. These results suggested that, at least in some patients, surprisingly few anti–MAGE-3.A1 T-cells could initiate a tumor regression process. To understand the role of these T cells, we carried out a functional analysis of anti–MAGE-3.A1 CTL clones derived from vaccinated patients who displayed tumor regression. The functional avidities of these CTL clones, evaluated in lysis assays, were surprisingly low, suggesting that high avidity was not part of the putative capability of these CTL to trigger tumor rejection. Most anti–MAGE-3.A1 CTL clones obtained after DC vaccination, but not after peptide or ALVAC vaccination, produced interleukin 10. Transcript profiling confirmed these results and indicated that approximately 20 genes, including CD40L, prostaglandin D2 synthase, granzyme K, and granzyme H, were highly differentially expressed between the anti–MAGE-3.A1 CTL clones derived from patients vaccinated with either peptide-ALVAC or peptide-pulsed DC. These results indicate that the modality of vaccination with a tumor-specific antigen influences the differentiation pathway of the antivaccine CD8 T-cells, which may have an effect on their capacity to trigger a tumor rejection response. [Cancer Res 2008;68(10):3931–40]
Cancer Immunotherapy UsingIn vitroGenetically Modified Targeted Dendritic Cells
Authors: Wei Huafeng , Wang Hao , Lu Bing , Li Bohua , Hou Sheng , Qian Weizhu , Fan Kexing , Dai Jianxin , Zhao Jian , Guo Yajun 
Published: May 2008

AbstractModest clinical outcomes of dendritic cell (DC) vaccine trials call for novel strategies. In this study, we have created a chimeric CD40 molecule that incorporates a single chain Fv (scFv) molecule specific for human ErbB2 antigen and fusing to the membrane spanning and cytosolic domains of murine CD40. After adenoviral transfer to bone marrow–derived DC, this chimeric receptor (CR) induced nuclear factor-κB (NF-κB)–dependent DC activation and effector function when cultured with immobilized ErbB2 protein or ErbB2-positive tumor cells in vitro. In vivo migration assays showed that ∼40% injected CR-modified DC (scFv-CD40-DC) effectively migrated to ErbB2-positive tumors, where they were activated after ErbB2 antigen stimulation, and sequentially homed into the draining lymph nodes. In murine ErbB2-positive D2F2/E2 breast tumor (BALB/c) and EL4/E2 thymoma (C57BL/6) models, i.v. injection of 1 × 106 scFv-CD40-DC significantly inhibited tumor growth and cured established tumors. Importantly, the cured mice treated by injection of scFv-CD40-DC were effective in preventing both ErbB2-positive and parental ErbB2-negative tumor rechallenge. Analysis of the underlying mechanism revealed that i.v. infusion of scFv-CD40-DC elicited tumor-specific CTL responses, and the transfer of CTLs from scFv-CD40-DC–treated mice protected naive mice against a subsequent tumor challenge. These results support the concept that genetic modification of DC with tumor-associated antigen-specific CD40 chimeric receptor might be a useful strategy for treatment of human cancers. [Cancer Res 2008;68(10):3854–62]
Characterization of TMPRSS2-ETS Gene Aberrations in Androgen-Independent Metastatic Prostate Cancer
Authors: Mehra Rohit , Tomlins Scott A. , Yu Jianjun , Cao Xuhong , Wang Lei , Menon Anjana , Rubin Mark A. , Pienta Kenneth J. , Shah Rajal B. , Chinnaiyan Arul M. 
Published: May 2008

Abstract
Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS transcription factor family members ERG, ETV1, and ETV4 have been identified as a critical event in prostate cancer development. In this study, we characterized the prevalence and diversity of these rearrangements in hormone-refractory metastatic prostate cancer. We used a fluorescence in situ hybridization (FISH) split probe strategy to comprehensively evaluate TMPRSS2-ETS aberrations across 97 nonosseous metastatic sites of prostate cancer from 30 rapid autopsies of men who died of androgen-independent disease. Tissue microarrays were constructed representing multiple metastatic sites from each patient, and split signal FISH probes for TMPRSS2, ERG, ETV1, and ETV4 were used to assess for TMPRSS2-ETS rearrangements. In patients exhibiting these aberrations, multiple sites from an individual case harbored the same gene fusion molecular subtype suggesting clonal expansion of disease. The most common prostate cancer gene fusion, TMPRSS2-ERG, can be generated by the mechanism of interstitial deletion (Edel) about 39% to 60% of the time in clinically localized disease. Interestingly, we observed that all of the androgen-independent metastatic prostate cancer sites harboring TMPRSS2-ERG were associated with Edel. These findings suggest that TMPRSS2-ERG with Edel is an aggressive and, in this study, uniformly lethal molecular subtype of prostate cancer associated with androgen-independent disease. [Cancer Res 2008;68(10):3584–90]
213Bi (α-Emitter)–Antibody Targeting of Breast Cancer Metastases in theneu-N Transgenic Mouse Model
Authors: Song Hong , Shahverdi Karineh , Huso David L. , Esaias Caroline , Fox James , Liedy Allison , Zhang Zhe , Reilly R. Todd , Apostolidis Christos , Morgenstern Alfred , Sgouros George 
Published: May 2008

AbstractTreatment failure in breast cancer is largely the failure to control metastatic dissemination. In this study, we investigated the efficacy of an antibody against the rat variant of HER-2/neu, labeled with the α-particle emitter 213Bi to treat widespread metastases in a rat/neu transgenic mouse model of metastatic mammary carcinoma. The model manifests wide-spread dissemination of tumor cells leading to osteolytic bone lesions and liver metastases, common sites of clinical metastases. The maximum tolerated dose was 120 μCi of 213Bi-7.16.4. The kinetics of marrow suppression and subsequent recovery were determined. Three days after left cardiac ventricular injection of 105 rat HER-2/neu--expressing syngeneic tumor cells, neu-N mice were treated with (a) 120 μCi 213Bi-7.16.4, (b) 90 μCi 213Bi-7.16.4, (c) 120 μCi 213Bi-Rituximab (unreactive control), and (d) unlabeled 7.16.4. Treatment with 120 μCi 213Bi-7.16.4 increased median survival time to 41 days compared with 28 days for the untreated controls (P &lt; 0.0001); corresponding median survival times for groups b, c, and d were 36 (P &lt; 0.001), 31 (P &lt; 0.01), and 33 (P = 0.05) days, respectively. Median survival relative to controls was not significantly improved in mice injected with 10-fold less cells or with multiple courses of treatment. We concluded that α-emitter 213Bi-labeled monoclonal antibody targeting the HER-2/neu antigen was effective in treating early-stage HER-2/neu--expressing micrometastases. Analysis of the results suggests that further gains in efficacy may require higher specific activity constructs or target antigens that are more highly expressed on tumor cells. [Cancer Res 2008;68(10):3873–80]
Myc-Mediated Transcriptional Repression by Recruitment of Histone Deacetylase
Authors: Kurland John F. , Tansey William P. 
Published: May 2008

Abstract
Myc is a transcription factor that features prominently in cancer. The oncogenicity of Myc stems from its ability to regulate expression of genes required for cell growth and proliferation. Although the mechanisms through which Myc activates transcription have been extensively studied, less is known about how Myc represses transcription. Recently, we reported that a conserved element within Myc–MbIII– is important for transcriptional repression. Here, we investigate the mechanism through which MbIII contributes to repression. We show that Myc represses transcription of target genes Id2 and Gadd153 by a process that involves histone deacetylation. We show that MbIII is important for repression of these genes and present evidence that this element contributes to repression by recruiting the histone deacetylase HDAC3 to the Id2 and Gadd153 promoters. These results describe a mechanistic role for MbIII in transcription, and reveal that recruitment of HDAC3 is a process by which Myc represses gene activity. [Cancer Res 2008;68(10):3624–9]
The Cannabinoid Receptors Are Required for Ultraviolet-Induced Inflammation and Skin Cancer Development
Authors: Zheng Duo , Bode Ann M. , Zhao Qing , Cho Yong-Yeon , Zhu Feng , Ma Wei-Ya , Dong Zigang 
Published: May 2008

AbstractSolar UV irradiation is an important carcinogen that leads to the development of skin cancer, which is the most common human cancer. However, the receptors that mediate UV-induced skin carcinogenesis have not yet been unequivocally identified. Here we showed that UV irradiation directly activates cannabinoid receptors 1 and 2 (CB1/2). Notably, our data indicated that the absence of the CB1/2 receptors in mice results in a dramatic resistance to UVB-induced inflammation and a marked decrease in UVB-induced skin carcinogenesis. A marked attenuation of UVB-induced activation of mitogen-activated protein kinases and nuclear factor- κB was associated with CB1/2 deficiency. These data provide direct evidence indicating that the CB1/2 receptors play a key role in UV-induced inflammation and skin cancer development. [Cancer Res 2008;68(10):3992–7]