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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 20 ( 2008-10-15), p. 8573-8581
    Kurzfassung: We have identified a natural compound that activates apoptosis of epithelial cancer cells through activation of tumor necrosis factor-α (TNF-α), TNF receptor (TNFR)-associated death domain (TRADD), and caspases. The molecule 1-hydroxy-5,7-dimethoxy-2-naphthalene-carboxaldehyde (HDNC, marmelin) was isolated and characterized from ethyl acetate fraction of extracts of Aegle marmelos. HDNC treatment inhibited the growth of HCT-116 colon cancer tumor xenografts in vivo. Immunostaining for CD31 showed that there was a significant reduction in microvessels in the HDNC-treated animals, coupled with decreased cyclooxygenase-2, interleukin-8, and vascular endothelial growth factor mRNA. Using hexoseaminidase assay, we determined that HDNC inhibits proliferation of HCT-116 colon and HEp-2 alveolar epithelial carcinoma cells. Furthermore, the cancer cells showed increased levels of activated caspase-3 and induced G1 cell cycle arrest, which was suppressed by caspase-3 inhibitors. HDNC induced TNF-α, TNFR1, and TRADD mRNA and protein expression. Moreover, caspase-8 and Bid activation, and cytochrome c release, were observed, suggesting the existence of a cross-talk between death receptor and the mitochondrial pathways. HDNC inhibited AKT and extracellular signal-regulated kinase phosphorylation both in cells in culture and in tumor xenografts. In addition, electrophoretic mobility shift assay and luciferase reporter assays showed that HDNC significantly suppressed TNF-α–mediated activation and translocation of nuclear factor-κB (NF-κB). This was further confirmed by Western blot analysis of nuclear extracts wherein levels of RelA, the p65 component of NF-κB, were significantly less in cells treated with HDNC. Together, the data suggest that the novel compound HDNC (marmelin) is a potent anticancer agent that induces apoptosis during G1 phase of the cell cycle and could be a potential chemotherapeutic candidate. [Cancer Res 2008;68(20):8573–81]
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2008
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Online-Ressource
    Online-Ressource
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-253-LB-253
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-253-LB-253
    Kurzfassung: Prostate cancer (PCa) is one of the leading causes of cancer deaths among men with limited treatment options. Accordingly, new approaches, such as immunotherapy, may represent important approaches for PCa treatment. Electroporation (EP) delivered DNA vaccines has recently shown promising results for therapeutic immunotherapy strategies has been limited to single antigen and epitope targets with limited success. We hypothesized that a broader collection of antigens adjuvanted by plasmid encoded IL-12 would bypass immune tolerance and improve the breadth and effectiveness of a PCa immunotherapy approach. We tested this hypothesis in NHP for immune tolerance effects as well as in the highly relevant TRAMP-C2 challenge model. We developed highly optimized DNA vectors encoding consensus antigens for important PCa targets prostate-specific antigen (SynCon PSA), prostate-specific membrane antigen (SynCon PSMA), and human six-transmembrane epithelial antigen of the prostate (STEAP). In mice the vaccines demonstrated potent IFNγ production by ELISpot (2740 SFU) and robust immune responses in the CD4+ (0.53%) and CD8+ (3.0%) T cell compartments. Further, sera from immunized mice reacted in ELISA with relevant targets and specifically stained LNCaP cells, a human PCa cell line, as well as human PCa tumor sections, supporting that the vaccine antigens induced relevant antibody responses. Vaccination of Rhesus Macaques, which share greater than 98% identity with humans, showed robust anti-PSA, PSMA and STEAP IFNγ production (612 SFU), potential for cytotoxic T cell function, and antigen specific seroconversion supporting the ability of these constructs to break tolerance. The therapeutic potential of PSMA, STEAP, and the combination of PSMA and STEAP, alone or with the molecular adjuvant IL-12, was evaluated in mice in the TRAMP-C2 tumor model. Alone, PSMA, STEAP or PSMA+STEAP demonstrated prolonged survival and a modest impact on tumor growth. However, the combination of synthetic vaccine antigens with IL-12 resulted in 100% efficacy in treatment and clearance of tumors resulting in 100% survival. These data support further study of this novel immune therapy of PCa. Citation Format: Bernadette Ferraro, Jewell N. Walters, Emma L. Reuschel, Amritha Balakrishnan, Matthew P. Morrow, Amir S. Khan, Niranjan Y. Sardesai, Laurent M. Humeau, David B. Weiner. Control of tumor growth in vivo by a synthetic multi-antigen DNA immune therapy for prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-253.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2016
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1190-1190
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1190-1190
    Kurzfassung: Background: The incidence of gastric cancer while declining in many places worldwide is characterized by considerable geographic variability in incidence rates and temporal trends. The United States has large racial, ethnic, and regional variation; we collected data from all 50 states to better characterize recent changes in gastric cancer incidence in the entire United States. Methods: We extracted data on the annual gastric cancer (ICD-O-3: C16.0-C16.9) incidence rates for the period 1999-2013 from the United Stated Cancer Statistics (USCS) registry, which covers 97% of the population. Both age-adjusted incidence rates and temporal trends of gastric cancer incidence were examined overall, as well as stratified by sociodemographic factors and at the state level. We used Joinpoint regression analysis to compute annual percent change (APC) and average annual percent change (AAPC) and corresponding 95% CIs. Heat maps were created to highlight the temporal trend in age-adjusted incidence rates in each state over three 5-year periods: 1999-2003, 2004-2008, and 2009-2013. As a secondary analysis, we also extracted data from the SEER 13 registries to examine the incidence rates and trends separately for cardia and non-cardia gastric cancers. Results: Overall gastric cancer incidence decreased from 7.64 per 100,000 in 1999 to 6.55 per 100,000 in 2013, decreasing by 1.02% (AAPC=-1.02; 95% CI, -1.28 to -0.76) annually between 1999 and 2013. However, while overall gastric cancer incidence rates decreased (1999-2008 APC=-1.75, 95% CI, -2.02 to -1.47) and then plateaued (2008-2013 APC=-0.24, 95% CI: -0.89, 0.42) among persons aged ≥50 years, the rates increased among persons aged & lt;50 years (AAPC=0.89, 95% CI: 0.61 to 1.16). Most notable increases were observed among non-Hispanic white females (AAPC=1.46, 95% CI: 0.87 to 2.06) and Hispanic females (AAPC=0.47, 95% CI: 0.10 to 0.84). Based on the analysis of SEER 13 registries, the decreasing trend among persons aged ≥50 years is mainly due to decreasing incidence of non-cardia gastric cancer (AAPC=-2.20, 95% CI, -2.51 to -1.90). Increasing rate of non-cardia cancer helped explain the uprising trend of gastric cancer among aged & lt;50 years (AAPC=0.69, 95% CI: -0.06 to 1.44). States with rapid increase of high risk population groups such as Hispanic females including California and Texas are among the top 5 states with both overall high incidence rate of gastric cancer (1999-2013) and high AAPC (California: 1.77, 95% CI, 0.52 to 2.34; Texas: 1.70, 95% CI, 0.25 to 3.17) within last 5 years (2009-2013) among females aged & lt;50 years. Conclusions: While gastric cancer, particularly non-cardia, rates have decreased rapidly among persons aged ≥50 years in the United States, the incidence rates among persons aged & lt;50 years have increased. Future studies on explanatory factors for this trend are warranted. Citation Format: Zhensheng Wang, Anam Khan, Maya Balakrishnan, Hashem B. El-Serag, Aaron P. Thrift. Incidence of gastric cancer in the United States during 1999 to 2013: A 50-state analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1190.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2018
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Online-Ressource
    Online-Ressource
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1858-1858
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1858-1858
    Kurzfassung: Background: Cancer cells have an altered glucose metabolism, which not only permits them to survive under hypoxic conditions but confers a distinct growth advantage by sustaining higher proliferation rates, invasiveness, and subsequent distant metastasis. This unique difference in glucose metabolism from healthy cells opens up a selective mechanism by which to kill cancer cells, bypassing normal healthy cells. Several enzymes in glucose metabolism are attractive targets for development of first-in-class therapeutic agents. We have undertaken development of a multiplex panel involving biomarkers involved in glucose metabolism to support drug development and to interrogate glycolytic pathway in cancer patients. Methods: The panel includes quantitative determinations of protein levels of hexokinase-2 (HK2), pyruvate kinase isoform-2 (PKM2), lactate dehydrogenase alpha (LDHa), and phosphorylated pyruvate dehydrogenase E1-alpha (phospho-PDHE1a). The sandwich immunoassays were built on the Luminex® xMAP technology platform using MagPlex magnetic beads and cloned proteins are employed as calibrators. The panel is designed to measure protein concentrations in fractionated cell extracts from flash frozen tumor biopsies. Results: We have completed development of three sandwich immunoassays for HK2, PK-M2, and LDHa on Luminex platform. Suitable capture antibodies as well as phycoerythrin labeled detection antibodies have been identified and tested for sandwich formation and multiplexing using recombinant calibrators and cell lysates. The multiplex is currently standardized for optimal assay performance. Known pharmacological modulators (3-bromopyruvate, bortezumib, oxamate, dichloroacetate) of HK2, PKM2, LDHa, and PDHE1a were used in vitro to demonstrate expected directional changes in biomarkers in the panel. Conclusions: We have developed a multiplex panel to measure protein levels of three key molecules involved in energy metabolism in cancer cells. The multiplex panel provides a critical tool, in the clinical setting, to support ongoing therapeutic strategies aimed at targeting the energy provision pathway in cancer patients. Importantly, the panel can be used to survey metabolic phenotype of different tumors to identify type and stage of cancer most susceptible to inhibition of glycolysis. Funded by NCI Contract No HHSN261200800001E. Citation Format: Meenakshi P. Balakrishnan, Ralph E. Parchment, Melinda G. Hollingshead, Joseph E. Tomaszewski, Robert J. Kinders, James H. Doroshow, Apurva K. Srivastava. Development of a multiplex panel of biomarkers to assess energy metabolism in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1858. doi:10.1158/1538-7445.AM2013-1858
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2013
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
    BibTip Andere fanden auch interessant ...
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