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  • Medicine  (16)
  • Cytomegalovirus
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  • 1
    In: Neuro-Oncology, 2015, Vol. 17(7), pp.1039-1039
    Description: The question of whether most gliomas are infected with human cytomegalovirus (HCMV) has been under dispute for more than 10 years. We recently reported our failure to detect HCMV in gliomas in Neuro-Oncology.1 Our article was accompanied by 2 related editorials,2,3 one of which boldly criticized our approach.3 Instead of fighting a petty, ivory tower dispute, we would like to lobby for a serious collaborative approach to providing conclusive evidence on the presence of HCMV in glioma (and other cancers). Since we developed the concept of oncomodulation (ie, that HCMV …
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    In: Neuro-Oncology, 2014, Vol. 16(11), pp.1469-1477
    Description: BACKGROUND: Experimental findings have suggested that human cytomegalovirus (HCMV) infection of tumor cells may exert oncomodulatory effects that enhance tumor malignancy. However, controversial findings have been published on the presence of HCMV in malignant tumors. Here, we present the first study that systematically investigates HCMV infection in human nervous system tumors by highly sensitive immunohistochemistry in correlation with the HCMV serostatus of the patients.METHODS: Immunohistochemical and quantitative PCR-based methods to detect different HCMV antigens and genomic HCMV DNA were optimized prior to the investigation of pathological samples. Moreover, the pathological results were matched with the HCMV serostatus of the patients.RESULTS: HCMV immediate-early, late, and pp65 antigens could be detected in single cells from HCMV strain Hi91-infected UKF-NB-4 neuroblastoma cells after 1:1024 dilution with noninfected UKF-NB-4 cells. Genomic HCMV DNA could be detected in copy numbers as low as 430 copies/mL. However, we did not detect HCMV in tumors from a cohort of 123 glioblastoma, medulloblastoma, or neuroblastoma patients. Notably, we detected nonspecifically positive staining in tumor tissues of HCMV seropositive and seronegative glioblastoma patients. The HCMV serostatus of 67 glioblastoma patients matched the general epidemiological prevalence data for Western countries (72% of female and 57% of male glioblastoma patients were HCMV seropositive). Median survival was not significantly different in HCMV seropositive versus seronegative glioblastoma patients.CONCLUSIONS: The prevalence of HCMV-infected tumor cells may be much lower than previously reported based on highly sensitive detection methods.
    Keywords: Cytomegalovirus ; Glioma ; Oncomodulation
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 3
    Language: English
    In: Journal of the National Cancer Institute, 01 April 2009, Vol.101(7), pp.441-3
    Description: Strååt et al. (1) show that human cytomegalovirus (HCMV) infection induces telomerase activation in human malignant glioma cells and fibroblasts. These results reveal a novel mechanism that may be relevant for the potential of HCMV to promote oncogenesis and thus provide another piece of the puzzle that has drawn the attention of oncologists and virologists for almost four decades.
    Keywords: Cytomegalovirus -- Metabolism ; Glioma -- Enzymology ; Immediate-Early Proteins -- Metabolism ; Oncogenic Viruses -- Metabolism ; Telomerase -- Metabolism
    ISSN: 00278874
    E-ISSN: 1460-2105
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  • 4
    Language: English
    In: The Journal of Infectious Diseases, 1 September 2000, Vol.182(3), pp.643-651
    Description: In fibroblasts, infection with human cytomegalovirus (HCMV) inhibits expression of the extracellular matrix proteins thrombospondin-1 and -2 (TSP-1 and TSP-2). These effects may depend on expression of HCMV immediate-early (IE) genes, which are activated by cellular transcription factor NF-kB. The influence of HCMV infection on TSP-1 and TSP-2 expression and the ability of different antiviral drugs to prevent these cellular changes in permissive cultures of human retinal glial cells were observed. Ganciclovir inhibited only HCMV late antigen (LA) expression, whereas antisense oligonucleotide ISIS 2922 and peptide SN50, inhibitors of HCMV IE expression and NF-kB activity, respectively, inhibited both IE and LA expression. ISIS 2922 and SN50, but not ganciclovir, prevented down-modulation of TSP1 and TSP-2. The results showed that HCMV-induced down-modulation of TSP-1 and TSP2 in retinal glial cells is prevented by inhibition of HCMV IE expression. These findings may be relevant to pathogenesis and treatment of HCMV retinitis.
    Keywords: Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Microbiology ; Health sciences -- Medical sciences -- Pharmaceutics ; Biological sciences -- Biology -- Microbiology ; Health sciences -- Medical conditions -- Infections ; Biological sciences -- Biochemistry -- Biomolecules ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Cytology ; Health sciences -- Medical conditions -- Diseases
    ISSN: 00221899
    E-ISSN: 15376613
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  • 5
    Language: English
    In: International Journal of Cancer, 01/03/1996, Vol.65(1), pp.90-96
    Description: Human neuroblastoma cell line UKF-NB-4 persistently infected with human cytomegalovirus (HCMV) strain AD169 was established to study the effects of long-term HCMV infection on virus production and phenotypic characteristics of tumour cells. The cells designated UKF-NB-4 super(AD169) were subcultured (80 subcultures) over a period of more than 2 years after initiation of infection. UKF-NB-4 super(AD169) cells continued to produce infectious virus in successive passages, with a titre ranging from 9 x 10 super(3) to 1 x 10 super(5) and from 2 x 10 super(1) to 2 x 10 super(2) plaque-forming units per 10 super(6) cells and 1 ml culture medium, respectively; 10-20% of the cells produced HCMV-specific antigens, while 6-13% produced infectious virus progeny. The number of HCMV-specific DNA copies ranged from 9 x 10 super(4) to 9 x 10 super(6) per 10 super(6) cells. Transmission electron microscopy confirmed the productive nature of HCMV infection. UKF-NB-4 super(AD169) cultures proliferated, with population doubling time ranging from 24.5 to 26.6 hr (19.5 to 20.3 hr for UKF-NB-4) and cell viability from 79% to 85% (91-96% for UKF-NB-4). Significantly lower amounts of tyrosine hydroxylase and decreased activity for dopamine- beta -hydroxylase than in uninfected cells were observed in UKF-NB-4 super(AD169) cells. However, the expression of N-myc oncoprotein was significantly increased in persistently infected cultures. Our results show that long-term productive HCMV infection of UKF-NB-4 cell line is associated with the modulation of phenotypic properties, which may be related to the biological behaviour of neuroblastoma cells.
    Keywords: Cytomegalovirus ; Cytomegalovirus ; Neuroblastoma Cells ; Man ; Tumor Cells ; Phenotyping ; Neuroblastoma Cells ; Man ; Tumor Cells ; Phenotyping ; Neurovirology ; Virus Behavior in Cell Culture ; Tyrosine 3-Monooxygenase ; Dopamine Beta -Monooxygenase ; N-Myc Protein ; Tyrosine 3-Monooxygenase ; Dopamine Beta -Monooxygenase ; N-Myc Protein ; N-Myc Protein ; Dopamine Beta -Monooxygenase ; Tyrosine 3-Monooxygenase;
    ISSN: 00207136
    E-ISSN: 10970215
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  • 6
    In: Cardiovascular Research, 2008, Vol. 77(3), pp.544-550
    Description: AIMS: The endothelium represents a natural site of human cytomegalovirus (HCMV) infection involved in viral spreading and persistence. Moreover, HCMV infection of endothelial cells has been associated with different pathological conditions of the cardiovascular system. Here, the influence of the antiepileptic drug valproic acid (VPA) was investigated on HCMV replication in human umbilical vein endothelial cells alone or in combination with the antiviral drugs ganciclovir, cidofovir or foscarnet.METHODS AND RESULTS: HCMV replication was observed by immunostaining for viral antigens and by virus yield assay. Protein expression and phosphorylation were examined by western blot. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction assay. Therapeutic VPA concentrations (〈 or =1 mM) increased HCMV immediate early antigen, late antigen, and viral titres of different endotheliotropic and non-endotheliotropic HCMV strains in a concentration- and time-dependent manner up to 30-fold. Moreover, VPA impaired the antiviral activity of the anti-HCMV drugs ganciclovir, cidofovir, and foscarnet. VPA inhibits histone deacetylases (HDAC) and induces HDAC-independently extracellular signal-regulated kinases 1/2 (ERK 1/2) phosphorylation in endothelial cells. Both effects observed, HCMV stimulation and interference with antiviral drugs, depend on HDAC inhibition but not on ERK 1/2 phosphorylation.CONCLUSION: These findings suggest to carefully monitor the frequency of HCMV reactivation in cardiovascular patients treated with VPA (or other HDAC inhibitors) in comparison to control individuals.
    Keywords: Human Cytomegalovirus ; Antiviral Therapy ; Endothelium
    ISSN: 0008-6363
    E-ISSN: 1755-3245
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  • 7
    In: Transplantation, 1999, Vol.68(11), pp.1753-1761
    Description: BACKGROUND.: Cytomegalovirus (CMV) infection is associated with acute and chronic allograft rejection. We have recently shown that rat CMV increases portal inflammation and bile duct destruction in a model of rat liver allograft rejection. Desferrioxamine (DFO), an iron chelator and antioxidant, has recently been demonstrated to have antiviral as well as immunomodulatory effects in vitro. We therefore investigated whether DFO inhibits (a) CMV infection and (b) graft destruction in our rat model. METHODS.: One day after liver transplantation, PVG (RT1) into BN(RT1), the rats were infected with rat CMV (RCMV, Maastricht strain; 10 plaque-forming units i.p.). The effects of 100 mg/kg body weight and 200 mg/kg body weight DFO were examined. RESULTS.: In the untreated group, the grafts were uniformly RCMV culture-positive. In the group receiving 200 mg/kg DFO, RCMV replication was effectively inhibited. Inflammatory response in the graft, and especially the number of macrophages, was significantly reduced by DFO. Portal inflammation and bile duct destruction were also significantly reduced. In the untreated group, the bile duct epithelial cells were found to be strongly positive for tumor necrosis factor-α and this expression was clearly decreased by DFO. In addition, DFO significantly inhibited vascular cell adhesion molecule-1 expression on sinusoidal endothelial cells. CONCLUSIONS.: Our in vivo transplant study strongly supports the inhibitory effects of metal chelators on CMV infection and their possible usefulness in the treatment of CMV-induced pathogenic changes.
    Keywords: Adjuvants, Immunologic–Pharmacology ; Animals–Pharmacology ; Antiviral Agents–Metabolism ; Cell Adhesion Molecules–Physiology ; Cytomegalovirus–Immunology ; Cytomegalovirus Infections–Virology ; Deferoxamine–Pharmacology ; Graft Rejection–Complications ; Liver–Drug Effects ; Liver Transplantation–Immunology ; Nephritis–Pathology ; Rats–Virology ; Rats, Inbred Bn–Etiology ; Rats, Inbred Strains–Pathology ; Transplantation, Homologous–Metabolism ; Tumor Necrosis Factor-Alpha–Drug Effects ; Virus Replication–Drug Effects ; Adjuvants, Immunologic ; Antiviral Agents ; Cell Adhesion Molecules ; Tumor Necrosis Factor-Alpha ; Deferoxamine;
    ISSN: 0041-1337
    E-ISSN: 15346080
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  • 8
    Language: English
    In: Trends in Molecular Medicine, 2004, Vol.10(1), pp.19-23
    Description: Recently, the term oncomodulation has been proposed to express the ability of human cytomegalovirus (HCMV) to modify tumor cell biology, a phenomenon that is independent from transformation. Because past studies have failed to show that HCMV can transform normal human cells, HCMV has not been regarded as an oncogenic tumor virus. However, recent investigations have revealed a high frequency of HCMV in tumor cells of malignancies such as colon cancer, malignant glioma, prostatic intraepithelial neoplasia, and carcinoma. Data from experiments with HCMV-infected tumor cell lines have highlighted the oncomodulatory potential of HCMV and provided important insights into the patho- mechanisms associated with aberrant signaling pathways and transcription factor and/or tumor suppressor function of the host cell.
    Keywords: Medicine ; Biology
    ISSN: 1471-4914
    E-ISSN: 1471-499X
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  • 9
    Language: English
    In: Graefe's Archive for Clinical and Experimental Ophthalmology, 2005, Vol.243(7), pp.671-676
    Description: Human cytomegalovirus (HCMV) retinitis frequently occurs in severely naturally and iatrogenically immunocompromised patients. It has been shown that the immune-privileged retina is a major site of HCMV infection in AIDS patients. It is conceivable either that during the immunosuppression HCMV infection reactivates in various other organs viremically affecting the retina or that HCMV persisting in the retina may locally reactivate and result in HCMV retinitis. As there is still controversy about the sites of HCMV latency and persistence we investigated 75 eyes of HIV-seronegative patients undergoing enucleation due to a variety of malignant and non-viral benign ophthalmic disorders for the retinal presence of HCMV antigen and DNA. None of the analyzed patients had symptoms of HCMV retinitis. Immunohistologic staining as well as Taq Man DNA PCR analysis showed all samples to be free of HCMV. Our data suggest that the human eye is rather unlikely to be a site of productive or latent HCMV persistence.
    Keywords: Cytomegalovirus -- Physiology ; Cytomegalovirus Retinitis -- Virology ; Retina -- Virology ; Virus Latency -- Physiology;
    ISSN: 0721-832X
    E-ISSN: 1435-702X
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  • 10
    Language: English
    In: Neoplasia, July 2004, Vol.6(4), pp.323-331
    Description: Pathologic data indicate that human cytomegalovirus (HCMV) infection might be associated with the pathogenesis of several human malignancies. However, no definitive evidence of a causal link between HCMV infection and cancer dissemination has been established to date. This study describes the modulation of the invasive behavior of NCAM-expressing tumor cell lines by HCMV. Neuroblastoma (NB) cells, persistently infected with the HCMV strain AD169 (UKF-NB-4 and MHH-NB-11 ), were added to endothelial cell monolayers and adhesion and penetration kinetics were measured. The 140- and 180-kDa isoforms of the adhesion receptor NCAM were evaluated by flow cytometry, Western blot, and reverse transcriptionpolymerase chain reaction (RT-PCR). The relevance of NCAM for tumor cell binding was proven by treating NB with NCAM antisense oligonucleotides or NCAM transfection. HCMV infection profoundly increased the number of adherent and penetrated NB, compared to controls. Surface expression of NCAM was significantly lower on UKF-NB-4 and MHH-NB-11 , compared to mock-infected cells. Western-blot and RT-PCR demonstrated reduced protein and RNA levels of the 140- and 180-kDa isoform. An inverse correlation between NCAM expression and adhesion capacity of NB has been shown by antisense and transfection experiments. We conclude that HCMV infection leads to downregulation of NCAM receptors, which is associated with enhanced tumor cell invasiveness.
    Keywords: Hcmv ; Ncam ; Tumor Dissemination ; N-Myc ; P73 ; Medicine
    ISSN: 1476-5586
    ISSN: 15228002
    E-ISSN: 1476-5586
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