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Berlin Brandenburg

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  • 1
    Language: English
    In: Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, 2009, Vol.18(F0020002), pp.83-94
    Description: Recently we showed that the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) sensitizes arsenic trioxide (As2O3)-resistant tumor cells to a clinically achievable concentration (1 μM) of As2O3 via a reactive oxygen species (ROS)-dependent mechanism. The aim of the present study was to evaluate, whether this combined effect of As2O3 and DHA is also applicable to other PUFAs [i.e., eicospentaenoic acid (EPA), arachidonic acid (AA), and gamma-linolenic acid (GLA)]. Fourteen tumor cell lines were incubated with As2O3 (1 μM), PUFA (25-100 μM), or the combination thereof (±vitamin E). Cell viability (colorimetric), apoptosis (bivariate annexin V/propidium iodide staining, detection of hypodiploid DNA), and thiobarbituric acid reactive substances (TBARS) were evaluated. Twelve of 14 As2O3-resistant cell lines tested were resistant to PUFA monotherapy. However, combined treatment with As2O3 and either PUFA significantly reduced cell viability in a dose-dependent manner with AA being the most potent As2O3 enhancer. The combined cytotoxic effect of As2O3/AA treatment was due to induction of apoptosis, preceded by increased intracellular TBARS and was abolished by the antioxidant vitamin E. Importantly, the combined effect of As2O3 and AA was selectively toxic for malignant cells because no cytotoxic effect was observed in normal skin fibroblasts and human microvascular endothelial cells. In conclusion, our study shows that also other PUFAs than DHA—and in particular the ω-6-PUFA AA—can be used as effective modulators of tumor cell chemosensitivity to clinically achievable concentrations of As2O3. Enhanced lipid peroxidation most likely constitutes the key mechanism for the combined effect.
    Keywords: Polyunsaturated Fatty Acids ; Arsenic Trioxide ; Apoptosis ; Lipid Peroxidation ; Tumor Cells ; Tumor Cells
    ISSN: 0965-0407
    Source: IngentaConnect
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  • 2
    Language: English
    In: The Journal of Virology, 2011, Vol. 85(5), p.2469
    Description: Segment 8 of the influenza A virus codes for two proteins (NS1 and NS2/NEP) via splicing. Here, we developed a viral vector expressing a cytokine or chemokine instead of the interferon antagonist NS1. To achieve both the desired genetic stability and high transgene expression levels, NS2/NEP mRNA splicing efficacy had to be fine-tuned by modification of splicing elements. Expression levels of secreted foreign proteins could be further enhanced by fusing the N-terminal 13 amino acids of NS1 with an IgK-derived secretion signal peptide. Thus, the first start codon was used for translation initiation of both NS2/NEP and the foreign protein.
    Keywords: Interferon ; Chemokines ; Splicing ; Amino Acids ; Secretion Signals ; Translation Initiation ; Transgenes ; Codons ; Influenza A Virus ; Genetics, Taxonomy & Structure ; Methods;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 3
    Language: English
    In: PLoS ONE, 2011, Vol.6(4), p.e18577
    Description: H5N1 influenza vaccines, including live intranasal, appear to be relatively less immunogenic compared to seasonal analogs. The main influenza virus surface glycoprotein hemagglutinin (HA) of highly pathogenic avian influenza viruses (HPAIV) was shown to be more susceptible to acidic pH treatment than that of human or low pathogenic avian influenza viruses. The acidification machinery of the human nasal passageway in response to different irritation factors starts to release protons acidifying the mucosal surface (down to pH of 5.2). We hypothesized that the sensitivity of H5 HA to the acidic environment might be the reason for the low infectivity and immunogenicity of intranasal H5N1 vaccines for mammals. ; We demonstrate that original human influenza viruses infect primary human nasal epithelial cells at acidic pH (down to 5.4), whereas H5N1 HPAIVs lose infectivity at pH≤5.6. The HA of A/Vietnam/1203/04 was modified by introducing the single substitution HA2 58K→I, decreasing the pH of the HA conformational change. The H5N1 reassortants containing the indicated mutation displayed an increased resistance to acidic pH and high temperature treatment compared to those lacking modification. The mutation ensured a higher viral uptake as shown by immunohistochemistry in the respiratory tract of mice and 25 times lower mouse infectious dose. Moreover, the reassortants keeping 58K→I mutation designed as a live attenuated vaccine candidate lacking an NS1 gene induced superior systemic and local antibody response after the intranasal immunization of mice. ; Our finding suggests that an efficient intranasal vaccination with a live attenuated H5N1 virus may require a certain level of pH and temperature stability of HA in order to achieve an optimal virus uptake by the nasal epithelial cells and induce a sufficient immune response. The pH of the activation of the H5 HA protein may play a substantial role in the infectivity of HPAIVs for mammals.
    Keywords: Research Article ; Biology ; Medicine ; Virology ; Immunology ; Infectious Diseases
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: PLoS ONE, 2009, Vol.4(1), p.e4122
    Description: A replication defective influenza A vaccine virus (delNS1 virus) was developed. Its attenuation is due to potent stimulation of the innate immune system by the virus. Since the innate immune system can also target cancer cells, we reasoned that delNS1 virus induced immune-stimulation should also lead to the induction of innate cytotoxic effects towards cancer cells. ; Peripheral blood mononuclear cells (PBMCs), isolated CD56+, CD3+, CD14+ and CD19+ subsets and different combinations of the above subsets were stimulated by delNS1, wild type (wt) virus or heat inactivated virus and co-cultured with tumor cell lines in the presence or absence of antibodies against the interferon system. Stimulation of PBMCs by the delNS1 virus effectively induced cytotoxicity against different cancer cell lines. Surprisingly, virus induced cytotoxicity was exerted by all major subtypes of PBMCs including CD56+, CD3+, CD14+ and CD19+ cells. Virus induced cytotoxicity in CD3+, CD14+ and CD19+ cells was dependent on virus replication, whereas virus induced cytotoxicity in CD56+ cells was only dependent on the binding of the virus. Virus induced cytotoxicity of isolated cell cultures of CD14+, CD19+ or CD56+ cells could be partially blocked by antibodies against type I and type II (IFN) interferon. In contrast, virus induced cytotoxicity in the complete PBMC preparation could not be inhibited by blocking type I or type II IFN, indicating a redundant system of activation in whole blood. ; Our data suggest that apart from their well known specialized functions all main subsets of peripheral blood cells also initially exert a cytotoxic effect upon virus stimulation. This closely links the innate immune system to the adaptive immune response and renders delNS1 virus a potential therapeutic tool for viro-immunotherapy of cancer.
    Keywords: Research Article ; Virology ; Immunology -- Immunity To Infections ; Immunology -- Innate Immunity
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Blood, 15 June 2003, Vol.101(12), pp.4990-7
    Description: Recent reports indicate a broad spectrum of antileukemic activity for arsenic trioxide (As(2)O(3)) due to its ability to induce apoptosis via intracellular production of reactive oxygen species (ROS). Despite its potent apoptotic mechanism, As(2)O(3) is not equally effective in all leukemic cells, which has prompted a search for agents enhancing As(2)O(3) efficacy. Recently, evidence has been gathered that the polyunsaturated fatty acid docosahexaenoic acid (DHA) may sensitize tumor cells to ROS-inducing anticancer agents. The aim of our investigation was to evaluate whether DHA enhances As(2)O(3)-mediated apoptosis in As(2)O(3)-resistant HL-60 cells. While 1 microM As(2)O(3) or 25 microM DHA reduced cell viability to 85.8% +/- 2.9% and 69.2% +/- 3.6%, combined treatment with As(2)O(3) and DHA reduced viability to 13.0% +/- 9.9% with a concomitant increase of apoptosis. Apoptotic cell death was preceded by collapse of the mitochondrial membrane potential, increased expression of proapoptotic B-cell lymphoma protein-2-associated X protein (Bax), and caspase-3 activation. Importantly, the combined effect of As(2)O(3) and DHA was associated with increased production of intracellular ROS and toxic lipid peroxidation products and was abolished by the antioxidant vitamin E or when oleic acid (a nonperoxidizable fatty acid) was used in place of DHA. Intracellular ROS and toxic lipid peroxidation products most likely constitute the key mediators contributing to the combined effect of As(2)O(3) and DHA. Our data provide the first evidence that DHA may help to extend the therapeutic spectrum of As(2)O(3) and suggest that the combination of As(2)O(3) and DHA could be more broadly applied in leukemia therapy.
    Keywords: Drug Resistance, Neoplasm ; Proto-Oncogene Proteins C-Bcl-2 ; Antineoplastic Agents -- Pharmacology ; Apoptosis -- Drug Effects ; Arsenicals -- Pharmacology ; Docosahexaenoic Acids -- Pharmacology ; Leukemia -- Pathology ; Oxides -- Pharmacology
    ISSN: 0006-4971
    E-ISSN: 15280020
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  • 6
    In: Pigment Cell & Melanoma Research, August 2011, Vol.24(4), pp.656-665
    Description: Human endogenous retroviruses (HERVs) represent a cellular reservoir of potentially pathogenic retroviral genes. A growing body of evidence indicates that the activation of endogenous retroviral sequences might be involved in the transformation of melanocytes. In this study, we investigated the effects of ultraviolet radiation (UVR) on the expression of human endogenous retrovirus type K (HERV‐K) in melanoma cells and non‐melanoma cells in vitro. Solely in melanoma cell lines, irradiation with UVB (200 mJ/cm) resulted in a significant transcriptional activation of the retroviral gene as well as in an enhanced expression of the retroviral envelope protein (env). In addition, UVB treatment induced the production of retroviral particles in the supernatants of melanoma cell lines. These data indicate that HERV‐K expression can be activated by UVB irradiation and suggest an involvement of HERV‐K in UVR‐related melanoma pathogenesis.
    Keywords: Melanoma ; Human Endogenous Retrovirus Type K ; Ultraviolet Radiation
    ISSN: 1755-1471
    E-ISSN: 1755-148X
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  • 7
    Language: English
    In: International Journal of Cancer, 20 November 2004, Vol.112(4), pp.707-712
    Description: It has been shown that the polyunsaturated fatty acid docosahexaenoic acid (DHA) can sensitize various tumor cells to reactive oxygen species (ROS)‐inducing anticancer agents. Recently, we demonstrated that DHA also enhances the apoptotic effect of clinically achievable concentrations (1–2 μM) of arsenic trioxide (AsO) in several AsO‐resistant human leukemic cell lines via a ROS‐dependent mechanism. The aim of the present study was to evaluate whether this combined effect of AsO and DHA is also applicable to AsO‐resistant solid tumor cells. We have tested 12 different tumor cell lines, including MDA‐MB‐468, SK‐BR‐3, MCF‐7 (breast cancer), ES‐2, SKOV‐3 (ovarian cancer), HT‐29, SW‐620, LS‐174T (colon cancer), PC‐3 (prostate cancer), HeLa (cervical cancer), PANC‐1 (pancreatic cancer) and one primary melanoma cell line. With the exception of MDA‐MB‐468 and ES‐2, all cells were resistant to treatment with either AsO or DHA alone. However, combined treatment with AsO and DHA significantly reduced viability in 7 of the 10 AsO‐resistant solid tumors tested. The cytotoxic effect of AsO and DHA was associated with the induction of apoptosis and a concomitant increase of intracellular lipid peroxidation products. Importantly, the combined effect of AsO and DHA was selectively toxic for malignant cells since no cytotoxic effect was observed in normal skin fibroblasts, human microvascular endothelial cells and peripheral blood mononuclear cells derived from healthy donors. Our data indicate that DHA may help to extend the therapeutic spectrum of AsO in the treatment of solid tumors since it may overcome or acquired resistance to AsO. © 2004 Wiley‐Liss, Inc.
    Keywords: Docosahexaenoic Acid ; Arsenic Trioxide ; Apoptosis ; Lipid Peroxidation ; Solid Tumor Cells
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 8
    Language: English
    In: Journal of Virology, 2011, Vol. 85(21), p.11139
    Description: In general, antibiotics are not rated as substances that inhibit or support influenza virus replication. We describe here the enhancing effect of the polyene antibiotic amphotericin B (AmB) on influenza virus growth in Vero cells. We show that isolation rates of influenza A and B viruses from clinical samples can be dramatically enhanced by adding AmB to the culture medium. We demonstrate that AmB promotes the viral uptake and endocytic processing of the virus particles. This effect is specific for Vero and human nasal epithelial cells and was not observed in Madin-Darby canine kidney cells. The effect of AmB was subtype specific and more prominent for human seasonal influenza strains but absent for H5N1 human viruses. The AmB-enhancing effect seemed to be solely due to the viral hemagglutinin function. Our results indicate that the use of AmB may facilitate influenza virus isolation and production in Vero cells.
    Keywords: Amphotericin B -- Metabolism; Antifungal Agents -- Metabolism; Influenza A Virus -- Drug Effects; Influenza B Virus -- Growth & Development; Virus Replication -- Drug Effects; Virus Replication -- Growth & Development; Virus Replication -- Drug Effects;
    ISSN: 1098-5514
    ISSN: 10985514
    ISSN: 0022538X
    Source: American Society of Microbiology
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  • 9
    Language: English
    In: Cancer Biology & Therapy, 15 September 2010, Vol.10(6), pp.592-599
    Description: Previously we have developed a prototype for conditionally replicating oncolytic influenza A virus which is based on deletions in the non-structural (NS1) protein. Multi-cycle replication of influenza A virus in malignant tissue is critically dependent on a protease which cleaves the viral...
    Keywords: Medicine
    ISSN: 1538-4047
    E-ISSN: 1555-8576
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  • 10
    Language: English
    In: Journal of Molecular Medicine, Feb, 1999, Vol.77(3), p.316(6)
    Description: Byline: Sanda Sturlan (1), S. Kapitanovic (1), Duje Kovacevic (3), Josip Lukac (3), Sime Spaventi (2), Radan Spaventi (4), Kresimir Pavelic (1) Keywords: Key words Colon cancer; Tumor suppressor genes; APC; DCC; Loss of heterozygosity Abstract: We examined 36 cases of human sporadic colon carcinoma and corresponding normal tissue samples to evaluate loss of heterozygosity at the APC and DCC tumor suppressor genes loci using restriction fragment length polymorphism polymerase chain reaction and variable nucleotide tandem repeat analysis. Observed informativity was 83% for APC and 75% for DCC. DNA from 6 (20%) of 30 informative tumors exhibited loss of heterozygosity at the APC locus. Loss of heterozygosity at the DCC locus was observed in 7 (26%) of 27 informative tumor DNAs. Our results support the view that malignant progression is a consequence of more than one genetic change and suggest that inactivation of APC and DCC genes plays a role in a multistep process of colon tumor progression. Author Affiliation: (1) Division of Molecular Medicine, Ruder Boskovic Institute, Bijenicka c. 54, HR-10000 Zagreb, Croatia e-mail: kapitan@rudjer.irb.hr, Tel.: +385-1-4680094, Fax: +385-1-4680094, XX (2) Croatian Academy of Sciences and Arts, Zagreb, Croatia, XX (3) Clinical Hospital "Sestre milosrdnice," Zagreb, Croatia, XX (4) PLIVA Research Institute, Zagreb, Croatia, XX Article note: Received: 7 August 1998 / Accepted: 15 December 1998
    Keywords: Key words Colon cancer ; Tumor suppressor genes ; APC ; DCC ; Loss of heterozygosity;
    ISSN: 0946-2716
    E-ISSN: 14321440
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