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Berlin Brandenburg

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  • 1
    In: Neuro-Oncology, 2014, Vol. 16(suppl3), pp.iii28-iii28
    Description: BACKGROUND: Tumor recurrence is the main cause of death for children with medulloblastoma, the most common malignant childhood brain tumor. The MYCN oncogene is a poor prognosis marker and is amplified in the molecularly defined SHH and Group 4 subgroups but rarely in WNT and Group 3 subgroups of human medulloblastoma. Recent findings on childhood brain tumor relapse mechanisms suggest spatiotemporal differences within these four subgroups. SOX9 is a transcription factor that is important for glial fate determination in the brain but has also been found to promote tumor metastasization. We previously showed how expression of SOX9 correlates well with human SHH tumors but only few scattered SOX9-positive cells are found in SHH-independent Group 3 and Group 4 human medulloblastoma. METHODS: In order to study recurrence processes experimentally, we used a previously described transgenic Tet-OFF (Glt1-tTA) inducible model of MYCN-driven SHH-independent medulloblastoma (GTML mouse). To recreate metastatic recurrence we further used a Tet-ON (SOX9-rtTA) model that drives MYCN expression from the SOX9 promoter upon doxycycline treatment. RESULTS: By crossing the GTML Tet-OFF model with a Tet-ON transgene we managed to study rare SOX9-positive tumor cells after SOX9-negative tumor cells were first depleted using doxycycline. SOX9-positive GTML cells were tumorigenic and reinitiated distant recurrences over time. The SOX9-positive cells further showed an increased resistance to MYCN-targeted therapies. Relapses showed similar histopathology but presented generally higher levels SOX9 as compared to primary GTML tumors. A similar correlation was found in Group 3 and Group 4 medulloblastoma patients where isolated metastases had consistently higher SOX9 levels as compared to corresponding primary tumors. Finally, we overexpressed SOX9 in normal cerebellar stem cells transduced with mutationally stabilized MYCN-T58A and injected them back into the cerebellum of adult mice. Surprisingly, SOX9-positive MYCN-T58A brain tumors migrated and developed in the forebrain in contrast to the cerebellar stem cells transduced with MYCN-T58A only. CONCLUSIONS: Our findings suggest that increased levels of SOX9 drives migration in MYCN-driven medulloblastoma. Rare SOX9-positive tumor cells show an increased therapy resistance and are alone capable of reinitiating childhood brain tumors. Further characterization of SOX9-positive cells in Group 3 and Group 4 tumors could help us understand what drives metastatic medulloblastoma relapse and could lead to new therapies directed against these particularly serious cell types. SECONDARY CATEGORY: Tumor Biology.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.2311-2311
    Description: Immunotherapy is currently being established as standard treatment for cancer. Immune checkpoint blockade antibodies can cure a large proportion of patients with refractory melanoma and lung cancer, and adoptive transfer of patient-derived CD19 chimeric antigen receptor (CAR) T cells results in complete remission in a majority of patient with refractory leukemia. Cancer vaccines based on patient-derived dendritic cells (DC) modified ex vivo to present tumor antigens are promising for cancer treatment especially when combined with immune checkpoint blockade antibodies. Ex vivo-modified DCs are however poor in migrating to secondary lymphoid organs after re-administration. In reality, it is more likely endogenous DC that endocytos the injected DC, mature and then migrate to lymph nodes where they present peptide fragments of tumor antigen to T cells together with required co-stimulation.
    Keywords: Cancer Vaccines ; Immunotherapy ; Remission ; Tumors ; Lymph Nodes ; Melanoma ; Dendritic Cells ; Leukemia ; Antibodies ; Antigen (Tumor-Associated) ; Lymphocytes T ; Adoptive Transfer ; Cell Migration ; Cd19 Antigen ; Lung Cancer ; Vaccines ; Oncology;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 3
    Language: English
    In: Cancer Research, 2014, Vol.74(19)
    Keywords: Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi
    ISSN: 0008-5472
    E-ISSN: 15387445
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  • 4
    Language: English
    In: CANCER IMMUNOLOGY RESEARCH, 2016, Vol.4(1)
    Keywords: Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi ; Medical And Health Sciences ; Basic Medicine ; Immunology In The Medical Area ; Medicin Och Hälsovetenskap ; Medicinska Och Farmaceutiska Grundvetenskaper ; Immunologi Inom Det Medicinska Området
    ISSN: 2326-6066
    E-ISSN: 23266074
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  • 5
    Language: English
    In: Human Gene Therapy, 2014, Vol.25(11), pp.A50-A50
    Keywords: Medical And Health Sciences ; Basic Medicine ; Medical Genetics ; Medicin Och Hälsovetenskap ; Medicinska Och Farmaceutiska Grundvetenskaper ; Medicinsk Genetik
    ISSN: 1043-0342
    Source: SwePub (National Library of Sweden)
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  • 6
    Language: English
    In: CANCER IMMUNOLOGY RESEARCH, 2016, Vol.4(1)
    Keywords: Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi ; Medical And Health Sciences ; Basic Medicine ; Immunology In The Medical Area ; Medicin Och Hälsovetenskap ; Medicinska Och Farmaceutiska Grundvetenskaper ; Immunologi Inom Det Medicinska Området
    ISSN: 2326-6066
    E-ISSN: 23266074
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  • 7
    Language: English
    In: EMBO Molecular Medicine, 2016, Vol. 8(7), pp. 702-711
    Description: Chimeric antigen receptor (CAR) T-cell therapy is a new successful treatment for refractory B-cell leukemia. Successful therapeutic outcome depends on long-term expression of CAR transgene in T cells, which is achieved by delivering transgene using integrating gamma retrovirus (RV) or lentivirus (LV). However, uncontrolled RV/LV integration in host cell genomes has the potential risk of causing insertional mutagenesis. Herein, we describe a novel episomal long-term cell engineering method using non-integrating lentiviral (NILV) vector containing a scaffold/matrix attachment region (S/MAR) element, for either expression of transgenes or silencing of target genes. The insertional events of this vector into the genome of host cells are below detection level. CD19 CAR T cells engineered with a NILV-S/MAR vector have similar levels of CAR expression as T cells engineered with an integrating LV vector, even after numerous rounds of cell division. NILV-S/MAR-engineered CD19 CAR T cells exhibited similar cytotoxic capacity upon CD19(+) target cell recognition as LV-engineered T cells and are as effective in controlling tumor growth in vivo We propose that NILV-S/MAR vectors are superior to current options as they enable long-term transgene expression without the risk of insertional mutagenesis and genotoxicity.
    Keywords: Medical And Health Sciences ; Basic Medicine ; Immunology In The Medical Area ; Medicin Och Hälsovetenskap ; Medicinska Och Farmaceutiska Grundvetenskaper ; Immunologi Inom Det Medicinska Området
    ISSN: 1757-4676
    E-ISSN: 17574684
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  • 8
    In: Engineering in Life Sciences, March 2015, Vol.15(2), pp.243-253
    Description: Polyunsaturated fatty acids, especially gamma linolenic acid (GLA), are potentially useful agents in the treatment of cancer. , a fungus species that is able to synthesize GLA, when cultivated under nitrogen‐limited conditions in a medium having glucose as carbon and energy source, accumulated 32–35% of lipids containing 11–18% GLA. The conversion yield of glucose to lipid was around 0.11 g per gram of glucose consumed while the lipid production was 5 g/L. Fatty acid lithium salts (FALS) were prepared from the total lipids and studied for their effects on HL‐60 human leukemic cells. Cytotoxicity of FALS on HL‐60 leukemic cells was linearly related to the FALS concentration. High FALS concentration (i.e. 15 and 20 μg/mL) induced DNA fragmentation, while concurrent treatment of cells with HO (at 100 μM) and FALS resulted in enhanced cytotoxicity of HO. However, when FALS were employed at low concentrations (i.e. 5 and 10 μg/mL), they demonstrated a protective effect on HL‐60 cells against HO genotoxicity, whereas at 20 μg/mL FALS enhanced the ability of HO to induce DNA fragmentation. It is concluded that FALS derived from lipids could be an effective preparation against HL‐60 human leukemic cells.
    Keywords: Cytotoxicity ; Gamma Linolenic Acid ; Genotoxicity ; Hl‐60 Leukemic Cells ; Lipid Accumulation
    ISSN: 1618-0240
    E-ISSN: 1618-2863
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  • 9
    Language: English
    In: Engineering in Life Sciences, 2015, Vol.15(2), p.243(11)
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/elsc.201400208/abstract Byline: Raghda Alakhras, Stamatia Bellou, Grammatiki Fotaki, Georgia Stephanou, Nikos A. Demopoulos, Seraphim Papanikolaou, George Aggelis Keywords: Cytotoxicity; Gamma linolenic acid; Genotoxicity; HL-60 leukemic cells; Lipid accumulation Polyunsaturated fatty acids, especially gamma linolenic acid (GLA), are potentially useful agents in the treatment of cancer. Cunninghamella echinulata, a fungus species that is able to synthesize GLA, when cultivated under nitrogen-limited conditions in a medium having glucose as carbon and energy source, accumulated 32-35% of lipids containing 11-18% GLA. The conversion yield of glucose to lipid was around 0.11 g per gram of glucose consumed while the lipid production was 5 g/L. Fatty acid lithium salts (FALS) were prepared from the total Cunninghamella lipids and studied for their effects on HL-60 human leukemic cells. Cytotoxicity of FALS on HL-60 leukemic cells was linearly related to the FALS concentration. High FALS concentration (i.e. 15 and 20 I1/4g/mL) induced DNA fragmentation, while concurrent treatment of cells with H.sub.2O.sub.2 (at 100 I1/4M) and FALS resulted in enhanced cytotoxicity of H.sub.2O.sub.2. However, when FALS were employed at low concentrations (i.e. 5 and 10 I1/4g/mL), they demonstrated a protective effect on HL-60 cells against H.sub.2O.sub.2 genotoxicity, whereas at 20 I1/4g/mL FALS enhanced the ability of H.sub.2O.sub.2 to induce DNA fragmentation. It is concluded that FALS derived from C. echinulata lipids could be an effective preparation against HL-60 human leukemic cells. Supporting information: Additional Supporting Information may be found in the online version of this article As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. CAPTION(S): Figure S1 Figure S2
    Keywords: Glucose ; Linolenic Acids ; Leukemia
    ISSN: 1618-0240
    Source: Cengage Learning, Inc.
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  • 10
    Language: English
    In: OncoImmunology, 04 March 2018, Vol.7(3)
    Description: Autologous patient-derived dendritic cells (DCs) modified ex vivo to present tumor-associated antigens (TAAs) are frequently used as cancer vaccines. However, apart from the stringent logistics in producing DCs on a patient basis, accumulating evidence indicate that ex vivo engineered DCs are...
    Keywords: Adjuvants ; Allogeneic Dendritic Cells ; Cell-Based Immunotherapy ; Tumor Microenvironment ; Tumor-Associated Antigen ; Biology
    ISSN: 21624011
    E-ISSN: 2162-402X
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