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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i130-i130
    Description: High-risk medulloblastoma (MB) is a deadly disease with poor overall survival. Survivors suffer from severe treatment-associated morbidity. Patients with Group 3 MB with an amplification of MYC show particularly poor outcome. Therefore novel therapies tailored to this subgroup are urgently needed. We have previously shown that MYC amplified MB cell lines are highly susceptible to inhibition of class I histone deacetylases (HDACs), including HDAC2. We here explore the functional interaction of HDAC2 and MYC.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: Cancer Research, 10/01/2018, Vol.78(19 Supplement), pp.IA11-IA11
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 3
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i106-i106
    Description: The main challenge in the clinical management of pilocytic astrocytoma (PA) is its unpredictable growth behavior. PA cells are driven into oncogene-induced senescence (OIS) by aberrant MAPK activation. In other senescence models OIS was shown to be regulated and maintained by the senescence-associated secretory phenotype (SASP). In this study, the first patient-derived cell culture model DKFZ-BT66 was used to show presence of the SASP in PA and to analyze its impact on OIS. This model allows for shifting between proliferation and senescence via doxycycline-inducible inhibition of the OIS-relevant p53/RB pathway. Both states were studied using gene-expression profiling (GEP), Western blot, qPCR, ELISA, and automated trypan blue exclusion staining. The GEP shows significant upregulation of SASP factors during OIS in DKFZ-BT66 cells. Conditioned medium of senescent DKFZ-BT66 cells is sufficient to induce growth arrest of proliferating DKFZ-BT66 cells. Upregulation of the SASP factors IL-1B and IL-6 was validated on mRNA and protein levels and both pathways are active during OIS. Stimulation of the IL-1 pathway reduces growth of proliferating DKFZ-BT66 cells. While pharmacological inhibition of single cytokines is not sufficient to overcome growth arrest during OIS, treatment with the anti-inflammatory drug dexamethasone induces regrowth of senescent cells. Overall, the primary PA model provides evidence of the presence of OIS in PA and exhibits increased activity of the SASP during senescence. Our data suggest that the SASP has an important impact on the growth regulation of senescent PA cells. Alteration of SASP factors may result in spontaneous regrowth of senescent PA tumors.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 4
  • 5
    Language: English
    In: Nature, July 2018, Vol.559(7714), pp.E10
    Description: In this Article, author Benedikt Brors was erroneously associated with affiliation number '8' (Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA); the author's two other affiliations (affiliations '3' and '7', both at the German Cancer Research Center (DKFZ)) were correct. This has been corrected online.
    Keywords: Cancer ; Medical Schools;
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 6
    In: Nature, 2018
    Description: Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 7
    Language: English
    In: Leukemia Research, 2011, Vol.35(4), pp.484-491
    Description: Chemotherapy for childhood acute lymphoblastic leukemia may cause severe immune damage. The lymphocyte compartment of 140 patients during and after a new strongly reduced (standard risk (SR), = 43) and intensive chemotherapy regimen (medium risk (MR), = 97) was studied between 2006 and 2009. Transitional and naive B cells and IgG /A , IgM and IgM only memory B cells were significantly reduced during chemotherapy; significantly more in MR group. One year after treatment CD27 IgG /A , IgM and IgM only memory B cells had still not fully recovered, but this was not confined to the MR group. The T cell compartment was less but also significantly affected during chemotherapy and recovered to normal levels. In the MR group, NK cells had not fully recovered to normal levels 1 year after treatment. Thus, intensive chemotherapy regimens cause severe, mainly B cell memory damage that persists even 1 year after treatment.
    Keywords: Acute Lymphoblastic Leukemia ; B-Lymphocyte Subsets ; T-Lymphocyte Subsets ; Child ; Immunologic Memory ; Toxicity ; Medicine
    ISSN: 0145-2126
    E-ISSN: 1873-5835
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  • 8
    Language: English
    In: Pediatric blood & cancer, March 2018, Vol.65(3)
    Description: Infants with low-grade glioma (LGG) and diencephalic syndrome have a poor outcome. The patient described here had a desmoplastic infantile astrocytoma harboring a BRAF V600E mutation. After relapse following initial standard chemotherapy treatment, he was successfully treated with the BRAF V600E inhibitor vemurafenib at the age of 3 years 11 months and 5 years 0 months. A rapid response was observed on both occasions. This illustrates the possibility of continuous oncogenic addiction and the therapeutic potential of BRAF V600E inhibitor monotherapy in LGG, even in very young severely compromised children. BRAF V600E inhibition in LGG and possible (re-)treatment regimens are briefly discussed.
    Keywords: Braf V600e Inhibitor ; Child ; Desmoplastic Infantile Astrocytoma ; Infant ; Low-Grade Glioma ; Vemurafenib ; Antineoplastic Agents -- Therapeutic Use ; Astrocytoma -- Drug Therapy ; Brain Neoplasms -- Drug Therapy ; Carcinoma, Small Cell -- Drug Therapy ; Neoplasm Recurrence, Local -- Drug Therapy ; Proto-Oncogene Proteins B-Raf -- Genetics ; Vemurafenib -- Therapeutic Use
    ISSN: 15455009
    E-ISSN: 1545-5017
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  • 9
    Language: English
    In: Pediatric Blood & Cancer, May 2012, Vol.58(5), pp.701-707
    Description: BACKGROUND: The consequences of current intensive chemotherapy for childhood acute lymphoblastic leukemia (ALL) for immune defense are a matter of concern. The purpose of this study was to examine the effect of reduced compared with intensive (conventional) ALL chemotherapy on serum immunoglobulin levels and specific antibody concentrations against vaccine-preventable diseases.PROCEDURE: Patients treated according to Dutch Childhood Oncology Group ALL 10 protocol were stratified by minimal residual disease to receive reduced (standard risk; SR) or intensive (medium risk; MR) intensification/maintenance treatment. Between November 2004 and July 2009 we compared serum immunoglobulins of 110 patients and specific antibodies against diphtheria toxin, tetanus toxin, and Bordetella pertussis antigens of 41 patients of SR and MR groups during chemotherapy.RESULTS: Immunoglobulin levels showed significantly different patterns between the SR and MR groups. In the MR group IgG, IgA, and IgM levels decreased towards the end of intensive treatment; in the SR group IgG levels increased while IgA and IgM stabilized. In both groups IgM and IgG levels were most affected. Specific antibody levels against vaccine-preventable diseases decreased in both groups, but more profound in MR group.CONCLUSIONS: Although reduced chemotherapy is beneficial for immunoglobulin level recovery and might prevent susceptibility for infections, specific antibodies remain decreased.
    Keywords: Acute Lymphoblastic Leukemia ; Child ; Immunodeficiency ; Immunoglobulins ; Secondary Specific Antibodies ; Toxicity
    ISSN: 1545-5009
    E-ISSN: 1545-5017
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  • 10
    Language: English
    In: British journal of haematology, February 2011, Vol.152(4), pp.433-40
    Description: Reducing infectious morbidity is an important goal to improve childhood acute lymphoblastic leukaemia (ALL) survival. To explore the impact of chemotherapy reduction on infectious morbidity, we compared outpatient and inpatient infectious morbidity of reduced versus intensive (conventional) chemotherapy. One hundred and seventy-one children newly diagnosed with ALL between 2004 and 2007 and treated according to the Dutch Childhood Oncology Group ALL 10 protocol were prospectively followed during the 2-year treatment course. Stratified by minimal residual disease, 54 patients received reduced (standard risk; SR) and 117 patients received intensive (medium risk; MR) intensification/maintenance treatment. SR outpatients had a median of 1 febrile episode versus 4 in MR outpatients (P=0·002). SR patients had fewer hospitalizations for fever. They were admitted a median of 0 times, with a median of 0days of hospitalization, median 0days of fever, median 0 times chemotherapy interruption and median 0 times intravenous antibiotics. MR patients were admitted for fever median 2 times (P〈0·001) with 10days of hospitalization (P〈0·001), 2days of fever (P〈0·001), one chemotherapy interruption (P〈0·001) and two intravenous antibiotics administration (P〈0·001). These data indicate that reduced intensification/maintenance compared to conventional intensive intensification/maintenance chemotherapy for good risk childhood ALL resulted in major decrease of infectious morbidity.
    Keywords: Antineoplastic Agents -- Administration & Dosage ; Opportunistic Infections -- Prevention & Control ; Precursor Cell Lymphoblastic Leukemia-Lymphoma -- Drug Therapy
    ISSN: 00071048
    E-ISSN: 1365-2141
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