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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 13 September 2011, Vol.108(37), pp.15336-41
    Description: Targeting the surface of malignant cells has evolved into a cornerstone in cancer therapy, paradigmatically introduced by the success of humoral immunotherapy against CD20 in malignant lymphoma. However, tumor cell susceptibility to immunochemotherapy varies, with mostly a fatal outcome in cases of resistant disease. Here, we show that lymphoma exosomes shield target cells from antibody attack and that exosome biogenesis is modulated by the lysosome-related organelle-associated ATP-binding cassette (ABC) transporter A3 (ABCA3). B-cell lymphoma cells released exosomes that carried CD20, bound therapeutic anti-CD20 antibodies, consumed complement, and protected target cells from antibody attack. ABCA3, previously shown to mediate resistance to chemotherapy, was critical for the amounts of exosomes released, and both pharmacological blockade and the silencing of ABCA3 enhanced susceptibility of target cells to antibody-mediated lysis. Mechanisms of cancer cell resistance to drugs and antibodies are linked in an ABCA3-dependent pathway of exosome secretion.
    Keywords: Immunotherapy ; ATP-Binding Cassette Transporters -- Immunology ; Exosomes -- Immunology ; Immune Evasion -- Immunology ; Immunity, Humoral -- Immunology ; Lymphoma, B-Cell -- Immunology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Chest, October 2012, Vol.142(4), pp.1020-1026
    Description: We previously identified amplification of the fibroblast growth factor receptor 1 gene ( ) as a potential therapeutic target for small-molecule inhibitor therapy in squamous cell lung cancer (L-SCC). Currently, clinical phase I trials are underway to examine whether patients with -amplified L-SCC benefit from a targeted therapy approach using small-molecule inhibitors. Because most patients with lung cancer present with metastatic disease, we investigated whether lymph node metastases in L-SCC share the amplification status of their corresponding primary tumor. The study cohort consisted of 72 patients with L-SCC, 39 with regional lymph node metastases. Tissue microarrays were constructed from formalin-fixed, paraffin-embedded tissue of the primary tumors and, where present, of the corresponding lymph node metastasis. A biotin-labeled target probe spanning the locus (8p11.22-23) was used to determine the amplification status by fluorescence in situ hybridization. amplification was detected in 16% (12 of 72) of all primary L-SCCs. In metastatic tumors, 18% (seven of 39) of the lymph node metastases displayed amplification with an exact correlation of amplification status between tumor and metastatic tissue. amplification is a common genetic event occurring at a frequency of 16% in L-SCCs. Moreover, lymph node metastases derived from -amplified L-SCCs also exhibit amplification. Therefore, we suggest that the amplification is a clonal event in tumor progression. Beyond this biologically relevant observation, the findings carry potential therapeutic implications in that small-molecule inhibitors may be applicable to the treatment of a subset of patients with metastatic L-SCC.
    Keywords: Medicine
    ISSN: 0012-3692
    E-ISSN: 1931-3543
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  • 3
    In: Nature, 2015
    Description: Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system (1). Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive (2-4). Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type (1,2,5). In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.
    Keywords: Genomics – Research ; Telomerase – Physiological Aspects ; Telomerase – Research ; Neuroblastoma – Development and Progression ; Neuroblastoma – Genetic Aspects ; Neuroblastoma – Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 4
  • 5
    Language: English
    In: Chemical Physics Letters, 2005, Vol.413(1), pp.42-46
    Description: We report a systematic study of the electronic structure of two members of the transition metal dihalide family, TiF and TiCl . Using the configuration interaction method in large basis sets we investigated the lowest 15 states of TiF and TiCl . We report bond lengths, frequencies and dissociation energies of both molecules. For TiF we found a near degeneracy of the ground and the first excited state with a possible breakdown of the Born–Oppenheimer approximation.
    Keywords: Chemistry
    ISSN: 0009-2614
    E-ISSN: 1873-4448
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  • 6
    Language: English
    In: Virchows Archiv, 2014, Vol.464(5), pp.547-551
    Description: Recently, the fibroblast growth factor receptor 1 (FGFR1) has been identified as the first actionable target in squamous cell lung cancer. Clinical trials testing specific FGFR inhibitors are in progress, and patients are selected based on their FGFR1 gene copy number status. Fluorescent in situ hybridization is the most commonly used method for detecting FGFR1 amplifications, but it has its limitations. In this paper, we describe a new non-fading and easy to assess assay for detecting FGFR1 amplification using a combination of chromogenic and silver in situ hybridization. We assessed 394 patients diagnosed with head and neck squamous cell carcinoma with the new assay and compared the results with those obtained by FGFR1 fluorescent in situ hybridization. We could assess copy number by the fluorescent in situ hybridization in 86.8 % (342/394) of cases, whereas with chromogenic and silver in situ hybridization, this was 79.4 % (313/394). By fluorescent in situ hybridization, a FGFR1 amplification was detected in 12.6 % (43/342) of cases, a low-level amplification (LLA) in 7.6 % (26/342) and a high-level amplification (HLA) in 5.0 % (17/342). By chromogenic and silver in situ hybridization, a FGFR1 amplification was found in 10.2 % (32/313) (5.7 % LLA, 4.5 % HLA). The two techniques showed highly concordant results (Pearson’s correlation coefficient = 0.971, p  〈 0.01).
    Keywords: FGFR1 ; FISH ; Amplification ; Head and neck squamous cancer ; SISH ; CISH
    ISSN: 0945-6317
    E-ISSN: 1432-2307
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  • 7
  • 8
    In: International Journal of Cancer, 15 November 2016, Vol.139(10), pp.2359-2369
    Description: Squamous cell carcinoma of the head and neck (HNSCC) is the tenth most common tumor entity in men worldwide. Nevertheless therapeutic options are mostly limited to surgery and radio‐chemotherapy resulting in 5‐year survival rates of around 50%. Therefore new therapeutic options are urgently needed. During the last years, targeting of receptor tyrosine kinases has emerged as a promising strategy that can complement standard therapeutical approaches. Here, we aimed at investigating if the receptor tyrosine kinase DDR2 is a targetable structure in HNSCC. DDR2 expression was assessed on a large HNSCC cohort (554 patients) including primary tumors, lymph node metastases and recurrences and normal mucosa as control. Subsequently, DDR2 was stably overexpressed in two different cell lines (FaDu and HSC‐3) using lentiviral technology. Different tumorigenic properties such as proliferation, migration, invasion, adhesion and anchorage independent growth were assessed with and without dasatinib treatment using cell models and zebrafish xenografts. DDR2 was overexpressed in all tumor tissues when compared to normal mucosa. DDR2 overexpression led to increased migration, invasion, adhesion and anchorage independent growth whereas proliferation remained unaltered. Upon dasatinib treatment migration, invasion and adhesion could be inhibited and whereas proliferation was unchanged. Our data suggest treatment with dasatinib as a promising new therapeutic option for patients suffering from DDR2 overexpressing HNSCC. Since dasatinib is already FDA‐approved we propose to test this drug in clinical trials so that patients could directly benefit from this new treatment option. What's new? Targeting of receptor tyrosine kinases has emerged as a promising cancer treatment strategy. Here, the authors investigated the receptor tyrosine kinase DDR2 as a potential target in squamous cell carcinoma of the head and neck (HNSCC). Using for the first time a large and diverse cohort of patients, they showed that DDR2 is overexpressed in head and neck tumor tissue as compared to normal mucosa. Moreover, migration, invasion, and adhesion were increased in cell models and zebrafish xenografts and could be reduced by dasatinib, providing a rationale for clinical testing of the FDA‐approved inhibitor in patients with DDR2‐positive HNSCC tumors.
    Keywords: Head And Neck Cancer ; Ddr2 ; Dasatinib ; Targeted Therapy
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 9
    In: International Journal of Cancer, 01 July 2014, Vol.135(1), pp.19-26
    Description: The mediator complex is an evolutionary conserved key regulator of transcription of protein‐coding genes and an integrative hub for diverse signaling pathways. In this study, we investigated whether the mediator subunit MED15 is implicated in castration‐resistant prostate cancer (CRPC). MED15 expression and copy number/rearrangement status were assessed by immunohistochemistry (IHC) and fluorescence hybridization (FISH), respectively on 718 prostate cancer (PCa) specimens and sequenced by Sanger on a subset. Furthermore, SMAD3 phosphorylation, androgen receptor (AR) and proliferation markers were evaluated by IHC. In PCa cells, siRNA/shRNA knockdown of MED15 was followed by proliferation assays with/without dihydrotestosterone (DHT), and treatments with recombinant TGF‐β3. Our results show that is overexpressed in 76% of distant metastatic CRPC (CRPC) and 70% of local‐recurrent CRPC (CRPC), in contrast to low frequencies in androgen‐sensitive PCa, and no expression in benign prostatic tissue. Furthermore, overexpression correlates with worse clinical outcome thus defining a highly lethal phenotype. Moreover, TGF‐β signaling activation associates with overexpression in PCa tissues, and leads to increased expression of MED15 in PCa cells. MED15 knockdown effects phosphorylation and shuttling of p‐SMAD3 to the nucleus as well as TGF‐β‐enhanced proliferation. In PCa tissues, overexpression associates with overexpression/amplification and correlates with high proliferative activity. MED15 knockdown decreases both androgen‐dependent and ‐independent proliferation in PCa cells. Taken together, these findings implicate MED15 in CRPC, and as MED15 is evolutionary conserved, it is likely to emerge as a lethal phenotype in other therapeutic‐resistant diseases, and not restricted to our disease model. What's new? MED15, a subunit of the Mediator transcriptional regulator complex, has been implicated in castration‐resistant prostate cancer (CRPC). This study shows that 70 percent of local‐recurrent CRPCs and 76 percent of distant metastatic CRPCs overexpress MED15 and that MED15 overexpression defines a highly lethal phenotype. expression was found to be increased by TGF‐ß activation, such that MED15 knockdown affected TGF‐β signaling and TGF‐β‐enhanced proliferation. Knockdown also resulted in decreased androgen‐dependent and ‐independent proliferative activity. The findings, taken together with the evolutionary conservation of MED15, suggest that MED15 in CRPC may be a model of therapeutic‐resistant disease.
    Keywords: Med15 ; Castration‐Resistant ; Prostate Cancer ; Tgf‐Β
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 10
    Language: English
    In: Science (New York, N.Y.), 07 December 2018, Vol.362(6419), pp.1165-1170
    Description: Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance-negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.
    Keywords: Neuroblastoma -- Classification ; Telomere Homeostasis -- Genetics
    ISSN: 00368075
    E-ISSN: 1095-9203
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