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  • 1
    Language: English
    In: Molecular cancer research, 2007-12-01, Vol.5 (12), p.1232-1240
    Description: Glioblastomas, the most malignant of all brain tumors, are characterized by cellular resistance to apoptosis and a highly invasive growth pattern. These factors contribute to the poor response of glioblastomas to radiochemotherapy and prevent their complete neurosurgical resection. However, the driving force behind the distinct motility of glioma cells is only partly understood. Here, we report that in the absence of cellular stress and proapoptotic stimuli, human glioblastoma cells exhibit a constitutive activation of caspases in vivo and in vitro . The inhibition of caspases by various peptide inhibitors decreases the migration of cells in scrape motility assays and the invasiveness of cells in spheroid assays. Similarly, specific small interfering RNA– or antisense-mediated down-regulation of caspase-3 and caspase-8 results in an inhibition of the migratory potential of glioma cells. The constitutive caspase-dependent motility of glioblastoma cells is independent of CD95 activation and it is not mediated by mitogen-activated protein/extracellular signal-regulated kinase kinase signaling. The basal caspase activity is accompanied by a constant cleavage of the motility-associated gelsolin protein, which may contribute to the caspase-mediated promotion of migration and invasiveness in glioblastoma cells. Our results suggest that the administration of low doses of caspase inhibitors that block glioma cell motility without affecting the execution of apoptotic cell death may be exploited as a novel strategy for the treatment of glioblastomas. (Mol Cancer Res 2007;5(12):1232–40)
    Subject(s): migration ; apoptosis ; brain tumors ; invasion ; gliomas ; caspases ; Brain Neoplasms - enzymology ; Glioblastoma - enzymology ; MAP Kinase Signaling System - physiology ; Gelsolin - metabolism ; Neoplasm Invasiveness ; Humans ; Brain Neoplasms - pathology ; Caspase 3 - metabolism ; Caspase 8 - metabolism ; Enzyme Inhibitors - pharmacology ; fas Receptor - metabolism ; Caspase Inhibitors ; Cell Movement - physiology ; Caspase 8 - genetics ; Glioblastoma - pathology ; Caspase 3 - genetics ; Cell Line, Tumor ; RNA, Small Interfering ; Index Medicus
    ISSN: 1541-7786
    E-ISSN: 1557-3125
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 2
    Language: English
    In: Cancer communications (London, England), 2019-11-09, Vol.39 (1), p.73-9
    Description: More than 25% of patients with solid cancers develop intracerebral metastases. Aside of surgery, radiation therapy (RT) is a mainstay in the treatment of intracerebral metastases. Postoperative fractionated stereotactic RT (FSRT) to the resection cavity of intracerebral metastases is a treatment of choice to reduce the risk of local recurrence. However, FSRT has to be delayed until a sufficient wound healing is attained; hence systemic therapy might be postponed. Neoadjuvant stereotactic radiosurgery (SRS) might offer advantages over adjuvant FSRT in terms of better target delineation and an earlier start of systemic chemotherapy. Here, we conducted a study to find the maximum tolerated dose (MTD) of neoadjuvant SRS for intracerebral metastases. This is a single-center, phase I dose escalation study on neoadjuvant SRS for intracerebral metastases that will be conducted at the Klinikum rechts der Isar Hospital, Technical University of Munich. The rule-based traditional 3 + 3 design for this trial with 3 dose levels and 4 different cohorts depending on lesion size will be applied. The primary endpoint is the MTD for which no dose-limiting toxicities (DLT) occur. The adverse events of each participant will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 continuously during the study until the first follow-up visit (4-6 weeks after surgery). Secondary endpoints include local control rate, survival, immunological tumor characteristics, quality of life (QoL), CTCAE grade of late clinical, neurological, and neurocognitive toxicities. In addition to the intracerebral metastasis which is treated with neoadjuvant SRS and resection up to four additional intracerebral metastases can be treated with definitive SRS. Depending on the occurrence of DLT up to 72 patients will be enrolled. The recruitment phase will last for 24 months. Neoadjuvant SRS for intracerebral metastases offers potential advantages over postoperative SRS to the resection cavity, such as better target volume definition with subsequent higher efficiency of eliminating tumor cells, and lower damage to surrounding healthy tissue, and much-needed systemic chemotherapy could be initiated more rapidly. Trial registration The local ethical review committee of Technical University of Munich (199/18S) approved this study on September 05, 2018. This trial was registered on German Clinical Trials Register (DRKS00016613; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016613) on January 29, 2019.
    Subject(s): Brain Neoplasms - secondary ; Maximum Tolerated Dose ; Neoadjuvant Therapy - adverse effects ; Humans ; Quality of Life ; Brain Neoplasms - radiotherapy ; Radiosurgery - adverse effects ; Clinical Trials, Phase I as Topic ; Intracerebral metastasis ; Stereotactic radiosurgery ; Microsurgical resection ; Fractionated stereotactic radiation therapy ; Neoadjuvant radiation therapy ; Cancer
    ISSN: 2523-3548
    E-ISSN: 2523-3548
    Source: PubMed Central
    Source: Directory of Open Access Journals
    Source: Alma/SFX Local Collection
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  • 3
    Language: English
    In: Cancer cell, 2008, Vol.13 (3), p.235-248
    Description: Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-β pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo.
    Subject(s): CELLBIO ; Neoplasm Transplantation ; Fas Ligand Protein - metabolism ; Glioblastoma - enzymology ; Matrix Metalloproteinases - genetics ; Humans ; Brain Neoplasms - pathology ; Glycogen Synthase Kinase 3 beta ; Phosphatidylinositol 3-Kinases - metabolism ; fas Receptor - metabolism ; Recombinant Fusion Proteins - metabolism ; Brain Neoplasms - metabolism ; Brain Neoplasms - immunology ; Transfection ; Glioblastoma - genetics ; RNA Interference ; Proto-Oncogene Proteins c-yes - genetics ; src-Family Kinases - metabolism ; Glioblastoma - metabolism ; Tumor Cells, Cultured ; Brain Neoplasms - enzymology ; Proto-Oncogene Proteins c-yes - metabolism ; Signal Transduction ; Neoplasm Invasiveness ; Brain Neoplasms - genetics ; Glycogen Synthase Kinase 3 - metabolism ; Transplantation, Isogeneic ; Animals ; Glioblastoma - immunology ; Glioblastoma - pathology ; Cell Line, Tumor ; Mice ; Matrix Metalloproteinases - metabolism ; Apoptosis ; Cell Movement ; Death Domain Receptor Signaling Adaptor Proteins - metabolism ; RNA, Small Interfering - metabolism ; Glucose metabolism ; Synthesis ; Glycogen ; Glioblastoma multiforme ; Index Medicus
    ISSN: 1535-6108
    E-ISSN: 1878-3686
    Source: Cell Press Collection [ECCPC]
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 4
    Language: English
    In: Medical Image Computing and Computer Assisted Intervention – MICCAI 2019, 2019-10-10, p.122-130
    Description: Clinicians implicitly incorporate the complementarity of multi-modal data for disease diagnosis. Often a varied order of importance for this heterogeneous data is considered for personalized decisions. Current learning-based methods have achieved better performance with uniform attention to individual information, but a very few have focused on patient-specific attention learning schemes for each modality. Towards this, we introduce a model which not only improves the disease prediction but also focuses on learning patient-specific order of importance for multi-modal data elements. In order to achieve this, we take advantage of LSTM-based attention mechanism and graph convolutional networks (GCNs) to design our model. GCNs learn multi-modal but class-specific features from the entire population of patients, whereas the attention mechanism optimally fuses these multi-modal features into a final decision, separately for each patient. In this paper, we apply the proposed approach for disease prediction task for Parkinson’s and Alzheimer’s using two public medical datasets.
    ISBN: 9783030322502
    ISBN: 3030322505
    ISSN: 0302-9743
    E-ISSN: 1611-3349
    Source: SpringerLINK Lecture Notes in Computer Science (2015)
    Source: Alma/SFX Local Collection
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