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  • MUTATIONS  (2)
  • Polymer and Materials Science  (2)
  • 1
    Keywords: GROWTH ; CELL LUNG-CANCER ; PATHWAYS ; MUTATIONS ; sensitivity ; FUTURE ; THERAPIES
    Abstract: PURPOSE: Multiple investigational drugs are currently explored in cancer patient populations defined by specific biomarkers. This demands a new process of patient selection for clinical trials. PATIENTS AND METHODS: Starting January 1, 2012, preemptive biomarker profiling was offered at the West German Cancer Center to all patients with advanced non-small-cell lung (NSCLC) or colorectal cancer (CRC), who met generic study inclusion criteria. Tumour specimens were subjected to prespecified profiling algorithms to detect 'actionable biomarkers' by amplicon sequencing, in situ hybridisation and immunohistochemistry. The clinical course was closely monitored to offer trial participation whenever applicable. RESULTS: Within 12 months, 267 patients (188 NSCLC, 79 CRC) were profiled. Estimated additional cost for biomarker profiling was 219615.51 EUR excluding histopathology workup and administration. The most prevalent biomarkers in pulmonary adenocarcinoma were KRAS mutations (29%), loss of PTEN expression (18%), EGFR mutations (9%), HER2 amplification (5%) and BRAF mutations (3%), while the prevalence of ALK translocations and PIK3CA mutations was extremely low. In pulmonary squamous cell carcinoma FGFR1 amplifications were found in 15%, PTEN expression was lost in 20% and DDR2 was mutated in a single case. KRAS mutations (41%) predominated in CRC, followed by loss of PTEN expression (16%), PIK3CA (5%) and BRAF (5%) mutations. So far 13 patients (5%) have entered biomarker-stratified clinical trials. Therapeutic decisions for approved drugs were guided in another 45 patients (17%). CONCLUSION: Preemptive biomarker profiling can be implemented into the diagnostic algorithm of a large Comprehensive Cancer Center. Substantial investments in diagnostics and administration are required.
    Type of Publication: Journal article published
    PubMed ID: 23876834
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  • 2
    Keywords: EXPRESSION ; ACTIVATION ; mechanisms ; CELL-DEATH ; PROSTATE-CANCER ; MUTATIONS ; PET ; PHASE-II TRIAL ; IMATINIB MESYLATE ; 2-DEOXY-D-GLUCOSE
    Abstract: Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is frequently used for visualizing gastrointestinal stromal tumors (GIST), which are highly glucose-avid tumors. Dramatic metabolic responses following imatinib treatment indicate a high, KIT-dependent glucose turnover which has been particularly helpful for predicting tumor response to imatinib. The glucose analogue 2-deoxyglucose (2DG) inhibits glucose metabolism in cancer cells that depend on aerobic glycolysis for ATP production. We show that 2DG inhibits proliferation in both imatinib-sensitive and imatinib-resistant GIST cell lines at levels that can be achieved clinically. KIT-negative GIST48B have 3-14-fold higher IC50 levels than KIT-positive GIST cells indicating that oncogenic KIT may sensitize cells to 2DG. GIST sensitivity to 2DG is increased in low-glucose media (110mg/dl). 2DG leads to dose- and glucose dependent inhibition of KIT glycosylation with resultant reduction of membrane-bound KIT, inhibition of KIT-phosphorylation and inactivation of KIT-dependent signaling intermediates. In contrast to imatinib, 2DG caused ER-stress and elicited the unfolded protein response (UPR). Mannose but not pyruvate rescued GIST cells from 2DG-induced growth arrest, suggesting that loss of KIT integrity is the predominant effect of 2DG in GIST. Additive anti-tumoral effects were seen with imatinib and BH3-mimetics. Our data provide the first evidence that modulation of the glucose-metabolism by 2DG may have a disease-specific effect and may be therapeutically useful in GIST.
    Type of Publication: Journal article published
    PubMed ID: 25781619
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  • 3
    Electronic Resource
    Electronic Resource
    New York : Wiley-Blackwell
    Biopolymers 18 (1979), S. 2135-2144 
    ISSN: 0006-3525
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The affinity of yeast glycogen synthetase to glycogen modified by crosslinking has been studied under various experimental conditions. It was found that the higher the degree of crosslinking, the lower the affinity of glycogen synthetase to glycogen. The amount of glycogen synthetase adsorbed from the solution depends on the amount of crosslinked glycogen added and is inversely proportional to the concentration of the soluble glycogen. The stability of the complex formed between yeast glycogen synthetase and the crosslinked glycogen was found to be maximal at neutral pH range. The presence of glucose 6-phosphate, uridine 5′-di-phosphate, and uridine 5′-diphosphate glucose enhanced the stability of the complex.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Knowledge of the characteristics of the blood-intima interface is important because it leads to information concerning (a) the normal antithrombotic mechanism (b) nature of interreactions between blood and intima (c) testing and selection of vascular wall substitutes which are antithrombotic and inhibit clotting. A technique for obtaining the electrical interfacial characteristics of blood vessel walls is by measuring streaming potentials. Experiments described in the present work are extensions of original in vivo streaming potential measurements. In vitro streaming potentials were measured across fresh canine aortae and carotid arteries using Krebs saline serum substitute, logarithmically varying both internal and external electrolyte concentrations. Positive streaming potentials were measured indicating that the blood vessel wall is negatively charged. Streaming potentials increased linearly with increasing flow rate, decreased with increasing internal electrolyte concentration, decreased with increasing external electrolyte concentration, and reversed, becoming positive, with aging of exteriorized artery. Thus the electrical characteristics of the blood vessel wall are dependent on an ionic balance between the blood vessel wall, flowing blood stream, and external environment. The information demonstrates the importance of electrochemical and physicochemical phenomena in the structure and function of the vascular interface and helps explain in vivo conditions conducive to or inhibitory of intravascular thrombosis.
    Additional Material: 12 Ill.
    Type of Medium: Electronic Resource
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