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  • Physical Chemistry  (10)
  • MUTATIONS  (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, NY : Wiley-Blackwell
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The kinetics of decomposition of trimethylene sulfide to ethylene and thioformaldehyde was investigated in a single-pulse shock tube using the «relative rate» technique. The extent of reaction was measured in the reflected shock regime from 860° to 1170°K, but experimental difficulties limited the useful data to the temperature range of 980°-1040°K. The first-order rate constant was found to be k = 1013.0 exp (-48,200/RT) sec-1. This result sets an upper limit of 50 kcal/mole for the standard enthalpy of formation of CH2S, with 35 kcal/mole as a more likely value. The isomerization of cyclopropane to propene was used for the reference reaction; in turn, this was checked, in a relative rate experiment, against the pyrolysis of cyclohexene.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    New York, NY : Wiley-Blackwell
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The available RRKM programs which cover the full pressure range (high → low-pressure limits) were written for nonreversible reactions. For reversible reactions the correct shapes of the fall-off curves can be estimated by applying a correction factor to the RRKM bimolecular rate constant, which depends on a ratio of state densities at the potential maximum. It is proposed that the analysis of such systems in terms of relaxation kinetics provides a more rational treatment, free of the ambiguities associated with specifying a “transition state.”
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    New York, NY : Wiley-Blackwell
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: As in our previous studies, 0(3P), generated by titration with NO of microwave discharged N2 (He carrier), was mixed with B10H14 vapor (Ar carrier) in a flow-tube reactor. Levels of product OH were determined via LIF on an absolute basis, for dwell times 4 to 18 ms. The system was calibrated with C2H6, run under identical conditions. The reactants comprised approximately 1% of the flowing mixture. OH production is ≈62 greater from B10H14 than from B5H9 (under similar conditions but at somewhat lower temperature). FTIR analyses of a solid product that condensed downstream on cold surfaces showed the presence of —B—O—H⃜O—B— hydrogen bonds and matched (but not perfectly) the calculated frequencies of HB(OH)2. © 1994 John Wiley & Sons, Inc.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    New York, NY : Wiley-Blackwell
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The homogeneous pyrolysis of 2-butene subjected to shock heating was studied in the limit of high pressures by a relative rate technique. Over the temperature range of 1150-1325°K nearly equal amounts of methane, propylene, and butadiene were formed starting with either the cis- or trans-2-butene, while isomerization remained far from equilibrium. The results are consistent with a simple free radical mechanism for which we find \documentclass{article}\pagestyle{empty}\begin{document}$$ k^\infty [{\rm C}_4 {\rm H}_8 \mathop \rightarrow\limits_{cis} {\rm CH}_3 + {\rm C}_3{\rm H}_5] = 10^{16} \exp (-80,000/RT)\sec^{-1} $$\end{document} as the initial rate-limiting step.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The high-temperature reaction between sulfur dioxide and acetylene in an excess of argon was studied in a 1-in. i.d. single-pulse shock tube. Mixtures ranging from 1.81% to 5.40% SO2 and 1.60% to 4.90% C2H2 were heated to reflected shock temperatures of 1550°-2150°K, for dwell times of about 0.6 msec and gas dynamically quenched. Total reaction densities were 0.89 to 5.4 × 10-2 moles/1. The reaction products were analyzed by gas chromatography. A technique was developed for separating Ar, C2H4, C2H2, SO2, CO, CO2, H2S, COS, and CS2. The major products of the reaction are CO, H2, CS2, and sulfur. The products observed were compared with those predicted on the assumption that equilibrium was attained. Several preliminary experiments were carried out with ethylene-sulfur dioxide mixtures, and the results indicated that for this combination the sulfur dioxide probably reacted with the acetylene generated from the decomposition of the ethylene, rather than directly with the ethylene. The rate of decline in the sulfur dioxide content in C2H2-SO2 mixtures was found to be approximately second order (total) and can be empirically represented by \documentclass{article}\pagestyle{empty}\begin{document}$$- \Delta ({\rm SO}_2)/\Delta t = 3.1 \times 10^{10} T^{1/2} \exp (- 40,800/RT)[{\rm Ar}]^{0.83} [{\rm SO}_{\rm 2}]^{0.87} [{\rm C}_2 {\rm H}_{\rm 2}]^{0.25} {\rm mole cm}^{{\rm - 3}} \sec ^{ - 1}$$\end{document}A mechanism is proposed to account for the overall reaction kinetics.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: We have demonstrated that reactions for which substantial activation energies are needed can be induced to occur at room temperature via specific vibrational excitation. Indeed, the indications are that the atom-switching reactions for which Ea 〉 25 kcal take place with high probability only when the activation energy is localized in the vibrational mode. In this preliminary report on the utilization of the stimulated Raman effect to generate substantial populations in the critical vibrational states required for the homogeneous atom exchange between H2 and D2, we first summarized the historical development of the concept. The experimental arrangement is then described and the analytical results tabulated; the observed dependence on relative concentrations is semiquantitatively rationalized on the basis of a model proposed in 1964. Independent shock tube and molecular beam investigations were similarly accounted for. Attention is called to the discrepancy between the generally concordant experimental results and the ab initio quantum mechanical calculations of the potential energy surface for 4H atoms.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    New York, NY : Wiley-Blackwell
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: An aged kineticist was awakened in 1989 from a 50-year slumber. After arduous study he sized-up the present situation, with occasional reflections on the state of knowledge in 1939.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    New York, NY : Wiley-Blackwell
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A high-pressure, high-temperature reactor unit was developed to test batch-wise inter-conversions of hydrocarbons. A major ambiguity characterizes this reactor, as it does all similar units that have been described, determination of the time-temperature profile for the reacting mixture. Here we report on a solution to this problem - use of a “chemical thermometer,” based on the kinetics of dissociation of C4F8. We propose a revised set of rate constants that permit calibration of the reactor operation. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 171-177, 1998.
    Additional Material: 10 Ill.
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