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Purpose: We sought to investigate the clinical response to MET inhibition in patients diagnosed with structural MET alterations and to characterize their functional relevance in cellular models.Experimental Design: Patients were selected for treatment with crizotinib upon results of hybrid capture–based next-generation sequencing. To confirm the clinical observations, we analyzed cellular models that express these MET kinase alterations.Results: Three individual patients were identified to harbor alterations within the MET receptor. Two patients showed genomic rearrangements, leading to a gene fusion of KIF5B or STARD3NL and MET. One patient diagnosed with an EML4-ALK rearrangement developed a MET kinase domain duplication as a resistance mechanism to ceritinib. All 3 patients showed a partial response to crizotinib that effectively inhibits MET and ALK among other kinases. The results were further confirmed using orthogonal cellular models.Conclusions: Crizotinib leads to a clinical response in patients with MET rearrangements. Our functional analyses together with the clinical data suggest that these structural alterations may represent actionable targets in lung cancer patients. Clin Cancer Res; 24(6); 1337–43. ©2017 AACR.

Purpose: We sought to investigate the clinical response to MET inhibition in patients diagnosed with structural MET alterations and to characterize their functional relevance in cellular models. Experimental Design: Patients were selected for treatment with crizotinib upon results of hybrid capture–based next-generation sequencing. To confirm the clinical observations, we analyzed cellular models that express these MET kinase alterations. Results: Three individual patients were identified to harbor alterations within the MET receptor. Two patients showed genomic rearrangements, leading to a gene fusion of KIF5B or STARD3NL and MET. One patient diagnosed with an EML4-ALK rearrangement developed a MET kinase domain duplication as a resistance mechanism to ceritinib. All 3 patients showed a partial response to crizotinib that effectively inhibits MET and ALK among other kinases. The results were further confirmed using orthogonal cellular models. Conclusions: Crizotinib leads to a clinical response in patients with MET rearrangements. Our functional analyses together with the clinical data suggest that these structural alterations may represent actionable targets in lung cancer patients. Clin Cancer Res; 24(6); 1337–43. ©2017 AACR.

The site exchange of an anion moiety (O, N, F, Ne, P, S, Cl, and Ar) with an oxygen vacancy in fluorite-structured CeO2 was studied by means of density functional theory (DFT) calculations. The obtained activation energies of migration vary between 0.2 and 0.9 eV, and increase with the formal valence of the migrating ion; the size of the migrating ion appears to play a minor role. An analysis of ion displacements suggests that repulsive Coulombic interactions between the migrating anion and oxygen ions as the next-nearest neighbors in the saddle-point configuration provide the dominant contribution to the activation energy of migration. As well as emphasizing the ease with which anion moieties are mobile in AO2 fluorite materials, these results suggest a new paradigm for understanding fast oxygen-ion conducting materials.

The migration of cerium ions in the model fluorite-structured oxide CeO2 was studied by means of static lattice simulations. Activation energies of migration were obtained from classical simulations, based on various sets of empirical pair potentials, and from quantum mechanical simulations, employing density-functional-theory calculations. Vacancy, interstitial, and interstitialcy mechanisms were considered. In addition, the influence of adjacent oxygen vacancies on cation-migration energetics was examined. Combining the calculated activation energies with the results of defect-chemical calculations, we conclude that cerium ions migrate by a vacancy mechanism in acceptor-doped CeO2.

Introduction Detection of somatic genomic alterations in the plasma of patients with cancer ("liquid biopsy") are increasingly being used in the clinic. However, the concordance of alterations identified in liquid biopsies with those detected in cancer specimens is not routinely being determined. Methods We sought to systematically compare alterations found by a massively parallel sequencing liquid biopsy assay covering 39 genes (NEOliquid [NEO New Oncology GmbH, Koln, Germany]) with those identified through routine diagnostic testing in a certified central pathology laboratory in a cohort of patients with nonsquamous NSCLC. NEOliquid is based on enrichment of the genomic territory of interest by hybrid capture and is thus capable of detecting point mutations, small insertions and deletions, copy number alterations, and gene rearrangements/fusions in a single assay. Results In a cohort of 82 patients with matched blood/tissue samples, the concordance between NEOliquid and tissue-based routine testing was 98%, the sensitivity of NEOliquid was higher than 70%, and the specificity was 100%. Discordant cases included those with insufficient amounts of circulaating tumor DNA in plasma and cases in which known driver mutations (e.g., isocitrate dehydrogenase (NADP(+)), 1 systolic gene [IDH1] R132H, kinesin family member 5B gene [KIF5b–ret proto-oncogene [RET], or MNNG HOS Transforming gene [MET] exon 14) were found in the plasma but were not interrogated by routine tissue analyses. Conclusions In summary, NEOliquid offers accurate and reliable detection of clinically relevant driver alterations in plasma of patients with cancer.

The rate of oxygen ion jumps in a solid oxide depends not only on the activation energy but also on the pre-exponential factor of diffusion. In order to allow a fully ab initio prediction of the oxygen ion conductivity in pure and samarium doped ceria, we calculated the attempt frequency for an oxygen ion jump from first principles combining DFT+U, the NEB method, phonon calculations and the transition state theory. Different definitions of the jump attempt frequency are presented. The equivalence of the Eyring and the Vineyard method is shown without restriction to the Gamma point. Convergence checks of the phonon mesh reveal that the common reduction to the Gamma point is not sufficient to calculate the attempt frequency. Calculations of Sm doped ceria revealed an increase of the prefactor. The attempt frequency for the constant pressure case in quasi-harmonic approximation is larger than the attempt frequency at constant volume in harmonic approximation. The calculated electronic energies, enthalpies and entropies of migration are in agreement with the experimental diffusion coefficients and activation energies.

We present a defect chemical treatment of ceria, CeO2- δ¸ based on formation energies of point defects which we calculated using density functional theory within the GGA+U approximation. All possible defect charge states are considered. In addition we consider polarons, associates of polarons with oxygen vacancies and vacancy-vacancy repulsion. Using the above ab initio data we calculate KrögerVink diagrams and compare them to experimental data.

The intrinsic point defects of $\ensuremath{\beta}$-${\mathrm{Ga}}_{2}{\mathrm{O}}_{3}$ are investigated using density functional theory. We have chosen two different exchange-correlation potentials: the generalized gradient approximation (GGA) and a hybrid potential (HSE06). Defect formation energies were determined taking into account finite-size effects. Schottky, anti-Frenkel, and Frenkel energies have been extracted for $T=0$ K. We calculate formation entropies for an oxygen and a gallium vacancy and determine the Gibbs energy of Schottky disorder. Furthermore, we investigate the defect concentrations as a function of the oxygen partial pressure. The obtained purely intrinsic defect concentrations for charged defects are very small and result in a $p{\mathrm{O}}_{2}$ dependence of the electron concentration of $[{\mathrm{e}}^{\ensuremath{'}}]\ensuremath{\sim}$ $p{\mathrm{O}}_{2}^{\ensuremath{-}1/6}$, whereas experimentally $[{\mathrm{e}}^{\ensuremath{'}}]\ensuremath{\sim}$ $p{\mathrm{O}}_{2}^{\ensuremath{-}1/4}$ is found. So we assume that, experimentally, a small unintentional donor doping is unavoidable. A small extrinsic donor concentration $[{\mathrm{D}}^{\ifmmode\cdot\else\textperiodcentered\fi{}}]$ $=$ 10${}^{18}$ cm${}^{\ensuremath{-}3}$ (10 ppm) changes the electron concentration to $[{\mathrm{e}}^{\ensuremath{'}}]\ensuremath{\sim}$ $p{\mathrm{O}}_{2}^{\ensuremath{-}1/4}$ and gives an activation energy of the conductivity $\ensuremath{\sigma}$ of 1.7 eV in good agreement to experimental values. So we propose as majority disorder $3[{\mathrm{V}}_{\mathrm{Ga}}^{\ensuremath{'}\ensuremath{'}\ensuremath{'}}]$ $=$ $[{\mathrm{D}}^{\ifmmode\cdot\else\textperiodcentered\fi{}}]$ with electrons being minority defects.

We calculate entropies of formation for fully charged point defects, including the small polaron Ce'(Ce), in undoped fluorite-structured ceria by means of density functional theory in the GGA + U approximation. We discuss the behaviour of the entropy for the constant volume and the constant pressure case. Our results for constant pressure (p = 0) suggest that the change in volume, due to the formation of defects, dominates the entropy of formation. From the individual entropies of formation the entropies of Frenkel, anti-Frenkel and Schottky disorder as well as the entropy of reduction of ceria are obtained. At temperatures of about 1000 K the entropic contributions to the Gibbs energy are up to 0.9 eV per defect and thus are no longer negligible. For our calculated entropy of reduction of about 17 kB we find a remarkable agreement with experimental data from the literature.