Intra- and intermolecular effects on the Compton profile of the ionic liquid 1,3-dimethylimidazolium chloride.

We present a comprehensive simulation study on the solid-liquid phase transition of the ionic liquid 1,3-dimethylimidazolium chloride in terms of the changes in the atomic structure and their effect on the Compton profile. The structures were obtained by using ab initio molecular dynamics simulations. Chosen radial distribution functions of the liquid structure are presented and found generally to be in good agreement with previous ab initio molecular dynamics and neutron scattering studies. The main contributions to the predicted difference Compton profile are found to arise from intermolecular changes in the phase transition. This prediction can be used for interpreting future experiments.

Temperature dependence of CO2 and N2 core-electron excitation spectra at high pressure.

We report a study on the temperature dependence of the core-electron excitation spectra of CO2 and N2, performed using non-resonant inelastic X-ray scattering spectroscopy. The spectra were measured at two temperatures (300 K and 850 K) and at high pressure (40 bar). For CO2 a clear temperature dependence was observed at the C and O near-edge regions. The spectra of CO2 were simulated by density functional theory calculations, and the temperature was accounted for by sampling the initial state molecular geometries using the Metropolis algorithm. This model is able to account for the experimentally observed temperature dependence of the spectrum. The experiment fortifies the status of the non-resonant inelastic X-ray scattering spectroscopy as a valuable technique for physics and chemistry for in situ studies under extreme sample conditions. Especially in the case of gas phase the sample conditions of considerably elevated temperature and pressure are unfeasible for many other spectroscopic techniques.

Measurement of two solvation regimes in water-ethanol mixtures using x-ray compton scattering.

Water-ethanol mixtures exhibit interesting anomalies in their macroscopic properties. Despite a lot of research, the origin of the anomalies and the microscopic structure itself is still far from completely known. We have utilized the synchrotron x-ray Compton scattering technique to elucidate the structure of aqueous ethanol from a new experimental perspective. The technique is uniquely sensitive to the local molecular geometries at the angstrom and subangstrom scales. The experiments reveal two distinct mixing regimes in terms of geometry: the dilute 5 mol % and the concentrated >15 mol % regimes. By comparing with pure liquids, the former regime is characterized by an intramolecular and the latter by an intermolecular change. The findings bring new light to evaluating the hypothesis of formation of clathratelike structures at the dilute concentrations.

Inelastic X-ray scattering and vibrational effects at the K-edges of gaseous N2, N2O, and CO2.

We report non-resonant inelastic X-ray scattering experiments of several gaseous samples in the inner-shell excitation energy range. The experimental near-edge spectra from all the K-edges of N(2), N(2)O, and CO(2) including the momentum transfer dependence are presented. The results are analyzed using density functional theory calculations that accurately reproduce the experimental spectral features. We observe vibrational effects in the measured spectrum and in the calculations the atomic motion is modeled using the Franck-Condon approximation and the linear coupling model. Our findings show that vibrational effects cannot be neglected in the analysis of high resolution inelastic X-ray scattering spectroscopy. The results also support the validity of the transition potential approximation for calculating core excited state potential energy surfaces.

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice.

Despite optimal surgery and chemotherapy, the prognosis of ovarian cancer patients remains poor and new treatments are urgently needed. Solid tumors require the formation of new vessels for growth and metastasis. In the present study, we have used soluble vascular endothelial growth factor (sVEGF) receptors sVEGFR-1 and -3, soluble receptors Tie1 and Tie2 and their combinations in an ovarian cancer xenograft model. Human ovarian cancer cells were injected intraperitoneally into nude mice (n=42) and magnetic resonance imaging (MRI) was used for confirming tumors before gene delivery. Treatment with combined AdsVEGFR-1, AdsVEGFR-3 and AdsTie2 significantly decreased the size of the intraperitoneal tumors compared with the controls (AdLacZ; P=0.038) with significantly less microvessels and vascular area. Unexpectedly, treatment with combined AdsTie1 and AdsTie2 led to a dramatic shortening of the survival which was not observed in the groups receiving either of the soluble receptors alone (P=0.031). The only difference to other treatments was liver toxicity observed after the combined Tie receptor treatment. In conclusion, combined inhibition of VEGFR-1, VEGFR-3 and Tie2 pathways was safe and provided efficient therapy for ovarian cancer in mice.

Universal signature of hydrogen bonding in the oxygen K-edge spectrum of alcohols.

We present a study of the local electronic structure surrounding the OH group in a series of alcohols by X-ray Raman scattering at the oxygen K edge. The samples include the linear alcohols from methanol to butanol as well as the isomers isopropanol, isobutanol, and 2-butanol. For interpretation and computational benchmarks, we combine classical molecular dynamics (MD) simulations and density functional theory (DFT) spectrum calculations. The results indicate that intramolecular structure influences the spectra considerably. Nevertheless, hydrogen bonding produces a clear spectral signature that is nearly identical in all of the alcohols. The spectral calculations using MD structures closely reproduce the experimental results and support the picture provided by the MD simulations.

Structure of liquid linear alcohols.

The properties of linear alcohols in the liquid phase are studied by molecular dynamics simulations. We analyze the effects of the use of bond length constraints on the simulation density, self-diffusion constant, and hydrogen-bonding characteristics of the alcohol series. We find that the densities are well-reproduced in each of the cases but that the constraints have clear effects on the value of the diffusion constant and hydrogen-bonding properties, which is probably caused by the use of a gas-phase reference value in the OH bond length constraint. Although finite size effects are found to be present in the hydrogen bond networks, the networks are determined to be composed of chain-type structures that are well-converged. The results indicate that liquid alcohols consist of hydrogen-bonded chains of molecules. This finding can likely be tested experimentally with inelastic X-ray techniques at modern synchrotron radiation sources.

Charge localization in alcohol isomers studied by Compton scattering.

The isomers of small molecule alcohols propanol (PrOH) and butanol (BuOH) are studied by x-ray Compton scattering experiments with synchrotron radiation and density-functional theory calculations. The lineshape of the measured spectra, i.e., the Compton profile, is a momentum-space property, and its changes reflect changes in the electronic charge density between the isomers. Compared to the linear alcohols (n-PrOH and n-BuOH), the Compton profiles of the branched alcohols (iso-PrOH, iso-BuOH, sec-BuOH) are found to be narrower, which indicates a more delocalized charge for the latter. The calculations are performed for systems consisting of one to three monomer units and are found to reproduce reasonably the experimental spectral features. The influence of the basis set and exchange-correlation scheme is studied in more detail. The results provide new insight into the isomeric differences in small molecule alcohols and show that quantum chemical calculations can be increasingly tested against the x-ray Compton scattering data.

Intrashell electron-interaction-mediated photoformation of hollow atoms near threshold.

Double photoionization (DPI) of an atom by a single photon is a direct consequence of electron-electron interactions within the atom. We have measured the evolution of the K-shell DPI from threshold up in transition metals by high-resolution x-ray emission spectroscopy of the Kh alpha hypersatellites, photoexcited by monochromatized synchrotron radiation. The measured evolution of the single-to-double photoionization cross-section ratio with excitation energy was found to be universal. Theoretical fits suggest that near threshold DPI is predominantly a semiclassical knockout effect, rather than the purely quantum-mechanical shake-off observed at the infinite photon energy limit.

Prognostic significance of extracellular matrix metalloproteinase inducer and matrix metalloproteinase 2 in epithelial ovarian cancer.

AIMS: We investigated the prognostic significance of extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase 2 (MMP-2) in epithelial ovarian cancer as well as their relation to hyaluronan (HA) expression. METHODS: The expression of EMMPRIN and MMP-2 was analyzed immunohistochemically in 295 primary epithelial ovarian cancer patients and 67 metastases. RESULTS: A low membranous EMMPRIN expression was detected more often in serous tumors than in other types (p < 0.0005) and it was associated with tumors of advanced stage (p = 0.012) or with a large primary residual (p = 0.011). A low expression of MMP-2 in cancer cells was associated with a high histologic grade (grade 3) of the tumor (p = 0.005) and endometrioid type of tumors (p < 0.0005). Stromal MMP-2 expression was significantly associated with strong stromal HA expression (p = 0.002, r = 0.187). In univariate analysis, 10-year disease-related (DRS) and recurrence-free survivals were significantly better when MMP-2 expression in cancer cells was high (p = 0.0057 and p = 0.0467, respectively). DRS was also better when membranous EMMPRIN expression was high (p = 0.013). In multivariate analysis, strong MMP-2 in cancer cells (RR = 1.48, CI = 1.07-2.04, p = 0.017) indicated favorable DRS. CONCLUSION: Our results show that EMMPRIN and MMP-2 in cancer cells are significant indicators of a favorable prognosis of epithelial ovarian cancer.

HER-2/neu and p27Kip1 in progression of Fallopian tube carcinoma: an immunohistochemical and array comparative genomic hybridization study.

AIMS: To determine expression of p53, HER-2/neu and p27(Kip1) in serous Fallopian tube carcinoma (FTC) in relation to stage and grade, and to investigate DNA copy number changes of HER-2 and P27KIP1 as a potential mechanism of altered expression status. METHODS AND RESULTS: Immunohistochemistry was performed on 28 serous FTCs and 10 normal Fallopian tubes. p53 protein accumulated and p27(Kip1) was down-regulated significantly in early-stage FTCs compared with normal Fallopian tubes. HER-2/neu overexpression was absent in normal Fallopian tubes and in all stage I FTCs (n = 6) but present in 57% (12/21) of advanced-stage FTCs. No differences in expression between grade 2 and 3 tumours were detected. HER-2 gain/amplification was found by array comparative genomic hybridization in 23% (3/13) of analysed FTCs and all showed overexpression. HER-2/neu overexpression also occurred without DNA copy number changes in three other cases. For p27(Kip1), expression and DNA copy number were unrelated. CONCLUSIONS: p53 accumulation and p27(Kip1) down-regulation seem to be early events in Fallopian tube carcinogenesis. HER-2/neu showed overexpression, caused by gain/amplification in 50%, and may be involved in progression of FTC. These data contribute to a better understanding of the molecular carcinogenesis of FTC and to possible new therapeutic approaches.

DNA profiling of primary serous ovarian and fallopian tube carcinomas with array comparative genomic hybridization and multiplex ligation-dependent probe amplification.

Primary serous ovarian carcinoma (OVCA) and serous Fallopian tube carcinoma (FTC), both belonging to the BRCA-linked tumour spectrum, share many properties and are treated similarly. However, a detailed molecular comparison has been lacking. We hypothesized that comparative genomic studies of serous OVCAs and FTCs should point to gene regions critically involved in their tumorigenesis. Array comparative genomic hybridization (array CGH) analysis indicated that serous OVCAs and serous FTCs displayed common but also more distinctive patterns of recurrent changes. Targeted gene identification using a dedicated multiplex ligation-dependent probe amplification (MLPA) probe set directly identified EIF2C2 on 8q as a potentially important driver gene. Other previously unappreciated gained/amplified genes included PSMB4 on 1q, MTSS1 on 8q, TEAD4 and TSPAN9 on 12p, and BCAS4 on 20q. SPINT2 and ACTN4 on 19q were predominantly found in FTCs. Gains/amplifications of CCNE1 and MYC, often in conjunction with changes in genes of the AKT pathway, EVI1 and PTK2, seemed to be involved at earlier stages, whereas changes of ERBB2 were associated with advanced stages. The only BRCA1-mutated FTC shared common denominators with the sporadic tumours. In conclusion, the data suggest that serous OVCAs and FTCs, although related, exhibit differences in genomic profiles. In addition to known pathways, new genes/pathways are likely to be involved, with changes in an miRNA-associated gene, EIF2C2, as one important new feature. Dedicated MLPA sets constitute potentially important tools for differential diagnosis and may provide footholds for tailored therapy.

Isotope quantum effects in the electron momentum density of water.

The isotope quantum effects in the ground-state electron momentum density of water are studied at temperatures ranging from 5 to 90 degrees C by combining Compton scattering experiments utilizing synchrotron radiation and computational analysis within density functional theory. We observe clear differences in the momentum density between normal and heavy water at room temperature, which are interpreted as predominantly reflecting intramolecular structural differences. The changes in the momentum density upon increasing the temperature are found to be larger for heavy than for normal water, which is attributed primarily to temperature-induced intramolecular structural effects. Both model computations and an ab initio approach qualitatively reproduce the changes in the momentum density as a function of temperature.

Configurational energetics in ice ih probed by compton scattering.

Temperature-induced changes in the ground-state electron momentum density of polycrystalline ice Ih are studied with high accuracy by Compton scattering utilizing synchrotron radiation. A unique feasibility of the technique to provide direct experimental information on configurational enthalpies and heat capacities is demonstrated. The configurational enthalpy, obtained with an accuracy of 1.5 meV, evolves linearly with temperature above T=100 K. Consequently the configurational heat capacity is found to be constant, c{p}{config}=(0.44+/-0.11) J g{-1} K-1, in this temperature regime. Obtaining these quantities experimentally is fundamentally important for evaluating the accuracy of molecular-dynamics simulations schemes.

Compton scattering study of water versus ice Ih: intra- and intermolecular structure.

The hydrogen-bond geometries in water and polycrystalline ice Ih are studied using synchrotron radiation-based Compton scattering data of unprecedented statistical accuracy and consistency. By combining the experimental data with model calculations utilizing density functional theory, we show that the technique provides unique and complementary information on hydrogen bonding in water. The comparison of water and ice indicates the necessity of including a local intra-intermolecular geometric correlation for water, relating the intramolecular O-H bond length to the corresponding hydrogen-bond geometry. By using the hydrogen-bond geometries obeying this correlation, we demonstrate a further constraint on the angular distortions of the hydrogen bonds in water.

Correlation of hydrogen bond lengths and angles in liquid water based on Compton scattering.

The temperature-dependent hydrogen-bond geometry in liquid water is studied by x-ray Compton scattering using synchrotron radiation combined with density functional theory analysis. Systematic changes, related to the weakening of hydrogen bonding, are observed in the shape of the Compton profile upon increasing the temperature. Using model calculations and published distribution functions of hydrogen-bond geometries obtained from a NMR study we find a significant correlation between the hydrogen-bond length and angle. This imposes a new constraint on the possible local structure distributions in liquid water. In particular, the angular distortions of the short hydrogen bonds are significantly restricted.

Comparison of two budesonide dry powder inhalers in the treatment of asthma in children.

The aim of this study was to compare the clinical efficacy, safety, and acceptability of budesonide inhaled from Easyhaler dry powder inhaler (DPI) (Giona Easyhaler, Orion Pharma, Finland) and from Turbuhaler DPI (Pulmicort Turbuhaler, AstraZeneca, Sweden) in the treatment of asthma in children. The 6-month, randomised, double-blind, double-dummy, parallel-group study was conducted in 229 completed, asthmatic children (5-10 years), who were symptomatic at study entry. For the first 2 months, children inhaled budesonide 2 x 200 microg b.i.d. (high-dose treatment period). Thereafter, the daily dose of inhaled budesonide was 2 x 100 microg for 4 months (low-dose treatment period). The study was carried out at 32 centers in Finland, Sweden, Norway, and Denmark. During the high-dose treatment period, the initially symptomatic patients improved in both treatment groups and the achieved control was maintained during the low-dose treatment period. An improvement was seen in the efficacy outcome parameters in the initially symptomatic patients in both treatment groups. Also, there were no differences in the number of asthma exacerbations between the treatments. The urinary free cortisol/creatinine (UCC) ratios were significantly lower in the Turbuhaler group compared to the Easyhaler group after the high-dose treatment period. In addition, there was a slight but statistically significant slower growth rate in the Turbuhaler group after the 6- month treatment period compared with the Easyhaler group. Pulmicort Turbuhaler and Giona Easyhaler are equally effective in the treatment of asthma in children aged 5-10 years old. Budesonide inhaled from Turbuhaler showed slightly greater systemic effects than budesonide inhaled from Easyhaler. The majority of children and parents preferred Easyhaler to Turbuhaler.

X-Ray Spectrometry of Copper: New Results on an Old Subject.

We review recent, and some less recent, measurements of several emission spectra of copper. The results are discussed with special emphasis on elucidating the structure of the Kα 1,2 and Kß 1,3 diagram lines and their underlying transitions. These lines are found to contain ≈30 % contribution from 3d spectator hole transitions. Other multielectronic transitions, the 2p spectator hole (satellites) and 1s spectator hole (hypersatellites) transitions were also measured. They are discussed paying special attention to the evolution of the lineshapes and intensities from the excitation threshold to saturation. Trends in the measured quantities depending on the spectator hole's shell and subshell are also discussed.

Diagram X-ray emission spectra of a hollow atom: the Kh alpha1,2 and Kh beta1,3 hypersatellites of Fe.

High-resolution Fe K(h) beta(1,3) and K(h) alpha(1,2) hypersatellite spectra were measured, using monochromatized synchrotron radiation photoexcitation. The lines' energies, splitting, excitation thresholds, and the K(h) alpha(1)/K(h) alpha(2) intensity ratio were derived with high accuracy. Having both spectra, not hitherto available for any atom with high resolution, allows separating out the energy shifts of the outer levels caused by a K shell spectator vacancy. Comparison with ab initio relativistic multiconfigurational Dirac-Fock calculations reveals that while the influence of relativity and QED effects is mostly accounted for, discrepancies remain in the lines' intensity ratio, which sensitively measures the intermediacy of the coupling. Similar discrepancies, of unknown origin, are found in the energy shifts of the outer levels due to the final-state K shell spectator vacancy.

Safety, tolerability and acceptability of two dry powder inhalers in the administration of budesonide in steroid-treated asthmatic patients.

The purpose of this randomized, double-blind parallel group study was to compare the safety, tolerability and acceptability of Easyhaler and Turbuhaler dry powder inhalers for the delivery of budesonide 800 microg day(-1) in adult asthmatic patients who had already been treated with inhaled corticosteroids for at least 6 months prior to the study Additionally the efficacy of the products was evaluated. The main objective was to evaluate the systemic safety of budesonide inhaled from Easyhaler (Giona Easyhaler, Orion Pharma, Finland) as determined by serum and urine cortisol measurements. The secondary objective was to compare the tolerability acceptability and efficacy of the two devices in the administration of budesonide. After a 2-week run-in period (baseline), patients were randomized on a 2:1 basis to receive budesonide from Easyhaler (n = 103) or from Turbuhaler (Pulmicort Turbuhaler, AstraZeneca, Sweden) (n = 58) 200 g dose(-1), two inhalations twice daily for 12 weeks. There was no statistically significant change in morning serum cortisol values from baseline to the end of treatment in either group. Urine free cortisol and urine cortisol/ creatinine ratio increased from baseline in both groups. There were no significant differences between the groups in terms of morning serum cortisol, urine cortisol, adverse events or efficacy variables, but Easyhaler was generally considered more acceptable to the patients. In conclusion, at 800 microg day(-1), Giona Easyhaler is as safe and efficacious as Pulmicort Turbuhaler in adult asthmatic patients previously treated with corticosteroids, but more acceptable to patients.