Higher capecitabine AUC in elderly patients with advanced colorectal cancer (SWOGS0030).

BACKGROUND: The aging process is accompanied by physiological changes including reduced glomerular filtration and hepatic function, as well as changes in gastric secretions. To investigate what effect would aging have on the disposition of capecitabine and its metabolites, the pharmacokinetics between patients ≥70 years and <60 years were compared in SWOG0030. METHODS: Twenty-nine unresectable colorectal cancer patients were stratified to either ≥70 or <60 years of age, where the disposition of capecitabine and its metabolites were compared. RESULTS: Notable increase in capecitabine area under the curve (AUC) was accompanied by reduction in capecitabine clearance in ≥70 years patients (P<0.05). No difference in 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine (DFUR), and 5-fluorouracil (5FU) AUCs between the two age groups, suggesting that carboxylesterase and cytidine deaminase (CDA) activity was similar between the two age groups. These results suggest that metabolic enzymes involved in converting capecitabine metabolites are not altered by age. An elevation in capecitabine Cmax and reduction in clearance was seen in females, where capecitabine AUC was 40.3% higher in women. Elevation of DFUR Cmax (45%) and AUC (46%) (P<0.05) was also noted, suggesting that CDA activity may be higher in females. CONCLUSION: Increases in capecitabine Cmax and AUC was observed in patients ≥70 years when compared with younger patients who were >60 years.

Angiotensin-(1-7) administration reduces oxidative stress in diabetic bone marrow.

Diabetics have an increased risk of developing cardiovascular disease, in part due to oxidative stress, resulting in endothelial nitric oxide synthase (eNOS) dysfunction. Studies have demonstrated that angiotensin-(1-7) [Ang-(1-7)] can activate eNOS activity. Because the bone marrow is a primary source of a number of progenitors important in physiological homeostasis and healing, the goal of this study was to evaluate the in vivo effects of Ang-(1-7) treatment on oxidative stress and the ensuing nitrative stress in diabetic bone marrow and its potential pathways. BKS.Cg-Dock7(m) +/+ Lepr(db)/J mice and their heterozygous controls were administered Ang-(1-7) alone or combined with A-779, losartan, PD123,319, nitro-l-arginine methyl ester, or icatibant sc for 14 d. The bone marrow was then collected to measure nitric oxide levels, eNOS phosphorylation, and expression of nitric oxide synthase, superoxide dismutase, and p22-phox. Nitric oxide levels in the bone marrow were significantly decreased in diabetic mice, and Ang-(1-7) treatment was able to significantly increase these measures (P < 0.01). This effect was blocked by the coadministration of PD123,319, A-779, nitro-l-arginine methyl ester, and icatibant. In addition, Ang-(1-7) treatment reversed the paradoxical increase in eNOS and neuronal nitric oxide synthase expression and decreased the phosphorylation of eNOS at Thr495 seen in diabetic mice. Ang-(1-7) also reversed diabetes-induced production of reactive oxygen species by decreasing p22-phox expression and increasing superoxide dismutase 3 expression, leading to a significant reduction in 3-nitrotyrosine formation in diabetic bone marrow (P < 0.05). Our findings demonstrate that Ang-(1-7) administration decreases diabetes-induced oxidative stress in the bone marrow and modifies pathways involved in eNOS dysfunction.

Orientation-dependent C60 electronic structures revealed by photoemission spectroscopy.

We observe, with angle-resolved photoemission, a dramatic change in the electronic structure of two C60 monolayers, deposited, respectively, on Ag (111) and (100) substrates, and similarly doped with potassium to half filling of the C60 lowest unoccupied molecular orbital. The Fermi surface symmetry, the bandwidth, and the curvature of the dispersion at Gamma point are different. Orientations of the C60 molecules on the two substrates are known to be the main structural difference between the two monolayers, and we present new band-structure calculations for some of these orientations. We conclude that orientations play a key role in the electronic structure of fullerides.

Cellular expression of estrogen and progesterone receptors in mammary glands: regulation by hormones, development and aging.

At present, there is an extensive body of literature documenting the participation of estrogen receptors (ER) and progesterone receptors (PR) in mammary gene expression. Yet, the precise roles of these receptors in regulating mammary development, carcinogenesis and the growth of a subset of tumors still remain unclear. Mammary glands are composed of various cell types with different developmental potentials. Further, ultimately, that it is their mutual interactions which dictate the behavior of mammary epithelial cells. Therefore, to resolve the roles of ER and PR in normal mammary growth, differentiation and carcinogenesis, analyses for the expression of these receptors at the level of individual cell types is of paramount importance. Accordingly, in the present studies using immunolocalization techniques, we document the ontogeny and cellular distribution of ER and PR during mammary development and in response to ovarian hormones and aging. In addition, we discuss the potential biological significances of the expression patterns of ER and PR during various physiological states. We believe that the observations reported here should provide a conceptual framework(s) for elucidating the roles of ER and PR in normal and neoplastic mammary tissues.

Anomalous quasiparticle lifetime in graphite: band structure effects.

We report ab initio calculations of quasiparticle lifetimes in graphite, as determined from the imaginary part of the self-energy operator within the GW approximation. The inverse lifetime in the energy range from 0.5 to 3.5 eV above the Fermi level presents significant deviations from the quadratic behavior naively expected from Fermi liquid theory. The deviations are explained in terms of the unique features of the band structure of this material. We also discuss the experimental results from different groups and make some predictions for future experiments.

Population pharmacokinetics and use of Monte Carlo simulation to evaluate currently recommended dosing regimens of ciprofloxacin in adult patients with cystic fibrosis.

Pharmacodynamic data on ciprofloxacin indicate that a target area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MIC ratio of >or=125 is necessary to achieve optimal bactericidal activity for the treatment of gram-negative pneumonia. The purpose of this prospective study was to (i) develop a pharmacokinetic (PK) model to be utilized for therapeutic drug monitoring (TDM) of ciprofloxacin and (ii) evaluate current ciprofloxacin dosing regimens for pneumonias in cystic fibrosis (CF) patients. Twelve adult CF patients received a single 400-mg dose of IV ciprofloxacin. Six blood samples were obtained over a 12-h interval. Serum drug concentrations were determined by high-pressure liquid chromotography and were fitted to one- and two-compartment models by using NPEM2. Ciprofloxacin MIC data for Pseudomonas aeruginosa were obtained from 1,213 CF patients enrolled in a large clinical trial. A Monte Carlo simulation was performed to estimate the fractional attainment of an AUC(0-24)/MIC ratio of >or=125. A two-compartment model best describes the serum drug concentration data. The mean fitted PK parameter values are volume of distribution in the central compartment, 0.29 liter/kg; volume of distribution at steady state, 1.1 liters/kg; total clearance, 0.34 liter/h/kg; distributional clearance, 0.89 liter/h/kg; half-life at alpha phase, 0.16 h; and half-life at beta phase, 2.9 h. The overall fractional attainment of achieving an AUC(0-24)/MIC ratio of >or=125 against P. aeruginosa isolates with ciprofloxacin (400 mg every 12 h [q12h] and 8 qh) were 10 and 30%, respectively. A clinical breakpoint MIC of <0.5 microg/ml for susceptibility is suggested, based on an examination of the fractional attainment of the AUC(0-24)/MIC target at each MIC. The recommended doses of 400 mg q8h or q12h may be inadequate to treat an acute pulmonary exacerbation when given alone. The poor and variable AUC(0-24)/MIC ratios support the use of TDM to monitor and adjust the dosage to optimize the efficacy of ciprofloxacin therapy in these patients.

Mechanical instability and ideal shear strength of transition metal carbides and nitrides.

The ideal shear strength of transition metal carbides and nitrides is calculated with the use of the ab initio pseudopotential density functional method. The microscopic mechanism that limits the ideal strength is studied using full atomic and structural relaxation and the results of electronic structure calculations. It is shown that plasticity in perfect crystals can be triggered by electronic instabilities at finite strains. Our study explicitly demonstrates that the ideal strength in these materials is limited by the elastic instability which is in turn initiated by electronic instabilities. The potential application of alloy hardening due to the onset of instabilities at different strains is also discussed.

Coupling of nonlocal potentials to electromagnetic fields.

Nonlocal Hamiltonians are used widely in first-principles quantum calculations; the nonlocality stems from eliminating undesired degrees of freedom, e.g., core electrons. To date, attempts to couple nonlocal systems to external electromagnetic (EM) fields have been heuristic or limited to weak or long wavelength fields. Using Feynman path integrals, we derive an exact, closed-form coupling of arbitrary EM fields to nonlocal systems. Our results justify and clarify the couplings used to date and are essential for systematic computation of linear and especially nonlinear responses.

Respiratory muscle strength, lung function, and dyspnea in patients with sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic granulomatous disorder that is estimated to involve the skeletal muscles in up to 50% of patients. There is little information on the relationship among respiratory muscle strength, lung volumes, and the degree of dyspnea in patients with sarcoidosis. DESIGN AND PATIENTS: Lung function and maximal respiratory muscle force generation were measured in 36 patients with sarcoidosis (24 patients with pulmonary parenchymal infiltration) and 25 control subjects free of cardiorespiratory disease. Dyspnea in the sarcoidosis patients was quantitated by a score based on an activity tolerance assessment scale (ranging from rest to climbing hills or stairs). SETTING: Outpatient clinics of two teaching hospitals. RESULTS: Mean FVC, maximal voluntary ventilation, total lung capacity (TLC), functional residual capacity, residual volume (RV), and diffusing capacity of the lung for carbon monoxide (DLCO) were all at least 16% less than corresponding control values (in all cases, p < 0.001), while maximal inspiratory mouth pressure (PImax) and maximal expiratory mouth pressure (PEmax) were 37% and 39% less, respectively, than control values (both at p < 0.0001). PImax and PEmax declined with increasing dyspnea in a more graded, steady manner than did spirometric and DLCO values. For all measurements, however, the lowest mean values were found in patients with the most severe level of dyspnea. Strong inverse relationships were observed between PEmax and PImax with dyspnea level (p < 0.0001 and p < 0.01, respectively). Both PImax and PEmax correlated best with absolute values of FVC, while only PEmax correlated with RV (absolute and percent predicted) and percent predicted values of TLC. CONCLUSIONS: Maximal respiratory pressures correlate more closely with dyspnea level than lung volumes and DLCO. Since dyspnea is the most common presentation in early to moderately advanced sarcoidosis, respiratory pressures may be a more reliable index of functional work capacity and reflection of activities of daily living than standard tests of lung function.

Vacancy hardening and softening in transition metal carbides and nitrides.

The effects of vacancies on mechanical properties of the transition metal carbides and nitrides are studied using the ab initio pseudopotential approach. Calculated shear elastic stiffness and electronic structures show that the vacancy produces entirely different effects on the mechanical strength of groups IVb nitrides and Vb carbides. It is found that the occupation of shear-unstable metallic dd bonding states changes essentially in an opposite way for the carbides and nitrides in the presence of vacancies, resulting in different responses to shear stress. Our study provides an atomistic understanding of the anomaly in hardness for these substoichiometric materials.

Computational design of direct-bandgap semiconductors that lattice-match silicon.

Crystalline silicon is an indirect-bandgap semiconductor, making it an inefficient emitter of light. The successful integration of silicon-based electronics with optical components will therefore require optically active (for example, direct-bandgap) materials that can be grown on silicon with high-quality interfaces. For well ordered materials, this effectively translates into the requirement that such materials lattice-match silicon: lattice mismatch generally causes cracks and poor interface properties once the mismatched overlayer exceeds a very thin critical thickness. But no direct-bandgap semiconductor has yet been produced that can lattice-match silicon, and previously suggested structures pose formidable challenges for synthesis. Much recent work has therefore focused on introducing compliant transition layers between the mismatched components. Here we propose a more direct solution to integrating silicon electronics with optical components. We have computationally designed two hypothetical direct-bandgap semiconductor alloys, the synthesis of which should be possible through the deposition of specific group-IV precursor molecules and which lattice-match silicon to 0.5-1% along lattice planes with low Miller indices. The calculated bandgaps (and hence the frequency of emitted light) lie in the window of minimal absorption in current optical fibres.

Quasiparticle effects on tunneling currents: a study of C2H4 adsorbed on the Si(001)- (2 x 1) surface.

We present a first-principles calculation of the quasiparticle electronic structure of ethylene adsorbed on the dimer reconstructed Si(001)-(2x1) surface. Within the GW approximation, the self-energy corrections for the adsorbate states are found to be about 1.5 eV larger than those for the states derived from bulk silicon. The calculated quasiparticle band structure is in excellent agreement with photoemission spectra. Finally, the effects of the quasiparticle corrections on the scanning tunneling microscope images of the adsorbed molecules are shown to be important as the lowering of the C2H4 energy levels within GW strongly reduces their tunneling probability.

High accuracy many-body calculational approaches for excitations in molecules.

Two state-of-the-art computational approaches: quantum Monte Carlo and GW with exciton effects [GW-BSE (Bethe-Salpeter equation)] are employed to calculate ionization potentials, electron affinities, and first excited singlet and triplet energies for the silane and methane molecules. Results are in excellent agreement between these dramatically different approaches and with available experiment. The optically forbidden triplet excitation in silane is predicted to lie roughly 1 eV higher than previously reported. In the GW-BSE method, we demonstrate that inclusion of off-diagonal matrix elements in the self-energy operator is crucial for an accurate picture.

Structural deformation and intertube conductance of crossed carbon nanotube junctions.

We present a first-principles study of the structure and quantum electronic conductance of junctions consisting of two crossed (5,5) single-walled carbon nanotubes. The structures are determined by constrained minimization of total energy at a given force between the two tubes, simulating the effects of substrate-tube attraction or an applied force. We find that the intertube contact distance is very sensitive to the applied force in the range of 0--10 nN. The intertube conductance is sizable for realistic deformation expected from substrate interaction. The results explain the recent transport data on crossed nanotubes and show that these systems may be potentially useful as electromechanical devices.

Estimation of creatinine clearance in patients with metastatic ovarian cancer.

The authors evaluated the predictive performance of four methods used to estimate creatinine clearance (Cl(cr)) in patients with metastatic ovarian cancer. Methods described by Cockcroft and Gault, Jelliffe, and two equations derived from cancer patients by Robinson and Tsubaki, were evaluated. Estimated Cl(cr) values obtained by each method using actual weight (ABW), ideal weight (IBW) and lower of ABW and IBW were compared with measured values determined by a 12- or 24-hour urine collection for 14 patients enrolled in a controlled clinical trial. The mean prediction errors (ME) and mean absolute errors (MAE) were calculated to evaluate the bias and precision, respectively, of each method. The relationship between predicted and measured Cl(cr) is poor (r = 0.38 to 0.54). Cockcroft and Gault using ABW (p = 0.21), Robinson using ABW (p = 0.44), and Jelliffe (p = 0.17) were equally unbiased predictors of measured Cl(cr). All other methods significantly underestimated measured Cl(cr). All methods appeared to be equally imprecise (p<0.05). The use of standard equations for estimating Cl(cr) in patients with ovarian cancer is predictive of the measured 24-hour value. The use of oncology specific equations does not improve the accuracy or precision of these estimates.

Structure and energy of the 90 degrees partial dislocation in diamond: a combined Ab initio and elasticity theory analysis.

The core structure and stability of the 90 degrees partial dislocation in diamond is studied within isotropic elasticity theory and ab initio total energy calculations. The double-period reconstruction is found to be more stable than the single-period reconstruction for a broad range of stress states. The analysis of the ab initio results shows further that elasticity theory is valid for dislocation spacings as small as 10-20 A, thus allowing ab initio calculations to provide reliable parameters for continuum theory analysis.

Ductal growth is impeded in mammary glands of C-neu transgenic mice.

The steroid hormone, estradiol, is essential for both the growth of normal breast and induction of mammary carcinomas. The growth promoting effects of estrogen are presumed to be mediated by growth factors, in particular, epidermal growth factor, which mediates its effects through erbB receptors, erbB1 and erbB2/C-neu. C-neu is amplified and over-expressed in a large number of human cancers and transgenic mice over-expressing C-neu also develop mammary tumors. However, as yet, the impact of C-neu over-expression on estrogen action during normal mammary development and hence, its precise role in carcinogenesis, remains unclear. In the present studies, we demonstrate that estradiol-dependent mammary ductal growth accompanying puberty is impaired in transgenic mice expressing wild type Cneu, and is intrinsic to the tissue. The impairment is not due to an overall impairment in estrogen action, since progesterone receptor expression is unaffected in C-neu mice. It is also not due to an intrinsic inability of the epithelial cells to proliferate, since impeded ductal growth co-exists with alveolar growth during pregnancy. Therefore, we propose that, depending on the physiological state, C-neu may either promote or inhibit the growth of mammary epithelial cells, and discuss its potential significance to carcinogenesis.

Kaposi's sarcoma: advances in tumor biology and pharmacotherapy.

Kaposi's sarcoma (KS) is a highly vascularized neoplasm that primarily results in raised, highly vascularized lesions. Before the 1980s, KS was a rare disorder that occurred predominantly in elderly men of Mediterranean or Eastern European Jewish descent. With the advent of the acquired immunodeficiency syndrome (AIDS) epidemic, its occurrence has increased dramatically. It can be classified into four types: classic, African endemic, iatrogenic or drug associated, and AIDS related. Classic KS usually follows an indolent and benign clinical course that rarely requires treatment. In contrast, AIDS-KS is a fulminant disease that requires aggressive pharmacotherapy, especially when it involves visceral organs. The epidemiology, clinical presentation, pathogenesis, and management strategies of AIDS-KS are reviewed, including recent pharmacologic advances.

Boron nitride nanotubes.

The successful synthesis of pure boron nitride (BN) nanotubes is reported here. Multi-walled tubes with inner diameters on the order of 1 to 3 nanometers and with lengths up to 200 nanometers were produced in a carbon-free plasma discharge between a BN-packed tungsten rod and a cooled copper electrode. Electron energy-loss spectroscopy on individual tubes yielded B:N ratios of approximately 1, which is consistent with theoretical predictions of stable BN tube structures.