Differentiation between intra-axial metastatic tumor progression and radiation injury following fractionated radiation therapy or stereotactic radiosurgery using MR spectroscopy, perfusion MR imaging or volume progression modeling

Objective

To determine the accuracy of magnetic resonance spectroscopy (MRS), perfusion MR imaging (MRP), or volume modeling in distinguishing tumor progression from radiation injury following radiotherapy for brain metastasis.

Methods

Twenty-six patients with 33 intra-axial metastatic lesions who underwent MRS (n=41) with or without MRP (n=32) after cranial irradiation were retrospectively studied. The final diagnosis was based on histopathology (n=4) or magnetic resonance imaging (MRI) follow-up with clinical correlation (n=29). Cho/Cr (choline/creatinine), Cho/NAA (choline/N-acetylaspartate), Cho/nCho (choline/contralateral normal brain choline) ratios were retrospectively calculated for the multi-voxel MRS. Relative cerebral blood volume (rCBV), relative peak height (rPH) and percentage of signal-intensity recovery (PSR) were also retrospectively derived for the MRPs. Tumor volumes were determined using manual segmentation method and analyzed using different volume progression modeling. Different ratios or models were tested and plotted on the receiver operating characteristic curve (ROC), with their performances quantified as area under the ROC curve (AUC). MRI follow-up time was calculated from the date of initial radiotherapy until the last MRI or the last MRI before surgical diagnosis.

Results

Median MRI follow-up was 16 months (range: 2-33). Thirty percent of lesions (n=10) were determined to be radiation injury; 70% (n=23) were determined to be tumor progression. For the MRS, Cho/nCho had the best performance (AUC of 0.612), and Cho/nCho >1.2 had 33% sensitivity and 100% specificity in predicting tumor progression. For the MRP, rCBV had the best performance (AUC of 0.802), and rCBV >2 had 56% sensitivity and 100% specificity. The best volume model was percent increase (AUC of 0.891); 65% tumor volume increase had 100% sensitivity and 80% specificity.

Conclusion

Cho/nCho of MRS, rCBV of MRP, and percent increase of MRI volume modeling provide the best discrimination of intra-axial metastatic tumor progression from radiation injury for their respective modalities. Cho/nCho and rCBV appear to have high specificities but low sensitivities. In contrast, percent volume increase of 65% can be a highly sensitive and moderately specific predictor for tumor progression after radiotherapy. Future incorporation of 65% volume increase as a pretest selection criterion may compensate for the low sensitivities of MRS and MRP.     

Ethynyl and Propynylpyrene Inhibitors of Cytochrome P450

Abstract  

The single-crystal X-ray structures and in vivo activities of three aryl acetylenic inhibitors of cytochromes P450 1A1, 1A2, 2A6, and 2B1 have been determined and are reported herein. These are 1-ethynylpyrene, 1-propynylpyrene, and 4-propynylpyrene. To investigate electronic influences on the mechanism of enzyme inhibition, the experimental electron density distribution of 1-ethynylpyrene has been determined using low-temperature X-ray diffraction measurements, and the resulting net atomic charges compared with various theoretical calculations. A total of 82,390 reflections were measured with Mo Kα radiation to a (sinθ/λ)_max = 0.985 Å⁻¹. Averaging symmetry equivalent reflections yielded 8,889 unique reflections. A least squares refinement procedure was used in which multipole parameters were added to describe the distortions of the atomic electron distributions from spherical symmetry. A map of the model electron density distribution of 1-ethynylpyrene was obtained. Net atomic charges calculated from refined monopole population parameters yielded charges that showed that the terminal acetylenic carbon atom (C18) is more negative than the internal carbon (C17). Net atomic charges calculated by ab initio, density functional theory, and semi-empirical methods are consistent with this trend suggesting that the terminal acetylenic carbon atom is more likely to be the site of oxidation. This is consistent with the inhibition mechanism pathway that results in the formation of a reactive ketene intermediate. This is also consistent with assay results that determined that 1-ethynylpyrene acts as a mechanism-based inhibitor of P450s 1A1 and 1A2 and as a reversible inhibitor of P450 2B1. Crystallographic data: 1-ethynylpyrene, C₁₈H₁₀, P2₁/c, a = 14.571(2) Å, b = 3.9094(5) Å, c = 20.242(3) Å, β = 105.042(2)°, V = 1,113.5(2) Å³; 1-propynylpyrene, C₁₉H₁₂, P2₁/n, a = 8.970(2) Å, b = 10.136(1) Å, c = 14.080(3) Å, β = 99.77(2)°, V = 1,261.5(4) Å³; 4-propynylpyrene, C₁₉H₁₂, Pbca, a = 9.904(1) Å, b = 13.174(2) Å, c = 19.401(1) Å, V = 2,531.4(5) Å³.     

Complete assignment of the 1H and 13C NMR spectra of antimicrobial 4‐arylamino‐ 3‐nitrocoumarin derivatives

Herein, we describe the synthesis and complete assignment of the ¹H and ¹³C NMR chemical shifts of a series of antimicrobial 4‐arylamino‐3‐nitrocoumarin derivatives based on a combination of ¹H and ¹³C NMR, ¹H‐¹H‐COSY, NOESY, HSQC and HMBC experiments. Conformational effects upon the chemical shifts of the coumarin moiety arising from the anisotropy of the aryl side group are briefly discussed. This study provides the first complete and fully assigned NMR data for this important group of antimicrobial compounds and bridges the gap existing in the literature with regard to NMR structural data for 4‐arylamino‐3‐nitrocoumarins. Copyright © 2010 John Wiley & Sons, Ltd.     

High Sensitive Microsensor Based on Organic‐Inorganic Composite for Two‐Dimensional Mapping of H2O2 by SECM

The present work describes the development of a selective, sensitive and stable sensing microsensor for scanning electrochemical microscopy (SECM) to measure H₂O₂ during electrochemical reduction of oxygen. The microsensor is based on graphene and Poly(3,4‐ethylenedioxythiophene) composite as support to iron (III) hexacyanoferrate (II) (PEDOT/graphene/Fe^III₄[Fe^II(CN)₆]₃ microsensor). The electrochemical properties of the PEDOT/graphene/Fe^III₄[Fe^II(CN)₆]₃ microsensor were investigated by cyclic voltammetry (CV) and scanning electrochemical microscopy (SECM). The PEDOT/graphene/Fe^III₄[Fe^II(CN)₆]₃ microsensor showed an excellent electrocatalytic activity toward hydrogen peroxide (H₂O₂) reduction with a diminution of the overpotential of about 500 mV in comparison to the process at a bare gold microelectrode. The microsensor presented excellent performance for two dimensional mapping of H₂O₂ by SECM in 0.1 mol L^?1 phosphate buffer solution (pH 7.0). Under optimized conditions, a linear response range from 1 up to 1000 µmol L^?1 was obtained with a sensitivity of 0.08 nA L µmol^?1 and limit of detection of 0.5 µmol L^?1.     

Variance of the virtual displacement

We show that the affine structure of the 3-dimensional space is deeply enmeshed with the static laws expression. The relevance of tensorial rules for calculus in mechanics is thus enhanced. The virtual work principle is stated precisely but a little twist is given to the usual statements: the tensorial nature of the so-called virtual displacement vector is asserted to be covariant. To cite this article: C. Vallée et al., C. R. Mecanique 332 (2004).

Résumé

Nous montrons que la structure affine de l'espace tridimensionnel est fortement imbriquée avec l'expression des lois de la statique. La pertinence de l'application des règles du calcul tensoriel à la mécanique est ainsi renforcée. Le principe des travaux virtuels est établi précisément avec une seule entorse aux exposés classiques : la nature tensorielle de l'habituel vecteur déplacement virtuel est affirmée covariante. Pour citer cet article : C. Vallée et al., C. R. Mecanique 332 (2004).     

Hindered coarsening of a phase-separating microemulsion due to dispersed colloidal particles

The addition of sterically stabilized colloidal particles to a phase-separating microemulsion leads to dramatic changes in its demixing behavior, especially during the later stages. Our microemulsion is composed of reverse micelles of sodium dodecyl sulfate, pentanol, and water in a dodecane continuous phase which separates into micelle-rich and micelle-poor phases above a lower critical solution temperature. The poly(methyl methacrylate) particles preferentially partition into the less structured, micelle-poor phase. Nucleation of the minority phase or spinodal decomposition close to criticality continue to occur in the presence of particles, albeit with pronounced pretransitional clustering of particles when the micelle-poor phase is in the minority. The coalescence of micelle-poor droplets and the coarsening of micelle-rich domains are both strongly modified due to the presence of colloidal particles. We use our observations of the early stages of phase separation to understand these late stage changes.     

ToF-SIMS imaging and depth profiling of HeLa cells treated with bromodeoxyuridine

Time of flight secondary ion mass spectrometry 2D images and molecular depth profiles of human HeLa cells treated with bromodeoxyuridine (BrdU) were acquired in the dual beam mode (Bi(3) (+) analysis beam, C(60) (+) etching beam). Several preparation protocols were investigated and were compared to a simple wash-and-dry method. The feasibility of using C(60) to clean the samples prior to imaging with Bi was also investigated quantitatively by calibrating full depth profiles of the cells using atomic force microscopy. BrdU was used as a marker for the cell nucleus, facilitating identification and localization of sub-cellular features during depth profiling. Results show that C(60) can be used to remove the surface contamination and to access different layers within the cells for 2D imaging. For a 1 nA, 10 keV C(60) (+) beam incident at 45° and rastered over a 500 × 500 μm(2) area, ~1 nm of biological material was sputtered every second. Our results show that HeLa cells were completely removed after etching with 1.3×10(15) C(60) (+) ions per cm(2), giving an average etching rate of 3.9 nm for every 10(13) C(60) per cm(2) at 10 keV and 45° incidence.     

Antisense and antigene inhibition of gene expression by cell-permeable oligonucleotide-oligospermine conjugates

Oligonucleotides and their derivatives are a proven chemical strategy for modulating gene expression. However, their negative charge remains a challenge for delivery and target recognition inside cells. Here we show that oligonucleotide-oligospermine conjugates (Zip nucleic acids or ZNAs) can help overcome these shortcomings by serving as effective antisense and antigene agents. Conjugates containing DNA and locked nucleic acid (LNA) oligonucleotides are active, and oligospermine conjugation facilitates carrier-free cell uptake at nanomolar concentrations. Conjugates targeting the CAG triplet repeat within huntingtin (HTT) mRNA selectively inhibit expression of the mutant huntingtin protein. Conjugates targeting the promoter of the progesterone receptor (PR) function as antigene agents to block PR expression. These observations support further investigation of ZNA conjugates as gene silencing agents.     

Experimental and theoretical studies of ammonia decomposition activity on Fe-Pt, Co-Pt, and Cu-Pt bimetallic surfaces

We investigate the decomposition of ammonia on bimetallic surfaces prepared by the deposition of a monolayer of Fe, Co, or Cu on a Pt(111) surface computationally and experimentally. We explore the correlation between predicted activities based on the nitrogen binding energies with experimental decomposition activity on these bimetallic and corresponding monometallic surfaces. Through density functional theory calculations and microkinetic modeling, it is predicted that the Fe-Pt-Pt(111) and Co-Pt-Pt(111) surfaces, with a monolayer of Fe or Co on top of Pt(111), are active toward decomposing ammonia. In contrast, the corresponding subsurface configurations, Pt-Fe-Pt(111) and Pt-Co-Pt(111) are inactive. These predictions were confirmed experimentally through temperature programmed desorption experiments. Decomposition was seen at temperatures below 350 K for the Fe-Pt-Pt(111) and Co-Pt-Pt(111) surfaces. For the Cu∕Pt(111) system, the surface, subsurface and parent metals were each predicted to be inactive, consistent with experiments, further validating the model predictions. The stability of these bimetallic surfaces in the presence of adsorbed nitrogen is also discussed.