Quantitative pharmacokinetic analysis of DCE-MRI data without an arterial input function: a reference region model

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumor perfusion, microvascular vessel wall permeability and extravascular-extracellular volume fraction. Analysis of DCE-MRI data is usually based on indicator dilution theory that requires knowledge of the concentration of the contrast agent in the blood plasma, the arterial input function (AIF). A method is presented that compares the tissues of interest (TOI) curve shape to that of a reference region (RR), thereby eliminating the need for direct AIF measurement. By assigning literature values for Ktrans (the blood perfusion-vessel permeability product) and v(e) (extravascular-extracellular volume fraction) in a reference tissue, it is possible to extract the Ktrans and v(e) values for a TOI without knowledge of the AIF. The operational RR equation for DCE-MRI analysis is derived, and its sensitivity to noise and incorrect assignment of the RR parameters is tested via simulations. The method is robust at noise levels of 10%, returning accurate (+/-20% in the worst case) and precise (+/-15% in the worst case) values. Errors in the TOI Ktrans and v(e) values scale approximately linearly with the errors in the assigned RR Ktrans and v(e) values. The methodology is then applied to a Lewis Lung Carcinoma mouse tumor model. A slowly enhancing TOI yielded Ktrans=0.039+/-0.002 min-1 and v(e)=0.46+/-0.01, while a rapidly enhancing region yielded Ktrans=0.35+/-0.05 min-1 and v(e)=0.31+/-0.01. Parametric Ktrans and v(e) mappings manifested a tumor periphery with elevated Ktrans (>0.30 min-1) and v(e) (>0.30) values. The main advantage of the RR approach is that it allows for quantitative assessment of tissue properties without having to obtain high temporal resolution images to characterize an AIF. This allows for acquiring images with higher spatial resolution and/or SNR, and therefore, increased ability to probe tissue heterogeneity.     

Estimating Sun Exposure of Children in Day Care Nurseries in South Oxfordshire,UK

Exposure to ultraviolet radiation and sunburn during childhood and adolescence is linked to increased risks of melanoma and basal cell carcinoma later in life. Infants and toddlers are thought to be unusually vulnerable to UVR because of lower levels of melanin, a thinner stratum corneum and a higher surface area/body mass ratio. The aim of this study was to assess variations in the available erythema effective radiant doses to young children in day care nurseries in South Oxfordshire, UK over 7 years between 2008 and 2014. The data were analyzed in three distinct seasons according to a series of realistic exposure scenarios taking into account nursery routines. The results indicate the time of year when high doses are to be expected and provide strong support for arguments in favor of raising public awareness of sun protection earlier in the year.     

Monomer, dimer, tetramer, polymer: structural diversity in zinc and cadmium complexes of chelate-tethered nucleobases

A series of ZnII and CdII complexes of adenine and guanine derivatives containing a diamine tether have been isolated from aqueous solutions and characterised by single crystal X-ray analysis. These studies reveal a wide range of structural types including monomeric, dimeric, tetrameric and polymeric architectures. The extended structures arise from the ability of the ligands to bridge metal ions using the chelating tether in conjunction with N7 of the nucleobase. Additional metal-nucleobase co-ordination is generally observed at the N3-site of the adenine derivatives. With CdII, ethylenediamine-N9-ethylguanine forms an inverted G-tetrad type structure.     

Experimental studies of the dynamics of the bond-forming reactions of CF2(2+) with H2O using position-sensitive coincidence spectroscopy

The dynamics of the product channels forming OCF(+)+H(+)+HF and HCF(2) (+)+H(+)+O following the collisions of CF(2) (2+) with H(2)O have been investigated with a new position-sensitive coincidence experiment at a center-of-mass collision energy of 5.6 eV. The results show the formation of OCF(+) occurs via the formation of a doubly charged collision complex [H(2)O-CF(2)](2+) which subsequently undergoes a charge separating dissociation to form H(+) and HOCF(2) (+). The HOCF(2) (+) monocation subsequently fragments to form HF+OCF(+). The lifetimes of the collision complex and the HOCF(2) (+) ion are at least of the order of their rotational period. The kinetic energy release in this reaction indicates that it involves the ground state of CF(2) (2+) and forms the ground electronic states of OCF(+) and HF. The mechanism for forming HCF(2) (+) involves the direct and rapid abstraction of a hydride ion from H(2)O by CF(2) (2+). The resulting OH(+) ion subsequently fragments to H(+)+O, on a time scale at least comparable with its rotational period.     

A Role for Hydrogen Peroxide in the Pro-apoptotic Effects of Photodynamic Therapy

Although the first reactive oxygen species (ROS) formed during irradiation of photosensitized cells is almost invariably singlet molecular oxygen (¹O₂), other ROS have been implicated in the phototoxic effects of photodynamic therapy (PDT). Among these are superoxide anion radical (^•O₂⁻), hydrogen peroxide (H₂O₂) and hydroxyl radical (^•OH). In this study, we investigated the role of H₂O₂ in the pro-apoptotic response to PDT in murine leukemia P388 cells. A primary route for detoxification of cellular H₂O₂ involves the peroxisomal enzyme catalase. Inhibition of catalase activity by 3-amino-1,2,4-triazole led to an increased apoptotic response. PDT-induced apoptosis was impaired by addition of an exogenous recombinant catalase analog (CAT- skl) that was specifically designed to enter cells and more efficiently localize in peroxisomes. A similar effect was observed upon addition of 2,2'-bipyridine, a reagent that can chelate Fe⁺², a co-factor in the Fenton reaction that results in the conversion of H₂O₂ to ^•OH. These results provide evidence that formation of H₂O₂ during irradiation of photosensitized cells contributes to PDT efficacy.     

Glycomimetic ligands for the human asialoglycoprotein receptor

The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding receptor expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery of therapeutic agents. We report several classes of galactosyl analogues with varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted for several trifluoromethylacetamide derivatives without covalent attachment to the protein. A variety of new ligands were obtained with affinity for ASGPR as good as or better than that of the parent N-acetylgalactosamine, showing that modification on either side of the key C3,C4-diol moiety is well tolerated, consistent with previous models of a shallow binding pocket. The galactosyl pyranose motif therefore offers many opportunities for the attachment of other functional units or payloads while retaining low-micromolar or better affinity for the ASGPR.     

Influence of the chelate ligand structure on the amide methanolysis reactivity of mononuclear zinc complexes

Zinc complexes of three new amide-appended ligands have been prepared and isolated. These complexes, [(dpppa)Zn](ClO4)2 (4(ClO4)2; dpppa = N-((N,N-diethylamino)ethyl)-N-((6-pivaloylamido-2-pyridyl)methyl)-N-((2-pyridyl)methyl)amine), [(bdppa)Zn](ClO4)2 (6(ClO4)2; bdppa = N,N-bis((N,N-diethylamino)ethyl)-N-((6-pivaloylamido-2-pyridyl)methyl)amine), and [(epppa)Zn](ClO4)2 (8(ClO4)2; epppa = N-((2-ethylthio)ethyl)-N-((6-pivaloylamido-2-pyridyl)methyl)-N-((2-pyridyl)methyl)amine), have been characterized by X-ray crystallography (4(ClO4)2 and 8(ClO4)2), 1H and 13C NMR, IR, and elemental analysis. Treatment of 4(ClO4)2 or 8(ClO4)2 with 1 equiv of Me4NOH.5H2O in methanol-acetonitrile (5:3) results in amide methanolysis, as determined by the recovery of primary amine-appended forms of the chelate ligand following removal of the zinc ion. These reactions proceed via the initial formation of a deprotonated amide intermediate ([(dpppa-)Zn]ClO4 (5) and [(epppa-)Zn]ClO4 (9)) which in each case has been isolated and characterized (1H and 13C NMR, IR, elemental analysis). Treatment of 6(ClO4)2 with Me4NOH.5H2O in methanol-acetonitrile results in the formation of a deprotonated amide complex, [(bdppa-)Zn]ClO4 (7), which was isolated and characterized. This complex does not undergo amide methanolysis after prolonged heating in a methanol-acetonitrile mixture. Kinetic studies and construction of Eyring plots for the amide methanolysis reactions of 4(ClO4)2 and 8(ClO4)2 yielded thermodynamic parameters that provide a rationale for the relative rates of the amide methanolysis reactions. Overall, we propose that the mechanistic pathway for these amide methanolysis reactions involves reaction of the deprotonated amide complex with methanol to produce a zinc methoxide species, the reactivity of which depends, at least in part, on the steric hindrance imparted by the supporting chelate ligand. Amide methanolysis involving a zinc complex supported by a N2S2 donor chelate ligand (3(ClO4)2) is more complicated, as in addition to the formation of a deprotonated amide intermediate free chelate ligand is present in the reaction mixture.