The radiation chemistry of some platinum-containing radiosensitizers and related compounds

Oxidation and reduction of cis- and trans-dichlorodiammine platinum II (cis- and trans-PDD), cis-dichlorobis(1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3)-p latinum II (cis-Flap), and cis-dichlorobis(isopropylamine)-trans-dihydroxyplatinum IV (Chip) have been studied using pulse radiolysis. Spectra corresponding to platinum in various oxidation states have been observed and several rate constants have been obtained. Reduction of all the compounds, except cis-Flap, produces species of a lower oxidation state of platinum which subsequently have both chloride ligands replaced. Ultimately, these products disproportionate. In the case of cis-Flap, reduction occurred on the nitroimidazole ligand. This was verified by the absence of platinum metal after disproportionation. Oxidation of all four compounds consists of production of a higher oxidation state of platinum followed by replacement of chloride ligands and finally disproportionation of the products. Only cis-Flap and Chip could be reduced by oxidized DNA bases. The one-electron reduction potential of cis-Flap was found to be -370 +/- 10 mV. trans-Flap had almost the same value. It was not possible to measure the potentials of the other compounds since their ligands were replaced rapidly but it is estimated that the one-electron reduction potentials decrease in the order cis- or trans-Flap greater than Chip greater than cis-PDD greater than trans-PDD.     

The Reductive Deglycosylation Of Adriamycin In Aqueous Medium: A Pulse Radiolysis Study

The free radical (II) produced by one-electron reduction of adriamycin (I) exists in aqueous solution at pH 7.0 in equilibrium with the parent and the two-electron reduced form (III). Over some hundreds of milliseconds deglycosylation takes place yielding an aglycone (IV) which subsequently rearranges to form a more stable aglycone. 7-deoxyadriamycinone (V). The changes in the optical absorption spectrum accompanying these processes are reported. The rate constant for III + IV is 1.1 s^-1 and for IV + V is 1.5 × 10^--² s.^-1. At pH 4.0 the two electron reduced form of adriamycin exists predominantly in a different tautomeric form (VII). It is suggested that this deglycosylates via a free radical mechanism involving the acidic form of the semiquinone free radical (VI)     

The MUC5AC gene: RFLP analysis with the Jer58 probe

We have recently obtained evidence that the locus corresponding to three groups of partial tracheobronchial cDNAs (A=Jer47, B=Jer57, C=Jer58) which mapped to chromosome 11p15 and was given the symbol MUC5 corresponds to two distinct genes which we have provisionally called MUC5B and MUC5AC. Here we describe the detection, using the Jer58 probe, which contains a 24-bp tandem repeat, of polymorphism in the MUC5AC gene with seven different restriction enzymes.     

Molecular cloning of cDNAs derived from a novel human intestinal mucin gene

A human small intestinal lambda gt11 cDNA library was screened with antibodies to deglycosylated small intestinal mucin. Four partial cDNA clones were isolated that define a novel human mucin gene. These include two partial cDNA clones, SIB 124 and SIB 139, that contain 51 nucleotide tandem repeats which encode a seventeen amino acid repetitive peptide with a consensus sequence of HSTPSFTSSITTTETTS. SIB 139 hybridized to messages produced by small intestine, colon, colonic tumors and also by high mucin variant LS174T colon cancer cells. The gene from which cDNAs SIB 124 and SIB 139 are derived (proposed name MUC 3) maps to chromosome 7, distinct from other known human mucin genes.     

Reactions of the NAD radical with higher oxidation states of horseradish peroxidase

The reactions of the NAD radical (NAD.) with ferric horseradish peroxidase and with compounds I and II were investigated by pulse radiolysis. NAD. reacted with the ferric enzyme and with compound I to form the ferrous enzyme and compound II with second-order rate constants of 8 X 10(8) and 1.5 X 10(8) M-1 s-1, respectively, at pH 7.0. In contrast, no reaction of NAD. with native compound II at pH 10.0 nor with diacetyldeutero-compound II at pH 5.0-8.0 could be detected. Other reducing species generated by pulse radiolysis, such as hydrated electron (eaq-), superoxide anion (O2-), and benzoate anion radical, could not reduce compound II of the enzyme to the ferric state, although the methylviologen radical reduced it. The results are discussed in relation to the mechanism of catalysis of the one-electron oxidation of substrates by peroxidase.     

Using group testing to estimate a proportion, and to test the binomial model

Group testing has been extensively studied as an efficient way to classify units as defective or satisfactory when the proportion (p) of defectives is small. It can also be used to estimate p, often substantially reducing the mean squared error (MSE) of p and cost per unit information. Group testing is useful for larger p in the estimation problem than in the classification problem, but for larger p more care must be taken in choosing the group size (k); k being too large not only increases MSE (p), but adversely affects the robustness of p to both errors in testing (misclassification) and errors in the assumed binomial model. Procedures that retest units from defective groups, if even feasible, are shown to reduce cost per unit information very little in the estimation problem, but can provide useful information for testing the model. Methods are given for using data from tests of unequal-sized groups to estimate p and for testing the validity of the binomial model.     

Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study

Background

Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.

Methods

We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV₁) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV₁ in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV₁ in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.

Results

We found a positive cross-sectional association between 25(OH)D and FEV₁ in FHS Offspring and Third Generation participants (P = 0.004). There was little or no association between 25(OH)D and longitudinal change in FEV₁ in Third Generation participants (P = 0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV₁ (gene-based P < 0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV₁ in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P = 0.09).

Conclusions

Serum 25(OH)D status was associated with cross-sectional FEV₁, but not longitudinal change in FEV₁. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV₁ and is a promising candidate gene for further studies.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0238-y) contains supplementary material, which is available to authorized users.