Use of NQO1 status as a selective biomarker for oesophageal squamous cell carcinomas with greater sensitivity to 17-AAG

Abstract Background Oesophageal squamous cell carcinoma (OSCC) is a major health burden in Sub-Saharan Africa, and novel chemotherapies are urgently required to combat this disease. The heat shock protein 90 (HSP90) inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) has previously been proposed as a possible candidate drug. NADPH quinone oxidoreductase 1 (NQO1) is known to increase the potency of 17-AAG, therefore we investigated the effects of 17-AAG in OSCC cell lines in the context of their NQO1 status. Methods We used MTT assays to compare the sensitivity of a panel of OSCC cell lines to 17-AAG. Western blotting, and RT-PCR were used to investigate NQO1 protein and mRNA levels, while an RFLP approach was used to investigate the NQO1 C609T SNP. Results Expression of NQO1 markedly increased sensitivity to 17-AAG in the OSCC cell lines, while normal fibroblasts, which expressed HSP90 at much lower levels, were more resistant to 17-AAG. In isolation, neither the C609T SNP, nor NQO1 mRNA levels was an accurate predictor of NQO1 protein levels. Conclusions Since NQO1 greatly enhances the anti-cancer effects of 17-AAG, this could be used as a selective marker for patients that would benefit most from 17-AAG chemotherapy at low doses. Testing for the presence of the C609T SNP in both alleles could be used as a screen to exclude potentially poor responders to 17-AAG treatment at low dosages

Elastic Angular Differential Cross Sections for Quasi-One-Electron Collision Systems at Intermediate Energies: (Na⁺, Li⁺)+H and (Mg⁺, Be⁺)+He

Measurements of elastic angular differential cross sections have been carried out for four quasi-one-electron collision systems at intermediate energies. Data are presented for Na++H collisions at laboratory energies of 35.94, 51.75, 63.89, and 143.75 keV, for Li++H collisions at energies of 19.44 and 43.75 keV, for Mg++He collisions at energies of 30, 66.7, and 150 keV, and for Be++He collisions at an energy of 56.25 keV. The highest energy in each case corresponds to a projectile velocity of (1/2 a.u. Born and Eikonal calculations, in which we model the projectile ion as a heavy structureless ion of charge +1e, are also presented. Our model calculations are in fair agreement with the experimental data over the range of measured scattering angles

Angular-Differential Studies of Excitation in Quasi-One-Electron Collisions at High Energy

Qualitative differences have been observed between two types of quasi-one-electron collision systems. We have studied valence-electron excitation at high energy (relative collision velocities up to 0.5 a.u.) in the Mg++He and Na++H collision systems, and find that while Mg++He collisions are dominated by direct excitation, the Na++H collisions exhibit significant molecular excitation, even at the highest velocities. This behavior can be understood in terms of the molecular structure of the respective collision complexes, and the energy separation between the ground and first excited states of the valence electron

Isotope Effect and Momentum-Transfer Scaling in the Elastic-Scattering Differential Cross Sections for Hydrogen-Isotope Collision Systems

A projectile-dependent isotope effect was found for the elastic-scattering differential cross sections in the hydrogen-isotope collision systems. All four differential cross sections lie on a common curve if they are divided by the square of the reduced mass and plotted against momentum transfer. The experimental results are in satisfactory agreement with a simple Glauber-approximation calculation

Elastic Differential Cross Sections for Small-Angle Scattering of 25-, 40-, and 60-keV Protons by Atomic Hydrogen

Elastic angular differential cross sections for small-angle scattering of protons by atomic hydrogen have been measured. The technique utilized unambigously distinguishes the elastically and inelastically scattered ions. The cross sections fall monotonically by 3 orders of magnitude in the angular range from 0.5 to 3.0 mrad, in the center-of-mass system. The experimental data obtained are in very good agreement with a multistate calculation and in fair agreement with both our Glauber-approximation and classical-trajectory Monte Carlo results

Angular Differential and Total Cross Sections for the Excitation of Atomic Hydrogen to Its n=2 Level by 25-150-kev Hydrogen Molecular Ions

Experimentally and theoretically determined differential and total cross sections are reported for excitation of atomic hydrogen to its n=2 level by 25-150-keV hydrogen molecular ions. The differential cross sections decrease 3-4 orders of magnitude over the measured center-of-mass scattering-angular range from 0 to 4.5 mrad. The results of a first Born approximation and two other theoretical calculations based upon the Glauber approximation are presented and compared with the experimental results. Both calculations based on the Glauber approximation agree fairly well with the experimental results. The Born approximation agrees moderately well with the experimental results at the very small scattering angles but is well below the experimental results at the larger scattering angles. None of the theoretical calculations presented agree well with the total cross section. However, the results for the total cross section of the two calculations based on the Glauber approximation agree with the experimental results in curve shape better than the Born-approximation results

Local knowledge, local learning and predicting election outcomes : voter assessments of likely party success in Scotland's constituencies at the 2015 and 2017 general elections

Political scientists often debate how much information people have and deploy when making electoral decisions. Some scholars suggest that voters are aware of which party is likely to win in their local constituency at British general elections; however, this might not be the case in situations when there is substantial and spatially varying change in the relative fortunes of two or more parties between elections. That argument is evaluated here using as a case study the 2015 and 2017 general elections in Scotland: at the first, the SNP's vote share more than doubled, and it won 56 of the country's 59 seats, having won just six at the previous contest; at the second, its vote share fell by about a third, and it lost 21 of those 56 seats. Analysis of British Election Survey data collected before and during the campaigns preceding those elections shows that most respondents were aware of the SNP's surge in 2015 and expected their victory in every constituency. In 2017, most voters were aware which of the SNP's three competitors was the biggest threat in each constituency, and that awareness became clearer during the campaign; yet, voters – especially those who identified with the SNP and were contacted by it during the campaign – still (incorrectly) anticipated a local SNP victory

Simple sequence repeat variation in the Daphnia pulex genome

Background: Simple sequence repeats (SSRs) are highly variable features of all genomes. Their rapid evolution makes them useful for tracing the evolutionary history of populations and investigating patterns of selection and mutation across gnomes. The recently sequenced Daphnia pulex genome provides us with a valuable data set to study the mode and tempo of SSR evolution, without the inherent biases that accompany marker selection. Results: Here we catalogue SSR loci in the Daphnia pulex genome with repeated motif sizes of 1-100 nucleotides with a minimum of 3 perfect repeats. We then used whole genome shotgun reads to determine the average heterozygosity of each SSR type and the relationship that it has to repeat number, motif size, motif sequence, and distribution of SSR loci. We find that SSR heterozygosity is motif specific, and positively correlated with repeat number as well as motif size. For non-repeat unit polymorphisms, we identify a motif-dependent end-nucleotide polymorphism bias that may contribute to the patterns of abundance for specific homopolymers, dimers, and trimers. Our observations confirm the high frequency of multiple unit variation (multistep) at large microsatellite loci, and further show that the occurrence of multiple unit variation is dependent on both repeat number and motif size. Using the Daphnia pulex genetic map, we show a positive correlation between dimer and trimer frequency and recombination. Conclusions: This genome-wide analysis of SSR variation in Daphnia pulex indicates that several aspects of SSR variation are motif dependent and suggests that a combination of unit length variation and end repeat biased base substitution contribute to the unique spectrum of SSR repeat loci

A Genome-Wide Analysis of Promoter-Mediated Phenotypic Noise in Escherichia coli

Gene expression is subject to random perturbations that lead to fluctuations in the rate of protein production. As a consequence, for any given protein, genetically identical organisms living in a constant environment will contain different amounts of that particular protein, resulting in different phenotypes. This phenomenon is known as “phenotypic noise.” In bacterial systems, previous studies have shown that, for specific genes, both transcriptional and translational processes affect phenotypic noise. Here, we focus on how the promoter regions of genes affect noise and ask whether levels of promoter-mediated noise are correlated with genes' functional attributes, using data for over 60% of all promoters in Escherichia coli. We find that essential genes and genes with a high degree of evolutionary conservation have promoters that confer low levels of noise. We also find that the level of noise cannot be attributed to the evolutionary time that different genes have spent in the genome of E. coli. In contrast to previous results in eukaryotes, we find no association between promoter-mediated noise and gene expression plasticity. These results are consistent with the hypothesis that, in bacteria, natural selection can act to reduce gene expression noise and that some of this noise is controlled through the sequence of the promoter region alon