Intramolecular Nitrofuran Diels-Alder Reactions: Extremely Substituent-Tolerant Cycloadditions via Asynchronous Transition States.

Nitrofurans undergo intramolecular Diels-Alder reactions with tethered electron-poor dienophiles more rapidly and in higher yield than non-nitrated furans. Computational studies indicate that increased stabilization of a partial positive charge on the nitro-substituted carbon in both transition state and product is the driving force for these reactions. Frontier molecular orbital energy differences indicate a switch from normal to inverse electron demand upon nitration. There does not appear to be a contribution from any differences in aromatic stabilization energy between furans and nitrofurans. Calculations show that the nitrofuran reactions proceed via a highly asynchronous transition state allowing easier bond formation between two sterically hindered carbons.

Unusual structure-energy correlations in intramolecular Diels-Alder reaction transition states.

Detailed analysis of calculated data from an experimental/computational study of intramolecular furan Diels-Alder reactions has led to the unusual discovery that the mean contraction of the newly forming C-C σ-bonds from the transition state to the product shows a linear correlation with both reaction Gibbs free energies and reverse energy barriers. There is evidence for a similar correlation in other intramolecular Diels-Alder reactions involving non-aromatic dienes. No such correlation is found for intermolecular Diels-Alder reactions.

Halogenation effects in intramolecular furan Diels-Alder reactions: broad scope synthetic and computational studies.

For the first time a comprehensive synthetic and computational study of the effect of halogen substitution on both furan and dienophile for the intramolecular Furan Diels-Alder (IMDAF) reaction has been undertaken. Contrary to our initial expectations, halogen substitution on the dienophile was found to have a significant effect, making the reactions slower and less thermodynamically favourable. However, careful choice of the site of furan halogenation could be used to overcome dienophile halogen substitution, leading to highly functionalised cycloadducts. These reactions are thought to be controlled by the interplay of three factors: positive charge stabilisation in the transition state and product, steric effects and a dipolar interaction term identified by high level calculations. Frontier orbital effects do not appear to make a major contribution in determining the viability of these reactions, which is consistent with our analysis of calculated transition state structural data.

Impact of Treating Physician on Radiation Therapy Related Severe Toxicities in Men with Prostate Cancer.

PURPOSE: The impact of treating physician on radiation therapy (RT) related toxicity is unclear. We carried out a secondary analysis of a randomized controlled study to determine whether the risk of RT-related late toxicities in patients with prostate cancer varies depending on the treating radiation oncologist. METHODS AND MATERIALS: This is a secondary analysis of a phase 3 randomized controlled study in which patients with prostate cancer with Gleason score ≤7, clinical stage T1b-T3a, and prostate-specific antigen <30 ng/mL were randomized to receive androgen suppression for 6 months, starting either 4 months before or concurrently with definitive prostate radiation therapy. Incidence of late RT-related toxicity was estimated using Kaplan-Meier methods. We applied multivariable semiparametric shared frailty models with gamma distribution to determine the between-physician variation in the hazard of late RT-related grade ≥3 gastrointestinal, genitourinary, or overall toxicity. Patient level covariables included age, risk group, year of enrollment, and treatment regimen. Frailty variance, a measure of unexplained heterogeneity, was estimated with 95% confidence intervals (CIs). Statistical significance was suggested when the lower limit of the 95% CI for the frailty variance was >0. The Commenges-Andersen test was used for P value estimation. RESULTS: Overall, 426 patients were treated by 9 radiation oncologists. On log-rank test, there was a significant difference in the cumulative incidence of overall grade ≥3 toxicities (P = .001) and grade ≥3 gastrointestinal toxicity (P = .01) among the physician-based clusters. The frailty variance for overall late grade ≥3 toxicity was 0.31 (95% CI, 0.02-1.39; P = .01). The frailty variance for the grade ≥3 gastrointestinal and genitourinary toxicity was 0.84 (95% CI, 0.00-4.20; P = .11) and 0.11 (95% CI, 0.00-1.13; P = .31), respectively. CONCLUSIONS: In our study, the hazard of overall RT-related late grade ≥3 toxicity varied significantly depending on treating radiation oncologist. Further studies are required to explore the underlying processes that lead to such variations in clinical trials involving radiation therapy in prostate cancer.

"Can it read my mind?" - What do the public and experts think of the current (mis)uses of neuroimaging?

Emerging applications of neuroimaging outside medicine and science have received intense public exposure through the media. Media misrepresentations can create a gulf between public and scientific understanding of the capabilities of neuroimaging and raise false expectations. To determine the extent of this effect and determine public opinions on acceptable uses and the need for regulation, we designed an electronic survey to obtain anonymous opinions from as wide a range of members of the public and neuroimaging experts as possible. The surveys ran from 1(st) June to 30 September 2010, asked 10 and 21 questions, respectively, about uses of neuroimaging outside traditional medical diagnosis, data storage, science communication and potential methods of regulation. We analysed the responses using descriptive statistics; 660 individuals responded to the public and 303 individuals responded to the expert survey. We found evidence of public skepticism about the use of neuroimaging for applications such as lie detection or to determine consumer preferences and considerable disquiet about use by employers or government and about how their data would be stored and used. While also somewhat skeptical about new applications of neuroimaging, experts grossly underestimated how often neuroimaging had been used as evidence in court. Although both the public and the experts rated highly the importance of a better informed public in limiting the inappropriate uses to which neuroimaging might be put, opinions differed on the need for, and mechanism of, actual regulation. Neuroscientists recognized the risks of inaccurate reporting of neuroimaging capabilities in the media but showed little motivation to engage with the public. The present study also emphasizes the need for better frameworks for scientific engagement with media and public education.

Elucidation of a structural basis for the inhibitor-driven, p62 (SQSTM1)-dependent intracellular redistribution of cAMP phosphodiesterase-4A4 (PDE4A4).

A survey of PDE4 inhibitors reveals that some compounds trigger intracellular aggregation of PDE4A4 into accretion foci through association with the ubiquitin-binding scaffold protein p62 (SQSTM1). We show that this effect is driven by inhibitor occupancy of the catalytic pocket and stabilization of a "capped state" in which a sequence within the enzyme's upstream conserved region 2 (UCR2) module folds across the catalytic pocket. Only certain inhibitors cause PDE4A4 foci formation, and the structural features responsible for driving the process are defined. Switching to the UCR2-capped state induces conformational transition in the enzyme's regulatory N-terminal portion, facilitating protein association events responsible for reversible aggregate assembly. PDE4-selective inhibitors able to trigger relocalization of PDE4A4 into foci can therefore be expected to exert actions on cells that extend beyond simple inhibition of PDE4 catalytic activity and that may arise from reconfiguring the enzyme's protein association partnerships.

Use of endoscopic mucosal clips in radiotherapy planning for oesophageal carcinoma: a series of three cases.

This paper describes the technique of placing endoscopic mucosal clips to localize oesophageal carcinoma and hence facilitate radiotherapy planning. This technique has been used on three patients in our centre. One was treated radically with external beam radiotherapy and two were treated palliatively (retreatment) with intraluminal brachytherapy. Mucosal hemoclips were placed at the time of endoscopy to indicate the superior and inferior extent of the tumour. The clips provided a radiologically-recognisable marker of the tumour extent and were visible on simulation films or planning CT scans. The radiation portal included the tumour as demarcated by the clips with an adequate margin. There were no complications related to the placement of the clips. All patients completed the radiotherapy course as planned.