Comparison of Different Treatment Modalities Outcomes in Clinically Node-positive Bladder Cancer: Analysis of a Population-based Cancer Registry

IntroductionPatients with clinically node-positive bladder cancer were historically considered to have uniformly poor prognosis and were frequently treated with palliative chemotherapy (CHT) only. Although retrospective data show that long-term survival with combined treatment (surgery + CHT) is possible in one-third of these patients, consensus on a treatment algorithm is still lacking. The aim of the study is to compare the efficacy of different treatment modalities based on data from a population-based cancer registry.Patients and MethodsThe study comprises 661 patients identified from the Czech National Cancer Registry (1996-2015) with cTanyN1-3M0 bladder cancer; 195 were treated with CHT alone, 234 underwent radical cystectomy alone (RC), and 232 received a combination of RC and perioperative CHT (RC + CHT). Multivariate Cox proportional hazard regression analyses were used to evaluate the effectiveness of various treatments.ResultsThe 5-year OS for CHT alone, RC alone, and RC + CHT were 21.7% (95% confidence interval [CI], 15.4%-28.0%), 12.1% (95% CI, 7.4%-16.7%), and 25.4% (95% CI, 18.9%-31.9%), respectively (P < .001). The median survivals were 17, 10, and 23 months, respectively. In multivariate analysis, age > 60 years (hazard ratio, 1.29; 95% CI, 1.06-1.56; P = .011) and clinical stage cT3-4 (hazard ratio, 1.39; 95% CI, 1.12-1.71; P = .002) were negative predictors of survival. When compared with CHT, RC + CHT reduced the risk of overall mortality by 21% (P = .044).ConclusionApproximately one-quarter of clinically node-positive patients may achieve long-term survival with combined treatment integrating RC and perioperative CHT. The overall survival of patients is significantly improved with a multimodal approach in comparison to CHT alone.     

The longitudinal association between external locus of control,social cognition and adolescent psychopathology

Purpose

To investigate the longitudinal associations between social cognitive ability an external locus of control (externality) and adolescent psychopathology.

Methods

7058 participants from a prospective population-based cohort provided data on externality, social communication, and emotion perception between 7 and 16 years and psychotic experiences and depressive symptoms at 12 and 18 years. Bivariate probit modelling was used to investigate associations between these risk factors and psychopathological outcomes.

Results

Externality was associated with psychopathology at 12 (psychotic experiences OR 1.23 95% CI 1.14, 1.33; depression OR 1.12 95% CI 1.02, 1.22) and 18 years (psychotic experiences OR 1.38 95% CI 1.23, 1.55; depression OR 1.40 95% CI 1.28, 1.52). Poor social communication was associated with depression at both ages (12 years OR 1.22 95% CI 1.11, 1.34; 18 years OR 1.21 95% CI 1.10, 1.33) and marginally associated with psychotic experiences. There was marginal evidence of a larger association between externality and psychotic experiences at 12 years (p?=?0.06) and between social communication and depression at 12 years (p?=?0.03).

Conclusions

Externality was more strongly associated with psychotic experiences. At 18 years change in externality, between 8 and 16 years were associated with a larger increase in the risk of depression. Poor social communication was more strongly associated with depression.

     

Cued memory reconsolidation in rats requires nitric oxide

It is well‐known that the reactivation of consolidated fear memory under boundary conditions of novelty and protein synthesis blockade results in an impairment of memory, suggesting that the reactivated memory is destabilized and requires synthesis of new proteins for reconsolidation. We tested the hypothesis of nitric oxide (NO) involvement in memory destabilization during the reconsolidation process in rats using memory reactivation under different conditions. We report that administration of NO‐synthase selective blockers 3‐Br‐7‐NI or ARL in the conditions of reactivation of memory under a protein synthesis blockade prevented destabilization of fear memory to the conditioned stimulus. Obtained results support the role of NO signaling pathway in the destabilization of existing fear memory triggered by reactivation, and demonstrate that the disruption of this pathway during memory reconsolidation may prevent changes in long‐term memory.     

Confirmation of the GNB4 gene as causal for Charcot–Marie–Tooth disease by a novel de novo mutation in a Czech patient

The association of GNB4 with Charcot–Marie–Tooth (CMT) has recently been described in a publication by Soong et al. (Soong, et al., 2013). Here we present a patient with CMT in whom whole exome sequencing identified the mutation p.Lys57Glu in the GNB4 gene (NM_021629.3:c.169A>G). The patient, now 41 years old, is a sporadic case in the family. At the age of 35 he presented with severe disability (CMT neuropathy score 29), profound muscle atrophies, pes cavus and scoliosis. Previously, the patient was tested for PMP22 duplications/deletions and later also with 64 CMT gene panel, with no causal variant found. Subsequently, whole exome sequencing was performed. The p.Lys57Glu in the GNB4 gene was identified as the most probable causal variant, the mutation is not present in the patient's parents, neither in his unaffected sister, therefore we assume that the mutation arose de novo. Taken together, these findings support the causal and pathogenic character of the variant. Our report provides important evidence that GNB4 should become an established CMT gene and our findings confirm the original publication by Soong et al. (2013).     

Treatment of Rhenium-Containing Effluents Using Environmentally Friendly Sorbent,Saccharomyces cerevisiae Biomass

Yeast Saccharomyces cerevisiae biomass was applied for rhenium and accompanying elements (copper and molybdenum) removal from single- and multi-component systems (Re, Re-Mo, Re-Cu, and Re-Mo-Cu). Yeast biomass was characterized using X-ray diffraction, scanning electron microscopy, and Fourier transform infrared spectroscopy. The effects of biosorption experimental parameters such as solution pH (2.0–6.0), rhenium concentration (10–100 mg/L), time of interaction (5–120 min), and temperature (20–50 °C) have been discussed in detail. Maximum removal of rhenium (75–84%) and molybdenum (85%) was attained at pH 2.0, while pH 3.0–5.0 was more favorable for copper ions removal (53–68%). The Langmuir, Freundlich, and Temkin isotherm models were used to describe the equilibrium sorption of rhenium on yeast biomass. Langmuir isotherm shows the maximum yeast adsorption capacities toward rhenium ions ranged between 7.7 and 33 mg/g. Several kinetic models (pseudo-first-order, pseudo-second-order, and Elovich) were applied to define the best correlation for each metal. Biosorption of metal ions was well-fitted by Elovich and pseudo-first-order models. The negative free energy reflected the feasibility and spontaneous nature of the biosorption process. Saccharomyces cerevisiae biomass can be considered as a perspective biosorbent for metal removal.     

Improved synthesis of chiral pyrrolidine inhibitors and their binding properties to neuronal nitric oxide synthase

We report an efficient synthetic route to chiral pyrrolidine inhibitors of neuronal nitric oxide synthase (nNOS) and crystal structures of the inhibitors bound to nNOS and to endothelial NOS. The new route enables versatile structure-activity relationship studies on the pyrrolidine-based scaffold, which can be beneficial for further development of nNOS inhibitors. The X-ray crystal structures of five new fluorine-containing inhibitors bound to nNOS provide insights into the effect of the fluorine atoms on binding.     

Symmetric double-headed aminopyridines, a novel strategy for potent and membrane-permeable inhibitors of neuronal nitric oxide synthase

We report novel neuronal nitric oxide synthase (nNOS) inhibitors based on a symmetric double-headed aminopyridine scaffold. The inhibitors were designed from crystal structures of leads 1 and 2 (Delker, S. L.; Ji, H.; Li, H.; Jamal, J.; Fang, J.; Xue, F.; Silverman, R. B.; Poulos, T. L. Unexpected binding modes of nitric oxide synthase inhibitors effective in the prevention of cerebral palsy . J. Am. Chem. Soc. 2010, 132, 5437-5442) and synthesized using a highly efficient route. The best inhibitor, 3j, showed low nanomolar inhibitory potency and modest isoform selectivity. It also exhibited enhanced membrane permeability. Inhibitor 3j binds to both the substrate site and the pterin site in nNOS but only to the substrate site in eNOS. These compounds provide a basis for further development of novel, potent, isoform selective, and bioavailable inhibitors for nNOS.     

A review of potential neurotoxic mechanisms among three chlorinated organic solvents

The potential for central nervous system depressant effects from three widely used chlorinated solvents, trichloroethylene (TCE), perchloroethylene (PERC), and dichloromethane (DCM), has been shown in human and animal studies. Commonalities of neurobehavioral and neurophysiological changes for the chlorinated solvents in in vivo studies suggest that there is a common mechanism(s) of action in producing resultant neurotoxicological consequences. The purpose of this review is to examine the mechanistic studies conducted with these chlorinated solvents and to propose potential mechanisms of action for the different neurological effects observed. Mechanistic studies indicate that this solvent class has several molecular targets in the brain. Additionally, there are several pieces of evidence from animal studies indicating this solvent class alters neurochemical functions in the brain. Although earlier evidence indicated that these three chlorinated solvents perturb the lipid bilayer, more recent data suggest an interaction between several specific neuronal receptors produces the resultant neurobehavioral effects. Collectively, TCE, PERC, and DCM have been reported to interact directly with several different classes of neuronal receptors by generally inhibiting excitatory receptors/channels and potentiating the function of inhibitory receptors/channels. Given this mechanistic information and available studies for TCE, DCM, and PERC, we provide hypotheses on primary targets (e.g. ion channel targets) that appear to be most influential in producing the resultant neurological effects.     

Liquid chromatography electrospray ionization tandem mass spectrometry for the detection of mesocarb abuse in horse doping

A method is described for the determination of mesocarb abuse in equestrian sport by combining gradient liquid chromatography and electrospray ionization tandem mass spectrometry. Mesocarb was administrated orally to two horses at a dose of 50 µg/kg. Urine samples were collected up to 120 h post administration. Hydrolyzed and conjugated urine fractions were handled using liquid‐liquid extraction (LLE). The identity of the parent drug and metabolites was confirmed using liquid chromatography combined with tandem mass spectrometry (MS/MS). Mesocarb and seven metabolites were detected in horse urine. Mono‐ and two di‐hydroxylated metabolites were the main metabolites observed in horse urine samples. Based on the differences in MS/MS spectra it was supposed that these metabolites were been formed by the hydroxylation of the phenylisopropyl moiety of mesocarb whilst the main process of hydroxylation of mesocarb in human occurred in the phenylcarbamoyl moiety. The main metabolites were almost completely glucuroconjugated. Minor metabolites such as p‐hydroxymesocarb and three di‐hydroxylated metabolites together with parent mesocarb were also presented in the free urine fraction. This study has shown that two mono‐ and two di‐hydroxylated metabolites are useful for controlling the abuse of mesocarb in horses. Copyright © 2011 John Wiley & Sons, Ltd.