Sulfur and selenium derivatives of quinazoline and pyrido[2,3-d]pyrimidine: synthesis and study of their potential cytotoxic activity in vitro

The synthesis, cytotoxic activities and selectivities of 35 derivatives related to quinazoline and pyrido[2,3-d]pyrimidine are described. The synthesized compounds were screened in?vitro against four tumoral cell lines - leukemia (CCRF-CEM), colon (HT-29), lung (HTB-54) and breast (MCF-7) - and two cell lines derived from non-malignant cell lines, one mammary (184B5) and one from bronchial epithelium (BEAS-2B). MCF-7 and HTB-54 were the most sensitive cell lines with GI(50) values below 10μM for eleven and ten compounds, respectively. Two compounds (2o and 3a) were identified that evoked a marked cytotoxic effect in all cell lines tested and one compound, 7h, was potent and selective against MCF-7. A preliminary study into the mechanism of the potent derivatives 2o, 3a and 7h indicated that the cytotoxic activities of these compounds might be mediated by inducing cell death without affecting cell cycle phases.     

One-year longitudinal study of young apprentices exposed to airway occupational sensitizers

Background: The prevalence of diagnosed asthma and wheezing in young subjects is increasing; among environmental risk factors, occupational exposure can play a relevant role. Study objectives: The purpose of the study was to evaluate the effects of occupational exposure to a large variety of irritants and/or sensitizers on the incidence of respiratory symptoms and pulmonary function impairment in a group of young apprentices during the first year of work exposure, and to determine the prevalence of asthma-like symptoms and the role of different risk factors (gender, smoking habit, atopy and occupational exposure) in this young population. Design and methods: We studied 448 young apprentices at the first pre-employment evaluation with a standardized questionnaire, spirometry and skin prick tests; in 244 of them clinical and functional evaluation was repeated after 1 year exposure to respiratory irritants or sensitizers. Results: At the first examination, males had higher prevalence of attacks of shortness of breath with wheeze, diagnosis of asthma, smoking habit and atopy than females. At the second examination there was no significant increase in the prevalence of respiratory symptoms. However, incident cases for cough, phlegm, wheezing, shortness of breath with wheeze (SOBWHZ) and asthma were all higher than remittent cases. Incidence of respiratory symptoms was associated with atopy and smoking habit. Conclusions: Respiratory symptoms slightly increase over 1 year occupational exposure to sensitizers or irritants. The loss at the follow-up of subjects with higher smoking habit suggests a small “health worker effect” and could underestimate the effect of occupational exposure in apprentices.     

Systematic evaluation of three different commercial software solutions for automatic segmentation for adaptive therapy in head-and-neck, prostate and pleural cancer

Purpose

To validate, in the context of adaptive radiotherapy, three commercial software solutions for atlas-based segmentation.

Methods and materials

Fifteen patients, five for each group, with cancer of the Head&Neck, pleura, and prostate were enrolled in the study. In addition to the treatment planning CT (pCT) images, one replanning CT (rCT) image set was acquired for each patient during the RT course. Three experienced physicians outlined on the pCT and rCT all the volumes of interest (VOIs). We used three software solutions (VelocityAI 2.6.2 (V), MIM 5.1.1 (M) by MIMVista and ABAS 2.0 (A) by CMS-Elekta) to generate the automatic contouring on the repeated CT. All the VOIs obtained with automatic contouring (AC) were successively corrected manually. We recorded the time needed for: 1) ex novo ROIs definition on rCT; 2) generation of AC by the three software solutions; 3) manual correction of AC. To compare the quality of the volumes obtained automatically by the software and manually corrected with those drawn from scratch on rCT, we used the following indexes: overlap coefficient (DICE), sensitivity, inclusiveness index, difference in volume, and displacement differences on three axes (x, y, z) from the isocenter.

Results

The time saved by the three software solutions for all the sites, compared to the manual contouring from scratch, is statistically significant and similar for all the three software solutions. The time saved for each site are as follows: about an hour for Head&Neck, about 40?minutes for prostate, and about 20?minutes for mesothelioma. The best DICE similarity coefficient index was obtained with the manual correction for: A (contours for prostate), A and M (contours for H&N), and M (contours for mesothelioma).

Conclusions

From a clinical point of view, the automated contouring workflow was shown to be significantly shorter than the manual contouring process, even though manual correction of the VOIs is always needed.     

Do Italian fire fighting recruits have an adequate physical fitness profile for fire fighting?

This study aimed to assess individual and gender differences in power spectra in the body sway time series and sway velocity time series during a static upright standing posture using 30 preschool children and their spectrum distribution characteristics. The center of pressure (COP) movement for 1 min was measured twice with a 1 min rest on an Anima stabilometer. The data sampling frequency was 20 Hz. A power spectrum was calculated by applying a fast Fourier transform to time series data of X (medial/lateral) and Y (anterior/posterior) directions. The coefficient of variation (CV) over 10.0 of power was large (from 0.06 to 1.4 Hz in both directions), and as the frequency increased, the CV decreased. There were significant gender differences in the low frequency bands (less than 2.0 Hz), and almost all power of body sway time series and velocity time series were found in the low frequency bands (A and B sections) of the international standard. Individual differences were also large. The distribution of power spectra of their time series was different in both directions. These results suggest that the evaluation section of the existing international standard cannot properly evaluate periodic characteristics of body sway time series and sway velocity time series of preschool children.     

Nerve growth factor and brain‐derived neurotrophic factor increase neurotransmitter release in the rat visual cortex

A number of experiments have shown that neurotrophins are involved in the development and plasticity of the visual cortex (Bonhoeffer, T., Curr. Op. Neurobiol., 6, 119 1996). A possible mechanism underlying these effects is the neurotrophin modulation of synaptic transmission. We investigated whether nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) can modulate the release of neurotransmitter in the rat visual cortex at the peak of the critical period for plasticity (P23). The release of glutamate, acetylcholine and gamma-aminobutyric acid (GABA) from visual cortical synaptosomes was analysed in continuous perfusion conditions. We found that NGF enhances the depolarization-evoked release of glutamate (≈ 90%) and acetylcholine (≈ 35%) but not that of GABA. By contrast, BDNF enhances the depolarization-evoked release of all three neurotransmitters investigated (≈ 30%). BDNF and NGF were ineffective on basal release of neurotransmitters. The effect of NGF was not blocked by cholinergic antagonists atropine and mecamylamine. NGF and BDNF potentiation of transmitter release was strongly but not completely blocked by K252a, a tyrosine kinase inhibitor. The role of TrkA and p75^NTR receptors was investigated in NGF-induced potentiation of glutamate release. Block of NGF binding to p75^NTR using specific blocking antibodies (REX-IgG) slightly but significantly reduced the effect of NGF. Activation of TrkA in isolation by RTA-IgG, an antibody that specifically activates TrkA, was less effective than activation of both receptors by NGF. These results show that neurotrophin action on neurotransmitter release was mostly mediated by Trk receptors with p75^NTR having a little but significant positive role. Antigen blot analysis showed the presence of TrkA, TrkB and p75^NTR receptors in the visual cortex.     

The Use of Tantalum Metaphyseal Cones for the Management of Severe Bone Defects in Septic Knee Revision

Background

Femoral and tibial massive bone defects are common findings in septic total knee revision and pose considerable challenges for the orthopedic surgeon. The aim of this study was to report the midterm clinical and radiographic outcomes with the use of tantalum cones for the management of massive bone defects after 2-stage knee revision.