Structure-based design of cyclooxygenase-2 selectivity into ketoprofen

We have recently described how to achieve COX-2 selectivity from the non-selective inhibitor indomethacin (1) using a combination of a pharmacophore and computer 3-D models based on the known X-ray crystal structures of cyclooxygenases. In the present study we have focused on the design of COX-2 selective analogues of the NSAID ketoprofen (2). The design is similarly based on the combined use of the previous pharmacophore together with traditional medicinal chemistry techniques motivated by the comparative modeling of the 3-D structures of 2 docked into the COX active sites. The analysis includes use of the program GRID to detect isoenzyme differences near the active site region and is aimed at suggesting modifications of the basic benzophenone frame of the lead compound 2. The resulting series of compounds bearing this central framework is exemplified by the potent and selective COX-2 inhibitor 17 (LM-1669).     

Synthesis and structure-activity relationships of piperidinylpyrrolopyridine derivatives as potent and selective H1 antagonists

The synthesis and structure-activity relationships of piperidinylpyrrolopyridines as potent and selective H(1) antagonists are discussed. It was found that the nature of the acid chain bonded to piperidine was a key feature for maintaining both the duration of action in vivo and lack of sedative properties.     

Automated Glioblastoma Segmentation Based on a Multiparametric Structured Unsupervised Classification

Automatic brain tumour segmentation has become a key component for the future of brain tumour treatment. Currently, most of brain tumour segmentation approaches arise from the supervised learning standpoint, which requires a labelled training dataset from which to infer the models of the classes. The performance of these models is directly determined by the size and quality of the training corpus, whose retrieval becomes a tedious and time-consuming task. On the other hand, unsupervised approaches avoid these limitations but often do not reach comparable results than the supervised methods. In this sense, we propose an automated unsupervised method for brain tumour segmentation based on anatomical Magnetic Resonance (MR) images. Four unsupervised classification algorithms, grouped by their structured or non-structured condition, were evaluated within our pipeline. Considering the non-structured algorithms, we evaluated K-means, Fuzzy K-means and Gaussian Mixture Model (GMM), whereas as structured classification algorithms we evaluated Gaussian Hidden Markov Random Field (GHMRF). An automated postprocess based on a statistical approach supported by tissue probability maps is proposed to automatically identify the tumour classes after the segmentations. We evaluated our brain tumour segmentation method with the public BRAin Tumor Segmentation (BRATS) 2013 Test and Leaderboard datasets. Our approach based on the GMM model improves the results obtained by most of the supervised methods evaluated with the Leaderboard set and reaches the second position in the ranking. Our variant based on the GHMRF achieves the first position in the Test ranking of the unsupervised approaches and the seventh position in the general Test ranking, which confirms the method as a viable alternative for brain tumour segmentation.     

Normal SUV Values Measured from NaF18- PET/CT Bone Scan Studies

Objectives

Cancer and metabolic bone diseases can alter the SUV. SUV values have never been measured from healthy skeletons in NaF18-PET/CT bone scans. The primary aim of this study was to measure the SUV values from normal skeletons in NaF18-PET/CT bone scans.

Methods

A retrospective study was carried out involving NaF18- PET/CT bone scans that were done at our institution between January 2010 to May 2012. Our excluding criteria was patients with abnormal real function and patients with past history of cancer and metabolic bone diseases including but not limited to osteoporosis, osteopenia and Paget’s disease. Eleven studies met all the criteria.

Results

The average normal SUV_max values from 11 patients were: cervical vertebrae 6.84 (range 4.38–8.64), thoracic vertebrae 7.36 (range 6.99–7.66), lumbar vertebrae 7.27 (range 7.04–7.72), femoral head 2.22 (range 1.1–4.3), humeral head 1.82 (range 1.2–2.9), mid sternum 5.51 (range 2.6–8.1), parietal bone 1.71 (range 1.3–2.4).

Conclusion

According to our study, various skeletal sites have different normal SUV values. SUV values can be different between the normal bones and bones with tumor or metabolic bone disease. SUV can be used to quantify NaF-18 PET/CT studies. If the SUV values of the normal skeleton are known, they can be used in the characterization of bone lesions and in the assessment of treatment response to bone diseases.     

Evidence for an even sex allocation in haplodiploid cyclical parthenogens

Recent theoretical work has shown that haplodiploid cyclical parthenogens, such as rotifers, are expected to have an equal frequency of male‐producing and resting‐egg producing females during their sexual phase. We tested this prediction by following sexual reproduction dynamics in two laboratory populations and one field population of the rotifer Brachionus plicatilis through two growing seasons. We recorded population density, proportion of sexual females, and sex allocation (the proportion of male‐producing sexual females as a fraction of total sexual females). We found this sex allocation ratio to vary from 0.3 to 1.0 in single sampling events. However, when we computed sex allocation by using the integrated densities of both male‐producing sexual females and resting‐egg producing sexual females over time, the two laboratory populations and one of the two field growing seasons showed sex allocation ratios that did not significantly differ from the expected value of 0.5.     

Your Morals Depend on Language

Should you sacrifice one man to save five? Whatever your answer, it should not depend on whether you were asked the question in your native language or a foreign tongue so long as you understood the problem. And yet here we report evidence that people using a foreign language make substantially more utilitarian decisions when faced with such moral dilemmas. We argue that this stems from the reduced emotional response elicited by the foreign language, consequently reducing the impact of intuitive emotional concerns. In general, we suggest that the increased psychological distance of using a foreign language induces utilitarianism. This shows that moral judgments can be heavily affected by an orthogonal property to moral principles, and importantly, one that is relevant to hundreds of millions of individuals on a daily basis.     

68Ga-PSMA11 PET/CT for biochemically recurrent prostate cancer: Influence of dual-time and PMT- vs SiPM-based detectors

Objectives⁶⁸Ga-PSMA11 PET/CT is excellent for evaluating biochemically recurrent prostate cancer (BCR PC). Here, we compared the positivity rates of dual-time point imaging using a PET/CT scanner (DMI) with silicon photomultiplier (SiPM) detectors and a PET/CT scanner (D690) with photomultiplier tubes (PMT), in patients with BCR PC.MethodsFifty-eight patients were prospectively recruited and randomized to receive scans on DMI followed by D690 or vice-versa. Images from DMI were reconstructed using the block sequential regularized expectation maximization (BSREM) algorithm and images from D690 were reconstructed using ordered subset expectation maximization (OSEM), according to the vendor''s recommendations. Two readers independently reviewed all images in randomized order, recorded the number and location of lesions, as well as standardized uptake value (SUV) measurements.ResultsTwenty-eight patients (group A) had DMI as first scanner followed by D690, while 30 patients (group B) underwent scans in reversed order. Mean PSA was 30±112.9 (range 0.3–600.66) ng/mL for group A and 41.5 ± 213.2 (range 0.21–1170) ng/mL for group B (P = 0.796). The positivity rate in group A was 78.6% (22/28 patients) vs. 73.3% (22/30 patients) in group B. Although the performance of the two scanners was equivalent on a per-patient basis, DMI identified 5 additional sites of suspected recurrent disease when used as first scanner. The second scan time point did not reveal additional abnormal uptake.ConclusionsThe delayed time point in ⁶⁸Ga-PSMA11 PET/CT did not show a higher positivity rate. SiPM-based PET/CT identified additional lesions. Further studies with larger cohorts are needed to confirm these results.     

Variability for mixis initiation in Brachionus plicatilis

Deductions from both evolutionary models and inductive argumentation from empirical data support the notion of intraspecific variability for the initiation of sexual reproduction (mixis) within rotifer populations. In this study, we focus on the time and density at which mixis is initiated in a growing population. Cyclical parthenogenetic clones of Brachionus plicatilis established by hatching of resting eggs, isolated from a natural habitat, have been tested at the start of their sexual phase. Clones exhibited great variation for this trait, their time of switching to sexual reproduction being correlated with population density. Most of the variation for mixis initiation has either low or no heritability and is caused by individual environmental factors.