Use of diffusion spectrum imaging in preliminary longitudinal evaluation of amyotrophic lateral sclerosis: Development of an imaging biomarker

Previous diffusion tensor imaging (DTI) studies have shown white matter pathology in amyotrophic lateral sclerosis (ALS), predominantly in the motor pathways. Further these studies have shown that DTI can be used longitudinally to track pathology over time, making white matter pathology a candidate as an outcome measure in future trials. DTI has demonstrated application in group studies, however its derived indices, for example fractional anisotropy, are susceptible to partial volume effects, making its role questionable in examining individual progression. We hypothesize that changes in the white matter are present in ALS beyond the motor tracts, and that the affected pathways and associated pattern of disease progression can be tracked longitudinally using automated diffusion connectometry analysis. Connectometry analysis is based on diffusion spectrum imaging and overcomes the limitations of a conventional tractography approach and DTI. The identified affected white matter tracts can then be assessed in a targeted fashion using High definition fiber tractography (a novel white matter MR imaging technique). Changes in quantitative and qualitative markers over time could then be correlated with clinical progression. We illustrate these principles toward developing an imaging biomarker for demonstrating individual progression, by presenting results for five ALS patients, including with longitudinal data in two. Preliminary analysis demonstrated a number of changes bilaterally and asymmetrically in motoric and extramotoric white matter pathways. Further the limbic system was also affected possibly explaining the cognitive symptoms in ALS. In the two longitudinal subjects, the white matter changes were less extensive at baseline, although there was evidence of disease progression in a frontal pattern with a relatively spared postcentral gyrus, consistent with the known pathology in ALS. © 2014 Abhinav, Yeh, El-Dokla, Ferrando, Chang, Lacomis, Friedlander and Fernandez-Miranda

Human cyclin dependent kinase 2 complexed with urea-based cdk4 kinase inhibitor (1GII):

<p>(A)The complex illustrated using the color codes that represent the different regions of the binding site: G-loop, Hyd1, alphaC, Hinge, HRD and DFG regions. The urea fragment binds to the Hinge region, (B) The corresponding field template derived from the complex. Color codes of the field template are listed in the supplementary data (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049284#pone.0049284.s002" target="_blank">Text S2</a>).</p

Applying Ligands Profiling Using Multiple Extended Electron Distribution Based Field Templates and Feature Trees Similarity Searching in the Discovery of New Generation of Urea-Based Antineoplastic Kinase Inhibitors

<div><p>This study provides a comprehensive computational procedure for the discovery of novel urea-based antineoplastic kinase inhibitors while focusing on diversification of both chemotype and selectivity pattern. It presents a systematic structural analysis of the different binding motifs of urea-based kinase inhibitors and the corresponding configurations of the kinase enzymes. The computational model depends on simultaneous application of two protocols. The first protocol applies multiple consecutive validated virtual screening filters including SMARTS, support vector-machine model (ROC = 0.98), Bayesian model (ROC = 0.86) and structure-based pharmacophore filters based on urea-based kinase inhibitors complexes retrieved from literature. This is followed by hits profiling against different extended electron distribution (XED) based field templates representing different kinase targets. The second protocol enables cancericidal activity verification by using the algorithm of feature trees (Ftrees) similarity searching against NCI database. Being a proof-of-concept study, this combined procedure was experimentally validated by its utilization in developing a novel series of urea-based derivatives of strong anticancer activity. This new series is based on 3-benzylbenzo[d]thiazol-2(3H)-one scaffold which has interesting chemical feasibility and wide diversification capability. Antineoplastic activity of this series was assayed in vitro against NCI 60 tumor-cell lines showing very strong inhibition of GI₅₀ as low as 0.9 uM. Additionally, its mechanism was unleashed using KINEX™ protein kinase microarray-based small molecule inhibitor profiling platform and cell cycle analysis showing a peculiar selectivity pattern against Zap70, c-src, Mink1, csk and MeKK2 kinases. Interestingly, it showed activity on syk kinase confirming the recent studies finding of the high activity of diphenyl urea containing compounds against this kinase. Allover, the new series, which is based on a new kinase scaffold with interesting chemical diversification capabilities, showed that it exhibits its “emergent” properties by perturbing multiple unexplored kinase pathways.</p> </div

Mean growth inhibition of 6 compounds at 10 µm dose (12b, 12d, 12e, 12i, 12j and 12k) while highlighting the selected ones for further IC₅₀ evaluation.

<p>Mean growth inhibition of 6 compounds at 10 µm dose (12b, 12d, 12e, 12i, 12j and 12k) while highlighting the selected ones for further IC₅₀ evaluation.</p

Synthesis of intermediates 11a–h.

<p>Reagents and conditions: (a) SOCl₂, reflux, 5 h; (b) NaN₃, acetone, −10°C, 30 min; (c) Benzene, 70°C, 3 hrs.</p

Inhibition percentage of compounds (12b, 12d, 12e, 12i, 12j and 12k) at 10 µm dose in the full panel of 60 cell line.

<p>Inhibition percentage of compounds (12b, 12d, 12e, 12i, 12j and 12k) at 10 µm dose in the full panel of 60 cell line.</p

IC₅₀ of the synthesized compounds on Huh-7 colorectal carcinoma cell line.

<p>IC₅₀ of the synthesized compounds on Huh-7 colorectal carcinoma cell line.</p

GI₅₀, TGI and LD₅₀ values mean and Full Panel GI₅₀ Mean Graph Mid-Point (MG-MID) for the selected four compounds (12b, 12d, 12e and 12k).

<p>GI₅₀, TGI and LD₅₀ values mean and Full Panel GI₅₀ Mean Graph Mid-Point (MG-MID) for the selected four compounds (12b, 12d, 12e and 12k).</p

Similarity of urea-based derivative 12a with a Syk kinase inhibitor using field alignment method.

<p>The boxes highlight regions of high field similarity. Both of the inhibitors are having thiazole moiety if we considered structural similarity.</p

Scaffold morphing observed in the hit was used as one of the selection criteria.

<p>The diversification is achieved by having different attachment points and thus different geometrical diversity in the virtual space of its substituents.</p