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

Relationship between numerical model grid spacing and accuracy of simulation results

Vita.It is well known that use of very coarse grid patterns in numerical models can lead to large errors in simulated performance. There is very little quantitative information on the relationship between grid spacing and errors. This research is concerned with developing guidelines for optimizing the grid patterns and establishing some practical limits of the numerical errors. The study includes one dimensional, linear flow, radial flow, and two-dimensional flow in a well having a vertical infinite conductivity fracture. For the one dimensional system, uniform distance breakup was found better than non-uniform breakup. The use of the Crank-Nicolson scheme results in much smaller errors than with the fully implicit scheme. With 8 uniform cells, and using the Crank-Nicolson scheme, the error at the production end is within 0.2 percent as early as 0.05 dimensionless time (compared to 1.8 percent with the implicit scheme). It is not possible to get reasonable error values earlier than a dimensionless time of 0.05 with the 8 cell system, no matter how small the time steps are. A finer space breakup is necessary, and with 20 uniform cells the error was within 0.05 percent as early as 0.0001 dimensionless time. With the radial system, it was found that a distance breakup according to the relation [equation in PDF] where c is a constant, resulted in smaller errors than for any other breakup tested. A 10 cell system with breakup according to the above relation will yield results in the well within 5 percent of the analytical values or better starting at 0.0001 dimensionless time. During semi-steady state, the results are within 0.5 percent of the analytical. With a 20 cell system, the early time results are within 1.5 percent of the analytical values. The size c f the maximum cell should be less than 25 to 30 percent of the total volume of the system. It was possible to obtain small errors near the outer boundary (<0.01 psi) by refining the grid close to that boundary.

Relationship between numerical model grid spacing and accuracy of simulation results

Vita.It is well known that use of very coarse grid patterns in numerical models can lead to large errors in simulated performance. There is very little quantitative information on the relationship between grid spacing and errors. This research is concerned with developing guidelines for optimizing the grid patterns and establishing some practical limits of the numerical errors. The study includes one dimensional, linear flow, radial flow, and two-dimensional flow in a well having a vertical infinite conductivity fracture. For the one dimensional system, uniform distance breakup was found better than non-uniform breakup. The use of the Crank-Nicolson scheme results in much smaller errors than with the fully implicit scheme. With 8 uniform cells, and using the Crank-Nicolson scheme, the error at the production end is within 0.2 percent as early as 0.05 dimensionless time (compared to 1.8 percent with the implicit scheme). It is not possible to get reasonable error values earlier than a dimensionless time of 0.05 with the 8 cell system, no matter how small the time steps are. A finer space breakup is necessary, and with 20 uniform cells the error was within 0.05 percent as early as 0.0001 dimensionless time. With the radial system, it was found that a distance breakup according to the relation [equation in PDF] where c is a constant, resulted in smaller errors than for any other breakup tested. A 10 cell system with breakup according to the above relation will yield results in the well within 5 percent of the analytical values or better starting at 0.0001 dimensionless time. During semi-steady state, the results are within 0.5 percent of the analytical. With a 20 cell system, the early time results are within 1.5 percent of the analytical values. The size c f the maximum cell should be less than 25 to 30 percent of the total volume of the system. It was possible to obtain small errors near the outer boundary (<0.01 psi) by refining the grid close to that boundary.

EFFECTS OF HIPPOCAMPECTOMY IN A ONE-TRIAL ELECTROCONVULSIVE SHOCK PARADIGM.

Abstract not availabl

Indolin-2-one derivatives as selective Aurora B kinase inhibitors targeting breast cancer

Aurora B is a pivotal cell cycle regulator where errors in its function results in polyploidy, genetic instability, and tumorigenesis. It is overexpressed in many cancers, consequently, targeting Aurora B with small molecule inhibitors constitutes a promising approach for anticancer therapy. Guided by structure-based design and molecular hybridization approach we developed a series of fifteen indolin-2-one derivatives based on a previously reported indolin-2-one-based multikinase inhibitor (1). Seven derivatives, 5g, 6a, 6c-e, 7, and 8a showed preferential antiproliferative activity in NCI-60 cell line screening and out of these, carbamate 6e and cyclopropylurea 8a derivatives showed optimum activity against Aurora B (IC50 = 16.2 and 10.5 nM respectively) and MDA-MB-468 cells (IC50 = 32.6 ± 9.9 and 29.1 ± 7.3 nM respectively). Furthermore, 6e and 8a impaired the clonogenic potential of MDA-MB-468 cells. Mechanistic investigations indicated that 6e and 8a induced G2/M cell cycle arrest, apoptosis, and necrosis of MDA-MB-468 cells and western blot analysis of 8a effect on MDA-MB-468 cells revealed 8a‘s ability to reduce Aurora B and its downstream target, Histone H3 phosphorylation. 6e and 8a displayed better safety profiles than multikinase inhibitors such as sunitinib, showing no cytotoxic effects on normal rat cardiomyoblasts and murine hepatocytes. Finally, 8a demonstrated a more selective profile than 1 when screened against ten related kinases. Based on these findings, 8a represents a promising candidate for further development to target breast cancer via Aurora B selective inhibition

Discovery of a Benzimidazole-based Dual FLT3/TrKA Inhibitor Targeting Acute Myeloid Leukemia

FMS-like tyrosine kinase 3 (FLT3) enzyme overexpression and mutations are the most common molecular abnormalities associated with acute myeloid leukemia (AML). In addition, recent studies investigated the role of tropomyosin receptor kinase A (TrKA) enzyme fusions in promoting AML growth and survival. Based on these premises, targeting both kinases using dual inhibitors would constitute a promising therapeutic approach to target resistant AML. Guided by ligand-based design and structure simplification of the FLT3 inhibitor, quizartinib, we developed a benzimidazole-based small molecule, 4ACP, that exhibited nanomolar activity against wild-type FLT3, FLT3-Internal tandem duplications (FLT3-ITD), and FLT3-D835Y (FLT3-TKD) mutation (IC50 = 43.8, 97.2, and 92.5 nM respectively). Additionally, 4ACP demonstrated potent activity against colon cancer KM12 cell line (IC50 = 358 nM) and subsequent mechanistic deconvolution identified TrKA enzyme as a second plausible target (IC50 = 23.6 nM) for our compound. 4ACP manifested preferential antiproliferative activity against FLT3-ITD positive AML cell lines (MV4-11 IC50 = 38.8 ± 10.7 nM and MOLM-13 IC50 = 54.9 ± 4.1 nM), while lacking activity against FLT3-ITD negative AML cell lines. Western blot analysis confirmed 4ACP ability to downregulate ERK1/2 and mTOR signaling downstream of FLT3-ITD in AML cells. Furthermore, 4ACP prompted apoptotic and necrotic cell death and G0/G1 cell cycle arrest as indicated by cell cycle analysis. 4ACP did not show cytotoxic effects on normal BNL and H9c2 cells and demonstrated decreased activity against c-Kit enzyme, hence, indicating lower probability of synthetic lethal toxicity and a relatively safer profile. In light of these data, 4ACP represents a novel FLT3/TrKA dual kinase inhibitor for targeted therapy of AML