ABT-888 restores sensitivity in temozolomide resistant glioma cells and xenografts.

BACKGROUND: Temozolomide (TMZ) is active against glioblastomas (GBM) in which the O6-methylguanine-DNA methyltransferase (MGMT) gene is silenced. However, even in responsive cases, its beneficial effect is undermined by the emergence of drug resistance. Here, we tested whether inhibition of poly (ADP-ribose) polymerase-1 and -2 (PARP) enhanced the effectiveness of TMZ. METHODS: Using patient derived brain tumor initiating cells (BTICs) and orthotopic xenografts as models of newly diagnosed and recurrent high-grade glioma, we assessed the effects of TMZ, ABT-888, and the combination of TMZ and ABT-888 on the viability of BTICs and survival of tumor-bearing mice. We also studied DNA damage repair, checkpoint protein phosphorylation, and DNA replication in mismatch repair (MMR) deficient cells treated with TMZ and TMZ plus ABT-888. RESULTS: Cells and xenografts derived from newly diagnosed MGMT methylated high-grade gliomas were sensitive to TMZ while those derived from unmethylated and recurrent gliomas were typically resistant. ABT-888 had no effect on the viability of BTICs or tumor bearing mice, but co-treatment with TMZ restored sensitivity in resistant cells and xenografts from newly diagnosed unmethylated gliomas and recurrent gliomas with MSH6 mutations. In contrast, the addition of ABT-888 to TMZ had little sensitizing effect on cells and xenografts derived from newly diagnosed methylated gliomas. In a model of acquired TMZ resistance mediated by loss of MMR gene MSH6, re-sensitization to TMZ by ABT-888 was accompanied by persistent DNA strand breaks, re-engagement of checkpoint kinase signaling, and interruption of DNA synthesis. CONCLUSION: In laboratory models, the addition of ABT-888 to TMZ overcame resistance to TMZ.

Differential validity for cognitive ability tests in employment and educational settings: not much more than range restriction?

The concept of differential validity suggests that cognitive ability tests are associated with varying levels of validity across ethnic groups, such that validity is lower in certain ethnic subgroups than in others. A recent meta-analysis has revived the viability of this concept. Unfortunately, data were not available in this meta-analysis to correct for range restriction within ethnic groups. We reviewed the differential validity literature and conducted 4 studies. In Study 1, we empirically demonstrated that using a cognitive ability test with a common cutoff decreases variance in test scores of Black subgroup samples more than in White samples. In Study 2, we developed a simulation that examined the effects of range restriction on estimates of differential validity. Results demonstrated that different levels of range restriction for subgroups can explain the apparent observed differential validity results in employment and educational settings (but not military settings) when no differential validity exists in the population. In Study 3, we conducted a simulation in which we examined how one corrects for range restriction affects the accuracy of these corrections. Results suggest that the correction approach using a common range restriction ratio for various subgroups may create or perpetuate the illusion of differential validity and that corrections are most accurate when done within each subgroup. Finally, in Study 4, we conducted a simulation in which we assumed differential validity in the population. We found that range restriction artificially increased the size of observed differential validity estimates when the validity of cognitive ability tests was assumed to be higher among Whites. Overall, we suggest that the concept of differential validity may be largely artifactual and current data are not definitive enough to suggest such effects exist.

Effects of interest-major congruence, motivation, and academic performance on timely degree attainment.

Using longitudinal student data from 15 four-year (n = 3,072) and 13 (n = 788) two-year postsecondary institutions, the authors tested the effects of interest-major congruence, motivation, and 1st-year academic performance on timely degree completion. Findings suggest that interest-major congruence has a direct effect on timely degree completion at both institutional settings and that motivation has indirect effects (via 1st-year academic performance). The total effects of both interest-major congruence and motivation on timely degree completion underscore the importance of both constructs in understanding student adjustment and postsecondary success. Implications for theory and counseling practice are discussed.

A novel rapid and effective donor arm disinfection method.

BACKGROUND: The aim of the study was to derive a donor arm disinfection technique that was rapid, but with a disinfection efficacy equivalent to a previous "best-practice" technique. This method consisted of a two-stage procedure with an initial application of 70% isopropyl alcohol and then 2% tincture of iodine (IATI). The total time for the IATI method was 2 minutes in duration. A rapid technique (1 min in duration) was needed to obviate potential problems due to increased donor waiting time, had the IATI method been implemented at blood donation sessions. STUDY DESIGN AND METHODS: A direct swabbing and plating technique was used to enumerate bacteria present before and after disinfection. In total, seven methods were evaluated. RESULTS: The chlorhexidine/alcohol applicator (CAA) disinfection device containing 1.5 mL of 2% chlorhexidine gluconate and 70% isopropyl alcohol (99.91% reduction; confidence limits, 99.55%, 99.98%) was shown to have equivalent disinfection efficacy as the IATI method (99.89% reduction; confidence limits, 99.36%, 99.98%; p = 0.86). Procedural time for the 1.5-mL CAA method was 1 minute thereby avoiding potential problems of increased donor waiting time, inherent in the IATI 2-minute procedure at blood donation sessions. CONCLUSIONS: The 1.5-mL CAA disinfection method offers blood services a rapid and effective donor arm disinfection procedure. In 2006, the 1.5-mL CAA procedure was implemented throughout the entire English blood service for all donations.

Precentral sulcal complex of the human brain: morphology and statistical probability maps.

The morphology of the precentral sulcus was examined via 3D visualization in 40 structural magnetic resonance images of the human brain to define its common features and their variability. The precentral sulcus is composed of two distinct sulcal configurations: 1) the inferior precentral sulcus (IP), situated caudal to the inferior frontal sulcus, and 2) the superior precentral sulcus (SP), caudal to the superior frontal sulcus. The SP was usually a single connected structure, and only in 24% of cases studied did it consist of two separate folds. The caudal end of the superior frontal sulcus and the SP merge on the surface of the brain. However, a clear separation can be established in 72% of cases by analyzing the morphology of the depth of this region in serial sections. Two or three small sulci can be identified in the area between the SP and the midline: the medial precentral sulcus, the marginal precentral sulcus, and a paramidline sulcus. The IP is composed of three different parts: a dorsal and a ventral branch, both oriented vertically, and a short horizontal extension. The ventral branch forms the caudal border of the inferior frontal gyrus, the dorsal branch forms the caudal border of the ventral portion of the middle frontal gyrus, and the horizontal extension runs in a rostrodorsal direction into the middle frontal gyrus. These three structures are closely related to each other but can, in most cases, be separated in the depth of the inferior precentral sulcal complex.

Unified statistical approach to cortical thickness analysis.

This paper presents a unified image processing and analysis framework for cortical thickness in characterizing a clinical population. The emphasis is placed on the development of data smoothing and analysis framework. The human brain cortex is a highly convoluted surface. Due to the convoluted non-Euclidean surface geometry, data smoothing and analysis on the cortex are inherently difficult. When measurements lie on a curved surface, it is natural to assign kernel smoothing weights based on the geodesic distance along the surface rather than the Euclidean distance. We present a new data smoothing framework that address this problem implicitly without actually computing the geodesic distance and present its statistical properties. Afterwards, the statistical inference is based on the random field theory based multiple comparison correction. As an illustration, we have applied the method in detecting the regions of abnormal cortical thickness in 16 high functioning autistic children.

Deformation-based surface morphometry applied to gray matter deformation.

We present a unified statistical approach to deformation-based morphometry applied to the cortical surface. The cerebral cortex has the topology of a 2D highly convoluted sheet. As the brain develops over time, the cortical surface area, thickness, curvature, and total gray matter volume change. It is highly likely that such age-related surface changes are not uniform. By measuring how such surface metrics change over time, the regions of the most rapid structural changes can be localized. We avoided using surface flattening, which distorts the inherent geometry of the cortex in our analysis and it is only used in visualization. To increase the signal to noise ratio, diffusion smoothing, which generalizes Gaussian kernel smoothing to an arbitrary curved cortical surface, has been developed and applied to surface data. Afterward, statistical inference on the cortical surface will be performed via random fields theory. As an illustration, we demonstrate how this new surface-based morphometry can be applied in localizing the cortical regions of the gray matter tissue growth and loss in the brain images longitudinally collected in the group of children and adolescents.