Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxynucleotide

Glioblastoma multiforme is the most common form of malignant brain cancer in adults and, unfortunately, is not amenable to treatment with current therapeutic modalities. Human glioblastoma U-87 has many of the distinguishing phenotypic features of primary glioblastoma, including an autocrine form of proliferation, high levels of protein kinase C alpha (PKC alpha), and infiltration via white matter tracts. We show that treatment of mice bearing U-87 xenografts with an antisense phosphorothioate oligodeoxynucleotide (S-oligodeoxynucleotide) against the 3'-untranslated region of PKC alpha mRNA results in suppression of tumor growth. Growth was inhibited in both subcutaneous and intracranial tumors, and in the latter instance, treatment with the antisense PKC alpha S-oligodeoxynucleotide resulted in a doubling in median survival time ( > 80 days), with 40% long term survivors. The antisense S-oligodeoxynucleotide did not produce systemic toxicity in mice with subcutaneous or intracranial tumors after daily intraperitoneal injection for 21 or 80 days, respectively, and a scrambled S-oligodeoxynucleotide with the same nucleotide composition as the antisense S-oligodeoxynucleotide did not produce an antitumor effect. The intratumoral levels of both antisense and scrambled S-oligodeoxynucleotide in subcutaneous tumors were 2 microM after 21 daily doses of 20 mg/kg S-oligodeoxynucleotide. The antisense S-oligodeoxynucleotide selectively reduced the levels of PKC alpha in subcutaneous tumors but not those of protein kinase C epsilon or protein kinase C zeta. This is the first demonstration that the growth of glioblastoma multiforme can be suppressed by an antisense PKC alpha S-oligodeoxynucleotide and suggests that this may represent an effective therapy for this type of malignancy.     

Expression of the beta 7 integrin by human endothelial cells

Integrin adhesion receptors mediate fundamental intercellular interactions of many cell types as well as cellular interactions with specific extracellular matrix molecules. To date, the beta 7 integrin has been shown to be expressed by leukocyte subsets and to mediate interactions of these cells with extracellular matrix molecules as well as with endothelial and epithelial cells. The data presented here indicate that human endothelial cells also express the beta 7 integrin both in vitro and in situ. Analysis of cDNA indicated that endothelial beta 7 was identical to that expressed by leukocytes. Cell surface expression of beta 7 was increased by exposure of the endothelium to the pro-inflammatory cytokines, tumor necrosis factor-alpha and interleukin-1 beta. In leukocytes, beta 7 complexes with alpha 4 or alpha E integrin chains. Endothelial cells also expressed a number of alpha-integrin chains, including alpha 4, but not alpha E. The expression and utilization of beta 7, presumably complexed with alpha 4, by endothelial cells may be instrumental in the maintenance of the function or phenotype of endothelial cells.     

Inhibition of triazolam clearance by macrolide antimicrobial agents: in vitro correlates and dynamic consequences

OBJECTIVE: To evaluate the ability of the DSM-IV criteria for the pervasive developmental disorders (PDD) to reliably and accurately differentiate PDD subtypes. METHOD: The sample consisted of 143 children with various types of developmental disabilities. A diagnosis of PDD and PDD subtype was made by one clinician using information obtained from the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule. The raw data from the Autism Diagnostic Interview-Revised, clinical notes (excluding diagnostic opinion), Autism Diagnostic Observation Schedule, IQ, and other available data were independently assessed by three experienced raters, each of whom then made a separate, blind diagnosis. If there was any disagreement, a consensus best-estimate (CBE) diagnosis was made after discussion. To assess reliability, the agreement between the three raters was calculated using k. Accuracy was assessed by calculating the agreement between the clinician's diagnosis and the CBE and by calculating the error rates associated with the three raters using latent class analysis. RESULTS: The current DSM-IV criteria show good to excellent reliability for the diagnosis of PDD, Asperger's disorder (AsD), and autism, but they show poor reliability for the diagnosis of atypical autism. The clinician (compared to the CBE) had little difficulty differentiating PDD from non-PDD children and autism from AsD but had more difficulty identifying children with atypical autism. The latent class analysis also showed that the average error rates of the three raters for a differentiation of atypical autism from autism were unacceptably high. CONCLUSIONS: Although the psychometric properties of the current DSM-IV criteria for autism and AsD appear quite acceptable, there is likely to be a high rate of misclassification of children given a diagnosis of atypical autism.     

Inelastic hot-electron Bloch scattering from quantum-confined systems

The phenomena of electric field-assisted inelastic Bloch-electron scattering from an atomically confined bound-state electron is reported. A novel formalism for treating Bloch electron dynamics and quantum transport in electric fields of arbitrary strength and time dependence is utilized. The two-electron inelastic scattering rate obtained herein shows an electric field-dependent broadening; as a novel addition, the calculated scattering rate includes an explicit dependence on band structure, predicting a strong influence from band non-parabolicity and anisotropy.     

Inhibition of prolactin secretion delays extinction of circadian LH surges in ovariectomized rats bearing estradiol implants

Ovariectomized rats bearing Silastic capsules containing estradiol exhibit a daily afternoon surge of luteinizing hormone (LH) which decreases with time until it is undetectable by Day 10 after implantation of estradiol. Increases in basal prolactin levels as well as afternoon surges are also observed. To determine if increased prolactin secretion contributed to the extinction of the circadian LH surges, we examined the patterns of LH and prolactin secretion in rats in which prolactin was suppressed by bromocriptine treatment. In vehicle-treated control rats, the magnitude of the LH surges decreased with time. Large LH surges were observed on Days 2 and 4. A significant decrease in the surge occurred on Day 6, and it disappeared by Day 10. Animals treated with bromocriptine also exhibited large LH surges on Days 2 and 4, and in addition, secreted a greater amount of LH than the control group on Days 6, 8, and 10. In ovariectomized rats bearing estradiol implants, large afternoon surges in prolactin were observed and by Day 6, basal prolactin levels were also elevated. Bromocriptine treatment completely suppressed prolactin secretion through Day 6, but a small afternoon rise was observed on Days 8 and 10. These findings suggest that elevated prolactin secretion may be one factor contributing to the extinction of circadian LH surges in the estrogen-treated rat.     

The ability of actinic light to modify the bacteriorhodopsin photocycle. Heterogeneity and/or photocooperativity?

The focus of this paper is on the established observation that the bacteriorhodopsin (BR) photocycle responds to the level of actinic light by altering the proportions of two forms of the M intermediate. The first form of M, called M-fast or MF, decays to the O intermediate. In contrast, the second form of M, called M-slow or MS, decays directly to the ground state, and its decay rate is slower than that of MF. Any proposed scheme for the BR photocycle must account for this light-dependent phenomenon. Several papers have attempted to explain the observation on the basis of photocooperativity, or on the basis of heterogeneous populations. In this paper, we test previously proposed cooperative models with experimental data, and find those models to be inadequate. We show that two new models, one purely cooperative, the other purely heterogeneous, can both fit the data, hence such modelling will not resolve the mechanism. Taking into account the demonstration of heterogeneity, the trimer structure of BR, and certain experimental evidence in favor of cooperativity, it appears likely that both heterogeneity and cooperativity are involved in the adaptation of the BR photocycle to different levels of actinic light.     

Clustering multidimensional sequences in spatial and temporal databases

Many environmental, scientific, technical or medical database applications require effective and efficient mining of time series, sequences or trajectories of measurements taken at different time points and positions forming large temporal or spatial databases. Particularly the analysis of concurrent and multidimensional sequences poses new challenges in finding clusters of arbitrary length and varying number of attributes. We present a novel algorithm capable of finding parallel clusters in different subspaces and demonstrate our results for temporal and spatial applications. Our analysis of structural quality parameters in rivers is successfully used by hydrologists to develop measures for river quality improvements.

Instantaneous characterization of time varying nonlinear systems[neurophysiological responses]

A nonlinear system may be characterized by an orthogonal functional power series (FPS) computed from cross correlations between input and output variables. "Is the response changing over the course of the experiment?" is a fundamental question encountered in the analysis of both FPS and evoked potentials (EP's). Regression on closed-form functions of time produces a time-varying FPS or EP. Evaluation of these functions at a specified time point produces a system characterization for that instant.