Cytotoxic activity of gemcitabine in cultured cell lines derived from histologically different types of bladder cancer: Role of thymidine kinase 2

World wide incidence of bladder cancer is rising with nearly 13,760 deaths attributed to bladder cancer in 2007 in the USA. Tumor types of the urothelium include transitional cell carcinomas, squamous cell carcinomas, and adenocarcinomas. This study was undertaken to determine gemcitabine's efficacy against bladder cancer cell lines of different origins (HTB2, a papilloma; HTB3, a squamous cell carcinoma; and HTB4, a transitional cell carcinoma). Roles of nucleoside transporters and key enzymes in gemcitabine pharmacology were examined on the premise that cells originating from different types of bladder cancer exhibit different levels and/or types of nucleoside transporters and enzymes and thus may respond differently to gemcitabine. HTB2 cells had the highest transport efficiency and were also most responsive to gemcitabine. HTB3 and HTB4 cells had similar transport efficiencies, but exhibited different sensitivities to gemcitabine (HTB4 > HTB3). The highest accumulation of [³H]gemcitabine was in HTB2 cells and the lowest was in HTB3 cells. Sequencing experiments revealed no mutations either in coding exons or intron-exon boundaries of the hENT1 genes of the three cell lines. HTB3 cells exhibited high thymidine kinase 2 (TK2) activity whereas HTB2 and HTB4 cells lacked detectable TK2 activity and pretreatment of HTB3 but not of HTB2 and HTB4 cells with extracellular thymidine resulted in enhanced sensitivity to gemcitabine. Our results highlight the importance of hENT1 and TK2 activities in response to gemcitabine. Elevated TK expression in squamous cell carcinomas warrants further study and offers new insights into rational treatment strategies based on bladder cancer phenotype.     

Multi-step treatment for acquired alexia and agraphia (part II): a dual-route error scoring system

Dual-route neuropsychological models posit two distinct but interrelated pathways for reading and writing: the lexical and the sublexical. Individuals with reading/writing deficits often rely on the combined power of the integrated system to perform print-processing tasks. The resultant errors reflect varying degrees of lexical and sublexical accuracy in a single production; however, no system presently exists to analyze errors robustly in both routes. The goal of this project was to develop a system that simultaneously, quantitatively, and qualitatively captures changes in lexical and sublexical errors following treatment. Errors are evaluated hierarchically in both routes according to proximity to a target. This dual-route error scoring (DRES) system was developed using data from a novel treatment study for eight patients with acquired alexia/agraphia; a computerised version of the system was also developed (ADRES). Repeated-measures multivariate analyses of variance and post hoc analyses revealed significant dual-route treatment effects. Qualitative analyses revealed unique patterns of change across participants, reflecting the benefits of error evaluation beyond a binary correct/incorrect judgment. Finally, categorical error shifts were observed via group-level analysis. The results of this study indicate that treatment-induced evolution of reading/writing can be meaningfully and comprehensively represented by this novel scoring system.     

Paralytic poliomyelitis in children under 6 years in Pondicherry: a community survey.

STUDY OBJECTIVES--To assess the amount of poliomyelitis and its epidemiological features including risk factors. DESIGN--This was a retrospective study of cases of paralytic poliomyelitis among children 0-6 years of age. SETTING--Pondicherry, India, 1983-89. SUBJECTS--A total of 47,960 children aged less than 6 years. MEASUREMENTS AND MAIN RESULTS--In 1989, 469 field workers undertook a door to door survey of children 0-6 years old to identify those with limb paralysis. This was followed by clinical examination to establish the cause, supplemented by case notes held by the Child Development Services. Altogether 203 cases of limb paralysis were identified, 188 of which were judged a result of paralytic poliomyelitis. The prevalence of poliomyelitis in 1989 was 3.9/1000 among children below 6 years of age. There was a male preponderance with a male:female ratio of 1.4:1. The prevalence was least in infants (1/1000) and highest in children aged 2 to 3 years (6.4/1000). The age at onset was less than 12 months in 42% of cases and less than 3 years in 98%. The median age at onset was 13.4 months. Time series analysis showed a high occurrence of cases from May to September between 1983 and 1989. The legs were affected in 97%. About 41% of children had received three doses of oral polio vaccine. There was a history of intramuscular injection, possibly provoking a paralytic attack, in 54% of cases. CONCLUSION--This retrospective community study involving the staff of the Integrated Child Development Services provided valid data about poliomyelitis with little additional cost and minimum training. Because the study covered a whole population of children under 6 years, rather than a sample, the data will help in monitoring and surveillance of poliomyelitis and also in planning strategies for effective control.     

The role of syntactic complexity in treatment of sentence deficits in agrammatic aphasia: the complexity account of treatment efficacy (CATE).

This experiment examined the hypothesis that training production of syntactically complex sentences results in generalization to less complex sentences that have processes in common with treated structures. Using a single subject experimental design, 4 individuals with agrammatic aphasia were trained to comprehend and produce filler-gap sentences with wh-movement, including, from least to most complex, object-extracted who-questions, object clefts, and sentences with object-relative clausal embedding. Two participants received treatment first on the least complex structure (who-questions), and 2 received treatment first on the most complex form (object-relative constructions), while untrained sentences and narrative language samples were tested for generalization. When generalization did not occur across structures, each was successively entered into treatment. Results showed no generalization across sentence types when who-questions were trained; however, as predicted, object-relative training resulted in robust generalization to both object clefts and who-questions. These findings support those derived from previous work, indicating not only that generalization occurs across structures that are linguistically related, but also that generalization is enhanced when the direction of treatment is from more complex to less complex constructions. This latter finding supports the authors' newly coined "complexity account of treatment efficacy" (CATE).     

Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1

Topical adenosine A2A receptor agonists promote wound healing by, among other effects, increasing microvessel formation. Results of representational display analysis of human umbilical vein endothelial cells suggested that A2A receptor occupancy modulates expression of the antiangiogenic matrix protein thrombospondin 1 (TSP1). We therefore determined whether A2A receptor occupation stimulates angiogenesis by modulating TSP1 secretion. Human microvascular endothelial cells (HMVEC) were treated with medium alone, 2-p-[2-carboxyethyl] phenethyl-amino-5'-N-ethylcarboxamido-adenosine (CGS-21680), or 2-[2-(4-chlorophenyl)ethoxy]adenosine (MRE0094), selective A2A receptor agonists. TSP1 protein secretion was down-regulated after treatment with the A2A agonists CGS-21680 or MRE0094 in a dose-dependent manner (EC50 = 6.65 nM and 0.23 microM respectively). The selective A2A receptor antagonist 4-[2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl]phenol (ZM241385) but not the A1 and A2B receptor antagonists diphenylcyclopentylxanthine, enprofylline, and N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide (MRS1706) completely abrogated the A2A receptor agonist-mediated effect on TSP1. Vascular tube formation by HMVEC was increased by adenosine A2A receptor agonists in a dose-dependent fashion (EC50 = 0.1 microM for both), and this effect was reversed by the A2A antagonist. Moreover, in the presence of antibodies to TSP1 and CD36, the receptor for TSP1, the adenosine A2A receptor agonists stimulated no increase in vascular tube formation. These results indicate that the angiogenic effects of adenosine A2A receptor activation are, at least in part, caused by the suppression of TSP1 secretion.