Induction of apoptosis by 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline via modulation of MAPKs (p38 and c-Jun N-terminal kinase) and c-Myc in HL-60 human leukemia cells

Recently, we reported that 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (AM6-36), sharing structural similarity with naturally occurring isoquinolines, induced activities mediated by retinoid X receptor (RXR) response element accompanied by antiproliferative effects on breast cancer cells. To further characterize the biologic potential of AM6-36, we currently report studies conducted with HL-60 human leukemia cells. AM6-36 significantly inhibited cellular proliferation in a dose- and time-dependent manner with an IC(50) value of 86 nM. When evaluated at low test concentrations (≤0.25 μM), AM6-36 induced arrest in the G2/M phase of the cell cycle. At higher concentrations (1 and 2 μM), the response shifted to apoptosis, which was consistent with the effect of AM6-36 on other apoptotic signatures including an increase of apoptotic annexin V(+) 7-AAD(-) cells, loss of mitochondrial membrane potential, induction of poly(ADP-ribose) polymerase cleavage, and activation of several caspases. These apoptotic effects are potentially due to up-regulation of p38 MAPK and JNK phosphorylation and down-regulation of c-Myc oncogene expression. Taken together, AM6-36 might serve as an effective anticancer agent by inducing G2/M cell cycle arrest and apoptosis through the activation of MAPKs and inhibition of c-Myc.     

Determining the content for an interactive training programme and interpretive guidelines for the Assistive Technology Device Predisposition Assessment

PURPOSE: Develop the content for interpretive guidelines and an interactive training programme for professionals administering the Assistive Technology Device Predisposition Assessment (ATD PA) consumer form, a self-report assessment tool for consumers to identify their perceived functional capabilities and limitations, satisfaction with and priorities for quality of life achievement, psychosocial characteristics and device preferences. METHOD: Twenty-two professionals (with 1-2 consumers each) completed surveys on their use of the ATD PA and recommendations for interpretive guidelines and an interactive training programme. Participants represent eight US states and the country of Italy. Fourteen women and eight men (professionals) participated, and 20% of the sample was comprised of US consumers from Hispanic or African-American ethnic groups. Professionals represented the following disciplines: occupational therapy (n=1); physical therapy (n=1); rehabilitation engineering (n=4); and vocational rehabilitation counselling (n=16). Additionally, an advisory committee of 14 persons was formed, comprising consumers as well as international AT experts. The committee members prioritized content areas for the training programme and interpretive guidelines. RESULTS/CONCLUSIONS: Responses strongly support the need for and the continued development of the training programme and interpretive guidelines. Content areas have been identified and prioritized.     

The reasons for geographic and racial differences in stroke study: objectives and design

The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study is a national, population-based, longitudinal study of 30,000 African-American and white adults aged > or =45 years. The objective is to determine the causes for the excess stroke mortality in the Southeastern US and among African-Americans. Participants are randomly sampled with recruitment by mail then telephone, where data on stroke risk factors, sociodemographic, lifestyle, and psychosocial characteristics are collected. Written informed consent, physical and physiological measures, and fasting samples are collected during a subsequent in-home visit. Participants are followed via telephone at 6-month intervals for identification of stroke events. The novel aspects of the REGARDS study allow for the creation of a national cohort to address geographic and ethnic differences in stroke.     

The effect of different doses of micronized 17beta-estradiol on C-reactive protein, interleukin-6, and lipids in older women

BACKGROUND: The authors evaluated the effect of 3 doses (0.25 mg/day, 0.5 mg/day, and 1 mg/day) of micronized 17beta-estradiol (E2) on C-reactive protein (CRP), interleukin-6 (IL-6), and lipids, compared with placebo, in healthy older women participating in an osteoporosis study. METHODS: This randomized, double-blind, placebo-controlled study was conducted in a University clinical research center. Participants were healthy, community-living women older than 65 years. The primary outcome measure of the study was bone metabolism as estimated by serum and urine markers of bone turnover. For this analysis, the authors measured serum markers of CRP, IL-6, lipids, intracellular adhesion molecule-1, and E-selectin at baseline, after 12 weeks of treatment, and after 12 weeks with no treatment. RESULTS: A significant dose-response effect of estrogen occurred on CRP levels. After 12 weeks of treatment, CRP decreased 59% in the 0.25 mg/day E2 group and increased 65% in the 1 mg/day E2 group, compared with placebo. The CRP level continued to be elevated (92%), compared with placebo, 12 weeks after treatment was discontinued in the 1 mg/day E2 group. High-density lipoprotein (HDL) and HDL2 cholesterol increased and low-density lipoprotein (LDL) cholesterol decreased at 12 weeks in the 1 mg/day E2 group, with a significant dose-response effect. E-selectin decreased significantly in the 1 mg/day E2 group 12 weeks after discontinuation of treatment (-7%), and there was a significant dose-response effect at this time. The 2 lower doses did not affect any of these parameters. Total and HDL3 cholesterol, triglycerides, lipoprotein(a), intracellular adhesion molecule-1, and IL-6 did not change with any dose of E2. CONCLUSIONS: C-reactive protein, an inflammation marker associated with increased risk for cardiovascular disease, decreased in women taking the lowest estrogen dose but increased in women assigned to the highest estrogen dose, suggesting decreased inflammation with lower dose E2. However, with 3 months of treatment, 0.25 or 0.5 mg/day E2 did not have the same beneficial effects on HDL or LDL cholesterol as did 1 mg/day E2. These data suggest that estradiol doses have differential short-term effects on markers of cardiovascular disease. Low-dose E2 decreased CRP, an important marker of inflammation, but did not affect lipid parameters, whereas the highest dose increased CRP and had a beneficial effect on lipid parameters. The long-term consequences of these effects are unknown, but it is possible that estradiol dose should be considered when risk:benefit ratios are evaluated for individual women before estrogen replacement therapy is initiated.     

The impact of venous thrombosis on quality of life

Quality of life (QOL) is increasingly seen as an important outcome in clinical care. Etiology, diagnosis, and management of venous thrombosis have been studied extensively, but only few studies have examined the impact of venous thrombosis on quality of life. The purpose of this study was to examine the impact of venous thrombosis on quality of life in a well-defined population of patients with venous thrombosis, by using both a generic and a disease-specific quality of life measure. A total of 45 patients from the thrombosis clinic of the University of Vermont in Burlington, VT, returned a mailed questionnaire including the Short-Form 36 (SF-36) and a disease-specific venous thrombosis-quality of life (VT-QOL) questionnaire about the problems faced by patients with venous thrombosis. The sample consisted of 13 men (28.9%) and 32 women (71.1%). The mean age was 44.1 years, with a range from 21 to 80 years. Compared with population norms of a general U.S. population that were adjusted for age and sex (N= 2463), venous thrombosis patients scored significantly lower (p < 0.05) on all subscales of the SF-36. Patients with the postthrombotic syndrome (PTS) appeared to have more impairment in their quality of life as measured by both the SF-36 and the disease-specific questionnaire. All correlations between the SF-36 subscales and the subscales of the VT-QOL were significant, most of them on a p < 0.01 level. Given the impact of venous thrombosis and the postthrombotic syndrome on quality of life, assessment of QOL should be included in future studies on the outcome of venous thrombosis.     

Effects of altering the electronics of 2-methoxyestradiol on cell proliferation, on cytotoxicity in human cancer cell cultures, and on tubulin polymerization

A series of new analogues of 2-methoxyestradiol (1) were synthesized to further elucidate the relationships between structure and activity. The compounds were designed to diminish the potential for metabolic deactivation at positions 2 and 17 and were analyzed as inhibitors of tubulin polymerization and for cytotoxicity. 17alpha-methyl-beta-estradiol (30), 2-propynyl-17alpha-methylestradiol (39), 2-ethoxy-17-(1'-methylene)estra-1,3,5(10)-triene-3-ol (50) and 2-ethoxy-17alpha-methylestradiol (51) showed similar or greater tubulin polymerization inhibition than 2-methoxyestradiol (1) and contained moieties that are expected to inhibit deactivating metabolic processes. All of the compounds tested were cytotoxic in the panel of 55 human cancer cell cultures, and generally, the derivatives that displayed the most activity against tubulin were also the most cytotoxic.