Enhancement of the antiplasmodial activity of quassin by transformation into a gamma-lactone

The naturally occurring bitter principle quassin (1) was converted chemically into the gamma-lactone quassilactone (13) in an attempt to enhance its antiplasmodial activity. The in vitro antiplasmodial activity of 13 against Plasmodium falciparum (K1) (IC(50) = 23 microM) was 40-fold greater than that of 1. However, one of the intermediates, compound 8, the 15beta-hydroxy,16-O-m-chlorobenzoyl analogue of 1, was 506-fold more active than 1 against P. falciparum (IC(50) = 1.8 microM) and only 3-fold less potent than chloroquine. In addition, 8 displayed the best cytotoxic/antiplasmodial ratio (112) of all of the compounds tested. In the course of this work a dimer, neoquassin ether (6), linked at C-16 was also prepared; 6 was found to have weak antiplasmodial activity (IC(50) = 9.7 microM).     

When is sentinel node biopsy for breast cancer contraindicated?

Sentinel node biopsy is an exciting new tool for staging the axilla in an accurate and less morbid way. It is becoming more apparent that sentinel node biopsy is appropriate in a variety of settings. When an experienced multidisciplinary team is present and patients are properly selected sentinel node biopsy can be performed with greater than 95% accuracy. The current data regarding contraindications for the use of sentinel lymph node biopsy and lymphatic mapping is reviewed.     

Avoidance and management of positive surgical margins before,during and after radical prostatectomy

Positive surgical margins after radical prostatectomy lead to an increased risk of progression and reduced disease free survival. Earlier detection of prostate cancer, appropriate patient selection and improved operative techniques can reduce the incidence of positive margins, though the risk can not be eliminated as pre-operative staging techniques are not sufficiently sensitive. Nerve sparing and bladder neck sparing do not adversely affect margin status in appropriately selected men. Once positive margins have been diagnosed the optimal management and the timing of treatment remains controversial. Adjuvant radiotherapy or salvage radiotherapy in men with a low PSA may improve local control and PSA free survival in some individuals, a survival benefit has not yet been established.     

Vitamin D receptor-dependent antitumour effects of 1,25-dihydroxyvitamin D3 and two synthetic analogues in three in vivo models of prostate cancer

OBJECTIVE: To determine the in vitro and in vivo effects of 1,25-dihydroxyvitamin D3 (calcitriol) and two newer less hypercalcaemic analogues, EB1089 and CB1093 (as the use of calcitriol as a therapeutic agent in humans has been limited by hypercalcaemia) in three rodent models of prostate cancer. MATERIALS AND METHODS: The highly metastatic MAT LyLu Dunning prostate model, PAIII tumours in Lobund-Wistar rats and LNCaP xenografts in nude mice were used. Vitamin D receptor (VDR) expression and binding were assessed in all cell lines. The effects of calcitriol, EB1089 and CB1093 on tumour growth, cell cycle and angiogenesis in vitro, and growth and serum calcium levels in vivo, were assessed. RESULTS: The growth of prostate adenocarcinoma was inhibited by calcitriol, EB1089 and CB1093 in the Dunning prostate model. Although both analogues increased serum calcium levels, the levels were significantly less than in rats treated with calcitriol. Tumour growth was also inhibited in male athymic nu/nu mice with LNCaP tumour xenografts. PAIII cells failed to express functional VDR and were insensitive to calcitriol and its analogues, either in vitro or in vivo. The analogues of calcitriol did not inhibit angiogenesis in a rat aorta assay. CONCLUSION: This is the first report comparing the actions of calcitriol and its analogues in different in vivo models. The results suggest that the newer less hypercalcaemic analogues of calcitriol may offer a novel therapeutic option for treating prostate cancer. VDR-dependent growth inhibition and not the inhibition of angiogenesis is the main mechanism of action of these compounds in vivo.     

Factors associated with local recurrence after skin-sparing mastectomy and immediate breast reconstruction for invasive breast cancer

OBJECTIVE: To examine the incidence of local recurrence (LR) and factors associated with it in a population of patients who underwent skin-sparing mastectomy (SSM) and immediate reconstruction for invasive carcinoma. SUMMARY BACKGROUND DATA: The efficacy of SSM has been challenged by concerns about increased risks of LR. METHODS: A consecutive series of 173 patients (176 cancers) with invasive carcinoma underwent SSM and immediate breast reconstruction (June 1986 to December 1997). Data were analyzed by the Kaplan-Meier method, the log-rank statistic test, and the Cox proportional hazards model. RESULTS: Mean patient age was 47 +/- 9 years (27% were 40 or younger). The AJCC stages were 1 = 43%, 2 = 52%, and 3 = 5%. Thirty percent of tumors were poorly differentiated. With a median follow-up of 73 months, the LR rate was 4.5%. The mean local relapse-free interval was 26 months. Seventy-five percent of patients who presented with LR developed distant metastases and died of disease within a mean of 21 months. On univariate analysis, factors associated with higher LR rate were tumor stage 2 or 3, tumor size larger than 2 cm, node-positive disease, and poor tumor differentiation. Actuarial 1-, 3-, and 5-year overall survival rates were 98%, 94%, and 88%, respectively. On multivariate analysis, factors associated with decreased survival were advanced stage, presence of LR, and absence of hormone therapy. LR was a highly significant predictor of tumor-related death. CONCLUSIONS: There is a low incidence of LR after SSM, and it is associated with advanced disease at presentation. LR is an independent risk factor for tumor-related death.     

The view from elsewhere: perspectives on ALife modeling

Many artificial life researchers stress the interdisciplinary character of the field. Against such a backdrop, this report reviews and discusses artificial life, as it is depicted in, and as it interfaces with, adjacent disciplines (in particular, philosophy, biology, and linguistics), and in the light of a specific historical example of interdisciplinary research (namely cybernetics) with which artificial life shares many features. This report grew out of a workshop held at the Sixth European Conference on Artificial Life in Prague and features individual contributions from the workshop's eight speakers, plus a section designed to reflect the debates that took place during the workshop's discussion sessions. The major theme that emerged during these sessions was the identity and status of artificial life as a scientific endeavor.     

Ambulation aid use during the rehabilitation of people with lower limb amputations

Our objective was to describe the progression of ambulation aid use by people with lower limb amputations during their initial rehabilitation. We prospectively studied 37 people with recent lower limb amputations and a mean (SD) age of 68 (13) years. Subjects were evaluated each weekday during gait-training physiotherapy sessions, and the type and order of ambulation aids used during ambulation training were documented. The total number of gait-training sessions that we observed was 605, with a mean (SD) of 16.4 (7.7) sessions per participant and a range of 5-47. Of the 37 participants, 33 (89%) were discharged with prostheses. The mean (SD) number of aids per person was 2.9 (1.0). The percentage of participants who used each aid (presented in the mean order in which they were first used) were 76% parallel bars, 60% four-footed walkers, 81% two-wheeled walkers, 11% two crutches, 8% four-wheeled walkers, 46% two canes, and 14% one cane. People with lower limb amputations generally use a number of ambulation aids in a fairly consistent order as they progress through their initial rehabilitation. These findings have implications for the process of providing ambulation aids and provide a foundation for further study.     

Estrogenic activity measured in a sewage treatment works treating industrial inputs containing high concentrations of alkylphenolic compounds--a case study

Chemical analyses were combined with a biological assay to investigate the main estrogenic chemicals as they passed through a sewage treatment works (STW) and entered a river. The STW studied was unusual in that it received wastewater from the textile trade. This wastewater was shown to contain high concentrations of alkylphenol polyethoxylates and their degradation products, such as nonylphenol. High-performance liquid chromatography fractionation, combined with biological assay, showed that the majority of the estrogenic activity was contributed by the alkylphenolic chemicals and the natural estrogens 17beta-estradiol and estrone. Despite removal of a high proportion of the alkylphenolic chemicals by the various treatment processes within the STW, concentrations in the final effluent were still high compared to most other STW effluents in the United Kingdom. The effluent was very estrogenic to caged fish, as was the river water 2 and 5 km downstream of the STW, even though less so. Using various approaches, attempts were made to determine which group of chemicals contributed most to the estrogenic activity of the effluent. The analysis suggested that, in this unusual situation, the alkylphenolic chemicals may contribute the majority of the estrogenic activity of the effluent. However, this conclusion was based on a number of uncertainties that are presently unresolved and hence can be considered only tentative.     

Dicinnamoylquinides in roasted coffee inhibit the human adenosine transporter

Preliminary screening of a minor, non-xanthine constituent of roasted coffee, 3,4-diferuloyl-1,5-quinolactone (DIFEQ), showed inhibition of the adenosine transporter at low micromolar concentration. DIFEQ is a neutral derivative of the chlorogenic acids, i.e. isomeric mono- and di-substituted coumaroyl-, caffeoyl-, and feruloyl-esters of quinic acid, formed in the roasting process of coffee. Displacement of the adenosine transporter antagonist [(3)H](S)-(nitrobenzyl)-6-thioinosine binding by DIFEQ in cultured U-937 cell preparations, expressing the human adenosine transporter protein (hENT1), showed a K(i) of 0.96+/-0.13 microM. Extracts of regular and decaffeinated coffee showed binding activities equivalent to 30-40 mg DIFEQ per three cups of coffee. Acute administration of a high dose of DIFEQ (100 mg/kg i.p.) reduced open field locomotion in mice for 20 min in correlation with brain levels of DIFEQ. Both 3,4-dicaffeoyl-1,5-quinide and 3,4-dicoumaroyl-1,5-quinide, two close structural analogs of DIFEQ also present in roasted coffee, showed similar affinities for the adenosine transporter, while the corresponding 3- and 4-mono caffeoyl- and feruloyl-quinides were one to two orders of magnitudes less active. This suggests that 3,4-dicinnamoyl-1,5-quinides in coffee could have the potential to raise extra-cellular adenosine levels, thereby counteracting the stimulant effect of caffeine.