Chemoprevention of spontaneous tumorigenesis in nullizygous p53- deficient mice by dehydroepiandrosterone and its analog 16alpha-fluoro- 5-androsten-17-one

Transgenic mice with both alleles of the p53 tumor suppressor gene product 'knocked out' by gene targeting are susceptible to early development of tumors, chiefly lymphomas and sarcomas. Compared with the control group, administration of dehydroepiandrosterone (DHEA) at 0.3% of the diet to male p53-deficient mice extended their lifespan by delaying death due to neoplasms (from 105 to 166 days on study, P = 0.002), primarily by suppressing lymphoblastic lymphoma (from 45 to 6% of neoplastic deaths, P = 0.010). Treatment with a synthetic DHEA analog, 16alpha-fluoro-5-androsten-17-one (compound 8354), at 0.15% of the diet also increased lifespan, to 140 days for mice that developed tumors (P = 0.037). The effects of these steroids on lifespan and tumor development did not appear to be strongly related to inhibition of food consumption and weight gain, in that a group pair-fed with control diet to the reduced food consumption of the DHEA-treated group developed and died of the same types of neoplasms at the same rate as the controls fed ad libitum. The chemopreventive effect of these steroids has been proposed to be due to suppression of DNA synthesis by inhibition of glucose 6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway. Although DHEA and its analog are strong non- competitive inhibitors of this enzyme in vitro, treatment with DHEA did not deplete cellular nucleotide pools in the liver, as would have been predicted. The chemopreventive effect of DHEA in this model may be due to steroid-induced thymic atrophy and suppression of T cell lymphoma, permitting these mice to survive long enough to develop tumors with longer latency.      

Long-term prognostic and predictive factors in 107 stage II/III breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy.

The heterogeneity of therapeutic modalities and eligibility criteria and the lack of long-term follow-up in most reports of neoadjuvant chemotherapy for breast cancer preclude us from drawing conclusions about its value in clinically relevant patient subgroups. The present study aims to identify predictive and prognostic factors in 107 non-inflammatory stage II/III breast cancer patients treated between November 1980 and October 1991 with an anthracycline-based induction regimen before locoregional surgery. Preoperative chemotherapy comprised 3-6 cycles of doxorubicin (pirarubicin after 1986), vindesine, cyclophosphamide and 5-fluorouracil. Type of subsequent surgery and adjuvant treatment were decided individually. In analysis of outcome, univariate comparisons of end points were made using the log-rank test, and significant (P < or = 0.05) pre- and post-therapeutic factors were incorporated in a Cox multivariate analysis. With a median follow-up of 81 months (range 32-164+ months), the median disease-free survival (DFS) is 90.5 months while median overall survival has not yet been reached. Cytoprognostic grade and histopathological response in both the primary and lymph nodes were independent covariates associated with locoregional relapse with or without DFS and overall survival. Eleven patients with pathological complete response remain free of disease with a 68-month median follow-up, while the 18 with residual microscopic disease on the specimen showed a 60% cumulative incidence of locoregional recurrence. Despite encouraging response rates based on clinical or radiological evaluation (87% or 70%), neither method showed any significant correlation with pathological response and failed to contribute prognostic information on patients'' outcome. Pathological evaluation of antitumoral activity of primary chemotherapy remains a major source of prognostic information and might be used to select patients in need of additional adjuvant treatment.     

Pharmaceutical applications for molecularly imprinted polymers

Molecular imprinting is a means of introducing sites of specific molecular arrangement into an otherwise uniform polymeric matrix. This is achieved by formation of a pre-polymerisation complex between complementary monomers and the template molecule. Subsequent polymerisation in the presence of a crosslinker, in a porogenic environment, results in the production of a macroporous polymer capable of specific molecular recognition. This paper considers potential roles for molecularly imprinted polymers within a pharmaceutical remit. Applications including controlled release, drug monitoring devices and biological receptor mimetics are discussed. Histamine and ephedrine molecularly imprinted polymers (MIPs) were studied as potential biological receptor mimics whilst a propranolol MIP was investigated for its use as a rate attenuating selective excipient in a transdermal controlled release device. Preliminary studies concerning the preparation of a theophylline selective transcutaneous monitoring device, using a theophylline MIP, are also described.     

Sexually dimorphic and radiation dose dependent effect of cranial irradiation on body mass index

OBJECTIVES—To investigate the relation between cranial irradiation received during treatment for childhood leukaemia and obesity at final height.DESIGN—Retrospective cross sectional study.SETTING—Paediatric oncology centres at Great Ormond Street Hospital for Children and the Royal Marsden Hospital.SUBJECTS—Survivors of childhood leukaemia who received cranial irradiation, were in continuous first remission, and had reached final height. An unirradiated group of patients from the United Kingdom acute lymphoblastic leukaemia XI trial was also included; these patients were in continuous first remission and had been followed for at least four years from diagnosis.MAIN OUTCOME MEASURES—Body mass index standard deviation score (BMI z score) at final height for irradiated patients and at most recent follow up for unirradiated patients. Regression analysis was used to examine the effect on BMI z score of sex, age at diagnosis, and the dose of radiation received.RESULTS—For cranially irradiated patients, an increase in the BMI z score at final height was associated with female sex and lower radiation dose, but not with age at diagnosis. Severe obesity, defined as a BMI z score of > 3 at final height, was only present in girls who received 18-20 Gy irradiation and had a prevalence of 8%. Both male and female unirradiated patients had raised BMI z scores at latest follow up and there was no association with age at diagnosis.CONCLUSIONS—These data are further evidence for a sexually dimorphic and dose dependent effect of radiation on the human brain.     

Persistent value of air-augmented radiograph in neonatal high gastrointestinal obstruction, despite more modern techniques

Air is a safe and effective natural contrast agent in neonatal high gastrointestinal (GIT) obstruction. Successful early decompression often results in plain abdominal radiographs of low diagnostic yield. We present a series of neonates with high GIT obstruction in whom air-augmented abdominal radiographs (AAAR) were performed instead. Fourteen neonates presented with suspected high GIT obstruction. In 12 sick babies, obstruction was confirmed and the level of obstruction was determined. The other two neonates required additional positive contrast upper GIT studies. These confirmed small bowel malrotation. For neonatal high GIT obstruction an AAAR can provide a rapid and accurate diagnosis. Positive contrast agent studies should be performed when the AAAR is non-diagnostic.     

B1 and B2 antagonists and bradykinin-induced blood flow in rat skin inflammation

OBJECTIVE AND DESIGN: The aim of the present study was to examine the contribution of the two kinin receptors B1 and B2 to the increased blood flow observed in response to bradykinin (BK) in a blister model under different injury conditions. MATERIAL: Young male Sprague-Dawley rats weighing 250-350 g were used. METHODS: A vacuum-induced blister was raised in the rat hind paw and blood flow measured in the superfused blister base under four different conditions including, early phase acute injury; late phase acute injury; recurrent injury and early phase acute injury in the setting of chronic nerve damage. BK (10 microM) was superfused alone, or in the presence of the B1 antagonist DesArg9Leu8BK (DALBK), (10 nM) and/or the B2 antagonist [D-Arg,Hyp3,Thi5 D-Tic7,Oic8] Bradykinin (HOE 140) (10 nM). RESULTS: HOE 140 significantly inhibited the BK response in all models. Significant inhibition of BK-induced vasodilatation by DALBK was only observed in the late phase acute and recurrent injury models. CONCLUSIONS: The results suggest that the involvement of the inducible B1 receptor in skin inflammation site is related to the site, duration and recurrence of the injury condition.     

Ruthenium red selectively inhibits oedema formation and increased blood flow induced by capsaicin in rabbit skin.

It has been suggested that ruthenium red has a selective inhibitory effect on capsaicin-induced nociceptor stimulation. We have investigated the effect of ruthenium red on oedema formation and vasodilatation induced by intradermal (i.d.) injection of capsaicin in the rabbit in vivo. Responses induced by capsaicin were inhibited by ruthenium red, but responses induced by bradykinin, N-formyl-methionyl-leucyl-phenylalanine (FMLP), platelet activating factor (PAF), histamine and calcitonin gene-related peptide (CGRP) were not affected. These results suggest that ruthenium red selectively inhibits capsaicin-induced local plasma protein leakage and vasodilatation in the rabbit skin microvasculature.