TRIO amplification and abundant mRNA expression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer

Studies by comparative genome hybridization have suggested that 5p amplification is related to tumor progression in urinary bladder cancer. In this study seven genes (TAS2R, ADCY2, DNAH5, CTNND2, TRIO, ANKH, and MYO10) located to 5p15.31-5p15.1 were analyzed by fluorescence in situ hybridization using a tissue microarray containing samples from tumors and cell lines with known 5p amplification by comparative genome hybridization. Amplification frequency was highest for TRIO, which maps to 5p15.2 and encodes a protein with a putative role in cell-cycle regulation. To further investigate the role of TRIO amplification in bladder cancer, a tissue microarray containing samples from 2317 bladder tumors was used for fluorescence in situ hybridization analysis. TRIO amplification was strongly associated with invasive tumor phenotype, high tumor grade, and rapid tumor cell proliferation (Ki67 LI) (P < 0.0001 each). Only 7 of 456 pTaG1/G2 tumors (1.5%) but 62 of 485 pT1-4 carcinomas (12.8%) had TRIO amplification. TRIO amplification was not associated with poor prognosis. Using a frozen bladder tumor tissue microarray RNA in situ hybridization confirmed that TRIO is up-regulated in amplified tumors. It is concluded that TRIO up-regulation through amplification has a potential role in bladder cancer progression.     

Tumor antigens and antigen-presenting capacity in breast cancer.

AIMS: Cancer cells frequently express antigens capable of being recognized by the host immune system; however, any resultant immune response is often ineffective. This may be related in part to tumor-induced defects in antigen presentation. We screened for dendritic cell infiltration, tumor MHC II expression and associated lymphocytic reaction in the context of three established breast tumor antigens. METHODS: Forty primary breast tumors were evaluated by immunohistochemical techniques for expression of her2/neu, p53, and MUC1 and MHC class II molecules. Twenty-five samples were further analyzed for p53 mutations by PCR-SSCP analysis and DNA sequencing. The phenotype of tumor-infiltrating inflammatory cells was evaluated using the following markers: CD1a, MHC Class II, CD3, CD45, and CD45RO. RESULTS: Tumors with p53 mutations and overexpression, but not her2/neu or MUC1 overexpressing tumors, more frequently harbored marked CD1a+ dendritic cell infiltrates. An overall correlation between CD1a+ cell infiltrates and HLA class II expression on tumor cells (p = 0.0008) was also observed and these tumors had greater CD45RO+ lymphocytic infiltrates. CONCLUSIONS: In breast cancer, p53 mutations may present a more visible signal to the immune system and hence provide a better target for immunotherapy. Infiltrating CD1a positive cells are associated with a more dense tumor lymphocytic infiltrate and tumor cell expression of MHC II molecules.     

Hepatitis B control in Europe by universal vaccination programmes: the situation in 2001

In the nine years since the Global Advisory Group of the Expanded Programme on Immunisation (WHO) set 1997 as the target for integrating hepatitis B vaccination into national immunisation programmes worldwide, 129 countries have included hepatitis B vaccine as part of their routine infant or adolescent immunisation programmes (June 2001). By the end of 2002, 41 out of the 51 countries of the WHO European Region will be implementing universal hepatitis B immunisation. The rewards of effective implementation of the programmes in countries that started 10 years ago are becoming apparent; and their success offers an exemplary model for other countries. Some other countries, however, have difficulties to incorporate hepatitis B vaccine into universal childhood immunisation programmes, because of major economic constrains and the inability to procure a constant vaccine supply. The next decade will be characterised by expanded use of hepatitis B vaccines and the increasing efforts to sustain vaccine programmes and make the vaccine available to those countries and regions that cannot afford it. In Europe, as well as in the rest of the world, work still remains to be done to support and implement interventions that will bring us closer to the WHO goal and to eradicate hepatitis B.     

Physical activity improves gaze and posture control in the elderly

Ageing is associated with a decrease in the quality of balance regulation, in particular through dysfunctions of gaze control and postural stabilization, which results in an increased risk of falling. Conversely, the practice of physical and sporting activities has been shown to improve every level of postural regulation. This study is to assess the effects of the practice of physical activities on vestibulospinal reflex and ocular movements of visual and vestibular origins in elderly people. Gaze control and posture stabilization were evaluated in 13 healthy aged women who regularly practised physical activities and in 13 healthy aged sedentary women of a similar age, by dynamic posturographic test with electromyography, as well as electronystagmography with caloric and rotational vestibular tests, ocular saccades, smooth pursuit and optokinetic tests. The gaze and posture control performance of the active group was better; the proprioceptive and vestibular sensitivities were higher, visual detection quality was good, and reaction time was low. Regular physical activity develops or maintains the efficiency of the reflexes involved in postural control, especially through adequate neurosensorial information, which allows the central integrative structures to generate a more appropriate motor response.     

In vivo efficacy of cefotaxime and amoxicillin against penicillin-susceptible, penicillin-resistant and penicillin-cephalosporin-resistant strains of Streptococcus pneumoniae in a mouse pneumonia model

Objective: To compare cefotaxime (CTX) to amoxicillin (AMO) (usually considered the definitive therapy for penicillinsusceptible Streptococcus pneumoniae infections) in an immunocompromised mouse pneumonia model.
Methods: Three S. pneumoniae clinical isolates were used: two serotype 19 strains, a penicillin-susceptible (P^s) strain (penicillin MIC = 0.03 μ/mL) and a highly penicillin-resistant (P^r) strain (penicillin MIC = 4 μ/mL), and one serotype 23F strain, a penicillin-cephalosporin-resistant (CFTR) strain (CTX MIC = 4 μ/mL).
Results: CTX activity in this mouse model of pneumonia induced by the highly penicillin-resistant strain of S. pneumoniae was lower than expected from its low MIC against this organism. Furthermore, AMO had greater efficacy than CTX against a CFTR S. pneumoniae strain.
Conclusion: Our data suggest that there is no major difference in the in vivo efficacy of the two agents, cefotaxime and amoxicillin, against penicillin-resistant and penicillin-cephalosporin-resistant S. pneumoniae.     

Evidence against the involvement of serotonergic neurons in the anti-punishment activity of diazepam in the rat

The effects of manipulating central serotonergic transmission were assessed on the anti-punishment effects of diazepam (2 mg/kg IP) in rats. In a paradigm involving the inhibition of pressing for food induced by the delivery of a signal previously associated with electric foot-shocks, lesioning serotonergic neurons of the dorsal raphé with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 1 g in 0.4 l) neither affected behavioral inhibition in control rats nor modified the ability of diazepam to release responding. Furthermore, suppression of pressing for food induced by a fixed ratio 7 schedule of shock presentation was reduced by bilateral infusion of 5,7-DHT (2 g in 0.5 l) into the substantia nigra, but the ability of diazepam to increase punished responding was preserved. Finally, blockade of benzodiazepine-induced decrease in serotonin release by application of the benzodiazepine receptor antagonist Ro 15-1788 (10^–5–10^–4 M in 0.2 l) into the dorsal raphé did not alter the releasing effect of diazepam on suppression of pressing for food caused by a signal of punishment. At these concentrations. Ro 15-1788 was devoid of any effect on behavioral inhibition in control rats. Taken together, these results indicate that the anti-punishment activity of benzodiazepines can be dissociated from the reduction in tryptaminergic transmission produced by these drugs.     

Dopamine in the conscious dog with chronic heart-block

Summary The chronotropic effects of dopamine were studied in the conscious dog with chronic A-V block. Dopamine at 12.5–200 g/kg and 12.5–50 g/kg/min lowered atrial rate independently of dose. After blockade of muscarine receptors or alpha-adrenoceptors, it raised atrial rate. After blockade of dopamine receptors, dopamine still lowered atrial rate, and did so dose-relatedly after blockade of beta-adrenoceptors. It raised ventricular rate, and at high doses also induced ventricular rhythm disorders. Blockade of muscarine receptors enhanced the ventricular cardioaccelerator effect of dopamine (P<0.025) at 100 g/kg, while blockade of alpha-adrenoceptors reduced it (P<0.05). Blockade of dopamine receptors did not modify this effect, but blockade of beta-adrenoceptors reversed it. Dopamine at 25–200 g/kg raised mean blood pressure. This effect was enhanced by blockade of muscarine receptors, reversed by blockade of alpha-adrenoceptors, and was unaffected by blockade of beta-adrenoceptors or dopamine receptors. These results show that the atrial cardiomoderator effect of dopamine is a vagal reflex response to its hypertensive action, and that it is limited by its direct beta-adrenergic stimulating action. They also show that the ventricular cardioaccelerator effect of dopamine is attenuated by a reflex vagal depressor effect consequent to the induced hypertension. No evidence was found for the existence of positive chronotropic dopamine receptors in either atria or ventricles.A preliminary report of these findings was presented at the Symposium on Peripheral Dopaminergic Receptors, July 1978, in Strasbourg, France (Boucher et al. 1979b)     

Cytotoxic properties of a new synthetic demethylpodophyllotoxin derivative,BN 58705, against human tumor cell lines

The in vitro cytotoxic properties of a newly synthesized demethylpodophyllotoxin derivative, 4-o-butanoyl-4-demethylpodophyllotoxin (BN 58705), were determined by using several human tumor cell lines of different histological origin and of different sensitivity to conventional chemotherapeutic drugs (Adriamycin andcis-diammine-dichloride platinum). BN 58705 is shown to be cytotoxic against various human tumor cell lines as assessed by the MTT assay. Furthermore, BN 58705 is shown to be cytotoxic against several drug-resistant tumor cell lines. BN 58705 is cytotoxic at concentrations 100- to 1000-fold lower than those of Adriamycin orcis-diammine-dichloride platinum required to achieve similar cytotoxicity. BN 58705 did not mediate DNA fragmentation of target cells, whereas the epipodophyllotoxin-like etoposide induced DNA cleavage by stabilizing the DNA-enzyme intermediate. Like vinca alkaloids, BN 58705 induced a block in the mitotic phase of the cell cycle. By comparison, BN 58705 exerted a stronger cytotoxic activity in vitro than did either etoposide, an epipodophyllotoxin, or vincristine, a vinca alkaloid. When BN 58705 was applied in vivo in mice, it resulted in low toxicity (50% lethal dose, 150 mg/kg). These results demonstrate than BN 58705 is cytotoxic to drug-resistant human tumor cell lines and is manyfold more potent than conventional drugs. The cytotoxic potency and low toxicity of BN 58705 are important criteria to establish its potential chemotherapeutic efficacy in vivo.Abbreviations cpm counts per minute - BN 58705 4-o-butanoyl-4-demethylpodophyllotoxin - MTT 3-(4,5-dimethyl-thiazoyl-2-yl)-2,5-diphenyl-tetrazolium bromide - OD optical density - TRIS TRIS (hydroxymethyl) aminomethane - EDTA ethylenediaminetetraacetic acid - FITC fluoresceinisothiocyanate - PI propidium iodide This work was supported by a grant from Institut Henri Beaufour, France