Biological indicators of aggressiveness in T1 ductal invasive breast cancer.

BACKGROUND: Apoptosis plays an important role in the maintenance of tissue homeostasis. When defective, this process could contribute to the pathogenesis and the progression of tumors. On this basis, we investigated the combined effect of Bcl-2 and Bax expression, known regulators of apoptotic processes, in the activation of apoptosis in breast cancer. Their relationship with DNA content and proliferative activity was also studied in order to more accurately define breast cancer patients' prognosis and treatment. MATERIALS AND METHODS: In this study we investigated 76 T1 ductal invasive breast cancers and 76 normal epithelium samples for Bcl-2 and Bax expression by immunohistochemistry, for apoptosis by tunel assay and for DNA content and proliferative activity by flow cytometry. RESULTS: High levels of Bcl-2 were associated with prevention of apoptosis. Conversely high Bax expression was found to be related to apoptosis. DNA ploidy was strictly related to the proliferative activity. In addition most of the tumors showing high Bcl-2 expression were aneuploid. CONCLUSION: This report suggests that Bax over-expression could accelerate apoptotic cell death by counteracting the ability of Bcl-2 to inhibit apoptosis. These data also suggest that the ratio Bcl-2/Bax and their relationship with the activation of apoptosis could be used as predictive indicators of breast cancer patients' prognosis and response to conventional therapy.

Evidence for an association between the SRD5A2 (type II steroid 5 alpha-reductase) locus and prostate cancer in Italian patients.

We have investigated the contributions of three polymorphic markers in the SRD5A2 gene to prostate cancer in a group of Italian patients. We have genotyped cases and controls for a polymorphic (TA)n dinucleotide repeat and two functional substitutions, A49T and V89L, substituting respectively alanine with threonine at codon 49, and valine to leucine at codon 89. We found a substantially increased but not significant risk associated with the 49T mutation and a reduction of risk for the V89L substitution. In conclusion, we report on preliminary evidence for both increased and decreased risk associated with separate markers at this locus.

Behavioural and electrocortical changes induced by paraquat after injection in specific areas of the brain of the rat.

The behavioural and electrocortical effects of paraquat were studied after its administration into the substantia nigra, pars compacta, an area where dopamine-(DA) containing cell bodies are present, into the caudate nucleus, where DA-containing nerve endings of the DA nigro-striatal system project, into the locus coeruleus, an area containing noradrenaline cell-bodies and into the n. raphe dorsalis or into the n. raphe medianus, two nuclei containing serotonin (5-HT) cell bodies. The intraventricular administration of paraquat (10 and 50 micrograms) produced an intense pattern of behavioural stimulation and an increase in locomotor activity, circling and the wet-dog syndrome. This symptomatology was accompanied by desynchronization of the electrocorticogram (ECoG) and the appearance of bilateral high voltage epileptogenic spikes, culminating in clonic convulsions. The infusion of paraquat into the s. nigra produced contralateral head and neck deviation, behavioural and motor stimulation, these effects being observed also with smaller doses (1 and 5 micrograms), than those used intraventricularly. The ECoG activity was desynchronized and characterized by high voltage spike discharges. A similar behavioural, postural and ECoG pattern was also observed after infusion of paraquat into the caudate nucleus (10, 25 and 50 micrograms). In addition, paraquat, infused into the locus coeruleus or into the raphe nuclei (5 and 10 micrograms), produced circling, escape responses, jumping and clonic convulsions accompanied by ECoG desynchronization and epileptic phenomena. In conclusion, the present experiments showed that paraquat was able to produce central neurotoxicological effects which did not seem to be specific, at least for the doses used, for the DA nigro-striatal system.

Behavioural and electrocortical changes induced by muscimol in rats withdrawn from chronic treatment with diazepam.

In rats withdrawn from a chronic treatment with diazepam, the effects of muscimol, given into the III cerebral ventricle, on behaviour and spectrum power of activity in the electrocorticogram (ECoG) were studied. In comparison to control rats which received only muscimol, in rats pretreated with diazepam (1 mg/kg/day for 30 consecutive days) the behavioural and ECoG effects of muscimol were significantly reduced or abolished. In fact, in rats pretreated with diazepam a small dose (50 ng) of muscimol did not affect behaviour or ECoG activity, in contrast to control animals in which the same dose produced, after a period of locomotor stimulation and ECoG desynchronization, typical and long-lasting behavioural sedation or sleep accompanied by a significant increase in total voltage power and in the lower frequency bands in the ECoG. In addition, larger doses (100 and 200 ng) of muscimol, which in control rats produced a typical biphasic pattern of ECoG and behavioural changes, i.e. an initial period of ECoG desynchronization and behavioural stimulation, followed by a second period of behavioural and ECoG sleep, in animals pretreated with diazepam, produced only an increase in total voltage power and in the lower frequency bands in the ECoG resembling the effects of the smaller (50 ng) dose. The present experiments suggest that, after chronic stimulation of benzodiazepine receptors a decrease in sensitivity of receptors for gamma-aminobutyric acid (GABA) occurs, since the effects of muscimol on behaviour and spectrum power were significantly reduced or abolished.

Evidence that locus coeruleus is the site where clonidine and drugs acting at alpha 1- and alpha 2-adrenoceptors affect sleep and arousal mechanisms.

The behavioural and electrocortical (ECoG) effects of clonidine were studied after microinjection into the third cerebral ventricle, or microinfusion into some specific areas of the rat brain rich in noradrenaline-containing cell bodies (locus coeruleus) or into areas receiving noradrenergic terminals (dorsal hippocampus, amygdaloid complex, thalamus, frontal and sensimotor cortex). The ECoG effects were continuously analysed and quantified by means of a Berg-Fourier analyser as total power and as power in preselected bands of frequency. Clonidine (9.4 to 75 nmol) given into the third cerebral ventricle produced behavioural sedation and sleep and a dose-dependent increase in ECoG total voltage power as well as in the lower frequency bands. Much lower doses were required to produce similar behavioural and ECoG spectrum power effects after either unilateral or bilateral microinfusion of clonidine into the locus coeruleus. Doses of clonidine equimolar to those given into the third cerebral ventricle, were almost ineffective in inducing behavioural and ECoG sleep after their microinfusion into the dorsal hippocampus. In addition, a dose (0.56 nmol) of clonidine which, given into the locus coeruleus, produced marked behavioural sleep and ECoG synchronization, lacked effects when given into the ventral or anterior thalamus, into the amygdaloid complex or onto the frontal and sensimotor cortex. The behavioural and ECoG spectrum power effects of clonidine given into the third cerebral ventricle or into the locus coeruleus were prevented by antagonists of alpha 2-adrenoceptors but not by alpha 1-adrenoceptor antagonists. Intraventricular microinjection, or microinfusion into the locus coeruleus, of yohimbine, a selective alpha 2-adrenoceptor antagonist, produced behavioural arousal, increase in locomotor and exploratory activity, tachypnoea and ECoG desynchronization with a significant reduction in total voltage power. Similar stimulatory effects were also observed after microinjection of phentolamine into the same sites. No significant effects on behaviour and ECoG activity were evoked after intraventricular injection or microinfusion into the locus coeruleus of prazosin or methoxamine.