Biomedical subjects

S Fenu

Publications and source records attributed to S Fenu.

At least 37 records · Page 2Linked to original sources

PubMed1997

Adenosine A2A receptor antagonism potentiates L-DOPA-induced turning behaviour and c-fos expression in 6-hydroxydopamine-lesioned rats.

In order to investigate the role of adenosine A2A receptor blockade on dopamine-mediated motor responses, contralateral turning behaviour and expression of the early-gene c-fos was evaluated in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway. SCH 58261, (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1 , 5-c]pyrimidine) a potent and selective antagonist of adenosine A2A receptors (5 mg/kg i.p.), induced a 70-fold increase in the contralateral turning behaviour induced by a low dose (2 mg/kg i.p.) of the dopamine precursor L-DOPA (L-3, 4-dihydroxyphenylalanine). Expression of c-fos as measured by Fos-like immunoreactivity after SCH 58261 plus L-DOPA was also potentiated as compared with L-DOPA alone, both in striatum and globus pallidus of the 6-hydroxydopamine-lesioned side of the brain. SCH 58261 induced a less marked potentiation (7-fold) of turning behaviour induced by dopamine D2 receptor stimulation with quinpirole, while Fos-like immunoreactivity in the striatum and globus pallidus was not affected. Previous studies have shown that SCH 58261 strongly potentiated dopamine D1 receptor-mediated responses. The results of the present study therefore indicate that the positive interaction between SCH 58261 and L-DOPA, in 6-hydroxydopamine-lesioned rats, is mainly due to an interaction with dopamine D1 receptors. The data also suggest that adenosine A2A receptor antagonists might be useful for potentiating the effects of L-DOPA in Parkinson's disease.

Animals↗

PubMed1996

Potentiometric alternating biosensing system for in continuum toxicity tests on cell population.

In this paper, we investigate the possibility to monitor, in continuum, changes of cellular metabolism. Examples of this feature are shown: metabolic changes due to drugs administration are evaluated as a decrease of extracellular acidification rate on CHO-K1 and HeLa cells. Parallel experiments with a standard test were performed to validate the results obtained with the biosensor.

Animals↗

PubMed1996

Effect of MK 801 on priming of D1-dependent contralateral turning and its relationship to c-fos expression in the rat caudate-putamen.

In rats with a unilateral 6-hydroxydopamine lesion of the ascending dopamine neurons, we investigated the relationship between the expression of Fos-like immunoreactivity in the caudate-putamen and contralateral turning behavior in response to dopamine agonists during the induction and expression of sensitization (priming) to D1-dependent turning behavior. Priming was induced by apomorphine (0.1 mg/kg s.c.) or by SKF 38393 (10 mg/kg s.c.) 14 days after 6-hydroxydopamine lesions and was expressed by challenge with SKF 38393 (3 mg/kg s.c.). In the induction phase of priming, administration of MK 801 (0.1 mg/kg s.c.) potentiated contralateral turning but differentially influenced stimulation of Fos expression in the caudate-putamen by apomorphine and by SKF 38393. Thus, MK 801 reduced in the expression phase of priming the stimulation of Fos expression by apomorphine in the dorsolateral caudate-putamen, but did not affect that by SKF 38393. MK 801, while preventing priming of SKF 38393-induced turning by apomorphine, failed to affect priming by SKF 38393. MK 801, given with apomorphine in the induction phase, reduced the stimulation of Fos expression in the dorsolateral caudate-putamen by SKF 38393. No such inhibitory effect of MK 801 on SKF 38393-stimulated Fos expression was observed in rats primed with SKF 38393. These results are consistent with the possibility that MK 801 disrupts sensitization of D1 transduction by reducing the activation of c-fos by the DA agonist during the induction phase of priming.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1996

Stem cell factor and PIXY-321 in acute lymphoblastic leukemia: in vitro study on proliferative effects and apoptosis.

Management of acute lymphoblastic leukemia (ALL) patients may include growth factors (GFs) to reduce post-chemotherapy aplasia. A potential risk of GF administration is a stimulatory signal on the leukemic population. In the present study we investigated the proliferative and programmed cell death (PCD) effect of two cytokines that have recently entered clinical use, stem cell factor (SCF) and the granulocyte colony stimulating factor/IL-3 fusion molecule (PIXY-321), on 14 ALL samples. The activity of IL-7, a cytokine involved in the regulation of ALL cell proliferation, was also tested alone and in combination with these two cytokines. Using the acridine orange flow cytometric technique and the clonogenic assay, we showed that none of these cytokines was capable of significantly increasing the mean percentage of S-phase cells and CFU-L number. A mean decrease of G0 cells from 60.6% to 52.6% (p = 0.02), coupled by a significant increase of G1 cells from 28.2% to 37.9% (p = 0.003) was demonstrated in the presence of PIXY-321. IL-7 alone and in combination with either PIXY-321 or SCF induced similar changes in the percentage of cells in G0 and G1. SCF showed no activity on G0 depletion. When each individual samples was analyzed separately, some heterogeneity was observed. An increase of S phase was recorded in a proportion of cases after SCF and PIXY-321 exposure. However, none of the cytokines evaluated by a clonogenic assay following liquid culture was capable of maintaining or promoting self-renewal of leukemic precursors, as determined by plating fresh cells at time 0. Detection of cytokine effects of apoptosis showed that SCF and PIXY-321 did not significantly reduce the mean percentage of cells in PCD, whereas a significant protective effect was observed in the presence of IL-7 (p = 0.02). We conclude that PIXY-321 and, to a further extent, SCF fail to induce leukemic lymphoid cell proliferation, and do not protect cells from entering apoptosis. These in vitro findings may be useful for ALL clinical trial design.

Adolescent↗

PubMed1995

Modulation of dopamine D1-mediated turning behavior and striatal c-fos expression by the substantia nigra.

In order to study the possible contribution of the substantia nigra (SN) in the positive interaction between dopamine D1 receptor agonists and glutamate antagonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, the effect of the D1 agonist, SKF 38393, was studied in combination with intranigral infusions of glutamate antagonists of the NMDA (MK 801, CPP) or AMPA (NBQX) type of receptor. Local infusion into the SN of the 6-OHDA lesioned side of MK 801, CPP or NBQX at doses inducing no or minimal behavioral effects significantly increased the turning behavior and the expression of c-fos induced, in the lesioned caudate-putamen (CPu), by a parenteral administration of SKF 38393. The same result was obtained after intra-SN infusion of the GABA agonist, muscimol. High doses of MK 801, CPP or muscimol infused into the SN produced intense contralateral turning per se and induced a sparse c-fos expression in the lesioned CPu which was antagonized by parenteral administration of MK 801. The results indicate that a depression of SN pars reticulata efferent neurons potentiates D1-mediated responses and suggest that this area may play a role in the positive interaction between glutamate antagonists and D1 receptor agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1995

Interleukin-3 priming in acute myeloid leukaemia patients.

Several studies have demonstrated that G-CSF, GM-CSF and, in particular, IL-3 can effectively recruit acute myeloid leukaemia (AML) blasts into the cell cycle, resulting in a significant increase in cytosine-arabinoside (Ara-C) mediated cytotoxicity in vitro. Since IL-3 has shown biological and clinical activity, we investigated the cell kinetic effects of rIL-3 and high-dose Ara-C/idarubicin in three patients with refractory AML selected for the presence of chromosome 7 monosomy; this enabled differentiation between the effects of IL-3 on leukaemic and on normal cells. The in vivo administration of rhIL-3 (250 micrograms/m2d s.c. for 6-10d) recruited AML blasts into the cell cycle in two of the three patients, and this effect resulted in an increase in in vitro growth of clonogenic cells (CFU-L) and of their S-phase fraction. The percentage of leukaemic cells with monosomy 7 increased only in the two cases who showed a proliferative response. Normal cells were not recruited, even when rhIL-3 was administered for up to 10 d. In vitro studies showed an increased Ara-C cytotoxicity on clonogenic AML cells, in particular with IL-3 plus GM-CSF, thus confirming the priming effects of IL-3 in the two responding cases. The results of this study suggest that rhIL-3 can selectively recruit leukaemic cells into the cell cycle. Although leukaemic blasts can be sensitized to Ara-C, other mechanisms of primary blast resistance may limit the clinical benefit of kinetic-based approaches.

Acute Disease↗

PubMed1995

Combined cytogenetic, FISH and molecular analysis in acute promyelocytic leukaemia at diagnosis and in complete remission.

This study reports the results of a simultaneous application of cytogenetic fluorescence in situ hybridization (FISH) and molecular analysis (RT-PCR) in 28 APL cases (23 M3 and five M3v; 26 studied at diagnosis and two at relapse). FISH on metaphases identified the t(15;17) in all cases who were positive for the PML/RAR alpha transcript by RT-PCR. Conventional cytogenetics revealed the t(15;17) in only 68% of cases. However, it enabled the detection of additional chromosome changes in five cases, three of whom were M3v. 11 patients were also investigated during complete remission (CR) by both FISH and RT-PCR, in order to evaluate residual disease; the duration of CR at the time of analysis ranged between 1 and 16 months, with three patients being studied twice. Comparison of RT-PCR and FISH results showed a very good correlation. In fact, of the 10 samples which were RT-PCR positive for residual disease, all were also recognized by interphase FISH, and eight were positive by metaphase FISH. Of the three samples negative at RT-PCR, all were also negative at the interphase FISH. The results of this study indicate that: (a) the t(15;17) is present in all cases positive for the PML/RAR alpha rearrangement, thus in virtually all true APLs; (b) standard cytogenetics, capable of unravelling the t(15;17) in only 68% of cases, enables recognition of additional chromosome changes of potential clinical and prognostic significance; (c) FISH on interphase nuclei is a reliable tool for the monitoring of residual disease, with a sensitivity greater than that of FISH on metaphase cells and superimposable to that of RT-PCR.

Adolescent↗

PubMed1995

Acute myeloid leukemias M2 potentially misdiagnosed as M3 variant French-American-Britain (FAB) subtype: a transitional form?

From 1990 to 1994, 3 patients with de novo acute myeloid leukemia (AML) in whom light microscopy and cytochemistry suggested a FAB subtype M3 variant were observed at our Institute. Immunophenotype showed HLA-DR-, CD13+, CD33+, CD2+, CD9+; promyelocytic features were also detected by electron microscopy. However, leukemic cells lacked both translocation t(15;17) and RAR alpha/PML genes rearrangement. These cases were considered to be 'M2 atypical' subtypes and they contribute to point out how cytogenetics and molecular biology are mandatory for a correct diagnosis of acute promyelocytic leukemia (APL) particularly because therapy with all trans retinoic acid (ATRA) is now the best treatment for APL. Nevertheless these 3 cases indicate that the atypical M2 subtype may be confused with the M3v if only cytochemistry, immunophenotype and electron microscopy are used in the defining the FAB subtypes.

Adult↗

PubMed1995

Intranigral injections of glutamate antagonists modulate dopamine D1-mediated turning behavior and striatal c-fos expression.

The contribution of the substantia nigra (SN) in the positive interaction between dopamine D1 receptor agonists and glutamate antagonists was studied in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of dopaminergic nigro-striatal pathway. Local infusion into the SN of the 6-OHDA lesioned side of NMDA glutamate antagonists MK 801 and CPP or the AMPA antagonist NBQX at doses inducing none or minimal behavioral effects, significantly increased the turning behavior and the expression of c-fos induced, in the lesioned caudate-putamen (CPu), by a parenteral administration of SKF 38393. High doses of MK 801 or CPP infused into the SN produced intense contralateral turning per-se but induced only sparse c-fos expression in the lesioned CPu. The results show that a depression of SN pars reticulata efferent neurons, potentiates D1-mediated responses and suggest that this area may play a role in the positive interaction between glutamate antagonists and D1 receptor agonists.

Animals↗

PubMed1994

Interleukin-2 may induce prolonged remissions in advanced acute myelogenous leukemia.

The administration of interleukin-2 (IL-2) may induce complete remissions in acute myelogenous leukemia (AML) patients with a low proportion of residual bone marrow (BM) blasts. To confirm this preliminary observation, we treated 14 AML patients with advanced disease and with a residual BM blastosis that ranged between 7% and 24% with repeated 5-day cycles of high-dose recombinant IL-2 administered by daily continuous intravenous infusion. Patients who responded have been subsequently submitted to a monthly maintenance scheme with subcutaneous IL-2 at lower doses. While using this schedule and closely monitoring clinical and laboratory conditions, side effects were acceptable and no toxic deaths recorded. Eight of the 14 patients treated with high-dose IL-2 obtained a complete remission (CR). Five remain in persistent CR (four in third CR and one in fourth CR) after a median follow-up time of 32 months (14, 30, 32, 33, and 68 months, respectively). In all five patients, the IL-2-induced remission is the longest in the natural history of the disease. These findings show that IL-2 displays an antileukemic effect in AML with limited residual disease, and suggest that IL-2 should be considered a therapeutic option for resistant or relapsed AML patients.

Adolescent↗

PubMed1994

Adenosine A2 receptors interact negatively with dopamine D1 and D2 receptors in unilaterally 6-hydroxydopamine-lesioned rats.

In rats bearing a unilateral 6-hydroxydopamine lesion of the dopaminergic nigro-striatal pathway, stimulation of adenosine A2 receptors by CGS 21680 reduced the contralateral turning behavior induced by L-3,4-dihydroxyphenylalanine (L-DOPA). Administration of CGS 21680 completely blocked the contralateral turning induced by the dopamine D1 receptor agonist, SKF 38393, and reduced the turning induced by the dopamine D2 receptor agonist, LY 171555. Quinolinic acid lesion of the striatum or 6-hydroxydopamine lesion of the dopaminergic nigro-striatal neurons demonstrated that [3H]CGS 21680 binding sites are associated to striatal intrinsic neurons. This study provides evidence for a negative postsynaptic interaction of both dopamine D1 and D2 receptors with adenosine A2 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1994

Differential effect of MK 801 and scopolamine on c-fos expression induced by L-dopa in the striatum of 6-hydroxydopamine lesioned rats.

In rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigro-striatal pathway, striatal D1-receptor-stimulated c-fos expression and turning behavior are positively modulated by D2 receptor stimulation and by blockade of N-methyl-D-aspartate (NMDA) or muscarinic receptors. Combined D1/D2 receptor stimulation by L-dopa activates c-fos in a manner not additive with muscarinic receptor blockade by scopolamine. On the other hand, blockade of NMDA receptors by MK 801 reduced c-fos expression induced by L-dopa while, depending on the dose of L-dopa, differentially affecting contralateral turning behavior. The results are interpreted to suggest that D2 receptor stimulation amplifies D1-receptor-mediated c-fos expression by two mechanisms differentially related to muscarinic and NMDA receptors.

Animals↗

PubMed1994

Myelodysplastic syndromes in childhood: description of seven cases.

Seven children with a primary myelodysplastic syndrome were seen at our center over a 9-year period. Two presented with refractory anemia, three with refractory anemia with excess of blasts, and two with refractory anemia with excess of blasts in transformation. All children received supportive therapy, including blood transfusions in five of them. Three patients developed acute myeloid leukemia and were treated with intensive chemotherapy, followed by allogeneic or autologous marrow transplantation in the two responders. All three died of either infection or progressive disease. The other four patients are still alive a median of 71 months (range 38-130) after diagnosis. These results confirm the difficulties in managing patients with myelodysplastic syndromes.

Anemia, Refractory↗

PubMed1994

Acute promyelocytic leukemia in children: experience of the Italian Pediatric Hematology and Oncology Group (AIEOP).

Scanty information is available on acute promyelocytic leukemia (APL) in children, and whether differences are present with respect to the adult form. The experience of the Italian Pediatric Hematology and Oncology Group (AIEOP) will be presented with respect to the following aspects: 1. Incidence of APL. The incidence of APL is generally considered to account for 3-9% of acute myelogenous leukemia (AML) in children and approximately 10-15% in adults. Recently a single Italian pediatric institution reported that APL constituted one third of observed acute nonlymphocytic leukemia (AnLL) cases. Data from the AIEOP cooperative study group have confirmed that APL in Italy is more frequently observed in children as compared to other countries. Environmental and/or genetic factors should be considered to explain such differences. 2. Diagnosis of M3v. The clinical and biological features of the largest series of childhood M3v will be presented and the problems encountered in the proper separation of 'classic' M3 and M3v in children will be discussed. 3. Clinical Aspects. The clinical features of the APL patients enrolled in the AIEOP study groups since 1989, will be presented with emphasis on the recent experience with the use of all-trans retinoic acid. 4. Analysis of PML/RAR alpha Fusion Transcripts. An RT-PCR analysis of 32 pediatric APL cases from cryopreserved bone marrow samples has been performed. It is concluded that APL in children did not differ significantly from the adult form, with the exception of a higher incidence of PML bcr3 breakpoint.

Age Factors↗

PubMed1994

Acute promyelocytic leukemia in children: experience of the Italian Pediatric Hematology and Oncology Group (AIEOP).

Adolescent↗

PubMed1993

L-dopa stimulates c-fos expression in dopamine denervated striatum by combined activation of D-1 and D-2 receptors.

Administration of L-dopa to unilaterally 6-hydroxydopamine-lesioned rats, activates the early gene c-fos in the lesioned caudate-putamen. D-1 receptor blockade by SCH 23390, prevented L-dopa-induced Fos-like immunoreactivity in the whole caudate-putamen, while D-2 receptor blockade by raclopride reduced Fos-like immunoreactivity only in the dorso-lateral portion. The results suggest that L-dopa induces c-fos primarily through an activation of D-1 receptors, while D-2 receptor stimulation plays a facilitatory influence on D-1-mediated c-fos expression.

Animals↗

PubMed1993

Reproducibility of the morphological diagnostic criteria for acute myeloid leukemia: the GIMEMA group experience.

Diagnostic reproducibility of the FAB morphological subtypes of acute leukemia is a basic step in the assessment of the clinical outcome in multicenter trials. Unusual cytologic variables and slightly different interpretations of the FAB morphological criteria have been the most significant factors affecting the overall diagnostic concordance rate among the various centers. An evaluation of the diagnostic concurrence between 35 institutions of the Italian Cooperative Study Group GIMEMA and two reviewers of the ad hoc morphological committee has been performed on 377 patients entering the AML 8A and AML 8B GIMEMA protocols. Overall concordance rate was 62.6%. The most significant differences were observed for M2 vs M4, M4 vs M5, M1 vs M2, and M2 vs M5 subtypes. In order to minimize the impact of some diagnostic deviations on the mean cytologic concordance rate, a distinction between "major" and "minor" discrepancies in the diagnostic procedures has been proposed. When the results of the single institutions were corrected by considering the "major" discrepancies only, a mean diagnostic agreement of 78.1% was reached.

Acute Disease↗

PubMed1993

Blockade of muscarinic receptors potentiates D1 dependent turning behavior and c-fos expression in 6-hydroxydopamine-lesioned rats but does not influence D2 mediated responses.

In rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway, blockade of muscarinic receptors by scopolamine potentiates the contralateral turning induced by selective dopaminergic D1 agonists (SKF 38393, A 68930), but does not influence the contralateral turning induced by the D2 agonist LY 171555. Studies on the expression of the early gene c-fos as reflected by the immunohistochemical demonstration of the Fos protein, show that administration of scopolamine (5 mg/kg, i.p.) potentiates c-fos expression elicited by SKF 38393 (1.5 mg/kg, s.c.) in the caudate-putamen of the lesioned side. The results indicate that cholinergic transmission is differentially involved in the behavioral expression of D1 versus D2 receptor stimulation in a denervated condition and suggest that blockade of central cholinergic transmission might be useful in improving the antiparkinsonian efficacy of D1 receptor agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗