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Biomedical subjects

S Fumagalli

Publications and source records attributed to S Fumagalli.

35 records · Page 2Linked to original sources
PubMed1994

Differential induction of the two early genes c-jun and c-fos in weakly and strongly metastatic murine lymphoma cell lines.

Induction of the 2 early-response genes c-jun and c-fos was investigated in the weakly metastatic T-lymphoma Eb line and the related strongly metastatic lymphomacrophage ESb line to find possible correlations with their different in vitro and in vivo phenotypes. The response of c-jun was elicited by the protein kinase-C activators TPA and A23187 in ESb but not in Eb cells. A much lower response of c-fos was also found in Eb than in ESb cells, in this case by means of serum and the cAMP elevator forskolin. However, both TPA and the calcium ionophore A23187 were similarly effective in inducing fos-mRNA in both cell lines. The uncoupling of c-jun and c-fos induction in Eb, but not in ESb cells, as well as the uncoupling of c-fos response to different stimulators, point to a differential activation of these 2 early-response genes by the main signal transduction pathways in the 2 cell types. The coordinate/uncoordinate availability of the fos/jun heterodimer may confer distinct regulatory patterns on different target genes in ESb/Eb cells. Activation of these genes may underlie the distinct differentiation phenotypes and in vivo behavior of Eb/ESb cells.

Animals↗
PubMed1994

Ex vivo optical properties of human colon tissue.

Using a spectrophotometer equipped with an internal integrating sphere, the absorption (mu a) and the reduced scattering (microseconds') coefficients of ex vivo human colon tissues were evaluated from reflectance and transmittance measurements. Mu a and microseconds' varied from 47.7 to 1.0 cm-1 and from 14.2 to 6.2 cm-1, respectively, on passing from 300 nm to 800 nm. These results can be used to estimate the optical penetration depths when photodynamic therapy or light-induced fluorescence procedures are used.

Absorption↗
PubMed1994

A mitotic function for Src?

During mitosis, the activity of the c-Src protein tyrosine kinase increases. The tyrosine phosphorylation of a 68 kDa protein (Sam68) also increases at this time, and recent studies have shown that Src and Sam68 interact. Sam68 is highly related to p62, a RasGAP-associated protein, and has homology to RNA-binding proteins. The relationship between p62 and Sam68, and their roles in Src signalling, need to be clarified, but these findings suggest that Src may participate in regulating RNA processing during the cell cycle.

Journal Article↗
PubMed1993

Csk inhibition of c-Src activity requires both the SH2 and SH3 domains of Src.

The protein tyrosine kinase c-Src is negatively regulated by phosphorylation of Tyr527 in its carboxy-terminal tail. A kinase that phosphorylates Tyr527, called Csk, has recently been identified. We expressed c-Src in yeast to test the role of the SH2 and SH3 domains of Src in the negative regulation exerted by Tyr527 phosphorylation. Inducible expression of c-Src in Schizosaccharomyces pombe caused cell death. Co-expression of Csk counteracted this effect. Src proteins mutated in either the SH2 or SH3 domain were as lethal as wild type c-Src, but were insensitive to Csk, even though they were substrates for Csk in vivo. Peptide binding experiments revealed that Src proteins with mutant SH3 domains adopted a conformation in which the SH2 domain was not interacting with the tail. These data support the model of an SH2 domain-phosphorylated tail interaction repressing c-Src activity, but expand it to include a role for the SH3 domain. We propose that the SH3 domain contributes to the maintenance of the folded, inactive configuration of the Src molecule by stabilizing the SH2 domain-phosphorylated tail interaction. Moreover, the system we describe here allows for further study of the regulation of tyrosine kinases in a neutral background and in an organism amenable to genetic analysis.

Amino Acid Sequence↗
PubMed1993

Acute and long-term effects of flosequinan in patients with chronic cardiac failure.

The acute and long-term effects of the orally active vasodilator flosequinan were assessed in 10 patients with New York Heart Association class II to IV cardiac failure. Baseline hemodynamics, exercise capacity, left and right ventricular ejection fraction, and pulmonary transit time were measured by right cardiac catheterization, bicycle ergometer stress testing, and nuclear angiocardiography during a run-in period on placebo. Acute hemodynamic effects of flosequinan were monitored for 48 hours; the drug was then given as a single 100 mg daily dose for 6 weeks. Exercise capacity was reevaluated every 2 weeks, and right cardiac catheterization and nuclear angiocardiography were repeated at the end of the 6-week period. Placebo did not exert any effect. Flosequinan reduced right atrial, pulmonary artery, and pulmonary artery wedge pressures from 60 minutes to 48 hours after dosing. Heart rate was minimally increased. Cardiac index, mean systemic arterial pressure, and systemic and pulmonary vascular resistance were substantially unaffected. These effects were maintained after 6 weeks. Exercise capacity was enhanced after 2, 4, and 6 weeks. Left ventricular ejection fraction was unchanged, whereas right ventricular ejection fraction and pulmonary transit time were improved. In conclusion, flosequinan exerted a potent, long-lasting, venodilating effect that was maintained long-term, without evidence of tolerance.

Aged↗
PubMed1993

Expression of the c-ski proto-oncogene in human melanoma cell lines.

The aim of this study was to establish whether the expression of proto-oncogene c-ski in melanoma might be related to alterations of chromosome 1q involving the native location of the gene. Six melanoma cell lines, including two carrying marker chromosomes derived from breakage at 1q12-q21, were studied. Expression of c-ski was observed in all cell lines, with very high levels in five of them. However no alteration in c-ski structure or dosage was found in any of the melanoma cell lines, including those with non-random breakpoints near the gene. c-ski Transcripts were detected in cell cultures from normal melanocytes, but at a much lower level than that observed in melanoma cell lines. Transcripts of c-myb and the beta-NGF gene were not detectable in any of the melanoma cell lines, whereas sis- and epidermal growth factor (EGF) receptor gene-specific transcripts were present in two and four melanoma cell lines, respectively. The constant expression of c-ski in the melanoma-derived cell lines at a level of expression much higher than that of normal melanocytes suggests that this proto-oncogene may play a role in melanocyte transformation.

Blotting, Northern↗
PubMed1993

The Src family of protein tyrosine kinases: regulation and functions.

Most of the nine members of the Src family of tyrosine kinases are restricted in their expression, often to cells of the haematopoietic lineage, while some, particularly Src, Fyn and Yes, are more ubiquitously expressed. We have been studying the functions of Src, Fyn and Yes in fibroblasts. We have shown that stimulation of quiescent fibroblasts with platelet-derived growth factor (PDGF) causes Src, Fyn and Yes to become activated, and to associate transiently with the PDGF receptor. To address the role of Src, Fyn and Yes in the response to PDGF, we have used a dominant negative approach, in which cells were engineered to express catalytically inactive forms of Src kinases. These cells were unable to enter S phase in response to PDGF, and we therefore conclude that Src family tyrosine kinases are required in order for the PDGF receptor to transmit a mitogenic signal. It has previously been shown that the kinase activity of Src is negatively regulated by phosphorylation of tyr 527 in its carboxy-terminal tail. A kinase, Csk, that phosphorylates tyr 527 has recently been identified. We expressed Src in yeast to test the model that phosphorylation of tyr 527 represses activity by promoting intramolecular association between the tail and the SH2 domain. Inducible expression of Src in S. pombe caused cell death. Co-expression of Csk counteracted this effect. Src proteins mutated in the SH2 domain were as lethal as wild-type Src, but were insensitive to Csk. We interpret these results in favour of an SH2 domain: phosphorylated tail interaction repressing Src activity. (ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Activation of c-fos and c-fes in metastatic lympho-macrophage hybrids.

The expression of proto-oncogenes involved in myelomonocytic differentiation was studied in 3 metastatic murine lympho-macrophage hybrids (ESb, EbF1, EbF2-C4) which display several antigenic and functional macrophage properties. Constitutive expressions of fos and fesmRNA, which were not detectable in the weakly metastatic parent lymphoma (Eb), was shown in all the proliferating hybrid lines. By contrast, c-myc and c-myc expressions were shared by the tumor parent and the hybrids. The c-fos transcripts observed in the hybrids were atypical in size, 2.3 kb, but standard 2.2-kb transcripts could be detected in serum-induced cells, even in the non-expressing Eb lymphoma. The kinetics of the induced fos mRNA was found to conform to the features reported in the literature for a large variety of cells. No structural alteration of the c-fos gene was detected by Southern analysis. PCR amplification of the 2.3- and 2.2-kb fos mRNA showed that they are identical in size in both the coding and the 3' untranscribed region. A longer poly A tail is thought to account for the additional 100 bp in the 2.3-kb fos mRNA, as both the 2.3- and 2.2-kb transcripts attain the same size following de-adenylation.

Animals↗
PubMed1991

No correlation between response and survival in patients with multiple myeloma treated with vincristine, melphalan, cyclophosphamide, and prednisone.

A vincristine, melphalan, cyclophosphamide, and prednisone (VMCP) multi-drug regimen was used in 85 previously untreated patients with multiple myeloma (MM) (symptomatic Durie Stages II and III) until they became refractory. The prognostic significance of various pretreatment characteristics was evaluated in terms of therapeutic response (according to Southwest Oncology Group [SWOG] and Chronic Leukemia-Myeloma Task Force [TF] criteria) and survival. Therapeutic responses, obtained in 31.2% (SWOG) and 68.7% (TF) of patients, had a significant inverse correlation with myeloma cell mass, serum calcium, and bone status. Median survival time of Stage II and Stage III patients was 39 and 34 months, respectively. Serum B2 microglobulin greater than or equal to 6 micrograms/ml was the only variable correlating unfavorably with survival duration after multi-variate analysis (increased risk = 2.79), although therapeutic response as a time-dependent variable had no effect on survival. These data suggest no correlation between response and survival, partially because of inadequate response assessment criteria and partially because no existing treatment is curative (although current therapeutic approaches may prevent death from complications).

Adult↗
PubMed1991

[Serology study for HBV and HIV-1 in a cohort of parenteral drug addicts].

We studied 335 subjects, all drug addicts for the presence of the following serological markers: HIV1 antibody, HBsAg, HBsAb, HBcAb totals. We conclude that subjects HIV1 positive (n. 149) present HBsAb in a significantly lower number (p greater than 0.001) than HIV1 negative subjects (n. 95). The presence of HBcAb isolated is significantly higher (p greater than 0.001) in subjects HIV1 positive. They show an altered serological response to HBV compared to subjects HIV1 negative.

Adolescent↗
PubMed1990

Age-related changes in the pharmacodynamics of intravenous glyceryl trinitrate.

Comparable hemodynamic effects were obtained administering a much lower intravenous dose of glyceryl trinitrate (GTN) in elderly than in younger patients. The pharmacodynamics and kinetics of GTN were thus assessed in 2 groups of patients with acute myocardial infarction (group A: less than or equal to 65 years, 6 patients; group B: greater than or equal to 75 years, 6 patients). The arterial and venous dose-concentration relationship and the associated hemodynamic changes at end-point (EP: 10% reduction in mean systemic arterial pressure) were similar in the 2 groups. However, in older subjects EP was reached at a lower GTN infusion rate (0.11 +/- 0.04 vs 0.33 +/- 0.11 micrograms.kg-1.min-1, mean +/- S.D.; p less than 0.001), and with lower arterial and venous drug concentrations (arterial [GTN]: 1.2 +/- 0.1 vs 4.6 +/- 1.2 ng.ml-1; p less than 0.01; venous [GTN]; 0.09 +/- 0.05 vs 0.35 +/- 0.15 ng.ml-1; p less than 0.05), whereas overall GTN kinetics appeared to be substantially independent of age. Thus, the enhanced efficacy of GTN in advanced age seems to stem mainly from pharmacodynamic changes, which may be the consequence of dampened baroreceptor reflexes, as suggested by a lower heart rate increase per unitary fall in systolic arterial pressure observed in group B (0.12 +/- 0.07 vs 0.41 +/- 0.29 b.min-1.mmHg-1; p less than 0.05).

Aged↗
PubMed1988

Age-related hemodynamic effects of intravenous nitroglycerin for acute myocardial infarction and left ventricular failure.

Acute hemodynamic effects of intravenous nitroglycerin (NTG) were assessed in 24 patients with acute myocardial infarction and left ventricular failure, and results were compared between 2 groups of different age (group A--65 years or less, n = 12; group B--75 years or more, n = 12). Overall, hemodynamic effects of NTG consisted of an increase in stroke volume index and left ventricular stroke work index (+21 and +23%), coupled with a 16% reduction in systemic vascular resistance, and of a marked decrease in right atrial and pulmonary artery (PA) pressures. The hemodynamic end-point (5 to 10% reduction in mean systemic arterial pressure) used for NTG titration was achieved with a significantly lower dose in group B, in which a greater percent reduction in mean PA and mean PA wedge pressures was also observed. However, because effects of NTG on systemic vascular resistance were similar in groups A and B, it was concluded that the vasodilating action of NTG is maintained in advanced age, as opposed to what has been demonstrated for beta-adrenergic agents.

Aged↗
PubMed1986

Metoclopramide increases vasopressin secretion.

The possibility that metoclopramide (MCP), a potent stimulator of aldosterone secretion, might influence vasopressin secretion in man was studied. MCP (10 mg, iv) increased plasma vasopressin (mean +/- SD) from 1.3 +/- 0.1 to 2.4 +/- 0.1 pg/ml at 10 min and to 2.65 +/- 0.1 pg/ml at 20 min (P less than 0.01) in 10 recumbent normal subjects. No changes in plasma osmolality or peripheral hemodynamics, which might have accounted for the increase in vasopressin, were found. Sulpiride (100 mg iv), haloperidol (2 mg, iv), and domperidone (20 mg, iv), three chemically unrelated antidopaminergic agents, as well as TRH (200 micrograms, iv), failed to modify plasma vasopressin, thus suggesting that the MCP effect on vasopressin is not linked to its antidopaminergic and/or PRL-releasing properties. MCP also was effective in releasing vasopressin in 5 dehydrated subjects, in whom plasma vasopressin increased from 1.9 +/- 0.2 to 3.1 +/- 4 pg/ml (P less than 0.05), and in 5 subjects during steady state water diuresis, in whom free water excretion decreased from 9 to 1 ml/min (P less than 0.01) and plasma vasopressin increased from 0.3 +/- 0.1 to 1.2 +/- 0.2 pg/ml (P less than 0.05). No changes in either vasopressin secretion or free water excretion occurred in 4 patients with severe central diabetes insipidus. These results suggest that MCP stimulates the release of biologically active vasopressin in man.

Adult↗
PubMedDate not supplied

Variable effect of comorbidity on the association of chronic cardiac failure with disability in community-dwelling older persons.

The effect of cardiac failure (CF) and comorbidity on disability in older persons was studied in a cross-sectional survey. The whole population aged 65 + years (n=652; 628 eligible) living in a small town near Florence (Italy) was enrolled. Finally, 459 individuals (73.0% of eligible) underwent a multidimensional evaluation. CF was defined as a NYHA II-IV class in the presence of an obviously abnormal ECG. Disability was assessed by the 14-item WHO scale. Comorbid conditions that had a prevalence >5% and might be considered pathophysiologically unrelated to CF were also identified. The univariate association of CF with disability was analyzed. Multivariate associations were estimated as well, by taking simultaneously into account the effect of comorbid conditions that had an independent effect on disability and were considered as either confounders or effect modifiers of that association. Prevalence of CF [6.1% in the whole study population) was higher with advancing age ( >or=75 years: 8.3 versus 65-74 years: 4.5%, odds ratio, OR: 1.93, 95% confidence interval, CI: 1.02-4.18), in the presence of hypertension (OR: 2.87, 95% CI: 1.32-6.23), and among individuals who were living alone (OR: 2.44, 95% CI: 1.10-5.56). CF was associated with a higher prevalence of disability (38.5 versus 19.5% OR 2.67, 95% CI: 1.21-5.92). Comorbidity modified the association of CF with disability following two patterns: while the independent effect of CF on the prevalence of disability was similar in the absence or in the presence of chronic obstructive pulmonary disease, hearing impairment, gastrointestinal tract disease, or osteoarthritis, such effect was much larger in the presence than in the absence of visual impairment, previous stroke, or urinary incontinence. The composite pathophysiological pathways of such different interactions are still to be elucidated.

Journal Article↗
PubMedDate not supplied

Lymphocyte-endothelium interaction in systemic sclerosis and Raynaud's phenomenon.

OBJECTIVE: To investigate interactions of immune cells with vascular endothelium in patients with systemic sclerosis (SSc) and in patients with idiopathic or autoimmune Raynaud's phenomenon (RP). METHODS: Lymphocytes obtained from 11 patients with SSc, 9 with RP and 14 control subjects were pre-stimulated in vitro with alloantigens and cultured together with human umbilical vein endothelial cells (HUVECs). Lymphocyte adhesion and induction of endothelial HLA-class 11 molecules were measured by flow cytometry. Lymphocyte cytotoxicity against HUVECs was also evaluated. In some cases cells were cultured under experimental conditions of hypoxia and reoxygenation. RESULTS: Lymphocyte adhesion and induction of endothelial cell expression of HLA-DR molecules were similar in controls and SSc patients, but significantly lower in RP (p < 0.05 and p < 0.03, respectively). Cytotoxic activity of lymphoblasts against endothelial cells was negligible in all patient groups. Under experimental conditions of hypoxia and reoxygenation lymphocyte adhesion was significantly greater than in normoxic conditions in SSc patients, while it was similar to normoxia in control subjects and RP patients. CONCLUSION: These results suggest that in RP patients there may be regulatory mechanisms of lymphocyte response able to control the processes that lead to lymphocyte adhesion and endothelial HLA-DR molecule induction. These mechanisms could play an important role in RP, and might possibly be lost in clinically evident SSc.

Adult↗