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Biomedical subjects

S Morelli

Publications and source records attributed to S Morelli.

At least 19 recordsLinked to original sources
PubMed1996

A bcl-2/IgH antisense transcript deregulates bcl-2 gene expression in human follicular lymphoma t(14;18) cell lines.

The 14;18 chromosome translocation, characteristic of most human follicular B-cell lymphomas, juxtaposes the bcl-2 gene with the IgH locus, creating a bcl-2/IgH hybrid gene. By mechanisms that are still under investigation, this event increases the cellular levels of the bcl-2 mRNA and thereby induces an overproduction of the antiapoptotic BCL-2 protein which is likely responsible for neoplastic transformation. In an effort to identify potential upregulators of bcl-2 activity in t(14;18) cells, we found, by strand-specific RT-PCR, a bcl-2 antisense transcript that is present in the t(14;18) DOHH2 and SU-DHL-4 but not in the t(14;18)-negative Raji and Jurkat lymphoid cell lines, and thus appears to be dependent on the bcl-2/IgH fusion. This antisense transcript is a hybrid bc1-2/IgH RNA, that originates in the IgH locus, encompasses the t(14;18) fusion site and spans at least the complete 3' UTR region of the bcl-2 mRNA. To achieve some insight into its biological function, we treated the t(14;18) DOHH2 cell line with oligonucleotides (ODNs) by specifically targeting the bc1-2/IgH antisense strand. These ODNs lowered bcl-2 gene expression, inhibited neoplastic cell growth by inducing apoptosis. We would like to propose the hypothesis that the bc1-2/IgH antisense transcript may contribute, by an unknown mechanism, to upregulation of bcl-2 gene expression in t(14;18) cells. The possibility has been considered that the hybrid antisense transcript mask AU-rich motifs present in the 3' UTR of the bcl-2 mRNA characterized in other genes as mRNA destabilizing elements.

Apoptosis↗
PubMed1996

Analysis of antisense oligonucleotides by capillary electrophoresis, gel-slab electrophoresis, and HPLC: a comparison.

Three techniques are evaluated for assessing the purity of synthetic oligodeoxyribonucleotides: reversed phase high-performance liquid chromatography (RP-HPLC), polyacrylamide gel-slab electrophoresis (PAGE), and capillary zone electrophoresis highly concentrated (18% T) entangled polymer networks (CZE). RP-HPLC does not seem to be able to discriminate and resolve the spectrum of failed sequences expected to accompany an oligonucleotide of a given length. The purity data, as given by the manufacturer, are most often close to 100%. PAGE in 20% T matrices, followed by ethidium bromide staining, gives a good resolution of failure sequences and purity assessments decidedly more realistic. CZE in 18% liquid polyacrylamide is able to resolve to baseline all shorter fragments and to give a precise evaluation of the amount of impurities, based on the intrinsic DNA absorbance at 254 nm. Most of the 18 mer oligonucleotides (and of their phosphorothioate derivatives) analyzed by us, as supplied by three different manufacturers, were found to be contaminated by a spectrum of failed and truncated sequences, ranging in size from 7 mer to 17 mer. The purity data rarely exceeded 80% and most often were of the order of 60%-70%. Conditions for a good routine performance of the CZE technique are described.

Base Sequence↗
PubMed1996

Oligonucleotides induce apoptosis restricted to the t(14;18) DHL-4 cell line.

Most human follicular B-cell lymphomas are associated with t(14;18) chromosome translocation that joins the bcl-2 gene with the IgH locus. This hybrid gene causes upregulation of BCL-2 protein expression, endowing cells with survival advantage. Although early BCL-2 overexpression is definitely responsible for immortalization/transformation, its exact role in the overt transformation as well as in the maintenance of the tumor phenotype is not known. The capacity of oligodeoxynucleotides (ODN) to modulate gene expression specifically has been exploited to downregulate the overexpression of BCL-2 protein in the SU-DHL-4 human follicular B-cell lymphoma line by the use of sense ODN or antisense ODN or antisense ODN designed to encompass the unique nucleotide sequence in the fusion region of the hybrid transcript. The specific downregulation of the bcl-2 transcript and of the relevant BCL-2 protein in the treated cells activated programed cell death and inhibited growing cells. The antitumor activity was restricted to the DHL-4 cell line carrying the specific nucleotide sequence at the bcl-2/IgH joining region. Thus, DHL-4 lymphoma cells derived from the acute phase of human follicular B-cell lymphoma, although endowed with additional activated oncogenes, were growth inhibited by bcl-2 downregulation with additional activated oncogenes, were growth inhibited by bcl-2 downregulation in a genetically restricted fashion. The biological activity was exerted exclusively by ODNs synthesized in the sense orientation. The sense ODNs have been proposed to anneal the hybrid bcl-2/IgH antisense RNA as identified in this study.

Amino Acid Sequence↗
PubMed1996

Twenty-four hour heart period variability in systemic sclerosis.

OBJECTIVE: In patients with systemic sclerosis (SSc), an autonomic dysfunction has been implicated in the pathogenesis of Raynaud's phenomenon and gastrointestinal symptoms. To evaluate cardiovascular autonomic function we analyzed the heart rate variability (HRV) on 24 h electrocardiogram recordings. METHODS: In 50 patients diagnosed with SSc and 24 control subjects HRV was analyzed for both frequency and time domain. RESULTS: Frequency domain analysis showed reduction of low frequency and high frequency values in the patients with SSc compared to controls (5.52 +/- 0.74 vs 6.04 +/- 0.78 In(ms2), p = 0.007; and 4.17 +/- 0.97 vs 4.74 +/- 0.97 In(ms2), p = 0.021, respectively). Analysis in time domain showed no significant differences in any variable between groups. There were no significant differences between the diffuse and the limited form of SSc. Number of ventricular ectopic beats, prevalence of frequent ventricular ectopy, and supraventricular tachycardia episodes were increased in the patients with SSc compared to controls. CONCLUSION: Spectral analysis of heart period variability suggests cardiovascular autonomic dysfunction in patients with SSc. Better understanding of this complication could help delineate new strategies for the treatment of SSc.

Adult↗
PubMed1996

Terminally L-modified oligonucleotides: pairing, stability and biological properties.

An oligodeoxynucleotide (ODN), capable of reducing the growth of human B lymphocytes carrying the t(14;18) chromosome translocation, was prepared in different 'chemical versions': unmodified phosphodiester, phosphorothioate and phosphodiester capped with L-2'-deoxycytidine. Their binding affinity to the complementary synthetic target was studied by the melting point assay. The ODNs, administered to DOHH2 cells, were compared for stability in the culture medium, cellular uptake, time course of the intact sequence concentration within the cell and ability to inhibit cell growth. The 5', 3'-L-capped derivative and the phosphorothioate had comparable potency, superior to that of the unmodified ODN, in agreement with the concentration of undegraded ODNs within the cell.

Antineoplastic Agents↗
PubMed1996

White-coat hypertension and cardiac organ damage in elderly subjects.

PURPOSE: The aim of this study was comparing the cardiac mass in elderly normotensive subjects and elderly white-coat hypertensive patients by examining in perspective, in consecutive patients, office blood pressure (BP), ambulatory BP, and echocardiographically determined left ventricular mass. PATIENTS AND METHODS: We studied 42 elderly patients attending a hypertension unit: of these, 22 (mean age 68.7 +/- 3.2 years) had persistent > 90 mm Hg office diastolic blood pressure (DBP), > 140 mm Hg systolic blood pressure (SBP) and < 142/90 mm Hg daytime ambulatory BP (white-coat positives); the remaining 20 (mean age 67.4 +/- 2.2 years) had < 90 mm Hg office DBP, < 140 mm Hg SBP and < 142/90 mm Hg daytime ambulatory BP (normotensives). White coat-patients (n = 22) were selected from a series of 75 consecutive newly diagnosed and never treated patients with mild hypertension (casual DBP constantly between 90 mm Hg and 105 mm Hg). RESULTS: Neither left ventricular mass index (89.9 +/- 23.1 vs 91.8 +/-25.4 P = NS and +/- 25.4 P = NS) and left ventricular mass/height, (115.4 +/- 17.1 vs 119.6 +/- 18.3 P = NS), nor relative wall thickness (0.31 +/- 0.44 vs 0.33 +/- 0.05 P = NS) were significantly higher in white-coat hypertensives as against normotensives. Neither did we find a relevant difference between left atrial diameters in the above considered groups (3.28 +/- 0.41 vs 3.32 +/- 0.37). In fact 81.8% of white-coat hypertensives had left ventricular normal geometry; whilst 13.6% only had concentric remodeling. Age and sex were associated with left ventricular mass index, left ventricular mass/height and relative wall thickness. Multiple regression analysis revealed that it is ambulatory, not office BP that carries independent information about relative wall thickness and left ventricular mass indices. CONCLUSIONS: Since elderly white-coat hypertensive subjects did not display a greater cardiac involvement than age-matched normotensives, they should be treated as such.

Aged↗
PubMed1995

1,25(OH)2-vitamin D-3 stimulates phospholipase A2 activity via a guanine nucleotide-binding protein in chick myoblasts.

The steroid hormone 1,25(OH)2-vitamin D-3 [1,25(OH)2D3] stimulated phospholipase A2 (PLA2) activity in embryonic chick myoblasts releasing [3H]arachidonic acid from the sn-2 position of phospholipids. GTP-binding protein mediation of 1,25(OH)2D3-dependent PLA2 activity was investigated in cells prelabeled with [3H]arachidonic acid. AIF4-, a G-protein activator, mimicked 1,25(OH)2D3-stimulated arachidonic acid release from myoblasts in a dose-dependent manner. Consistent with the involvement of a G-protein in the activation of PLA2 by the hormone, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), a stable GTP analogue which activates G-protein mediated signals, strongly enhanced arachidonic acid release in myoblasts. Guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), which competitively inhibits G-protein activation by GTP and its analogues, abolished 1,25(OH)2D3-dependent arachidonic acid release. Bordetella pertussis toxin pretreatment significantly suppressed the hormone action whereas cholera toxin had minor effects on 1,25(OH)2D3 action. Hormone-induced activation of PLA2 was mimicked by the Ca2+ ionophore A23187 and blocked by nifedipine, but was unaffected by neomycin, a phospholipase C inhibitor, ruling out the contribution of phosphoinositide metabolism to arachidonic acid release. These results suggest that 1,25(OH)2D3-stimulation of PLA2 activity in embryonic chick myoblasts is mediated by a pertussis toxin-sensitive GTP-binding protein coupled to influx of extracellular calcium.

Animals↗
PubMed1995

Efficacy of photodynamic therapy against doxorubicin-resistant murine tumors.

Photodynamic therapy (PDT) is a relatively new cancer treatment modality that employs light excitation of a photosensitizer to yield cytotoxic oxygen-related species. In the present study we explored whether PDT would have therapeutic effect against doxorubicin-resistant murine tumors. We compared the efficacy of PDT with aluminium disulphonated phthalocyanine (A1S2Pc) and laser light on the doxorubicin-sensitive murine tumors, B16 melanoma (B16), L1210 leukemia (L1210), P388 lymphoma (P388) and the corresponding doxorubicin-resistant lines (B16/Dx, L1210/Dx and P388/Dx). Mice bearing L1210-L1210/Dx, P388-P388/Dx and B16-B16/Dx, were treated with 5 mg/kg of A1S2Pc and laser light (100 mW/cm2 x 10 min of exposure) or with doxorubicin (10 or 12 mg/kg i.v.). The results show that PDT is active versus all tumors while doxorubicin is effective only against the three sensitive tumor lines (L1210, P388 and B16). These observations suggest that PDT might be a beneficial alternative treatment for drug-resistant tumors.

Animals↗
PubMed1995

Clastogenicity of anthraquinones in V79 and in three derived cell lines expressing P450 enzymes.

The clastogenicity of seven anthraquinones was investigated in a V79 Chinese hamster cell line expressing only the reductive pathway enzymes and in three derived cell lines transfected and expressing three rat cytochrome P450 (1A1, 1A2, 2B1). The results have shown that chromosomal aberrations are modulated in similar manner both in parental and transfected V79 cell lines, suggesting that the clastogenicity of these compounds is not mediated by cytochrome P450 dependent monooxygenases.

Animals↗
PubMed1995

Atrial septal aneurysm and cardiac arrhythmias.

Atrial septal aneurysm has been associated with thromboembolic events, interatrial shunting, mitral valve prolapse, and systolic click. An association between atrial septal aneurysm and cardiac arrhythmias has been also described. Twenty patients with atrial septal aneurysm and 19 control subjects performed 24-h Holter monitoring. Frequent (> 10/h) atrial premature beats were observed in seven patients vs. none of the controls (P = 0.008). The mean number of episodes of supraventricular tachycardia and the prevalence of ventricular tachycardia were also higher in the atrial septal aneurysm group (P = 0.044 and P = 0.046, respectively). Left atrial enlargement, mitral valve prolapse and left ventricular hypertrophy were more frequent than in the normal subjects. In conclusion, atrial and ventricular 'complex' arrhythmias occurred more frequently in patients with atrial septal aneurysm than in normal subjects. Further studies in patients with atrial septal aneurysm without other associated echocardiographic abnormalities need to be done to ascertain a potential arrhythmogenicity of this condition.

Adult↗
PubMed1995

Plasma endothelin-1 levels, pulmonary hypertension, and lung fibrosis in patients with systemic sclerosis.

PURPOSE: To investigate the behavior of circulating endothelin (ET)-1 concentrations in patients affected by systemic sclerosis, and to elucidate the possible relationships existing in this disease among plasma peptide levels, pulmonary hypertension, and lung fibrosis. PATIENTS AND METHODS: Circulating ET-1 levels were determined by reverse-phase, high-pressure liquid chromatography followed by sensitive radioimmunoassay in 20 patients affected by systemic sclerosis (18 women and 2 men, mean age 48.1 +/- 13.7 years) with or without pulmonary hypertension as evaluated by Doppler echocardiography, or lung fibrosis as measured by a score method based on lung examination by high-resolution computed tomography (HRCT). A group of 18 normal volunteers served as controls (15 women and 3 men, mean age 45.0 +/- 10.1 years). RESULTS: Plasma ET-1 levels were significantly higher (P < 0.001) in patients with systemic sclerosis (1.72 +/- 0.28 pg/mL) than in control subjects (0.63 +/- 0.06 pg/mL). Pulmonary artery systolic hypertension was detected in 10 patients (50%) with systemic sclerosis (56.2 +/- 18.0 mm Hg, range 37 to 97) versus none of the control subjects (30.2 +/- 2.2 mm Hg, P < 0.0001). Lung fibrosis was present in 12 patients (60%), with an HRCT overall score of 9.0 +/- 4.6. There were no significant differences in plasma ET-1 levels between patients with pulmonary hypertension (1.58 +/- 0.20 pg/mL) or without it (1.76 +/- 0.39 pg/mL, P = 0.188, not significant [NS]); or between patients with lung fibrosis (1.65 +/- 0.14 pg/mL) or without fibrosis (1.78 +/- 0.37 pg/mL, P = 0.290, NS). In particular, 6 patients had neither pulmonary hypertension nor lung fibrosis. In these patients, plasma ET-1 levels were similar compared with the others (1.85 +/- 0.49 versus 1.66 +/- 0.13, respectively; P = 0.180, NS). No correlations were observed between ET-1 levels and either pulmonary pressure levels or HRCT overall scores. CONCLUSIONS: The use of a sensitive assay, highly selective for ET-1, showed higher levels of circulating peptide in patients affected by systemic sclerosis than in control subjects. Neither pulmonary hypertension nor lung fibrosis was accompanied by a further rise in plasma ET-1 concentrations.

Adult↗
PubMed1995

Plasma endothelin-1 levels in patients with systemic sclerosis: influence of pulmonary or systemic arterial hypertension.

OBJECTIVES: To investigate the behaviour of circulating endothelin-1 (ET-1) in patients affected by systemic sclerosis and to elucidate the relationship between systemic and pulmonary plasma peptide and arterial pressure levels. METHODS: Plasma ET-1 concentrations were determined in 48 patients affected by systemic sclerosis (41 women, seven men; mean age 47.2 (SD 5.5) years) with or without systemic or pulmonary hypertension (or both). A group of 18 normal volunteers served as controls (15 women, three men; mean age 45.0 (10.1) years). RESULTS: Plasma ET-1 levels were significantly greater in patients affected by systemic sclerosis (1.65 (0.29) pg/ml) than in controls (0.63 (0.19) pg/ml) (p < 0.0001). Pulmonary artery systolic hypertension alone was present in 14 patients with systemic sclerosis (50.5 (8.49) mm Hg, range 37-67 mm Hg), and systemic hypertension alone (160.7 (5.9)/100.6 (3.2) mm Hg) was present in 11 patients. Both conditions were present in 12 patients, while 11 patients had systemic hypertension. There were no significant differences in plasma ET-1 levels between patients with pulmonary hypertension alone (1.62 (0.21) pg/ml) and those with systemic hypertension alone (1.65 (0.43) pg/ml). In particular, patients with normal pulmonary artery and systemic pressures (n = 11) had plasma ET-1 concentrations identical to those found in patients (n = 12) with both pulmonary and systemic hypertension (1.70 (0.15) v 1.64 (0.35) pg/ml, respectively). No correlations were observed between plasma ET-1 and either pulmonary or systemic pressures. CONCLUSION: Systemic sclerosis is characterised by increased plasma ET-1 levels, but neither pulmonary nor systemic hypertension are accompanied by further increase in plasma peptide levels.

Endothelins↗
PubMed1995

[Planar determination of the aortic valve area with transesophageal echocardiography with multiplanar probe in patients with aortic stenosis and insufficiency. Comparison with transthoracic Doppler echocardiography].

BACKGROUND: The simple determination of transaortic pressure gradient does not accurately assess the severity of an aortic valve stenosis. Thus, estimating the aortic valve area (AVA) is vital for clinical decision-making. Cardiac catheterization has been considered the "gold-standard" for the quantification of the stenotic valve area, but this technique may underestimate the actual valve area when aortic regurgitation is associated. Doppler transthoracic echocardiography (TTE) with the continuity equation method is usually employed for AVA estimation. Recently, in pure aortic stenosis, transesophageal echocardiography (TEE) has provided AVA values well-correlated to hemodynamic invasive results. METHODS: In this study, we correlated AVA values by TTE and multiplane TEE in 18 patients with combined aortic valve stenosis and regurgitation. RESULTS: The mean values of AVA by TEE and TTE were 0.74 +/- 0.12 and 0.68 +/- 0.55 cm2, respectively (p = NS). TEE-derived AVA correlated well to TTE-derived AVA (r = 0.816; p < 0.0001). Critical aortic stenosis was predicted by TEE with 100% sensitivity and specificity. Total time of examination was significantly longer for TTE (p < 0.00001). CONCLUSIONS: In conclusion, direct planimetry by multiplane TEE is a reliable method for AVA determination in aortic stenoinsufficiency. For this purpose, when the technical quality of TTE study is poor or when the patient is critically ill and does not tolerate a longer lasting TTE, multiplane TEE should be considered.

Adult↗