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Biomedical subjects

D Romeo

Publications and source records attributed to D Romeo.

At least 19 recordsLinked to original sources
PubMed2001

Sequential tamoxifen and aminoglutethimide versus tamoxifen alone in the adjuvant treatment of postmenopausal breast cancer patients: results of an Italian cooperative study.

PURPOSE: To determine whether switching patients from tamoxifen to antiaromatase treatment would prevent some of the relapses or deaths that we assume would occur if tamoxifen were continued. PATIENTS AND METHODS: Three hundred eighty postmenopausal breast cancer patients receiving adjuvant tamoxifen treatment for 3 years were randomized to either continue tamoxifen for 2 more years or to switch to low-dose aminoglutethimide (250 mg daily) for 2 years. RESULTS: At a median follow-up of 61 months (range, 5 to 94 months), 59 events occurred in the tamoxifen group, and 55 occurred in the aminoglutethimide group. More treatment failures at distant sites, such as viscera (P =.02), were observed in the tamoxifen group. Although no differences in disease-free survival between the two groups have emerged so far, a significant trend favors aminoglutethimide in overall survival (P =.005) and breast cancer-specific survival (P =.06). Even if more patients in the antiaromatase group complained of drug-related side effects and more of them discontinued treatment (P =.0001), the number of cardiovascular events and, in general, of life-threatening adverse events was higher in the tamoxifen arm. CONCLUSION: Switching patients from tamoxifen to aminoglutethimide treatment resulted in comparable event-free survival, but longer overall survival was achieved in patients who were switched to aminoglutethimide as compared with those who continued to receive tamoxifen. Should these preliminary results be confirmed by larger studies with a similar design, which are now testing the effectiveness of the new, more active, and tolerable aromatase inhibitors, sequencing tamoxifen with an aromatase inhibitor could become a preferable alternative to tamoxifen alone in early breast cancer patients.

Aged↗
PubMed2001

Serial color-word test predicts outcome of pharmacological treatment for panic disorder.

A group of 50 outpatients with Panic Disorder were given the Serial Color-Word Test at the beginning of a standard pharmacological treatment (selective serotonin reuptake inhibitors and benzodiazepines). A single treating psychiatrist, blind to test results, judged therapy outcome at a 5-mo. follow-up. Among the main types of adaptation to conflict assessed by the test (Stabilized, Cumulative, Dissociative, and Cumulative-Dissociative), the Stabilized pattern predicted a good therapy outcome. Response to therapy among the patients with a Stabilized pattern was judged as more often good and less often moderate or poor, compared with the members of the other three adaptation classes (p=.004), and specifically with the patients resorting to a Cumulative strategy (p=.005).

Adaptation, Psychological↗
PubMed2000

Aspartic protease inhibitors. An integrated approach for the design andsynthesis of diaminodiol-based peptidomimetics.

Aspartic proteases play key roles in a variety of pathologies, including acquired immunodeficiency syndrome. Peptidomimetic inhibitors can act as drugs to combat these pathologies. We have developed an integrated methodology for preparing human immunodeficiency virus (HIV)-1 aspartic protease diaminodiol inhibitors, based on a computational method that predicts the potential inhibitory activity of the designed structures in terms of calculated enzyme-inhibitor complexation energies. This is combined with a versatile synthetic strategy that couples a high degree of stereochemical control in the central diaminodiol module with complete flexibility in the choice of side chains in the core and in flanking residues. A series of 23 tetrameric, pentameric and hexameric inhibitors, with a wide range of calculated relative complexation energies (-47.2 to +117 kJ.mol-1) and predicted hydrophobicities (logPo/w = 1.8-8.4) was thus assembled from readily available amino acids and carboxylic acids. The IC50 values for these compounds ranged from 3.2 nM to 90 microM, allowing study of correlations between structure and activity, and individuation of factors other than calculated complexation energies that determine the inhibition potency. Multivariable regression analysis revealed the importance of side-chain bulkiness and rigidity at the P2, P2' positions, suggesting possible improvements for the prediction process used to select candidate structures.

Computational Biology↗
PubMed2000

Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. boccardo@hp380.ist.unige.it.

PURPOSE: To compare the efficacy of chemotherapy versus that of tamoxifen plus ovarian suppression in pre-/perimenopausal estrogen receptor-positive patients with early breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive either six cycles of a standard regimen of cyclophosphamide 100 mg/m(2) orally days 1 to 14, methotrexate 40 mg/m(2) intravenously (IV) days 1 and 8, and fluorouracil 600 mg/m(2) IV days 1 and 8 (CMF), with all drugs restarted on day 29, or 5 years of tamoxifen, 30 mg/d, plus ovarian suppression with surgical oophorectomy, ovarian irradiation, or monthly goserelin 3.6-mg injections. Disease-free survival was the main study end point. Overall survival and toxicity were additional end points. RESULTS: Between 1989 and 1997, 120 patients were assigned to CMF and 124 to tamoxifen and ovarian suppression (oophorectomy, n = 6; ovarian irradiation, n = 31; and goserelin injections, n = 87). At the time of analysis (median follow-up time, 76 months; range, 9 to 121 months), 82 patients had relapsed and 39 had died. No difference between groups had emerged with respect to either disease-free or overall survival. Treatments were comparable even in respect to age, tumor size, and nodal status, although a nonsignificant trend favored patients with poorly differentiated tumors treated with CMF. Leukopenia, nausea, vomiting, stomatitis, and alopecia were significantly more common in patients treated with CMF. There were few patients who developed benign gynecologic changes in either group, and numbers were comparable. CONCLUSION: The combination of tamoxifen with ovarian suppression seems to be safe and to yield comparable results relative to standard CMF.

Adult↗
PubMed2000

[The capacity of the rest-dobutamine gated SPECT protocol to predict contractile recovery after revascularization of myocardial dysinergic areas].

INTRODUCTION AND AIM: Gated-SPECT is a promising method to analyze myocardial viability. We have assessed the accuracy of a new protocol of rest/Dobutamine gated-SPECT, based on the evaluation of contractile reserve induced by 10 microg/kg/min of Dobutamine, to predict contractile recovery after revascularization of dysinergic myocardial territories. PATIENTS AND METHODS: In a group of 36 patients submitted to percutaneous revascularization, we selected 40 vascular territories (21 left descending artery, 19 right coronary-circumflex) with severely depressed contractility (contrast ventriculography, center line method). Follow up evaluation at 6 months showed the absence of angiographic restenosis and control contrast ventriculography assessed the contractile changes of the selected territories, considering those with contractile restoration as viable. Before revascularization, rest/Dobutamine gated-SPECT study was applied and viability was defined as the presence of contractile reserve (positive or improvement [n = 21] and negative or impairment [n = 7]) with non viability being the absence of contractile reserve (n = 12). We analyzed the evolution of the ejection fraction in a group of 27 patients with impaired ventricular function and complete revascularization. RESULTS: Gated-SPECT showed a sensitivity of 0.96 (95% CI 0.78-0.99) and a specificity of 0.78 (95% CI 0.48-0.94) in the diagnosis of viability. The ejection fraction (median [interquartile range]) increased after revascularization: 0.42 (0.15) vs 0.55 (0.22), Z = -3.9; p < 0. 001. The diagnosis of viability by gated-SPECT (p < 0.001) and the extent of severely depressed myocardium (p = 0.04) independently predicted the increase of the ejection fraction after revascularization. CONCLUSIONS: The analysis of contractile reserve by rest/Dobutamine gated-SPECT is adequate to diagnose viability in territories with severely depressed contractility and independently predicts the increase of ejection fraction after revascularization.

Adrenergic beta-Agonists↗
PubMed1999

[Validation of the three-dimensional method of sestamibi gated-SPECT in the calculation of the left ventricular ejection fraction in patients with ischemic heart disease. Comparison with contrast ventriculography].

INTRODUCTION AND OBJECTIVE: Tomography with acquisition synchronized with electrocardiography, gated-tomography, allows the assessment of left ventricular contractile function. The accuracy of a new method of gated-tomography, based on the three dimensional representation of the left ventricle to calculate the ejection fraction was validated by means of comparison with contrast ventriculography. METHODS: We studied 85 patients with ischemic cardiopathy, and ejection fraction was calculated by contrast ventriculography and sestamibi-gated-tomography, at rest and throughout 10 micrograms/kg/min of dobutamine. Furthermore, we assessed the extent of perfusion defect, as well as the number of segments with activity below 50% of the total 13 segments in which the tomographic slices were divided. RESULTS: Gated-tomography was significantly correlated to contrast ventriculography in the calculation of ejection fraction, both with acquisition at rest (r = 0.80) and throughout Dobutamine (r = 0.82). The average underestimation of gated-tomography calculation of ejection fraction was significantly greater for the rest study (-0.12 [IC 95% 0.04, -0.30]) than the dobutamine study (-0.07 [IC 95% 0.09, -0.24]). Patients with greater perfusion defects (4 o more segments) had no differences in underestimation of ejection fraction (-0.13 [IC 95% 0.03, -0.30] versus -0.11 [IC 95% 0.07, -0.29]). CONCLUSIONS: The three-dimensional method of gated-tomography accurately assesses the ejection fraction. The underestimation determined by this method was lower in the study done with viable doses of dobutamine. The extent of perfusion defect had no deleterious effect on gated-tomography in the calculation of ejection fraction.

Adult↗
PubMed1998

Identification of the start sites for the 1.9- and 1.4-kb rat transforming growth factor-beta1 transcripts and their effect on translational efficiency.

Three distinct transforming growth factor-beta1 (TGF-beta1) transcripts of 2.5, 1.9 and 1.4kb have been described, but the start sites and functional significance of the shorter transcripts are unknown. Here, we have cloned and sequenced a rat genomic fragment encoding approximately 1250 bases upstream of the start of the TGF-beta1 open reading frame. Using a combination of ribonuclease protection and 5' RACE-PCR analysis, we have mapped the start sites for the two shorter TGF-beta1 transcripts in NRP152 cells, a rat prostatic epithelial cell line that expresses all three transcripts at high levels. The 1.4-kb mRNA starts 25 bases upstream of the initiator AUG, whereas the 1.9-kb mRNA has two start sites 366 and 401 bases upstream of the AUG. Polysome analysis of the NRP152 cells indicates that the 1.9-kb transcript is very efficiently translated, whereas the 2.5- and 1.4-kb transcripts appear to be poorly translated. Differential regulation of TGF-beta1 transcript size may therefore represent an important mechanism for regulating TGF-beta1 protein levels.

Animals↗
PubMed1998

Wide-spectrum antibiotic activity of synthetic, amphipathic peptides.

PGYa and PGAa are synthetic, amphipathic, alpha-helical peptides that were designed using a novel "sequence template" approach. Their antimicrobial activity was tested against several pathogenic clinical isolates, most of which were multiply resistant to conventional antibiotics. PGYa appeared to be more active towards Gram-positive species (MIC = 0.5-4 microM), towards such Gram negative species as P. aeruginosa, X. maltophilia, E. coli, K. pneumoniae and S. enteritidis (MIC = 1.4 microM), and towards the filamentous fungus A. niger (MIC = 8 microM). Conversely, PGAa showed the greater activity towards three Candida species (MIC = 2.16 microM). The peptides were shown to have a bactericidal activity, resulting in a decrease of viability for both Gram-positive and -negative bacteria of 3-6 logs within 60 min. Scanning electron microscopy of S. aureus and E. coli treated with PGYa shows considerable roughening and blebbing of the bacterial surfaces providing conclusive evidence that the peptide is membrane active.

Anti-Bacterial Agents↗
PubMed1998

A computational study of the resistance of HIV-1 aspartic protease to the inhibitors ABT-538 and VX-478 and design of new analogues.

Recent experimental findings with HIV-1 protease (HIV-1 PR) mutants containing variations at four residues, M46I, L63P, V82T and I84V, have shown that only mutants containing the latter two exhibit cross resistance to the inhibitors ABT-538 and VX-478. The V82T and I84V modifications in fact concern residues in the active site while the other two are in the flap (M46I) and hinge (L63P) domains of the enzyme. We have modelled the M46I/L63P, V82T/I84V and M46I/L63P/ V82T/I84V (4X) mutants of HIV-PR and computed their complexation energies with these two inhibitors. A good correlation was found between these complexation energies and the trend in published inhibition constants for these inhibitors. Reasons for the decrease in binding affinities with the two critical mutants (V82T/I84V and 4X) have also been elucidated in detail. Based on these findings, we have designed several analogues of ABT-538 and VX-478, some of which show a better calculated binding affinity towards both mutant and wild type PR.

Binding Sites↗
PubMed1998

Rational design of inhibitors for drug-resistant HIV-1 aspartic protease mutants.

This report describes a method for the assessment of inhibitor binding affinities to wild type HIV-1 aspartic protease and to its drug-resistant mutant forms. We have elaborated a refined method for molecular modeling of the 3D structures of mutant enzymes and enzyme-inhibitor complexes based on the crystal structure of the wild type form, which employs a full thermodynamic cycle. Model complexes of four HIV-1 aspartic protease mutants with ten analogs of the A77003 inhibitor were considered. Predictions of inhibition efficiency, resistance potential, and hydrophilicity of the redesigned A77003 analogs were obtained by employing molecular mechanics for the evaluation of enzyme-inhibitor complexation energy and the polarizable continuum model for the estimation of solvent effects. Simple qualitative indicators for structural modifications aimed at overcoming the emergence of HIV resistance to protease inhibitors and at increasing the bioavailability of pseudopeptide inhibitors are examined. A semi-quantitative method for the description of enzyme-ligand binding and its implications for the rational design of inhibitors with higher binding affinity towards emerging HIV PR mutants is presented.

Aspartic Acid Endopeptidases↗
PubMed1997

Design of synthetic antimicrobial peptides based on sequence analogy and amphipathicity.

Novel alpha-helical antimicrobial peptides have been devised by comparing the N-terminal sequences of many of these peptides from insect, frog and mammalian families, extracting common features, and creating sequence templates with which to design active peptides. Determination of the most frequent amino acids in the first 20 positions for over 80 different natural sequences allowed the design of one peptide, while a further three were based on the comparison of the sequences of alpha-helical antimicrobial peptides derived from the mammalian cathelicidin family of precursors. These peptides were predicted to assume a highly amphipathic alpha-helical conformation, as indicated by high mean hydrophobic moments. In fact, circular dichroism experiments showed clear transitions from random coil in aqueous solution to an alpha-helical conformation on addition of trifluoroethanol. All four peptides displayed a potent antibacterial activity against selected gram-positive and gram-negative bacteria (minimum inhibitory concentrations in the range 1-8 microM), including some antibiotic resistant strains. Permeabilization of both the outer and cytoplasmic membranes of the gram-negative bacterium, Escherichia coli, by selected peptides was quite rapid and a dramatic drop in colony forming units was observed within 5 min in time-killing experiments. Permeabilization of the cytoplasmic membrane of the gram-positive bacterium, Staphylococcus aureus, was instead initially quite slow, gathering speed after 45 min, which corresponds to the time required for significant inactivation in time-killing studies. The cytotoxic activity of the peptides, determined on several normal and transformed cell lines, was generally low at values within the minimum inhibitory concentration range.

Amino Acid Sequence↗
PubMed1997

Recharacterization of the start sites for the major human transforming growth factor-beta 1 mRNA.

The start sites for the major human TGF-beta 1 transcripts have been reexamined. A comparison of ribonuclease and S1 nuclease protection analyses on native TGF-beta 1 mRNA and in vitro transcribed human TGF-beta 1 transcripts of defined sizes places the most 5' start site for the native TGF-beta 1 message approx. 50 nucleotides upstream from the previously published start site at base +1. Furthermore, the same techniques indicate that the apparent downstream start site at base +271 is an artefact due to the presence of an A + T-rich island in the middle of an otherwise highly G + C-rich sequence. This is not apparent if S1 nuclease protection is used alone, which emphasizes the importance of using the two techniques in combination for this type of analysis. Thus the major 2.5 kb TGF-beta 1 band seen on Northern blots comprises only mRNA transcribed from the more upstream of the two previously characterized promoters. This has important implications both for the transcriptional and translational regulation of this growth factor.

Base Composition↗
PubMed1997

Healthcare decisions and product labeling: results of a consumer comprehension study of prototype labeling for proposed over-the-counter cholestyramine.

This study was designed to determine whether randomly selected subjects could comprehend prototype consumer-oriented package labeling and inserts for over-the-counter cholestyramine, a nonsystemic lipid-lowering agent. The primary messages communicated in the label were that consumers should see their doctor before taking cholestyramine and should read the full package insert. In addition, the label communicated indication, dosage, and preparation, as well as key warnings about use with other medications. The insert reinforced the message about seeing the doctor before taking cholestyramine and before taking concurrent medications, further explained the purpose of the drug and its correct use, and provided information about the two types of cholesterol, risk factors for heart disease, and the importance of diet and exercise. A total of 1,806 randomly selected subjects were interviewed in their homes in 40 geographic regions. After examining the product container with one of the three labels being tested, they were given a questionnaire to test their understanding of the label communication points. They were then asked to read the package insert and tested on their understanding of the messages it communicated. Responses were analyzed by gender, age, and education level, as well as by label format. For the education-level subgroup analysis, the high-school-nongraduate group was supplemented by 419 subjects, for a total of 2,225 subjects. Statistical analyses were performed on completed questionnaires by an independent data analysis company. The net correct response to the two primary communication objectives was 99% among the total population. Responses to questions addressing the use of concurrent medications; types of cholesterol; purpose, dosage, and preparation of the medication; and diet and exercise were also clearly understood. This study showed a high level of comprehension of the purpose and correct use of cholestyramine among both high-school graduates and nongraduates.

Adolescent↗
PubMed1996

Purification and structural characterization of bovine cathelicidins, precursors of antimicrobial peptides.

Cathelicidins are a novel family of antimicrobial peptide precursors from mammalian myeloid cells. They are characterized by a conserved N-terminal region while the C-terminal antimicrobial domain can vary considerably in both primary sequence and length. Four cathelicidins, proBac5, proBac7, prododecapeptide and proBMAP-28, have been concurrently purified from bovine neutrophils, using simple and rapid methodologies. The correlation of ES-MS data from the purified proteins with their cDNA-deduced sequences has revealed several common features of their primary sequence, such as the presence of N-terminal 5-oxoproline (pyroglutamate) residues and two disulfide bridges in a 1-2, 3-4 arrangement. The N-terminal domains of the cathelicidins present one or two Asp-Pro bonds, which are particularly acid-labile in proBac5 and proBac7, but stable in prododecapeptide. This suggests that the spatial organization around these bonds may vary in different cathelicidins, and favour hydrolysis in some cases. An unexpected feature of the prododecapeptide is that it exists as dimers formed by three possible combinations of its two isoforms. The isolation of a truncated, monomeric form of this protein, lacking the cysteine-containing antimicrobial dodecapeptide, indicates that dimerization occurs via disulfide bridge formation at the level of the C-terminal domain and that the dodecapeptide is likely released as a dimer from its precursor. Sequence-based secondary structure predictions and CD results indicate for cathelicidins a 30-50% content of extended conformation and <20% content of alpha-helical conformation, with the alpha-helical segment placed near the N-terminus. Finally, similarity searching and topology-based structure prediction underline a significant sequential and structural similarity between the conserved N-terminal domain of cathelicidins and cystatin-like domains, placing this family within the cystatin superfamily. When assayed against cathepsin L, unlike the potent cystatin inhibitors, three of the four cathelicidins show only a poor inhibitory activity (Ki = 0.6-3 microM).

Amino Acid Sequence↗
PubMed1995

Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain.

A novel protein family, showing a conserved proregion and a variable C-terminal antimicrobial domain, and named cathelicidin, has been identified in mammalian myeloid cells. The conserved proregion shows sequence similarity to members of the cystatin superfamily of cysteine proteinase inhibitors. Cathelicidins are stored in the cytoplasmic granules of neutrophil leukocytes and release the antimicrobial peptides upon leukocyte activation. Some of these peptides can assume an alpha-helical conformation, others contain one or two disulfide bonds, still others are Pro- and Arg-rich, or Trp-rich. In addition to bacterial killing, some of these peptides exert additional functions related to host defense such as LPS-neutralization and promotion of wound healing.

Amino Acid Sequence↗
PubMed1994

Molecular cloning of Bac7, a proline- and arginine-rich antimicrobial peptide from bovine neutrophils.

Bac7 is a 7 kDa proline- and arginine-rich antimicrobial peptide which was purified from bovine neutrophils. We have used PCR to clone the cDNA of Bac7 precursor, a polypeptide of 21,569 Da. This cDNA is highly conserved in the 5' region, with respect to the corresponding region in the precursors of several other structurally unrelated myeloid antimicrobial peptides. Furthermore, a 148 nt non-coding region at the 3' end is 75% homologous to a corresponding region of the cDNA of the precursor of PR-39, a porcine antibacterial peptide which is also proline- and arginine-rich.

Amino Acid Sequence↗