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Biomedical subjects

P Paoletti

Publications and source records attributed to P Paoletti.

At least 19 recordsLinked to original sources
PubMed2001

Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors.

Pemetrexed disodium (ALIMTA), "pemetrexed") is a novel, multi-targeted antifolate that has demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung, breast, mesothelioma, colorectal, pancreatic, gastric, bladder, cervix, and head and neck. Pemetrexed inhibits multiple folate-dependent enzymes involved in both purine and pyrimidine synthesis including thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase. As a single agent, pemetrexed exhibits a moderate toxicity profile at a dose of 500 mg/m(2) by 10-minute infusion once every 21 days with myelosuppression being the dose-limiting toxicity. Folic acid added to the diet in preclinical studies reduced toxicities while maintaining antitumor activity. Based on this observation and clinical toxicities, folic acid and vitamin B(12) dietary supplementation has been recently introduced into all ongoing trials. Studies combining pemetrexed with other active chemotherapeutic agents demonstrate that these combination therapies may become important treatment regimens in a variety of cancer types. Currently, pemetrexed phase III trials are ongoing in mesothelioma and non-small cell lung cancer with future trials planned to explore this unique multitargeted antifolate.

Clinical Trials as Topic↗
PubMed2000

Molecular organization of a zinc binding n-terminal modulatory domain in a NMDA receptor subunit.

Ionotropic glutamate receptors (iGluRs) bind agonists in a domain that has been crystallized and shown to have a bilobed structure. Eukaryotic iGluRs also possess a second extracellular N-terminal domain related to the bacterial periplasmic binding protein LIVBP. In NMDA receptors, the high-affinity Zn inhibition is eliminated by mutations in the LIVBP-like domain of the NR2A subunit. Using LIVBP structure, we have modeled this domain as two lobes connected by a hinge and show that six residues controlling Zn inhibition form two clusters facing each other across a central cleft. Upon Zn binding the two lobes close tightly around the divalent cation. Thus, the extracellular region of NR2A consists of a tandem of Venus flytrap domains, one binding the agonist and the other a modulatory ligand. Such a functional organization may apply to other eukaryotic iGluRs.

Animals↗
PubMed1999

Higher dosage nicotine patches increase one-year smoking cessation rates: results from the European CEASE trial. Collaborative European Anti-Smoking Evaluation. European Respiratory Society.

The Collaborative European Anti-Smoking Evaluation (CEASE) was a European multicentre, randomized, double-blind placebo controlled smoking cessation study. The objectives were to determine whether higher dosage and longer duration of nicotine patch therapy would increase the success rate. Thirty-six chest clinics enrolled a total of 3,575 smokers. Subjects were allocated to one of five treatment arms: placebo and either standard or higher dose nicotine patches (15 mg and 25 mg daily) each given for 8 or 22 weeks with adjunctive moderately intensive support. The 12 month sustained success rates were: 25 mg patch for 22 weeks (L-25), 15.4%; 25 mg patch for 8 weeks (S-25), 15.9%; 15 mg patch for 22 weeks (L-15), 13.7%; 15 mg patch for 8 weeks (S-15), 11.7%; and placebo (P-0) 9.9% (placebo versus 15 mg, p<0.05; 25 mg versus 15 mg, p<0.03; 25 mg versus placebo, p<0.001, Chi-squared test). There was no significant difference in success rate between the two active treatment durations. Of the first week abstainers (n=1,698), 25.1% achieved success at 12 months as opposed to first week smokers, 2.7% of 1,877 subjects (p< 0.001). In summary, a higher than standard dose of nicotine patch was associated with an increase in the long-term success in smoking cessation but continuation of treatment beyond 8-12 weeks did not increase the success rates.

Administration, Cutaneous↗
PubMed1999

C-Linker of cyclic nucleotide-gated channels controls coupling of ligand binding to channel gating.

Cyclic nucleotide-gated channels are composed of a core transmembrane domain, structurally homologous to the voltage-gated K+ channels, and a cytoplasmic ligand-binding domain. These two modules are joined by approximately 90 conserved amino acids, the C-linker, whose precise role in the mechanism of channel activation by cyclic nucleotides is poorly understood. We examined cyclic nucleotide-gated channels from bovine photoreceptors and Caenorhabditis elegans sensory neurons that show marked differences in cyclic nucleotide efficacy and sensitivity. By constructing chimeras from these two channels, we identified a region of 30 amino acids in the C-linker (the L2 region) as an important determinant of activation properties. An increase in both the efficacy of gating and apparent affinity for cGMP and cAMP can be conferred onto the photoreceptor channel by the replacement of its L2 region with that of the C. elegans channel. Three residues within this region largely account for this effect. Despite the profound effect of the C-linker region on ligand gating, the identity of the C-linker does not affect the spontaneous, ligand-independent open probability. Based on a cyclic allosteric model of activation, we propose that the C-linker couples the opening reaction in the transmembrane core region to the enhancement of the affinity of the open channel for agonist, which underlies ligand gating.

Amino Acid Sequence↗
PubMed1998

Serum antibodies to benzo(a)pyrene diol epoxide-DNA adducts in the general population: effects of air pollution, tobacco smoking, and family history of lung diseases.

Polycyclic aromatic hydrocarbons (PAHs) are almost ubiquitous pollutants that may interact with metabolic systems in human tissues and eventually cause cancer. PAH-adducted DNA becomes antigenic and antibodies anti-benzo(a)pyrene diol epoxide (BPDE)-DNA may be found in serum of PAH-exposed subjects. The presence of serum antibodies anti-BPDE-DNA adduct was investigated in 1345 individuals from family clusters of the general population of a small area in central Italy in whom information about smoking habits, site of residence, and personal and family history of lung diseases, including cancer, were obtained. Anti-BPDE-DNA antibodies in the sera were detected with a direct ELISA and the association of anti-BPDE-DNA antibodies with subjects' data from a standardized respiratory questionnaire including age, occupation, tobacco smoking habits, respiratory symptoms, and family history of respiratory diseases was subsequently tested by multivariate logistic regression analysis. The overall prevalence of subjects with anti-BPDE-DNA antibodies was 21.0% (n=283), with no differences between males and females. Anti-BPDE-DNA positivity was associated with living in the urban area [odds ratio (OR), 1.49; 95% confidence interval (CI), 1.16-1.92], with active tobacco smoking (OR, 1.25; 95% CI, 1.06-1.48), and with family history of lung cancer (OR, 1.30; 95% CI, 0.90-1.88), and positivity increased with the number of members in the family cluster positive to anti-BPDE-DNA antibodies (OR, 1.30; 95% CI, 1.03-1.65). This study on a large general population sample indicates that serum anti-BPDE-DNA antibodies may be considered as biomarkers of exposure to environmental carcinogens and of DNA damage. The genetic and familial components of their association with tobacco smoking lend further support to the argument about the familial predisposition to lung cancer.

Adolescent↗
PubMed1998

Predictive value of interleukin 6 (IL-6), interleukin 8 (IL-8) and gastric intramucosal pH (pH-i) in major abdominal surgery.

OBJECTIVE: To study plasma concentrations of interleukin 6 (IL-6) and interleukin 8 (IL-8) in patients with splanchnic hypoxia, as documented by gastric intramucosal measurements (pH-i), during major abdominal surgery and the relationship between IL-6 and IL-8 concentrations and postoperative complications as well as clinical outcome. DESIGN: A prospective study. PATIENTS: Twelve patients scheduled for major abdominal surgery with no evidence of coexisting infectious disease. RESULTS: Six out of seven samples from patients with postoperative complications showed intraoperative pH-i levels lower than 7.32 and IL-6 levels higher than 300 pg/ml. Seven out of nine samples from patients without complications showed pH-i levels higher than 7.32 and IL-6 levels lower than 300 pg/ml. The difference in the pattern of distribution was statistically significant (p < 0.01). Only two out of seven samples of patients with postoperative complications showed intraoperative pH-i levels lower than 7.32 and IL-8 levels higher than 60 pg/ml. It was not possible to identify a clear distribution pattern of data points for IL-6 and IL-8 during the postoperative period. CONCLUSIONS: Intraoperative splanchnic ischemia, as documented by gastric intramucosal pH-i, is directly correlated to the increase of IL-6 plasma levels and to the incidence of postoperative complications, while IL-8 levels showed no correlation with surgical complications.

Adult↗
PubMed1998

Constraining ligand-binding site stoichiometry suggests that a cyclic nucleotide-gated channel is composed of two functional dimers.

Cyclic nucleotide-gated ion channels are composed of four pore-forming subunits. Binding of cyclic nucleotide to a site in the intracellular carboxyl terminus of each subunit leads to channel activation. Since there are four subunits, four binding events are possible. In this study, we investigate the effects of individual binding events on activation by studying channels containing one, two, three, or four functional binding sites. The binding of a single ligand significantly increases opening, although four ligands are required for full activation. The data are inconsistent with models in which the four subunits activate in a single concerted step (Monod-Wyman-Changeux model) or in four independent steps (Hodgkin-Huxley model). Instead, the four subunits may associate and activate as two independent dimers.

Animals↗
PubMed1998

The Po River Delta Respiratory Epidemiological Survey: an analysis of factors related to level of total serum IgE.

The purpose of the present study was to analyse whether sex, age, skin test reactivity, cigarette smoking and occupational exposure were related to the total serum immunoglobulin (Ig)E concentrations (kU x L[-1]), in a general population sample. We studied 1,905 subjects (915 males, 990 females) of a general population sample (n=2,841, 8-73 yrs) participating in the second cross-sectional respiratory epidemiological survey in the rural Po Delta area (near Venice, North Italy). Distribution of total serum IgE concentrations was skewed, thus a log-transformation was performed to obtain a Gaussian shape. Significantly higher values of IgE were found in males compared to females. In general, a peak of IgE concentration was found at 8-14 yrs. IgE values tended to be lower in older than younger adults. Significantly higher serum IgE levels were shown in subjects with a positive skin-prick test index (ST+) than in those with a negative skin-prick test index (ST-). There was a significant relationship of total IgE levels with skin reactivity to pollens and house-dust mites. In both sexes higher values of IgE were found in current smokers than in ex-nonsmokers, regardless of skin-test reactivity. There was no significant difference in IgE values between ex- and nonsmokers. Passive smoking and occupational exposure were significantly related to increased IgE values. Our results confirm that in a general population sample immunoglobulin E concentrations are related not only to skin-prick test reactivity to common aeroallergens, but also to other risk factors for chronic obstructive lung diseases, such as sex, active/ passive smoking and occupational exposure.

Adolescent↗
PubMed1997

High-affinity zinc inhibition of NMDA NR1-NR2A receptors.

Micromolar concentrations of extracellular Zn2+ are known to antagonize native NMDA receptors via a dual mechanism involving both a voltage-independent and a voltage-dependent inhibition. We have tried to evaluate the relative importance of these two effects and their subunit specificity on recombinant NMDA receptors expressed in HEK 293 cells and Xenopus oocytes. The comparison of NR1a-NR2A and NR1a-NR2B receptors shows that the voltage-dependent inhibition is similar in both types of receptors but that the voltage-independent inhibition occurs at much lower Zn2+ concentrations in NR1a-NR2A receptors (IC50 in the nanomolar range) than in NR1a-NR2B receptors (IC50 in the micromolar range). The high affinity of the effect observed with NR1a-NR2A receptors was found to be attributable mostly to the slow dissociation of Zn2+ from its binding site. By analyzing the effects of Zn2+ on varied combinations of NR1 (NR1a or NR1b) and NR2 (NR2A, NR2B, NR2C), we show that both the NR1 and the NR2 subunits contribute to the voltage-independent Zn2+ inhibition. We have observed further that under control conditions, i.e., in zero nominal Zn2+ solutions, the addition of low concentrations of heavy metal chelators markedly potentiates the responses of NR1a-NR2A receptors, but not of NR1a-NR2B receptors. This result suggests that traces of a heavy metal (probably Zn2+) contaminate standard solutions and tonically inhibit NR1a-NR2A receptors. Chelation of a contaminant metal also could account for the rapid NR2A subunit-specific potentiations produced by reducing compounds like DTT or glutathione.

Animals↗
PubMed1997

Evaluation of DNA damage in leukocytes of ex-smokers by single cell gel electrophoresis.

Single cell gel electrophoresis (SCGE), or comet assay, appears to be a promising tool to estimate DNA damage at the single cell level and it provides information on the presence of damage among individual cells. A follow-up study of 90 smokers who ceased smoking was undertaken to determine the possible decrease of DNA damage in their leukocytes. Before beginning the trial, volunteers smoked on average 26.1 +/- 8.4 cigarettes/day. Comet length did not correlate with the number of cigarettes/day or with the condensate tar content. At the end of the study, 28 volunteers had abandoned the trial, 40 volunteers relapsed into smoking at different times, but with a reduced number of cigarettes/day, whereas 22 fully succeeded in smoking cessation. Throughout the 5 sampling times, a great variability of comet length at individual level was found. However, after 1 year of follow-up, comet length means were found to be significantly shorter (p < 0.0001) in those volunteers who completely quit smoking compared to those who relapsed into smoking (27.2 +/- 1.6 vs. 31.9 +/- 5.1 microns, respectively), irrespective of the amount of cigarettes previously smoked. No effect of age or sex was found. Six months later, these results were confirmed by a further study carried out on a reduced sample of volunteers. The present data strongly suggest that, in spite of the great variability observed, 1 year of smoking cessation is associated with a significant reduction of DNA damage in circulating leukocytes.

Adult↗
PubMed1997

Presence and persistence of serum anti-benzo[a]pyrene diolepoxide-DNA adduct antibodies in smokers: effects of smoking reduction and cessation.

Among biomarkers of tobacco smoke (TS)-induced genotoxic damage, benzo[a]pyrene diolepoxide-DNA adducts (BPDE-DNA) are extensively studied. Adducted DNA becomes antigenic and antibodies anti-BPDE-DNA (BPDE-DNA-Abs) may be found in serum of exposed subjects. Little is known about the persistence of BPDE-DNA, and no study has been performed to evaluate the persistence of BPDE-DNA-Abs after cessation of exposure. Fifty heavy smokers, enrolled in a smoking cessation program with nicotine patch substitution therapy, were evaluated for the presence of BPDE-DNA-Abs before (w0) and 1, 3, 6 and 12 weeks (w1-12) after the start of the program. Nicotine or placebo patches were randomly assigned to the subjects. BPDE-DNA-Abs were determined in serum by non-competitive ELISA. After the start of the cessation program, 28 subjects quit smoking (group Q) and the other 22 reduced by about 75% the number of cigarettes smoked per day (group R). At the start of the program (w0) 8% of subjects were positive. At w1 the prevalence of positivity had increased both in subjects who quit smoking (Q: 21%) and in subjects who had reduced the number of cigarettes per day (R: 27%). Positivity remained stable up to w12 (21%) for group Q, whereas it increased to 41% in group R. Serum BPDE-DNA-Abs can be detected in smokers, and their persistence for months after smoking cessation suggests their usefulness for relatively long-term surveys. The low percentage of positivity in actual heavy smokers and the increase in antibody positivity with smoking cessation or reduction must be taken into account when interpreting serum BPDE-DNA-Ab measurement in exposed individuals.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1997

Mortality rates for respiratory disorders in Italy (1979-1990).

Trends in mortality rates for respiratory disorders were investigated in Italy from 1979 to 1990, using data from the Italian Central Statistical Institute (ISTAT). Mortality from lung cancer increased in all age groups, except for those aged 45-64 yrs after 1985. Respiratory diseases showed a consistent reduction; in particular, mortality from emphysema decreased slowly, and mortality from chronic bronchitis showed a significant reduction in all age groups. However, mortality from asthma increased markedly in all age groups up to 1985, and then levelled off and slightly decreased, although remaining at a higher level than in the 1970s. In 1990, data stratified for age group and gender indicated a higher mortality rate in males, that tended to be age-dependent, with the highest rate ratio male/female in those aged 65-74 yrs. Overall, these data indicate a trend to increased mortality from lung cancer and asthma in Italy in the 1980s.

Asthma↗
PubMed1996

Skin prick test reactivity to common aeroallergens in relation to total IgE, respiratory symptoms, and smoking in a general population sample of northern Italy.

Skin prick test (SPT) reactivity to common airborne allergens and its relationships to sex, age, smoking habits, and respiratory symptoms/diseases were evaluated in a general population sample (n = 2841, 8-75 years of age) living in the Po delta area (northern Italy). Subjects completed a standardized questionnaire and underwent prick tests (12 local allergens, a negative and a positive control) and determination of total serum IgE. Atopy was evaluated by measuring the maximal diameter for each allergen, after subtracting that of the negative control. Thirty-one percent of subjects showed a positive skin response at a 3-mm threshold. Pollens, Dermatophagoides pteronyssinus, and D. farinae caused the highest frequencies of reactions. Young people and those who had never smoked had higher prevalence rates of SPT reactivity. Asthma, asthma symptoms, and rhinitis were significantly associated with SPT reactivity in both sexes (cough only in females) and with the number of positive reactions. IgE values were also significantly associated with SPT reactivity. In conclusion, our findings indicate that almost one-third of the general population of an Italian rural area is skin test positive, emphasizing the importance of assessing atopy in respiratory epidemiologic surveys.

Adolescent↗