In this paper we present a methodology for the self-calibration of two microphone arrays based on... more In this paper we present a methodology for the self-calibration of two microphone arrays based on the localization of acoustic sources from volumetric acoustic maps, one for each array. A set of correspondences are obtained moving the acoustic source at different locations in space. The proposed algorithm estimates the rigid motion that brings the coordinate system of the second microphone array to the first one through the solution of a least squares problem. The approach presented here enables the self-calibration even ...
To evaluate changes in qualitative and quantitative parameters at high resolution CT (HRCT) and i... more To evaluate changes in qualitative and quantitative parameters at high resolution CT (HRCT) and in respiratory function indexes (RFI) after bronchodilator administration in COPD patients. Fifteen former smokers (9 male and 6 female, mean age 65 years), with COPD were studied. Patients with asthmatic or pulmonary diseases were excluded. After informed consent, the patients underwent blood gas analysis, baseline RFI (respiratory function index), inspiratory/expiratory HRCT, administration of salbutamol and bromide (by metered-dose inhaler), RFI after 45 minutes, and inspiratory/expiratory HRCT. First, we performed a visual qualitative analysis (by means of a preformed questionnaire), and then a quantitative analysis by "density mask" programme at three levels: aortic arch, carina, and supradiaphragmatic level. By using this diagnostic approach we were able to determined the global area of each lung, dependent and independent of density, bronchus-artery ratio, emphysema extension, air trapping, morphologic distortion of the airways. Data correlation analysed through linear regression statistical test. Outstanding correlations were found between the RFI (Raw, SVC, IC, RV, FEV1, VP70) and, respectively, density, global lung areas, and bronchus-artery ratio changes before and after bronchodilators administration. Our study confirmed the usefulness of bronchodilators and the need for a multiparametric and comparative (radiological and functional) approach to COPD, as well as the usefulness of HRCT in evaluating the response to visible airway physiologic stimulus and extension, and reversibility of air trapping.
Twenty asthmatic subjects had two successive methacholine challenges, two successive challenges w... more Twenty asthmatic subjects had two successive methacholine challenges, two successive challenges with ultrasonically nebulized distilled water (UNDW) and an UNDW followed by methacholine on three separate days. Only ten subjects showed a refractory period to repeated UNDW stimulation. Prior stimulation with UNDW provoked increased methacholine responsiveness in the non-refractory group and a more rapid recovery from methacholine-induced bronchoconstriction in the refractory subset.
Proceedings of the National Academy of Sciences, 2015
With its noncatalytic domains, DNA-binding regions, and a catalytic core targeting the histone ta... more With its noncatalytic domains, DNA-binding regions, and a catalytic core targeting the histone tails, LSD1-CoREST (lysine-specific demethylase 1; REST corepressor) is an ideal model system to study the interplay between DNA binding and histone modification in nucleosome recognition. To this end, we covalently associated LSD1-CoREST to semisynthetic nucleosomal particles. This enabled biochemical and biophysical characterizations of nucleosome binding and structural elucidation by small-angle X-ray scattering, which was extensively validated through binding assays and site-directed mutagenesis of functional interfaces. Our results suggest that LSD1-CoREST functions as an ergonomic clamp that induces the detachment of the H3 histone tail from the nucleosomal DNA to make it available for capture by the enzyme active site. The key notion emerging from these studies is the inherently competitive nature of the binding interactions because nucleosome tails, chromatin modifiers, transcription factors, and DNA represent sites for multiple and often mutually exclusive interactions. nucleosome | histone tails | molecular recognition | chromatin modification | small-angle X-ray scattering
The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a key regu... more The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a key regulator of angiogenesis. Here we show that VEGFR2 is acetylated in endothelial cells both at four lysine residues forming a dense cluster in the kinase insert domain and at a single lysine located in the receptor activation loop. These modifications are under dynamic control of the acetyltransferase p300 and two deacetylases HDAC5 and HDAC6. We demonstrate that VEGFR2 acetylation essentially regulates receptor phosphorylation. In particular, VEGFR2 acetylation significantly alters the kinetics of receptor phosphorylation after ligand binding, allowing receptor phosphorylation and intracellular signaling upon prolonged stimulation with VEGF. Molecular dynamics simulations indicate that acetylation of the lysine in the activation loop contributes to the transition to an open active state, in which tyrosine phosphorylation is favored by better exposure of the kinase target residues. These findings indicate that post-translational modification by acetylation is a critical mechanism that directly affects VEGFR2 function.
We describe 1,3,4-oxadiazole-containing hydroxamates (2) and 2-aminoanilides (3) as histone deace... more We describe 1,3,4-oxadiazole-containing hydroxamates (2) and 2-aminoanilides (3) as histone deacetylase inhibitors. Among them, 2t, 2x, and 3i were the most potent and selective against HDAC1. In U937 leukemia cells, 2t was more potent than SAHA in inducing apoptosis, and 3i displayed cell differentiation with a potency similar to MS-275. In several acute myeloid leukemia (AML) cell lines, as well as in U937 cells in combination with doxorubicin, 3i showed higher antiproliferative effects than SAHA.
Human femoral arteries were cultured up to 56 days. Samples were processed for light, immunohisto... more Human femoral arteries were cultured up to 56 days. Samples were processed for light, immunohistochemical, and transmission electron microscopy. Arteries became rapidly depopulated; at day 42, an endothelial lining (CD31(+), Weibel-Palade bodies) developed on the intima; endothelium was in continuity with mesenchymal stromal cells (CD44(+), CD90(low), CD105(low)) placed on adventitia. The media-adventitia area showed heterogeneous cell populations. In long-term organ culture, femoral artery develops a continuous cell coverage that differentiates to endothelium on the intima exclusively. This suggests that distinct topographical factors, such as resident progenitors and/or matrix signals, are able to regulate vascular homeostasis in adult life.
The International Journal of Biochemistry & Cell Biology, 2009
Aroyl-pyrrolyl-hydroxy-amides (APHAs) are a class of synthetic HDAC inhibitors described by us si... more Aroyl-pyrrolyl-hydroxy-amides (APHAs) are a class of synthetic HDAC inhibitors described by us since 2001. Through structure-based drug design, two isomers of the APHA lead compound 1, the 3-(2-benzoyl-1-methyl-1H-pyrrol-4-yl)-N-hydroxy-2-propenamide 2 and the 3-(2-benzoyl-1-methyl-1H-pyrrol-5-yl)-N-hydroxy-2-propenamide 3 (iso-APHAs) were designed, synthesized and tested in murine leukemia cells as antiproliferative and cytodifferentiating agents. To improve their HDAC activity and selectivity, chemical modifications at the benzoyl moieties were investigated and evaluated using three maize histone deacetylases: HD2, HD1-B (class I human HDAC homologue), and HD1-A (class II human HDAC homologue). Docking experiments on HD1-A and HD1-B homology models revealed that the different compounds selectivity profiles could be addressed to different binding modes as observed for the reference compound SAHA. Smaller hydrophobic cap groups improved class II HDAC selectivity through the interaction with HD1-A Asn89-Ser90-Ile91, while bulkier aromatic substituents increased class I HDAC selectivity.
Regenerative medicine challenges researchers to find noncontroversial, safe and abundant stem cel... more Regenerative medicine challenges researchers to find noncontroversial, safe and abundant stem cell sources. In this context, harvesting from asystolic donors could represent an innovative and unlimited reservoir of different stem cells. In this study, cadaveric vascular tissues were established as an alternative source of human cadaver mesenchymal stromal/stem cells (hC-MSCs). We reported the successful cell isolation from postmortem arterial segments stored in a tissue-banking facility for at least 5 years. After thawing, hC-MSCs were isolated with a high efficiency (12×10⁶) and characterized with flow cytometry, immunofluorescence, molecular and ultrastructural approaches. In early passages, hC-MSCs were clonogenic, highly proliferative and expressed mesenchymal (CD44, CD73, CD90, CD105, HLA-G), stemness (Stro-1, Oct-4, Notch-1), pericyte (CD146, PDGFR-β, NG2) and neuronal (Nestin) markers; hematopoietic and vascular markers were negative. These cells had colony and spheroid-forming abilities, multipotency for their potential to differentiate in multiple mesengenic lineages and immunosuppressive activity to counteract proliferation of phytohemagglutinin-stimulated blood mononuclear cells. The efficient procurement of stem cells from cadaveric sources, as postmortem vascular tissues, demonstrates that such cells can survive to prolonged ischemic insult, anoxia, freezing and dehydration injuries, thus paving the way for a scientific revolution where cadaver stromal/stem cells could effectively treat patients demanding cell therapies.
Static and dynamic lung volumes, arterial blood gases, alveolar ventilation and ventilation-perfu... more Static and dynamic lung volumes, arterial blood gases, alveolar ventilation and ventilation-perfusion (VA/Q) relationships were studied in 14 mild asthmatic patients and in 7 normal subjects (as controls) before and after fenoterol inhalation. Multiple nitrogen washout curves were analyzed by a bicompartmental distribution model, in order to assess the distribution of ventilation and VA/Q mismatch. At baseline, asthmatics showed mild airway obstruction and gas exchange impairment [forced expiratory volume in 1 s (FEV1) = 79% pred; PaO2 = 87.4; alveolar-arterial oxygen tension gradient (AaPO2) = 22.9 mm Hg]. By analysing nitrogen washout curves, an alveolar slow space representing 45.1% of total lung volume (vs. 36.8% in normals; p = 0.044) was identified; its alveolar ventilation per minute per unit lung volume (VA2/L2) was lower than in normals (p = 0.01). beta-Agonist inhalation by the asthmatics, which reversed airway obstruction (FEV1 = 98% pred.; p < 0.001) and improved gas exchange (PaO2 = 92.6 mm Hg, p < 0.001; AaPO2 = 16.8 mm Hg, p = 0.003), led to a highly significant increase in VA2/L2 (p = 0.001). The improvement in PaO2 was associated with the increase in VA2/L2 (r2 = 0.39; p = 0.017), but not with the increase in FEV1. Lastly, the changes in FEV1 and VA2/L2 were not correlated with each other. We conclude that even in mild stable asthma there is substantial unevenness of ventilation, detectable by bicompartmental analysis of nitrogen washout curves, which is responsible for gas exchange impairment and is not related to common spirometric parameters. In addition, the improvement in gas exchange is probably due to the effect of fenoterol on the tributary airways of the alveolar slow compartment. This effect can be assessed by this simple method, which can be used in clinical pharmacology studies and in the follow-up of asthmatic patients.
Background and purpose: To evaluate the benefits and the drawbacks of post-operative radiotherapy... more Background and purpose: To evaluate the benefits and the drawbacks of post-operative radiotherapy in completely resected Stage I (a and b) non-small cell lung cancer (NSCLC).
The reversible histone acetylation and deacetylation are epigenetic phenomena that play critical ... more The reversible histone acetylation and deacetylation are epigenetic phenomena that play critical roles in the modulation of chromatin topology and the regulation of gene expression. Aberrant transcription due to altered expression or mutation of genes that encode histone acetyltransferase (HAT) or histone deacetylase (HDAC) enzymes or their binding partners, has been clearly linked to carcinogenesis. The histone deacetylase inhibitors are a new promising class of anticancer agents (some of which in clinical trials), that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell-cycle arrest, terminal differentiation, and/or apoptosis. This report reviews the chemistry and the biology of HDACs and HDAC inhibitors, laying particular emphasis on agents actually in clinical trials for cancer therapy and on new potential anticancer lead compounds more selective and less toxic. ß 2005 Wiley Periodicals, Inc. Med Res Rev, 25, No. 3, 261-309, 2005
A new series of 2-, 3-, and 4-acylaminocinnamyl-N-hydroxyamides 1-3 have been prepared, and their... more A new series of 2-, 3-, and 4-acylaminocinnamyl-N-hydroxyamides 1-3 have been prepared, and their anti-HDAC (against maize HD2, HD1-B, and HD1-A enzymes) activities have been assessed. Cinnamyl-hydroxyamides bearing acylamino substituents at the C2 position of the benzene ring (compounds 1a-g) showed very low HDAC inhibiting activities, with IC(50) values in the high micromolar range. By shifting the same acylamino groups from C2 to C3 (compounds 2a-g) as well as C4 (compounds 3a-f) position of the benzene ring, a number of highly potent HDAC inhibitors have been obtained. In the anti-HD2 assay 3c (IC(50) = 11 nM) was the most potent compound, being >11600-, 4.5-, and 10-fold more potent than sodium valproate, SAHA, and HC-toxin, respectively, and showing the same activity as trapoxin. HD1-B and HD1-A assays have been performed to screen the inhibitory action of 1-3 against mammalian class I (HD1-B) and class II (HD1-A) HDAC homologous enzymes. From the corresponding IC(50) data, a selectivity ratio has been calculated. In general, compounds 1-3 showed no or little selectivity towards the class II homologue HD1-A, the most selective being 2a with class II selectivity ratio = 4.3. About the inhibitory potency, the 4-(2-naphthoylamino)cinnamyl-N-hydroxyamide 3f showed the highest inhibiting effect against the two enzymes (IC(50-HD1-B) = 36 nM; IC(50-HD1-A) = 42 nM). Selected 2 and 3 compounds will be evaluated to determine their antiproliferative and cyto differentiating activities on HL-60 cells.
Purpose: To report the evidence of a phase I trial planned to determine the maximum-tolerated dos... more Purpose: To report the evidence of a phase I trial planned to determine the maximum-tolerated dose (MTD) and related toxicity of weekly gemcitabine (GEM) and concurrent radiotherapy in patients with nonsmall-cell lung cancer (NSCLC). In addition, the response to treatment was evaluated and reported.
We have developed a mixed ester of hyaluronan with butyric and retinoic acid (HBR) that acted as ... more We have developed a mixed ester of hyaluronan with butyric and retinoic acid (HBR) that acted as a novel cardiogenic/vasculogenic agent in human mesenchymal stem cells isolated from bone marrow, dental pulp, and fetal membranes of term placenta (FMhMSCs). HBR remarkably enhanced vascular endothelial growth factor (VEGF), KDR, and hepatocyte growth factor (HGF) gene expression and the secretion of the angiogenic, mitogenic, and antiapoptotic factors VEGF and HGF, priming stem cell differentiation into endothelial cells. HBR also increased the transcription of the cardiac lineage-promoting genes GATA-4 and Nkx-2.5 and the yield of cardiac markerexpressing cells. These responses were notably more pronounced in FMhMSCs. FMhMSC transplantation into infarcted rat hearts was associated with increased capillary density, normalization of left ventricular function, and significant decrease in scar tissue. Transplantation of HBR-preconditioned FMhM-SCs further enhanced capillary density and the yield of human vWF-expressing cells, additionally decreasing the infarct size. Some engrafted, HBR-pretreated FMhMSCs were also positive for connexin 43 and cardiac troponin I. Thus, the beneficial effects of HBR-exposed FMhMSCs may be mediated by a large supply of angiogenic and antiapoptotic factors, and FMhMSC differentiation into vascular cells. These findings may contribute to further development in cell therapy of heart failure.
International Journal of Environmental Research and Public Health, 2014
Output water from dental unit waterlines (DUWLs) may be a potential source of infection for both ... more Output water from dental unit waterlines (DUWLs) may be a potential source of infection for both dental healthcare staff and patients. This study compared the efficacy of different disinfection methods with regard to the water quality and the presence of biofilm in DUWLs. Five dental units operating in a public dental health care setting were selected. The control dental unit had no disinfection system; two were disinfected intermittently with peracetic acid/hydrogen peroxide 0.26% and two underwent continuous disinfection with hydrogen peroxide/silver ions (0.02%) and stabilized chlorine dioxide (0.22%), respectively. After three months of applying the disinfection protocols, continuous disinfection systems OPEN ACCESS Int. J. Environ. Res. Public Health 2014, 11 2065
Acute mountain sickness is a common discomfort experienced by unacclimatized persons on ascent to... more Acute mountain sickness is a common discomfort experienced by unacclimatized persons on ascent to high altitude. We tested the hypothesis that exposure to high altitude affects cortical excitability using transcranial magnetic stimulation. We specifically analyzed the motor cortex excitability in normal subjects at high altitude and in a control condition near sea level. Mean resting motor threshold (RMT) was significantly higher at high altitude than at sea level (69.3 +/- 10.4 versus 56.3 +/- 10.9%; P = 0.042). Mean short intracortical inhibition (SICI) was significantly lower at high altitude than at sea level (percentage of test motor-evoked potential = 79.3 +/- 19.8 versus 28.7 +/- 17.5%; P = 0.0004). Symptoms of acute mountain sickness correlated with resting motor threshold changes induced by high altitude (R 2 = 0.53, P = 0.037). SaO2 correlated with SICI changes induced by high altitude (R 2 = 0.45, P = 0.036). We suggest that high altitude deeply changes cortical excitability by affecting both inhibitory and excitatory circuits and that this is reflected in acute mountain sickness symptoms.
In this paper we present a methodology for the self-calibration of two microphone arrays based on... more In this paper we present a methodology for the self-calibration of two microphone arrays based on the localization of acoustic sources from volumetric acoustic maps, one for each array. A set of correspondences are obtained moving the acoustic source at different locations in space. The proposed algorithm estimates the rigid motion that brings the coordinate system of the second microphone array to the first one through the solution of a least squares problem. The approach presented here enables the self-calibration even ...
To evaluate changes in qualitative and quantitative parameters at high resolution CT (HRCT) and i... more To evaluate changes in qualitative and quantitative parameters at high resolution CT (HRCT) and in respiratory function indexes (RFI) after bronchodilator administration in COPD patients. Fifteen former smokers (9 male and 6 female, mean age 65 years), with COPD were studied. Patients with asthmatic or pulmonary diseases were excluded. After informed consent, the patients underwent blood gas analysis, baseline RFI (respiratory function index), inspiratory/expiratory HRCT, administration of salbutamol and bromide (by metered-dose inhaler), RFI after 45 minutes, and inspiratory/expiratory HRCT. First, we performed a visual qualitative analysis (by means of a preformed questionnaire), and then a quantitative analysis by "density mask" programme at three levels: aortic arch, carina, and supradiaphragmatic level. By using this diagnostic approach we were able to determined the global area of each lung, dependent and independent of density, bronchus-artery ratio, emphysema extension, air trapping, morphologic distortion of the airways. Data correlation analysed through linear regression statistical test. Outstanding correlations were found between the RFI (Raw, SVC, IC, RV, FEV1, VP70) and, respectively, density, global lung areas, and bronchus-artery ratio changes before and after bronchodilators administration. Our study confirmed the usefulness of bronchodilators and the need for a multiparametric and comparative (radiological and functional) approach to COPD, as well as the usefulness of HRCT in evaluating the response to visible airway physiologic stimulus and extension, and reversibility of air trapping.
Twenty asthmatic subjects had two successive methacholine challenges, two successive challenges w... more Twenty asthmatic subjects had two successive methacholine challenges, two successive challenges with ultrasonically nebulized distilled water (UNDW) and an UNDW followed by methacholine on three separate days. Only ten subjects showed a refractory period to repeated UNDW stimulation. Prior stimulation with UNDW provoked increased methacholine responsiveness in the non-refractory group and a more rapid recovery from methacholine-induced bronchoconstriction in the refractory subset.
Proceedings of the National Academy of Sciences, 2015
With its noncatalytic domains, DNA-binding regions, and a catalytic core targeting the histone ta... more With its noncatalytic domains, DNA-binding regions, and a catalytic core targeting the histone tails, LSD1-CoREST (lysine-specific demethylase 1; REST corepressor) is an ideal model system to study the interplay between DNA binding and histone modification in nucleosome recognition. To this end, we covalently associated LSD1-CoREST to semisynthetic nucleosomal particles. This enabled biochemical and biophysical characterizations of nucleosome binding and structural elucidation by small-angle X-ray scattering, which was extensively validated through binding assays and site-directed mutagenesis of functional interfaces. Our results suggest that LSD1-CoREST functions as an ergonomic clamp that induces the detachment of the H3 histone tail from the nucleosomal DNA to make it available for capture by the enzyme active site. The key notion emerging from these studies is the inherently competitive nature of the binding interactions because nucleosome tails, chromatin modifiers, transcription factors, and DNA represent sites for multiple and often mutually exclusive interactions. nucleosome | histone tails | molecular recognition | chromatin modification | small-angle X-ray scattering
The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a key regu... more The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a key regulator of angiogenesis. Here we show that VEGFR2 is acetylated in endothelial cells both at four lysine residues forming a dense cluster in the kinase insert domain and at a single lysine located in the receptor activation loop. These modifications are under dynamic control of the acetyltransferase p300 and two deacetylases HDAC5 and HDAC6. We demonstrate that VEGFR2 acetylation essentially regulates receptor phosphorylation. In particular, VEGFR2 acetylation significantly alters the kinetics of receptor phosphorylation after ligand binding, allowing receptor phosphorylation and intracellular signaling upon prolonged stimulation with VEGF. Molecular dynamics simulations indicate that acetylation of the lysine in the activation loop contributes to the transition to an open active state, in which tyrosine phosphorylation is favored by better exposure of the kinase target residues. These findings indicate that post-translational modification by acetylation is a critical mechanism that directly affects VEGFR2 function.
We describe 1,3,4-oxadiazole-containing hydroxamates (2) and 2-aminoanilides (3) as histone deace... more We describe 1,3,4-oxadiazole-containing hydroxamates (2) and 2-aminoanilides (3) as histone deacetylase inhibitors. Among them, 2t, 2x, and 3i were the most potent and selective against HDAC1. In U937 leukemia cells, 2t was more potent than SAHA in inducing apoptosis, and 3i displayed cell differentiation with a potency similar to MS-275. In several acute myeloid leukemia (AML) cell lines, as well as in U937 cells in combination with doxorubicin, 3i showed higher antiproliferative effects than SAHA.
Human femoral arteries were cultured up to 56 days. Samples were processed for light, immunohisto... more Human femoral arteries were cultured up to 56 days. Samples were processed for light, immunohistochemical, and transmission electron microscopy. Arteries became rapidly depopulated; at day 42, an endothelial lining (CD31(+), Weibel-Palade bodies) developed on the intima; endothelium was in continuity with mesenchymal stromal cells (CD44(+), CD90(low), CD105(low)) placed on adventitia. The media-adventitia area showed heterogeneous cell populations. In long-term organ culture, femoral artery develops a continuous cell coverage that differentiates to endothelium on the intima exclusively. This suggests that distinct topographical factors, such as resident progenitors and/or matrix signals, are able to regulate vascular homeostasis in adult life.
The International Journal of Biochemistry & Cell Biology, 2009
Aroyl-pyrrolyl-hydroxy-amides (APHAs) are a class of synthetic HDAC inhibitors described by us si... more Aroyl-pyrrolyl-hydroxy-amides (APHAs) are a class of synthetic HDAC inhibitors described by us since 2001. Through structure-based drug design, two isomers of the APHA lead compound 1, the 3-(2-benzoyl-1-methyl-1H-pyrrol-4-yl)-N-hydroxy-2-propenamide 2 and the 3-(2-benzoyl-1-methyl-1H-pyrrol-5-yl)-N-hydroxy-2-propenamide 3 (iso-APHAs) were designed, synthesized and tested in murine leukemia cells as antiproliferative and cytodifferentiating agents. To improve their HDAC activity and selectivity, chemical modifications at the benzoyl moieties were investigated and evaluated using three maize histone deacetylases: HD2, HD1-B (class I human HDAC homologue), and HD1-A (class II human HDAC homologue). Docking experiments on HD1-A and HD1-B homology models revealed that the different compounds selectivity profiles could be addressed to different binding modes as observed for the reference compound SAHA. Smaller hydrophobic cap groups improved class II HDAC selectivity through the interaction with HD1-A Asn89-Ser90-Ile91, while bulkier aromatic substituents increased class I HDAC selectivity.
Regenerative medicine challenges researchers to find noncontroversial, safe and abundant stem cel... more Regenerative medicine challenges researchers to find noncontroversial, safe and abundant stem cell sources. In this context, harvesting from asystolic donors could represent an innovative and unlimited reservoir of different stem cells. In this study, cadaveric vascular tissues were established as an alternative source of human cadaver mesenchymal stromal/stem cells (hC-MSCs). We reported the successful cell isolation from postmortem arterial segments stored in a tissue-banking facility for at least 5 years. After thawing, hC-MSCs were isolated with a high efficiency (12×10⁶) and characterized with flow cytometry, immunofluorescence, molecular and ultrastructural approaches. In early passages, hC-MSCs were clonogenic, highly proliferative and expressed mesenchymal (CD44, CD73, CD90, CD105, HLA-G), stemness (Stro-1, Oct-4, Notch-1), pericyte (CD146, PDGFR-β, NG2) and neuronal (Nestin) markers; hematopoietic and vascular markers were negative. These cells had colony and spheroid-forming abilities, multipotency for their potential to differentiate in multiple mesengenic lineages and immunosuppressive activity to counteract proliferation of phytohemagglutinin-stimulated blood mononuclear cells. The efficient procurement of stem cells from cadaveric sources, as postmortem vascular tissues, demonstrates that such cells can survive to prolonged ischemic insult, anoxia, freezing and dehydration injuries, thus paving the way for a scientific revolution where cadaver stromal/stem cells could effectively treat patients demanding cell therapies.
Static and dynamic lung volumes, arterial blood gases, alveolar ventilation and ventilation-perfu... more Static and dynamic lung volumes, arterial blood gases, alveolar ventilation and ventilation-perfusion (VA/Q) relationships were studied in 14 mild asthmatic patients and in 7 normal subjects (as controls) before and after fenoterol inhalation. Multiple nitrogen washout curves were analyzed by a bicompartmental distribution model, in order to assess the distribution of ventilation and VA/Q mismatch. At baseline, asthmatics showed mild airway obstruction and gas exchange impairment [forced expiratory volume in 1 s (FEV1) = 79% pred; PaO2 = 87.4; alveolar-arterial oxygen tension gradient (AaPO2) = 22.9 mm Hg]. By analysing nitrogen washout curves, an alveolar slow space representing 45.1% of total lung volume (vs. 36.8% in normals; p = 0.044) was identified; its alveolar ventilation per minute per unit lung volume (VA2/L2) was lower than in normals (p = 0.01). beta-Agonist inhalation by the asthmatics, which reversed airway obstruction (FEV1 = 98% pred.; p < 0.001) and improved gas exchange (PaO2 = 92.6 mm Hg, p < 0.001; AaPO2 = 16.8 mm Hg, p = 0.003), led to a highly significant increase in VA2/L2 (p = 0.001). The improvement in PaO2 was associated with the increase in VA2/L2 (r2 = 0.39; p = 0.017), but not with the increase in FEV1. Lastly, the changes in FEV1 and VA2/L2 were not correlated with each other. We conclude that even in mild stable asthma there is substantial unevenness of ventilation, detectable by bicompartmental analysis of nitrogen washout curves, which is responsible for gas exchange impairment and is not related to common spirometric parameters. In addition, the improvement in gas exchange is probably due to the effect of fenoterol on the tributary airways of the alveolar slow compartment. This effect can be assessed by this simple method, which can be used in clinical pharmacology studies and in the follow-up of asthmatic patients.
Background and purpose: To evaluate the benefits and the drawbacks of post-operative radiotherapy... more Background and purpose: To evaluate the benefits and the drawbacks of post-operative radiotherapy in completely resected Stage I (a and b) non-small cell lung cancer (NSCLC).
The reversible histone acetylation and deacetylation are epigenetic phenomena that play critical ... more The reversible histone acetylation and deacetylation are epigenetic phenomena that play critical roles in the modulation of chromatin topology and the regulation of gene expression. Aberrant transcription due to altered expression or mutation of genes that encode histone acetyltransferase (HAT) or histone deacetylase (HDAC) enzymes or their binding partners, has been clearly linked to carcinogenesis. The histone deacetylase inhibitors are a new promising class of anticancer agents (some of which in clinical trials), that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell-cycle arrest, terminal differentiation, and/or apoptosis. This report reviews the chemistry and the biology of HDACs and HDAC inhibitors, laying particular emphasis on agents actually in clinical trials for cancer therapy and on new potential anticancer lead compounds more selective and less toxic. ß 2005 Wiley Periodicals, Inc. Med Res Rev, 25, No. 3, 261-309, 2005
A new series of 2-, 3-, and 4-acylaminocinnamyl-N-hydroxyamides 1-3 have been prepared, and their... more A new series of 2-, 3-, and 4-acylaminocinnamyl-N-hydroxyamides 1-3 have been prepared, and their anti-HDAC (against maize HD2, HD1-B, and HD1-A enzymes) activities have been assessed. Cinnamyl-hydroxyamides bearing acylamino substituents at the C2 position of the benzene ring (compounds 1a-g) showed very low HDAC inhibiting activities, with IC(50) values in the high micromolar range. By shifting the same acylamino groups from C2 to C3 (compounds 2a-g) as well as C4 (compounds 3a-f) position of the benzene ring, a number of highly potent HDAC inhibitors have been obtained. In the anti-HD2 assay 3c (IC(50) = 11 nM) was the most potent compound, being >11600-, 4.5-, and 10-fold more potent than sodium valproate, SAHA, and HC-toxin, respectively, and showing the same activity as trapoxin. HD1-B and HD1-A assays have been performed to screen the inhibitory action of 1-3 against mammalian class I (HD1-B) and class II (HD1-A) HDAC homologous enzymes. From the corresponding IC(50) data, a selectivity ratio has been calculated. In general, compounds 1-3 showed no or little selectivity towards the class II homologue HD1-A, the most selective being 2a with class II selectivity ratio = 4.3. About the inhibitory potency, the 4-(2-naphthoylamino)cinnamyl-N-hydroxyamide 3f showed the highest inhibiting effect against the two enzymes (IC(50-HD1-B) = 36 nM; IC(50-HD1-A) = 42 nM). Selected 2 and 3 compounds will be evaluated to determine their antiproliferative and cyto differentiating activities on HL-60 cells.
Purpose: To report the evidence of a phase I trial planned to determine the maximum-tolerated dos... more Purpose: To report the evidence of a phase I trial planned to determine the maximum-tolerated dose (MTD) and related toxicity of weekly gemcitabine (GEM) and concurrent radiotherapy in patients with nonsmall-cell lung cancer (NSCLC). In addition, the response to treatment was evaluated and reported.
We have developed a mixed ester of hyaluronan with butyric and retinoic acid (HBR) that acted as ... more We have developed a mixed ester of hyaluronan with butyric and retinoic acid (HBR) that acted as a novel cardiogenic/vasculogenic agent in human mesenchymal stem cells isolated from bone marrow, dental pulp, and fetal membranes of term placenta (FMhMSCs). HBR remarkably enhanced vascular endothelial growth factor (VEGF), KDR, and hepatocyte growth factor (HGF) gene expression and the secretion of the angiogenic, mitogenic, and antiapoptotic factors VEGF and HGF, priming stem cell differentiation into endothelial cells. HBR also increased the transcription of the cardiac lineage-promoting genes GATA-4 and Nkx-2.5 and the yield of cardiac markerexpressing cells. These responses were notably more pronounced in FMhMSCs. FMhMSC transplantation into infarcted rat hearts was associated with increased capillary density, normalization of left ventricular function, and significant decrease in scar tissue. Transplantation of HBR-preconditioned FMhM-SCs further enhanced capillary density and the yield of human vWF-expressing cells, additionally decreasing the infarct size. Some engrafted, HBR-pretreated FMhMSCs were also positive for connexin 43 and cardiac troponin I. Thus, the beneficial effects of HBR-exposed FMhMSCs may be mediated by a large supply of angiogenic and antiapoptotic factors, and FMhMSC differentiation into vascular cells. These findings may contribute to further development in cell therapy of heart failure.
International Journal of Environmental Research and Public Health, 2014
Output water from dental unit waterlines (DUWLs) may be a potential source of infection for both ... more Output water from dental unit waterlines (DUWLs) may be a potential source of infection for both dental healthcare staff and patients. This study compared the efficacy of different disinfection methods with regard to the water quality and the presence of biofilm in DUWLs. Five dental units operating in a public dental health care setting were selected. The control dental unit had no disinfection system; two were disinfected intermittently with peracetic acid/hydrogen peroxide 0.26% and two underwent continuous disinfection with hydrogen peroxide/silver ions (0.02%) and stabilized chlorine dioxide (0.22%), respectively. After three months of applying the disinfection protocols, continuous disinfection systems OPEN ACCESS Int. J. Environ. Res. Public Health 2014, 11 2065
Acute mountain sickness is a common discomfort experienced by unacclimatized persons on ascent to... more Acute mountain sickness is a common discomfort experienced by unacclimatized persons on ascent to high altitude. We tested the hypothesis that exposure to high altitude affects cortical excitability using transcranial magnetic stimulation. We specifically analyzed the motor cortex excitability in normal subjects at high altitude and in a control condition near sea level. Mean resting motor threshold (RMT) was significantly higher at high altitude than at sea level (69.3 +/- 10.4 versus 56.3 +/- 10.9%; P = 0.042). Mean short intracortical inhibition (SICI) was significantly lower at high altitude than at sea level (percentage of test motor-evoked potential = 79.3 +/- 19.8 versus 28.7 +/- 17.5%; P = 0.0004). Symptoms of acute mountain sickness correlated with resting motor threshold changes induced by high altitude (R 2 = 0.53, P = 0.037). SaO2 correlated with SICI changes induced by high altitude (R 2 = 0.45, P = 0.036). We suggest that high altitude deeply changes cortical excitability by affecting both inhibitory and excitatory circuits and that this is reflected in acute mountain sickness symptoms.
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Papers by S. Valente