domenico mattoscio | Ifom Ieo Campus (original) (raw)

Papers by domenico mattoscio

Research paper thumbnail of The SUMO conjugating enzyme UBC9 as a biomarker for cervical HPV infections

Ecancermedicalscience, 2015

Human papillomaviruses (HPVs) infect stratified epithelium and are the causative agents of cervic... more Human papillomaviruses (HPVs) infect stratified epithelium and are the causative agents of cervical cancer, the second most common cause of cancer-related death in women. A critical aspect that still persists in the HPV field is the selection of very sensitive and specific HPV diagnostic assays. Here, we provide evidence that the crucial small ubiquitin-like modifier (SUMO) E2-conjugating enzyme Ubc9 is strongly upregulated in cervical lesions. Ubc9 detection could thus be used in diagnosing and/or monitoring the progression of an HPV oncogenic infection.

Research paper thumbnail of SUMO pathway components as possible cancer biomarkers

Future Oncology, 2015

ABSTRACT SUMOylation is a key post-translational modification that regulates crucial cellular fu... more ABSTRACT SUMOylation is a key post-translational modification that regulates crucial cellular functions and pathological processes. Recently, Small Ubiquitin-related MOdifier (SUMO) modification has emerged as a fundamental route that may drive different steps of human tumorigenesis. Indeed, alteration in expression or activity of one of the different SUMO pathway components may completely subvert cellular properties through fine-tuning modulation of protein(s) involved in carcinogenic pathways, leading to altered cell proliferation, apoptosis resistance and metastatic potential. Here we describe some of the most interesting findings pointing to a clear link between SUMO pathway and human malignancies. Importantly, a putative role for SUMO enzymes to predict cancer behavior can be speculated, and thus the possible application of alterations in SUMO pathway components as tumor biomarkers is discussed.

Research paper thumbnail of Viral manipulation of cellular protein conjugation pathways: The SUMO lesson

World journal of virology, Jan 12, 2013

Small ubiquitin-like modifier (SUMO)ylation is a key post-translational modification mechanism th... more Small ubiquitin-like modifier (SUMO)ylation is a key post-translational modification mechanism that controls the function of a plethora of proteins and biological processes. Given its central regulatory role, it is not surprising that it is widely exploited by viruses. A number of viral proteins are known to modify and/or be modified by the SUMOylation system to exert their function, to create a cellular environment more favorable for virus survival and propagation, and to prevent host antiviral responses. Since the SUMO pathway is a multi-step cascade, viral proteins engage with it at many levels, to advance and favor each stage of a typical infection cycle: replication, viral assembly and immune evasion. Here we review the current knowledge on the interplay between the host SUMO system and viral lifecycle.

Research paper thumbnail of The Contribution of COX-1 and COX-2 to Platelet Activation in Essential Thrombocythemia: A Clinical Paradigm of Aspirin-resistant Thromboxane Biosynthesis

Research paper thumbnail of SUMO Ubc9 enzyme as a viral target

IUBMB Life, 2014

Viruses alter specific host cell targets to counteract possible defense mechanisms aimed at elimi... more Viruses alter specific host cell targets to counteract possible defense mechanisms aimed at eliminating infectivity and viral propagation. The SUMO conjugating enzyme Ubc9 functions as a hub for protein sumoylation, whilst also providing an interactive surface for sumoylated proteins through noncovalent interactions. The targeting of Ubc9 by viruses and viral proteins is thus highly beneficial for the disruption of both protein modification and protein-protein interaction mechanisms with which proteins increase their functional repertoire in cells. This review explores some of the clever mechanisms adopted by viruses to deregulate Ubc9, influence effector pathways and positively impact viral persistence consequently.

Research paper thumbnail of Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target

Research paper thumbnail of Circulating endothelial progenitor cells and cellular membrane microparticles in db/db diabetic mouse: possible implications in cerebral ischemic damage

AJP: Endocrinology and Metabolism, 2011

Research paper thumbnail of Cystic fibrosis transmembrane conductance regulator and Na+ channel subunits mRNA transcripts, and Cl- efflux, show a different distribution in rat duodenum and colon

Acta Physiologica Scandinavica, 2003

Research paper thumbnail of BC-box protein domain-related mechanism for VHL protein degradation

Proceedings of the National Academy of Sciences, 2013

The tumor suppressor VHL (von Hippel-Lindau) protein is a substrate receptor for Ubiquitin Cullin... more The tumor suppressor VHL (von Hippel-Lindau) protein is a substrate receptor for Ubiquitin Cullin Ring Ligase complexes (CRLs), containing a BC-box domain that associates to the adaptor Elongin B/C. VHL targets hypoxia-inducible factor 1α to proteasome-dependent degradation. Gam1 is an adenoviral protein, which also possesses a BC-box domain that interacts with the host Elongin B/C, thereby acting as a viral substrate receptor. Gam1 associates with both Cullin2 and Cullin5 to form CRL complexes targeting the host protein SUMO enzyme SAE1 for proteasomal degradation. We show that Gam1 protein expression induces VHL protein degradation leading to hypoxia-inducible factor 1α stabilization and induction of its downstream targets. We also characterize the CRL-dependent mechanism that drives VHL protein degradation via proteasome. Interestingly, expression of Suppressor of Cytokine Signaling (SOCS) domain-containing viral proteins and cellular BC-box proteins leads to VHL protein degradation, in a SOCS domain-containing manner. Our work underscores the exquisite ability of viral domains to uncover new regulatory mechanisms by hijacking key cellular proteins.

Research paper thumbnail of The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes

Journal of thrombosis and haemostasis : JTH, 2012

See also Lordkipanidze M, Harrison P. Aspirin twice a day keeps new COX-1 at bay. This issue, pp ... more See also Lordkipanidze M, Harrison P. Aspirin twice a day keeps new COX-1 at bay. This issue, pp 1217-9.

Research paper thumbnail of Cyanidin reduces preadipocyte differentiation and relative ChREBP expression

Journal of biological regulators and homeostatic agents

Adipogenesis is a continuous process even in adult adipose tissue for the presence of preadipocyt... more Adipogenesis is a continuous process even in adult adipose tissue for the presence of preadipocytes that, when subjected to appropriate stimuli can proliferate and differentiate. ChREBP, the essential transcription factor for lipogenesis, is expressed in all tissues, but mainly in lipogenic organs. In this study, we focused on ChREBP expression during preadipocytes differentiation. Since it was found that cyanidin-3 reduces body weight in mice even in the presence of a high-fat diet, by decreasing levels of blood glucose and by improving insulin sensitivity, we studied the effect of this substance on adipogenic differentiation. For this purpose we used preadipocytes obtained from subcutaneous and visceral human adipose explant tissue, characterized and stimulated to differentiate in selective media. On cytofluorimetric analysis these cells showed mesenchymal markers (CD29, CD90, CD44), whereas they were negative for hematopoietic markers (CD45, CD10, CD117,CD31). ChREBP expression levels were quantified by immunoelectron-microscopy and western blotting analysis. In this report we show that ChREBP is expressed in preadipocytes (both nuclear and cytoplasmic compartments); the cytoplasmic level of ChREBP increased by 50 percent on day seven of differentiation into mature adipocytes. Cyanidin reduced differentiation by 20 percent (as evaluated by red oil O staining) and the expression of ChREBP. In addition, cyanidin-treated cells showed abnormal morphology, a square shape with irregular size, probably due to the fact that cyanidin may interfere with the extracellular matrix. These findings suggest that dietary cyanidin, may have inhibitory effects on adipogenesis.

Research paper thumbnail of Clinical and laboratory phenotype associated with the aspirin-like defect

British Journal of Haematology, 2010

Research paper thumbnail of Transcriptional regulation of the human FPR2/ALX gene: evidence of a heritable genetic variant that impairs promoter activity

The FASEB Journal, Jan 1, 2012

Research paper thumbnail of CIRCULATING ENDOTHELIAL PROGENITOR CELLS AND RESIDUAL IN

Polycythemia vera (PV) is associated with high morbidity and mortality for thrombosis.

Research paper thumbnail of ASPIRIN-INSENSITIVE THROMBOXANE BIOSYNTHESIS IN POLYCYTHEMIA VERA

European Journal of …, Jan 1, 2008

The median survival for FHC/IgM stage I, II and III was 81.2, 41.5 and 27.3 months respectively, ... more The median survival for FHC/IgM stage I, II and III was 81.2, 41.5 and 27.3 months respectively, whereas that of FHC/platelet count was 89.3 (stage I), 44.1 (stage II) and 27.3 (stage III) respectively, the difference in their median survival being highly significant (FHC/IgM: p<0.0001, x2= 26.37; FHC/platelet: p<0.0001, x2=23.76). Similar results were obtained when the analysis was restricted to the 144 MM patients without renal insufficiency (FHC/IgM: p<0.0001, x2= 20.48; FHC/platelets: p<0.0001, x2=17.68) and to the 146 patients with active disease (at diagnosis and at relapse) (FHC/IgM: p<0.0001, x2= 22.74; FHC/platelets: p<0.0001, x2=19.36). However, in the subset of 100 patients at diagnosis the FHC/IgM (p=0.001, x2=13.02) was more effective than FHC/platelet SS (p=0.04, x2=6.44) in the three risk groups stratification. The results indicate that FHC levels, serum IgM and platelet count are independent prognostic markers of disease activity in MM and provide two easily achievable SS which are not affected by renal insufficiency and are effective for evaluating MM patients at presentation and during follow-up.

Research paper thumbnail of Proteomics investigation of human platelets in healthy donors and cystic fibrosis patients by shotgun nUPLC-MSE and 2DE: a comparative study

Mol. BioSyst., Jan 1, 2011

Research paper thumbnail of Cystic fibrosis transmembrane conductance regulator (CFTR) expression in human platelets: impact on mediators and mechanisms of the inflammatory response

The FASEB Journal, Jan 1, 2010

Research paper thumbnail of Circulating endothelial progenitor cells and residual in vivo thromboxane biosynthesis in low-dose aspirin-treated polycythemia vera patients

…, Jan 1, 2008

Although depression is known to be an independent risk factor for cardiovascular disorders, the m... more Although depression is known to be an independent risk factor for cardiovascular disorders, the mechanisms behind this connection are not well understood. However, the reduction in the number of endothelial progenitor cells (EPCs) in patients with cardiovascular risk factors has led us to hypothesize that depression influences the number of EPCs. EPCs labeled with CD34, CD133 and vascular endothelial growth factor receptor-2 (VEGFR2) antibodies were counted by flow cytometry in the peripheral blood (PB) of 33 patients with a current episode of major depression and of 16 control subjects. Mature (CD34 þ /VEGFR2 þ ) and immature (CD133 þ / VEGFR2 þ ) EPC counts were decreased in patients (vs controls; P < 0.01 for both comparisons), and there was a significant inverse relationship between EPC levels and the severity of depressive symptoms (P < 0.01 for both EPC phenotypes). Additionally, we assayed the plasma levels of VEGF, C-reactive protein (CRP) and tumor necrosis factor (TNF)-a and observed significantly elevated TNF-a concentrations in patients (vs controls; P < 0.05) and, moreover, a significant inverse correlation between TNF-a and EPC levels (P < 0.05). Moreover, by means of a quantitative RT-PCR approach, we measured CD34, CD133 and VEGFR2 mRNA levels of PB samples and found a net trend toward a decrease in all the investigated EPC-specific mRNA levels in patients as compared with controls. However, statistical significance was reached only for VEGFR2 and CD133 levels (P < 0.01 for both markers). This is the first paper that demonstrates evidence of decreased numbers of circulating EPCs in patients with a current episode of major depression.

Research paper thumbnail of The contribution of cyclooxygenase-1 and-2 to persistent thromboxane biosynthesis in aspirin-treated essential thrombocythemia: implications for antiplatelet therapy

…, Jan 1, 2010

We tested whether cyclooxygenase 2 (COX-2) expression and unacetylated COX-1 in newly formed plat... more We tested whether cyclooxygenase 2 (COX-2) expression and unacetylated COX-1 in newly formed platelets might contribute to persistent thromboxane (TX) biosynthesis in aspirin-treated essential thrombocythemia (ET). Forty-one patients on chronic aspirin (100 mg/day) and 24 healthy subjects were studied. Platelet COX-2 expression was significantly increased in patients and correlated with thiazole orange-positive platelets (r = 0.71, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001). The rate of TXA(2) biosynthesis in vivo, as reflected by urinary 11-dehydro-TXB(2) (TXM) excretion, and the maximal biosynthetic capacity of platelets, as reflected by serum TXB(2), were higher in patients compared with aspirin-treated healthy volunteers. Serum TXB(2) was significantly reduced by the selective COX-2 inhibitor NS-398 added in vitro. Patients were randomized to adding the selective COX-2 inhibitor, etoricoxib, or continuing aspirin for 7 days. Etoricoxib significantly reduced by approximately 25% TXM excretion and serum TXB(2). Fourteen of the 41 patients were studied again 21 (+/- 7) months after the first visit. Serum TXB(2) was consistently reduced by approximately 30% by adding NS398 in vitro, while it was completely suppressed with 50 microM aspirin. Accelerated platelet regeneration in most aspirin-treated ET patients may explain aspirin-persistent TXA(2) biosynthesis through enhanced COX-2 activity and faster renewal of unacetylated COX-1. These findings may help in reassessing the optimal antiplatelet strategy in ET.

Research paper thumbnail of The SUMO conjugating enzyme UBC9 as a biomarker for cervical HPV infections

Ecancermedicalscience, 2015

Human papillomaviruses (HPVs) infect stratified epithelium and are the causative agents of cervic... more Human papillomaviruses (HPVs) infect stratified epithelium and are the causative agents of cervical cancer, the second most common cause of cancer-related death in women. A critical aspect that still persists in the HPV field is the selection of very sensitive and specific HPV diagnostic assays. Here, we provide evidence that the crucial small ubiquitin-like modifier (SUMO) E2-conjugating enzyme Ubc9 is strongly upregulated in cervical lesions. Ubc9 detection could thus be used in diagnosing and/or monitoring the progression of an HPV oncogenic infection.

Research paper thumbnail of SUMO pathway components as possible cancer biomarkers

Future Oncology, 2015

ABSTRACT SUMOylation is a key post-translational modification that regulates crucial cellular fu... more ABSTRACT SUMOylation is a key post-translational modification that regulates crucial cellular functions and pathological processes. Recently, Small Ubiquitin-related MOdifier (SUMO) modification has emerged as a fundamental route that may drive different steps of human tumorigenesis. Indeed, alteration in expression or activity of one of the different SUMO pathway components may completely subvert cellular properties through fine-tuning modulation of protein(s) involved in carcinogenic pathways, leading to altered cell proliferation, apoptosis resistance and metastatic potential. Here we describe some of the most interesting findings pointing to a clear link between SUMO pathway and human malignancies. Importantly, a putative role for SUMO enzymes to predict cancer behavior can be speculated, and thus the possible application of alterations in SUMO pathway components as tumor biomarkers is discussed.

Research paper thumbnail of Viral manipulation of cellular protein conjugation pathways: The SUMO lesson

World journal of virology, Jan 12, 2013

Small ubiquitin-like modifier (SUMO)ylation is a key post-translational modification mechanism th... more Small ubiquitin-like modifier (SUMO)ylation is a key post-translational modification mechanism that controls the function of a plethora of proteins and biological processes. Given its central regulatory role, it is not surprising that it is widely exploited by viruses. A number of viral proteins are known to modify and/or be modified by the SUMOylation system to exert their function, to create a cellular environment more favorable for virus survival and propagation, and to prevent host antiviral responses. Since the SUMO pathway is a multi-step cascade, viral proteins engage with it at many levels, to advance and favor each stage of a typical infection cycle: replication, viral assembly and immune evasion. Here we review the current knowledge on the interplay between the host SUMO system and viral lifecycle.

Research paper thumbnail of The Contribution of COX-1 and COX-2 to Platelet Activation in Essential Thrombocythemia: A Clinical Paradigm of Aspirin-resistant Thromboxane Biosynthesis

Research paper thumbnail of SUMO Ubc9 enzyme as a viral target

IUBMB Life, 2014

Viruses alter specific host cell targets to counteract possible defense mechanisms aimed at elimi... more Viruses alter specific host cell targets to counteract possible defense mechanisms aimed at eliminating infectivity and viral propagation. The SUMO conjugating enzyme Ubc9 functions as a hub for protein sumoylation, whilst also providing an interactive surface for sumoylated proteins through noncovalent interactions. The targeting of Ubc9 by viruses and viral proteins is thus highly beneficial for the disruption of both protein modification and protein-protein interaction mechanisms with which proteins increase their functional repertoire in cells. This review explores some of the clever mechanisms adopted by viruses to deregulate Ubc9, influence effector pathways and positively impact viral persistence consequently.

Research paper thumbnail of Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target

Research paper thumbnail of Circulating endothelial progenitor cells and cellular membrane microparticles in db/db diabetic mouse: possible implications in cerebral ischemic damage

AJP: Endocrinology and Metabolism, 2011

Research paper thumbnail of Cystic fibrosis transmembrane conductance regulator and Na+ channel subunits mRNA transcripts, and Cl- efflux, show a different distribution in rat duodenum and colon

Acta Physiologica Scandinavica, 2003

Research paper thumbnail of BC-box protein domain-related mechanism for VHL protein degradation

Proceedings of the National Academy of Sciences, 2013

The tumor suppressor VHL (von Hippel-Lindau) protein is a substrate receptor for Ubiquitin Cullin... more The tumor suppressor VHL (von Hippel-Lindau) protein is a substrate receptor for Ubiquitin Cullin Ring Ligase complexes (CRLs), containing a BC-box domain that associates to the adaptor Elongin B/C. VHL targets hypoxia-inducible factor 1α to proteasome-dependent degradation. Gam1 is an adenoviral protein, which also possesses a BC-box domain that interacts with the host Elongin B/C, thereby acting as a viral substrate receptor. Gam1 associates with both Cullin2 and Cullin5 to form CRL complexes targeting the host protein SUMO enzyme SAE1 for proteasomal degradation. We show that Gam1 protein expression induces VHL protein degradation leading to hypoxia-inducible factor 1α stabilization and induction of its downstream targets. We also characterize the CRL-dependent mechanism that drives VHL protein degradation via proteasome. Interestingly, expression of Suppressor of Cytokine Signaling (SOCS) domain-containing viral proteins and cellular BC-box proteins leads to VHL protein degradation, in a SOCS domain-containing manner. Our work underscores the exquisite ability of viral domains to uncover new regulatory mechanisms by hijacking key cellular proteins.

Research paper thumbnail of The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes

Journal of thrombosis and haemostasis : JTH, 2012

See also Lordkipanidze M, Harrison P. Aspirin twice a day keeps new COX-1 at bay. This issue, pp ... more See also Lordkipanidze M, Harrison P. Aspirin twice a day keeps new COX-1 at bay. This issue, pp 1217-9.

Research paper thumbnail of Cyanidin reduces preadipocyte differentiation and relative ChREBP expression

Journal of biological regulators and homeostatic agents

Adipogenesis is a continuous process even in adult adipose tissue for the presence of preadipocyt... more Adipogenesis is a continuous process even in adult adipose tissue for the presence of preadipocytes that, when subjected to appropriate stimuli can proliferate and differentiate. ChREBP, the essential transcription factor for lipogenesis, is expressed in all tissues, but mainly in lipogenic organs. In this study, we focused on ChREBP expression during preadipocytes differentiation. Since it was found that cyanidin-3 reduces body weight in mice even in the presence of a high-fat diet, by decreasing levels of blood glucose and by improving insulin sensitivity, we studied the effect of this substance on adipogenic differentiation. For this purpose we used preadipocytes obtained from subcutaneous and visceral human adipose explant tissue, characterized and stimulated to differentiate in selective media. On cytofluorimetric analysis these cells showed mesenchymal markers (CD29, CD90, CD44), whereas they were negative for hematopoietic markers (CD45, CD10, CD117,CD31). ChREBP expression levels were quantified by immunoelectron-microscopy and western blotting analysis. In this report we show that ChREBP is expressed in preadipocytes (both nuclear and cytoplasmic compartments); the cytoplasmic level of ChREBP increased by 50 percent on day seven of differentiation into mature adipocytes. Cyanidin reduced differentiation by 20 percent (as evaluated by red oil O staining) and the expression of ChREBP. In addition, cyanidin-treated cells showed abnormal morphology, a square shape with irregular size, probably due to the fact that cyanidin may interfere with the extracellular matrix. These findings suggest that dietary cyanidin, may have inhibitory effects on adipogenesis.

Research paper thumbnail of Clinical and laboratory phenotype associated with the aspirin-like defect

British Journal of Haematology, 2010

Research paper thumbnail of Transcriptional regulation of the human FPR2/ALX gene: evidence of a heritable genetic variant that impairs promoter activity

The FASEB Journal, Jan 1, 2012

Research paper thumbnail of CIRCULATING ENDOTHELIAL PROGENITOR CELLS AND RESIDUAL IN

Polycythemia vera (PV) is associated with high morbidity and mortality for thrombosis.

Research paper thumbnail of ASPIRIN-INSENSITIVE THROMBOXANE BIOSYNTHESIS IN POLYCYTHEMIA VERA

European Journal of …, Jan 1, 2008

The median survival for FHC/IgM stage I, II and III was 81.2, 41.5 and 27.3 months respectively, ... more The median survival for FHC/IgM stage I, II and III was 81.2, 41.5 and 27.3 months respectively, whereas that of FHC/platelet count was 89.3 (stage I), 44.1 (stage II) and 27.3 (stage III) respectively, the difference in their median survival being highly significant (FHC/IgM: p<0.0001, x2= 26.37; FHC/platelet: p<0.0001, x2=23.76). Similar results were obtained when the analysis was restricted to the 144 MM patients without renal insufficiency (FHC/IgM: p<0.0001, x2= 20.48; FHC/platelets: p<0.0001, x2=17.68) and to the 146 patients with active disease (at diagnosis and at relapse) (FHC/IgM: p<0.0001, x2= 22.74; FHC/platelets: p<0.0001, x2=19.36). However, in the subset of 100 patients at diagnosis the FHC/IgM (p=0.001, x2=13.02) was more effective than FHC/platelet SS (p=0.04, x2=6.44) in the three risk groups stratification. The results indicate that FHC levels, serum IgM and platelet count are independent prognostic markers of disease activity in MM and provide two easily achievable SS which are not affected by renal insufficiency and are effective for evaluating MM patients at presentation and during follow-up.

Research paper thumbnail of Proteomics investigation of human platelets in healthy donors and cystic fibrosis patients by shotgun nUPLC-MSE and 2DE: a comparative study

Mol. BioSyst., Jan 1, 2011

Research paper thumbnail of Cystic fibrosis transmembrane conductance regulator (CFTR) expression in human platelets: impact on mediators and mechanisms of the inflammatory response

The FASEB Journal, Jan 1, 2010

Research paper thumbnail of Circulating endothelial progenitor cells and residual in vivo thromboxane biosynthesis in low-dose aspirin-treated polycythemia vera patients

…, Jan 1, 2008

Although depression is known to be an independent risk factor for cardiovascular disorders, the m... more Although depression is known to be an independent risk factor for cardiovascular disorders, the mechanisms behind this connection are not well understood. However, the reduction in the number of endothelial progenitor cells (EPCs) in patients with cardiovascular risk factors has led us to hypothesize that depression influences the number of EPCs. EPCs labeled with CD34, CD133 and vascular endothelial growth factor receptor-2 (VEGFR2) antibodies were counted by flow cytometry in the peripheral blood (PB) of 33 patients with a current episode of major depression and of 16 control subjects. Mature (CD34 þ /VEGFR2 þ ) and immature (CD133 þ / VEGFR2 þ ) EPC counts were decreased in patients (vs controls; P < 0.01 for both comparisons), and there was a significant inverse relationship between EPC levels and the severity of depressive symptoms (P < 0.01 for both EPC phenotypes). Additionally, we assayed the plasma levels of VEGF, C-reactive protein (CRP) and tumor necrosis factor (TNF)-a and observed significantly elevated TNF-a concentrations in patients (vs controls; P < 0.05) and, moreover, a significant inverse correlation between TNF-a and EPC levels (P < 0.05). Moreover, by means of a quantitative RT-PCR approach, we measured CD34, CD133 and VEGFR2 mRNA levels of PB samples and found a net trend toward a decrease in all the investigated EPC-specific mRNA levels in patients as compared with controls. However, statistical significance was reached only for VEGFR2 and CD133 levels (P < 0.01 for both markers). This is the first paper that demonstrates evidence of decreased numbers of circulating EPCs in patients with a current episode of major depression.

Research paper thumbnail of The contribution of cyclooxygenase-1 and-2 to persistent thromboxane biosynthesis in aspirin-treated essential thrombocythemia: implications for antiplatelet therapy

…, Jan 1, 2010

We tested whether cyclooxygenase 2 (COX-2) expression and unacetylated COX-1 in newly formed plat... more We tested whether cyclooxygenase 2 (COX-2) expression and unacetylated COX-1 in newly formed platelets might contribute to persistent thromboxane (TX) biosynthesis in aspirin-treated essential thrombocythemia (ET). Forty-one patients on chronic aspirin (100 mg/day) and 24 healthy subjects were studied. Platelet COX-2 expression was significantly increased in patients and correlated with thiazole orange-positive platelets (r = 0.71, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001). The rate of TXA(2) biosynthesis in vivo, as reflected by urinary 11-dehydro-TXB(2) (TXM) excretion, and the maximal biosynthetic capacity of platelets, as reflected by serum TXB(2), were higher in patients compared with aspirin-treated healthy volunteers. Serum TXB(2) was significantly reduced by the selective COX-2 inhibitor NS-398 added in vitro. Patients were randomized to adding the selective COX-2 inhibitor, etoricoxib, or continuing aspirin for 7 days. Etoricoxib significantly reduced by approximately 25% TXM excretion and serum TXB(2). Fourteen of the 41 patients were studied again 21 (+/- 7) months after the first visit. Serum TXB(2) was consistently reduced by approximately 30% by adding NS398 in vitro, while it was completely suppressed with 50 microM aspirin. Accelerated platelet regeneration in most aspirin-treated ET patients may explain aspirin-persistent TXA(2) biosynthesis through enhanced COX-2 activity and faster renewal of unacetylated COX-1. These findings may help in reassessing the optimal antiplatelet strategy in ET.