Publications by authors named "Francesca Martini"

74 Publications

LPHN3, a presynaptic adhesion-GPCR implicated in ADHD, regulates the strength of neocortical layer 2/3 synaptic input to layer 5.

Neural Dev 2014 Apr 17;9. Epub 2014 Apr 17.

Neurobiology Section, Division of Biology, University of California San Diego, La Jolla, CA 92093, USA.

Background: Latrophilins (LPHNs) are a small family of neuronal adhesion-GPCRs originally discovered as receptors for the black widow spider toxin α-latrotoxin. Mutations in LPHN3 have recently been identified as risk factors for attention deficit hyperactivity disorder (ADHD) in humans, but their physiological function has remained elusive. In this study, we tested two hypotheses regarding LPHN3 function: (1) LPHN3 regulates synaptic transmission by modulating probability of release; and (2) LPHN3 controls synapse development and the abundance of synapses.

Results: We manipulated LPHN3 expression in mouse layer 2/3 (L2/3) pyramidal neurons and examined the consequences on the L2/3 to L5 cortical microcircuit. Employing an optogenetic strategy combined with shRNA knockdown of LPHN3, we found that LPHN3 did not influence probability of release at synapses formed by L2/3 neurons onto L5 pyramidal cells. The strength of L2/3 afferent input to L5, however, was weakened by loss of LPHN3. Using Synaptophysin-GFP as an anatomical marker of presynaptic terminals, we found that the density of synapses formed by L2/3 axons in L5 was reduced when LPHN3 was lost. Finally, we investigated the structural organization of the extracellular domain of LPHN3. We used single particle negative stain electron microscopy to image the extracellular domain of LPHN3 and showed that the Olfactomedin and Lectin domains form a globular domain on an elongated stalk. Cell-based binding experiments with mutant proteins revealed that the Olfactomedin domain was required for binding to FLRT3, whereas both the Olfactomedin and Lectin domains were involved in binding to Teneurin 1. Mutant LPHN3 lacking the Olfactomedin domain was not capable of rescuing the deficit in presynaptic density following knockdown of endogenous LPHN3.

Conclusions: We find that LPHN3 regulates the number of synapses formed by L2/3 neurons in L5 and the strength of synaptic drive from the L2/3-L5 pathway. The Olfactomedin domain of LPHN3 is required for this effect on synapse number and binding to its postsynaptic ligand FLRT3. We propose that LPHN3 functions in synaptic development and is important in determining the connectivity rates between principal neurons in the cortex.
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http://dx.doi.org/10.1186/1749-8104-9-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996519PMC
April 2014

Modulation of COX, LOX and NFκB activities by Xanthium spinosum L. root extract and ziniolide.

Fitoterapia 2013 Dec 1;91:284-289. Epub 2013 Oct 1.

Departament de Farmacologia, Facultat de Farmacia, Universitat de Valencia, Av. Vicent Andrés Estellés, s/n. 46100 Burjassot, València, Spain; Centre for Pharmacognosy and Phytotherapy, University College London School of Pharmacy, 29-39 Brunswick Square, WC1N 1AX London, United Kingdom. Electronic address:

Xanthium spinosum L. (Asteraceae) is a medicinal weed distributed worldwide. Many of its diverse ethnopharmacological uses - namely diarrhoea, inflammation, liver disorders, snake bite and fever - are linked - at least in part - to an uncontrolled release of arachidonic acid metabolites. The crude extract of X. spinosum roots from Jordanian origin dose-dependently inhibited the 5-LOX (IC50 is approximately equal to 10 μg/mL), COX-1(IC50 is approximately equal to 50 μg/mL), and 12-LOX (IC50 is approximately equal to 170 μg/mL) enzymatic pathways in intact pro-inflammatory cells. A direct activity at the level of PLA2 is not probable, but the extract induced the synthesis of the anti-inflammatory eicosanoid 15(S)-HETE, which may in turn inhibit this enzyme. 5-LOX bioguided fractionation of the crude extract led to the isolation of ziniolide, a known 12,8-guaianolide sesquiterpene lactone, from the hydro-alcoholic fraction of the n-hexane extract (IC50=69 μM). Both the plant extract and ziniolide are in vitro inhibitors of the phorbol-induced NFκB activation, a key regulator of the arachidonic pathway.
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http://dx.doi.org/10.1016/j.fitote.2013.09.015DOI Listing
December 2013

Adaptive immunity, inflammation, and cardiovascular complications in type 1 and type 2 diabetes mellitus.

J Diabetes Res 2013 23;2013:184258. Epub 2013 May 23.

Institute of Cardiology, Catholic University, Largo A. Gemelli, Rome, Italy.

Diabetes mellitus (DM) is a pandemics that affects more than 170 million people worldwide, associated with increased mortality and morbidity due to coronary artery disease (CAD). In type 1 (T1) DM, the main pathogenic mechanism seems to be the destruction of pancreatic β -cells mediated by autoreactive T-cells resulting in chronic insulitis, while in type 2 (T2) DM primary insulin resistance, rather than defective insulin production due to β -cell destruction, seems to be the triggering alteration. In our study, we investigated the role of systemic inflammation and T-cell subsets in T1- and T2DM and the possible mechanisms underlying the increased cardiovascular risk associated with these diseases.
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http://dx.doi.org/10.1155/2013/184258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676957PMC
January 2014

When early experiences build a wall to others' emotions: an electrophysiological and autonomic study.

PLoS One 2013 10;8(4):e61004. Epub 2013 Apr 10.

Dept. of Neuroscience, Section of Physiology, University of Parma, Parma, Italy.

Facial expression of emotions is a powerful vehicle for communicating information about others' emotional states and it normally induces facial mimicry in the observers. The aim of this study was to investigate if early aversive experiences could interfere with emotion recognition, facial mimicry, and with the autonomic regulation of social behaviors. We conducted a facial emotion recognition task in a group of "street-boys" and in an age-matched control group. We recorded facial electromyography (EMG), a marker of facial mimicry, and respiratory sinus arrhythmia (RSA), an index of the recruitment of autonomic system promoting social behaviors and predisposition, in response to the observation of facial expressions of emotions. Results showed an over-attribution of anger, and reduced EMG responses during the observation of both positive and negative expressions only among street-boys. Street-boys also showed lower RSA after observation of facial expressions and ineffective RSA suppression during presentation of non-threatening expressions. Our findings suggest that early aversive experiences alter not only emotion recognition but also facial mimicry of emotions. These deficits affect the autonomic regulation of social behaviors inducing lower social predisposition after the visualization of facial expressions and an ineffective recruitment of defensive behavior in response to non-threatening expressions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061004PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622660PMC
October 2013

The oxidative modification of von Willebrand factor is associated with thrombotic angiopathies in diabetes mellitus.

PLoS One 2013 31;8(1):e55396. Epub 2013 Jan 31.

Institute of Internal Medicine and Geriatrics and Haemostasis Research Centre, Catholic University School of Medicine, Rome, Italy.

The thrombogenic activity of Von Willebrand factor (VWF) is proportional to its molecular size and inversely related to its proteolysis by ADAMTS-13. Oxidation of VWF severely impairs its proteolysis by the metalloprotease. This study was aimed at assessing in patients with type 1 and type 2 diabetes whether protein carbonyls, marker of oxidative stress, are associated with both the level and oxidation status of VWF as well as with micro- and macroangiopathic complications. Eighty-three diabetic patients (41 type 1 and 42 type 2 diabetic subjects) and their respective eighty-three healthy controls were studied after verifying the availability, through institutional databases, of clinical biochemistry records spanning at least 3 years. VWF and protein carbonyls were measured by immunoassays, whereas VWF multimers were studied by SDS-agarose gel electrophoresis. Type 2 diabetic subjects had higher levels of VWF antigen (VWF:ag), VWF activity (VWF:act) and plasma proteins' carbonyls compared to both their controls and type 1 diabetic subjects. Moreover, high molecular weight VWF multimers and specific VWF-bound carbonyls were significantly increased in subjects with micro- and macro-angiopathic complications. In both type 1 and type 2 diabetic subjects, ADAMTS-13 activity was in the normal range. In a multivariable analysis, only VWF-bound carbonyls were significantly associated with any form of thrombotic angiopathy in the entire group of T1- and T2 diabetic patients. These data provide first evidence that not only high VWF levels but also its oxidation status and the presence of high molecular weight VWF multimers that are not observed in SDS-agarose gel electrophoresis of normal subjects are associated with thrombotic angiopathies in diabetes mellitus. These findings may help identify diabetic patients particularly at risk for these complications and elucidate a new pathophysiological mechanism of thrombotic angiopathies in this clinical setting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055396PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561310PMC
July 2013

Effects of GLP-1 on forearm vasodilator function and glucose disposal during hyperinsulinemia in the metabolic syndrome.

Diabetes Care 2013 Mar 15;36(3):683-9. Epub 2012 Oct 15.

Department of Internal Medicine, University of Tor Vergata, Rome, Italy.

Objective: Patients with the metabolic syndrome (MetS) have impaired insulin-induced enhancement of vasodilator responses. The incretin hormone glucagon-like peptide 1 (GLP-1), beyond its effects on blood glucose, has beneficial actions on vascular function. This study, therefore, aimed to assess whether GLP-1 affects insulin-stimulated vasodilator reactivity in patients with the MetS.

Research Design And Methods: Forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in MetS patients before and after the addition of GLP-1 to an intra-arterial infusion of saline (n = 5) or insulin (n = 5). The possible involvement of oxidative stress in the vascular effects of GLP-1 in this setting was investigated by infusion of vitamin C (n = 5). The receptor specificity of GLP-1 effect during hyperinsulinemia was assessed by infusing its metabolite GLP-1(9-36) (n = 5). The metabolic actions of GLP-1 were also tested by analyzing forearm glucose disposal during hyperinsulinemia (n = 5).

Results: In MetS patients, GLP-1 enhanced endothelium-dependent and -independent responses to ACh and SNP, respectively, during hyperinsulinemia (P < 0.001 for both), but not during saline (P > 0.05 for both). No changes in vasodilator reactivity to ACh and SNP were seen after GLP-1 was added to insulin and vitamin C (P > 0.05 for both) and after GLP-1(9-36) was given during hyperinsulinemia (P > 0.05 for both). Also, GLP-1 did not affect forearm glucose extraction and uptake during hyperinsulinemia (P > 0.05 for both).

Conclusions: In patients with the MetS, GLP-1 improves insulin-mediated enhancement of endothelium-dependent and -independent vascular reactivity. This effect may be influenced by vascular oxidative stress and is possibly exerted through a receptor-mediated mechanism.
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http://dx.doi.org/10.2337/dc12-0763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579378PMC
March 2013

Novel high-sensitive D-dimer determination predicts chemotherapy-associated venous thromboembolism in intermediate risk lung cancer patients.

Clin Lung Cancer 2012 Nov 15;13(6):482-7. Epub 2012 May 15.

Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, Rome, Italy.

Introduction: We hypothesized that the use of a novel high sensitivity (HS) assay for D-dimer determination might ameliorate venous thromboembolism (VTE) risk prediction in intermediate risk lung cancer patients in whom chemotherapy could act as a trigger for VTE onset.

Patients And Methods: Pretreatment HS D-dimer levels were retrospectively evaluated in 108 lung cancer outpatients using a novel automated latex enhanced turbidimetric immunoassay. All patients were at the start of a new platinum-based chemotherapy regimen and were classified as intermediate risk according to Khorana's assessment model. Patients were followed-up for a median period of 6.9 months.

Results: Receiver operating characteristic (ROC) curves and corresponding Bayesian analysis showed that the best performance was obtained at a cutoff level of 1500 ng/mL, which resulted in a sensitivity of 81%, a specificity of 69%, a positive predictive value (PPV) of 31%, a negative predictive value (NPV) of 96%, and an accuracy of 70%. Patients with HS D-dimer levels above the cutoff had a worse VTE-free survival (60%) compared with those with levels below the cutoff (95%; P = .0001). Multivariate Cox proportional hazards survival analysis confirmed that pretreatment HS D-dimer levels were able to significantly predict VTE with a hazard ratio of 11 (95% confidence interval, 2.62-46.2; P = .001), independently of classic VTE risk factors.

Conclusions: The use of HS D-dimer determination prior to chemotherapy might allow for VTE risk stratification of intermediate risk cancer patients, helping in identifying those individuals who could benefit from thromboprophylaxis.
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http://dx.doi.org/10.1016/j.cllc.2012.03.005DOI Listing
November 2012

Association between increased tumor necrosis factor alpha levels and acquired activated protein C resistance in patients with metastatic colorectal cancer.

Int J Colorectal Dis 2012 Dec 12;27(12):1561-7. Epub 2012 May 12.

Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele Pisana, Via della Pisana 235, 00163, Rome, Italy.

Purpose: The purpose of this study was to investigate the possible association between tumor necrosis factor-α (TNF-α) levels and defects in the activated protein C (APC) system as a determinant of venous thromboembolism (VTE) in metastatic colorectal cancer patients (mCRC) undergoing chemotherapy.

Methods: TNF-α levels (measured by immunoassay) and abnormalities in the APC system [evaluated by an APC-dependent thrombin generation assay (ThromboPath-ThP)] were evaluated in 45 mCRC patients undergoing chemotherapy. VTE events were recorded during follow-up.

Results: TNF-α levels were increased (p < 0.01), and APC functionality was decreased (p < 0.0001) in mCRC patients compared to age- and sex-matched controls. An inverse correlation was observed between TNF-α and APC impairment in mCRC (p < 0.0001). TNF-α was confirmed as an independent predictor (p = 0.007) for APC abnormalities at multivariate regression analysis. Nine (20 %) of 45 mCRC patients experienced VTE during chemotherapy. Bayesian analysis of combined ThP/TNF-α showed a positive predictive value of 0.67 in predicting VTE (p = 0.01). Cox proportional hazards survival analysis confirmed the predictive value of combined ThP/TNF-α determination in VTE risk assessment of mCRC patients (either negative vs. both positive: HR = 0.02; p = 0.001), and Kaplan-Meier analysis demonstrated that mCRC patients with either negative TNF-α or ThP values prior to chemotherapy were less likely to experience VTE (13 %) than patients with abnormalities of both markers (67 %, p = 0.002).

Conclusions: These results suggest that the host inflammatory response to cancer cells and/or tumor-derived cytokines could be responsible for an impairment of the APC system and a switch toward a pro-thrombotic state, which might predispose to the occurrence of VTE in mCRC patients undergoing chemotherapy.
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http://dx.doi.org/10.1007/s00384-012-1493-8DOI Listing
December 2012

Palliative sedation in end-of-life care and survival: a systematic review.

J Clin Oncol 2012 Apr 12;30(12):1378-83. Epub 2012 Mar 12.

Istituto Scientifico Romagnolo per lo Studio e lCura dei Tumori, Meldola, Italy.

Purpose: Palliative sedation is a clinical procedure aimed at relieving refractory symptoms in patients with advanced cancer. It has been suggested that sedative drugs may shorten life, but few studies exist comparing the survival of sedated and nonsedated patients. We present a systematic review of literature on the clinical practice of palliative sedation to assess the effect, if any, on survival.

Methods: A systematic review of literature published between January 1980 and December 2010 was performed using MEDLINE and EMBASE databases. Search terms included palliative sedation, terminal sedation, refractory symptoms, cancer, neoplasm, palliative care, terminally ill, end-of-life care, and survival. A manual search of the bibliographies of electronically identified articles was also performed.

Results: Eleven published articles were identified describing 1,807 consecutive patients in 10 retrospective or prospective nonrandomized studies, 621 (34.4%) of whom were sedated. One case-control study was excluded from prevalence analysis. The most frequent reason for sedation was delirium in the terminal stages of illness (median, 57.1%; range, 13.8% to 91.3%). Benzodiazepines were the most common drug category prescribed. Comparing survival of sedated and nonsedated patients, the sedation approach was not shown to be associated with worse survival.

Conclusion: Even if there is no direct evidence from randomized clinical trials, palliative sedation, when appropriately indicated and correctly used to relieve unbearable suffering, does not seem to have any detrimental effect on survival of patients with terminal cancer. In this setting, palliative sedation is a medical intervention that must be considered as part of a continuum of palliative care.
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http://dx.doi.org/10.1200/JCO.2011.37.3795DOI Listing
April 2012

A case of esomeprazole-induced transient diabetes and hepatitis: the role of liver inflammation in the pathogenesis of insulin resistance.

Acta Diabetol 2014 Feb 3;51(1):151-3. Epub 2012 Mar 3.

Diabetes Care Unit, Catholic University, A. Gemelli Hospital, L. Go A. Gemelli, 00168, Rome, Italy,

We describe a case report of a patient who developed transient type 2 diabetes after a drug-induced (esomeprazole) sub-acute hepatitis. This case evidences the pathophysiological relevance, also in humans, of liver inflammation in the pathogenesis of type 2 diabetes.
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http://dx.doi.org/10.1007/s00592-012-0382-5DOI Listing
February 2014

Factor seven activating protease activity levels in women with recurrent pregnancy loss.

Reprod Sci 2012 Mar;19(3):317-21

Department of Laboratory Medicine & Advanced Biotechnologies, IRCCS San Raffaele Pisana, Rome, Italy.

This study was designed to analyze the changes in circulating factor seven activating protease (FSAP) levels in association with the thrombophilic state of 40 women with recurrent pregnancy loss (RPL). All women were trying to conceive and were prospectively followed up until the achievement of spontaneous pregnancy. The results obtained showed that plasma FSAP activity levels were higher in RPL than in fertile women (P < .001) and represented an adverse predictor of pregnancy at multivariate analysis (P = .002). In 7 consenting RPL women, FSAP activity levels increased continuously during pregnancy until the third trimester, remained elevated immediately after delivery, and declined 6-week postpartum, although at levels that were still above the range of control women. These results suggest that FSAP activity levels might provide useful information during pregnancy progression in at-risk women, possibly acting as a predictive factor for adverse pregnancy outcome in RPL even in the absence of other well recognized thrombophilic conditions.
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http://dx.doi.org/10.1177/1933719111424442DOI Listing
March 2012

Prospective comparison of prognostic scores in palliative care cancer populations.

Oncologist 2012 29;17(3):446-54. Epub 2012 Feb 29.

Palliative Care Clinic, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Via P. Maroncelli 40, 47014 Meldola (FC), Italy.

Purpose: Predicting prognosis in advanced cancer aids physicians in clinical decision making and can help patients and their families to prepare for the time ahead.

Materials And Methods: This multicenter, observational, prospective, nonrandomized population-based study evaluated life span prediction of four prognostic scores used in palliative care: the original palliative prognostic score (PaP Score), a variant of PaP Score including delirium (D-PaP Score), the Palliative Performance Scale, and the Palliative Prognostic Index.

Results: A total of 549 patients were enrolled onto the study. Median survival of the entire group was 22 days (95% confidence intervals [95% CI] = 19-24). All four prognostic models discriminated well between groups of patients with different survival probabilities. Log-rank tests were all highly significant (p < .0001). The PaP and D-PaP scores were the most accurate, with a C index of 0.72 (95% CI = 0.70-0.73) and 0.73 (95% CI = 0.71-0.74), respectively.

Conclusion: It can be confirmed that all four prognostic scores used in palliative care studies accurately identify classes of patients with different survival probabilities. The PaP Score has been extensively validated and shows high accuracy and reproducibility in different settings.
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http://dx.doi.org/10.1634/theoncologist.2011-0397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316931PMC
September 2012

Prospective observational Italian study on palliative sedation in two hospice settings: differences in casemixes and clinical care.

Support Care Cancer 2012 Nov 24;20(11):2829-36. Epub 2012 Feb 24.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy.

Purpose: Palliative sedation (PS) has been defined as the use of sedative medications to relieve intolerable suffering from refractory symptoms by a reduction in patient consciousness. It is sometimes necessary in end-of-life care when patients present refractory symptoms. We investigated PS for refractory symptoms in different hospice casemixes in order to (1) assess clinical decision-making, (2) monitor the practice of PS, and (3) examine the impact of PS on survival.

Methods: This observational longitudinal cohort study was conducted over a period of 9 months on 327 patients consecutively admitted to two 11-bed Italian hospices (A and B) with different casemixes in terms of median patient age (hospice A, 66 years vs. hospice B, 73 years; P = 0.005), mean duration of hospice stay (hospice A, 13.5 days vs. hospice B, 18.3 days; P = 0.005), and death rate (hospice A, 57.2% vs. hospice B, 89.9%; P < 0.0001). PS was monitored using the Richmond Agitation-Sedation Scale (RASS). Sedated patients constituted 22% of the total admissions and 31.9% of deceased patients, which did not prove to be significantly different in the two hospices after adjustment for casemix.

Results: Patient involvement in clinical decision-making about sedation was significantly higher in hospice B (59.3% vs. 24.4%; P = 0.007). Family involvement was 100% in both hospices. The maximum level of sedation (RASS, -5) was necessary in only 58.3% of sedated patients. Average duration of sedation was similar in the two hospices (32.2 h [range, 2.5-253.0]). Overall survival in sedated and nonsedated patients was superimposable, with a trend in favor of sedated patients.

Conclusions: PS represents a highly reproducible clinical intervention with its own indications, assessment methodologies, procedures, and results. It does not have a detrimental effect on survival.
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http://dx.doi.org/10.1007/s00520-012-1407-xDOI Listing
November 2012

Early changes of a novel APC-dependent thrombin generation assay during chemotherapy independently predict venous thromboembolism in cancer patients--a pilot study.

Support Care Cancer 2012 Nov 10;20(11):2713-20. Epub 2012 Feb 10.

Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele Pisana, Via della Pisana 235, 00163, Rome, Italy.

Purpose: Identifying cancer patients who are most at risk for venous thromboembolism (VTE) is essential to improve timely delivery of chemotherapy. Several studies have been performed to identify novel candidate biomarkers, but no agreement has yet been reached. In this light, we sought to analyze whether a dynamic evaluation of early changes of activated protein C (APC) function during chemotherapy could be predictive of a first VTE episode in cancer outpatients, thus improving risk stratification.

Methods: A retrospective single-center pilot study was conducted to investigate the adequacy of a dynamic evaluation of a novel APC-dependent thrombin generation assay (HemosIL ThromboPath (ThP)) in predicting VTE in 208 ambulatory cancer patients, enrolled on the basis of tight inclusion criteria, prior to start and before the second cycle of a new chemotherapy regimen.

Results: Retrospective analysis of samples showed the occurrence of an acquired APC resistance during chemotherapy, which was predictive of VTE. Univariate Cox proportional hazards survival analysis showed that early ThP changes predicted VTE (stable vs. decreasing ThP: hazard ratio (HR) 0.21; 95% CI 0.10-0.19; p < 0.0001), which was confirmed in the multivariate model (HR 0.25; CI 0.12-0.52, p < 0.0001). Stratification of patients according to a risk assessment model showed a 0.18 HR for stable vs. decreasing ThP assay results in an intermediate risk group.

Conclusions: We may thus conclude that early changes of ThP assay in patients on active chemotherapy enhance VTE risk stratification, helping in identifying a population of cancer patients who might benefit from thromboprophylaxis.
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http://dx.doi.org/10.1007/s00520-012-1391-1DOI Listing
November 2012

Semiempirical Hamiltonian for simulation of azobenzene photochemistry.

J Phys Chem A 2012 Jan 22;116(1):98-110. Epub 2011 Dec 22.

Dipartimento di Chimica e Chimica Industriale, Università di Pisa, v. Risorgimento 35, I-56126 Pisa, Italy.

We present a semiempirical Hamiltonian that provides an accurate description of the first singlet and triplet potential energy surfaces of azobenzene for use in direct simulations of the excited-state dynamics. The parameterization made use of spectroscopic and thermochemical data and the best ab initio results available to date. Two-dimensional potential energy surfaces based on constrained geometry optimizations are presented for the states that are most relevant for the photochemistry of azobenzene, namely, S(0), S(1), and S(2). In order to run simulations of the photodynamics of azobenzene in hydrocarbons or hydroxylic solvents, we determined the interactions of methane and methanol with the azo group by ab initio calculations and fitted the interactions with a QM/MM interaction Hamiltonian.
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http://dx.doi.org/10.1021/jp208574qDOI Listing
January 2012

Functional impairment in video terminal operators is related to low-grade inflammation.

Int Arch Occup Environ Health 2011 Oct 14;84(7):745-51. Epub 2010 Dec 14.

Laboratory of Thrombosis and Haemostasis, Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, Via della Pisana 235, Rome, Italy.

Purpose: Progressive functional impairments develop with chronic repetitive tasks possibly involving inflammatory mediators. Aim of this study was to analyze systemic inflammatory changes in relation to the possible occurrence of pain and/or disability in video terminal operators (VTOs) undergoing upper-extremity repetitive stress due to chronic overuse.

Methods: Pain assessments, classification, and grade of impairment relied on self-report questionnaires administered to 21 VTOs and to 21 matched controls. The inflammatory status of the enrolled subjects was analyzed by determination of serum high sensitive C-reactive protein (hs-CRP) as well as systemic levels or monocyte expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α).

Results: Serum levels of both cytokines were increased in VTOs compared to controls (P = 0.005 for TNF-α and P = 0.004 for IL-6). TNF-α levels correlated to IL-6 (P = 0.019), which, in turn, was associated to increased hs-CRP (P = 0.012). DASH score allowed to categorize VTOs according to disability. VTOs with mild (DASH = 22) or moderate (DASH = 46) disability (n = 10) had higher serum hs-CRP (P = 0.001) and IL-6 (P = 0.035) levels than VTOs without disabilities (DASH < 17) (n = 11). Monocyte stimulatory TNF-α expression was increased in individuals with mild/moderate disability. Monocyte expression of TNF-α was independently associated to that of IL-6, which, in turn, was associated to increased systemic hs-CRP levels together with mild/moderate functional impairment and weekly commitment to the display screen.

Conclusions: The results here reported indicate the occurrence of a low-grade inflammatory condition in VTOs with mild/moderate disability, which might allow the early recognition of arising musculoskeletal disorders induced by repetitive stress.
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http://dx.doi.org/10.1007/s00420-010-0605-4DOI Listing
October 2011

Platelet activation and vascular endothelial growth factor 165 release in hepatocellular cancer.

Clin Chim Acta 2011 Feb 25;412(5-6):450-4. Epub 2010 Nov 25.

Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, Rome, Italy.

Background: Vascular endothelial growth factor (VEGF₁₆₅) is stored, transported and released by platelets. Platelet functional abnormalities have been described in patients with hepatocellular carcinoma (HCC). Thus, this study was designed to investigate the behavior of VEGF₁₆₅ with respect to platelet activation in HCC.

Methods: Plasma and serum VEGF₁₆₅ and plasma sP-selectin levels were analyzed in patients with HCC (n=70) or cirrhosis (n=45) and control subjects (n=70). Given the thrombocytopenia that characterizes both HCC and cirrhotic patients, plasma VEGF₁₆₅ and sP-selectin as well as serum VEGF (plt-VEGF₁₆₅-load) levels were normalized by platelet counts.

Results: Median concentrations of plasma VEGF₁₆₅/platelet (p=0.002) and sP-selectin/platelet (p<0.0001) were higher in HCC or cirrhotic patients compared to controls. Moreover, sP-selectin/platelet was the only independent variable predictive of plasma VEGF₁₆₅/platelet at multivariate analysis (p<0.0001). Conversely, plt-VEGF₁₆₅-load correlated with tumor diameter (p<0.05) but not with sP-selectin/platelet and was an independent predictor for 5year overall survival (p=0.012).

Conclusions: The results obtained are suggestive for VEGF₁₆₅ release by tumor in HCC. It is plt-VEGF₁₆₅-load, but not plasma VEGF₁₆₅ or serum VEGF₁₆₅ that is an independent predictor for overall survival of HCC patients.
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http://dx.doi.org/10.1016/j.cca.2010.11.026DOI Listing
February 2011

Severe leucopenia associated with Sitagliptin use.

Diabetes Res Clin Pract 2011 Feb 29;91(2):e30-2. Epub 2010 Oct 29.

Department of Internal Medicine, Diabetes Care Unit, Catholic University School of Medicine, Rome, Italy.

We report the case of a type 2 diabetes subject who developed severe leucopenia associated with treatment with the dipeptidil-peptidase 4 enzyme inhibitor Sitagliptin and highlights DPP4 inhibitors as a possible cause of unexplained hematolgical abnormalities in patients receiving DPP4-inhibitor treatment.
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http://dx.doi.org/10.1016/j.diabres.2010.10.004DOI Listing
February 2011

VEGF-A gene promoter polymorphisms and microvascular complications in patients with essential hypertension.

Clin Biochem 2010 Sep 16;43(13-14):1090-5. Epub 2010 Jul 16.

Department of Laboratory Medicine & Advanced Biotechnologies, IRCCS San Raffaele, Rome, Italy.

Objectives: We investigated the possible involvement of vascular endothelial growth factor (VEGF-A) gene promoter polymorphisms in essential hypertension (EH).

Design And Methods: 1225bp of the VEGF-A gene promoter were screened for polymorphisms using PCR amplification and direct DNA sequence analysis in 62 EH and 62 normotensive (HS) individuals. Circulating VEGF-A levels were determined by immunoassay.

Results: -152G/A (p=0.009) and -116G/A (p=0.016) polymorphisms were correlated to hypertension (p<0.05). Median platelet VEGF-A load in EH was 2.10fg/plt. Patients with microvascular complications (MC) had higher platelet VEGF-A load than those without (p=0.005). Multivariate analyses showed that -116 A allele was an independent predictor of microalbuminuria (p=0.014) and increased platelet VEGF-A load (p=0.009) in EH. Platelet VEGF-A load independently predicted MC (p=0.049) in addition to -116G/A polymorphism (p=0.035).

Conclusions: Abnormal regulation of VEGF-A due to polymorphism at position -116 might represent a genetic factor for increased VEGF-A production and MC in EH.
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http://dx.doi.org/10.1016/j.clinbiochem.2010.06.020DOI Listing
September 2010

Increased plasma levels of soluble CD40 ligand correlate with platelet activation markers and underline the need for standardized pre-analytical conditions.

Clin Biochem 2010 May 11;43(7-8):666-70. Epub 2010 Jan 11.

Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, Rome, Italy.

Objectives: To investigate whether sCD40L dosage might represent a useful tool to explore in vivo platelet function.

Design And Methods: sCD40L and sP-selectin levels and light transmission aggregometry (LTA) were analyzed in 69 healthy donors. Immunoassays were performed on platelet-depleted citrate plasma samples. The effects of in vitro aspirin treatment on the release of sCD40L were investigated in 15 subjects following platelet stimulation. The effects of a 1-month therapeutic course of low-dose aspirin on sP-selectin and sCD40L levels were also investigated.

Results: A significant correlation was observed between sCD40L and sP-selectin (p<0.01). In vitro aspirin treatment remarkably decreased sCD40L levels following platelet activation by exogenous agonists. sCD40L directly correlated with LTA (Rho=0.62, p<0.0001). In vivo aspirin treatment significantly reduced both sP-selectin and sCD40L levels (both p<0.01) in a direct correlation (Rho=0.66, p<0.05).

Conclusions: Citrated plasma samples reflect sCD40L released from platelets, thus yielding the most valid estimates of in vivo circulating levels of this platelet activation markers.
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http://dx.doi.org/10.1016/j.clinbiochem.2009.12.021DOI Listing
May 2010

Role of asymmetric-dimethyl-L-arginine (ADMA) and nitrite/nitrate (NOx) in the pathogenesis of oxidative stress in female subjects with uncomplicated type 1 diabetes mellitus.

Diabetes Res Clin Pract 2009 Dec;86(3):173-6

Diabetologia, Catholic University, Rome, Italy.

Aims: To explore the role of asymmetric-dimethyl-L-arginine (ADMA), an endogenous nitric oxide synthetases (NOS) inhibitor, and nitrite/nitrate (NOx) in the pathogenesis of oxidative stress in early stages of type 1 diabetes mellitus.

Methods: We measured in 99 female subjects with uncomplicated type 1 diabetes (duration disease <10 years) and in 44 sex-matched controls (comparable for age, smoking habit, diet and physical activity) plasma levels of NOx, glycosylated haemoglobin (HbA1c), glucose, uric acid, total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides and serum ADMA.

Results: Type 1 diabetic subjects have higher levels of glycemia, HbA1c, LDL cholesterol and NOx, but lower ADMA and serum uric acid (UA), compared with the control group; no further differences were found. A significant linear and inverse correlation was found between NOx and ADMA levels (R(2)=0.237, p<0.001).

Conclusions: This study suggests a reduced ADMA inhibition of NOS as possible mechanism involved in the pathogenesis of oxidative stress in female subjects with a short duration and uncomplicated type 1 diabetes.
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http://dx.doi.org/10.1016/j.diabres.2009.09.019DOI Listing
December 2009

Predictive value of thrombopath determination in women with infertility and pregnancy complications.

Clin Chim Acta 2010 Jan 3;411(1-2):37-42. Epub 2009 Oct 3.

Dept. of Laboratory Medicine & Advanced Biotechnologies, IRCCS San Raffaele Pisana, 00163, Rome, Italy.

Background: A condition of maternal thrombophilia, either inherited or acquired, can compromise the success of implantation and foetal survival.

Methods: Malfunctions in protein C pathway were evaluated using a novel assay [HemosIL ThromboPath (ThP)] in a case-control study of 172 women with a history of recurrent miscarriage or infertility and 86 age-matched unrelated fertile women.

Results: Thrombophilia was ascertained in 13% of the cases. ThP values were lower in women either with or without thrombophilia compared to controls (both p<0.0001). Abnormal ThP values (below the mean minus 1SD of controls) were found in 62% of cases compared to 12% of controls (p<0.0001). Non-thrombophilic women who achieved spontaneous pregnancy had higher ThP values compared to those who did not (p<0.05). Elevated ThP values were an independent predictor for pregnancy (p<0.01) in women without thrombophilia. A decrease of ThP values was observed during pregnancy progression, which correlated with that of protein S (p<0.05). Miscarriage or major complications occurred in women in whom ThP percent change was approximately 2-fold higher than that observed in women who achieved successful pregnancy (p<0.05).

Conclusions: ThP might represent an efficient assay for screening women with pregnancy complications and might provide prognostic information during pregnancy progression.
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http://dx.doi.org/10.1016/j.cca.2009.09.035DOI Listing
January 2010

Prognostic significance of serum adipokine levels in colorectal cancer patients.

Anticancer Res 2009 Aug;29(8):3321-7

Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, Via della Pisana 235, 00163 Rome, Italy.

Background: Adipokines may significantly influence the growth and proliferation of tumor stroma and malignant cells within. Reduced adiponectin and increased leptin serum levels were found in colorectal cancer (CRC) patients. Recently, it has been demonstrated that tumor necrosis factor-alpha (TNF-alpha) is able to induce dose-dependent changes in serum adipokine levels. Thus, aims of this study were to evaluate the possible associations between adipokines, TNF-alpha and clinicopathological variables of CRC patients and to analyze their possible prognostic value in predicting relapse-free and overall survival.

Materials And Methods: Baseline leptin, adiponectin and TNF-alpha levels were analyzed in 90 patients with histologically diagnosed primary or newly diagnosed metastatic CRC treated at 'Tor Vergata' Clinical Center and followed up for a median period of 3 years.

Results: Serum leptin levels were higher in CRC patients than in controls (p<0.0001). Conversely, serum adiponectin levels were lower in CRC patients than in controls (p<0.0001). Leptin inversely correlated with adiponectin (p<0.005). The leptin/adiponectin (L/A) ratio was eight-fold greater in CRC compared to controls (p<0.0001). Kaplan-Meier analysis of relapse-free and overall survival time showed that the L/A ratio was an independent predictor for adverse outcome in CRC.

Conclusion: Serum adipokine levels might have a role in the biology of CRC and the combined measurement of leptin and adiponectin levels might provide useful prognostic information in the management of patients with CRC.
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August 2009

Association between osteoprotegerin G1181C and T245G polymorphisms and diabetic charcot neuroarthropathy: a case-control study.

Diabetes Care 2009 Sep 5;32(9):1694-7. Epub 2009 Jun 5.

Institute of Internal Medicine, Policlinico A. Gemelli, Rome, Italy.

Objective: Charcot neuroarthropathy is a disabling complication of diabetes. Although its pathogenesis remains unknown, we suppose that genetics may play a relevant role.

Research Design And Methods: We performed a case-control study with 59 subjects with diabetic Charcot neuroarthropathy (Ch group), 41 with diabetic neuropathy without Charcot neuroarthropathy (ND group), and 103 healthy control subjects (H group) to evaluate the impact of two single nucleotide polymorphisms (SNPs) of the osteoprotegerin gene (G1181C and T245G) on the risk of Charcot neuroarthropathy.

Results: Regarding the SNPs of G1181C, we found a significant linkage between the G allele and Charcot neuroarthropathy (Ch vs. ND, odds ratio [OR] 2.32 [95% CI 1.3-4.1], P = 0.006; Ch vs. H, 2.10 [1.3-3.3], P = 0.002; and ND vs. H, 0.90 [0.7-1.9], P = 0.452); similarly, we found a linkage with the G allele of T245G (Ch vs. ND, 6.25 [2.2-19.7], P < 0.001; Ch vs. H, 3.56 [1.9-6.7], P = 0.001; and ND vs. H, 0.54 [0.6-5.7], P = 0.304), supporting a protective role for the allele C and T, respectively. For this reason we investigated the frequency of the protective double homozygosis CC + TT (7% in Ch) that was significantly lower in Ch compared with H (0.18 [0.06-0.5], P = 0.002) and with ND (0.17 [0.05-0.58], P = 0.006), whereas there was no difference between H and ND (1.05 [0.43-2.0], P = 0.468). In a multivariate logistic backward regression model, only weight and the lack of CC and TT genotypes were independently associated with the presence of Charcot neuroarthropathy.

Conclusions: This is the first study that shows an association between genetic regulation of bone remodeling and Charcot neuroarthropathy.
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http://dx.doi.org/10.2337/dc09-0243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732132PMC
September 2009

Prognostic value of pre-surgical plasma PAI-1 (plasminogen activator inhibitor-1) levels in breast cancer.

Thromb Res 2009 Sep 5;124(4):403-8. Epub 2009 Apr 5.

Department of Laboratory Medicine & Advanced Biotechnologies, IRCCS San Raffaele Pisana, Via della Pisana 235, Rome, Italy.

Introduction: Plasminogen activator inhibitor (PAI-1) may have an independent prognostic value in breast cancer (BC). PAI-1 4G/5G polymorphism may have significance for antigen expression. Thus, we analyzed the possible associations between PAI-1 4G/5G polymorphism, plasma PAI-1 levels, and clinicopathological features of breast cancer (BC) patients.

Patients And Methods: PAI-1 4G/5G polymorphism (both on germinal and tumor DNA) and plasma PAI-1 levels were investigated in 99 BC patients and 50 unrelated healthy women similar for age and menopausal status.

Results: No association was found between allele frequencies and clinicopathological features of BC or plasma antigen levels. Plasma PAI-1 levels were higher in BC compared to controls (p=0.002), particularly in patients with large tumors (p<0.001). 5-year follow-up was achieved in 79 patients: 30% had relapsing disease, 63% with positive compared to 37% with negative PAI-1 levels (p<0.05). 5-year relapse-free survival rate of positive PAI-1 was 46% vs., 77% of negative patients (p=0.02).

Conclusions: We may conclude that plasma PAI-1 levels in BC patients could represent a useful prognostic variable for relapse, although PAI-1 polymorphism might not represent a genetic susceptibility factor.
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http://dx.doi.org/10.1016/j.thromres.2009.02.014DOI Listing
September 2009

Soluble P-selectin as a marker of in vivo platelet activation.

Clin Chim Acta 2009 Jan 21;399(1-2):88-91. Epub 2008 Sep 21.

Laboratory of Thrombosis and Haemostasis, Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, Via della Pisana 235, 00163 Rome, Italy.

Background: Platelets are the major source of circulating sP-selectin. Elevated levels of this protein have been found in many atherothrombotic disorders. Thus, we investigated whether sP-selectin dosage might reflect platelet function in patients with risk factors for or with established cardiovascular diseases and whether its levels can be modulated by aspirin therapy.

Methods: Plasma sP-selectin levels and light transmission platelet aggregometry (LTA) were analyzed in 152 outpatients. The effects of a 6-month aspirin therapeutic course on sP-selectin levels and LTA in 51 consecutive patients have been also investigated.

Results: Significant correlations were observed between sP-selectin and Mx% LTA in response to epinephrine (p=0.022) and arachidonic acid (p=0.006), or between sP-selectin and collagen lag-phase (p=0.016). Multiple regression analysis showed that the only predictors of sP-selectin levels were platelet number (p<0.001) and collagen-induced lag-phase (p<0.01). Aspirin-treated patients showed a significant reduction of sP-selectin levels by 13% (p=0.021) which significantly correlated with collagen-induced lag-phase (p=0.005).

Conclusions: sP-selectin dosage could be proposed as a reliable marker of platelet activation in patients with major atherosclerotic risk factors either in the absence of clinically overt disease, and might represent a valid tool to asses in vivo platelet behavior.
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http://dx.doi.org/10.1016/j.cca.2008.09.018DOI Listing
January 2009

In vivo platelet activation is responsible for enhanced vascular endothelial growth factor levels in hypertensive patients.

Clin Chim Acta 2008 Feb 9;388(1-2):33-7. Epub 2007 Oct 9.

Department of Laboratory Medicine & Advanced Biotechnologies, IRCCS San Raffaele, Via della Pisana 235, Rome, Italy.

Background: Essential hypertension may be a consequence of an abnormal regulation of vascular endothelial growth factor (VEGF). In vivo activation of platelets does result in the release of VEGF. Thus, we investigated whether VEGF production in hypertensive patients is related to in vivo platelet activation, and whether it may be modified by aspirin treatment.

Methods: Plasma VEGF, soluble (s)P-selectin and thrombin-anti-thrombin complex (TATc) were analyzed in 80 patients with therapeutically controlled essential hypertension and 40 age and sex-matched healthy normotensive controls. The effects of a 6-month treatment with aspirin 100 mg/day on VEGF levels of 20 hypertensive patients were also studied.

Results: Plasma VEGF (p<0.0001), sP-selectin (p=0.01) and TATc (p=0.02) levels were higher in hypertensives compared to controls. Multivariate analysis including age, sex, risk factors, cardiovascular disease, anti-hypertensive treatment, sP-selectin and TATc showed that only sP-selectin was an independent predictor of VEGF (beta=0.40, p<0.03). Aspirin treated hypertensives showed a significant reduction of sP-selectin (-26%, p<0.01) and VEGF (-33%, p<0.01) levels. Moreover, the reduction of plasma VEGF levels directly correlated with that of sP-selectin (Rho=0.46, p=0.04).

Conclusions: In vivo activation of platelets in hypertensive patients is responsible for enhanced circulating VEGF levels, which are significantly lowered by aspirin treatment.
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http://dx.doi.org/10.1016/j.cca.2007.09.026DOI Listing
February 2008

Prognostic value of carcinoembryonic antigen and vascular endothelial growth factor tumor tissue content in colorectal cancer.

Oncology 2006 23;71(3-4):176-84. Epub 2007 Jul 23.

Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele Pisana, Rome, Italy.

Aim: This study was designed to assess the prognostic significance of the combined measurement of vascular endothelial growth factor (VEGF) and carcinoembryonic antigen (CEA) tissue content with respect to relapse-free and overall survival of patients with colorectal cancer (CRC).

Methods: Quantitative evaluation of VEGF and CEA content was performed on protein extracts obtained from tissue biopsies from 69 CRC patients and 15 healthy donors.

Results: VEGF significantly correlated with CEA content of either tumor tissues (rho = 0.55, p < 0.0001) or corresponding normal mucosa (rho = 0.34, p < 0.005). General regression analyses demonstrated that CEA was an independent predictor of VEGF tissue content either in CRC biopsies (regression coefficient = 0.57, p < 0.0001) or normal mucosa (regression coefficient = 0.25, p < 0.05). Cox proportional hazards survival analysis showed that tumor tissue content of both VEGF and CEA had an independent prognostic value in predicting both relapse-free (hazards ratio = 5.98, p = 0.002) and overall (hazards ratio = 4.73, p = 0.007) survival, irrespective of Dukes' stage. Kaplan-Meier analysis demonstrated that an elevated tumor content of both CEA and VEGF had a negative prognostic value in respect to either relapse-free (log-rank test: 10.4, p = 0.001) or overall survival (log-rank test: 7.33, p = 0.007).

Conclusion: Tumor tissue VEGF and CEA content determination might add useful prognostic information in the management of patients with CRC.
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http://dx.doi.org/10.1159/000106072DOI Listing
August 2007