Publications by authors named "Roberto Caporale"

42 Publications

Downstream or upstream administration of P2Y12 receptor blockers in non-ST elevated acute coronary syndromes: study protocol for a randomized controlled trial.

Trials 2020 Nov 24;21(1):966. Epub 2020 Nov 24.

Division of Cardiology, Azienda Sanitaria Ospedaliera Ordine Mauriziano, Torino, Italy.

Background: The optimal timing to administer a P2Y12 inhibitor in patients presenting with a non-ST elevation acute coronary syndrome remains a topic of debate. Pretreatment with ticagrelor before coronary anatomy is known as a widely adopted strategy. However, there is poor evidence on how this compares with administration of a P2Y12 inhibitor after defining coronary anatomy (i.e., downstream administration). Moreover, there are limited head-to-head comparisons of the two P2Y12 inhibitors-ticagrelor and prasugrel-currently recommended by the guidelines.

Study Design: DUBIUS is a phase 4, multicenter, parallel-group, double randomized study conducted in NSTE-ACS patients designed to compare a pretreatment strategy (including only ticagrelor) versus a downstream strategy (including prasugrel or ticagrelor) and to compare downstream prasugrel with downstream ticagrelor. A total of 2520 patients will be randomly assigned to pretreatment with ticagrelor or to no pretreatment. The PCI group of the downstream arm will be further randomized to receive prasugrel or ticagrelor. The two primary hypotheses are that the downstream strategy is superior to the upstream strategy and that downstream ticagrelor is non-inferior to downstream prasugrel, both measured by the incidence of a composite efficacy and safety endpoint of death from vascular causes, non-fatal MI, or non-fatal stroke, and Bleeding Academic Research Consortium (BARC) type 3, 4, and 5 bleedings.

Conclusions: The DUBIUS study will provide important evidence related to the benefits and risks of pretreatment with ticagrelor compared with a strategy of no pretreatment. Moreover, the clinical impact of using downstream ticagrelor compared with downstream prasugrel will be assessed.

Trial Registration: ClinicalTrials.gov NCT02618837 . Registered on 1 December 2015.
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http://dx.doi.org/10.1186/s13063-020-04859-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686679PMC
November 2020

Insulin resistance and obesity affect monocyte-derived dendritic cell phenotype and function.

Diabetes Res Clin Pract 2020 Dec 4;170:108528. Epub 2020 Nov 4.

Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy. Electronic address:

Aim: Cardiovascular disease (CVD) is prevalent in women after menopause, which may be associated with obesity, insulin resistance and metaflammation. Despite the recognized role of immunological mechanisms in vascular remodeling, the role of dendritic cells (DCs) is still unclear. The aim was to characterize monocyte-derived DCs (Mo-DC) in post-menopausal patients with type 2 diabetes (T2DM) and obese woman, without clinical manifestations of atherosclerosis.

Methods: Obese post-menopausal women with or without T2DM were enrolled and were compared to age-matched healthy women. DCs obtained from patients were phenotypically and functionally characterized by flow cytometry and mixed lymphocyte reaction. MRNA integrins expression was assessed by real time RT-PCR; circulating fetuin-A and adiponectin levels were measured by ELISA.

Results: Phenotypic dysregulation of Mo-DC reported was related to a defective allogenic lymphocyte stimulation and to an increased mRNA of CD11c, CD18 and DC-SIGN/CD209 which regulate their adhesion to vascular wall cells. Fetuin-A and adiponectin levels were significantly altered and negatively correlated. Hyperglycaemia significantly impaired CD14 transdifferentiation into Mo-DC.

Conclusions: These data show a dysfunction of Mo-DCs obtained from precursors isolated from T2DM obese post-menopausal woman without any documented clinical CV event. Association of obesity to diabetes seems to worsen DC's phenotype and function and increase vascular inflammation.
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http://dx.doi.org/10.1016/j.diabres.2020.108528DOI Listing
December 2020

Multilineage Dysplasia as Assessed by Immunophenotype in Acute Myeloid Leukemia: A Prognostic Tool in a Genetically Undefined Category.

Cancers (Basel) 2020 Oct 30;12(11). Epub 2020 Oct 30.

Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy.

Acute myeloid leukemia (AML) "with myelodysplasia-related changes (MRC)" is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for , and (TN-AML). In this context, the lack of dysplastic features (IPS_0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML.
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http://dx.doi.org/10.3390/cancers12113196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693580PMC
October 2020

Timing of Oral P2Y Inhibitor Administration in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

J Am Coll Cardiol 2020 11 31;76(21):2450-2459. Epub 2020 Aug 31.

Division of Cardiology, Azienda Sanitaria Ospedaliera Ordine Mauriziano, Torino, Italy.

Background: Although oral P2Y inhibitors are key in the management of patients with non-ST-segment elevation acute coronary syndrome, the optimal timing of their administration is not well defined.

Objectives: The purpose of this study was to compare downstream and upstream oral P2Y inhibitors administration strategies in patients with non-ST-segment elevation acute coronary syndrome undergoing invasive treatment.

Methods: We performed a randomized, adaptive, open-label, multicenter clinical trial. Patients were randomly assigned to receive pre-treatment with ticagrelor before angiography (upstream group) or no pre-treatment (downstream group). Patients in the downstream group undergoing percutaneous coronary intervention were further randomized to receive ticagrelor or prasugrel. The primary hypothesis was the superiority of the downstream versus the upstream strategy on the combination of efficacy and safety events (net clinical benefit).

Results: We randomized 1,449 patients to downstream or upstream oral P2Y inhibitor administration. A pre-specified stopping rule for futility at interim analysis led the trial to be stopped. The rate of the primary endpoint, a composite of death due to vascular causes; nonfatal myocardial infarction or nonfatal stroke; and Bleeding Academic Research Consortium type 3, 4, and 5 bleeding through day 30, did not differ significantly between the downstream and upstream groups (percent absolute risk reduction: -0.46; 95% repeated confidence interval: -2.90 to 1.90). These results were confirmed among patients undergoing percutaneous coronary intervention (72% of population) and regardless of the timing of coronary angiography (within or after 24 h from enrollment).

Conclusions: Downstream and upstream oral P2Y inhibitor administration strategies were associated with low incidence of ischemic and bleeding events and minimal numeric difference of event rates between treatment groups. These findings led to premature interruption of the trial and suggest the unlikelihood of enhanced efficacy of 1 strategy over the other. (Downstream Versus Upstream Strategy for the Administration of P2Y Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication [DUBIUS]; NCT02618837).
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http://dx.doi.org/10.1016/j.jacc.2020.08.053DOI Listing
November 2020

Quantitative and qualitative alterations of circulating myeloid cells and plasmacytoid DC in SARS-CoV-2 infection.

Immunology 2020 12 6;161(4):345-353. Epub 2020 Oct 6.

Flow Cytometry Diagnostic Center and Immunotherapy (CDCI), AOU Careggi, Florence, Italy.

SARS-CoV-2 is responsible for a new infectious disease (COVID-19) in which individuals can either remain asymptomatic or progress from mild to severe clinical conditions including acute respiratory distress syndrome and multiple organ failure. The immune mechanisms that potentially orchestrate the pathology in SARS-CoV-2 infection are complex and only partially understood. There is still paucity of data on the features of myeloid cells involved in this viral infection. For this reason, we investigated the different activation status profiles and the subset distribution of myeloid cells and their correlation with disease progression in 40 COVID-19 patients at different stages of disease. COVID-19 patients showed a decrease in the absolute number of plasmacytoid and myeloid dendritic cells, different subset distribution of monocytes and different activation patterns of both monocytes and neutrophils, coupled to a significant reduction of HLA-DR monocyte levels. We found that some of these alterations are typical of all COVID-19 patients, while some others vary at different stages of the disease and correlate with biochemical parameters of inflammation. Collectively, these data suggest that not only the lymphoid, but also the myeloid compartment, is severely affected by SARS-CoV-2 infection.
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http://dx.doi.org/10.1111/imm.13254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692244PMC
December 2020

In Vitro Comparison of the Effects of Imatinib and Ponatinib on Chronic Myeloid Leukemia Progenitor/Stem Cell Features.

Target Oncol 2020 10;15(5):659-671

Department of Experimental and Clinical Biomedical Science, University of Florence, Viale GB Morgagni 50, 50134, Florence, Italy.

Background: The development of molecularly tailored therapeutic agents such as the BCR/ABL-active tyrosine kinase inhibitors (TKi) resulted in an excellent treatment option for chronic myeloid leukemia (CML) patients. However, following TKi discontinuation, disease relapses in 40-60% of patients, an occurrence very likely due to the persistence of leukemic stem cells that are scarcely sensitive to TKi. Nevertheless, TKi are still the only current treatment option for CML patients.

Objective: The aim of this study was to compare the effects of TKi belonging to different generations, imatinib and ponatinib (first and third generation, respectively), on progenitor/stem cell expansion potential and markers.

Patients And Methods: We used stabilized CML cell lines (KCL22, K562 and LAMA-84 cells), taking advantage of the previous demonstration of ours that cell lines contain cell subsets endowed with progenitor/stem cell properties. Primary cells explanted from CML patients were also used. The effects of TKi on the expression of stem cell related genes were compared by quantitative PCR. Flow cytometry was performed to evaluate aldehyde-dehydrogenase (ALDH) activity and the expression of cluster of differentiation (CD) cell surface hematopoietic stem cell markers. Progenitor/stem cell potential was estimated by serial colony formation ability (CFA) assay.

Results: Ponatinib was more effective than imatinib for the reduction of cells with ALDH activity and progenitor/stem cell potential of CML patient-derived cells and cell lines. Furthermore, ponatinib was more effective than imatinib in reducing the percentage of CD26-expressing cells in primary CML cells, whereas imatinib and ponatinib showed similar efficacy on KCL22 cells. Both drugs strongly upregulated NANOG and SOX2 in CML cell lines, but in KCL22 cells this upregulation was significantly lower with ponatinib than with imatinib, an outcome compatible with a lower level of enrichment of the stem cell compartment upon ponatinib treatment.

Conclusion: Ponatinib seems to target CML progenitor/stem cells better than imatinib.
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http://dx.doi.org/10.1007/s11523-020-00741-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568716PMC
October 2020

Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent.

J Clin Invest 2020 09;130(9):4694-4703

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

BACKGROUNDCoronavirus disease 19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Antiviral immune response is crucial to achieve pathogen clearance; however, in some patients an excessive and aberrant host immune response can lead to an acute respiratory distress syndrome. The comprehension of the mechanisms that regulate pathogen elimination, immunity, and pathology is essential to better characterize disease progression and widen the spectrum of therapeutic options.METHODSWe performed a flow cytometric characterization of immune cell subsets from 30 patients with COVID-19 and correlated these data with clinical outcomes.RESULTSPatients with COVID-19 showed decreased numbers of circulating T, B, and NK cells and exhibited a skewing of CD8+ T cells toward a terminally differentiated/senescent phenotype. In agreement, CD4+ T and CD8+ T, but also NK cells, displayed reduced antiviral cytokine production capability. Moreover, a reduced cytotoxic potential was identified in patients with COVID-19, particularly in those who required intensive care. The latter group of patients also showed increased serum IL-6 levels that inversely correlated to the frequency of granzyme A-expressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells.CONCLUSIONThe association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore antiviral mechanisms.FUNDINGThis study was supported by funds from the Department of Experimental and Clinical Medicine of University of Florence (the ex-60% fund and the "Excellence Departments 2018-2022 Project") derived from Ministero dell'Istruzione, dell'Università e della Ricerca (Italy).
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http://dx.doi.org/10.1172/JCI138554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456250PMC
September 2020

[ANMCO/SIC/GISE/ARCA/SIRM Consensus document: Description of coronary atherosclerosis for diagnostic, prognostic and therapeutic purposes].

G Ital Cardiol (Rome) 2019 Jul-Aug;20(7):439-468

U.O.C. di Cardiologia, Ospedale Garibaldi-Nesima, Azienda di Rilievo Nazionale e Alta Specializzazione "Garibaldi", Catania - Presidente Fondazione per il Tuo cuore, Firenze.

Both conventional coronary angiography and cardiac computed tomography have greatly improved our diagnostic and prognostic evaluation of patients with either suspected or confirmed coronary artery disease. Although several other tools can provide information about coronary anatomy or function, invasive coronary angiography and, more recently, coronary computed tomography angiography (CCTA) are the most commonly used imaging modalities. Coronary atherosclerosis is the most common disease of the coronary arteries and its presence identifies patients at increased risk of events. As a matter of fact, coronary atherosclerosis represents the major determinant for the occurrence of events and the development of ischemic heart disease. Coronary atherosclerosis can translate into plaques that may eventually progress to critical stenosis causing myocardial ischemia. More commonly, atherosclerotic lesions are non-obstructive. Their presence, number and extent negatively affect prognosis independently of other mechanisms. In order to improve prognosis, optimal medical therapy should be initiated to halt disease progression and/or to stabilize atherosclerotic plaques. It is therefore of paramount importance to describe the presence of atherosclerotic lesions well beyond those lesions potentially or undoubtedly capable of inducing myocardial ischemia. These latter lesions may in fact benefit from an interventional or surgical treatment. However, most events are caused by non-obstructive lesions that may often be missed.In common practice, the description of coronary anatomy is not structured in a universal model and each Center applies its own (albeit arbitrary) rules. This consensus document is a collaborative work of some of the major Italian Scientific Societies to offer scientific support to those healthcare professionals who, at different levels, report on coronary anatomy or receive the description of coronary anatomy of patients. After a brief description of the available techniques used to explore the coronary anatomy, the best available evidence in support of a detailed description of coronary atherosclerosis is summarized. In order to promote a useful translation of the information into practice, several recommendations for the correct reporting of coronary anatomy and the suggested treatment for the different clinical scenarios are provided. The aim of this consensus document is to refine the description of coronary anatomy as offered by both invasive coronary angiography and CCTA to improve risk stratification of patients undergoing coronary imaging in clinical practice and to select the most appropriate treatment for improving cardiovascular outcomes.
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http://dx.doi.org/10.1714/3190.31688DOI Listing
February 2020

[ANMCO/FADOI/SIAARTI/SIC/SIMG/SIMI/SIMEU consensus document: The clinical care pathway of acute heart failure patients from symptom onset to discharge from the emergency department].

G Ital Cardiol (Rome) 2019 May;20(5):289-334

S.C. Cardiovascolare e Medicina dello Sport, Azienda Sanitaria Universitaria Integrata, Trieste.

Acute heart failure (AHF) represents a relevant burden for emergency departments worldwide. AHF patients have markedly worse long-term outcomes than patients with other acute cardiac diseases (e.g. acute coronary syndromes); mortality or readmissions rates at 3 months approximate 33%, whereas 1-year mortality from index discharge ranges from 25% to 50%.The multiplicity of healthcare professionals acting across the care pathway of AHF patients represents a critical factor, which generates the need for integrating the different expertise and competence of general practitioners, emergency physicians, cardiologists, internists, and intensive care physicians to focus on care goals able to improve clinical outcomes.This consensus document results from the cooperation of the scientific societies representing the different healthcare professionals involved in the care of AHF patients and describes shared strategies and pathways aimed at ensuring both high quality care and better outcomes. The document describes the patient journey from symptom onset to the clinical suspicion of AHF and home management or referral to emergency care and transportation to the hospital, through the clinical diagnostic pathway in the emergency department, acute treatment, risk stratification and discharge from the emergency department to ordinary wards or home. The document analyzes the potential role of a cardiology fast-track and Observation Units and the transition to outpatient care by general practitioners and specialist heart failure clinics.The increasing care burden and complex problems generated by AHF are unlikely to be solved without an integrated multidisciplinary approach. Efficient networking among emergency departments, intensive care units, ordinary wards and primary care settings is crucial to achieve better outcomes. Thanks to the joint effort of qualified scientific societies, this document aims to achieve this goal through an integrated, shared and applicable pathway that will contribute to a homogeneous care management of AHF patients across the country.
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http://dx.doi.org/10.1714/3151.31321DOI Listing
May 2019

Features, reason for testing, and changes with time of 583 paroxysmal nocturnal hemoglobinuria clones from 529 patients: a multicenter Italian study.

Ann Hematol 2019 May 13;98(5):1083-1093. Epub 2019 Mar 13.

CEINGE Biotecnologie Avanzate, Naples, Italy.

In this study, we aimed at disclosing the main features of paroxysmal nocturnal hemoglobinuria (PNH) clones, their association with presentation syndromes, and their changes during follow-up. A large-scale, cooperative collection (583 clones from 529 patients) of flow cytometric and clinical data was entered into a national repository. Reason for testing guidelines were provided to the 41 participating laboratories, which followed the 2010 technical recommendations for PNH testing by Borowitz. Subsequently, the 30 second-level laboratories adopted the 2012 guidelines for high-resolution PNH testing, both upon order by the local clinicians and as an independent laboratory initiative in selected cases. Type3 and Type2 PNH clones (total and partial absence of glycosyl-phosphatidyl-inositol-anchor, respectively) were simultaneously present in 54 patients. In these patients, Type3 component was sevenfold larger than Type2 (p < 0.001). Frequency distribution analysis of solitary Type3 clone size (N = 442) evidenced two discrete patterns: small (20% of peripheral neutrophils) and large (> 70%) clones. The first pattern was significantly associated with bone marrow failure and myelodysplastic syndromes, the second one with hemolysis, hemoglobinuria, and thrombosis. Pediatric patients (N = 34) showed significant preponderance of small clones and bone marrow failure. The majority of PNH clones involved neutrophils, monocytes, and erythrocytes. Nevertheless, we found clones made exclusively by white cells (N = 13) or erythrocytes (N = 3). Rare cases showed clonal white cells restricted only to monocytes (6 cases) or neutrophils (3 cases). Retesting over 1-year follow-up in 151 cases showed a marked clone size increase in 4 cases and a decrease in 13, demonstrating that early breaking-down of PNH clones is not a rare event (8.6% of cases). This collaborative nationwide study demonstrates a clear-cut difference in size between Type2 and Type3 clones, emphasizes the existence of just two classes of PNH presentations based on Type3 clone size, depicts an asymmetric cellular composition of PNH clones, and documents the possible occurrence of changes in clone size during the follow-up.
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http://dx.doi.org/10.1007/s00277-019-03644-8DOI Listing
May 2019

Consensus Document ANMCO/ANCE/ARCA/GICR-IACPR/GISE/SICOA: Long-term Antiplatelet Therapy in Patients with Coronary Artery Disease.

Eur Heart J Suppl 2018 May 31;20(Suppl F):F1-F74. Epub 2018 May 31.

U.O.C. Cardiologia, Ospedale San Giovanni Evangelista, Tivoli, Roma, Italy.

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y receptor inhibitor is the cornerstone of pharmacologic management of patients with acute coronary syndrome (ACS) and/or those receiving coronary stents. Long-term (>1 year) DAPT may further reduce the risk of stent thrombosis after a percutaneous coronary intervention (PCI) and may decrease the occurrence of non-stent-related ischaemic events in patients with ACS. Nevertheless, compared with aspirin alone, extended use of aspirin plus a P2Y receptor inhibitor may increase the risk of bleeding events that have been strongly linked to adverse outcomes including recurrent ischaemia, repeat hospitalisation and death. In the past years, multiple randomised trials have been published comparing the duration of DAPT after PCI and in ACS patients, investigating either a shorter or prolonged DAPT regimen. Although the current European Society of Cardiology guidelines provide a backup to individualised treatment, it appears to be difficult to identify the ideal patient profile which could safely reduce or prolong the DAPT duration in daily clinical practice. The aim of this consensus document is to review contemporary literature on optimal DAPT duration, and to guide clinicians in tailoring antiplatelet strategies in patients undergoing PCI or presenting with ACS.
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http://dx.doi.org/10.1093/eurheartj/suy019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978022PMC
May 2018

[ANMCO/ANCE/ARCA/GICR-IACPR intersociety consensus document: long-term antiplatelet therapy in patients with coronary artery disease].

G Ital Cardiol (Rome) 2018 May;19(5):263-331

U.O.C. Cardiologia, Ospedale San Giovanni Evangelista, Tivoli (RM).

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the cornerstone of the pharmacologic management of patients with acute coronary syndrome (ACS) and/or receiving coronary stents. Long-term (>1 year) DAPT may further reduce the risk of stent thrombosis after percutaneous coronary intervention (PCI) and may decrease the occurrence of non-stent-related ischemic events in patients with ACS. Nevertheless, compared with aspirin alone, extended use of aspirin plus a P2Y12 receptor inhibitor may increase the risk of bleeding events that have been strongly linked to adverse outcomes including recurrent ischemia, repeat hospitalization, and death. Over the last years, multiple randomized clinical trials have been published comparing duration of DAPT after PCI and in ACS patients investigating either a shorter or prolonged DAPT regimen.Although current European Society of Cardiology guidelines provide backup to individualize treatment, it seems difficult to identify the ideal patient profile who could safely reduce or prolong DAPT duration in daily clinical practice. The aim of this consensus document is to review the contemporary literature on optimal DAPT duration and to guide clinicians in tailoring antiplatelet strategies in patients undergoing PCI or presenting with ACS.
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http://dx.doi.org/10.1714/2907.29280DOI Listing
May 2018

ANMCO Position Paper: hospital discharge planning: recommendations and standards.

Eur Heart J Suppl 2017 05 2;19(Suppl D):D244-D255. Epub 2017 May 2.

Cardiology Unit, Ospedale dell'Angelo, Mestre (VE), Italy.

The hospital discharge is often poorly standardized and affected by discontinuity and fragmentation of care, putting patients at high risk of both post-discharge adverse events and early readmission. The present ANMCO document reviews the modifiable components of the hospital discharge process related to adverse events or re-hospitalizations and suggests the optimal methods for redesigning the whole discharge process. The key principles for proper hospital discharge or transfer of care acknowledge that the hospital discharge: • is not an isolated event, but a process that has to be planned as soon as possible after the admission, ensuring that the patient and the caregiver understand and contribute to the planned decisions, as equal partners; • is facilitated by a comprehensive systemic approach that begins with a multidimensional evaluation process; • must be organized by an operator who is responsible for the coordination of all phases of the hospital patient journey, involving afterward the general practitioner and transferring to them the information and responsibility at discharge; • is the result of an integrated multidisciplinary team approach; • appropriately uses the transitional and intermediate care services; • is carried out in an organized system of care and continuum of services; and • programs the passage of information to after-discharge services.
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http://dx.doi.org/10.1093/eurheartj/sux011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526471PMC
May 2017

Consensus Document of the Italian Association of Hospital Cardiologists (ANMCO), Italian Society of Cardiology (SIC), Italian Association of Interventional Cardiology (SICI-GISE) and Italian Society of Cardiac Surgery (SICCH): clinical approach to pharmacologic pre-treatment for patients undergoing myocardial revascularization procedures.

Eur Heart J Suppl 2017 May 2;19(Suppl D):D151-D162. Epub 2017 May 2.

Heart Surgery Unit, Ospedale Policlinico S. Orsola-Malpighi, Bologna, Italy.

The wide availability of effective drugs in reducing cardiovascular events together with the use of myocardial revascularization has greatly improved the prognosis of patients with coronary artery disease. The combination of antithrombotic drugs to be administered before the knowledge of the coronary anatomy and before the consequent therapeutic strategies, can allow to anticipate optimal treatment, but can also expose the patients at risk of bleeding that, especially in acute coronary syndromes, can significantly weigh on their prognosis, even more than the expected theoretical benefit. In non ST-elevation acute coronary syndromes patients in particular, we propose a 'selective pre-treatment' with P2Y inhibitors, based on the ischaemic risk, on the bleeding risk and on the time scheduled for the execution of coronary angiography. Much of the problems concerning this issue would be resolved by an early access to coronary angiography, particularly for patients at higher ischaemic and bleeding risk.
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http://dx.doi.org/10.1093/eurheartj/sux010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520758PMC
May 2017

-double-mutated acute myeloid leukemia displays a unique phenotypic profile: a reliable screening method and insight into biological features.

Haematologica 2017 03 10;102(3):529-540. Epub 2016 Nov 10.

Unità Funzionale di Ematologia, Università degli Studi, AOU Careggi, Firenze, Italy.

Mutations in CCAAT/enhancer binding protein α () occur in 5-10% of cases of acute myeloid leukemia. -double-mutated cases usually bear biallelic N- and C-terminal mutations and are associated with a favorable clinical outcome. Identification of mutants is challenging because of the variety of mutations, intrinsic characteristics of the gene and technical issues. Several screening methods (fragment-length analysis, gene expression array) have been proposed especially for large-scale clinical use; although efficient, they are limited by specific concerns. We investigated the phenotypic profile of blast and maturing bone marrow cell compartments at diagnosis in 251 cases of acute myeloid leukemia. In this cohort, 16 (6.4%) patients had two mutations, whereas ten (4.0%) had a single mutation. First, we highlighted that the -double-mutated subset displays recurrent phenotypic abnormalities in all cell compartments. By mutational analysis after cell sorting, we demonstrated that this common phenotypic signature depends on -double-mutated multi-lineage involvement. From a multidimensional study of phenotypic data, we developed a classifier including ten core and widely available parameters. The selected markers on blasts (CD34, CD117, CD7, CD15, CD65), neutrophil (SSC, CD64), monocytic (CD14, CD64) and erythroid (CD117) compartments were able to cluster -double-mutated cases. In a validation set of 259 AML cases from three independent centers, our classifier showed excellent performance with 100% specificity and 100% sensitivity. We have, therefore, established a reliable screening method, based upon multidimensional analysis of widely available phenotypic parameters. This method provides early results and is suitable for large-scale detection of -double-mutated status, allowing gene sequencing to be focused in selected cases.
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http://dx.doi.org/10.3324/haematol.2016.151910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394975PMC
March 2017

[ANMCO Position paper: Hospital discharge planning].

G Ital Cardiol (Rome) 2016 Sep;17(9):657-686

U.O. Cardiologia, Ospedale dell'Angelo, Mestre (VE).

Hospital discharge is often poorly standardized and is characterized by discontinuity and fragmentation of care, putting patients at high risk of post-discharge adverse events and early readmission. The present ANMCO position paper reviews the modifiable components of the hospital discharge process related to adverse events or rehospitalizations and suggests the optimal methods for redesign the whole discharge process. The key principles for proper hospital discharge or transfer of care acknowledge that hospital discharge:- is not an isolated event, but a process that has to be planned immediately after admission, ensuring that the patient and the caregiver understand and contribute to the planned decisions as equal partners;- is facilitated by a comprehensive systemic approach that begins with a multidimensional evaluation process;- must be organized by an operator who is responsible for the coordination of all phases of the hospital patient pathway, involving afterwards the physician and transferring to them the information and responsibility;- is the result of an integrated multidisciplinary team approach;- uses appropriately the transitional and intermediate care services;- is carried out in an organized system of care and continuum of services;- programs the passage of information to after-discharge services.
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http://dx.doi.org/10.1714/2448.25660DOI Listing
September 2016

[ANMCO/SIC/SICI-GISE/SICCH Consensus document: Clinical approach to pharmacological pretreatment for patients undergoing myocardial revascularization].

G Ital Cardiol (Rome) 2016 Jun;17(6):462-90

U.O. Cardiochirurgia, Ospedale Policlinico S. Orsola-Malpighi, Bologna.

The wide availability of drugs effective in reducing cardiovascular events and the use of myocardial revascularization have greatly improved the prognosis of patients with coronary artery disease. However, the combination of antithrombotic drugs to be administered before the exact knowledge of the coronary anatomy and before the consequent therapeutic strategy can, on one hand, allow to anticipate an optimal treatment but, on the other hand, may expose the patient to a bleeding risk not always necessary. In patients with ST-elevation acute coronary syndrome with an indication to primary angioplasty, the administration of unfractionated heparin and aspirin is considered the pre-procedural standard treatment. The upstream administration of an oral P2Y12 inhibitor, even if not supported by randomized controlled trials, appears reasonable in view of the very high likelihood of treatment with angioplasty. In patients with non-ST elevation acute coronary syndrome, in which it is not always chosen an invasive strategy, the occurrence of bleeding can significantly weigh on prognosis, even more than the theoretical benefit of pretreatment. Fondaparinux is the anticoagulant with the most favorable efficacy/safety profile. Antiplatelet pretreatment must be selective, guided by the ischemic risk conditions, the risk of bleeding and the time schedule for coronary angiography.In patients with stable coronary artery disease, generally treated with aspirin, pretreatment with clopidogrel is advisable in case of already scheduled angioplasty, and it appears reasonable in case of high likelihood, at least in patients at low bleeding risk. In patients candidate to surgical revascularization, aspirin is typically maintained and the oral P2Y12-inhibitor discontinued, with i.v. antiplatelet drug bridging in selected cases.Anti-ischemic drugs are useful in controlling symptoms, but they have no specific indications with regard to revascularization procedures. Statins showed protective effects on periprocedural damage and late clinical events, when administered early. Although randomized data are lacking, it seems reasonable their pre-procedural administration, due to potential advantages without significant adverse effects.
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http://dx.doi.org/10.1714/2262.24352DOI Listing
June 2016

Dysregulation of sphingosine 1 phosphate receptor-1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound.

Brain Behav Immun 2015 Nov 27;50:78-86. Epub 2015 Jun 27.

Headache Center and Clinical Pharmacology Unit, Department of Health Sciences, Careggi University Hospital, Italy; Pharmacology and Oncology Unit, Department of Health Sciences, University of Florence, Italy.

Fingolimod affords protection from MS by sequestering lymphocytes in secondary lymphoid organs via down regulation of their sphingosine 1 phosphate receptor (S1P1). Unexpectedly, accumulating evidence indicates that patients who discontinue fingolimod treatment may be at risk of rehearsal of magnetic resonance (MR) and clinical disease activity, sometimes featuring dramatic rebound. We therefore developed in vivo and in vitro models of post-fingolimod MS rebound to unravel its cellular and molecular mechanisms. The impact of fingolimod withdrawal on T regulatory lymphocytes was also investigated by means of cytofluorimetric analysis and antigen-specific lymphocyte proliferation assays. We show that mice with relapsing-remitting experimental autoimmune encephalomyelitis (EAE) undergo extremely severe, chronic disease rebound upon discontinuation of fingolimod. Remarkably, rebound is preceded by a burst of S1P1 overexpression in lymph node-entrapped lymphocytes that correlates with subsequent massive lymphocyte egress and widespread CNS immune infiltration. Also, consistent with the ability of S1P1 to counteract polarization and function of T regulatory lymphocytes their number and suppression of effector T cells is reduced by fingolimod suspension. Data disclose the first pathogenic mechanisms of post-fingolimod rebound that may be targeted for therapeutic intervention.
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http://dx.doi.org/10.1016/j.bbi.2015.06.019DOI Listing
November 2015

Multilineage dysplasia as assessed by immunophenotype has no impact on clinical-biological features and outcome of NPM1-mutated acute myeloid leukemia.

Exp Hematol 2015 Oct 20;43(10):869-879.e22. Epub 2015 Jun 20.

Unità Funzionale di Ematologia, Università degli Studi, AOU Careggi, Florence, Italy; Istituto Toscano Tumori, Florence, Italy.

The presence of multilineage dysplasia (MLD) by morphology at diagnosis in acute myeloid leukemia (AML) defines a separate subset in the World Health Organization classification with still-debated prognostic value. A major controversy concerns MLD's role in NPM1-mutated (NPM1⁺) AML, which correlates with good prognosis. We used flow cytometry (FC), an emerging technique for assessing dysplasia, to investigate MLD in NPM1⁺ AML by an immunophenotypic score (IPS), a technique previously adopted in myelodysplastic syndrome. Eighty-five intensively treated NPM1⁺ AML cases were studied. Patients were grouped according to the combination of data in maturing cell compartments. FC-assessed dysplasia showed a significant correlation with morphology-assessed dysplasia, showing the efficacy of this method in highlighting dysplasia in AML. Except for MLD, IPS did not influence any patient- or disease-related characteristics at diagnosis. Furthermore, IPS did not influence complete remission rate, disease-free survival, or overall survival. By investigating NPM1 status on separated cell compartments, we established a correlation between FC-assessed MLD and belonging to AML clone. This study shows that dysplasia evaluated by immunophenotype has no impact on clinical-biological characteristics or on outcome of NPM1⁺ AML. Dysplasia is part of the spectrum of NPM1⁺ AML, and the prognostic stratification of this category of patients should not be based upon it.
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http://dx.doi.org/10.1016/j.exphem.2015.06.003DOI Listing
October 2015

Endothelial Soluble Factors Mediate Differentiation of Circulating Endothelial Precursors.

J Cardiovasc Pharmacol 2015 Aug;66(2):223-7

*Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy; †Blood Transfusion Centre, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; and ‡Central Laboratory, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

Although endothelial progenitor cells have been used in clinical trials with promising preliminary results, the mechanism by which these cells interact with vascular wall cells and ischemic tissues remains unclear. We have previously reported that human coronary artery endothelial cells cocultured with peripheral blood mononuclear cell (PBMC) can stimulate their early differentiation toward a pre-endothelial phenotype. This study was aimed to assess possible soluble factors, released from the coculture, and involved in endothelial progenitor cell differentiation. Among cytokines and chemokines measured by means of Milliplex assay, interleukin (IL)-6, IL-8, endothelial growth factor, and CCL-2 were released in cocultures, and those levels were significantly higher than that found in human coronary artery endothelial cells or in PBMCs alone. To check their involvement in PBMC differentiation, blocking experiments with neutralizing antibodies were performed. Flow cytometry analysis confirmed an impairment of PBMC differentiation toward a pre-endothelial phenotype when IL-6, IL-8 and with a lesser extent CCL-2 were blocked. These data add a new insight into the mechanisms by which endothelial precursors interact with vascular wall, thus suggesting future directions in understanding and treating ischemic injury.
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http://dx.doi.org/10.1097/FJC.0000000000000263DOI Listing
August 2015

Contemporary antithrombotic strategies in patients with acute coronary syndrome admitted to cardiac care units in Italy: The EYESHOT Study.

Eur Heart J Acute Cardiovasc Care 2015 Oct 20;4(5):441-52. Epub 2014 Nov 20.

Division of Cardiology, Fondazione IRCCS Policlinico San Matteo, Italy.

Background: Several new antithrombotic therapies have emerged for the treatment of acute coronary syndrome (ACS). We sought to assess contemporary patterns of antithrombotic therapies use in patients with ACS.

Methods And Results: EYESHOT (EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in iTalian cardiac care units) was a nationwide, prospective registry aimed to evaluate antithrombotic strategies employed in patients admitted to intensive cardiac care units (CCUs) for an ACS in Italy. Over a three-week period, 203 CCUs enrolled 2585 consecutive patients: 41.2% with ST-elevation myocardial infarction (STEMI) and 58.8% with non-ST elevation ACS (NSTE-ACS). During hospitalisation, low-molecular-weight heparins, aspirin, and clopidogrel were the most commonly used antithrombotic therapies. Among patients treated with percutaneous coronary intervention (PCI, n=1755), any crossover of heparin therapy occurred in 30.8% of cases, while switching from one P2Y12 inhibitor to another occurred in 3.6% of cases in the CathLab and in 14.2% before discharge. Of the 790 patients who did not receive revascularisation, switching of a P2Y12 inhibitor occurred in 5.7% of cases. At discharge, a new P2Y12 inhibitor (ticagrelor or prasugrel) in association with aspirin was prescribed in 59.5% of STEMI and 33.9% of NSTE-ACS patients: the most powerful predictor for prescription was PCI (odds ratio (OR) 6.18; 95% confidence interval (CI) 4.76-8.01; p<0.0001), whereas age ≥ 75 years was strongly associated with clopidogrel use (OR 0.28; 95% CI 0.22-0.36; p<0.0001).

Conclusions: The EYESHOT registry shows the current pattern of antithrombotic treatments for ACS patients admitted to Italian CCUs and provides insights which may help to improve the clinical care of such patients.
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http://dx.doi.org/10.1177/2048872614560505DOI Listing
October 2015

Stimulatory interactions between human coronary smooth muscle cells and dendritic cells.

PLoS One 2014 16;9(6):e99652. Epub 2014 Jun 16.

Department of Health Sciences, Clinical Pharmacology and Oncology Unit, University of Florence, Florence, Italy.

Despite inflammatory and immune mechanisms participating to atherogenesis and dendritic cells (DCs) driving immune and non-immune tissue injury response, the interactions between DCs and vascular smooth muscle cells (VSMCs) possibly relevant to vascular pathology including atherogenesis are still unclear. To address this issue, immature DCs (iDCs) generated from CD14+ cells isolated from healthy donors were matured either with cytokines (mDCs), or co-cultured (ccDCs) with human coronary artery VSMCs (CASMCs) using transwell chambers. Co-culture induced DC immunophenotypical and functional maturation similar to cytokines, as demonstrated by flow cytometry and mixed lymphocyte reaction. In turn, factors from mDCs and ccDCs induced CASMC migration. MCP-1 and TNFα, secreted from DCs, and IL-6 and MCP-1, secreted from CASMCs, were primarily involved. mDCs adhesion to CASMCs was enhanced by CASMC pre-treatment with IFNγ and TNFα ICAM-1 and VCAM-1 were involved, since the expression of specific mRNAs for these molecules increased and adhesion was inhibited by neutralizing antibodies to the counter-receptors CD11c and CD18. Adhesion was also inhibited by CASMC pre-treatment with the HMG-CoA-reductase inhibitor atorvastatin and the PPARγ agonist rosiglitazone, which suggests a further mechanism for the anti-inflammatory action of these drugs. Adhesion of DCs to VSMCs was shown also in vivo in rat carotid 7 to 21 days after crush and incision injury. The findings indicate that DCs and VSMCs can interact with reciprocal stimulation, possibly leading to perpetuate inflammation and vascular wall remodelling, and that the interaction is enhanced by a cytokine-rich inflammatory environment and down-regulated by HMGCoA-reductase inhibitors and PPARγ agonists.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099652PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059651PMC
January 2015

Diagnosis of a T-lineage acute lymphoblastic leukemia through digitalized cell analysis of the pleural effusion.

Int Med Case Rep J 2013 1;6:77-80. Epub 2013 Nov 1.

General Laboratory Unit (Microscopy and Clinical Cytometry Unit), Firenze, Italy.

Introduction: Pleural effusion as the first clinical manifestation of acute lymphoblastic leukemia (ALL) is a relatively rare event. An early and accurate diagnosis of this clinical picture is very important for adequate patient management.

Case Presentation: We report the atypical onset of T-lineage ALL in a 31-year-old man. The patient was admitted to the emergency room due to lung failure; at that moment, the patient's initial blood count was normal; the chest X-ray radiography showed a massive pleural effusion and a thoracentesis was carried out. Routine investigations performed on the pleural fluid using a new technology system and digitalized cell analysis demonstrated infiltration by immature cells. Therefore, bone marrow aspirate and flow cytometry analyses were performed, leading to the diagnosis of T-lineage ALL. A cord blood transplantation procedure was performed at the first hematological remission following chemotherapy regimens. The patient died of septic shock.

Conclusion: The case we reported underlines the usefulness of using automated instruments to identify abnormal lymphoid cells in body fluids.
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http://dx.doi.org/10.2147/IMCRJ.S49278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818024PMC
November 2013

Modulation of the immune and inflammatory responses by Plasmodium falciparum schizont extracts: role of myeloid dendritic cells in effector and regulatory functions of CD4+ lymphocytes.

Infect Immun 2013 May 18;81(5):1842-51. Epub 2013 Mar 18.

Department of Clinical Physiopathology, University of Florence, Italy.

The optimal immune response to malaria infection comprises rapid induction of inflammatory responses promptly counteracted by regulatory mechanisms to prevent immunopathology. To evaluate the role of dendritic cells (DC) in the balance of parasite-induced inflammatory/anti-inflammatory mechanisms, we studied the activity of monocyte-derived dendritic cells (MDDC), previously exposed to soluble extracts of Plasmodium falciparum-infected red blood cells (PfSE), in the differentiation of CD4 cells isolated from donors never exposed to malaria infection. We show that MDDC exposed to PfSE are extremely efficient to induce a contemporary differentiation of TH1 effector cells and T regulatory (Treg) cells in CD4 T cells even when exposed to low concentrations of parasitic extracts. Treg cells induced by MDDC infected with PfSE (MDDC-PfSE) produce transforming growth factor beta (TGF-β) and interleukin 10 (IL-10) and are endowed with strong suppressive properties. They also show phenotypical and functional peculiarities, such as the contemporary expression of markers of Treg and TH1 differentiation and higher sensitivity to TLR4 ligands both inducing an increasing production of suppressive cytokines. On the whole, our data indicate that MDDC exposed to PfSE orchestrate a well-balanced immune response with timely differentiation of TH1 and Treg cells in CD4 cells from nonimmune donors and suggest that, during the infection, the role of MDCC could be particularly relevant in low-parasitemia conditions.
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http://dx.doi.org/10.1128/IAI.01226-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648022PMC
May 2013

The frequency of granulocytes with spontaneous somatic mutations: a wide distribution in a normal human population.

PLoS One 2013 14;8(1):e54046. Epub 2013 Jan 14.

Laboratory of Cancer Genetics and Gene Transfer, Core Research Laboratory-CRL, Istituto Toscano Tumori-ITT, Firenze, Italy.

Germ-line mutation rate has been regarded classically as a fundamental biological parameter, as it affects the prevalence of genetic disorders and the rate of evolution. Somatic mutation rate is also an important biological parameter, as it may influence the development and/or the course of acquired diseases, particularly of cancer. Estimates of this parameter have been previously obtained in few instances from dermal fibroblasts and lymphoblastoid cells. However, the methodology required has been laborious and did not lend itself to the analysis of large numbers of samples. We have previously shown that the X-linked gene PIG-A, since its product is required for glycosyl-phosphatidylinositol-anchored proteins to become surface bound, is a good sentinel gene for studying somatic mutations. We now show that by this approach we can accurately measure the proportion of PIG-A mutant peripheral blood granulocytes, which we call mutant frequency, ƒ. We found that the results are reproducible, with a variation coefficient (CV) of 45%. Repeat samples from 32 subjects also had a CV of 44%, indicating that ƒ is a relatively stable individual characteristic. From a study of 142 normal subjects we found that log ƒ is a normally distributed variable; ƒ variability spans a 80-fold range, from less than 1×10⁻⁶ to 37.5×10⁻⁶, with a median of 4.9×10⁻⁶. Unlike other techniques commonly employed in population studies, such as comet assay, this method can detect any kind of mutation, including point mutation, as long as it causes functional inactivation of PIG-A gene. Since the test is rapid and requires only a small sample of peripheral blood, this methodology will lend itself to investigating genetic factors that underlie the variation in the somatic mutation rate, as well as environmental factors that may affect it. It will be also possible to test whether ƒ is a determinant of the risk of cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054046PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3544671PMC
August 2013

Distinct signal transduction abnormalities and erythropoietin response in bone marrow hematopoietic cell subpopulations of myelodysplastic syndrome patients.

Clin Cancer Res 2012 Jun 11;18(11):3079-89. Epub 2012 Apr 11.

FU Hematology and Department of Laboratory Medicine, Azienda Ospedaliero Universitaria (AOU) Careggi, University of Florence, Florence, Italy.

Purpose: Myelodysplastic syndromes (MDS) are heterogeneous clonal diseases characterized by cytopenias as a result of ineffective hematopoiesis. Little is known about alterations in signal transduction pathways in MDS.

Experimental Design: Multiparameter flow cytometry was used to evaluate the proteolytic activation of caspase-3 and the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and STAT5 specifically in defined CD34(+), CD45(+), or CD71(+)CD45(-) bone marrow (BM) cells from 60 MDS cases and normal controls, both at baseline and following stimulation with granulocyte colony-stimulating factor (G-CSF) and erythropoietin.

Results: In CD71(+)CD45(-) cells from a subpopulation of 36 MDS cases who were predicted to be responsive by clinical parameters (endogenous erythropoietin levels, transfusion dependency, percentage of blasts in the BM), erythropoietin failed to activate ERK1/2 or STAT5 in 23 of 36 cases, but it was effective in 13 of 36 cases, although to a significantly lower degree than in CD71(+)CD45(-) cells from healthy donor BM. The erythropoietin response in vivo correlated with in vitro erythropoietin-dependent STAT5 activation in 20 of 22 cases. STAT5 was significantly activated at baseline in MDS cells compared with normal controls, whereas caspase-3 was activated in CD34(+) and CD45(+) MDS cells, and was activated more often in the RA and RAEB-1 MDS subtypes. G-CSF stimulation activated ERK1/2 and STAT5 equally in MDS and normal CD34(+) cells.

Conclusions: Abnormalities in the response to growth factors are restricted to erythropoietin stimulation in CD71(+)CD45(-) cells and correlate with the clinical response to erythropoietin. Activation of baseline signal transduction for proliferative and apoptotic signals is altered in MDS but with different patterns among the various BM subpopulations.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-0686DOI Listing
June 2012

Physical activity and circulating endothelial progenitor cells: an intervention study.

Eur J Clin Invest 2012 Sep 29;42(9):927-32. Epub 2012 Mar 29.

Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Florence, Italy.

Background: To assess the effect of a personalized physical activity programme on weight and circulating (CPC) and endothelial progenitor cells (EPC) in overweight and obese subjects.

Materials And Methods: Anthropometric measurements with body composition, cardiopulmonary test, maximal stress exercise test with maximal oxygen uptake (VO(2max) ) and a series of biochemical analyses were taken before (T0) and after 3 months of physical activity (T1) in a total of 80 overweight and obese subjects. CPC and EPC were determined using flow cytometry and were defined as CD34+, CD133+ and CD34+/CD133+ for CPC and CD34+KDR+, CD133+KDR+ and CD34+CD133+KDR+ for EPC.

Results: At the end of the programme, we divided the population into two groups, compliant individuals (group A, n = 47) and noncompliant individuals (group B, n = 33). Group A reported significant reductions of weight by 3·1% (P < 0·0001) and fat mass by 4·4% (P < 0·0001), while group B showed a percentage of increase in fat mass by 1·5% at T1. In group A, a trend of increase at T1 for circulating levels of CPC and EPC was observed, reaching the statistical significance for all the three types of EPC. On the contrary, group B showed no significant increase in CPC and EPC. Furthermore, a significant correlation between decrease in fat mass and increase in CD133+/KDR+ EPC was reported in group A (r = 0·50; P = 0·04).

Conclusion: Three months of physical activity significantly improved anthropometric measurements. A beneficial effect of increased number of EPC in compliant individuals, in relation to weight loss, was observed.
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http://dx.doi.org/10.1111/j.1365-2362.2012.02670.xDOI Listing
September 2012

Plasmodium falciparum soluble extracts potentiate the suppressive function of polyclonal T regulatory cells through activation of TGFβ-mediated signals.

Cell Microbiol 2011 Sep 23;13(9):1328-38. Epub 2011 Jun 23.

Department of Clinical Physiopathology, University of Firenze, Firenze, Italy.

Increased numbers of T regulatory cells (Tregs), key mediators of immune homeostasis, were reported in human and murine malaria and it is current opinion that these cells play a role in balancing protective immunity and pathogenesis during infection. However, the mechanisms governing their expansion during malaria infection are not completely defined. In this article we show that soluble extracts of Plasmodium falciparum (PfSEs), but not equivalent preparation of uninfected erythrocytes, induce the differentiation of polyclonally activated CD4(+) cells in Tregs endowed with strong suppressive activity. PfSEs activate latent TGFβ bound on the membrane of Treg cells, thus allowing the cytokine interaction with TGFβ receptor, and inducing Foxp3 gene expression and TGFβ production. The activation of membrane-bound latent TGFβ by PfSEs is significantly reduced by a broad-spectrum metalloproteinases inhibitor with Zn(++) -chelating activity, and completely inhibited by the combined action of such inhibitor and antibodies to a P. falciparum thrombospondin-related adhesive protein (PfTRAP). We conclude that Pf-Zn(++) -dependent proteinases and, to a lesser extent, PfTRAP molecules are involved in the activation of latent TGFβ bound on the membrane of activated Treg cells and suggest that, in malaria infection, this mechanism could contribute to the expansion of Tregs with different antigen specificity.
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http://dx.doi.org/10.1111/j.1462-5822.2011.01622.xDOI Listing
September 2011

High platelet turnover and reactivity in renal transplant recipients patients.

Thromb Haemost 2010 Oct 5;104(4):804-10. Epub 2010 Aug 5.

Department of Medical and Surgical Critical Care, Thrombosis Centre, Center for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, University of Florence, Italy.

Renal transplant recipients (RTRs) patients are at increased risk of cardiovascular morbidity and mortality. We aimed this study to assess reticulated platelets (RP), platelet reactivity and von Willebrand factor (vWF) levels in RTRs patients. In 150 RTRs patients [84 (56%) not on acetylsalicylic acid (ASA) treatment, group A; 66 (44%) on ASA 100 mg treatment, group B] and in 60 healthy control subjects, RP were measured by a Sysmex XE-2100 and were expressed as the percentage of RP of the total optical platelet count (immature platelet fraction; IPF), as the percentage of RP highly fluorescent (H-IPF) and as the absolute number of RP (IPF#). Platelet function was assessed by optical aggregometry (PA) induced by 1 mmol arachidonic acid (AA-PA), 2 and 10 μM ADP (ADP2-PA and ADP10-PA) and 2 μg/ml collagen (Coll-PA). vWF levels were measured by using a miniVidas analyser. Group A and group B showed significant higher values of RP than controls. At a multiple linear regression analysis IPF and IPF# were significantly and positively related to collagen-PA. By analysing group B according to residual platelet reactivity (RPR), we observed a significant higher number of RP among patients with RPR by collagen. Moreover at a multiple logistic regression analysis, IPF# significantly affected the risk of having a RPR by collagen. With regard to vWF, RTRs patients showed higher levels than control subjects. We documented a higher platelet turn-over in both groups of RTRs patients and increased platelet reactivity in RTRs patients not on ASA therapy than controls.
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http://dx.doi.org/10.1160/TH10-02-0124DOI Listing
October 2010