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Tagliaferri A.,University of Parma | di Perna C.,University of Parma | Santoro C.,University of Rome La Sapienza | Schinco P.,University of Turin | And 5 more authors.
Journal of Thrombosis and Haemostasis | Year: 2012

Summary. Background:The increased life expectancy of the hemophilia population, primarily as a result of advances in factor replacement therapy, has enabled hemophiliacs to reach an older age. Consequently, age-related diseases, such as cardiovascular disorders and cancers, are being increasingly recognized in such patients. However, only few data are available on such co-morbidities, their management and impact on the primary bleeding disorders. Objectives:With the aim of investigating several still unclear issues regarding cancers in hemophilia patients, we conducted, on behalf the Italian Association of Hemophilia Centers (AICE), a study on cancers among Italian hemophiliacs. Patients:Data pertaining to 122 hemophiliacs with 127 cancers between 1980 and 2010 were retrospectively collected in 21 centers of the AICE which chose to participate. Results: Sixty-nine percent of cancers were recorded during the decade 2001-2010. Eighty-three percent of patients were infected with hepatitis C virus (HCV) and 22% of them were also co-infected with human immunodeficiency virus (HIV). Forty-three percent of cancers were HCV-related, whereas 9% were HIVrelated. Virus-related cancers were more frequent and non-virus-related cancers less frequent in patients with severe hemophilia than in those with mild/moderate forms (P=0.0004). The non-virus-related standardized mortality ratio (SMR) was 0.3. Hemorrhagic complications occurred more frequently in patients undergoing chemotherapy (14%) or radiotherapy (19%). Conclusions:The results of the present study confirm that cancers have become a new challenge for physicians working in hemophilia centers and underline the need for prospective trials to better assess the epidemiology and to optimize the management of hemophiliacs with cancer. © 2011 International Society on Thrombosis and Haemostasis. Source

Franchini M.,Immunohematology and Transfusion Center | Lippi G.,Clinical Chemistry Laboratory
Thrombosis Research | Year: 2010

Several inherited prothrombotic risk factors have been identified so far. Among them, the factor V (FV) Leiden mutation causes a reduced ability of activated protein C to inactivate activated FV and is the most frequent genetic predisposing factor for venous thromboembolism. However, the high prevalence of FV Leiden (up to 15%) in the Caucasian population suggests that this mutation might confer an evolutionary survival advantage. Indeed, there is mounting evidence about the role of FV Leiden in modulating the clinical phenotype of some physiological and pathological conditions, including hemophilia. The existing literature on the interaction between FV Leiden and hemophilia-related factor VIII or IX mutations is analyzed in this review focusing on the clinical effects and possible pathogenic mechanisms. In summary, current evidence suggests that this prothrombotic mutation may compensate for the low factor VIII or IX levels, resulting in more efficient thrombin generation and ensuing attenuation of clinical symptoms. On the other hand, the association of this prothrombotic mutation with other acquired or inherited thrombophilic factors might overcome the congenital bleeding tendency in hemophiliacs, thereby increasing the risk of thrombotic complications. © 2009 Elsevier Ltd. All rights reserved. Source

Calcaterra V.,University of Pavia | Martinetti M.,Immunohematology and Transfusion Center | Salina A.,Pediatric Clinic | Aloi C.,Pediatric Clinic | Larizza D.,University of Pavia
Acta Diabetologica | Year: 2012

Even though autoantibodies to pancreatic islet cells are normally found in type 1 diabetes and insulin-resistance due to overweight is more reminiscent of type 2 diabetes, some studies have described β-cell antibodies also in maturity-onset diabetes of the young (MODY) and in type 2 diabetes. A 7-year-old girl was referred to our Unit for incidental hyperglycemia and family history of MODY2 and type 2 diabetes. Genetic evaluation confirmed mutation L134P in exon 4 of the glucokinase gene and a high HLA-risk of type 1 diabetes. During follow-up, she developed type 1 diabetes and overweight-induced metabolic syndrome. The coexistence of MODY, type 1 diabetes and overweight-induced metabolic syndrome confirms that diabetes subtype probably represents a continuum of immune and metabolic dysfunction modified by genetic factors. © 2011 Springer-Verlag. Source

Franchini M.,Immunohematology and Transfusion Center | Mannucci P.M.,Scientific Direction
Thrombosis Research | Year: 2012

It is well recognized that the exposure to air pollution is associated with many adverse effects on health. A strong epidemiological association has been particularly observed between acute and chronic exposure to air pollutants and the occurrence of cardiovascular diseases. The pathophysiological mechanisms underlying these effects have not been fully identified but potential pathways include endothelial or autonomic dysfunction and systemic reactions such as hypercoagulability, inflammation and oxidative stress. The current knowledge of the short-term and long-term cardiovascular effects of particulate air pollutants is discussed in this review article. © 2011 Elsevier Ltd. All rights reserved. Source

Neri L.M.,University of Ferrara | Cani A.,University of Ferrara | Martelli A.M.,University of Bologna | Martelli A.M.,National Research Council Italy | And 8 more authors.
Leukemia | Year: 2014

B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G 0/G 1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL. © 2014 Macmillan Publishers Limited. Source

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