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Barcellini W.,Uo Ematologia E Centro Trapianti Of Midollo | Imperiali F.G.,Uo Ematologia E Centro Trapianti Of Midollo | Zaninoni A.,Uo Ematologia E Centro Trapianti Of Midollo | Reda G.,Uo Ematologia E Centro Trapianti Of Midollo | And 9 more authors.
Leukemia and Lymphoma | Year: 2014

Toll-like receptors (TLRs) represent major agents of innate immunity and initiators of adaptive immunity. TLR4 and TLR9 gene expression was related to the occurrence of infections, autoimmunity and disease progression in 95 patients with B-chronic lymphocytic leukemia (B-CLL), grouped according to stage, therapy and known prognostic markers, and followed prospectively (median 33.6 months, range 25-50). A retrospective analysis (median 6.8 years, range 6-26) was also performed. TLR4 gene expression was decreased and TLR9 increased in patients versus controls, the former being more pronounced in advanced and multi-treated disease, and in patients with unmutated immunoglobulin heavy chain variable (IgVH) region and unfavorable cytogenetics. Patients with reduced TLR4 had an increased risk of disease progression and development of autoimmune complications. No relationship was found between reduced TLR4 expression and infectious episodes, which were observed in advanced stages and treated patients. These findings suggest that impaired innate immunity identifies patients with B-CLL with a poor prognosis and reduced ability to silence autoreactive phenomena. © 2014 Informa UK, Ltd. Source


Barcellini W.,Uo Ematologia E Centro Trapianti Of Midollo | Iurlo A.,Uo Ematologia E Centro Trapianti Of Midollo | Radice T.,Uo Ematologia E Centro Trapianti Of Midollo | Imperiali F.G.,Uo Ematologia E Centro Trapianti Of Midollo | And 7 more authors.
Leukemia Research | Year: 2013

Autoimmune phenomena and cytokines were investigated in 100 patients with myelofibrosis (MF) and related to marrow fibrosis and clinical risk. Anti-erythrocyte antibodies by mitogen-stimulated direct antiglobulin test (MS-DAT) were positive in 45%, anti-platelets in 15% and organ/non organ-specific in 57% of cases, without clinically overt disease, and mostly in low-risk/intermediate-risk-1 and MF-0/MF-1. TGF-β and IL-8 were increased in MS-DAT positive cases, and IFN-γ in patients with serological autoantibodies. TGF-β and IL-17 were elevated in early clinical and morphological stages, while IL-8 increased in advanced stages. These data suggest that autoimmune phenomena and cytokine disregulation are particularly relevant in early MF. © 2013 Elsevier Ltd. Source


Fermo E.,Uo Ematologia E Centro Trapianti Of Midollo | Bianchi P.,Uo Ematologia E Centro Trapianti Of Midollo | Chiarelli L.R.,University of Pavia | Maggi M.,University of Pavia | And 8 more authors.
Molecular Genetics and Metabolism | Year: 2012

Phosphoglycerate kinase (PGK) is a key glycolytic enzyme that catalyzes the reversible phosphotransfer reaction from 1,3-bisphosphoglycerate to MgADP, to form 3-phosphoglycerate and MgATP. Two isozymes encoded by distinct genes are present in humans: . PGK-1, located on Xq-13.3, encodes a ubiquitous protein of 417 amino acids, whereas . PGK-2 is testis-specific.PGK1 deficiency is characterized by mild to severe hemolytic anemia, neurological dysfunctions and myopathy; patients rarely exhibit all three clinical features. Nearly 40 cases have been reported, 27 of them characterized at DNA or protein level, and 20 different mutations were described.Here we report the first Italian case of PGK deficiency characterized at a molecular and biochemical level. The patient presented during infancy with hemolytic anemia, increased CPK values, and respiratory distress; the study of red blood cell enzymes showed a drastic reduction in PGK activity. In adulthood he displayed mild hemolytic anemia, mental retardation and severe myopathy.PGK-1 gene sequencing revealed the new missense mutation c.1112T>A (p.Ile371Lys). The mutation was not found among 100 normal alleles, and even if located in the third to the last nucleotide of exon 9, it did not alter mRNA splicing. The p.Ile371Lys mutation falls in a conserved region of the enzyme, near the nucleotide binding site. The mutant enzyme shows reduced catalytic rates toward both substrates (apparent kcat values, 12-fold lower than wild-type) and a decreased affinity toward MgATP (apparent Km, 6-fold higher than wild-type). Moreover, it lost half of activity after nearly 9-min incubation at 45°C, a temperature that did not affect the wild-type enzyme (t1/2>1h). The possible compensatory expression of PGK2 isoenzyme was investigated in the proband and in the heterozygote healthy sisters, and found to be absent. Therefore, the highly perturbed catalytic properties of the new variant p.Ile371Lys, combined with protein instability, account for the PGK deficiency found in the patient and correlate with the clinical expression of the disease. © 2012 Elsevier Inc. Source

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