Sorafenib was as safe as effective in DIAB and in nDIAB patients. The longer TTP observed among DIAB than in nDIAB patients might suggest a better anticancer effect of sorafenib in patients with diabetes.

No abstract

Peroxiredoxin-2 (Prx2), a typical 2-cysteine (Cys) peroxiredoxin, is a key anti-oxidant system in both normal and pathological erythropoiesis characterized by oxidative stress such as b-thalassemia. We recently showed that the absence of Prx2 worsens ß-thalassemic erythropoiesis and related iron-overload (Matte A et al. Antioxid Redox Signal, 2015). Here, we studied the effects of iron overload in a mouse model genetically lacking Prx2 (Prx2-/-). Two months old female wild-type (WT) and Prx2-/- pure bred mice were fed with a diet containing 2.5% carbonyl-iron compared to standard diet treated mice. We evaluated hematologic parameters, red cell indices and reticulocyte count in both mouse strains at baseline and at 30, 49, 60 and 90 days of treatment with carbonyl-iron. We observed a rapid drop in Hct and reticulocyte count in Prx2-/- mice compared to wild-type mice between 30-49 days of iron supplementation with the appearance of severe hyporegenerative anemia at 60 days of treatment in Prx2-/- characterized by a significant reduction in CD44+TER119+Fsc high cells. This was associated with marked increases in apoptotic Prx2-/- orthochromatic erythroblast compared to either baseline values or WT treated mice. In sorted erythroid precursors from iron overload WT mice, Prx2 expression was significantly increased compared to WT under standard diet. We observed a modulation of Erythropherrone (Erfe) expression during erythropoiesis with upregulation of Erfe in WT orthochromatic erythroblast compared to Prx2-/- erythroblasts. In liver from Prx2-/- mice exposed to iron-overload, we found liver iron content similar to WT mice but Pearls stain analysis showed differential iron distribution in cellular components of liver. While iron accumulated in hepatocytes and Kuppfer cells in Prx2-/- mice, iron-deposits were present only in hepatocytes of WT liver. Oxyblot analysis and liver MDA levels were significantly higher in Prx2-/- mice indicating that the absence of Prx2 promotes a severe liver oxidative stress. In WT liver, Prx2 expression was marked increased in a time depend way during iron supplementation, indicating that Prx2 is part of an adaptive cellular response to iron overload. This is in agreement with increased levels of ferritin-H in Prx2-/- mice compared to WT mice. Hepcidin (HAMP) expression was markedly increased in iron-overload WT mice compared to untreated control group, while no major changes were observed in Prx2-/- mice. Tfr2 expression was significantly increased only in livers of iron-overload WT mice, whereas phospho smad 1-5 was significantly increased in both mouse strains in response to iron-overload. The activation of the signaling pathway through Erk-1/2 only in iron-overload WT mice but not in Prx2-/- mice is most likely related to severe oxidative stress in Prx2-/- resulting in switching off of the Erks pathway. Importantly, administration of PEP1-Prx2 fusion protein rescue almost completely the hematologic phenotype with modulation of Erk signaling pathway towards Tfr2 and the smad system, validating our hypothesis of a role for Erk signaling for the observed phenoytpes. Our data highlight Prx2 as novel factor involved in iron homestasis through the control of oxidative stress modulating signaling pathway towards hepcidin expression. Disclosures No relevant conflicts of interest to declare.

X-linked intellectual deficiency (XLID) is a widely heterogeneous group of genetic disorders that involves more than 100 genes. The mediator of RNA polymerase II subunit 12 (MED12) is involved in the regulation of the majority of RNA polymerase II-dependent genes and has been shown to cause several forms of XLID, including Opitz-Kaveggia syndrome also known as FG syndrome (MIM #305450), Lujan-Fryns syndrome (MIM #309520) and the X-linked Ohdo syndrome (MIM #300895). Here, we report on two first cousins with X-linked Ohdo syndrome with a missense mutation in MED12 gene, identified through whole exome sequencing. The probands had facial features typical of X-linked Ohdo syndrome, including blepharophimosis, ptosis, a round face with a characteristic nose and a narrow mouth. Nextera DNA Exome kit (Illumina Inc., San Diego, CA, USA) was used for exome capture. The variant identified was a c.887G > A substitution in exon 7 of the MED12 gene leading to the substitution of a glutamine for a highly conserved arginine (p. Arg296Gln). Although the variant described has been previously reported in the literature, our study contributes to the expanding phenotypic spectrum of MED12-related disorders and above all, it demonstrates the phenotypic variability among different affected patients despite harboring identical mutations.

Stomatocytosis is an inherited autosomal dominant hemolytic anemia and includes overhydrated hereditary stomatocytosis (OHS), dehydrated hereditary stomatocytosis (DHS), hereditary cryohydrocytosis (CHC) and familial pseudohyperkalemia (FP). Here, we report a novel variant of hereditary stomatocytosis due to a de-novo band 3 mutation due to G>A transition at nucleotide 2500 in exon 17 (p. G796R, band3CEINGE) associated with dyserythropoietic phenotype. This 43-years-old Caucasian female (II-2) with unrelated parents was admitted to our hospital for mild anemia evaluation. The patient was in good health until 7 years when she frequently experienced asthenia. Anemia was first recognized at the age of eighth years with presence of jaundice and hyperchromic urine, but she had never received blood transfusions. We observed a mild hypochromic macrocytic anemia with a hemoglobin level of 11.5 g/dL, a mean cell volume (MCV) of 110 fL, and a mean hemoglobin concentration (MCH) of 36.1 pg, the reticulocyte count was 64 × 103/μL. There was a typical hemolytic features: high levels of indirect bilirubin (3.48 mg/dL) and lactate dehydrogenase ( 567 U/l, v.n. 240– 480 U/l ) with negativity at direct and indirect Coomb’s test. Spleen was enlarged and ultrasonography detected 15 cm of longitudinal size. She was cholecystectomized at the age of 14 years because of numerous symptomatic small stones. Serum iron, soluble transferrin receptor, serum ferritin and transferrin saturation levels were all increased, while the transferrin was in the normal range.Other blood tests including osmotic fragility with incubated and fresh erythrocytes, serum electrolytes, B12 and folate levels, erythrocyte enzyme levels, EMA test and Pink test were normal. Peripheral blood smear showed anisopoikilocytosis with rare stomatocytes and no spherocytes. Bone marrow aspirate showed remarkable dyserythropoiesis with increased number of erythroblasts and binucleate erythroblasts, basophilic erythroblasts with alterations, irregular nuclei maturation, intererythroblastic bridges and erythroblasts with basophilic stippling. She received since the age of 14 yrs a diagnosis for congenital dyserythropoietic anemia type I. Patients red cells showed increase Na+ content and decrease K+ content; reduced Na-K pump activity and increased Na-H exchange, NKCC cotransport and KCC cotransport activities. We then functionally characterized band 3 CEINGE in Xenopus oocytes, showing that the mutated band 3 is converted from anion exchanger (Cl−, HCO3 −) function to unregulated cation pathway for Na+ and K+. The mutated band 3 was also associated with increased tyrosine phosphorylation pattern of some red cell membrane proteins. During erythropoiesis band 3 protein is the last cytoskeletal protein to appear, thus the dyserythropoietic phenotype may be related to a possible role of the mutated band 3 in perturbation of cytoskeleton assembly in the late stage of erythropoiesis, allowing us to conclude for a new variant of stomatocytosis with dyserythropoietic phenotype.