The transcription factor Nrf2 (nuclear factor E2-related factor 2) regulates the expression of antioxidant phase II genes and contributes to preserve redox homeostasis and cell viability in response to oxidant insults. Nrf2 should be coordinated with the canonical cell survival pathway represented by phosphatidylinositol 3-kinase (PI3K) and the Ser/Thr kinase Akt but so far the mechanistic connections remain undefined. Here we identify glycogen synthase kinase-3␤ (GSK-3␤), which is inhibited by Akt-mediated phosphorylation, as the link between both processes. Using heme oxygenase-1 (HO-1) as a model phase II gene, we found that both PI3K and Akt increased mRNA and protein levels of this enzyme. Pharmacological inhibitors (LiCl and PDZD-8) and genetic variants of GSK-3␤ (constitutively active and dominant negative mutants) indicated that PI3K/Akt activates and GSK-3␤ inhibits the antioxidant response elements of the ho1 promoter and pointed Nrf2 as directly involved in this process. Indeed, GSK-3␤ phosphorylated Nrf2 in vitro and in vivo. Immunocytochemistry and subcellular fractionation analyses demonstrated that the effect of GSK-3␤-mediated phosphorylation of Nrf2 is to exclude this transcription factor from the nucleus. Nrf2 up-regulated the expression of HO-1, glutathione peroxidase, glutathione S-transferase A1, NAD(P)H: quinone oxidoreductase and glutamate-cysteine ligase and protected against hydrogen peroxide-induced glutathione depletion and cell death, whereas co-expression of active GSK-3␤ attenuated both phase II gene expression and oxidant protection. These results contribute to clarify the cross-talk between the survival signal elicited by PI3K/Akt and the antioxidant phase II cell response, and introduce GSK-3␤ as the key mediator of this regulation mechanism.

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A 26-year-old previously healthy Paraguayan woman consulted because of persistent fever and painful cutaneous lesions of the arms and legs of 2 weeks duration. Physical examination revealed: numerous two cm diameter brown subcutaneous nodules, and ulcers of both feet (left); supraclavicular, axillary and inguinal lymphadenopathy; hepatosplenomegaly; and thermal hypoesthesia and decreased pain sensitivity in legs and arms.A blood film showed atypical lymphocytes, so a bone marrow aspiration and trephine biopsy were performed. A ZiehlNeelsen stain revealed numerous acid-fast bacilli (right). A week later, a biopsy of a cutaneous lesion showed panniculitis with mycobacteria and an infiltration by microvacuolated histiocytes, confirming the diagnosis of lepromatous leprosy.The patient was discharged home after clinical improvement with rifampicin, dapsone and clofazimine.Although the bone marrow is usually affected in lepromatous leprosy, the diagnosis is commonly made by skin biopsy. This case illustrates the importance of bone marrow aspiration in the differential diagnosis of fever of unknown origin.

Double-hit lymphoma (DHL) is a rare type of lymphoma with concurrent chromosomal translocations of C-MYC with BCL2 or BCL6, associated with unfavorable prognosis. We describe a case of DHL in a 79-year-old female patient previously diagnosed with diffuse large B-cell lymphoma (DLBCL) with an early relapse in the ascitic fluid. A seven-color multiparametric flow cytometry immunophenotyping study of the ascitic fluid was carried out, and revealed 99.78% of large in size and high cellular complexity B-cells positive for CD19, CD10 (64.27%), CD45 dim, CD22 dim, CD25 (60%), CD43 bright, CD38 bright, and IgM (18.53%); and negative for CD20, CD5, CD23, CD79b, CD103, CD200, CD11c, and FMC7, and 78.99% without light chain expression and 21% with Lambda chain restriction. Due to the expression of CD19 and CD10 with overexpression of BCL-2 protein and due to CD43 and CD38 positivity detected, those cells showed features between DLBCL and Burkitt lymphoma. Fluorescence in situ hybridization (FISH) confirmed both c-MYC/IGH and BCL2/IGH rearrangement. Our findings may help to identify cases requiring additional cytogenetic analysis. © 2015 International Clinical Cytometry Society.