Dengue Fever Complicated By Hemophagocytosis – A Difficult To Manage Case

Dengue fever, which is transmitted by the mosquito Aedes aegypti is a common acute viral febrile illness, affecting 390 million people worldwide every year. It is endemic in several countries. Although the usual presentation is that of a self-limiting illness, its complications are protean. Infection Associated with Hemophagocytic Syndrome (IAHS) is a rare and fatal complication of dengue fever. It should be suspected in a patient with fever beyond seven days, associated with hepatosplenomegaly, hyperferritinemia, worsening cytopenias and development of multiorgan dysfunction(MOD). We report a 19-year-old female, who presented with an acute febrile illness and was diagnosed with primary dengue fever. Despite appropriate supportive therapy, she worsened clinically during the course of hospitalisation. A disproportionately high ferritin level and persistent bicytopenia prompted investigations for hemophagocytic lymphohistiocytosis (HLH). Further evaluation revealed features of HLH, as per the diagnostic criteria laid down by the Histiocyte Society. She was successfully treated with glucocorticoids, etoposide and intravenous immunoglobin and other supportive therapy. She had severe cytopenia and cardiac dysfunction during the course of her illness and its management. This case adds to the limited adult cases of dengue-associated hemophagocytic syndrome and shows its difficulty in management due to associated extra complications.

Novel Role of Ras-GTPase Activating Protein SH3 Domain-Binding Protein G3BP in Adhesion and Migration of 32D Myeloid Progenitor Cells

Rho GTPases are involved in homing and mobilization of hematopoietic stem and progenitor cells due to their impact on cytoskeleton remodeling. We have previously shown that inhibition of Rho, Rac and Cdc42 clearly impairs adhesion of normal and leukemic hematopoietic progenitor cells (HPC) to fibronectin and migration in a three-dimensional stromal cell model. Here, we identified the Ras GTPase-Activating Protein SH3 Domain-Binding Protein (G3BP) as a target gene of Rho GTPases and analysed its role in regulating HPC motility. Overexpression of G3BP significantly enhanced adhesion of murine 32D HPC to fibronectin and human umbilical vein endothelial cells, increased the proportion of adherent cells in a flow chamber assay and promoted cell migration in a transwell assay and a three-dimensional stromal cell model suggesting a strong impact on the cytoskeleton. Immunofluorescent staining of G3BP-overexpressing fibroblasts revealed a Rho-like phenotype characterized by formation of actin stress fibers in contrast to the Rac-like phenotype of control fibroblasts. This is the first report implicating a role for G3BP in Rho GTPase-mediated signalling towards adhesion and migration of HPC. Our results may be of clinical importance, since G3BP was found overexpressed in human cancers.

Targeting the Oligomerization of BCR/ABL by Membrane Permeable Competitive Peptides Inhibits the Proliferation of Philadelphia Chromosome Positive Leukemic Cells

The BCR/ABL fusion protein is the hallmark of Philadelphia Chromosome positive (Ph+) leukemia. The constitutive activation of the ABL-kinase in BCR/ABL cells induces the leukemic phenotype. Targeted inhibition of BCR/ABL by small molecule inhibitors reverses the transformation potential of BCR/ABL. Recently, we definitively proved that targeting the tetramerization of BCR/ABL mediated by the N-terminal coiled-coil domain (CC) using competitive peptides, representing the helix-2 of the CC, represents a valid therapeutic approach for treating Ph+ leukemia. To further develop competitive peptides for targeting BCR/ABL, we created a membrane permeable helix-2 peptide (MPH-2) by fusing the helix-2 peptide with a peptide transduction tag. In this study, we report that the MPH-2: (i) interacted with BCR/ABL in vivo; (ii) efficiently inhibited the autophosphorylation of BCR/ABL; (iii) suppressed the growth and viability of Ph+ leukemic cells; and (iv) was efficiently transduced into mononuclear cells (MNC) in an in vivo mouse model. This study provides the first evidence that an efficient peptide transduction system facilitates the employment of competitive peptides to target the oligomerization interface of BCR/ABL in vivo.

Features of Chronic Active Epstein-Barr virus Infection and Related Human Diseases

A chronic undefined illness characterized by infectious mononucleosis (IM)-like symptoms and signs, possibly associated with Epstein-Barr virus (EBV) infection, designated as so-called chronic active EBV infection (CAEBV), is focused and discussed in this mini-review. Patients with CAEBV often develop T cell lymphoproliferative disorder (LPD)/lymphoma or NK cell LPD/lymphoma. Unique manifestations with generally poor prognosis of the disease prompt us to understand in particular the entity, diagnosis and treatment.

AGEM400(HES), a Novel Erythropoietin Mimetic Peptide Conjugated to Hydroxyethyl Starch with Excellent In Vitro Efficacy

We developed and tested a compound called AGEM400(HES) that consists of a novel erythropoietin mimetic peptide (EMP) which is produced as a continuous N- to C-linked dimer and is conjugated to biodegradable hydroxyethyl starch (HES). In various in vitro assays, AGEM400(HES) demonstrated excellent efficacy, better than the peptide alone, and comparable to the efficacy of erythropoietin (EPO) and Aranesp (Darbepoietin alpha). The assays included survival assays on EPO-responsive cell lines (EC50 below 1 ng/ml peptide) and clonogenic assays on human bone marrow cells (EC50 1 to 10 ng/ml). AGEM400(HES) caused phosphorylation of STAT5 and ERK signalling proteins in UT7/EPO cells in a similar fashion as EPO. AGEM400(HES) replaced EPO from its receptor and the in vitro activity of AGEM400 (HES) was inhibited by soluble EPO receptor. Antibodies generated in mice and rabbits against EPO did not recognize AGEM400(HES) peptide, and vice versa. A sensitive ELISA was able to detect AGEM400(HES) at low nanogram per ml concentrations which allows for bioanalytics of AGEM400(HES) serum levels in future in vivo studies. As a result, AGEM400(HES) is a promising drug candidate for anemias related to renal insufficiency and/or in oncological settings.