Interleukin-3 : identification, characterization and molecular evolution

Blood contains large numbers of various cell types. The mature blood cell types exert highly specialized functions such as oxygen and carbon dioxide transport, blood clotting and defense against infections by antibody production, cell mediated immunity and phagocytosis. Most of these mature blood cell types have a limited life span and therefore need to be produced continuously. This process of blood cell formation, termed hemopoiesis, is impressive since daily approximately 1011 new blood cells are generated in man. In steady state situations, the continuous replacement of terminally differentiated cells is tuned with great precision but the hemopoietic system can respond dramatically to environmental stress, such as bleeding or infection. The primary site of hemopoiesis is the bone marrow which permits the formation of all blood cell types i.e., erythrocytes, platelets, monocytes, neutrophils, basophils, eosinophils and lymphocytes. The continuous replenishment of functionally mature hemopoietic cells ill vivo is strictly dependent on the presence of a small but persistent pool of bone marrow plmipotent hemopoietic stem cells. The mechanism(s) controlling hemopoiesis appear to involve regulation mediated by a group of interacting specific glycoproteins designated hemopoietic growth factors. Furthermore, it has been implied that microenvironmental stromal cells support hemopoiesis as well. Several mechanisms through which stromal cells affect hemopoiesis have been postulated, i.e., a direct cell contact regulated mechanism, secretion of CSFs; expression of antagonists of differentiation-inducing factor(s) and/or self-renewal mediators

Evaluación de aves en la laguna El Paraiso, Lima, Perú

This study was carried out at El Paraíso lagoon, Lima, Peru, from April 1999 to April 2000. The main goals was determinated the birds specifi c diversity, the population density of main cinegetic bird families and the determination of the most important microhabitats for the studied groups. 81 birds species (19 species are new for the area) were reported, distribuited in 62 generas and 35 families. 46% of the diversity is given for the following families: Scolopacidae (14%), Ardeidae (10%), Laridae (7%), Anatidae (5%), Charadriidae (5%) and Columbidae (5%). The Rallidae family is the most abundant and is represented for two species Gallinula chloropus“Common Moorhen” y Fulica ardesiaca“Slate-colored Coot”. It is given recommendations for the conservation of the area.Este estudio se realizó en la laguna El Paraíso, departamento de Lima, Perú, de abril de 1999 a abril del 2000. Tuvo como objetivos la determinación de la diversidad específi ca en aves; la densidad poblacional de las principales familias de uso cinegético y la determinación de los microhábitats más importantes para los grupos evaluados. Se reportaron 81 especies de aves las cuales pertenecen a 62 géneros y a 35 familias. En esta cifra se reportan 19 especies nuevas para el área de Paraíso; el 46% de la diversidad de aves está dada por las familias Scolopacidae (14%), Ardeidae (10%), Laridae (7%), Anatidae (5%), Charadriidae (5%) y Columbidae (5%). La familia Rallidae es la más abundante y está representada por dos especies Gallinula chloropus “polla de agua” y Fulica ardesiaca“gallareta”, siendo la primera más numerosa. Asimismo, se dan las recomendaciones para la conservación del área

Inactivation of the Saccharomyces cerevisiae SKY1 gene induces a specific modification of the yeast anticancer drug sensitivity profile accompanied by a mutator phenotype

The therapeutic potential of the highly active anticancer agent cisplatin is severely limited by the occurrence of cellular resistance. A better understanding of the molecular pathways involved in cisplatin-induced cell death could potentially indicate ways to overcome cellular unresponsiveness to the drug and thus lead to better treatment results. We used the budding yeast Saccharomyces cerevisiae as a model organism to identify and characterize novel genes involved in cisplatin-induced cell kill, and found that SKY1 (SR-protein-specific kinase from budding yeast) is a cisplatin sensitivity gene whose disruption conferred cisplatin resistance. In cross-resistance studies, we observed resistance of yeast sky1 Delta cells (i.e., cells from which the SKY1 gene had been disrupted) to cisplatin, carboplatin (but not oxaliplatin), doxorubicin and daunorubicin, and hypersensitivity to cadmium chloride and 5-fluorouracil. Furthermore, these cells did not display reduced platinum accumulation, DNA platination or doxorubicin accumulation, indicating that the resistance is unrelated to decreased drug import or increased drug export. Based on the modification of the anticancer drug sensitivity profile and our finding that sky1 Delta cells display a mutator phenotype, we propose that Sky1p might play a significant role in specific repair and/or tolerance pathways. Disruption of the S. cerevisiae SKY1 gene would thus result in deregulation of such mechanisms and, consequently, lead to altered drug sensitivity

Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump

Imatinib mesylate (STI571), a potent tyrosine kinase inhibitor, is successfully used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. However, the intended chronic oral administration of imatinib may lead to development of cellular resistance and subsequent treatment failure. Indeed, several molecular mechanisms leading to imatinib resistance have already been reported, including overexpression of the MDR1/ABCB1 drug pump. We examined whether imatinib is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump that is frequently overexpressed in human tumors. Using a panel of well-defined BCRP-overexpressing cell lines, we provide the first evidence that imatinib is a substrate for BCRP, that it competes with mitoxantrone for drug export, and that BCRP-mediated efflux can be reversed by the fumitremorgin C analog Ko-143. Since BCRP is highly expressed in the gastrointestinal tract, BCRP might not only play a role in cellular resistance of tumor cells but also influence the gastrointestinal absorption of imatinib

Evaluación de aves en la laguna El Paraiso, Lima, Perú

Este estudio se realizó en la laguna El Paraíso, departamento de Lima, Perú, de abril de 1999 a abril del 2000. Tuvo como objetivos la determinación de la diversidad específi ca en aves; la densidad poblacional de las principales familias de uso cinegético y la determinación de los microhábitats más importantes para los grupos evaluados. Se reportaron 81 especies de aves las cuales pertenecen a 62 géneros y a 35 familias. En esta cifra se reportan 19 especies nuevas para el área de Paraíso; el 46% de la diversidad de aves está dada por las familias Scolopacidae (14%), Ardeidae (10%), Laridae (7%), Anatidae (5%), Charadriidae (5%) y Columbidae (5%). La familia Rallidae es la más abundante y está representada por dos especies Gallinula chloropus “polla de agua” y Fulica ardesiaca“gallareta”, siendo la primera más numerosa. Asimismo, se dan las recomendaciones para la conservación del área

Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia

Bruton's tyrosine kinase (BTK) is a cytoplasmic protein found in all hematopoietic cell lineages except for T cells. BTK mediates signalling downstream of a number of receptors. Pharmacological targeting of BTK using ibrutinib (previously PCI-32765) has recently shown encouraging clinical activity in a range of lymphoid malignancies. This study reports for the first time that ibrutinib inhibits blast proliferation from human acute myeloid leukaemia (AML) and that treatment with ibrutinib significantly augmented cytotoxic activities of standard AML chemotherapy cytarabine or daunorubicin. Here we describe that BTK is constitutively phosphorylated in the majority of AML samples tested, with BTK phosphorylation correlating highly with the cell's cytotoxic sensitivity towards ibrutinib. BTK targeted RNAi knock-down reduced colony forming capacity of primary AML blasts and proliferation of AML cell lines. We showed ibrutinib binds at nanomolar range to BTK. Furthermore, we also showed ibrutinib's anti-proliferative effects in AML are mediated via an inhibitory effect on downstream nuclear factor-κB (NF-κB) survival pathways. Moreover, ibrutinib inhibited AML cell adhesion to bone marrow stroma. Furthermore, these effects of ibrutinib in AML were seen at comparable concentrations efficacious in chronic lymphocytic leukemia (CLL). These results provide a biologic rationale for clinical evaluation of BTK inhibition in AML patients

SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line

The therapeutic potential of cisplatin, one of the most active and widely used anticancer drugs, is severely limited by the occurrence of cellular resistance. In this study, using budding yeast Saccharomyces cerevisiae as a model organism to identify novel drug resistance genes, we found that disruption of the yeast gene SKY1 (serine/arginine-rich protein-specific kinase from budding yeast) by either transposon insertion or one-step gene replacement conferred cellular resistance to cisplatin. Heterologous expression of the human SKY1 homologue SRPK1 (serine/arginine-rich protein-specific kinase) in SKY1 deletion mutant yeast cells restored cisplatin sensitivity, suggesting that SRPK1 is a cisplatin sensitivity gene, the inactivation of which could lead to cisplatin resistance. Subsequently, we investigated the role of SRPK1 in cisplatin sensitivity and resistance in human ovarian carcinoma A2780 cells using antisense oligodeoxynucleotides. Treatment of A2780 cells with antisense oligodeoxynucleotides directed against the translation initiation site of SRPK1 led to down-regulation of SRPK1 protein and conferred a 4-fold resistance to cisplatin. The human SRPK1 gene has not been associated with drug resistance before. Our new findings strongly suggest that SRPK1 is involved in cisplatin-induced cell kill and indicate that SRPK1 might potentially be of importance for studying clinical drug resistance

RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response

PURPOSE: The aim of this study was to investigate whether expression of particular drug resistance genes in primary operable breast cancer correlates with response to first-line chemotherapy in advanced disease. EXPERIMENTAL DESIGN: We determined mRNA levels of BCRP, LRP, MRP1, MRP2, and MDR1 in 59 primary breast tumor specimens of patients who

Why pay NGOs to involve the community?

We examine the case for donors providing financial incentives to, i.e. subsidizing, NGOs to increase community participation. We show that the introduction of such a ‘participation subsidy’ may reduce beneficiary welfare. Thus, eliminating community participation from the set of conditions for funding an NGO may in fact benefit target communities. We show how our theoretical analysis may be operationalized by applying it to data from the NGO sector in Uganda. Our empirical findings appear to reject the case for providing a participation subsidy in that context

The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells

CLL cell trafficking between blood and tissue compartments is an integral part of the disease process. Idelalisib, a phosphoinositide 3-kinase delta (PI3K\u3b4) inhibitor causes rapid lymph node shrinkage, along with an increase in lymphocytosis, prior to inducing objective responses in CLL patients. This characteristic activity presumably is due to CLL cell redistribution from tissues into the blood, but the underlying mechanisms are not fully understood. We therefore analyzed idelalisib effects on CLL cell adhesion to endothelial and bone marrow stromal cells (EC, BMSC). We found that idelalisib inhibited CLL cell adhesion to EC and BMSC under static and shear flow conditions. TNF\u3b1-induced VCAM-1 (CD106) expression in supporting layers increased CLL cell adhesion and accentuated the inhibitory effect of idelalisib. Co-culture with EC and BMSC also protected CLL from undergoing apoptosis, and this EC- and BMSC-mediated protection was antagonized by idelalisib. Furthermore, we demonstrate that CLL cell adhesion to EC and VLA-4 (CD49d) resulted in the phosphorylation of Akt, which was sensitive to inhibition by idelalisib. These findings demonstrate that idelalisib interferes with integrin-mediated CLL cell adhesion to EC and BMSC, providing a novel mechanism to explain idelalisib-induced redistribution of CLL cells from tissues into the blood