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Response: MHC class I chain-related gene A (MICA) in unrelated donor transplantationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Blood)
Source: Blood - November 19, 2009 Category: Hematology Authors: Fernandez-Vina, M., Parmar, S., Champlin, R., de Lima, M. Tags: CORRESPONDENCE Source Type: journals

Limited role of MHC class I chain-related gene A (MICA) typing in assessing graft-versus-host disease risk after fully human leukocyte antigen-matched unrelated donor transplantationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Blood)
Source: Blood - November 19, 2009 Category: Hematology Authors: Anderson, E., Grzywacz, B., Wang, H., Wang, T., Haagenson, M., Spellman, S., Blazar, B. R., Miller, J. S., Verneris, M. R. Tags: CORRESPONDENCE Source Type: journals

Mutation of the H-bond acceptor S119 in the ADAMTS13 metalloprotease domain reduces secretion and substrate turnover in a patient with congenital thrombotic thrombocytopenic purpuraEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study the functional and structural role of a recently identified ADAMTS13 metalloprotease domain mutation S119F was investigated. Secretion from heterologous cells was hampered but not completely eliminated. Secreted S119F was active toward multimeric VWF and FRETS-VWF73 but with abnormal kinetics, having a significantly reduced overall catalytic rate (kcat; 0.88 ± 0.04 s–1 vs 2.78 ± 0.11 s–1) and slightly smaller Michaelis constant (KM; 1.4 ± 0.2µM vs 2.3 ± 0.3µM). A computational model of the metalloprotease domain demonstrates both steric and polar interaction...
Source: Blood - November 19, 2009 Category: Hematology Authors: Feys, H. B., Pareyn, I., Vancraenenbroeck, R., De Maeyer, M., Deckmyn, H., Van Geet, C., Vanhoorelbeke, K. Tags: Thrombosis and Hemostasis, Brief Reports Source Type: journals

A role for thrombin in the initiation of the immune response to therapeutic factor VIIIEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Administration of human factor VIII (FVIII) to FVIII knockout hemophilia mice is a useful small animal model to study the physiologic response in patients iatrogenically immunized to this therapeutic protein. These mice manifest a robust, T cell–dependent, antibody response to exogenous FVIII treatment, even when encountered through traditionally tolerogenic routes. Thus, FVIII given via these routes elicits both T- and B-cell responses, whereas a control, foreign protein, such as ovalbumin (OVA), is poorly immunogenic. When FVIII is heat inactivated, it loses function and much of its immunogenicity. This suggests th...
Source: Blood - November 19, 2009 Category: Hematology Authors: Skupsky, J., Zhang, A.-H., Su, Y., Scott, D. W. Tags: Immunobiology, Thrombosis and Hemostasis Source Type: journals

Platelet protein disulfide isomerase is localized in the dense tubular system and does not become surface expressed after activationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Evidence is accumulating that circulating tissue factor (TF) contributes to the initiation of coagulation and the formation of fibrin. The majority of circulating TF is cryptic, and it has been suggested that close vicinity with anionic phospholipids on the cell surface increases the active conformation of TF. Two recent papers have shown that encryption of TF and initiation of coagulation are facilitated by the enzyme protein disulfide isomerase (PDI), possibly on the surface of activated platelets or endothelial cells. In this brief report, we demonstrate that the majority of PDI in platelets is intracellular where it is...
Source: Blood - November 19, 2009 Category: Hematology Authors: van Nispen tot Pannerden, H. E., van Dijk, S. M., Du, V., Heijnen, H. F. G. Tags: Platelets and Thrombopoiesis, Thrombosis and Hemostasis, Brief Reports Source Type: journals

Platelet-associated IgAs and impaired GPVI responses in platelets lacking WIPEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The role of the Wiskott-Aldrich syndrome protein (WASp) in platelet function is unclear because platelets that lack WASp function normally. WASp constitutively associates with WASp-interacting protein (WIP) in resting and activated platelets. The role of WIP in platelet function was investigated using mice that lack WIP or WASp. WIP knockout (KO) platelets lack WASp and thus are double deficient. WIP KO mice have a thrombocytopenia, similar to WASp KO mice, resulting in part from enhanced platelet clearance. Most WIP KO, but not WASp KO, mice evolved platelet-associated immunoglobulins (Ig) of the IgA class, which normaliz...
Source: Blood - November 19, 2009 Category: Hematology Authors: Falet, H., Marchetti, M. P., Hoffmeister, K. M., Massaad, M. J., Geha, R. S., Hartwig, J. H. Tags: Platelets and Thrombopoiesis Source Type: journals

The transcription factors STAT5A/B regulate GM-CSF-mediated granulopoiesisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Neutrophils play a vital role in the immune defense, which is evident by the severity of neutropenia causing life-threatening infections. Granulocyte macrophage-colony stimulating factor (GM-CSF) controls homeostatic and emergency development of granulocytes. However, little is known about the contribution of the downstream mediating transcription factors signal transducer and activator of transcription 5A and 5B (STAT5A/B). To elucidate the function of this pathway, we generated mice with complete deletion of both Stat5a/b genes in hematopoietic cells. In homeostasis, peripheral neutrophils were markedly decreased in thes...
Source: Blood - November 19, 2009 Category: Hematology Authors: Kimura, A., Rieger, M. A., Simone, J. M., Chen, W., Wickre, M. C., Zhu, B.-M., Hoppe, P. S., O'Shea, J. J., Schroeder, T., Hennighausen, L. Tags: Hematopoiesis and Stem Cells, Phagocytes, Granulocytes, and Myelopoiesis Source Type: journals

Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapyEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
An important hallmark of cancer progression is the ability of tumor cells to evade immune recognition. Understanding the relationship between neoplastic cells and the immune microenvironment should facilitate the design of improved immunotherapies. Here we identify impaired T-cell immunologic synapse formation as an active immunosuppressive mechanism in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). We found a significant reduction in formation of the F-actin immune synapse in tumor-infiltrating T cells (P < .01) from lymphoma patients compared with age-matched healthy donor cells. Peripheral blood ...
Source: Blood - November 19, 2009 Category: Hematology Authors: Ramsay, A. G., Clear, A. J., Kelly, G., Fatah, R., Matthews, J., MacDougall, F., Lister, T. A., Lee, A. M., Calaminici, M., Gribben, J. G. Tags: Immunobiology, Lymphoid Neoplasia Source Type: journals

TAPP2 links phosphoinositide 3-kinase signaling to B-cell adhesion through interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesion-promoting complex in B-cell leukemiaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We examined whether TAPP can regulate cell adhesion, a known function of utrophin/syntrophin in other cell types. Expression of membrane-targeted TAPP2 enhanced B-cell adhesion to fibronectin and laminin, whereas PH domain–mutant TAPP2 inhibited adhesion. siRNA knockdown of TAPP2 or utrophin, or treatment with PI3K inhibitors, significantly inhibited adhesion. These findings identify TAPP2 as a novel link between PI3K signaling and the cytoskeleton with potential relevance for leukemia progression. (Source: Blood)
Source: Blood - November 19, 2009 Category: Hematology Authors: Costantini, J. L., Cheung, S. M. S., Hou, S., Li, H., Kung, S. K., Johnston, J. B., Wilkins, J. A., Gibson, S. B., Marshall, A. J. Tags: Lymphoid Neoplasia Source Type: journals

Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behaviorEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hairy cell leukemia (HCL) is generally responsive to single-agent cladribine, and only a minority of patients are refractory and with poor prognosis. HCLs generally express mutated (M) and, in a minority, unmutated (UM) IGHV. In a multicenter clinical trial in newly diagnosed HCL, we prospectively investigated clinical and molecular parameters predicting response and event-free survival after single-agent cladribine. Of 58 HCLs, 6 expressed UM-IGHV (UM-HCL) and 52 M-IGHV (M-HCL). Beneficial responses were obtained in 53 of 58 patients (91%), whereas treatment failures were observed in 5 of 58 patients (9%). Failures were a...
Source: Blood - November 19, 2009 Category: Hematology Authors: Forconi, F., Sozzi, E., Cencini, E., Zaja, F., Intermesoli, T., Stelitano, C., Rigacci, L., Gherlinzoni, F., Cantaffa, R., Baraldi, A., Gallamini, A., Zaccaria, A., Pulsoni, A., Gobbi, M., Tassi, M., Raspadori, D., Leoncini, L., Rinaldi, A., Sabattini, E. Tags: Free Research Articles, Lymphoid Neoplasia, Clinical Trials and Observations Source Type: journals

VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapyEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hairy cell leukemia variant (HCLv) presents with high disease burden, lack of typical antigens like CD25, and poor response to standard treatments like cladribine. Occasionally, patients with classic HCL respond poorly. Clinical and molecular features of HCL and HCLv has not been compared. Rearrangements expressing immunoglobulin VH chain were sequenced, including 22 from 20 patients with HCLv and 63 from 62 patients with classic HCL. Most patients were seeking relapsed/refractory trials, representing a poor-prognosis population. VH4-34, a gene commonly used in autoimmune disorders, was observed in 8 (40%) HCLv and 6 (10%)...
Source: Blood - November 19, 2009 Category: Hematology Authors: Arons, E., Suntum, T., Stetler-Stevenson, M., Kreitman, R. J. Tags: Free Research Articles, Lymphoid Neoplasia, Clinical Trials and Observations Source Type: journals

High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemiaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Although activation of the B-cell receptor (BCR) signaling pathway is implicated in the pathogenesis of chronic lymphocytic leukemia (CLL), its clinical impact and the molecular correlates of such response are not clearly defined. T-cell leukemia 1 (TCL1), the AKT modulator and proto-oncogene, is differentially expressed in CLL and linked to its pathogenesis based on CD5+ B-cell expansions arising in TCL1-transgenic mice. We studied here the association of TCL1 levels and its intracellular dynamics with the in vitro responses to BCR stimulation in 70 CLL cases. The growth kinetics after BCR engagement correlated strongly w...
Source: Blood - November 19, 2009 Category: Hematology Authors: Herling, M., Patel, K. A., Weit, N., Lilienthal, N., Hallek, M., Keating, M. J., Jones, D. Tags: Lymphoid Neoplasia, Clinical Trials and Observations Source Type: journals

Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study identifies the E-cadherin/catenin complex as a discriminative, partly polyamine-regulated feature of IL-4/IL-13–exposed alternatively activated macrophages that contributes to homotypic and heterotypic cellular interactions. (Source: Blood)
Source: Blood - November 19, 2009 Category: Hematology Authors: Van den Bossche, J., Bogaert, P., van Hengel, J., Guerin, C. J., Berx, G., Movahedi, K., Van den Bergh, R., Pereira-Fernandes, A., Geuns, J. M. C., Pircher, H., Dorny, P., Grooten, J., De Baetselier, P., Van Ginderachter, J. A. Tags: Immunobiology, Phagocytes, Granulocytes, and Myelopoiesis Source Type: journals

The role and regulation of friend of GATA-1 (FOG-1) during blood development in the zebrafishEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The nuclear protein FOG-1 binds transcription factor GATA-1 to facilitate erythroid and megakaryocytic maturation. However, little is known about the function of FOG-1 during myeloid and lymphoid development or how FOG-1 expression is regulated in any tissue. We used in situ hybridization, gain- and loss-of-function studies in zebrafish to address these problems. Zebrafish FOG-1 is expressed in early hematopoietic cells, as well as heart, viscera, and paraspinal neurons, suggesting that it has multifaceted functions in organogenesis. We found that FOG-1 is dispensable for endoderm specification but is required for endoderm...
Source: Blood - November 19, 2009 Category: Hematology Authors: Amigo, J. D., Ackermann, G. E., Cope, J. J., Yu, M., Cooney, J. D., Ma, D., Langer, N. B., Shafizadeh, E., Shaw, G. C., Horsely, W., Trede, N. S., Davidson, A. J., Barut, B. A., Zhou, Y., Wojiski, S. A., Traver, D., Moran, T. B., Kourkoulis, G., Hsu, K., Tags: Hematopoiesis and Stem Cells Source Type: journals

Identification of novel regulators of hematopoietic stem cell development through refinement of stem cell localization and expression profilingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The first adult-repopulating hematopoietic stem cells (HSCs) are detected starting at day 10.5 of gestation in the aorta-gonads-mesonephros (AGM) region of the mouse embryo. Despite the importance of the AGM in initiating HSC production, very little is currently known about the regulators that control HSC emergence in this region. We have therefore further defined the location of HSCs in the AGM and incorporated this information into a spatial and temporal comparative gene expression analysis of the AGM. The comparisons included gene expression profiling (1) in the newly identified HSC-containing region compared with the r...
Source: Blood - November 19, 2009 Category: Hematology Authors: Mascarenhas, M. I., Parker, A., Dzierzak, E., Ottersbach, K. Tags: Hematopoiesis and Stem Cells Source Type: journals

Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, increase in hemoglobin F in sickle cell disease may be associated with relatively lower tissue oxygen delivery as reflected in higher erythropoietin concentration. Greater levels of erythropoietin or hemoglobin F were independently associated with higher tricuspid regurgitation velocity after adjustment for degree of hemolysis, suggesting an independent relationship of hypoxia with higher systolic pulmonary artery pressure. The hemolysis-lowering and hemoglobin F–augmenting effects of hydroxyurea may exert countervailing influences on pulmonary blood pressure in sickle cell disease. (Source: Blood)
Source: Blood - November 19, 2009 Category: Hematology Authors: Gordeuk, V. R., Campbell, A., Rana, S., Nouraie, M., Niu, X., Minniti, C. P., Sable, C., Darbari, D., Dham, N., Onyekwere, O., Ammosova, T., Nekhai, S., Kato, G. J., Gladwin, M. T., Castro, O. L. Tags: Free Research Articles, Red Cells, Iron, and Erythropoiesis, Clinical Trials and Observations Source Type: journals

Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injuryEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Chronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) w...
Source: Blood - November 19, 2009 Category: Hematology Authors: Adamkiewicz, T. V., Abboud, M. R., Paley, C., Olivieri, N., Kirby-Allen, M., Vichinsky, E., Casella, J. F., Alvarez, O. A., Barredo, J. C., Lee, M. T., Iyer, R. V., Kutlar, A., McKie, K. M., McKie, V., Odo, N., Gee, B., Kwiatkowski, J. L., Woods, G. M., C Tags: Free Research Articles, Red Cells, Iron, and Erythropoiesis, Clinical Trials and Observations Source Type: journals

How I treat postthrombotic syndromeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Postthrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT) that reduces quality of life and has important socioeconomic consequences. More than one-third of patients with DVT will develop PTS, and 5% to 10% of patients will develop severe PTS, which may manifest as venous ulceration. The principal risk factors for PTS are persistent leg symptoms 1 month after the acute episode of DVT, extensive DVT, recurrent ipsilateral DVT, obesity, and older age. Daily use of elastic compression stockings (ECSs) for 2 years after proximal DVT appears to reduce the risk of PTS; however, there is uncertainty a...
Source: Blood - November 19, 2009 Category: Hematology Authors: Kahn, S. R. Tags: How I Treat, Free Research Articles, Thrombosis and Hemostasis Source Type: journals

Mechanisms underlying neutrophil-mediated monocyte recruitmentEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Extravasation of polymorphonuclear leukocytes (PMNs) to the site of inflammation precedes a second wave of emigrating monocytes. That these events are causally connected has been established a long time ago. However, we are now just beginning to understand the molecular mechanisms underlying this cellular switch, which has become even more complex considering the emergence of monocyte subsets, which are affected differently by signals generated from PMNs. PMN granule proteins induce adhesion as well as emigration of inflammatory monocytes to the site of inflammation involving β2-integrins and formyl-peptide receptors....
Source: Blood - November 19, 2009 Category: Hematology Authors: Soehnlein, O., Lindbom, L., Weber, C. Tags: Immunobiology, Phagocytes, Granulocytes, and Myelopoiesis, Review Articles Source Type: journals

Cracking the platelet WIPEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Blood)
Source: Blood - November 19, 2009 Category: Hematology Authors: Poole, A. W. Tags: INSIDE BLOOD Source Type: journals

IG genes and hairy cell leukemiaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Blood)
Source: Blood - November 19, 2009 Category: Hematology Authors: Caligaris-Cappio, F. Tags: INSIDE BLOOD Source Type: journals

Macrophage fusion cuisineEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Blood)
Source: Blood - November 19, 2009 Category: Hematology Authors: Sica, A., Mantovani, A. Tags: INSIDE BLOOD Source Type: journals

van de Vosse et al. Antisense-mediated exon skipping to correct IL-12R{beta}1 deficiency in T cells. Blood. 2009;113(19):4548-4555.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Blood)
Source: Blood - November 12, 2009 Category: Hematology Tags: ERRATA Source Type: journals

Allogeneic transplantation for children and adolescents with Hodgkin lymphomaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Blood)
Source: Blood - November 12, 2009 Category: Hematology Authors: Schmitz, N., Sureda, A., Dini, G., Claviez, A., on behalf of the Lymphoma and Pediatric Diseases Working Parties Tags: CORRESPONDENCE Source Type: journals

Response: Elevated fibrinogen {gamma}' ratios and clinical outcomesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Blood)
Source: Blood - November 12, 2009 Category: Hematology Authors: Nowak-Gottl, U., Weiler, H., Stoll, M. Tags: CORRESPONDENCE Source Type: journals

Elevated fibrinogen {gamma}' ratio is associated with cardiovascular diseases and acute phase reaction but not with clinical outcomeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Blood)
Source: Blood - November 12, 2009 Category: Hematology Authors: Cheung, E. Y. L., Vos, H. L., Kruip, M. J. H. A., den Hertog, H. M., Jukema, J. W., de Maat, M. P. M. Tags: CORRESPONDENCE Source Type: journals

Response: NPM1-mutated AML is an entity irrespective of whether or not chromosomal aberrations are presentEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Blood)
Source: Blood - November 12, 2009 Category: Hematology Authors: Haferlach, C., Vignetti, M., Haferlach, T., Falini, B. Tags: CORRESPONDENCE Source Type: journals

The role of cytogenetic abnormalities in acute myeloid leukemia with NPM1 mutations and no FLT3 internal tandem duplicationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Blood)
Source: Blood - November 12, 2009 Category: Hematology Authors: Micol, J. B., Boissel, N., Renneville, A., Castaigne, S., Gardin, C., Preudhomme, C., Dombret, H. Tags: CORRESPONDENCE Source Type: journals

A novel interplay between Epac/Rap1 and mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) regulates thrombospondin to control angiogenesisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we show that activation of Epac or Rap1 leads to potent inhibition of angiogenesis in vivo. Epac/Rap1 activation down-regulates inhibitor of differentiation 1 (Id1), which negatively regulates thrombospondin-1 (TSP1), an inhibitor of angiogenesis. Consistent with this mechanism, activation of Epac/Rap 1 induces expression of TSP1; conversely, depletion of Epac reduces TSP1 levels in endothelial cells. Blockade of TSP1 binding to its receptor, CD36, rescues inhibition of chemotaxis or angiogenesis by activated Epac/Rap1. Mitogen-activated protein kinase kinase 5, a downstream mediator of vascular endothelial ...
Source: Blood - November 12, 2009 Category: Hematology Authors: Doebele, R. C., Schulze-Hoepfner, F. T., Hong, J., Chlenski, A., Zeitlin, B. D., Goel, K., Gomes, S., Liu, Y., Abe, M. K., Nor, J. E., Lingen, M. W., Rosner, M. R. Tags: Vascular Biology Source Type: journals

Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hematogenous metastasis is promoted by interactions of tumor cells with leukocytes, platelets, and the endothelium in the local intravascular microenvironment. Here we show that the activation of the microvascular endothelium results in recruitment of monocytes to metastatic tumor cells and promotes the establishment of the metastatic microenvironment. This inflammatory-like endothelial response was observed in microvascular endothelial cells only. Microarray analysis of microvascular endothelial cells cocultured with tumor cells in the presence of leukocytes and platelets revealed a specific gene expression profile. Selec...
Source: Blood - November 12, 2009 Category: Hematology Authors: Laubli, H., Spanaus, K.-S., Borsig, L. Tags: Vascular Biology Source Type: journals

Superagonistic CD28 stimulation of allogeneic T cells protects from acute graft-versus-host diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Acute graft-versus-host disease (aGVHD) often precludes successful immunotherapy of hematologic malignancies with allogeneic T cells. Therefore, we investigated the effect of immunomodulatory superagonistic anti-CD28 monoclonal antibodies (CD28-SA) on the capacity of allogeneic T cells to mediate both aGVHD and the protective graft-versus-tumor (GVT) response. In vivo pretreatment of donor C57BL/6 mice or short-term in vitro culture of donor lymph node cells with a CD28-SA efficiently protected BALB/c recipient mice from aGVHD. This protection strongly relied on the presence of CD28-SA–activated CD4+ CD25+ Foxp3+ reg...
Source: Blood - November 12, 2009 Category: Hematology Authors: Beyersdorf, N., Ding, X., Hunig, T., Kerkau, T. Tags: Transplantation Source Type: journals

Bone marrow as an alternative site for islet transplantationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, BM is an attractive and safe alternative site for pancreatic islet transplantation. The results of our study open a research line with potentially significant clinical impact, not only for the treatment of diabetes, but also for other diseases amenable to treatment with cellular transplantation. (Source: Blood)
Source: Blood - November 12, 2009 Category: Hematology Authors: Cantarelli, E., Melzi, R., Mercalli, A., Sordi, V., Ferrari, G., Lederer, C. W., Mrak, E., Rubinacci, A., Ponzoni, M., Sitia, G., Guidotti, L. G., Bonifacio, E., Piemonti, L. Tags: Transplantation Source Type: journals

Recombinant canine B-domain-deleted FVIII exhibits high specific activity and is safe in the canine hemophilia A modelEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Production of recombinant B-domain–deleted canine factor VIII (cFVIII-BDD) unexpectedly revealed superior protein yields with 3-fold increased specific activity relative to human FVIII-BDD (hFVIII-BDD). We also determined that activated cFVIII-BDD is more stable than activated hFVIII-BDD. Furthermore, cFVIII-BDD is efficient at inducing hemostasis in human plasma containing FVIII inhibitors. Infusion of cFVIII-BDD in hemophilia A dogs resulted in correction of the disease phenotype with a pharmacokinetic profile similar to clinical experience with hFVIII-BDD. Notably, immune tolerance challenges with cFVIII-BDD in yo...
Source: Blood - November 12, 2009 Category: Hematology Authors: Sabatino, D. E., Freguia, C. F., Toso, R., Santos, A., Merricks, E. P., Kazazian, H. H., Nichols, T. C., Camire, R. M., Arruda, V. R. Tags: Thrombosis and Hemostasis, Brief Reports Source Type: journals

The therapeutic effect of bone marrow-derived liver cells in the phenotypic correction of murine hemophilia AEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The transdifferentiation of bone marrow cells (BMCs) into hepatocytes has created enormous interest in applying this process to the development of cellular medicine for degenerative and genetic diseases. Because the liver is the primary site of factor VIII (FVIII) synthesis, we hypothesized that the partial replacement of mutated liver cells by healthy cells in hemophilia A mice could manage the severity of the bleeding disorder. We perturbed the host liver with acetaminophen to facilitate the engraftment and hepatic differentiation of lineage-depleted enhanced green fluorescent protein-expressing BMCs. Immunohistochemistr...
Source: Blood - November 12, 2009 Category: Hematology Authors: Yadav, N., Kanjirakkuzhiyil, S., Kumar, S., Jain, M., Halder, A., Saxena, R., Mukhopadhyay, A. Tags: Thrombosis and Hemostasis Source Type: journals

Specific iron chelators determine the route of ferritin degradationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Deferoxamine (DFO) is a high-affinity Fe (III) chelator produced by Streptomyces pilosus. DFO is used clinically to remove iron from patients with iron overload disorders. Orally administered DFO cannot be absorbed, and therefore it must be injected. Here we show that DFO induces ferritin degradation in lysosomes through induction of autophagy. DFO-treated cells show cytosolic accumulation of LC3B, a critical protein involved in autophagosomal-lysosomal degradation. Treatment of cells with the oral iron chelators deferriprone and desferasirox did not show accumulation of LC3B, and degradation of ferritin occurred through t...
Source: Blood - November 12, 2009 Category: Hematology Authors: De Domenico, I., Ward, D. M., Kaplan, J. Tags: Red Cells, Iron, and Erythropoiesis Source Type: journals

Platelet-associated complement factor H in healthy persons and patients with atypical HUSEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Atypical hemolytic uremic syndrome (aHUS) is associated with complement system dysregulation, and more than 25% of pediatric aHUS cases are linked to mutations in complement factor H (CFH) or CFH autoantibodies. The observation of thrombocytopenia and platelet-rich thrombi in the glomerular microvasculature indicates that platelets are intimately involved in aHUS pathogenesis. It has been reported that a releasable pool of platelet CFH originates from -granules. We observed that platelet CFH can arise from endogenous synthesis in megakaryocytes and that platelets constitutively lacking -granules contain CFH. Electron and h...
Source: Blood - November 12, 2009 Category: Hematology Authors: Licht, C., Pluthero, F. G., Li, L., Christensen, H., Habbig, S., Hoppe, B., Geary, D. F., Zipfel, P. F., Kahr, W. H. A. Tags: Platelets and Thrombopoiesis Source Type: journals

The small Rho GTPase Cdc42 regulates neutrophil polarity via CD11b integrin signalingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Neutrophil migration to sites of infection is the first line of cellular defense. A key event of migration is the maintenance of a polarized morphology, which is characterized by a single leading edge of filamentous actin and a contractile uropod devoid of filamentous actin protrusions. Using a mouse model of high Cdc42 activity, we previously demonstrated the importance of Cdc42 activity in neutrophil migration. However, the specific functions of Cdc42 in this process remain to be understood. Using neutrophils genetically deficient in Cdc42, we show that Cdc42 regulates directed migration by maintaining neutrophil polarit...
Source: Blood - November 12, 2009 Category: Hematology Authors: Szczur, K., Zheng, Y., Filippi, M.-D. Tags: Phagocytes, Granulocytes, and Myelopoiesis Source Type: journals

GM-CSF and IL-4 induce dendritic cell differentiation and disrupt osteoclastogenesis through M-CSF receptor shedding by up-regulation of TNF-{alpha} converting enzyme (TACE)Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Monocytes give rise to macrophages, osteoclasts (OCs), and dendritic cells (DCs). Macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB (RANK) ligand induce OC differentiation from monocytes, whereas granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) trigger monocytic differentiation into DCs. However, regulatory mechanisms for the polarization of monocytic differentiation are still unclear. The present study was undertaken to clarify the mechanism of triggering the deflection of OC and DC differentiation from monocytes. GM-CSF and IL-4 abolished monocy...
Source: Blood - November 12, 2009 Category: Hematology Authors: Hiasa, M., Abe, M., Nakano, A., Oda, A., Amou, H., Kido, S., Takeuchi, K., Kagawa, K., Yata, K., Hashimoto, T., Ozaki, S., Asaoka, K., Tanaka, E., Moriyama, K., Matsumoto, T. Tags: Phagocytes, Granulocytes, and Myelopoiesis Source Type: journals

The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathwaysEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Mechanisms underlying apoptosis induced by concomitant interruption of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 (MEK/ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways were investigated in human leukemia cells. Inhibition of these pathways using the MEK inhibitor PD184352 or U0126 and the PI3K/Akt inhibitor perifosine strikingly induced apoptosis in multiple malignant human hematopoietic cells, and substantially reduced the colony-forming capacity of primary acute myeloblastic leukemia, but not normal CD34+ cells. These events were associated with pronounced Bim up-re...
Source: Blood - November 12, 2009 Category: Hematology Authors: Rahmani, M., Anderson, A., Habibi, J. R., Crabtree, T. R., Mayo, M., Harada, H., Ferreira-Gonzalez, A., Dent, P., Grant, S. Tags: Myeloid Neoplasia Source Type: journals

Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entitiesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
STATs are constitutively activated in several malignancies. In primary mediastinal large B-cell lymphoma and Hodgkin lymphoma (HL), inactivating mutations in SOCS1, an inhibitor of JAK/STAT signaling, contribute to deregulated STAT activity. Based on indications that the SOCS1 mutations are caused by the B cell–specific somatic hypermutation (SHM) process, we analyzed B-cell non-HL and normal B cells for mutations in SOCS1. One-fourth of diffuse large B-cell lymphoma and follicular lymphomas carried SOCS1 mutations, which were preferentially targeted to SHM hotspot motifs and frequently obviously inactivating. Rare m...
Source: Blood - November 12, 2009 Category: Hematology Authors: Mottok, A., Renne, C., Seifert, M., Oppermann, E., Bechstein, W., Hansmann, M.-L., Kuppers, R., Brauninger, A. Tags: Lymphoid Neoplasia, Brief Reports Source Type: journals

A human monoclonal antibody drug and target discovery platform for B-cell chronic lymphocytic leukemia based on allogeneic hematopoietic stem cell transplantation and phage displayEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potentially curative treatment available for patients with B-cell chronic lymphocytic leukemia (B-CLL). Here, we show that post-alloHSCT antibody repertoires can be mined for the discovery of fully human monoclonal antibodies to B-CLL cell-surface antigens. Sera collected from B-CLL patients at defined times after alloHSCT showed selective binding to primary B-CLL cells. Pre-alloHSCT sera, donor sera, and control sera were negative. To identify post-alloHSCT serum antibodies and subsequently B-CLL cell-surface antigens they recognize, we generated a ...
Source: Blood - November 12, 2009 Category: Hematology Authors: Baskar, S., Suschak, J. M., Samija, I., Srinivasan, R., Childs, R. W., Pavletic, S. Z., Bishop, M. R., Rader, C. Tags: Transplantation, Lymphoid Neoplasia Source Type: journals

Gene expression-based classification and regulatory networks of pediatric acute lymphoblastic leukemiaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Pediatric acute lymphoblastic leukemia (ALL) contains cytogenetically distinct subtypes that respond differently to cytotoxic drugs. Subtype classification can be also achieved through gene expression profiling. However, how to apply such classifiers to a single patient and correctly diagnose the disease subtype in an independent patient group has not been addressed. Furthermore, the underlying regulatory mechanisms responsible for the subtype-specific gene expression patterns are still largely unknown. Here, by combining 3 published microarray datasets on 535 mostly white children's samples and generating a new dataset on...
Source: Blood - November 12, 2009 Category: Hematology Authors: Li, Z., Zhang, W., Wu, M., Zhu, S., Gao, C., Sun, L., Zhang, R., Qiao, N., Xue, H., Hu, Y., Bao, S., Zheng, H., Han, J.-D. J. Tags: Lymphoid Neoplasia Source Type: journals

Generation of CD8+ T cell-mediated immunity against idiotype-negative lymphoma escapeesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We investigated the ability of CpG-oligodeoxynucleotide to generate an anti-tumor CD8+ T-cell immune response and to synergize with passive antibody therapy. For these studies, we generated an antibody against the idiotype on the A20 B-cell lymphoma line. This antibody caused the regression of established tumors, but ultimately the tumors relapsed. The escaping surface IgG-negative tumor cells were resistant to both antibody-dependent cellular cytotoxicity and signaling-induced cell death. Addition of intratumoral CpG to antibody therapy cured large established tumors and prevented the occurrence of tumor escapees. The fai...
Source: Blood - November 12, 2009 Category: Hematology Authors: Varghese, B., Widman, A., Do, J., Taidi, B., Czerwinski, D. K., Timmerman, J., Levy, S., Levy, R. Tags: Immunobiology, Lymphoid Neoplasia Source Type: journals

Chronic lymphocytic leukemia of E{micro}-TCL1 transgenic mice undergoes rapid cell turnover that can be offset by extrinsic CD257 to accelerate disease progressionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We examined leukemia cell turnover in Eµ-TCL1 transgenic (TCL1-Tg) mice, which develop a CLL-like disease at 8 to 12 months of age. We found that leukemia cells in these mice not only had higher proportions of proliferating cells but also apoptotic cells than did nonleukemic lymphocytes. We crossed TCL1-Tg with BAFF-Tg mice, which express high levels of CD257. TCL1xBAFF-Tg mice developed CLL-like disease at a significantly younger age and had more rapid disease progression and shorter survival than TCL1-Tg mice. Leukemia cells of TCL1xBAFF-Tg mice had similar proportions of proliferating cells, but fewer proportions ...
Source: Blood - November 12, 2009 Category: Hematology Authors: Enzler, T., Kater, A. P., Zhang, W., Widhopf, G. F., Chuang, H.-Y., Lee, J., Avery, E., Croce, C. M., Karin, M., Kipps, T. J. Tags: Lymphoid Neoplasia Source Type: journals

Extensive intraclonal diversification in a subgroup of chronic lymphocytic leukemia patients with stereotyped IGHV4-34 receptors: implications for ongoing interactions with antigenEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Several studies indicate that the development of chronic lymphocytic leukemia (CLL) may be influenced by antigen recognition through the clonotypic B-cell receptors (BCRs). However, it is still unclear whether antigen involvement is restricted to the malignant transformation phase or whether the putative antigen(s) may continuously trigger the CLL clone and affect not only the progenitor cell but also the leukemic cells themselves. To address this issue, we conducted a large-scale subcloning study of rearranged immunoglobulin heavy variable (IGHV) genes of diverse mutational status from 71 CLL cases (total, 1496 subcloned ...
Source: Blood - November 12, 2009 Category: Hematology Authors: Sutton, L.-A., Kostareli, E., Hadzidimitriou, A., Darzentas, N., Tsaftaris, A., Anagnostopoulos, A., Rosenquist, R., Stamatopoulos, K. Tags: Lymphoid Neoplasia Source Type: journals

Stage-specific Arf tumor suppression in Notch1-induced T-cell acute lymphoblastic leukemiaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Frequent hallmarks of T-cell acute lymphoblastic leukemia (T-ALL) include aberrant NOTCH signaling and deletion of the CDKN2A locus, which contains 2 closely linked tumor suppressor genes (INK4A and ARF). When bone marrow cells or thymocytes transduced with a vector encoding the constitutively activated intracellular domain of Notch1 (ICN1) are expanded ex vivo under conditions that support T-cell development, cultured progenitors rapidly induce CD4+/CD8+ T-ALLs after infusion into healthy syngeneic mice. Under these conditions, enforced ICN1 expression also drives formation of T-ALLs in unconditioned CD-1 nude mice, bypas...
Source: Blood - November 12, 2009 Category: Hematology Authors: Volanakis, E. J., Williams, R. T., Sherr, C. J. Tags: Lymphoid Neoplasia Source Type: journals

Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistanceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Marrow stromal cells (MSCs) provide important survival and drug resistance signals to chronic lymphocytic leukemia (CLL) cells, but current models to analyze CLL–MSC interactions are heterogeneous. Therefore, we tested different human and murine MSC lines and primary human MSCs for their ability to protect CLL cells from spontaneous and drug-induced apoptosis. Our results show that both human and murine MSCs are equally effective in protecting CLL cells from fludarabine-induced apoptosis. This protective effect was sustained over a wide range of CLL–MSC ratios (5:1 to 100:1), and the levels of protection were r...
Source: Blood - November 12, 2009 Category: Hematology Authors: Kurtova, A. V., Balakrishnan, K., Chen, R., Ding, W., Schnabl, S., Quiroga, M. P., Sivina, M., Wierda, W. G., Estrov, Z., Keating, M. J., Shehata, M., Jager, U., Gandhi, V., Kay, N. E., Plunkett, W., Burger, J. A. Tags: Lymphoid Neoplasia Source Type: journals

The thymus-independent immunity conferred by a pneumococcal polysaccharide is mediated by long-lived plasma cellsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
It was recently shown that bacterial thymus-independent (TI) antigens confer long-lasting immunity and generate memory B lymphocytes. However, reactivation of TI memory B cells is repressed in immunocompetent mice, thus raising the issue of the mechanism whereby TI vaccines confer immune protection. Here, we propose an explanation to this apparent paradox by showing that a Streptococcus pneumoniae capsular polysaccharide (PS) generates long-lived bone marrow (BM) plasma cells which frequency can be increased by CpG oligodeoxynucleotides (ODNs). The adjuvant effect of CpG ODNs on the PS3 Ab response is directly targeted to ...
Source: Blood - November 12, 2009 Category: Hematology Authors: Taillardet, M., Haffar, G., Mondiere, P., Asensio, M.-J., Gheit, H., Burdin, N., Defrance, T., Genestier, L. Tags: Immunobiology Source Type: journals

CD56+ human blood dendritic cells effectively promote TH1-type {gamma}{delta} T-cell responsesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
CD56+ human dendritic cells (DCs) have recently been shown to differentiate from monocytes in response to GM-CSF and type 1 interferon in vitro. We show here that CD56+ cells freshly isolated from human peripheral blood contain a substantial subset of CD14+CD86+HLA-DR+ cells, which have the appearance of intermediate-sized lymphocytes but spontaneously differentiate into enlarged DC-like cells with substantially increased HLA-DR and CD86 expression or into fully mature CD83+ DCs in response to appropriate cytokines. Stimulation of CD56+ cells containing both DCs and abundant T cells with zoledronate and interleukin-2 (IL-2...
Source: Blood - November 12, 2009 Category: Hematology Authors: Gruenbacher, G., Gander, H., Rahm, A., Nussbaumer, W., Romani, N., Thurnher, M. Tags: Immunobiology Source Type: journals

Homeostasis of dendritic cells in lymphoid organs is controlled by regulation of their precursors via a feedback loopEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Dendritic cells (DCs) are key coordinators of the immune response, governing the choice between tolerance and immunity. Despite their importance, the mechanisms controlling the size of the DC compartment are largely unknown. Using a mouse model allowing continuous DC depletion, we show that maintenance of DC numbers in spleen is an active process mediated by Flt3-L–dependent regulation of precursor differentiation into DCs, rather than by changes in proliferation of the differentiated DCs. In particular, the frequency and differentiation potential of intrasplenic DC precursors increased in response to reduced DC numb...
Source: Blood - November 12, 2009 Category: Hematology Authors: Hochweller, K., Miloud, T., Striegler, J., Naik, S., Hammerling, G. J., Garbi, N. Tags: Immunobiology Source Type: journals