MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Blood' source. Wed, 08 Feb 2012 17:41:57 +0100 http://www.medworm.com/index.php?rid=5649279&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1322%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649279 Thu, 02 Feb 2012 05:00:00 +0100 5649279 http://www.medworm.com/index.php?rid=5649278&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1321%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649278 Thu, 02 Feb 2012 05:00:00 +0100 5649278 http://www.medworm.com/index.php?rid=5649277&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1320%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649277 Thu, 02 Feb 2012 05:00:00 +0100 5649277 http://www.medworm.com/index.php?rid=5649276&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1318%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649276 Thu, 02 Feb 2012 05:00:00 +0100 5649276 http://www.medworm.com/index.php?rid=5649275&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1316%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649275 Thu, 02 Feb 2012 05:00:00 +0100 5649275 http://www.medworm.com/index.php?rid=5649274&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1314%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649274 Thu, 02 Feb 2012 05:00:00 +0100 5649274 http://www.medworm.com/index.php?rid=5649273&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1302%3Frss%3D1 Lewis Y Ag (LeY) is a cell-surface tetrasaccharide that participates in angiogenesis. Recently, we demonstrated that LeY is a specific ligand of the recombinant lectin-like domain of thrombomodulin (TM). However, the biologic function of interaction between LeY and TM in endothelial cells has never been investigated. Therefore, the role of LeY in tube formation and the role of the recombinant lectin-like domain of TM—TM domain 1 (rTMD1)—in antiangiogenesis were investigated. The recombinant TM ectodomain exhibited lower angiogenic activity than did the recombinant TM domains 2 and 3. rTMD1 interacted with soluble LeY and membrane-bound LeY and inhibited soluble LeY-mediated chemotaxis of endothelial cells. LeY was highly expressed on membrane ruffles and protrusions during tube... Blood journals http://www.medworm.com/rss/comments.php?id=5649273 Thu, 02 Feb 2012 05:00:00 +0100 5649273 http://www.medworm.com/index.php?rid=5649272&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1292%3Frss%3D1 We report a novel mechanism by which HIF-1α is degraded after glycogen synthase kinase-3 (GSK-3)–induced phosphorylation and recruitment of the ubiquitin ligase and tumor suppressor F-box and WD protein Fbw7. Further, experiments with GSK-3β and Fbw7-deficient cells revealed that GSK-3β and Fbw7-dependent HIF-1α degradation can be antagonized by ubiquitin-specific protease 28 (USP28). In agreement with this, Fbw7 and USP28 reciprocally regulated cell migration and angiogenesis in an HIF-1α–dependent manner. Therefore, we have identified a new pathway that could be targeted at the level of GSK-3, Fbw7, or USP28 to influence HIF-1α–dependent processes like angiogenesis and metastasis. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649272 Thu, 02 Feb 2012 05:00:00 +0100 5649272 http://www.medworm.com/index.php?rid=5649271&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1283%3Frss%3D1 Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), "MonoMAC" syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or "MonoMAC" syndrome patients with GATA2 deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurri... Blood journals http://www.medworm.com/rss/comments.php?id=5649271 Thu, 02 Feb 2012 05:00:00 +0100 5649271 http://www.medworm.com/index.php?rid=5649270&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1274%3Frss%3D1 Histone methylation is thought to be important for regulating Ag-driven T-cell responses. However, little is known about the effect of modulating histone methylation on inflammatory T-cell responses. We demonstrate that in vivo administration of the histone methylation inhibitor 3-deazaneplanocin A (DZNep) arrests ongoing GVHD in mice after allogeneic BM transplantation. DZNep caused selective apoptosis in alloantigen-activated T cells mediating host tissue injury. This effect was associated with the ability of DZNep to selectively reduce trimethylation of histone H3 lysine 27, deplete the histone methyltransferase Ezh2 specific to trimethylation of histone H3 lysine 27, and activate proapoptotic gene Bim repressed by Ezh2 in antigenic-activated T cells. In contrast, DZNep did not affect t... Blood journals http://www.medworm.com/rss/comments.php?id=5649270 Thu, 02 Feb 2012 05:00:00 +0100 5649270 http://www.medworm.com/index.php?rid=5649269&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1263%3Frss%3D1 When refrigerated platelets are rewarmed, they secrete active sialidases, including the lysosomal sialidase Neu1, and express surface Neu3 that remove sialic acid from platelet von Willebrand factor receptor (VWFR), specifically the GPIbα subunit. The recovery and circulation of refrigerated platelets is greatly improved by storage in the presence of inhibitors of sialidases. Desialylated VWFR is also a target for metalloproteinases (MPs), because GPIbα and GPV are cleaved from the surface of refrigerated platelets. Receptor shedding is inhibited by the MP inhibitor GM6001 and does not occur in Adam17Zn/Zn platelets expressing inactive ADAM17. Critically, desialylation in the absence of MP-mediated receptor shedding is sufficient to cause the rapid clearance of platelets from c... Blood journals http://www.medworm.com/rss/comments.php?id=5649269 Thu, 02 Feb 2012 05:00:00 +0100 5649269 http://www.medworm.com/index.php?rid=5649268&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1256%3Frss%3D1 Tissue factor pathway inhibitor (TFPI) produces factor Xa-dependent feedback inhibition of factor VIIa/tissue factor-induced coagulation. Messages for 2 isoforms of TFPI have been identified. TFPIα mRNA encodes a protein with an acidic N-terminus, 3 Kunitz-type protease inhibitor domains and a basic C-terminus that has been purified from plasma and culture media. TFPIβ mRNA encodes a form in which the Kunitz-3 and C-terminal domains of TFPIα are replaced with an alternative C-terminus that directs the attachment of a glycosylphosphatidylinositol (GPI) anchor, but whether TFPIβ protein is actually expressed is not clear. Moreover, previous studies have suggested that the predominant form of TFPI released from cells by phosphatidylinositol-specific phospholipase C (PIPL... Blood journals http://www.medworm.com/rss/comments.php?id=5649268 Thu, 02 Feb 2012 05:00:00 +0100 5649268 http://www.medworm.com/index.php?rid=5649267&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1248%3Frss%3D1 Heparin is a widely used anticoagulant. Because of its negative charge, it forms complexes with positively charged platelet factor 4 (PF4). This can induce anti-PF4/heparin IgG Abs. Resulting immune complexes activate platelets, leading to the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). HIT requires treatment with alternative anticoagulants. Approved for HIT are 2 direct thrombin inhibitors (DTI; lepirudin, argatroban) and danaparoid. They are niche products with limitations. We assessed the effects of the DTI dabigatran, the direct factor Xa-inhibitor rivaroxaban, and of 2-O, 3-O desulfated heparin (ODSH; a partially desulfated heparin with minimal anticoagulant effects) on PF4/heparin complexes and the interaction of anti-PF4/heparin Abs with platelets. Ne... Blood journals http://www.medworm.com/rss/comments.php?id=5649267 Thu, 02 Feb 2012 05:00:00 +0100 5649267 http://www.medworm.com/index.php?rid=5649266&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1240%3Frss%3D1 The deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S... Blood journals http://www.medworm.com/rss/comments.php?id=5649266 Thu, 02 Feb 2012 05:00:00 +0100 5649266 http://www.medworm.com/index.php?rid=5649265&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1228%3Frss%3D1 Survival signaling by the erythropoietin (Epo) receptor (EpoR) is essential for erythropoiesis and for its acceleration in hypoxic stress. Several apparently redundant EpoR survival pathways were identified in vitro, raising the possibility of their functional specialization in vivo. Here we used mouse models of acute and chronic stress, including a hypoxic environment and β-thalassemia, to identify two markedly different response dynamics for two erythroblast survival pathways in vivo. Induction of the antiapoptotic protein Bcl-xL is rapid but transient, while suppression of the proapoptotic protein Bim is slower but persistent. Similar to sensory adaptation, however, the Bcl-xL pathway "resets," allowing it to respond afresh to acute stress superimposed on a chronic stress stimulus.... Blood journals http://www.medworm.com/rss/comments.php?id=5649265 Thu, 02 Feb 2012 05:00:00 +0100 5649265 http://www.medworm.com/index.php?rid=5649264&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1217%3Frss%3D1 The core pathology of sickle cell disease (SCD) starts with the erythrocyte (RBC). Aberration in MAPK/ERK1/2 signaling, which can regulate cell adhesion, occurs in diverse pathologies. Because RBCs contain abundant ERK1/2, we predicted that ERK1/2 is functional in sickle (SS) RBCs and promotes adherence, a hallmark of SCD. ERK1/2 remained active in SS but not normal RBCs. β2-adrenergic receptor stimulation by epinephrine can enhance ERK1/2 activity only in SS RBCs via PKA- and tyrosine kinase p72syk-dependent pathways. ERK signaling is implicated in RBC ICAM-4 phosphorylation, promoting SS RBC adhesion to the endothelium. SS RBC adhesion and phosphorylation of both ERK and ICAM-4 all decreased with continued cell exposure to epinephrine, implying that activation of ICAM-4–mediat... Blood journals http://www.medworm.com/rss/comments.php?id=5649264 Thu, 02 Feb 2012 05:00:00 +0100 5649264 http://www.medworm.com/index.php?rid=5649263&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1214%3Frss%3D1 Neutrophil extracellular traps (NETs) are DNA structures released by dying neutrophils and claimed to constitute a new microbicidal mechanism. Killing by NET-forming cells is ascribed to these structures because it is prevented by preincubation with DNase, which has been shown to dismantle NETs, before addition of the target microorganisms. Curiously, the possibility that the microorganisms ensnared in NETs are alive has not been considered. Using Staphylococcus aureus and Candida albicans blastospores, we demonstrate that the microorganisms captured by NETs and thought to be killed are alive because they are released and recovered in cell medium by incubation with DNase. It is concluded that NETs entrap but do not kill microbes. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649263 Thu, 02 Feb 2012 05:00:00 +0100 5649263 http://www.medworm.com/index.php?rid=5649262&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1208%3Frss%3D1 The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an add... Blood journals http://www.medworm.com/rss/comments.php?id=5649262 Thu, 02 Feb 2012 05:00:00 +0100 5649262 http://www.medworm.com/index.php?rid=5649261&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1200%3Frss%3D1 Gene regulatory networks that govern hematopoietic stem cells (HSCs) and leukemia-initiating cells (L-ICs) are deeply entangled. Thus, the discovery of compounds that target L-ICs while sparing HSC is an attractive but difficult endeavor. Presently, most screening approaches fail to counter-screen compounds against normal hematopoietic stem/progenitor cells (HSPCs). Here, we present a multistep in vitro and in vivo approach to identify compounds that can target L-ICs in acute myeloid leukemia (AML). A high-throughput screen of 4000 compounds on novel leukemia cell lines derived from human experimental leukemogenesis models yielded 80 hits, of which 10 were less toxic to HSPC. We characterized a single compound, kinetin riboside (KR), on AML L-ICs and HSPCs. KR demonstrated comparable effic... Blood journals http://www.medworm.com/rss/comments.php?id=5649261 Thu, 02 Feb 2012 05:00:00 +0100 5649261 http://www.medworm.com/index.php?rid=5649260&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1190%3Frss%3D1 The JAK2V617F mutation is present in the majority of patients with polycythemia vera and one-half of those with essential thrombocythemia and primary myelofibrosis. JAK2V617F is a gain-of-function mutation resulting in constitutive JAK2 signaling involved in the pathogenesis of these diseases. JAK2V617F has been shown to promote S-phase entry. Here, we demonstrate that the CDC25A phosphatase, a key regulator of the G1/S cell-cycle transition, is constitutively overexpressed in JAK2V617F-positive cell lines, JAK2-mutated patient CD36+ progenitors, and in vitro–differentiated proerythroblasts. Accordingly, CDC25A is overexpressed in BM and spleen of Jak2V617F knock-in mice compared with wild-type littermates. By using murine FDC-P1–EPOR and human HEL and SET-2 cell lines, we foun... Blood journals http://www.medworm.com/rss/comments.php?id=5649260 Thu, 02 Feb 2012 05:00:00 +0100 5649260 http://www.medworm.com/index.php?rid=5649259&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1182%3Frss%3D1 In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhib... Blood journals http://www.medworm.com/rss/comments.php?id=5649259 Thu, 02 Feb 2012 05:00:00 +0100 5649259 http://www.medworm.com/index.php?rid=5649258&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1173%3Frss%3D1 The Really Interesting New Gene (RING) Finger Protein 4 (RNF4) represents a class of ubiquitin ligases that target Small Ubiquitin-like Modifier (SUMO)–modified proteins for ubiquitin modification. To date, the regulatory function of RNF4 appears to be ubiquitin-mediated degradation of sumoylated cellular proteins. In the present study, we show that the Human T-cell Leukemia Virus Type 1 (HTLV-1) oncoprotein Tax is a substrate for RNF4 both in vivo and in vitro. We mapped the RNF4-binding site to a region adjacent to the Tax ubiquitin/SUMO modification sites K280/K284. Interestingly, RNF4 modification of Tax protein results in relocalization of the oncoprotein from the nucleus to the cytoplasm. Overexpression of RNF4, but not the RNF4 RING mutant, resulted in cytoplasmic enrichment o... Blood journals http://www.medworm.com/rss/comments.php?id=5649258 Thu, 02 Feb 2012 05:00:00 +0100 5649258 http://www.medworm.com/index.php?rid=5649257&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1162%3Frss%3D1 Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition–induced expression of miR-1... Blood journals http://www.medworm.com/rss/comments.php?id=5649257 Thu, 02 Feb 2012 05:00:00 +0100 5649257 http://www.medworm.com/index.php?rid=5649256&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1151%3Frss%3D1 Mixed lineage leukemia (MLL) is a key epigenetic regulator of normal hematopoietic development and chromosomal translocations involving MLL are one of the most common genetic alterations in human leukemia. Here we show that ASB2, a component of the ECSASB E3 ubiquitin ligase complex, mediates MLL degradation through interaction with the PHD/Bromodomain region of MLL. Forced expression of ASB2 degrades MLL and reduces MLL transactivation activity. In contrast, the MLL-AF9 fusion protein does not interact with ASB2 and is resistant to ASB2 mediated degradation. Increased expression of ASB2 during hematopoietic differentiation is associated with decreased levels of MLL protein and down-regulation of MLL target genes. Knockdown of ASB2 leads to increased expression of HOXA9 and delayed cell di... Blood journals http://www.medworm.com/rss/comments.php?id=5649256 Thu, 02 Feb 2012 05:00:00 +0100 5649256 http://www.medworm.com/index.php?rid=5649255&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1139%3Frss%3D1 In conclusion, this new LV will facilitate HSC-based gene therapy by directly targeting these primitive cells in BM aspirates or total cord blood. Most importantly, in the future, RDTR/SCF-LVs might completely obviate ex vivo handling and simplify gene therapy for many hematopoietic defects because of their applicability to direct in vivo inoculation. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649255 Thu, 02 Feb 2012 05:00:00 +0100 5649255 http://www.medworm.com/index.php?rid=5649254&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1130%3Frss%3D1 In conclusion, conditioning with 211At-labeled anti-CD45 mAb is safe and efficacious and provides a platform for future clinical trials of nonmyeloablative transplantation with radioimmunotherapy-based conditioning. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649254 Thu, 02 Feb 2012 05:00:00 +0100 5649254 http://www.medworm.com/index.php?rid=5649253&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1123%3Frss%3D1 This study was registered at ClinicalTrials.gov: NCT00481247. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649253 Thu, 02 Feb 2012 05:00:00 +0100 5649253 http://www.medworm.com/index.php?rid=5649252&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1117%3Frss%3D1 High-dose melphalan (HDM) plus stem cell transplantation is an effective treatment for light-chain amyloidosis (AL), but is associated with high treatment-related mortality in patients with cardiac involvement. We studied 187 patients with cardiac involvement with AL who underwent HDM between 1996 and 2008. The median age was 57 years and the median time from diagnosis to HDM was 3.6 months. Half of the patients received reduced-dose melphalan (100-160 mg/m2). The median overall survival (OS) was 66 months, 54 months from diagnosis and HDM, respectively, and 91 patients (49%) were alive at the last follow-up 52 months (median) from HDM. Thirty patients (16%) died within 100 days of transplantation; only low serum albumin predicted early deaths. Overall, hematologic response (HR) and cardia... Blood journals http://www.medworm.com/rss/comments.php?id=5649252 Thu, 02 Feb 2012 05:00:00 +0100 5649252 http://www.medworm.com/index.php?rid=5649251&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1107%3Frss%3D1 The genetic engineering of hematopoietic stem cells is the basis for potentially treating a large array of hereditary and acquired diseases, and stands as the paradigm for stem cell engineering in general. Recent clinical reports support the formidable promise of this approach but also highlight the limitations of the technologies used to date, which have on occasion resulted in clonal expansion, myelodysplasia, or leukemogenesis. New research directions, predicated on improved vector designs, targeted gene delivery or the therapeutic use of pluripotent stem cells, herald the advent of safer and more effective hematopoietic stem cell therapies that may transform medical practice. In this review, we place these recent advances in perspective, emphasizing the solutions emerging from a wave o... Blood journals http://www.medworm.com/rss/comments.php?id=5649251 Thu, 02 Feb 2012 05:00:00 +0100 5649251 http://www.medworm.com/index.php?rid=5649250&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1105%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649250 Thu, 02 Feb 2012 05:00:00 +0100 5649250 http://www.medworm.com/index.php?rid=5649249&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1103%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649249 Thu, 02 Feb 2012 05:00:00 +0100 5649249 http://www.medworm.com/index.php?rid=5649248&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1102%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649248 Thu, 02 Feb 2012 05:00:00 +0100 5649248 http://www.medworm.com/index.php?rid=5649247&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1100%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649247 Thu, 02 Feb 2012 05:00:00 +0100 5649247 http://www.medworm.com/index.php?rid=5649246&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1099%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649246 Thu, 02 Feb 2012 05:00:00 +0100 5649246 http://www.medworm.com/index.php?rid=5649245&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1097%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649245 Thu, 02 Feb 2012 05:00:00 +0100 5649245 http://www.medworm.com/index.php?rid=5649244&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1096%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649244 Thu, 02 Feb 2012 05:00:00 +0100 5649244 http://www.medworm.com/index.php?rid=5649243&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F5%2F1095%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5649243 Thu, 02 Feb 2012 05:00:00 +0100 5649243 http://www.medworm.com/index.php?rid=5629900&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1093%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629900 Thu, 26 Jan 2012 05:00:00 +0100 5629900 http://www.medworm.com/index.php?rid=5629899&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1091%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629899 Thu, 26 Jan 2012 05:00:00 +0100 5629899 http://www.medworm.com/index.php?rid=5629898&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1090%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629898 Thu, 26 Jan 2012 05:00:00 +0100 5629898 http://www.medworm.com/index.php?rid=5629897&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1088%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629897 Thu, 26 Jan 2012 05:00:00 +0100 5629897 http://www.medworm.com/index.php?rid=5629896&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1087%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629896 Thu, 26 Jan 2012 05:00:00 +0100 5629896 http://www.medworm.com/index.php?rid=5629895&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1086%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629895 Thu, 26 Jan 2012 05:00:00 +0100 5629895 http://www.medworm.com/index.php?rid=5629894&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1075%3Frss%3D1 Allogeneic hematopoietic stem cell transplantation (HSCT) can eradicate chemorefractory leukemia through the graft-versus-leukemia (GVL) activity of donor T cells. However, the clinical success of allo-HSCT is limited by the graft-versus-host disease (GVHD) activity of donor T cells. We have reported previously that donor bone marrow precursors of plasmacytoid dendritic cells (pre-pDCs) can activate donor T cells toward T-helper 1 immune polarization in murine allogeneic HSCT. To optimize the GVL activity of these activated donor T cells and limit their graft versus host activity, we engineered the cellular constituents of an allogeneic hematopoietic stem cell graft with highly purified hematopoietic stem cells, T cells, and pre-pDCs and studied their GVL and GVHD activities in a murine mo... Blood journals http://www.medworm.com/rss/comments.php?id=5629894 Thu, 26 Jan 2012 05:00:00 +0100 5629894 http://www.medworm.com/index.php?rid=5629893&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1064%3Frss%3D1 Circulating platelets contain high concentrations of TGF-β1 in their α-granules and release it on platelet adhesion/activation. We hypothesized that uncontrolled in vitro release of platelet TGF-β1 may confound measurement of plasma TGF-β1 in mice and that in vivo release and activation may contribute to cardiac pathology in response to constriction of the transverse aorta, which produces both high shear and cardiac pressure overload. Plasma TGF-β1 levels in blood collected from C57Bl/6 mice by the standard retro-bulbar technique were much higher than those obtained when prostaglandin E1 was added to inhibit release or when blood was collected percutaneously from the left ventricle under ultrasound guidance. Even with optimal blood drawing, plasma TGF-β1 was ... Blood journals http://www.medworm.com/rss/comments.php?id=5629893 Thu, 26 Jan 2012 05:00:00 +0100 5629893 http://www.medworm.com/index.php?rid=5629892&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1054%3Frss%3D1 In this study, we analyzed the in vitro and in vivo consequences of megakaryocyte- and platelet-specific RhoA gene deletion in mice. We found a pronounced macrothrombocytopenia in RhoA-deficient mice, with platelet counts of approximately half that of wild-type controls. The mutant cells displayed an altered shape but only a moderately reduced life span. Shape change of RhoA-deficient platelets in response to G13-coupled agonists was abolished, and it was impaired in response to Gq stimulation. Similarly, RhoA was required for efficient secretion of α and dense granules downstream of G13 and Gq. Furthermore, RhoA was essential for integrin-mediated clot retraction but not for actomyosin rearrangements and spreading of activated platelets on fibrinogen. In vivo, RhoA deficiency result... Blood journals http://www.medworm.com/rss/comments.php?id=5629892 Thu, 26 Jan 2012 05:00:00 +0100 5629892 http://www.medworm.com/index.php?rid=5629891&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1045%3Frss%3D1 The normal accumulation of β-globin protein in terminally differentiating erythroid cells is critically dependent on the high stability of its encoding mRNA. The molecular basis for this property, though, is incompletely understood. Factors that regulate β-globin mRNA within the nucleus of early erythroid progenitors are unlikely to account for the constitutively high half-life of β-globin mRNA in the cytoplasm of their anucleate erythroid progeny. We conducted in vitro protein-RNA binding analyses that identified a cytoplasm-restricted β-globin messenger ribonucleoprotein (mRNP) complex in both cultured K562 cells and erythroid-differentiated human CD34+ cells. This novel mRNP targets a specific guanine-rich pentanucleotide in a region of the β-globin 3'untranslat... Blood journals http://www.medworm.com/rss/comments.php?id=5629891 Thu, 26 Jan 2012 05:00:00 +0100 5629891 http://www.medworm.com/index.php?rid=5629890&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1036%3Frss%3D1 In this study, we investigated the effect of various cell-division inhibitors on cytokinesis and enucleation. For this purpose, we used human colony-forming unit-erythroid (CFU-E) and mature erythroblasts generated from purified CD34+ cells as target cells for cytokinesis and enucleation assay, respectively. Here we show that the inhibition of myosin by blebbistatin, an inhibitor of non-muscle myosin II ATPase, blocks both cell division and enucleation, which suggests that non-muscle myosin II plays an essential role not only in cytokinesis but also in enucleation. When the function of non-muscle myosin heavy chain (NMHC) IIA or IIB was inhibited by an exogenous expression of myosin rod fragment, myosin IIA or IIB, each rod fragment blocked the proliferation of CFU-E but only the rod fragm... Blood journals http://www.medworm.com/rss/comments.php?id=5629890 Thu, 26 Jan 2012 05:00:00 +0100 5629890 http://www.medworm.com/index.php?rid=5629889&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1032%3Frss%3D1 The palmitoylation/depalmitoylation cycle of posttranslational processing is a potential therapeutic target for selectively inhibiting the growth of hematologic cancers with somatic NRAS mutations. To investigate this question at the single-cell level, we constructed murine stem cell virus vectors and assayed the growth of myeloid progenitors. Whereas cells expressing oncogenic N-RasG12D formed cytokine-independent colonies and were hypersensitive to GM-CSF, mutations within the N-Ras hypervariable region induced N-Ras mislocalization and attenuated aberrant progenitor growth. Exposing transduced hematopoietic cells and bone marrow from Nras and Kras mutant mice to the acyl protein thioesterase inhibitor palmostatin B had similar effects on protein localization and colony growth. Important... Blood journals http://www.medworm.com/rss/comments.php?id=5629889 Thu, 26 Jan 2012 05:00:00 +0100 5629889 http://www.medworm.com/index.php?rid=5629888&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1029%3Frss%3D1 Women treated at young ages with supradiaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide association studies have identified 14 independently replicated common single nucleotide polymorphisms that influence breast cancer risk. To examine whether these variants contribute to risk of radiation-associated breast cancer in HL, we analyzed 2 independent case-control series, from the United Kingdom and The Netherlands, totaling 693 HL patients, 232 with breast cancer and 461 without. rs1219648, which annotates the FGFR2 gene, was associated with risk in both series (com... Blood journals http://www.medworm.com/rss/comments.php?id=5629888 Thu, 26 Jan 2012 05:00:00 +0100 5629888 http://www.medworm.com/index.php?rid=5629887&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1018%3Frss%3D1 Tumor progression usually proceeds through several sequential stages, any of which could be targets for interrupting the progression process if one understood these steps at the molecular level. We extracted nascent plasma cell tumor (PCT) cells from within inflammatory oil granulomas (OG) isolated from IP pristane-injected BALB/c.iMycEμ mice at 5 different time points during tumor progression. We used laser capture microdissection to collect incipient PCT cells and analyzed their global gene expression on Affymetrix Mouse Genome 430A microarrays. Two independent studies were performed with different sets of mice. Analysis of the expression data used ANOVA and Bayesian estimation of temporal regulation. Genetic pathway analysis was performed using MetaCore (GeneGo) and IPA (Ingenuity). ... Blood journals http://www.medworm.com/rss/comments.php?id=5629887 Thu, 26 Jan 2012 05:00:00 +0100 5629887 http://www.medworm.com/index.php?rid=5629886&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F1008%3Frss%3D1 Induction of EBV lytic-phase gene expression, combined with exposure to an antiherpes viral drug, represents a promising targeted therapeutic approach to EBV-associated lymphomas. Short-chain fatty acids or certain chemotherapeutics have been used to induce EBV lytic-phase gene expression in cultured cells and mouse models, but these studies generally have not translated into clinical application. The recent success of a clinical trial with the pan-histone deacetylase (pan-HDAC) inhibitor arginine butyrate and the antiherpes viral drug ganciclovir in the treatment of EBV lymphomas prompted us to investigate the potential of several HDAC inhibitors, including some new, highly potent compounds, to sensitize EBV+ human lymphoma cells to antiviral agents in vitro. Our study included short-chai... Blood journals http://www.medworm.com/rss/comments.php?id=5629886 Thu, 26 Jan 2012 05:00:00 +0100 5629886 http://www.medworm.com/index.php?rid=5629885&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F997%3Frss%3D1 Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist about its role in chronic lymphocytic leukemia (CLL). Here, we demonstrate that the expression of essential HH pathway components like GLI1, PTCH1, and the HH ligands is highly diverse in CLL. A subset of 36.7% of 60 tested CLL samples responded to all 3 SMOOTHENED (SMO) inhibitors, whereas 40% were completely resistant. Responsiveness correlated with elevated GLI1 and PTCH1 transcript levels and the presence of trisomy 12, whereas no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DESERT HH (DHH) ligand secretion, which could be blocked by the HH-blocking Ab 5E1. Cocultures with DHH-expressing BM stromal c... Blood journals http://www.medworm.com/rss/comments.php?id=5629885 Thu, 26 Jan 2012 05:00:00 +0100 5629885 http://www.medworm.com/index.php?rid=5629884&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F990%3Frss%3D1 In recent decades, attention has focused on reducing long-term, treatment-related morbidity and mortality in Hodgkin lymphoma (HL). In the present study, we looked for trends in relative survival for all patients diagnosed with HL in Sweden from 1973-2009 (N = 6949; 3985 men and 2964 women; median age, 45 years) and followed up for death until the end of 2010. Patients were categorized into 6 age groups and 5 calendar periods (1973-1979, 1980-1986, 1987-1994, 1994-2000, and 2001-2009). Relative survival improved in all age groups, with the greatest improvement in patients 51-65 years of age (P < .0005). A plateau in relative survival was observed in patients below 65 years of age during the last calendar period, suggesting a reduced long-term, treatment-related mortality. The 10-year re... Blood journals http://www.medworm.com/rss/comments.php?id=5629884 Thu, 26 Jan 2012 05:00:00 +0100 5629884 http://www.medworm.com/index.php?rid=5629883&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F978%3Frss%3D1 B lymphocyte recirculation through lymph nodes (LNs) requires crossing endothelial barriers and chemoattractant-triggered cell migration. Here we show how LN anatomy and chemoattractant receptor signaling organize B lymphocyte LN trafficking. Blood-borne B cells predominately used CCR7 signaling to adhere to high endothelial venules (HEVs). New B cell emigrants slowly transited the HEV perivenule space, and thereafter localized nearby, avoiding the follicle. Eventually, the newly arrived B cells entered the basal portion of the follicle gradually populating it. In contrast, newly arriving activated B cells rapidly crossed HEVs and migrated toward the lymph node follicle. During their LN residency, recirculating B cells reacquired their sphingosine-1 phospate receptor 1 (S1P1) receptors and... Blood journals http://www.medworm.com/rss/comments.php?id=5629883 Thu, 26 Jan 2012 05:00:00 +0100 5629883 http://www.medworm.com/index.php?rid=5629882&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F967%3Frss%3D1 Aspergillus fumigatus is a model fungal pathogen and a common cause of severe infections and diseases. CD8+ T cells are present in the human and murine T-cell repertoire to the fungus. However, CD8+ T-cell function in infection and the molecular mechanisms that control their priming and differentiation into effector and memory cells in vivo remain elusive. In the present study, we report that both CD4+ and CD8+ T cells mediate protective memory responses to the fungus contingent on the nature of the fungal vaccine. Mechanistically, class I MHC-restricted, CD8+ memory T cells were activated through TLR3 sensing of fungal RNA by cross-presenting dendritic cells. Genetic deficiency of TLR3 was associated with susceptibility to aspergillosis and concomitant failure to activate memory-protectiv... Blood journals http://www.medworm.com/rss/comments.php?id=5629882 Thu, 26 Jan 2012 05:00:00 +0100 5629882 http://www.medworm.com/index.php?rid=5629881&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F957%3Frss%3D1 We explored adeno-associated viral vector (AAV)–mediated gene transfer in the perinatal period in animal models of severe congenital factor VII (FVII) deficiency, a disease associated with early postnatal life-threatening hemorrhage. In young adult mice with plasma FVII < 1% of normal, a single tail vein administration of AAV (1 x 1013 vector genomes [vg]/kg) resulted in expression of murine FVII at 266% ± 34% of normal for ≥ 67 days, which mediated protection against fatal hemorrhage and significantly improved survival. Codon optimization of human FVII (hFVIIcoop) improved AAV transgene expression by 37-fold compared with the wild-type hFVII cDNA. In adult macaques, a single peripheral vein injection of 2 x 1011 vg/kg of the hFVIIcoop AAV vector resulted in therapeutic ... Blood journals http://www.medworm.com/rss/comments.php?id=5629881 Thu, 26 Jan 2012 05:00:00 +0100 5629881 http://www.medworm.com/index.php?rid=5629880&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F949%3Frss%3D1 Pediatric arterial ischemic stroke (AIS) is increasingly diagnosed and carries significant risks of recurrence, morbidity, and mortality. Anticoagulant therapy (ACT) is commonly prescribed in childhood AIS. Hemorrhagic complication rates in pediatric stroke are unknown, and adult safety data are of limited applicability. We analyzed a prospectively enrolled cohort of children (aged 1 month-18 years) with acute AIS selected using standardized criteria for protocol-based ACT over14-year period. We assessed ACT-associated intracranial hemorrhage (ICH), including frequency, clinical and radiologic characteristics, predictors, and outcome. Among 215 children with AIS, 123 received ACT within 7 days after diagnosis. During anticoagulation, 14 (11%) children developed new or increased ICH, all wi... Blood journals http://www.medworm.com/rss/comments.php?id=5629880 Thu, 26 Jan 2012 05:00:00 +0100 5629880 http://www.medworm.com/index.php?rid=5629879&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F940%3Frss%3D1 In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13). This trial is registered at the International Standard Randomised Controlled Trial Number Register as ISRCTN64455289. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629879 Thu, 26 Jan 2012 05:00:00 +0100 5629879 http://www.medworm.com/index.php?rid=5629878&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F933%3Frss%3D1 This study was registered at www.clinicaltrials.gov as #NCT00551928. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629878 Thu, 26 Jan 2012 05:00:00 +0100 5629878 http://www.medworm.com/index.php?rid=5629877&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F924%3Frss%3D1 It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that a... Blood journals http://www.medworm.com/rss/comments.php?id=5629877 Thu, 26 Jan 2012 05:00:00 +0100 5629877 http://www.medworm.com/index.php?rid=5629876&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F911%3Frss%3D1 An important mediator of cytokine signaling implicated in regulation of hematopoiesis is the PI3K/protein kinase B (PKB/c-Akt) signaling module. Constitutive activation of this signaling module has been observed in a large group of leukemias. Because activation of this signaling pathway has been demonstrated to be sufficient to induce hematologic malignancies and is thought to correlate with poor prognosis and enhanced drug resistance, it is considered to be a promising target for therapy. A high number of pharmacologic inhibitors directed against either individual or multiple components of this pathway have already been developed to improve therapy. In this review, the safety and efficacy of both single and dual-specificity inhibitors will be discussed as well as the potential of combinat... Blood journals http://www.medworm.com/rss/comments.php?id=5629876 Thu, 26 Jan 2012 05:00:00 +0100 5629876 http://www.medworm.com/index.php?rid=5629875&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F910%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629875 Thu, 26 Jan 2012 05:00:00 +0100 5629875 http://www.medworm.com/index.php?rid=5629874&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F907%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629874 Thu, 26 Jan 2012 05:00:00 +0100 5629874 http://www.medworm.com/index.php?rid=5629873&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F906%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629873 Thu, 26 Jan 2012 05:00:00 +0100 5629873 http://www.medworm.com/index.php?rid=5629872&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F4%2F905%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5629872 Thu, 26 Jan 2012 05:00:00 +0100 5629872 http://www.medworm.com/index.php?rid=5610068&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F894%3Frss%3D1 The endothelial ETS transcription factor Erg plays an important role in homeostasis and angiogenesis by regulating many endothelial functions including survival and junction stability. Here we show that Erg regulates endothelial cell (EC) migration. Transcriptome profiling of Erg-deficient ECs identified ~ 80 genes involved in cell migration as candidate Erg targets, including many regulators of Rho- GTPases. Inhibition of Erg expression in HUVECs resulted in decreased migration in vitro, while Erg overexpression using adenovirus caused increased migra-tion. Live-cell imaging of Erg-deficient HUVECs showed a reduction in lamellipodia, in line with decreased motility. Both actin and tubulin cytoskeletons were disrupted in Erg-deficient ECs, with a dramatic increase in tubulin acetylation. A... Blood journals http://www.medworm.com/rss/comments.php?id=5610068 Thu, 19 Jan 2012 05:00:00 +0100 5610068 http://www.medworm.com/index.php?rid=5610067&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F884%3Frss%3D1 Antiphospholipid Abs (APLAs) are associated with thrombosis and recurrent fetal loss. These Abs are primarily directed against phospholipid-binding proteins, particularly β2GPI, and activate endothelial cells (ECs) in a β2GPI-dependent manner after binding of β2GPI to EC annexin A2. Because annexin A2 is not a transmembrane protein, the mechanisms of APLA/anti-β2GPI Ab–mediated EC activation are uncertain, although a role for a TLR4/myeloid differentiation factor 88–dependent pathway leading to activation of NF-B has been proposed. In the present study, we confirm a critical role for TLR4 in anti-β2GPI Ab–mediated EC activation and demonstrate that signaling through TLR4 is mediated through the assembly of a multiprotein signaling complex on the E... Blood journals http://www.medworm.com/rss/comments.php?id=5610067 Thu, 19 Jan 2012 05:00:00 +0100 5610067 http://www.medworm.com/index.php?rid=5610066&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F874%3Frss%3D1 The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a protease-activated receptor-1 (PAR-1) and endothelial protein C receptor-dependent mechanism. Conversely, the signaling mechanism through which aPC protects podocytes remains unknown. While exploring the latter, we identified a novel aPC/PAR-dependent cytoprotective signaling mechanism. In podocytes, aPC inhibits apoptosis through proteolytic activation of PAR-3 independent of endothelial protein C receptor. PAR-3 is not signaling competent itself as it requires aPCinduced heterodimerization with PAR-2... Blood journals http://www.medworm.com/rss/comments.php?id=5610066 Thu, 19 Jan 2012 05:00:00 +0100 5610066 http://www.medworm.com/index.php?rid=5610065&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F868%3Frss%3D1 Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (–1639G > A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin... Blood journals http://www.medworm.com/rss/comments.php?id=5610065 Thu, 19 Jan 2012 05:00:00 +0100 5610065 http://www.medworm.com/index.php?rid=5610064&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F861%3Frss%3D1 Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the m... Blood journals http://www.medworm.com/rss/comments.php?id=5610064 Thu, 19 Jan 2012 05:00:00 +0100 5610064 http://www.medworm.com/index.php?rid=5610063&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F857%3Frss%3D1 Enhanced erythropoietic drive and iron deficiency both influence iron homeostasis through the suppression of the iron regulatory hormone hepcidin. Hypoxia also suppresses hepcidin through a mechanism that is unknown. We measured iron indices and plasma hepcidin levels in healthy volunteers during a 7-day sojourn to high altitude (4340 m above sea level), with and without prior intravenous iron loading. Without prior iron loading, a rapid reduction in plasma hepcidin was observed that was almost complete by the second day at altitude. This occurred before any index of iron availability had changed. Prior iron loading delayed the decrease in hepcidin until after the transferrin saturation, but not the ferritin concentration, had normalized. We conclude that hepcidin suppression by the hypoxi... Blood journals http://www.medworm.com/rss/comments.php?id=5610063 Thu, 19 Jan 2012 05:00:00 +0100 5610063 http://www.medworm.com/index.php?rid=5610062&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F847%3Frss%3D1 Integrin α2β1–mediated adhesion of human platelets to monomeric type I collagen or to the GFOGER peptide caused a time-dependent activation of PI3K and Akt phosphorylation. This process was abrogated by pharmacologic inhibition of PI3Kβ, but not of PI3K or PI3Kα. Moreover, Akt phosphorylation was undetectable in murine platelets expressing a kinase-dead mutant of PI3Kβ (PI3KβKD), but occurred normally in PI3KKD platelets. Integrin α2β1 failed to stimulate PI3Kβ in platelets from phospholipase C2 (PLC2)–knockout mice, and we found that intracellular Ca2+ linked PLC2 to PI3Kβ activation. Integrin α2β1 also caused a time-dependent stimulation of the focal kinase Pyk2 downstream of PLC2 and intracellular Ca2+. Whereas ... Blood journals http://www.medworm.com/rss/comments.php?id=5610062 Thu, 19 Jan 2012 05:00:00 +0100 5610062 http://www.medworm.com/index.php?rid=5610061&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F838%3Frss%3D1 Megakaryocytes are large, polyploid cells that produce platelets. We have previously reported that calcium- and integrin-binding protein 1 (CIB1) regulates endomitosis in Dami cells. To further characterize the role of CIB1 in megakaryopoiesis, we used a Cib1–/– mouse model. Cib1–/– mice have more platelets and BM megakaryocytes than wild-type (WT) controls (P < .05). Furthermore, subsequent analysis of megakaryocyte-CFU production revealed an increase with Cib1 deletion compared with WT (P < .05). In addition, BM from Cib1–/– mice, cultured with thrombopoietin (TPO) for 24 hours, produced more highly polyploid megakaryocytes than WT BM (P < .05). Subsequent analysis of TPO signaling revealed enhanced Akt and ERK1/2 phosphorylation, whereas FAKY... Blood journals http://www.medworm.com/rss/comments.php?id=5610061 Thu, 19 Jan 2012 05:00:00 +0100 5610061 http://www.medworm.com/index.php?rid=5610060&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F826%3Frss%3D1 Myeloid cell leukemia-1 (Mcl-1) protein is an anti-apoptotic Bcl-2 family protein that plays essential roles in multiple myeloma (MM) survival and drug resistance. In MM, it has been demonstrated that proteasome inhibition can trigger the accumulation of Mcl-1, which has been shown to confer MM cell resistance to bortezomib-induced lethality. However, the mechanisms involved in this unwanted Mcl-1 accumulation are still unclear. The aim of the present study was to determine whether the unwanted Mcl-1 accumulation could be induced by the unfolded protein response (UPR) and to elucidate the role of the endoplasmic reticulum stress response in regulating Mcl-1 expression. Using quantitative RT-PCR and Western blot, we found that the translation of activating transcription factor-4 (ATF4), an ... Blood journals http://www.medworm.com/rss/comments.php?id=5610060 Thu, 19 Jan 2012 05:00:00 +0100 5610060 http://www.medworm.com/index.php?rid=5610059&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F817%3Frss%3D1 Traditionally, GRP78 is regarded as protective against hypoxia and nutrient starvation prevalent in the microenvironment of solid tumors; thus, its role in the development of hematologic malignancies remains to be determined. To directly elucidate the requirement of GRP78 in leukemogenesis, we created a biallelic conditional knockout mouse model of GRP78 and PTEN in the hematopoietic system. Strikingly, heterozygous knockdown of GRP78 in PTEN null mice is sufficient to restore the hematopoietic stem cell population back to the normal percentage and suppress leukemic blast cell expansion. AKT/mTOR activation in PTEN null BM cells is potently inhibited by Grp78 heterozygosity, corresponding with suppression of the PI3K/AKT pathway by GRP78 knockdown in leukemia cell lines. This is the first ... Blood journals http://www.medworm.com/rss/comments.php?id=5610059 Thu, 19 Jan 2012 05:00:00 +0100 5610059 http://www.medworm.com/index.php?rid=5610058&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F810%3Frss%3D1 The MUC1-C oncoprotein is aberrantly expressed in most multiple myeloma cells. However, the functional significance of MUC1-C expression in multiple myeloma is not known. The present studies demonstrate that treatment of multiple myeloma cells with a MUC1-C inhibitor is associated with increases in reactive oxygen species (ROS), oxidation of mitochondrial cardiolipin, and loss of the mitochondrial transmembrane potential. The MUC1-C inhibitor-induced increases in ROS were also associated with down-regulation of the p53-inducible regulator of glycolysis and apoptosis (TIGAR). In concert with the decrease in TIGAR expression, which regulates the pentose phosphate pathway, treatment with the MUC1-C inhibitor reduced production of NADPH, and in turn glutathione (GSH) levels. TIGAR protects aga... Blood journals http://www.medworm.com/rss/comments.php?id=5610058 Thu, 19 Jan 2012 05:00:00 +0100 5610058 http://www.medworm.com/index.php?rid=5610057&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F805%3Frss%3D1 T-cell acute lymphoblastic lymphomas commonly demonstrate activating Notch1 mutations as well as mutations or deletions in Fbxw7. However, because Fbxw7 targets Notch1 for degradation, genetic alterations in these genes are expected to be mutually exclusive events in lymphomagenesis. Previously, by using a radiation-induced Tp53-deficient mouse model for T-cell acute lymphoblastic lymphoma, we reported that loss of heterozygosity at the Fbxw7 locus occurs frequently in a Tp53-dependent manner. In the current study, we show that these thymic lymphomas also commonly exhibit activating Notch1 mutations in the proline-glutamic acid-serine-threonine (PEST) domain. Moreover, concurrent activating Notch1 PEST domain mutations and single-copy deletions at the Fbxw7 locus occur with high frequency ... Blood journals http://www.medworm.com/rss/comments.php?id=5610057 Thu, 19 Jan 2012 05:00:00 +0100 5610057 http://www.medworm.com/index.php?rid=5610056&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F798%3Frss%3D1 CD4+ Th cells are pivotal for the generation and maintenance of CD8+ T-cell responses. "Helped" CD8+ T cells receive signals during priming that prevent the induction of the proapoptotic molecule TNF-related apoptosis-inducing ligand (TRAIL) during reactivation, thereby enabling robust secondary expansion. Conversely, "helpless" CD8+ T cells primed in the absence of Th induce TRAIL expression after restimulation and undergo activation-induced cell death. In the present study, we investigated the molecular basis for the differential regulation of TRAIL in helped versus helpless CD8+ T cells by comparing their transcriptional profiles, and have identified a transcriptional corepressor, NGFI-A binding protein 2 (Nab2), that is selectively induced in helped CD8+ T cells. Enforced expression of... Blood journals http://www.medworm.com/rss/comments.php?id=5610056 Thu, 19 Jan 2012 05:00:00 +0100 5610056 http://www.medworm.com/index.php?rid=5610055&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F786%3Frss%3D1 The Nef protein of HIV-1 facilitates viral replication and disease progression in vivo. Nef disturbs the organization of immunological synapses between infected CD4+ T lymphocytes and antigen-presenting B-lymphocytes to interfere with TCR proximal signaling. Paradoxically, Nef enhances distal TCR signaling in infected CD4+ T lymphocytes, an effect thought to be involved in its role in AIDS pathogenesis. Using quantitative confocal microscopy and cell fractionation of Nef-expressing cells and HIV-1–infected primary human T lymphocytes, we found that Nef induces intracellular compartmentalization of TCR signaling to adjust TCR responses to antigenic stimulation. Nef reroutes kinase-active pools of the TCR signaling master switch Lck away from the plasma membrane (PM) to the trans-Golgi... Blood journals http://www.medworm.com/rss/comments.php?id=5610055 Thu, 19 Jan 2012 05:00:00 +0100 5610055 http://www.medworm.com/index.php?rid=5610054&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F777%3Frss%3D1 The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) plays a crucial role within the immune system. It regulates the interaction between T cells and antigen-presenting cells and facilitates T-cell adhesion to the endothelium, a process that is important for lymphocyte extravasation and homing. Signals mediated via the T-cell receptor and the chemokine receptor CCR7 activate LFA-1 through processes known as inside-out signaling. The molecular mechanisms underlying inside-out signaling are not completely understood. Here, we have assessed the role of the ADAP/SKAP55 module for CCR7-mediated signaling. We show that loss of the module delays homing and reduces intranodal T-cell motility in vivo. This is probably because of a defect in CCR7-mediated adhesion that affects both a... Blood journals http://www.medworm.com/rss/comments.php?id=5610054 Thu, 19 Jan 2012 05:00:00 +0100 5610054 http://www.medworm.com/index.php?rid=5610053&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F767%3Frss%3D1 MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression and are important for pre-B and follicular B lymphopoiesis as demonstrated, respectively, by mb-1-Cre– and cd19-Cre–mediated deletion of Dicer, the RNase III enzyme critical for generating mature miRNAs. To explore the role of miRNAs in B-cell terminal differentiation, we use Aicda-Cre to specifically delete Dicer in activated B cells where activation-induced cytidine deaminase is highly expressed. We demonstrate that mutant mice fail to produce high-affinity class-switched antibodies and generate memory B and long-lived plasma cells on immunization with a T cell–dependent antigen. More importantly, germinal center (GC) B-cell formation is drastically compromised in the absence of Dicer, as a result... Blood journals http://www.medworm.com/rss/comments.php?id=5610053 Thu, 19 Jan 2012 05:00:00 +0100 5610053 http://www.medworm.com/index.php?rid=5610052&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F756%3Frss%3D1 Dendritic cells (DCs) are the most potent APCs. Whereas immature DCs down-regulate T-cell responses to induce/maintain immunologic tolerance, mature DCs promote immunity. To amplify their functions, DCs communicate with neighboring DCs through soluble mediators, cell-to-cell contact, and vesicle exchange. Transfer of nanovesicles (< 100 nm) derived from the endocytic pathway (termed exosomes) represents a novel mechanism of DC-to-DC communication. The facts that exosomes contain exosome-shuttle miRNAs and DC functions can be regulated by exogenous miRNAs, suggest that DC-to-DC interactions could be mediated through exosome-shuttle miRNAs, a hypothesis that remains to be tested. Importantly, the mechanism of transfer of exosome-shuttle miRNAs from the exosome lumen to the cytosol of targ... Blood journals http://www.medworm.com/rss/comments.php?id=5610052 Thu, 19 Jan 2012 05:00:00 +0100 5610052 http://www.medworm.com/index.php?rid=5610051&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F745%3Frss%3D1 Sema4D, also known as CD100, is a constitutively expressed immune semaphorin on T cells and NK cells. CD100 has important immune regulatory functions that improve antigen-specific priming by antigen-presenting cells, and can also act as a costimulatory molecule on T cells. We investigated the consequence of HIV-1 infection on CD100 expression by T cells, and whether CD100 expression signifies functionally competent effector cells. CD100 expression on T cells from healthy individuals was compared with HIV-1–infected subjects including elite controllers, noncontrollers, and patients receiving antiretroviral therapy. The frequency and fluorescence intensity of CD100 on CD8+ and CD4+ T cells were decreased during HIV-1 infection. Furthermore, the absolute number of CD100-expressing CD8+ ... Blood journals http://www.medworm.com/rss/comments.php?id=5610051 Thu, 19 Jan 2012 05:00:00 +0100 5610051 http://www.medworm.com/index.php?rid=5610050&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F736%3Frss%3D1 Hematopoietic stem cells (HSCs) interact with osteoblastic, stromal, and vascular components of the BM hematopoietic microenvironment (HM) that are required for the maintenance of long-term self-renewal in vivo. Osteoblasts have been reported to be a critical cell type making up the HSC niche in vivo. Rac1 GTPase has been implicated in adhesion, spreading, and differentiation of osteoblast cell lines and is critical for HSC engraftment and retention. Recent data suggest a differential role of GTPases in endosteal/osteoblastic versus perivascular niche function. However, whether Rac signaling pathways are also necessary in the cell-extrinsic control of HSC function within the HM has not been examined. In the present study, genetic and inducible models of Rac deletion were used to demonstrat... Blood journals http://www.medworm.com/rss/comments.php?id=5610050 Thu, 19 Jan 2012 05:00:00 +0100 5610050 http://www.medworm.com/index.php?rid=5610049&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F727%3Frss%3D1 Self-renewal activity is essential for the maintenance and regeneration of the hematopoietic system. The search for molecules capable of promoting self-renewal and expanding hematopoietic stem cells (HSCs) has met with limited success. Here, we show that a short isoform (AML1a) of RUNX1/AML1 has such activities. Enforced AML1a expression expanded functionally defined HSCs, with an efficiency that was at least 20 times greater than that of the control in vivo and by 18-fold within 7 days ex vivo. The ex vivo–expanded HSCs could repopulate hosts after secondary transplantations. Moreover, AML1a expression resulted in vigorous and long-term (> 106-fold at 4 weeks) ex vivo expansion of progenitor cell populations capable of differentiating into multilineages. Gene expression analysis ... Blood journals http://www.medworm.com/rss/comments.php?id=5610049 Thu, 19 Jan 2012 05:00:00 +0100 5610049 http://www.medworm.com/index.php?rid=5610048&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F717%3Frss%3D1 Alterations of the BM microenvironment have been shown to occur after chemoradiotherapy, during aging, and after genetic manipulations of telomere length. Nevertheless, whether BM stromal cells adopt senescent features in response to these events is unknown. In the present study, we provide evidence that exposure to ionizing radiation (IR) leads murine stromal BM cells to express senescence markers, namely senescence-associated β-galactosidase and increased p16INK4a/p19ARF expression. Long (8 weeks) after exposure of mice to IR, we observed a reduction in the number of stromal cells derived from BM aspirates, an effect that we found to be absent in irradiated Ink4a/arf-knockout mice and to be mostly independent of the CFU potential of the stroma. Such a reduction in the number of BM s... Blood journals http://www.medworm.com/rss/comments.php?id=5610048 Thu, 19 Jan 2012 05:00:00 +0100 5610048 http://www.medworm.com/index.php?rid=5610047&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F707%3Frss%3D1 CXCL12 and VCAM1 retain hematopoietic stem cells (HSCs) in the BM, but the factors mediating HSC egress from the BM to the blood are not known. The sphingosine-1-phosphate receptor 1 (S1P1) is expressed on HSCs, and S1P facilitates the egress of committed hematopoietic progenitors from the BM into the blood. In the present study, we show that both the S1P gradient between the BM and the blood and the expression of S1P1 are essential for optimal HSC mobilization by CXCR4 antagonists, including AMD3100, and for the trafficking of HSCs during steady-state hematopoiesis. We also demonstrate that the S1P1 agonist SEW2871 increases AMD3100-induced HSC and progenitor cell mobilization. These results suggest that the combination of a CXCR4 antagonist and a S1P1 agonist may prove to be sufficient f... Blood journals http://www.medworm.com/rss/comments.php?id=5610047 Thu, 19 Jan 2012 05:00:00 +0100 5610047 http://www.medworm.com/index.php?rid=5610046&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F696%3Frss%3D1 The costimulatory effects of CD27 on T lymphocyte effector function and memory formation has been confined to evaluations in mouse models, in vitro human cell culture systems, and clinical observations. Here, we tested whether CD27 costimulation actively enhances human T-cell function, expansion, and survival in vitro and in vivo. Human T cells transduced to express an antigen-specific chimeric antigen receptor (CAR-T) containing an intracellular CD3 zeta (CD3) chain signaling module with the CD27 costimulatory motif in tandem exerted increased antigen-stimulated effector functions in vitro, including cytokine secretion and cytotoxicity, compared with CAR-T with CD3 alone. After antigen stimulation in vitro, CD27-bearing CAR-T cells also proliferated, up-regulated Bcl-XL protein expression... Blood journals http://www.medworm.com/rss/comments.php?id=5610046 Thu, 19 Jan 2012 05:00:00 +0100 5610046 http://www.medworm.com/index.php?rid=5610045&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F692%3Frss%3D1 We investigated a recent (January 1999 to December 2009) cohort of 95 elderly Hodgkin lymphoma subjects. At diagnosis, median age was 67 years (range, 60-89 years), whereas 61% had significant comorbidity, 26% were unfit, 17% had a geriatric syndrome, and 13% had loss of activities of daily living. Overall response rate to therapy was 85%, whereas incidence of bleomycin lung toxicity was 32% (with associated mortality rate, 25%). With 66-month median follow-up, 2-year and 5-year overall survival were 73% and 58%, respectively (advanced-stage, 63% and 46%, respectively). Most International Prognostic Score factors were not prognostic on univariate analyses, whereas Cox multivariate regression identified 2 risk factors associated with inferior overall survival: (1) age more than 70 years (2.... Blood journals http://www.medworm.com/rss/comments.php?id=5610045 Thu, 19 Jan 2012 05:00:00 +0100 5610045 http://www.medworm.com/index.php?rid=5610044&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F687%3Frss%3D1 The achievement of complete response (CR) after high-dose therapy/autologous stem cell transplantation (HDT/ASCT) is a surrogate for prolonged survival in multiple myeloma; however, patients who lose their CR status within 1 year of HDT/ASCT (unsustained CR) have poor prognosis. Thus, the identification of these patients is highly relevant. Here, we investigate which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day +100 after HDT/ASCT who were enrolled in the Spanish GEM2000 (n = 140) and GEM2005 < 65y (n = 101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median overall survival 39 months). The presence of baseline high-risk cytogenetics by FISH (hazard ratio 17.3; P = .002) and persistent minimal residu... Blood journals http://www.medworm.com/rss/comments.php?id=5610044 Thu, 19 Jan 2012 05:00:00 +0100 5610044 http://www.medworm.com/index.php?rid=5610043&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F673%3Frss%3D1 EBV-associated T/NK–cell lymphoproliferative disease (T/NK-LPD) is defined as a systemic illness characterized by clonal proliferation of EBV-infected T or NK cells. We prospectively enrolled 108 nonimmunocompromised patients with this disease (50 men and 58 women; median onset age, 8 years; age range, 1-50 years) evidenced by expansion of EBV+ T/NK cells in the peripheral blood; these were of the T-cell type in 64 cases and of the NK-cell type in 44, and were clinically categorized into 4 groups: 80 cases of chronic active EBV disease, 15 of EBV-associated hemophagocytic lymphohistiocytosis, 9 of severe mosquito bite allergy, and 4 of hydroa vacciniforme. These clinical profiles were closely linked with the EBV+ cell immunophenotypes. In a median follow-up period of 46 months, 47 pa... Blood journals http://www.medworm.com/rss/comments.php?id=5610043 Thu, 19 Jan 2012 05:00:00 +0100 5610043 http://www.medworm.com/index.php?rid=5610042&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F666%3Frss%3D1 Current factor IX (FIX) products display a half-life (t1/2) of ~ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG1, to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With ... Blood journals http://www.medworm.com/rss/comments.php?id=5610042 Thu, 19 Jan 2012 05:00:00 +0100 5610042 http://www.medworm.com/index.php?rid=5610041&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F651%3Frss%3D1 Although activity that induced tumor regression was observed and termed tumor necrosis factor (TNF) as early as the 1960s, the true identity of TNF was not clear until 1984, when Aggarwal and coworkers reported, for the first time, the isolation of 2 cytotoxic factors: one, derived from macrophages (molecular mass 17 kDa), was named TNF, and the second, derived from lymphocytes (20 kDa), was named lymphotoxin. Because the 2 cytotoxic factors exhibited 50% amino acid sequence homology and bound to the same receptor, they came to be called TNF-α and TNF-β. Identification of the protein sequences led to cloning of their cDNA. Based on sequence homology to TNF-α, now a total of 19 members of the TNF superfamily have been identified, along with 29 interacting receptors, and sev... Blood journals http://www.medworm.com/rss/comments.php?id=5610041 Thu, 19 Jan 2012 05:00:00 +0100 5610041 http://www.medworm.com/index.php?rid=5610040&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F650%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5610040 Thu, 19 Jan 2012 05:00:00 +0100 5610040 http://www.medworm.com/index.php?rid=5610039&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F648%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5610039 Thu, 19 Jan 2012 05:00:00 +0100 5610039 http://www.medworm.com/index.php?rid=5610038&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F646%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5610038 Thu, 19 Jan 2012 05:00:00 +0100 5610038 http://www.medworm.com/index.php?rid=5610037&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2F645%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5610037 Thu, 19 Jan 2012 05:00:00 +0100 5610037 http://www.medworm.com/index.php?rid=5610036&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2Fe22%3Frss%3D1 Understanding the cellular mechanisms of platelet activation and their pharmacologic modulation is of major interest for basic and clinical research. Here we introduce a comprehensive human platelet repository (PlateletWeb) for systems biologic analysis of platelets in the functional context of integrated networks. Functional, drug, and pathway associations provide a first systemic insight into various aspects of platelet functionality and pharmacologic regulation. Detailed manual curation of recent platelet proteome and transcriptome studies yielded more than 5000 platelet proteins. Integration of protein-protein interactions with kinase-substrate relationships unraveled the platelet signaling network involving more than 70% of all platelet proteins. Analysis of the platelet kinome in the... Blood journals http://www.medworm.com/rss/comments.php?id=5610036 Thu, 19 Jan 2012 05:00:00 +0100 5610036 http://www.medworm.com/index.php?rid=5610035&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F3%2Fe9%3Frss%3D1 Nodal marginal zone lymphoma (NMZL) is a small B-cell neoplasm whose molecular pathogenesis is still essentially unknown and whose differentiation from other small B-cell lymphomas is hampered by the lack of specific markers. We have analyzed gene expression, miRNA profile, and copy number data from 15 NMZL cases. For comparison, 16 follicular lymphomas (FLs), 9 extranodal marginal zone lymphomas, and 8 reactive lymph nodes and B-cell subtypes were included. The results were validated by quantitative RT-PCR in an independent series, including 61 paraffin-embedded NMZLs. NMZL signature showed an enriched expression of gene sets identifying interleukins, integrins, CD40, PI3K, NF-B, and TGF-β, and included genes expressed by normal marginal zone cells and memory B cells. The most highly... Blood journals http://www.medworm.com/rss/comments.php?id=5610035 Thu, 19 Jan 2012 05:00:00 +0100 5610035 http://www.medworm.com/index.php?rid=5583407&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F637%3Frss%3D1 While testing the effect of the (β15-66)2 fragment, which mimics a pair of fibrin βN-domains, on the morphology of endothelial cells, we found that this fragment induces redistribution of vascular endothelial–cadherin in a process that is inhibited by the receptor-associated protein (RAP). Based on this finding, we hypothesized that fibrin may interact with members of RAP-dependent low-density lipoprotein (LDL) receptor family. To test this hypothesis, we examined the interaction of (β15-66)2, fibrin, and several fibrin-derived fragments with 2 members of this family by ELISA and surface plasmon resonance. The experiments showed that very LDL (VLDL) receptor (VLDLR) interacts with high affinity with fibrin through its βN-domains, and this interaction is inhibited ... Blood journals http://www.medworm.com/rss/comments.php?id=5583407 Thu, 12 Jan 2012 05:00:00 +0100 5583407 http://www.medworm.com/index.php?rid=5583406&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F629%3Frss%3D1 The ovarian peptide hormone, relaxin, circulates during pregnancy, contributing to profound maternal vasodilation through endothelial and nitric oxide (NO)–dependent mechanisms. Circulating numbers of bone marrow–derived endothelial cells (BMDECs), which facilitate angiogenesis and contribute to repair of vascular endothelium, increase during pregnancy. Thus, we hypothesized that relaxin enhances BMDEC NO production, circulating numbers, and function. Recombinant human relaxin-2 (rhRLX) stimulated PI3K/Akt B-dependent NO production in human BMDECs within minutes, and activated BMDEC migration that was inhibited by L-NG-nitroarginine methyl ester. In BMDECs isolated from relaxin/insulin-like family peptide receptor 2 gene (Rxfp2) knockout and wild-type mice, but not Rxfp1 knocko... Blood journals http://www.medworm.com/rss/comments.php?id=5583406 Thu, 12 Jan 2012 05:00:00 +0100 5583406 http://www.medworm.com/index.php?rid=5583405&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F619%3Frss%3D1 In rodent graft-versus-host disease (GVHD) models, anti–IL-21 neutralizing mAb treatment ameliorates lethality and is associated with decreases in Th1 cytokine production and gastrointestinal tract injury. GVHD prevention was dependent on the in vivo generation of donor-inducible regulatory T cells (Tregs). To determine whether the IL-21 pathway might be targeted for GVHD prevention, skin and colon samples obtained from patients with no GVHD or grade 2 to 4 GVHD were analyzed for IL-21 protein expression. By immunohistochemistry staining, IL-21 protein-producing cells were present in all gastrointestinal tract samples and 54% of skin samples obtained from GVHD patients but not GVHD-free controls. In a human xenogeneic GVHD model, human IL-21–secreting cells were present in the ... Blood journals http://www.medworm.com/rss/comments.php?id=5583405 Thu, 12 Jan 2012 05:00:00 +0100 5583405 http://www.medworm.com/index.php?rid=5583404&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F612%3Frss%3D1 Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVIII over the entire age range was well described by a 2-compartment model and a previously reported problem, resulting from differences in blood sampling, to compare findings from children and adults wa... Blood journals http://www.medworm.com/rss/comments.php?id=5583404 Thu, 12 Jan 2012 05:00:00 +0100 5583404 http://www.medworm.com/index.php?rid=5583403&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F602%3Frss%3D1 The complex of the serine protease factor IX (FIX) and its cofactor, factor VIII (FVIII), is crucial for propagation of the intrinsic coagulation cascade. Absence of either factor leads to hemophilia, a disabling disorder marked by excessive hemorrhage after minor trauma. FVIII is the more commonly affected protein, either by X-chromosomal gene mutations or in autoimmune-mediated acquired hemophilia. Whereas substitution of FVIII is the mainstay of hemophilia A therapy, treatment of patients with inhibitory Abs remains challenging. In the present study, we report the development of FIX variants that can propagate the intrinsic coagulation cascade in the absence of FVIII. FIX variants were expressed in FVIII-knockout (FVIII-KO) mice using a nonviral gene-transfer system. Expression of the v... Blood journals http://www.medworm.com/rss/comments.php?id=5583403 Thu, 12 Jan 2012 05:00:00 +0100 5583403 http://www.medworm.com/index.php?rid=5583402&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F591%3Frss%3D1 In this study, we have therefore shown that microhomology in this area of chromosome 1 predisposes to disease associated genomic disorders and that the complement regulatory function of fH at the cell surface is critically dependent on the structural integrity of the whole molecule. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583402 Thu, 12 Jan 2012 05:00:00 +0100 5583402 http://www.medworm.com/index.php?rid=5583401&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F587%3Frss%3D1 This study highlights a role of HIF-2 in the dysregulation of iron absorption and chronic iron accumulation, as observed in patients with hemochromatosis. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583401 Thu, 12 Jan 2012 05:00:00 +0100 5583401 http://www.medworm.com/index.php?rid=5583400&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F583%3Frss%3D1 Patients with Glanzmann thrombasthenia or Leukocyte Adhesion Deficiency-III syndrome (LAD-III or LAD-1/variant) present with increased bleeding tendency because of the lack or dysfunction of the fibrinogen receptor GPIIb/IIIa (integrin αIIbβ3), respectively. Although the bleeding disorder is more severe in LAD-III patients, classic aggregometry or perfusion of Glanzmann or LAD-III platelets over collagen-coated slides under physiologic shear rate does not discriminate between these 2 conditions. However, in a novel flow cytometry-based aggregation assay, Glanzmann platelets were still capable of forming small aggregates upon collagen stimulation, whereas LAD-III platelets were not. These aggregates required functional GPIa/IIa (integrin α2β1) instead of integrin &alph... Blood journals http://www.medworm.com/rss/comments.php?id=5583400 Thu, 12 Jan 2012 05:00:00 +0100 5583400 http://www.medworm.com/index.php?rid=5583399&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F573%3Frss%3D1 In this study, we report for the first time the properties of full-length ARHGAP25 protein, and show that it is specifically expressed in hematopoietic cells, and acts as a RacGAP both in vitro and in vivo. By silencing and overexpressing the protein in neutrophil model cell lines (PLB-985 and CosPhoxFcR, respectively) and in primary macrophages, we demonstrate that ARHGAP25 is a negative regulator of phagocytosis acting probably via modulation of the actin cytoskeleton. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583399 Thu, 12 Jan 2012 05:00:00 +0100 5583399 http://www.medworm.com/index.php?rid=5583398&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F569%3Frss%3D1 SF3B1 mutations were recently reported in myelodysplastic syndromes (MDSs), especially in the presence of ring sideroblasts (RSs). We sought to define the interaction between SF3B1 mutations, morphology, karyotype, and prognosis in MDS with more than or equal to 15% RS (MDS-RS). We studied 107 patients with MDS-RS, including 48 with refractory anemia with RS (RARS), 43 with refractory cytopenia with multilineage dysplasia (RCMD)-RS, 11 with refractory anemia with excess blasts-1 (RAEB1)–RS, and 5 with RAEB2-RS. SF3B1 mutations were detected in 53 (~ 50%) patients: 35 RARS (73%), 16 RCMD-RS (37%), and 2 RAEB1-RS (18%). In univariate analysis, the presence of SF3B1 mutations was associated with better overall (P < .01) and leukemia-free (P < .01) survival; however, in both instan... Blood journals http://www.medworm.com/rss/comments.php?id=5583398 Thu, 12 Jan 2012 05:00:00 +0100 5583398 http://www.medworm.com/index.php?rid=5583397&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F559%3Frss%3D1 In conclusion, DNMT3A mutations are associated with distinct clinical and biologic features and poor prognosis in de novo AML patients. Furthermore, the DNMT3A mutation may be a potential biomarker for monitoring of minimal residual disease. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583397 Thu, 12 Jan 2012 05:00:00 +0100 5583397 http://www.medworm.com/index.php?rid=5583396&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F551%3Frss%3D1 We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK+ patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK MK+. MK+ patients were significantly older (P = .0001), had lower white blood counts (P = .0006), and lower percentages of BM blasts (P = .0004); MK was associated with the presence of –5/5q–, –7, 7q–, abnl(12p), abnl(17p), –18/18q–, –20/20q–, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)–related cytogenetic abnormalities (P < .0001, each); and NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P... Blood journals http://www.medworm.com/rss/comments.php?id=5583396 Thu, 12 Jan 2012 05:00:00 +0100 5583396 http://www.medworm.com/index.php?rid=5583395&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F540%3Frss%3D1 Pancytopenia is a major cause of morbidity in acute myeloid leukemia (AML), yet its cause is unclear. Normal osteoblastic cells have been shown to support hematopoiesis. To define the effects of leukemia on osteoblastic cells, we used an immunocompetent murine model of AML. Leukemic mice had inhibition of osteoblastic cells, with decreased serum levels of the bone formation marker osteocalcin. Osteoprogenitor cells and endosteal-lining osteopontin+ cells were reduced, and osteocalcin mRNA in CD45– marrow cells was diminished. This resulted in severe loss of mineralized bone. Osteoclasts were only transiently increased without significant increases in bone resorption, and their inhibition only partially rescued leukemia-induced bone loss. In vitro data suggested that a leukemia-derive... Blood journals http://www.medworm.com/rss/comments.php?id=5583395 Thu, 12 Jan 2012 05:00:00 +0100 5583395 http://www.medworm.com/index.php?rid=5583394&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F530%3Frss%3D1 BCR-ABL overexpression and stem cell quiescence supposedly contribute to the failure of imatinib mesylate (IM) to eradicate chronic myeloid leukemia (CML). However, BCR-ABL expression levels of persisting precursors and the impact of long-term IM therapy on the clearance of CML from primitive and mature bone marrow compartments are unclear. Here, we have shown that the number of BCR-ABL–positive precursors decreases significantly in all bone marrow compartments during major molecular remission (MMR). More importantly, we were able to demonstrate substantially lower BCR-ABL expression levels in persisting MMR colony-forming units (CFUs) compared with CML CFUs from diagnosis. Critically, lower BCR-ABL levels may indeed cause IM insensitivity, because primary murine bone marrow cells en... Blood journals http://www.medworm.com/rss/comments.php?id=5583394 Thu, 12 Jan 2012 05:00:00 +0100 5583394 http://www.medworm.com/index.php?rid=5583393&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F521%3Frss%3D1 Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were used as training (n = 309) and validation (n = 230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P < .001). Multivariate analysis selected NOTCH1 mutations as an independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1 mutations was externally confirmed... Blood journals http://www.medworm.com/rss/comments.php?id=5583393 Thu, 12 Jan 2012 05:00:00 +0100 5583393 http://www.medworm.com/index.php?rid=5583392&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F513%3Frss%3D1 HGAL, a prognostic biomarker in patients with diffuse large B-cell lymphoma and classic Hodgkin lymphoma, inhibits lymphocyte and lymphoma cell motility by activating the RhoA signaling cascade and interacting with actin and myosin proteins. Although HGAL expression is limited to germinal center (GC) lymphocytes and GC-derived lymphomas, little is known about its regulation. miR-155 is implicated in control of GC reaction and lymphomagenesis. We demonstrate that miR-155 directly down-regulates HGAL expression by binding to its 3'-untranslated region, leading to decreased RhoA activation and increased spontaneous and chemoattractant-induced lymphoma cell motility. The effects of miR-155 on RhoA activation and cell motility can be rescued by transfection of HGAL lacking the miR-155 binding s... Blood journals http://www.medworm.com/rss/comments.php?id=5583392 Thu, 12 Jan 2012 05:00:00 +0100 5583392 http://www.medworm.com/index.php?rid=5583391&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F503%3Frss%3D1 IL-6 signaling can be enhanced through transsignaling by the soluble IL-6 receptor (sIL-6r), allowing for the pleiotropic cytokine to affect cells it would not ordinarily have an effect on. Serum levels of sIL-6r can be used as an independent prognostic indicator and further stratify the GEP 70-gene low-risk group to identify an intermediate-risk group in multiple myeloma (MM). By analyzing more than 600 MM patients with ELISA, genotyping, and gene expression profiling tools, we show how the combination of 2 independent molecular genetic events is related to synergistic increases in sIL-6r levels. We also show that the rs2228145 minor allele is related to increased expression levels of an IL-6r splice variant that purportedly codes exclusively for a sIL-6r isoform. Together, the SNP rs2228... Blood journals http://www.medworm.com/rss/comments.php?id=5583391 Thu, 12 Jan 2012 05:00:00 +0100 5583391 http://www.medworm.com/index.php?rid=5583390&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F494%3Frss%3D1 We report that Bmi1 transforms and reprograms CML B-lymphoid progenitors into stem cell leukemia (Scl) promoter-driven, self-renewing, leukemia-initiating cells to result in B-lymphoid leukemia (B-ALL) in vivo. In vitro, highly proliferating and serially replatable myeloid and lymphoid colony-forming cultures could be established from BCR-ABL and Bmi1 coexpressing progenitors. However, unlike in vivo expanded CML B-lymphoid progenitors, hematopoietic stem cells, or multipotent progenitors, coexpressing BCR-ABL and Bmi1 did not initiate or propagate leukemia in a limiting dilution assay. Inducible genetic attenuation of BCR-ABL reversed Bmi1-driven B-ALL development, which was accompanied by induction of apoptosis of leukemic B-lymphoid progenitors and by long-term animal survival, suggesti... Blood journals http://www.medworm.com/rss/comments.php?id=5583390 Thu, 12 Jan 2012 05:00:00 +0100 5583390 http://www.medworm.com/index.php?rid=5583389&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F488%3Frss%3D1 This study evaluated immunohistochemistry as a diagnostic tool for the differentiation of amyloid subentities, which is warranted for accurate treatment. A total of 117 patients were systematically investigated by clinical examination, laboratory tests, genotyping, and immunohistochemistry on biopsy specimens. Immunohistochemistry enabled the classification in 94% of the cases. For subsequent analysis, the patient population was divided into 2 groups. The first group included all patients whose diagnosis could be verified by typical clinical signs or an inherited amyloidogenic mutation. In this group, immunohistochemical subtyping was successful in 49 of 51 cases and proved accurate in each of the 49 cases, corresponding to a sensitivity of 96% and a specificity of 100%. The second group i... Blood journals http://www.medworm.com/rss/comments.php?id=5583389 Thu, 12 Jan 2012 05:00:00 +0100 5583389 http://www.medworm.com/index.php?rid=5583388&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F476%3Frss%3D1 The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and antiapoptotic signaling in lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are usually partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing divers lymphoid malignancies. In contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analy... Blood journals http://www.medworm.com/rss/comments.php?id=5583388 Thu, 12 Jan 2012 05:00:00 +0100 5583388 http://www.medworm.com/index.php?rid=5583387&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F469%3Frss%3D1 Nodular sclerosing Hodgkin lymphoma (NSHL) is a distinct, highly heritable Hodgkin lymphoma subtype. We undertook a genome-wide meta-analysis of 393 European-origin adolescent/young adult NSHL patients and 3315 controls using the Illumina Human610-Quad Beadchip and Affymetrix Genome-Wide Human SNP Array 6.0. We identified 3 single nucleotide polymorphisms (SNPs) on chromosome 6p21.32 that were significantly associated with NSHL risk: rs9268542 (P = 5.35 x 10–10), rs204999 (P = 1.44 x 10–9), and rs2858870 (P = 1.69 x 10–8). We also confirmed a previously reported association in the same region, rs6903608 (P = 3.52 x 10–10). rs204999 and rs2858870 were weakly correlated (r2 = 0.257), and the remaining pairs of SNPs were not correlated (r2 < 0.1). In an independent ... Blood journals http://www.medworm.com/rss/comments.php?id=5583387 Thu, 12 Jan 2012 05:00:00 +0100 5583387 http://www.medworm.com/index.php?rid=5583386&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F465%3Frss%3D1 The splenic marginal zone (MZ) is comprised of specialized populations of B cells, dendritic cells, and macrophages that are uniquely arrayed outside the white pulp follicles to screen the blood for bacterial and other particulate Ags. Mechanisms responsible for MZ B-cell formation, localization, retention, and function are understood to include antigenic specificity, transcription factors, integrins, and surface receptors for soluble ligands such as S1P. Here, we add to this repertoire by demonstrating that the receptor for CXCL12, CXCR7, is expressed on MZ but not on follicular B cells. Treatment of mice with CXCR7 inhibitors led to disruption of MZ architecture, reduced numbers of MZ B cells, and altered granulocyte homeostasis associated with increasing serum levels of CXCL12. CXCR7 th... Blood journals http://www.medworm.com/rss/comments.php?id=5583386 Thu, 12 Jan 2012 05:00:00 +0100 5583386 http://www.medworm.com/index.php?rid=5583385&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F454%3Frss%3D1 Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFN-α/β) in response to viral or endogenous nucleic acids through activation of their endosomal Toll-like receptors (TLR-7 and TLR-9). Enhanced TLR-7–mediated IFN-α production by pDCs in women, compared with men, has been reported, but whether sex hormones, such as estrogens, are involved in this sex-based difference is unknown. Here we show, in humanized mice, that the TLR-7–mediated response of human pDCs is increased in female host mice relative to male. In a clinical trial, we establish that treatment of postmenopausal women with 17β-estradiol markedly enhances TLR-7– and TLR-9–dependent production of IFN-α by pDCs stimulated by synthetic ligands or by nu... Blood journals http://www.medworm.com/rss/comments.php?id=5583385 Thu, 12 Jan 2012 05:00:00 +0100 5583385 http://www.medworm.com/index.php?rid=5583384&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F445%3Frss%3D1 ERM (ezrin, radixin moesin) proteins in lymphocytes link cortical actin to plasma membrane, which is regulated in part by ERM protein phosphorylation. To assess whether phosphorylation of ERM proteins regulates lymphocyte migration and membrane tension, we generated transgenic mice whose T-lymphocytes express low levels of ezrin phosphomimetic protein (T567E). In these mice, T-cell number in lymph nodes was reduced by 27%. Lymphocyte migration rate in vitro and in vivo in lymph nodes decreased by 18% to 47%. Lymphocyte membrane tension increased by 71%. Investigations of other possible underlying mechanisms revealed impaired chemokine-induced shape change/lamellipod extension and increased integrin-mediated adhesion. Notably, lymphocyte homing to lymph nodes was decreased by 30%. Unlike mo... Blood journals http://www.medworm.com/rss/comments.php?id=5583384 Thu, 12 Jan 2012 05:00:00 +0100 5583384 http://www.medworm.com/index.php?rid=5583383&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F434%3Frss%3D1 This study shows that HBZ inhibits CD4 T-cell responses by directly interfering with the host cell-signaling pathway, resulting in impaired cell-mediated immunity in vivo. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583383 Thu, 12 Jan 2012 05:00:00 +0100 5583383 http://www.medworm.com/index.php?rid=5583382&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F422%3Frss%3D1 Human mucosal associated invariant T (MAIT) CD8+ and Tc17 cells are important tissue-homing cell populations, characterized by high expression of CD161 (++) and type-17 differentiation, but their origins and relationships remain poorly defined. By transcriptional and functional analyses, we demonstrate that a pool of polyclonal, precommitted type-17 CD161++CD8αβ+ T cells exist in cord blood, from which a prominent MAIT cell (TCR Vα7.2+) population emerges post-natally. During this expansion, CD8αα T cells appear exclusively within a CD161++CD8+/MAIT subset, sharing cytokine production, chemokine-receptor expression, TCR-usage, and transcriptional profiles with their CD161++CD8αβ+ counterparts. Our data demonstrate the origin and differentiation pathw... Blood journals http://www.medworm.com/rss/comments.php?id=5583382 Thu, 12 Jan 2012 05:00:00 +0100 5583382 http://www.medworm.com/index.php?rid=5583381&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F411%3Frss%3D1 In response to microenvironmental signals, macrophages undergo different activation, including the "classic" proinflammatory phenotype (also called M1), the "alternative" activation induced by the IL-4/IL-13 trigger, and the related but distinct heterogeneous M2 polarization associated with the anti-inflammatory profile. The latter is induced by several stimuli, including IL-10 and TGF-β. Macrophage-polarized activation has profound effects on immune and inflammatory responses and in tumor biology, but information on the underlying molecular pathways is scarce. In the present study, we report that alternative polarization of macrophages requires the transcription factor c-MYC. In macrophages, IL-4 and different stimuli sustaining M2-like polarization induce c-MYC expression and its tr... Blood journals http://www.medworm.com/rss/comments.php?id=5583381 Thu, 12 Jan 2012 05:00:00 +0100 5583381 http://www.medworm.com/index.php?rid=5583380&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F399%3Frss%3D1 In this study, we analyzed the development of NK cells after intrabone umbilical cord blood (CB) transplantation in 18 adult patients with hematologic malignancies. Our data indicate that, also in this transplantation setting, NK cells are the first lymphoid population detectable in peripheral blood. However, different patterns of NK-cell development could be identified. Indeed, in a group of patients, a relevant fraction of NK cells expressed a mature phenotype characterized by the KIR+NKG2A– signature 3-6 months after transplantation. In other patients, most NK cells maintained an immature phenotype even after 12 months. A possible role for cytomegalovirus in the promotion of NK-cell development was suggested by the observation that a more rapid NK-cell maturation together with exp... Blood journals http://www.medworm.com/rss/comments.php?id=5583380 Thu, 12 Jan 2012 05:00:00 +0100 5583380 http://www.medworm.com/index.php?rid=5583379&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F388%3Frss%3D1 The clustered homeobox proteins play crucial roles in development, hematopoiesis, and leukemia, yet the targets they regulate and their mechanisms of action are poorly understood. Here, we identified the binding sites for Hoxa9 and the Hox cofactor Meis1 on a genome-wide level and profiled their associated epigenetic modifications and transcriptional targets. Hoxa9 and the Hox cofactor Meis1 cobind at hundreds of highly evolutionarily conserved sites, most of which are distant from transcription start sites. These sites show high levels of histone H3K4 monomethylation and CBP/P300 binding characteristic of enhancers. Furthermore, a subset of these sites shows enhancer activity in transient transfection assays. Many Hoxa9 and Meis1 binding sites are also bound by PU.1 and other lineage-rest... Blood journals http://www.medworm.com/rss/comments.php?id=5583379 Thu, 12 Jan 2012 05:00:00 +0100 5583379 http://www.medworm.com/index.php?rid=5583378&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F377%3Frss%3D1 Hematopoietic stem/progenitor cell (HSPC) traits differ between genetically distinct mouse strains. For example, DBA/2 mice have a higher HSPC frequency compared with C57BL/6 mice. We performed a genetic screen for micro-RNAs that are differentially expressed between LSK, LS–K+, erythroid and myeloid cells isolated from C57BL/6 and DBA/2 mice. This analysis identified 131 micro-RNAs that were differentially expressed between cell types and 15 that were differentially expressed between mouse strains. Of special interest was an evolutionary conserved miR cluster located on chromosome 17 consisting of miR-99b, let-7e, and miR-125a. All cluster members were most highly expressed in LSKs and down-regulated upon differentiation. In addition, these microRNAs were higher expressed in DBA/2 c... Blood journals http://www.medworm.com/rss/comments.php?id=5583378 Thu, 12 Jan 2012 05:00:00 +0100 5583378 http://www.medworm.com/index.php?rid=5583377&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F368%3Frss%3D1 In this study, we examined the feasibility of adoptive therapy using redirected T cells expressing an HLA-A*0201–restricted AURKA207-215-specific T-cell receptor (TCR). Retrovirally transduced T cells recognized relevant peptide-pulsed but not control target cells. Furthermore, TCR-redirected CD8+ T cells lysed AURKA-overexpressing human leukemic cells in an HLA-A*0201–restricted manner, but did not kill HLA-A*0201+ normal cells, including hematopoietic progenitors. In addition, AURKA207-215-specific TCR-transduced CD4+ T cells displayed target-responsive Th1 cytokine production. Finally, AURKA207-215-specific TCR-transduced CD8+ T cells displayed antileukemia efficacy in a xenograft mouse model. Collectively, these data demonstrate the feasibility of redirected T cell–ba... Blood journals http://www.medworm.com/rss/comments.php?id=5583377 Thu, 12 Jan 2012 05:00:00 +0100 5583377 http://www.medworm.com/index.php?rid=5583376&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F364%3Frss%3D1 To evaluate the association between fetal hemoglobin (HbF) levels and morbidity in β-thalassemia intermedia (TI), we analyzed data from 63 untransfused patients who had also never received HbF induction therapy. Patient records were reviewed for any history of 10 predefined morbidities. Laboratory measurements for markers of ineffective erythropoiesis were also obtained. The mean age of patients was 32.1 years, 47.6% were males, and the median HbF level was 37.2%. HbF levels correlated positively with total hemoglobin, yet negatively with growth differentiation factor-15 and non–transferrin-bound iron levels. Median HbF levels were significantly lower in patients with the majority of evaluated morbidities than in those without. There was a strong negative adjusted linear correla... Blood journals http://www.medworm.com/rss/comments.php?id=5583376 Thu, 12 Jan 2012 05:00:00 +0100 5583376 http://www.medworm.com/index.php?rid=5583375&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F355%3Frss%3D1 This study is registered at www.clinicaltrials.gov as NCT00226993. (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583375 Thu, 12 Jan 2012 05:00:00 +0100 5583375 http://www.medworm.com/index.php?rid=5583374&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F345%3Frss%3D1 Antithymocyte globulin (ATG) + cyclosporine is effective in restoring hematopoiesis in severe aplastic anemia (SAA). We hypothesized that the humanized anti-CD52 mAb alemtuzumab might be active in SAA because of its lymphocytotoxic properties. We investigated alemtuzumab monotherapy from 2003-2010 in treatment-naive, relapsed, and refractory SAA in 3 separate research protocols at the National Institutes of Health. Primary outcome was hematologic response at 6 months. For refractory disease, patients were randomized between rabbit ATG + cyclosporine (n = 27) and alemtuzumab (n = 27); the response rate for alemtuzumab was 37% (95% confidence interval [CI], 18%-57%) and for rabbit ATG 33% (95% CI, 14%-52%; P = .78). The 3-year survival was 83% (95% CI, 68%-99%) for alemtuzumab and 60% (95% C... Blood journals http://www.medworm.com/rss/comments.php?id=5583374 Thu, 12 Jan 2012 05:00:00 +0100 5583374 http://www.medworm.com/index.php?rid=5583373&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F342%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583373 Thu, 12 Jan 2012 05:00:00 +0100 5583373 http://www.medworm.com/index.php?rid=5583372&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F332%3Frss%3D1 The choice of either induction or postremission therapy for adults with acute myeloid leukemia is still largely based on the "one size fits all" principle. Moreover, pretreatment prognostic parameters, especially chromosome and gene abnormalities, may fail in predicting individual patient outcome. Measurement of minimal residual disease (MRD) is nowadays recognized as a potential critical tool to assess the quality of response after chemotherapy and to plan postremission strategies that are, therefore, driven by the individual risk of relapse. PCR and multiparametric flow cytometry have become the most popular methods to investigate MRD because they have been established as sensitive and specific enough to allow MRD to be studied serially. In the present review, we examine the evidence sup... Blood journals http://www.medworm.com/rss/comments.php?id=5583372 Thu, 12 Jan 2012 05:00:00 +0100 5583372 http://www.medworm.com/index.php?rid=5583371&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F329%3Frss%3D1 Two recent studies reported wholegenome sequencing of chronic lymphocytic leukemia (CLL) samples and found repeated mutations in the XPO1 and NOTCH1 genes. XPO1 was found mutated in 2.4% of cases, while NOTCH1 was found mutated in 12.2% or 15.1% of CLL samples. Here we report the results of sequencing of XPO1 and NOTCH1 in 186 CLL cases. Our results confirmed frequency of XPO1 mutations. However, we found only 5 NOTCH1 mutations in 127 IGVH unmutated/ZAP70+ CLL samples (4%), and one mutation was found in IGVH mutated/ZAP70– CLL for a total percentage of 1.5%. Because 4 of 6 mutated samples also showed trisomy 12, we sequenced NOTCH1 in an additional 77 cases with trisomy 12 CLLs, including 47 IGVH unmutated/ZAP70+ cases. Importantly, we found 41.9% NOTCH1 mutation frequency in aggres... Blood journals http://www.medworm.com/rss/comments.php?id=5583371 Thu, 12 Jan 2012 05:00:00 +0100 5583371 http://www.medworm.com/index.php?rid=5583370&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F328%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583370 Thu, 12 Jan 2012 05:00:00 +0100 5583370 http://www.medworm.com/index.php?rid=5583369&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F326%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583369 Thu, 12 Jan 2012 05:00:00 +0100 5583369 http://www.medworm.com/index.php?rid=5583368&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F325%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583368 Thu, 12 Jan 2012 05:00:00 +0100 5583368 http://www.medworm.com/index.php?rid=5583367&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F323%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583367 Thu, 12 Jan 2012 05:00:00 +0100 5583367 http://www.medworm.com/index.php?rid=5583366&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F322%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583366 Thu, 12 Jan 2012 05:00:00 +0100 5583366 http://www.medworm.com/index.php?rid=5583365&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2F321%3Frss%3D1 (Source: Blood) Blood journals http://www.medworm.com/rss/comments.php?id=5583365 Thu, 12 Jan 2012 05:00:00 +0100 5583365 http://www.medworm.com/index.php?rid=5583364&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F2%2Fe1%3Frss%3D1 Infection of erythrocytes with the human malaria parasite, Plasmodium falciparum, results in dramatic changes to the host cell structure and morphology. The predicted functional localization of the STEVOR proteins at the erythrocyte surface suggests that they may be involved in parasite-induced modifications of the erythrocyte membrane during parasite development. To address the biologic function of STEVOR proteins, we subjected a panel of stevor transgenic parasites and wild-type clonal lines exhibiting different expression levels for stevor genes to functional assays exploring parasite-induced modifications of the erythrocyte membrane. Using this approach, we show that stevor expression impacts deformability of the erythrocyte membrane. This process may facilitate parasite sequestration ... Blood journals http://www.medworm.com/rss/comments.php?id=5583364 Thu, 12 Jan 2012 05:00:00 +0100 5583364 http://www.medworm.com/index.php?rid=5561302&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F1%2F308%3Frss%3D1 Increased endothelial permeability contributes to the morbidity and mortality associated with chronic inflammatory diseases, including acute lung injury. Cyclic AMP response element-binding protein (CREB) transcriptional factor induces genes that regulate inflammation and vascular remodeling. However, the role of CREB in regulating endothelial barrier function is unknown. Here, we demonstrate that CREB maintains basal endothelial barrier function and suppresses endothelial permeability increase by diverse agonists such as thrombin, lipopolysaccharide, histamine, and VEGF. We show that CREB transcriptionally controls the expression of p190RhoGAP-A, a GTPase-activating protein that inhibits small GTPase RhoA. Impairing CREB function using small interfering RNA or dominant-negative (dn)&ndash... Blood journals http://www.medworm.com/rss/comments.php?id=5561302 Thu, 05 Jan 2012 05:00:00 +0100 5561302 http://www.medworm.com/index.php?rid=5561301&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F1%2F296%3Frss%3D1 Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (9... Blood journals http://www.medworm.com/rss/comments.php?id=5561301 Thu, 05 Jan 2012 05:00:00 +0100 5561301 http://www.medworm.com/index.php?rid=5561300&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F1%2F285%3Frss%3D1 Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-–deficient and IL-17–deficient mice as donors. Infusion of IFN-–/– or IL... Blood journals http://www.medworm.com/rss/comments.php?id=5561300 Thu, 05 Jan 2012 05:00:00 +0100 5561300 http://www.medworm.com/index.php?rid=5561299&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F1%2F273%3Frss%3D1 Among hematologic neoplasms, chronic myeloid leukemia (CML) is exquisitely sensitive to graft-versus-leukemia (GVL) because patients relapsing after allogeneic hematopoietic stem-cell transplantation (alloHSCT) can be cured by donor leukocyte infusion (DLI); however, the cellular mechanisms and strategies to separate GVL from GVHD are unclear. We used a BCR-ABL1 transduction/transplantation mouse model to study the mechanisms of DLI in MHC-matched, minor histocompatibility antigen–mismatched allogeneic chimeras with CML-like leukemia, in which DLI can be administered at the time of transplantation (early) or after recovery of hematopoiesis (delayed). After early DLI, CML-like leukemia cannot be transferred into immunocompetent secondary recipients as soon as 4 days after primary tran... Blood journals http://www.medworm.com/rss/comments.php?id=5561299 Thu, 05 Jan 2012 05:00:00 +0100 5561299 http://www.medworm.com/index.php?rid=5561298&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F1%2F262%3Frss%3D1 Diamond-Blackfan anemia (DBA) is associated with developmental defects and profound anemia. Mutations in genes encoding a ribosomal protein of the small (eg, RPS19) or large (eg, RPL11) ribosomal subunit are found in more than half of these patients. The mutations cause ribosomal haploinsufficiency, which reduces overall translation efficiency of cellular mRNAs. We reduced the expression of Rps19 or Rpl11 in mouse erythroblasts and investigated mRNA polyribosome association, which revealed deregulated translation initiation of specific transcripts. Among these were Bag1, encoding a Hsp70 cochaperone, and Csde1, encoding an RNA-binding protein, and both were expressed at increased levels in erythroblasts. Their translation initiation is cap independent and starts from an internal ribosomal ... Blood journals http://www.medworm.com/rss/comments.php?id=5561298 Thu, 05 Jan 2012 05:00:00 +0100 5561298 http://www.medworm.com/index.php?rid=5561297&cid=s_29474_19_f&fid=29474&url=http%3A%2F%2Fbloodjournal.hematologylibrary.org%2Fcgi%2Fcontent%2Fshort%2F119%2F1%2F251%3Frss%3D1 Platelets are activated on increase of cytosolic Ca2+ activity ([Ca2+]i), accomplished by store-operated Ca2+ entry (SOCE) involving the pore-forming ion channel subunit Orai1. Here, we show, for the first time, that the serum- and glucocorticoid-inducible kinase 1 (SGK1) is expressed in platelets and megakaryocytes. SOCE and agonist-induced [Ca2+]i increase are significantly blunted in platelets from SGK1 knockout mice (sgk1–/–). Similarly, Ca2+-dependent degranulation, integrin αIIbβ3 activation, phosphatidylserine exposure, aggregation, and in vitro thrombus formation were significantly impaired in sgk1–/– platelets, whereas tail bleeding time was not significantly enhanced. Platelet and megakaryocyte Orai1 transcript levels and membrane protein abunda... Blood journals http://www.medworm.com/rss/comments.php?id=5561297 Thu, 05 Jan 2012 05:00:00 +0100 5561297