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Blood

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https://www.readbyqxmd.com/read/28729433/selective-factor-viii-activation-by-the-tissue-factor-factor-viia-factor-xa-complex
#1
Yuichi Kamikubo, G Loredana Mendolicchio, Antonella Zampolli, Patrizia Marchese, Andrea S Rothmeier, Jennifer Nagrampa Orje, Andrew J Gale, Sriram Krishnaswamy, András Gruber, Henrik Østergaard, Lars C Petersen, Wolfram Ruf, Zaverio M Ruggeri
Safe and effective antithrombotic therapy requires understanding of mechanisms that contribute to pathological thrombosis but have lesser impact on hemostasis. We found that the extrinsic tissue factor (TF) coagulation initiation complex can selectively activate the anti-hemophilic cofactor, FVIII, triggering the hemostatic intrinsic coagulation pathway independently of thrombin feedback loops. In a mouse model with a relatively mild thrombogenic lesion, TF-dependent FVIII activation sets the threshold for thrombus formation through contact phase-generated FIXa...
July 20, 2017: Blood
https://www.readbyqxmd.com/read/28729432/tropomodulin1-controls-erythroblast-enucleation-via-regulation-of-f-actin-in-the-enucleosome
#2
Roberta B Nowak, Julien Papoin, David S Gokhin, Carla Casu, Stefano Rivella, Jeffrey M Lipton, Lionel Blanc, Velia M Fowler
Biogenesis of mammalian red blood cells requires nuclear expulsion by orthochromatic erythoblasts late in terminal differentiation (enucleation), but the mechanism is largely unexplained. Here, we employed high resolution confocal microscopy to analyze nuclear morphology and F-actin rearrangements during the initiation, progression and completion of mouse and human erythroblast enucleation in vivo Mouse erythroblast nuclei acquire a dumbbell-shaped morphology during enucleation, while human bone marrow erythroblast nuclei unexpectedly retain their spherical morphology...
July 20, 2017: Blood
https://www.readbyqxmd.com/read/28724541/stim1-and-stim2-cooperatively-regulate-mouse-neutrophil-store-operated-calcium-entry-and-cytokine-production
#3
Regina A Clemens, Joshua Chong, Derayvia Grimes, Yongmei Hu, Clifford A Lowell
Neutrophils are key effector cells of the innate immune system. Calcium-dependent signaling pathways initiated by store-operated calcium entry (SOCE) are known to regulate neutrophil activation, however the precise mechanism of this process remains unclear. STIM1 and STIM2 are calcium sensing molecules that link calcium depletion of the endoplasmic reticulum with opening of plasma membrane calcium channels. While a role for STIM1 in neutrophil SOCE and activation has been established, the function of STIM2 is unknown...
July 19, 2017: Blood
https://www.readbyqxmd.com/read/28724540/targeting-bcl-2-in-b-cell-lymphomas
#4
Matthew S Davids
The B-cell leukemia/lymphoma-2 (BCL-2) family of proteins governs the intrinsic pathway of mitochondrial apoptosis. Dysregulation of BCL-2 has long been known to be a crucial part of the pathophysiology of B-cell lymphomas, yet several early attempts to target this pathway therapeutically were unsuccessful due to toxicity, lack of efficacy, or both. Recently, a highly potent and selective oral BCL-2 antagonist, venetoclax, was approved in chronic lymphocytic leukemia (CLL), where it has proven to be highly active, even in patients with high risk del(17p) disease...
July 19, 2017: Blood
https://www.readbyqxmd.com/read/28724539/racial-and-ethnic-disparities-in-hematologic-malignancies
#5
Kedar Kirtane, Stephanie J Lee
Racial and ethnic disparities in patients with solid malignancies have been well documented. Less is known about these disparities in patients with hematologic malignancies. With the advent of novel chemotherapeutics and targeted molecular, cellular, and immunologic therapies, it is important to identify differences in care that may lead to disparate outcomes. This review provides a critical appraisal of the empirical research on racial and ethnic disparities in incidence, survival, and outcomes in patients with hematologic malignancies...
July 19, 2017: Blood
https://www.readbyqxmd.com/read/28720587/platelet-soluble-cd40-ligand-level-is-associated-with-transfusion-adverse-reactions-in-a-mixed-threshold-and-hit-model
#6
Fabrice Cognasse, Caroline Sut, Elisa Fromont, Sandrine Laradi, Hind Hamzeh-Cognasse, Olivier Garraud
No abstract text is available yet for this article.
July 18, 2017: Blood
https://www.readbyqxmd.com/read/28720586/a-malt-lymphoma-prognostic-index-generated-from-the-dataset-of-the-ielsg-19-prospective-clinical-trial
#7
Catherine Thieblemont, Luciano Cascione, Annarita Conconi, Barbara Kiesewetter, Markus Raderer, Gianluca Gaidano, Maurizio Martelli, Daniele Laszlo, Bertrand Coiffier, Armando Lopez Guillermo, Valter Torri, Franco Cavalli, Peter W Johnson, Emanuele Zucca
There are no widely accepted prognostic indices for extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). This study aimed to develop and validate a specific prognostic tool to personalize and optimize lymphoma treatment of patients with MALT lymphoma. A prognostic index was built by Cox regression (stepwise selection) using data from 401 patients enrolled in the international randomized IELSG-19 trial (NCT 00210353). A validation set, including 633 patients, was obtained by merging three independent cohorts of MALT lymphoma patients...
July 18, 2017: Blood
https://www.readbyqxmd.com/read/28716862/gene-therapy-for-wiskott-aldrich-syndrome-in-a-severely-affected-adult
#8
Emma C Morris, Thomas Fox, Ronjon Chakraverty, Rita Tendeiro, Katie Snell, Christine Rivat, Sarah Grace, Kimberly Gilmour, Sarita Workman, Karen Buckland, Katie Butler, Ronnie Chee, Alan D Salama, Hazem Ibrahim, Havinder Hara, Cecile Duret, Fulvio Mavilio, Frances Male, Frederick D Bushman, Anne Galy, Siobhan O Burns, H Bobby Gaspar, Adrian J Thrasher
Until recently hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a ϒ-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harbouring integrations near oncogenes...
July 17, 2017: Blood
https://www.readbyqxmd.com/read/28716861/allogeneic-hematopoietic-cell-transplantation-for-high-risk-cll-10-year-follow-up-of-the-gcllsg-cll3x-trial
#9
Isabelle Krämer, Stephan Stilgenbauer, Sascha Dietrich, Sebastian Böttcher, Matthias Zeis, Michael Stadler, Jörg Bittenbring, Lutz Uharek, Christof Scheid, Ute Hegenbart, Anthony Ho, Michael Hallek, Michael Kneba, Norbert Schmitz, Hartmut Döhner, Peter Dreger
No abstract text is available yet for this article.
July 17, 2017: Blood
https://www.readbyqxmd.com/read/28716860/novel-mechanisms-of-piezo1-dysfunction-in-hereditary-xerocytosis
#10
Edyta Glogowska, Eve R Schneider, Yelena Maksimova, Vincent P Schulz, Kimberly Lezon-Geyda, John Wu, Kottayam Radhakrishnan, Siobán B Keel, Donald Mahoney, Alison M Freidmann, Rachel A Altura, Elena O Gracheva, Sviatoslav N Bagriantsev, Theodosia A Kalfa, Patrick G Gallagher
Mutations in PIEZO1 are the primary cause of hereditary xerocytosis, a clinically heterogeneous, dominantly inherited disorder of erythrocyte dehydration. We utilized next generation sequencing-based techniques to identify PIEZO1 mutations in individuals from 9 kindreds referred with suspected HX and/or undiagnosed congenital hemolytic anemia. Mutations were primarily found in the highly conserved, COOH-terminal pore region domain. Several mutations were novel and demonstrated ethnic specificity. We characterized these mutations using genomic, bioinformatic, cell biology, and physiology-based functional assays...
July 17, 2017: Blood
https://www.readbyqxmd.com/read/28710059/a-foxo1-induced-oncogenic-network-defines-the-aml1-eto-pre-leukemic-program
#11
Shan Lin, Anetta Ptasinska, Xiaoting Chen, Mahesh Shrestha, Salam A Assi, Paulynn S Chin, Maria R Imperato, Bruce Aronow, Jingsong Zhang, Matthew T Weirauch, Constanze Bonifer, James C Mulloy
Understanding and blocking the self-renewal pathway of pre-leukemia stem cells could prevent acute myeloid leukemia (AML) relapse. In this study we show that increased FOXO1 represents a critical mechanism driving aberrant self-renewal in pre-leukemic cells expressing the t(8;21)-associated oncogene AML1-ETO (AE). Though generally considered as a tumor suppressor, FOXO1 is consistently upregulated in t(8;21) AML. Expression of FOXO1 in human CD34+ cells promotes a pre-leukemic state with enhanced self-renewal and dysregulated differentiation...
July 14, 2017: Blood
https://www.readbyqxmd.com/read/28705839/circulating-dsdna-endothelial-injury-and-complement-activation-in-thrombotic-microangiopathy-and-gvhd
#12
Nicholas J Gloude, Pooja Khandelwal, Nathan Luebbering, Dana T Lounder, Sonata Jodele, Matthew N Alder, Adam Lane, Alyss Wilkey, Kelly E Lake, Bridget Litts, Stella M Davies
TA-TMA is a common and poorly recognized complication of HSCT associated with excessive complement activation, likely triggered by endothelial injury. An important missing piece is the link between endothelial injury and complement activation. We hypothesized that neutrophil extracellular traps (NETs) mechanistically link endothelial damage with complement activation and subsequent TA-TMA. Neutrophil activation releases granule proteins together with double stranded DNA (dsDNA), to form extracellular fibers known as NETs...
July 13, 2017: Blood
https://www.readbyqxmd.com/read/28705838/leukofiltration-plus-pathogen-reduction-prevents-alloimmune-platelet-refractoriness-in-a-dog-transfusion-model
#13
Sherrill J Slichter, Esther Pellham, S Lawrence Bailey, Todd Christoffel, Irena Gettinger, Lakshmi Gaur, Yvette Latchman, Karen Nelson, Doug Bolgiano
Human Lymphocyte Antigen (HLA) alloimmunization to filter leukoreduced (F-LR) platelets occurs in about 18% of immunosuppressed thrombocytopenic hematology/oncology patients and represents a significant challenge for effective chemotherapy. In a dog platelet transfusion model, we have evaluated other methods of preventing alloimmune platelet refractoriness and demonstrated that successful methods in our dog model are transferable to man. In the present study, donor/recipient pairs were dog lymphocyte antigen (DLA) DR-B incompatible (88% of the pairs), and recipient dogs received up to 8 weekly treated transfusions from a single donor (a highly immunogenic stimulus), or until platelet refractoriness...
July 13, 2017: Blood
https://www.readbyqxmd.com/read/28701367/a-fdg-pet-driven-consolidation-strategy-in-diffuse-large-b-cell-lymphoma-final-results-of-a-randomized-phase-ii-study
#14
Rene-Olivier Casasnovas, Loic Ysebaert, Catherine Thieblemont, Emmanuel Bachy, Pierre Feugier, Alain Delmer, Sabine Tricot, Jean Gabarre, Marc Andre, Christophe Fruchart, Nicolas Mounier, Richard Delarue, Michel Meignan, Alina Berriolo-Riedinger, Stephane Bardet, Jean-Francois Emile, Jean-Philippe Jais, Corinne Haioun, Herve Tilly, Franck Morschhauser
Dose-dense induction and upfront consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating high-risk diffuse large B cell lymphoma patients. GELA designed a randomized phase II trial evaluating the efficacy of either R-ACVBP or R-CHOP14 induction and a PET-driven ASCT or standard immunochemotherapy (SIC) consolidation in aaIPI2-3 patients. PET was done at baseline, after 2 (PET2) and 4 induction cycles (PET4) and centrally assessed using international harmonization project (IHP) criteria...
July 12, 2017: Blood
https://www.readbyqxmd.com/read/28698207/strict-tropism-for-cd71-cd234-human-reticulocytes-limits-plasmodium-cynomolgi-s-zoonotic-potential
#15
Varakorn Kosaisavee, Rossarin Suwanarusk, Adeline C Y Chua, Dennis E Kyle, Benoit Malleret, Rou Zhang, Mallika Imwong, Rawiwan Imerbsin, Ratawan Ubalee, Hugo Sámano-Sánchez, Bryan K S Yeung, Jessica Ong, Eric Lombardini, François Nosten, Kevin S W Tan, Pablo Bifani, Georges Snounou, Laurent Rénia, Bruce Russell
Two malaria parasites of Southeast Asian macaques, Plasmodium knowlesi and P. cynomolgi, can infect humans experimentally. In Malaysia, where both species are common, zoonotic knowlesi malaria has recently become dominant, and cases are recorded throughout the region. By contrast, to date only a single case of naturally acquired P. cynomolgi has been found in humans. In this study we show that whereas P. cynomolgi merozoites invade monkey red blood cells (RBCs) indiscriminately in vitro, for humans they are restricted to reticulocytes expressing both transferrin receptor 1 (Trf1 or CD71) and the Duffy antigen/chemokine receptor (DARC or CD234)...
July 11, 2017: Blood
https://www.readbyqxmd.com/read/28698206/expression-of-pim-kinases-in-reed-sternberg-cells-fosters-immune-privilege-and-tumor-cell-survival-in-hodgkin-lymphoma
#16
Maciej Szydłowski, Monika Prochorec-Sobieszek, Anna Szumera-Cieckiewicz, Edyta Derezinska, Grazyna Hoser, Danuta Wasilewska, Olga Szymanska-Giemza, Ewa Jabłonska, Emilia Białopiotrowicz, Tomasz Sewastianik, Anna Polak, Wojciech Czardybon, Michał Gałezowski, Renata Windak, Jan Maciej Zaucha, Krzysztof Warzocha, Krzysztof Brzózka, Przemysław Juszczynski
Reed-Sternberg (RS) cells of classical Hodgkin lymphoma (cHL) express multiple immunoregulatory proteins that shape the cHL microenvironment and allow tumor cells to evade immune surveillance. Expression of certain immunoregulatory proteins is modulated by pro-survival transcription factors, such as NFκB and STATs. Since these factors also induce expression of the oncogenic PIM1/2/3 serine/threonine kinases, and since PIMs modulate transcriptional activity of NFκB and STATs, we hypothesized that these kinases support RS cell survival and foster their immune privilege...
July 11, 2017: Blood
https://www.readbyqxmd.com/read/28698205/an-fc-engineered-cd19-antibody-eradicates-mrd-in-patient-derived-mll-rearranged-acute-lymphoblastic-leukemia-xenografts
#17
Denis M Schewe, Ameera Alsadeq, Cornelia Sattler, Lennart Lenk, Fotini Vogiatzi, Gunnar Cario, Simon Vieth, Thomas Valerius, Sophia Rosskopf, Fabian Meyersieck, Julia Alten, Martin Schrappe, Martin Gramatzki, Matthias Peipp, Christian Kellner
Antibody therapy constitutes a major advance in the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). To evaluate the efficacy and the mechanisms of action of CD19 monoclonal antibody therapy in pediatric BCP-ALL, an Fc engineered CD19 antibody carrying the S239D/I332E mutation for improved effector cell recruitment (CD19-DE) was tested. Patient derived xenografts (PDX) of pediatric MLL-rearranged ALL were established in NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG) mice. Antibody CD19-DE was efficient in prolonging the survival of NSG mice in a minimal residual disease (MRD) model...
July 11, 2017: Blood
https://www.readbyqxmd.com/read/28698204/hematologic-relapse-in-al-amyloidosis-after-high-dose-melphalan-and-stem-cell-transplantation
#18
Sabrina Browning, Karen Quillen, J Mark Sloan, Gheorghe Doros, Shayna Sarosiek, Vaishali Sanchorawala
No abstract text is available yet for this article.
July 11, 2017: Blood
https://www.readbyqxmd.com/read/28698203/post-transplant-feasibility-study-of-nilotinib-prophylaxis-for-high-risk-philadelphia-chromosome-positive-leukemia
#19
Paul A Carpenter, Laura Johnston, Hugo F Fernandez, Jerald P Radich, Michael J Mauro, Mary E D Flowers, Paul J Martin, Theodore A Gooley
No abstract text is available yet for this article.
July 11, 2017: Blood
https://www.readbyqxmd.com/read/28694326/genomic-analysis-of-220-ctcls-identifies-a-novel-recurrent-gain-of-function-alteration-in-rltpr-p-q575e
#20
Joonhee Park, Jingyi Yang, Alexander T Wenzel, Akshaya Ramachandran, Wung J Lee, Jay C Daniels, Juhyun Kim, Estela Martinez-Escala, Nduka Amankulor, Barbara Pro, Joan Guitart, Marc L Mendillo, Jeffrey N Savas, Titus J Boggon, Jaehyuk Choi
Cutaneous T cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of the skin-homing T cell. In early stage disease, lesions are limited to the skin, but in later stage disease, the tumor cells can escape into the blood, the lymph nodes, and at times the visceral organs. To clarify the genomic basis of CTCL, we performed genomic analysis of 220 CTCLs. Our analyses identify 55 putative driver genes, including 17 genes not previously implicated in CTCL. These novel mutations are predicted to affect chromatin (BCOR, KDM6A, SMARCB1, TRRAP), immune surveillance (CD58, RFXAP), MAPK signaling (MAP2K1, NF1), NF-κB signaling (PRKCB, CSNK1A1), PI-3-Kinase signaling (PIK3R1, VAV1), RHOA/cytoskeleton remodeling (ARHGEF3), RNA-splicing (U2AF1), T cell receptor signaling (PTPRN2, RLTPR), and T cell differentiation (RARA)...
July 10, 2017: Blood
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