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https://www.readbyqxmd.com/read/28336528/platelet-cd36-promotes-thrombosis-by-activating-redox-sensor-erk5-in-hyperlipidemic-conditions
#1
Moua Yang, Brian C Cooley, Wei Li, Yiliang Chen, Jeannette Vasquez-Vivar, Na'il O Scoggins, Scott J Cameron, Craig N Morrell, Roy L Silverstein
Atherothrombosis is a process mediated by dysregulated platelet activation that can cause life-threatening complications and is the leading cause of death by cardiovascular disease. Platelet reactivity in hyperlipidemic conditions is enhanced when platelet scavenger receptor CD36 recognizes oxidized lipids in LDL particles, a process which induces an overt prothrombotic phenotype. The mechanisms by which CD36 promotes platelet activation and thrombosis remain incompletely defined. In this study, we identify a mechanism for CD36 to promote thrombosis by increasing activation of MAP kinase ERK5, a protein kinase known to be exquisitely sensitive to redox stress, through a signaling pathway requiring Src kinases, NADPH oxidase, superoxide radical anion and hydrogen peroxide...
March 23, 2017: Blood
https://www.readbyqxmd.com/read/28336527/a-phase-i-clinical-trial-of-single-agent-selinexor-in-acute-myeloid-leukemia
#2
Ramiro Garzon, Michael Savona, Rachid Baz, Michael Andreeff, Nashat Gabrail, Martin Gutierrez, Lynn Savoie, Morten Mau-Sorensen, Nina Wagner-Johnston, Karen Yee, T J Unger, Jean Richard Saint-Martin, Robert Carlson, Tami Rashal, Trinayan Kashyap, Boris Klebanov, Sharon Shacham, Michael Kauffman, Richard Stone
Selinexor is a novel, first-in-class, Selective Inhibitor of Nuclear Export (SINE) compound, which blocks XPO1 function, leads to nuclear accumulation of tumor suppressor proteins (TSPs) and induces cancer cell death. A phase I dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8 or 10 doses of selinexor in 21- or 28-day cycle...
March 23, 2017: Blood
https://www.readbyqxmd.com/read/28336526/identification-of-unipotent-megakaryocyte-progenitors-in-human-hematopoiesis
#3
Kohta Miyawaki, Hiromi Iwasaki, Takashi Jiromaru, Hirotake Kusumoto, Ayano Yurino, Takeshi Sugio, Yasufumi Uehara, Jun Odawara, Shinya Daitoku, Yuya Kunisaki, Yasuo Mori, Yojiro Arinobu, Hirofumi Tsuzuki, Yoshikane Kikushige, Tadafumi Iino, Koji Kato, Katsuto Takenaka, Toshihiro Miyamoto, Takahiro Maeda, Koichi Akashi
The developmental pathway for human megakaryocytes remains unclear and the definition of pure unipotent megakaryocyte progenitor is still controversial. Using single-cell transcriptome analysis, we have identified a cluster of cells within immature hematopoietic stem and progenitor cell populations that specifically express genes related to the megakaryocyte lineage. We used CD41 as a positive marker to identify these cells within the CD34(+)CD38(+)IL-3Rα(dim)CD45RA(-) common myeloid progenitor (CMP) population...
March 23, 2017: Blood
https://www.readbyqxmd.com/read/28331056/monitoring-of-childhood-all-using-bcr-abl1-genomic-breakpoints-identifies-a-subgroup-with-cml-like-biology
#4
Lenka Hovorkova, Marketa Zaliova, Nicola C Venn, Kirsten Bleckmann, Marie Trkova, Eliska Potuckova, Martina Vaskova, Jana Linhartova, Katerina Machova Polakova, Eva Fronkova, Walter Muskovic, Jodie E Giles, Peter J Shaw, Gunnar Cario, Rosemary Sutton, Jan Stary, Jan Trka, Jan Zuna
We used the genomic breakpoint between BCR and ABL1 genes for the DNA-based monitoring of minimal residual disease (MRD) in 48 patients with childhood acute lymphoblastic leukemia (ALL). Comparing the results with standard MRD monitoring based on immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements and with quantification of IKZF1 deletion, we observed very good correlation for the methods in a majority of patients; however, over 20% of children (25% [8/32] with minor and 12.5% [1/8] with Major-BCR-ABL1 variants in the consecutive cohorts) had significantly (>1 log) higher levels of BCR-ABL1 fusion than Ig/TCR rearrangements and/or IKZF1 deletion...
March 22, 2017: Blood
https://www.readbyqxmd.com/read/28331055/reticular-dysgenesis-international-survey-on-clinical-presentation-transplantation-and-outcome
#5
Manfred Hoenig, Chantal Lagresle-Peyrou, Ulrich Pannicke, Luigi D Notarangelo, Fulvio Porta, Andrew R Gennery, Mary Slatter, Morton J Cowan, Polina Stepensky, Hamoud Al-Mousa, Daifulah Al-Zahrani, Sung-Yun Pai, Waleed Al Herz, Hubert B Gaspar, Paul Veys, Koichi Oshima, Kohsuke Imai, Hiromasa Yabe, Lenora M Noroski, Nico M Wulffraat, Karl-Walter Sykora, Pere Soler-Palacin, Hideki Muramatsu, Mariam Al Hilali, Despina Moshous, Klaus-Michael Debatin, Catharina Schuetz, Eva-Maria Jacobsen, Ansgar S Schulz, Klaus Schwarz, Alain Fischer, Wilhelm Friedrich, Marina Cavazzana
Reticular Dysgenesis (RD) is a rare congenital disorder defined clinically by the combination of severe combined immunodeficiency (SCID), agranulocytosis and sensorineural deafness. Mutations in the gene encoding Adenylate Kinase 2 (AK2) were identified to cause the disorder. Hematopoietic stem cell transplantation (HSCT) is the only option to cure this otherwise fatal disease. Retrospective data on clinical presentation, genetics and outcome of HSCT were collected from centers in Europe, Asia and North America for a total of 32 patients born between 1982 and 2011...
March 22, 2017: Blood
https://www.readbyqxmd.com/read/28325865/venetoclax-and-obinutuzumab-in-chronic-lymphocytic-leukemia
#6
Kirsten Fischer, Othman Al-Sawaf, Anna-Maria Fink, Mark Dixon, Jasmin Bahlo, Simon Warburton, Thomas J Kipps, Robert Weinkove, Sue Robinson, Till Seiler, Stephen Opat, Carolyn Owen, Javier López, Kathryn Humphrey, Rod Humerickhouse, Eugen Tausch, Lukas Frenzel, Barbara Eichhorst, Clemens-M Wendtner, Stephan Stilgenbauer, Anton W Langerak, Jacque J M van Dongen, Sebastian Boettcher, Matthias Ritgen, Valentin Goede, Mehrdad Mobasher, Michael Hallek
No abstract text is available yet for this article.
March 21, 2017: Blood
https://www.readbyqxmd.com/read/28325864/idelalisib-is-effective-in-patients-with-high-risk-follicular-lymphoma-and-early-relapse-after-initial-chemoimmunotherapy
#7
Ajay K Gopal, Brad S Kahl, Christopher R Flowers, Peter Martin, Stephen M Ansell, Esteban Abella-Dominicis, Brian Koh, Wei Ye, Paul M Barr, Gilles A Salles, Jonathan W Friedberg
No abstract text is available yet for this article.
March 21, 2017: Blood
https://www.readbyqxmd.com/read/28325863/pharmacological-targeting-of-plasmin-prevents-lethality-in-a-murine-model-of-macrophage-activation-syndrome
#8
Hiroshi Shimazu, Shinya Munakata, Yoshihiko Tashiro, Yousef Salama, Douaa Dhahri, Salita Eiamboonsert, Yasunori Ota, Haruo Onoda, Yuko Tsuda, Yoshio Okada, Hiromitsu Nakauchi, Beate Heissig, Koichi Hattori
Macrophage activation syndrome (MAS) is a life-threatening disorder characterized by a cytokine storm and multiorgan dysfunction due to excessive immune activation. Although abnormalities of coagulation and fibrinolysis are major components of MAS, the role of the fibrinolytic system and its key player, plasmin, in the development of MAS remains to be solved. We established a murine model of fulminant MAS by repeated injections of Toll-like receptor-9 (TLR-9) agonist and D-galactosamine (DG) in immunocompetent mice...
March 21, 2017: Blood
https://www.readbyqxmd.com/read/28325862/reduced-pu-1-expression-underlies-aberrant-neutrophil-maturation-and-function-in-%C3%AE-thalassemia-mice-and-patients
#9
Panjaree Siwaponanan, Jurre Ynze Siegers, Razi Ghazali, Thian Ng, Bradley McColl, Garrett Zhen-Wei Ng, Philip Sutton, Nancy Wang, Isabelle Ooi, Chayada Thiengtavor, Suthat Fucharoen, Pornthip Chaichompoo, Saovaros Svasti, Odilia Louise Wijburg, Jim Vadolas
β-Thalassemia is associated with several abnormalities of the innate immune system. Neutrophils in particular are defective, predisposing patients to life-threatening bacterial infections. The molecular and cellular mechanisms involved in impaired neutrophil function remain incompletely defined. We used the Hbb(th3/+) β-thalassemia mouse and HbE/β-thalassemia patients to investigate dysregulated neutrophil activity. Mature neutrophils from Hbb(th3/+) mice displayed a significant reduction in chemotaxis, opsonophagocytosis and production of reactive oxygen species (ROS), closely mimicking the defective immune functions observed in β-thalassemia patients...
March 21, 2017: Blood
https://www.readbyqxmd.com/read/28320710/myeloid-p53-regulates-macrophage-polarization-and-venous-thrombus-resolution-by-inflammatory-vascular-remodeling-in-mice
#10
Subhradip Mukhopadhyay, Toni M Antalis, Khanh P Nguyen, Mark H Hoofnagle, Rajabrata Sarkar
Deep venous thrombosis (DVT) remains a common and serious cardiovascular problem with both fatal and long-term consequences. The consequences of DVT include the development of post-thrombotic syndrome (PTS) in 25-60% of DVT patients. Despite the clinical importance of venous thrombus resolution, the cellular and molecular mediators involved are poorly understood, and currently there is no molecular therapy to accelerate this process. Several lines of evidence suggest that a complex and interrelated array of molecular signaling processes are involved in the inflammatory vascular remodeling associated with the resolution of DVT...
March 20, 2017: Blood
https://www.readbyqxmd.com/read/28320709/plasmin-and-plasminogen-induce-macrophage-reprogramming-and-regulate-key-steps-of-inflammation-resolution-via-annexin-a1
#11
Michelle A Sugimoto, Ana Luíza C Ribeiro, Bruno R C Costa, Juliana P Vago, Kátia M Lima, Fernanda S Carneiro, Mylena Maira O Ortiz, Graziele Letícia N Lima, Aline A F Carmo, Renata M Rocha, Denise A Perez, Alessandra C Reis, Vanessa Pinho, Lindsey A Miles, Cristiana C Garcia, Mauro M Teixeira, Lirlândia P Sousa
Inflammation resolution is an active process that functions to restore tissue homeostasis. Participation of the plasminogen/plasmin (Plg/Pla) system in the productive phase of inflammation is well known, but its involvement in the resolution phase remains unclear. Therefore, we aimed to investigate the potential role of Plg/Pla in key events during the resolution of acute inflammation and its underlying mechanisms. Plg/Pla injection into the pleural cavity of BALB/c mice induced a time-dependent influx of mononuclear cells that were primarily macrophages of anti-inflammatory (M2 - F4/80(high) Gr1(-) CD11b(high)) and proresolving (Mres - F4/80(med) CD11b(low)) phenotypes, without changing the number of macrophages with a pro-inflammatory profile (M1 - F4/80(low) Gr1(+) CD11b(med))...
March 20, 2017: Blood
https://www.readbyqxmd.com/read/28314734/fndc3b-is-another-novel-partner-fused-to-rara-in-the-t-3-17-q26-q21-variant-of-acute-promyelocytic-leukemia
#12
Chi Keung Cheng, Angela Z Wang, Terry H Y Wong, Thomas S K Wan, Joyce S Cheung, Radha Raghupathy, Natalie P H Chan, Margaret H L Ng
No abstract text is available yet for this article.
March 17, 2017: Blood
https://www.readbyqxmd.com/read/28302615/impact-of-doxorubicin-dose-capping-on-the-outcome-of-dlbcl-patients-with-elevated-body-surface-area
#13
Caroline Gay, Richard Delarue, Noel Milpied, Lucie Oberic, Bertrand Coiffier, Sami Boussetta, Corinne Haioun, Hervé Tilly, Gilles Salles, Thierry Lamy, Marie-Antoinette Lester, Roch Houot
No abstract text is available yet for this article.
March 16, 2017: Blood
https://www.readbyqxmd.com/read/28292947/mobilization-of-allogeneic-peripheral-blood-stem-cell-donors-with-intravenous-plerixafor-mobilizes-a-unique-graft
#14
Mark A Schroeder, Michael P Rettig, Sandra Lopez, Stephanie Christ, Mark Fiala, William Eades, Fazia A Mir, Jin Shao, Kyle McFarland, Kathryn Trinkaus, William Shannon, Elena Deych, Jinsheng Yu, Ravi Vij, Keith Stockerl-Goldstein, Amanda F Cashen, Geoffery L Uy, Camille N Abboud, Peter Westervelt, John F DiPersio
A single subcutaneous (SC) injection of plerixafor results in rapid mobilization of hematopoietic progenitors but fails to mobilize 33% of normal allogeneic sibling donors in one apheresis. We hypothesized that changing the route of administration of plerixafor from SC to intravenous (IV) may overcome the low stem cell yields and allow collection in one day. A phase I trial followed by a phase II efficacy trial was conducted in allogeneic sibling donors. The optimal dose of IV plerixafor was determined to be 0...
March 14, 2017: Blood
https://www.readbyqxmd.com/read/28288980/human-neutrophils-mediate-trogocytosis-rather-than-phagocytosis-of-cll-b-cells-opsonized-with-anti-cd20-antibodies
#15
Rut Valgardsdottir, Irene Cattaneo, Christian Klein, Martino Introna, Marina Figliuzzi, Josée Golay
Polymorphonuclear neutrophils (PMN) have previously been reported to mediate phagocytosis of anti-CD20 opsonized B-cells from CLL patients. However recent data have suggested that PMN, like macrophages, can also mediate trogocytosis. We have performed experiments to more precisely investigate this point and discriminate between trogocytosis and phagocytosis. In live cell time-lapse microscopy experiments, we could not detect any significant phagocytosis by purified PMN of anti-CD20-opsonized CLL B-cells, but only the repeated close contact between effectors and targets, suggesting trogocytosis...
March 13, 2017: Blood
https://www.readbyqxmd.com/read/28288979/crebbp-loss-cooperates-with-bcl2-over-expression-to-promote-lymphoma-in-mice
#16
Idoia García-Ramírez, Saber Tadros, Inés González-Herrero, Alberto Martín-Lorenzo, Guillermo Rodríguez-Hernández, Dalia Moore, Lucía Ruiz-Roca, Oscar Blanco, Diego Alonso-López, Javier De Las Rivas, Keenan Hartert, Romain Duval, David Klinkebiel, Martin Bast, Julie Vose, Matthew Lunning, Kai Fu, Timothy Greiner, Fernando Rodrigues-Lima, Rafael Jiménez, Francisco Javier García Criado, María Begoña García Cenador, Paul Brindle, Carolina Vicente-Dueñas, Ash Alizadeh, Isidro Sánchez-García, Michael R Green
CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits in B-cell development and can cooperate with Bcl2 over-expression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B-cells we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the proximal regulatory regions of these genes...
March 13, 2017: Blood
https://www.readbyqxmd.com/read/28283481/inhibition-of-pol-i-transcription-treats-murine-and-human-aml-by-targeting-the-leukemia-initiating-cell-population
#17
Nadine Hein, Donald P Cameron, Katherine M Hannan, Nhu-Y N Nguyen, Chun Yew Fong, Jirawas Sornkom, Meaghan Wall, Megan Pavy, Carleen Cullinane, Jeannine Diesch, Jennifer R Devlin, Amee J George, Elaine Sanij, Jaclyn Quin, Gretchen Poortinga, Inge Verbrugge, Adele Baker, Denis Drygin, Simon J Harrison, James D Rozario, Jason A Powell, Stuart M Pitson, Johannes Zuber, Ricky W Johnstone, Mark A Dawson, Mark A Guthridge, Andrew Wei, Grant A McArthur, Richard B Pearson, Ross D Hannan
Despite the development of novel drugs, prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA Polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including MLL-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461, the induction of p53-dependant apoptotic cell death, inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo...
March 10, 2017: Blood
https://www.readbyqxmd.com/read/28283480/leveraging-increased-cytoplasmic-nucleoside-kinase-activity-to-target-mtdna-and-oxidative-phosphorylation-in-aml
#18
Sanduni U Liyanage, Rose Hurren, Veronique Voisin, Gaëlle Bridon, Xiaoming Wang, ChangJiang Xu, Neil MacLean, Thirushi P Siriwardena, Marcela Gronda, Dana Yehudai, Shrivani Sriskanthadevan, Daina Avizonis, Aisha Shamas-Din, Mark D Minden, Gary D Bader, Rebecca Laposa, Aaron D Schimmer
Mitochondrial DNA (mtDNA) biosynthesis requires replication factors and adequate nucleotide pools from the mitochondria and cytoplasm. We performed gene expression profiling analysis of 542 human AML samples and identified 55% with upregulated mtDNA biosynthesis pathway expression compared to normal hematopoietic cells. Genes that support mitochondrial nucleotide pools, including mitochondrial nucleotide transporters and a subset of cytoplasmic nucleoside kinases, were also increased in AML compared to normal hematopoietic samples...
March 10, 2017: Blood
https://www.readbyqxmd.com/read/28279965/lower-levels-of-vitamin-a-are-associated-with-increased-gastrointestinal-graft-versus-host-disease-in-children
#19
Dana T Lounder, Pooja Khandelwal, Christopher Dandoy, Sonata Jodele, Michael Grimley, Gregory Wallace, Adam Lane, Cynthia Taggart, Ashley Teusink-Cross, Kelly Lake, Stella M Davies
Vitamin A promotes development of mucosal tolerance and enhances differentiation of regulatory T cells. Vitamin A deficiency impairs epithelial integrity, increasing intestinal permeability. We hypothesized that higher vitamin A levels would reduce risk of graft versus host disease through reduced intestinal permeability, reduced mucosal injury, and reduced lymphocyte homing to the gut. We tested this hypothesis in a cohort study of 114 consecutive patients undergoing allogeneic stem cell transplant. Free vitamin A levels were measured in plasma at day 30 post-transplant...
March 9, 2017: Blood
https://www.readbyqxmd.com/read/28275090/how-i-manage-the-toxicities-of-myeloma-drugs
#20
Michel Delforge, Heinz Ludwig
The treatment of multiple myeloma is considered a continuously evolving paradigm as a result of the growing availability of new and highly effective drugs, including first-and second-generation proteasome inhibitors, immunomodulatory agents and monoclonal antibodies. Clinical trials advocate long-term rather than short-term treatment schedules with combinations of these new anti-myeloma drug classes. Although the overall toxicity profile of the recommended regimens can be considered favorable, their increasing complexity and prolonged use warrants a heightened vigilance for early and late side-effects, a priori because real-life patients can be more frail or present with one or more comorbidities...
March 8, 2017: Blood
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