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Blood Advances

Radomir Kratchmarov, Arthur M Magun, Steven L Reiner
Expression of the transcription factor T-cell factor 1 (TCF1) identifies antigen-experienced murine CD8+ T cells that retain potential for lymphoid recirculation and the ability to self-renew while producing more differentiated effector cells. We found that CD8+ T cells in the blood of both healthy and chronically infected humans expressed TCF1 at 3 distinct levels: high (TCF1-hi), intermediate (TCF1-int), and low (TCF1-lo). TCF1-hi cells could be found within both the naive and memory compartments and were characterized by relative quiescence and lack of immediate effector function...
July 24, 2018: Blood Advances
Srila Gopal, Qing Lu, Joshua J Man, Wendy Baur, Sitara P Rao, Lev Litichevskiy, Malvina Papanastasiou, Amanda L Creech, Katherine C DeRuff, James Mullahoo, Adam Officer, Shawn B Egri, Desiree Davison, Jacob D Jaffe, Iris Z Jaffe
No abstract text is available yet for this article.
July 24, 2018: Blood Advances
Derek Hoi-Hang Ho, Roger Hoi-Fung Wong
Fumagillin is an antiangiogenic and antineoplastic fungal natural product, and TNP-470 is one of its most potent analogs. Decades of studies revealed that TNP-470 has potent anticancer activities via destruction of neovasculature. In stark contrast, TNP-470 has been reported to suppress lymphocyte proliferation, thereby limiting its clinical potentials. In an attempt to investigate whether the similar or opposite immunomodulatory effect of TNP-470 could act on myeloid cells, we found that TNP-470 potentiates the immunogenicity of dendritic cells (DCs) toward a phenotype with T helper cell type 1 (Th1)-stimulatory features...
July 24, 2018: Blood Advances
Rick Kapur, Michael Kim, Johan Rebetz, Björn Hallström, Jonas T Björkman, Alisa Takabe-French, Noel Kim, Jonathan Liu, Shanjeevan Shanmugabhavananthan, Stefan Milosevic, Mark J McVey, Edwin R Speck, John W Semple
Transfusion-related acute lung injury (TRALI) is a syndrome of respiratory distress upon blood transfusion and is the leading cause of transfusion-related fatalities. Whether the gut microbiota plays any role in the development of TRALI is currently unknown. We observed that untreated barrier-free (BF) mice suffered from severe antibody-mediated acute lung injury, whereas the more sterile housed specific pathogen-free (SPF) mice and gut flora-depleted BF mice were both protected from lung injury. The prevention of TRALI in the SPF mice and gut flora-depleted BF mice was associated with decreased plasma macrophage inflammatory protein-2 levels as well as decreased pulmonary neutrophil accumulation...
July 10, 2018: Blood Advances
Sumithira Vasu, Jessica Kohlschmidt, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Deedra Nicolet, Lisa J Sterling, Heiko Becker, Klaus H Metzeler, Dimitrios Papaioannou, Bayard L Powell, Jonathan E Kolitz, Joseph O Moore, Maria R Baer, Gail J Roboz, Richard M Stone, John C Byrd, Andrew J Carroll, Clara D Bloomfield
The probability that adult patients with de novo acute myeloid leukemia (AML) receiving intensive chemotherapy in the absence of allogeneic hematopoietic stem cell transplantation (Allo-HCT) in first complete remission (CR1) will be disease-free at 10 years after diagnosis, a long-term surrogate of cure, is unknown. To address this question, we examined 2551 AML patients (1607 aged <60 years, and 944 aged ≥60 years) enrolled in Cancer and Leukemia Group B treatment protocols and the cytogenetics companion protocol 8461 between 1983 and 2004...
July 10, 2018: Blood Advances
Ajai Chari, A Keith Stewart, Stuart D Russell, Philippe Moreau, Joerg Herrmann, Jose Banchs, Roman Hajek, John Groarke, Alexander R Lyon, George N Batty, Sunhee Ro, Mei Huang, Karim S Iskander, Daniel Lenihan
Carfilzomib is a selective proteasome inhibitor approved for the treatment of relapsed and/or refractory multiple myeloma (RRMM). It has significantly improved outcomes, including overall survival (OS), and shown superiority vs standard treatment with lenalidomide plus dexamethasone and bortezomib plus dexamethasone. The incidence rate of cardiovascular (CV) events with carfilzomib treatment has varied across trials. This analysis evaluated phase 1-3 trials with >2000 RRMM patients exposed to carfilzomib to describe the incidence of CV adverse events (AEs)...
July 10, 2018: Blood Advances
Kristian Reckzeh, Hüsün Kizilkaya, Alexandra Søgaard Helbo, Montserrat Estruch Alrich, André Gundersen Deslauriers, Amit Grover, Nicolas Rapin, Fazila Asmar, Kirsten Grønbæk, Bo Porse, Niels Borregaard, Dietmar Vestweber, Claus Nerlov, Kim Theilgaard-Mönch
No abstract text is available yet for this article.
July 10, 2018: Blood Advances
Paola Rivera-Munoz, Anouchka P Laurent, Aurelie Siret, Cecile K Lopez, Cathy Ignacimouttou, Melanie G Cornejo, Olivia Bawa, Philippe Rameau, Olivier A Bernard, Philippe Dessen, Gary D Gilliland, Thomas Mercher, Sébastien Malinge
JAK3-activating mutations are commonly seen in chronic or acute hematologic malignancies affecting the myeloid, megakaryocytic, lymphoid, and natural killer (NK) cell compartment. Overexpression models of mutant JAK3 or pharmacologic inhibition of its kinase activity have highlighted the role that these constitutively activated mutants play in the T-cell, NK cell, and megakaryocytic lineages, but to date, the functional impact of JAK3 mutations at an endogenous level remains unknown. Here, we report a JAK3A572V knockin mouse model and demonstrate that activated JAK3 leads to a progressive and dose-dependent expansion of CD8+ T cells in the periphery before colonization of the bone marrow...
July 10, 2018: Blood Advances
Sundar Jagannath, Rafat Abonour, Brian G M Durie, Mohit Narang, Howard R Terebelo, Cristina J Gasparetto, Kathleen Toomey, James W Hardin, Lynne Wagner, Amit Agarwal, Shankar Srinivasan, Amani Kitali, E Dawn Flick, Michael Sturniolo, Robert M Rifkin
Autologous stem cell transplantation (ASCT) followed by lenalidomide maintenance therapy is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Clinical trials show progression-free survival (PFS) benefits, with some studies (Cancer and Leukemia Group [CALGB] trial and meta-analysis) also showing overall survival (OS) benefits, but applicability to real-world clinical settings is unclear. Using data from Connect MM, the largest US-based observational registry of NDMM patients, we analyzed effects of maintenance therapy on long-term outcomes in 1450 treated patients enrolled from 2009 to 2011...
July 10, 2018: Blood Advances
James L Rubenstein, Huimin Geng, Eleanor J Fraser, Paul Formaker, Lingjing Chen, Jigyasa Sharma, Phoebe Killea, Kaylee Choi, Jenny Ventura, John Kurhanewicz, Clifford Lowell, Jimmy Hwang, Patrick Treseler, Penny K Sneed, Jing Li, Xiaomin Wang, Nianhang Chen, Jon Gangoiti, Pamela N Munster, Bertil Damato
There is an unmet need for effective biological therapies for relapsed central nervous system (CNS) lymphoma. Lenalidomide is active in activated B-cell type diffuse large B-cell lymphoma and rituximab is effective in CNS lymphoma. These observations are the basis for this first trial of an immunomodulatory drug as monotherapy in CNS lymphoma, and, in patients with inadequate responses to lenalidomide, with rituximab. In an independent cohort, we evaluated lenalidomide maintenance after salvage with high-dose methotrexate or focal irradiation in relapsed primary CNS lymphoma (PCNSL)...
July 10, 2018: Blood Advances
Ahmad H Mufti, Kenichi Ogiwara, Laura L Swystun, Jeroen C J Eikenboom, Ulrich Budde, Wilma M Hopman, Christer Halldén, Jenny Goudemand, Ian R Peake, Anne C Goodeve, David Lillicrap, Daniel J Hampshire
Plasma levels of von Willebrand factor (VWF) vary considerably in the general population and this variation has been linked to several genetic and environmental factors. Genetic factors include 2 common single nucleotide variants (SNVs) located in VWF , rs1063856 (c.2365A>G) and rs1063857 (c.2385T>C), although to date the mechanistic basis for their association with VWF level is unknown. Using genotypic/phenotypic information from a European healthy control population, in vitro analyses of recombinant VWF expressing both SNVs, and in vivo murine models, this study determined the precise nature of their association with VWF level and investigated the mechanism(s) involved...
July 10, 2018: Blood Advances
Hyun Don Yun, Martin Felices, Daniel A Vallera, Peter Hinderlie, Sarah Cooley, Michel Arock, Jason Gotlib, Celalettin Ustun, Jeffrey S Miller
No abstract text is available yet for this article.
July 10, 2018: Blood Advances
Anne-Sophie Bouillon, Monica S Ventura Ferreira, Shady Adnan Awad, Johan Richter, Andreas Hochhaus, Volker Kunzmann, Jolanta Dengler, Jeroen Janssen, Gert Ossenkoppele, Peter E Westerweel, Peter A W Te Boekhorst, Francois-Xavier Mahon, Henrik Hjorth-Hansen, Susanne Isfort, Thoas Fioretos, Sebastian Hummel, Mirle Schemionek, Stefan Wilop, Steffen Koschmieder, Susanne Saußele, Satu Mustjoki, Fabian Beier, Tim H Brümmendorf
Telomere length (TL) in peripheral blood (PB) cells of patients with chronic myeloid leukemia (CML) has been shown to correlate with disease stage, prognostic scores, response to therapy, and disease progression. However, due to considerable genetic interindividual variability, TL varies substantially between individuals, limiting its use as a robust prognostic marker in individual patients. Here, we compared TL of BCR-ABL- , nonleukemic CD34+ CD38- hematopoietic stem cells (HSC) in the bone marrow of CML patients at diagnosis to their individual BCR-ABL+ leukemic stem cell (LSC) counterparts...
July 10, 2018: Blood Advances
C Madsen, M R Clausen, T L Plesner, A Pasanen, T Kuismanen, H H Bentzen, J M Jørgensen, I B Sillesen, B M Himmelstrup, D Rønnov-Jessen, K R Jensen, A M Pettinger, M Ludvigsen, S Leppä, F A d'Amore
The introduction of the anti-CD20 antibody rituximab in combination with chemotherapy (R-chemo) has improved the prognosis of patients with follicular lymphoma (FL). During the last decade, the addition of a maintenance treatment with rituximab (MR) after R-chemo has been tested with the hope of further improving the outcome of these patients. Using 2 independent population-based cohorts, we investigated the effect of up-front MR on time related end points as well as the risk of histological transformation (HT)...
July 10, 2018: Blood Advances
Silvia Mele, Stephen Devereux, Andrea G Pepper, Elvira Infante, Anne J Ridley
CD38 is a transmembrane exoenzyme that is associated with poor prognosis in chronic lymphocytic leukemia (CLL). High CD38 levels in CLL cells are linked to increased cell migration, but the molecular basis is unknown. CD38 produces nicotinic acid adenine dinucleotide phosphate and adenosine 5'-diphosphate-ribose, both of which can act to increase intracellular Ca2+ levels. Here we show that CD38 expression increases basal intracellular Ca2+ levels and stimulates CLL cell migration both with and without chemokine stimulation...
July 10, 2018: Blood Advances
Michael A Spinner, Ranjana H Advani, Richard T Hoppe, Robert Lowsky, Lori S Muffly
No abstract text is available yet for this article.
July 10, 2018: Blood Advances
Thomas Yssing Michaelsen, Julia Richter, Rasmus Froberg Brøndum, Wolfram Klapper, Hans Erik Johnsen, Mads Albertsen, Karen Dybkær, Martin Bøgsted
Gene expression profiling (GEP) by microarrays of diffuse large B-cell lymphoma (DLBCL) has enabled the categorization of DLBCL into activated B-cell-like and germinal center B-cell-like subclasses. However, as this does not fully embrace the great diversity of B-cell subtypes, we recently developed a gene expression assay for B-cell-associated gene signature (BAGS) classification. To facilitate quick and easy-to-use BAGS profiling, we developed in this study the NanoString-based BAGS2Clinic assay. Microarray data from 4 different cohorts (n = 970) were used to select genes and train the assay...
July 10, 2018: Blood Advances
Marius Flasinski, Kira Scheibke, Martin Zimmermann, Ursula Creutzig, Katarina Reinhardt, Femke Verwer, Valerie de Haas, Vincent H J van der Velden, Christine von Neuhoff, C Michel Zwaan, Dirk Reinhardt, Jan-Henning Klusmann
Approximately 5% to 10% of children with Down syndrome (DS) are diagnosed with transient myeloproliferative disorder (TMD). Approximately 20% of these patients die within 6 months (early death), and another 20% to 30% progress to myeloid leukemia (ML-DS) within their first 4 years of life. The aim of the multicenter, nonrandomized, historically controlled TMD Prevention 2007 trial was to evaluate the impact of low-dose cytarabine treatment on survival and prevention of ML-DS in patients with TMD. Patients received cytarabine (1...
July 10, 2018: Blood Advances
Anthony S Stein, Richard A Larson, Andre C Schuh, William Stevenson, Ewa Lech-Maranda, Qui Tran, Zachary Zimmerman, William Kormany, Max S Topp
In the phase 3 TOWER study, blinatumomab demonstrated an overall survival benefit over standard-of-care chemotherapy (SOC) in adults with relapsed or refractory (r/r) Philadelphia chromosome-negative (Ph- ) B-precursor acute lymphoblastic leukemia (ALL). Nearly all patients in both treatment arms experienced an adverse event (AE), and the incidence rate of serious AEs was higher for blinatumomab. However, as treatment exposure differed between the 2 arms, we conducted an exploratory safety analysis comparing exposure-adjusted event rates (EAERs) of blinatumomab vs SOC...
July 10, 2018: Blood Advances
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