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Eileen M Boyle, Cody Ashby, Christopher P Wardell, Dorota Rowczenio, Sajitha Sachchithanantham, Yan Wang, Sarah K Johnson, Michael A Bauer, Niels Weinhold, Martin F Kaiser, David C Johnson, John R Jones, Charlotte Pawlyn, Paula Proszek, Carolina Schinke, Thierry Facon, Charles Dumontet, Faith E Davies, Gareth J Morgan, Brian A Walker, Ashutosh D Wechalekar
No abstract text is available yet for this article.
November 16, 2018: Blood
Xiaoyu Qu, Hongli Li, Rita M Braziel, Verena Passerini, Lisa M Rimsza, Eric D Hsi, John P Leonard, Sonali M Smith, Robert Kridel, Oliver Press, Oliver Weigert, Michael LeBlanc, Jonathan W Friedberg, Min Fang
Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy number aberrations (CNAs) and copy neutral loss of heterozygosity (cnLOH) identified by chromosome genomic array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in SWOG S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression free survival (PFS), and overall survival (OS)...
November 16, 2018: Blood
Jessica L Brady, Michael S Binkley, Carla Hajj, Monica Chelius, Karen Chau, Alex Balogh, Mario Levis, Andrea Riccardo Filippi, Michael Jones, Michael Mac Manus, Andrew Wirth, Masahiko Oguchi, Anders Krog Vistisen, Therese Youssef Andraos, Andrea K Ng, Berthe M P Aleman, Seo Hee Choi, Youlia Kirova, Sara Hardy, Gabriele Reinartz, Hans T Eich, Scott V Bratman, Louis S Constine, Chang-Ok Suh, Bouthaina Dabaja, Tarec C El-Galaly, David C Hodgson, Umberto Ricardi, Joachim Yahalom, Richard T Hoppe, N George Mikhaeel
Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40-50%. As 18 F-FDG PET-CT upstages 10-60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study. Inclusion criteria were: RT alone for untreated stage I-II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow up ≥3 months...
November 16, 2018: Blood
Farhad Ravandi
The introduction of agents targeted at specific molecular events is changing the treatment paradigms in a number of malignancies. Historically, we have relied entirely on DNA-interactive, cytotoxic drugs for treating patients with leukemia. Increased understanding of the leukemic cell biology and pathogenesis, and the ways they evade the immune surveillance mechanisms, will likely lead to the development of more effective agents, and regimens less reliant on chemotherapy, able to achieve deep levels of disease eradication...
November 15, 2018: Blood
Miguel Alejandro Lopez-Ramirez, Angela Pham, Romuald Girard, Tine Wyseure, Preston Hale, Atsuki Yamashita, Janne Koskimäki, Sean Polster, Laleh Saadat, Ignacio A Romero, Charles T Esmon, Frederic Lagarrigue, Issam A Awad, Laurent O Mosnier, Mark H Ginsberg
Cerebral cavernous malformations (CCM) are common brain vascular dysplasias prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here we show that central nervous system (CNS) hemorrhage in CCM is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions and in the plasma of patients with CCMs...
November 15, 2018: Blood
Rami Abu-Fanne, Victoria Stepanova, Rustem I Litvinov, Suhair Abdeen, Khalil Bdeir, Mohamed Higazi, Emad Maraga, Chandrasekaran Nagaswami, Alexander R Mukhitov, John W Weisel, Douglas B Cines, Abd Al-Roof Higazi
Inflammation and thrombosis are integrated, mutually reinforcing processes, but the inter-regulatory mechanisms are incompletely defined. Here, we examined the contribution of α-defensins (α-defs), antimicrobial proteins released from activated human neutrophils, on clot formation in vitro and in vivo. Activation of the intrinsic pathway of coagulation stimulates release of α-defs from neutrophils. α-defs accelerate fibrin polymerization, increase fiber density and branching, incorporate into nascent fibrin clots, and impede fibrinolysis in vitro...
November 15, 2018: Blood
Thomas Bromberger, Sarah Klapproth, Ina Rohwedder, Liang Zhu, Laura Mittmann, Christoph A Reichel, Markus Sperandio, Jun Qin, Markus Moser
Targeting Talin1 to the plasma membrane is a crucial step in integrin activation, which in leukocytes is mediated by a Rap1/RIAM/Talin1 pathway whereas in platelets is RIAM-independent. Recent structural, biochemical and cell biological studies suggested a direct Rap1/Talin1 interaction as an alternative mechanism to recruit Talin1 to the membrane and induce integrin activation. To test whether this pathway is of relevance in vivo, we generated Rap1-binding-deficient Talin1 knockin (Tln13mut ) mice. Although Tln13mut mice show no obvious abnormalities, their platelets exhibit reduced integrin activation, aggregation, adhesion and spreading resulting in prolonged tail-bleeding times and delayed thrombus formation and vessel occlusion in vivo...
November 15, 2018: Blood
Thomas D Coates, Mario Cazzola
No abstract text is available yet for this article.
November 14, 2018: Blood
Zoltan Nagy, Timo Vögtle, Mitchell J Geer, Jun Mori, Silke Heising, Giada Di Nunzio, Ralph Gareus, Alexander Tarakhovsky, Arthur Weiss, Benjamin G Neel, Guillaume E Desanti, Alexandra Mazharian, Yotis A Senis
Conditional knockout (KO) mouse models are invaluable for elucidating the physiological roles of platelets. The Pf4-Cre transgenic mouse is the current model of choice for generating megakaryocyte/platelet-specific KO mice. Platelets and leukocytes work closely together in a wide range of disease settings, yet the specific contribution of platelets to these processes remains unclear. This is partially due to the Pf4-Cre transgene being expressed in a variety of leukocyte populations. To overcome this issue, we developed a Gp1ba-Cre transgenic mouse strain in which Cre expression in driven by the endogenous Gp1ba locus...
November 14, 2018: Blood
Alice Cleynen, Mehmet Samur, Aurore Perrot, Laure Buisson, Sabrina Maheo, Mariateresa Fulciniti, Michel Attal, Nikhil Munshi, Hervé Avet-Loiseau, Jill Corre
No abstract text is available yet for this article.
November 14, 2018: Blood
John M Gansner, Mahboubeh Rahmani, A Helena Jonsson, Brooke M Fortin, Idayat Brimah, Martha Ellis, Robin Smeland-Wagman, Zhihan J Li, Jason M Schenkel, Michael B Brenner, Revital Yefidoff-Freedman, Steven R Sloan, Nancy Berliner, Nicolas C Issa, Lindsey R Baden, Dan L Longo, Duane R Wesemann, Donna Neuberg, Deepak A Rao, Richard M Kaufman
Over one million apheresis platelet collections are performed annually in the United States. After two healthy plateletpheresis donors were incidentally found to have low CD4+ T-lymphocyte counts, we investigated whether plateletpheresis causes lymphopenia. We conducted a cross-sectional, single-center study of platelet donors undergoing plateletpheresis with the Trima Accel, which removes leukocytes continuously with its leukoreduction system chamber. We recruited three groups of platelet donors based on the total number of plateletpheresis sessions in the prior 365 days: 1-2, 3-19, or 20-24...
November 14, 2018: Blood
Maryam Sarraf Yazdy, Anthony R Mato, Bruce D Cheson
The treatment landscape for chronic lymphocytic leukemia (CLL) is rapidly evolving. Targeted agents (TA) have demonstrated impressive single agent activity, and therefore have been replacing chemoimmunotherapy (CIT). Despite their efficacy, the optimal use of the current TAs remains challenging. Perhaps the major dilemma is whether these drugs are best-utilized in sequence, or in combinations. Most patients tolerate TA well, notably early during treatment; however, a substantial number discontinue therapy due to toxicities...
November 14, 2018: Blood
Sarah H O'Brien
Heavy menstrual bleeding (HMB) is frequently reported by adolescents. The role of the hematologist is threefold in the evaluation of such patients: 1) perform a clinical and laboratory evaluation for an underlying bleeding disorder based on the degree of clinical suspicion, 2) identify and manage any concomitant iron deficiency, and 3) provide input to the referring provider regarding the management of HMB, particulary for patients with identified hemostatic defects. Several clues in the menstrual history should raise suspicion for an underlying bleeding disorder, such as menses lasting >7 days, menstrual flow which soaks >5 products daily or requires product change during the night, passage of large blood clots, or failure to respond to conventional therapies...
November 14, 2018: Blood
Zhenzhen Zhao, Yi Wu, Junsong Zhou, Fengwu Chen, Aizhen Yang, David W Essex
Secreted platelet protein disulfide isomerases, PDI, ERp57, ERp5 and ERp72, have important roles as positive regulators of platelet function and thrombosis. Thioredoxin-related transmembrane protein 1 (TMX1) was the first described transmembrane member of the protein disulfide isomerase family of enzymes. Using a specific antibody, recombinant TMX1 protein (rTMX1), a knockout mouse model, and thiol-labeling approach, we examined the role of TMX1 in platelet function and thrombosis. Expression of TMX1 on the platelet surface increased with thrombin stimulation...
November 13, 2018: Blood
David K Edwards, Kevin Watanabe-Smith, Angela Rofelty, Alisa Damnernsawad, Ted Laderas, Adam Lamble, Evan F Lind, Andy Kaempf, Motomi Mori, Mara Rosenberg, Amanda d'Almeida, Nicola Long, Anupriya Agarwal, David Tyler Sweeney, Marc Loriaux, Shannon K McWeeney, Jeffrey W Tyner
To identify new therapeutic targets in AML, we performed small-molecule and siRNA screens of primary AML patient samples. In 23% of samples, we found sensitivity to inhibition of CSF1R, a receptor tyrosine kinase responsible for survival, proliferation, and differentiation of myeloid-lineage cells. Sensitivity to the CSF1R inhibitor GW-2580 was found preferentially in de novo and favorable risk patients, and resistance to GW-2580 was associated with reduced overall survival. Using flow cytometry, we discovered that CSF1R is not expressed on the majority of leukemic blasts but instead on a subpopulation of supportive cells...
November 13, 2018: Blood
Patrice N Wagner, Qiong Shi, Christi T Salisbury-Ruf, Jing Zou, Michael R Savona, Yuri Fedoriw, Sandra S Zinkel
Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The two major modes of programmed cell death (PCD), apoptosis and necroptosis, share molecular machinery, but diverge in outcome with important implications for the microenvironment: apoptotic cells are removed in an immune silent process, whereas necroptotic cells leak cellular contents that incite inflammation. Given the importance of cytokine directed cues for hematopoietic cell survival and differentiation, the impact on hematopoietic homeostasis of biasing cell death fate to necroptosis is substantial and poorly understood...
November 9, 2018: Blood
Amaris K Balitsky, John G Kelton, Donald M Arnold
No abstract text is available yet for this article.
November 8, 2018: Blood
Alessandro Matte, Antonio Recchiuti, Enrica Federti, Bérengère Koehl, Thomas Mintz, Wassim El Nemer, Pierre-Louis Tharaux, Valentine Brousse, Immacolata Andolfo, Alessia Lamolinara, Olga Weinberg, Angela Siciliano, Paul C Norris, Ian R Riley, Achille Iolascon, Charles N Serhan, Carlo Brugnara, Lucia De Franceschi
The endogenous lipid mediators Resolvins (Rv) play a key role in the resolution of inflammation. Sickle cell disease (SCD), a genetic disorder of hemoglobin, is characterized by inflammatory and vaso-occlusive pathologies. We document in humanized SCD mice altered pro-resolving events following hypoxia/reperfusion. We demonstrate novel protective actions of 17 R -RvD1 (7 S , 8 R , 17 R -trihydroxy-4 Z , 9 E , 11 E , 13 Z , 15 E , 19 Z -docosahexaenoic acid), in reducing ex vivo human SCD blood leukocyte recruitment by microvascular endothelial cells and in vivo neutrophil adhesion and transmigration...
November 7, 2018: Blood
Uwe Platzbecker, Pierre Fenaux, Lionel Adès, Aristoteles Giagounidis, Valeria Santini, Arjan A van de Loosdrecht, David Bowen, Theo de Witte, Guillermo Garcia-Manero, Eva Hellström-Lindberg, Ulrich Germing, Reinhard Stauder, Luca Malcovati, Mikkael Sekeres, David P Steensma, Silke Gloaguen
The heterogeneity of myelodysplastic syndromes (MDS) has made evaluating patient response to treatment challenging. In 2006, an International Working Group (IWG) proposed a revision to previously published standardized response criteria (IWG 2000) for uniformly evaluating clinical responses in MDS. These IWG 2006 criteria have been used prospectively in many clinical trials in MDS, but proved challenging in several of them, especially for the evaluation of erythroid response. In this report, we provide rationale for modifications (IWG 2018) of these recommendations, mainly for "hematological improvement" criteria used for lower risk MDS, based on recent practical and reported experience in clinical trials...
November 7, 2018: Blood
Janine Schmidt, Joan Enric Ramis-Zaldivar, Irina Bonzheim, Julia Steinhilber, Inga Müller, Andrea Haake, Shan Chi Yu, Mark Raffeld, Falko Fend, Itziar Salaverria, Reiner Siebert, Elaine S Jaffe, Leticia Quintanilla-Martinez
No abstract text is available yet for this article.
November 6, 2018: Blood
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