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Paul S de Vries, Maria Sabater-Lleal, Jennifer E Huffman, Jonathan Marten, Ci Song, Nathan Pankratz, Traci M Bartz, Hugoline G de Haan, Graciela E Delgado, John D Eicher, Angel Martinez-Perez, Cavin K Ward-Caviness, Jennifer A Brody, Ming-Huei Chen, Moniek P M de Maat, Mattias Frånberg, Dipender Gill, Marcus E Kleber, Fernando Rivadeneira, José Manuel Soria, Weihong Tang, Geoffrey H Tofler, André G Uitterlinden, Astrid van Hylckama Vlieg, Sudha Seshadri, Eric Boerwinkle, Neil M Davies, Anne-Katrin Giese, M Kamran Ikram, Steven J Kittner, Barbara McKnight, Bruce M Psaty, Alex P Reiner, Muralidharan Sargurupremraj, Kent D Taylor, Myriam Fornage, Anders Hamsten, Winfried März, Frits R Rosendaal, Juan Carlos Souto, Abbas Dehghan, Andrew D Johnson, Alanna C Morrison, Christopher J O'Donnell, Nicholas L Smith
Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of nine genome-wide association studies of plasma FVII levels (seven FVII activity and two FVII antigen) among 27,495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis...
January 14, 2019: Blood
Xianchi Dong, Nina C Leksa, Ekta Seth Chhabra, Joseph W Arndt, Qi Lu, Kevin E Knockenhauer, Robert T Peters, Timothy A Springer
D assemblies comprise half of von Willebrand factor yet are of unknown structure. D1 and D2 in the prodomain and D'D3 in mature VWF at Golgi pH form helical VWF tubules in Weibel Palade bodies and template dimerization of D3 through disulfides to form ultralong VWF concatemers. D'D3 forms the binding site for factor VIII. The crystal structure of monomeric D'D3 with cysteine residues required for dimerization mutated to alanine was determined at endoplasmic reticulum (ER)-like pH. The smaller C8-3, TIL3 and E3 modules pack through specific interfaces as they wind around the larger, N-terminal, Ca2+ -binding VWD3 module to form a wedge shape...
January 14, 2019: Blood
Deborah M Stephens, John C Byrd
Chronic lymphocytic leukemia (CLL) therapy has changed dramatically with the introduction of several targeted therapeutics. Ibrutinib was the first approved for use in 2014 and now is used for initial and salvage therapy of CLL patients. With its widespread use in clinical practice, ibrutinib's common and uncommon adverse events reported less frequently in earlier clinical trials have been experienced more frequently in real-world practice. In particular, atrial fibrillation, bleeding, infections, and arthralgias have been reported...
January 14, 2019: Blood
Eimear Dunne, Qin M Qi, Eric S Shaqfeh, Jamie M O'Sullivan, Ingmar Schoen, Antonio J Ricco, James S O'Donnell, Dermot Kenny
Blood Type O is associated with a lower risk of myocardial infarction. Platelets play a critical role in myocardial infarction. It is not known whether the expression of blood group antigens on platelet proteins alters platelet function; we hypothesized that platelet function would be different between donors with blood type O and those with non-O. To address this hypothesis, we perfused blood from healthy type O donors (n=33) or non-O donors (n=54) over pooled plasma derived von Willebrand factor (VWF) protein and purified blood-type-specific VWF at arterial shear and measured platelet translocation dynamics...
January 14, 2019: Blood
Shaun P Jackson, Roxane Darbousset, Simone M Schoenwaelder
Thrombosis with associated inflammation (thromboinflammation) occurs commonly in a broad range of human disorders. It is well recognized clinically in the context of superficial thrombophlebitis (thrombosis and inflammation of superficial veins), however it is more dangerous when it develops in the microvasculature of injured tissues and organs. Microvascular thrombosis with associated inflammation is well recognized in the context of sepsis and ischemia-reperfusion injury, however it also occurs in organ transplant rejection, major trauma, severe burns, the antiphospholipid syndrome, preeclampsia, sickle cell disease and biomaterial-induced thromboinflammation...
January 14, 2019: Blood
Rein Willemze, Lorenzo Cerroni, Werner Kempf, Emilio Berti, Fabio Facchetti, Steven H Swerdlow, Elaine S Jaffe
Primary cutaneous lymphomas are a heterogeneous group of T-cell lymphomas and B-cell lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. In the last decade the 2005 WHO-EORTC consensus classification has served as a golden standard for the diagnosis and classification of these conditions. In September 2018 an updated version of the WHO-EORTC was published in the 4th edition of the WHO classification for Skin Tumours Blue Book. In this classification primary cutaneous acral CD8+ T-cell lymphoma and EBV-positive mucocutaneous ulcer are included as new provisional entities, and a new section on cutaneous forms of chronic active EBV disease has been added...
January 11, 2019: Blood
Iris Z Uras, Barbara Maurer, Harini Nivarthi, Philipp Jodl, Karoline Kollmann, Michaela Prchal-Murphy, Jelena D Milosevic Feenstra, Markus Zojer, Sabine Lagger, Reinhard Grausenburger, Beatrice Grabner, Raimund Holly, Anoop Kavirayani, Christoph Bock, Heinz Gisslinger, Peter Valent, Robert Kralovics, Veronika Sexl
Over 80% of patients with myeloproliferative neoplasms (MPNs) harbour the acquired somatic Jak2V617F mutation. JAK inhibition is not curative and fails to induce a persistent response in most patients, illustrating the need for the development of novel therapeutic approaches. We describe a critical role for CDK6 in MPN evolution. The absence of Cdk6 ameliorates clinical symptoms and prolongs survival. The CDK6 protein interferes with three hallmarks of disease: besides regulating malignant stem cell quiescence, it promotes NFκB signaling and contributes to cytokine production while inhibiting apoptosis...
January 11, 2019: Blood
Paul J Orchard, David R Nascene, Weston P Miller, Ashish Gupta, Dan Kenney-Jung, Troy C Lund
Adrenoleukodystrophy (ALD) is caused by mutations within the X-linked ABCD1 gene resulting in the inability to transport acylated very long chain fatty acids (VLCFA) into the peroxisome for degradation. VLCFA subsequently accumulate in tissues, including the central nervous system. Up to 40% of boys develop a severe, progressive demyelinating form of ALD, cerebral ALD (cALD), resulting in regions of demyelination observed on brain magnetic resonance imaging (MRI) that are associated with a "garland ring" of gadolinium contrast enhancement...
January 11, 2019: Blood
Gerwin Huls, Dana A Chitu, Violaine Havelange, Mojca Jongen-Lavrencic, Arjan A van de Loosdrecht, Bart J Biemond, Harm Sinnige, Beata Hodossy, Carlos Graux, Rien van Marwijk Kooy, Okke de Weerdt, Dimitri Breems, Saskia Klein, Jürgen Kuball, Dries Deeren, Wim Terpstra, Marie-Christiane Vekemans, Gert J Ossenkoppele, Edo Vellenga, Bob Löwenberg
The prevention of relapse is the major therapeutic challenge in older patients with acute myeloid leukemia (AML) who have obtained a complete remission (CR) on intensive chemotherapy. In this randomized phase III study (HOVON97) in older patients (≥ 60 years) with AML or MDS-RAEB, in CR/CRi after at least 2 cycles of intensive chemotherapy, we assessed the value of azacitidine as post remission therapy with respect to the disease free survival (DFS; primary endpoint) and overall survival (OS; secondary endpoint)...
January 10, 2019: Blood
David J H F Knapp, Colin A Hammond, Fangwu Wang, Nima Aghaeepour, Paul H Miller, Philip A Beer, Davide Pellacani, Michael VanInsberghe, Carl Hansen, Sean C Bendall, Garry P Nolan, Connie J Eaves
Recent advances in single-cell molecular analytical methods and clonal growth assays are enabling more refined models of human hematopoietic lineage restriction processes to be conceptualized. Here, we report the results of integrating single-cell proteome measurements with clonally-determined lymphoid, neutrophilic/monocytic, and/or erythroid progeny outputs from over 1,000 index-sorted CD34+ human cord blood cells in short-term cultures with and without stromal cells. Surface phenotypes of functionally examined cells were individually mapped onto a molecular landscape of the entire CD34+ compartment constructed from single-cell mass cytometric measurements of 14 cell surface markers, 20 signaling/cell cycle proteins and 6 transcription factors in approximately 300,000 cells...
January 8, 2019: Blood
Antonio Piga, Silverio Perrotta, Maria Rita Gamberini, Ersi Voskaridou, Angela Melpignano, Aldo Filosa, Vincenzo Caruso, Antonello Pietrangelo, Filomena Longo, Immacolata Tartaglione, Caterina Borgna-Pignatti, Xiaosha Zhang, Abderrahmane Laadem, Matthew L Sherman, Kenneth M Attie
Beta-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. This study aim was to determine whether luspatercept could improve anemia and disease complications in patients with beta-thalassemia. This open-label, nonrandomized, uncontrolled study (NCT01749540 and NCT02268409) consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5 year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion-dependent (mean hemoglobin <10...
January 7, 2019: Blood
Magdalena Klanova, Laurie H Sehn, Isabelle Bence-Bruckler, Federica Cavallo, Jie Jin, Maurizio Martelli, Douglas Stewart, Umberto Vitolo, Francesco Zaja, Qingyuan Zhang, Federico Mattiello, Gila Sellam, Elizabeth A Punnoose, Edith Szafer-Glusman, Christopher R Bolen, Mikkel Z Oestergaard, Guenter R Fingerle-Rowson, Tina Nielsen, Marek Trneny
Central nervous system (CNS) relapse carries a poor prognosis in diffuse large B-cell lymphoma (DLBCL). Integrating biomarkers into the CNS International Prognostic Index (CNS-IPI) risk model may improve identification of patients at high risk of developing secondary CNS disease. CNS relapse was analyzed in 1,418 DLBCL patients treated with obinutuzumab or rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy in the phase III GOYA study. Cell-of-origin (COO) was assessed using gene expression profiling...
January 7, 2019: Blood
Gabriella E Martyn, Beeke Wienert, Ryo Kurita, Yukio Nakamura, Kate G R Quinlan, Merlin Crossley
β-hemoglobinopathies, such as sickle cell disease and β-thalassemia result from mutations in the adult β-globin gene. Reactivating the developmentally silenced fetal γ-globin gene elevates fetal hemoglobin levels and ameliorates symptoms of β-hemoglobinopathies. The continued expression of fetal γ-globin into adulthood occurs naturally in a genetic condition termed Hereditary Persistence of Fetal Hemoglobin (HPFH). Point mutations in the fetal γ-globin proximal promoter can cause HPFH. The -113A>G HPFH mutation falls within the -115 cluster of HPFH mutations, a binding site for the fetal globin repressor BCL11A...
January 7, 2019: Blood
Hye-Sook Kwon, Aaron C Logan, Akanksha Chhabra, Wendy W Pang, Agnieszka Czechowicz, Keri Tate, Alan Le, Jessica Poyser, Roger Hollis, Benjamin V Kelly, Donald B Kohn, Irving L Weissman, Susan S Prohaska, Judith A Shizuru
No abstract text is available yet for this article.
January 7, 2019: Blood
Bruno M Grande, Daniela S Gerhard, Aixiang Jiang, Nicholas B Griner, Jeremy S Abramson, Thomas B Alexander, Hilary Allen, Leona W Ayers, Jeffrey M Bethony, Kishor Bhatia, Jay Bowen, Corey Casper, John Kim Choi, Luka Culibrk, Tanja M Davidsen, Maureen A Dyer, Julie M Gastier-Foster, Patee Gesuwan, Timothy C Greiner, Thomas G Gross, Benjamin Hanf, Nancy Lee Harris, Yiwen He, John D Irvin, Elaine S Jaffe, Steven J M Jones, Patrick Kerchan, Nicole Knoetze, Fabio E Leal, Tara M Lichtenberg, Yussanne Ma, Jean Paul Martin, Marie-Reine Martin, Sam M Mbulaiteye, Charles G Mullighan, Andrew J Mungall, Constance Namirembe, Karen Novik, Ariela Noy, Martin D Ogwang, Abraham Omoding, Jackson Orem, Steven J Reynolds, Christopher K Rushton, John T Sandlund, Roland Schmitz, Cynthia Taylor, Wyndham H Wilson, George W Wright, Eric Y Zhao, Marco A Marra, Ryan D Morin, Louis M Staudt
Though generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in over 90% of cases in malaria-endemic regions and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and AICDA activity...
January 7, 2019: Blood
Eric Oksenhendler, David Boutboul, Lionel Galicier
Kaposi's sarcoma-associated herpesvirus/Human herpesvirus 8 (KSHV/HHV-8) is associated with multicentric Castleman disease (MCD) and primary effusion lymphoma (PEL), two unique lymphoproliferative disorders (LPDs). In MCD, KSHV/HHV-8-infected B cells, although polyclonal, express a monotypic IgMλ phenotype, probably through revision of the B cell receptor and editing towards lambda light chain in mature B cells. Despite a phenotype of plasmablasts, they do not harbor somatic mutations and are considered to originate from pre-germinal center (GC) naive B cells...
January 4, 2019: Blood
Friederike Christen, Kaja Hoyer, Kenichi Yoshida, Hsin-An Hou, Nils Waldhueter, Michael Heuser, Robert K Hills, Willy Chan, Raphael Hablesreiter, Olga Blau, Yotaro Ochi, Piroska Klement, Wen-Chien Chou, Igor-Wolfgang Blau, Jih-Luh Tang, Tomasz Zemojtel, Yuichi Shiraishi, Yusuke Shiozawa, Felicitas Thol, Arnold Ganser, Bob Löwenberg, David C Linch, Lars Bullinger, Peter J M Valk, Hwei-Fang Tien, Rosemary E Gale, Seishi Ogawa, Frederik Damm
Acute myeloid leukemia (AML) with t(8;21)(q22;q22) is characterized by considerable clinical and biological heterogeneity leading to relapse in up to 40%. We sequenced coding regions or hotspot areas of 66 recurrently mutated genes in a cohort of 331 t(8;21) patients. At least one mutation in addition to t(8;21) was identified in 95% with a mean of 2.2 driver mutations per patient. Recurrent mutations occurred in genes related to RAS/RTK signaling (63.4%), epigenetic regulators (45%), cohesin complex (13.6%), MYC signaling (10...
January 4, 2019: Blood
Catherine Cargo, Matthew Cullen, Jan Taylor, Mike Short, Paul Glover, Suzan Van Hoppe, Alex Smith, Paul Evans, Simon Crouch
The diagnosis of chronic myelomonocytic leukaemia (CMML) remains centred on morphology, meaning the distinction from a reactive monocytosis is challenging. Mutational analysis and immunophenotyping have been proposed as potential tools for diagnosis however have not been formally assessed in combination. We aimed to investigate the clinical utility of these technologies by performing targeted sequencing, in parallel to current gold standard techniques, on consecutive samples referred for investigation of monocytosis over a 2-year period (n=283)...
January 3, 2019: Blood
Pierre Fenaux, Jean Jacques Kiladjian, Uwe Platzbecker
Anemia of lower risk MDS and PMF generally becomes resistant to available treatments, leading to RBC transfusions, iron overload, shortened survival and poor quality of life. The TGF-β superfamily, including activins and growth differentiation factors (GDF), is aberrantly expressed in lower risk MDS and PMF. Luspatercept (and Sotatercept), ligand traps that particularly inhibit GDF 11, lead to RBC transfusion independence in 10-50% of lower risk MDS resistant to available treatments, and have started to be used in PMF...
January 2, 2019: Blood
Alessandro Donada, Nathalie Balayn, Dominika Sliwa, Larissa Lordier, Valentina Ceglia, Francesco Baschieri, Cyril Goizet, Rémi Favier, Lucie Tosca, Gérard Tachdjian, Cecile V Denis, Isabelle Plo, William Vainchenker, Najet Debili, Jean-Philippe Rosa, Marijke Bryckaert, Hana Raslova
Filamin A (FLNa) links the cell membrane with the cytoskeleton and is central in several cellular processes. Heterozygous mutations in the X-linked FLNA gene are associated with a large spectrum of conditions called filaminopathies that include macrothrombocytopenia. Here we show, using an isogenic pluripotent stem cell model derived from patients, that the absence of the FLNa protein in megakaryocytes (MKs) leads to their incomplete maturation, and particularly the inability to produce proplatelets. The reduction in the proplatelet formation potential is associated with a defect in the acto-myosin contractility, due to inappropriate RhoA activation...
January 2, 2019: Blood
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