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https://www.readbyqxmd.com/read/28916584/novel-insights-into-the-clinical-phenotype-and-pathophysiology-underlying-low-vwf-levels
#1
Michelle Lavin, Sonia Aguila, Sonja Schneppenheim, Niall Dalton, Kenneth L Jones, Jamie M O'Sullivan, Niamh M O'Connell, Kevin Ryan, Barry White, Mary Byrne, Marie Rafferty, Mairead M Doyle, Margaret Nolan, Roger J S Preston, Ulrich Budde, Paula James, Jorge Di Paola, James S O'Donnell
Critical clinical questions remain unanswered regarding diagnosis and management of patients with Low VWF levels (30-50 IU/dL). To address these questions, the Low VWF Ireland Cohort (LoVIC) study investigated 126 patients registered with Low VWF. Interestingly, despite their marginally reduced plasma VWF levels, ISTH BAT and Condensed MCMDM-1 VWD scores both confirmed significant bleeding phenotypes in the majority of LoVIC patients. For example, among female patients with Low VWF, 77% had ISTH BAT scores ≥6...
September 15, 2017: Blood
https://www.readbyqxmd.com/read/28912376/a-recombinant-human-adamts-13-first-in-human-study-evaluating-pharmacokinetics-safety-and-tolerability-in-cttp-patients
#2
Marie Scully, Paul Knöbl, Karim Kentouche, Lawrence Rice, Jerzy Windyga, Reinhard Schneppenheim, Johanna A Kremer Hovinga, Michiko Kajiwara, Yoshihiro Fujimura, Caterina Maggiore, Jennifer Doralt, Christopher Hibbard, Leah Martell, Bruce Ewenstein
Safety, tolerability and pharmacokinetics of recombinant ADAMTS-13 (rADAMTS-13; BAX 930; SHP655) were investigated in 15 patients diagnosed with severe congenital ADAMTS-13 deficiency (plasma ADAMTS-13 activity < 6%) in a prospective phase 1, first-in-human, multicenter dose escalation study. BAX 930 was well tolerated, no serious adverse events occurred, and no anti-ADAMTS-13 antibodies were observed. Following single dose administration of BAX 930 at 5, 20, or 40 U/kg body weight to adolescents and adults, there was approximate dose proportionality with respect to Cmax and AUC...
September 14, 2017: Blood
https://www.readbyqxmd.com/read/28903944/a-dual-role-for-the-class-iii-pi3k-vps34-in-platelet-production-and-thrombus-growth
#3
Colin Valet, Marie Levade, Gaëtan Chicanne, Benoit Bilanges, Cendrine Cabou, Julien Viaud, Marie-Pierre Gratacap, Frédérique Gaits-Iacovoni, Bart Vanhaesebroeck, Bernard Payrastre, Sonia Severin
To uncover the role of Vps34, the sole class III phosphoinositide 3-kinase, in megakaryocytes (MKs) and platelets, we created a mouse model with Vps34 deletion in the MK/platelet lineage (Pf4-Cre/Vps34(lox/lox)). Deletion of Vps34 in MKs led to the loss of its regulator protein Vps15, and was associated with microthrombocytopenia and platelet granule abnormalities. While Vps34 deficiency did not impact on MK polyploidisation or proplatelet formation, it dampened MK granule biogenesis and directional migration towards an SDF1α gradient, leading to ectopic platelet release within the bone marrow...
September 13, 2017: Blood
https://www.readbyqxmd.com/read/28903943/therapeutic-potential-of-sgn-cd19b-a-pbd-based-anti-cd19-drug-conjugate-for-treatment-of-b-cell-malignancies
#4
Maureen C Ryan, Maria Corinna Palanca-Wessels, Brian Schimpf, Kristine A Gordon, Heather Kostner, Brad Meyer, Changpu Yu, Heather Van Epps, Dennis Benjamin
Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia (B-ALL) have a poor prognosis. Despite measurable clinical activity with new targeted therapies, many patients do not achieve a complete or durable response suggesting an opportunity to improve upon existing therapies. Here we describe SGN-CD19B, a pyrrolobenzodiazepine (PBD)-based anti-CD19 antibody drug conjugate (ADC) being investigated for treatment of B-cell malignancies, which has improved potency compared to other ADCs...
September 13, 2017: Blood
https://www.readbyqxmd.com/read/28903942/wip-deficiency-severely-affects-human-lymphocyte-architecture-during-migration-and-synapse-assembly
#5
Laurène Pfajfer, Markus G Seidel, Raïssa Houmadi, Javier Rey-Barroso, Tatjana Hirschmugl, Elisabeth Salzer, Inés María Antón, Christian Urban, Wolfgang Schwinger, Kaan Boztug, Loïc Dupré
No abstract text is available yet for this article.
September 13, 2017: Blood
https://www.readbyqxmd.com/read/28899854/non-classical-fcgr2c-haplotype-is-associated-with-protection-from-red-blood-cell-allo-immunization-in-sickle-cell-disease
#6
Sanne M Meinderts, Joep W R Sins, Karin Fijnvandraat, Sietse Q Nagelkerke, Judy Geissler, Michael W Tanck, Christine Bruggeman, Bart J Biemond, Anita W Rijneveld, Jean-Louis H Kerkhoffs, Sadaf Pakdaman, Anoosha Habibi, Robin van Bruggen, Taco W Kuijpers, France Pirenne, Timo K van den Berg
Red blood cell (RBC) transfusions are of vital importance in patients with sickle cell disease (SCD). However, a major complication of transfusion therapy is allo-immunization. The low-affinity Fc gamma receptors (FcγRs), expressed on immune cells, are important regulators of antibody responses. Genetic variation in FCGR genes has been associated with various auto- and allo-immune diseases. The aim of this study was to evaluate the association between genetic variation of FCGR and RBC allo-immunization in SCD...
September 12, 2017: Blood
https://www.readbyqxmd.com/read/28899853/the-potential-for-chemotherapy-free-strategies-in-mantle-cell-lymphoma
#7
Peter Martin, Jia Ruan, John P Leonard
Mantle cell lymphoma (MCL) may be one of the few cancers where multiple chemotherapy and non-chemotherapy regimens are considered as standard. Despite the significant activity of chemotherapy in the first-line setting and beyond, its limitations are reflected in the relatively poor ultimate outcomes of patients with MCL treated in the real world. Highly proliferative MCL and those with TP53 mutations tend to respond poorly despite intensive cytotoxic therapies. Patients with co-morbidities and those that are geographically isolated may not have access to the regimens that may appear most promising in clinical trials...
September 12, 2017: Blood
https://www.readbyqxmd.com/read/28899852/identification-of-extant-vertebrate-myxine-glutinosa-vwf-evolutionary-conservation-of-primary-hemostasis
#8
Marianne A Grant, David L Beeler, Katherine C Spokes, Junmei Chen, Harita Dharaneeswaran, Tracey E Sciuto, Ann M Dvorak, Gianluca Interlandi, José A Lopez, William C Aird
Hemostasis in vertebrates involves both a cellular and protein component. Previous studies in jawless vertebrates (cyclostomes) suggest that the protein response, which involves thrombin-catalyzed conversion of a soluble plasma protein, fibrinogen, into a polymeric fibrin clot, is conserved in all vertebrates. However, similar data are lacking for the cellular response, which in gnathostomes, is regulated by von Willebrand factor (VWF), a glycoprotein that mediates the adhesion of platelets to the subendothelial matrix of injured blood vessels...
September 12, 2017: Blood
https://www.readbyqxmd.com/read/28893734/origins-of-myelodysplastic-syndromes-after-aplastic-anemia
#9
Eiju Negoro, Yasunobu Nagata, Michael J Clemente, Naoko Hosono, Wenyi Shen, Aziz Nazha, Tetsuichi Yoshizato, Cassandra Hirsch, Bartlomiej Przychodzen, Reda Z Mahfouz, Teodora Kuzmanovic, Mikkael A Sekeres, Hideki Makishima, Seishi Ogawa, Jaroslaw P Maciejewski
No abstract text is available yet for this article.
September 11, 2017: Blood
https://www.readbyqxmd.com/read/28893733/topological-analysis-reveals-a-pd-l1-associated-microenvironmental-niche-for-reed-sternberg-cells-in-hodgkin-lymphoma
#10
Christopher D Carey, Daniel Gusenleitner, Mikel Lipschitz, Margaretha G M Roemer, Edward C Stack, Evisa Gjini, Xihao Hu, Robert Redd, Gordon J Freeman, Donna Neuberg, F Stephen Hodi, Xiaole Shirley Liu, Margaret A Shipp, Scott J Rodig
Signaling between programmed cell death protein 1 (PD-1) and the programmed cell death -1 ligands (PD-1 ligands, PD-L1, PD-L2) is essential for malignant Hodgkin Reed-Sternberg (HRS) cells to evade anti-tumor immunity in classical Hodgkin lymphoma (cHL). Copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) contribute to robust PD-L1 and PD-L2 expression by HRS cells. PD-L1 is also expressed by non-malignant tumor-associated macrophages (TAMs) but the relationships between PD-L1+ HRS cells, PD-L1+ TAMs, and PD-1+ T-cells remain undefined...
September 11, 2017: Blood
https://www.readbyqxmd.com/read/28887325/at-least-20-donor-myeloid-chimerism-is-necessary-to-reverse-the-sickle-phenotype-after-allogeneic-hsct
#11
Courtney D Fitzhugh, Stefan Cordes, Tiffani Taylor, Wynona Coles, Katherine Roskom, Mary Link, Matthew M Hsieh, John F Tisdale
Novel curative therapies employing genetic transfer of normal globin-producing genes into autologous hematopoietic stem cells (HSCs) are in clinical trials for patients with sickle cell disease (SCD). The percentage of transferred globin necessary to cure SCD is currently not known. In the setting of allogeneic nonmyeloablative hematopoietic stem cell transplants (HSCT), stable mixed chimerism is sufficient to reverse the disease. We regularly monitored 67 patients after HSCT. After initially robust engraftment, three of these patients experienced declining donor myeloid chimerism (DMC) levels with eventual return of disease...
September 8, 2017: Blood
https://www.readbyqxmd.com/read/28882883/cytoprotective-activated-protein-c-averts-nlrp3-inflammasome-induced-ischemia-reperfusion-injury-via-mtorc1-inhibition
#12
Sumra Nazir, Ihsan Gadi, Moh'd Mohanad Al-Dabet, Ahmed Elwakiel, Shrey Kohli, Sanchita Ghosh, Jayakumar Manoharan, Satish Ranjan, Fabian Bock, Ruediger C Braun-Dullaeus, Charles T Esmon, Tobias B Huber, Eric Camerer, Chris Dockendorff, John H Griffin, Berend Isermann, Khurrum Shahzad
Cytoprotection by activated protein C (aPC) following ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation and hence conceptually cell-death forms disjunct from immunologically silent apoptosis are more likely to be relevant. As pyroptosis, cell death resulting from inflammasome activation, is typically observed in IRI we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRI...
September 7, 2017: Blood
https://www.readbyqxmd.com/read/28882882/how-i-treat-patients-with-hiv-related-hematological-malignancies-using-hematopoietic-cell-transplantation
#13
Joseph C Alvarnas, John A Zaia, Stephen J Forman
Hematopoietic cell transplantation (HCT) has now been shown to be safe and effective for selected HIV-infected patients with hematological malignancies. Autologous HCT is now standard of care for patients with HIV-related lymphomas who otherwise meet standard transplant criteria. Limited data also supports use of allogeneic HCT (alloHCT) in selected HIV-infected patients who meet standard transplant criteria. We recommend enrolling patients on clinical trials that offer access to CCR5Δ32 homozygous donors, if available...
September 7, 2017: Blood
https://www.readbyqxmd.com/read/28874350/prognostic-significance-of-baseline-metabolic-tumor-volume-in-relapsed-and-refractory-hodgkin-lymphoma
#14
Alison J Moskowitz, Heiko Schöder, Somali Gavane, Katie L Thoren, Martin Fleisher, Joachim Yahalom, Susan J McCall, Briana R Cadzin, Stephanie Y Fox, John Gerecitano, Ravinder Grewal, Paul A Hamlin, Steven M Horwitz, Anita Kumar, Matthew Matasar, Andy Ni, Ariela Noy, M Lia Palomba, Miguel-Angel Perales, Carol S Portlock, Craig Sauter, David Straus, Anas Younes, Andrew D Zelenetz, Craig H Moskowitz
Identification of prognostic factors for patients with relapsed or refractory (rel/ref) Hodgkin lymphoma (HL) is essential for optimizing therapy with risk-adapted approaches. In our phase II study of PET-adapted salvage therapy with brentuximab vedotin (BV) and augmented ifosfamide, carboplatin, etoposide (augICE) we assessed clinical factors, quantitative PET assessments, and cytokines/chemokine values. Transplant-eligible patients with rel/ref HL received 2 (cohort 1) or 3 (cohort 2) cycles of weekly BV; PET-negative (Deauville ≤ 2) patients proceeded to autologous stem cell transplant (ASCT) while PET-positive patients received augICE before ASCT...
September 5, 2017: Blood
https://www.readbyqxmd.com/read/28874349/inflammation-a-key-regulator-of-hematopoietic-stem-cell-fate-in-health-and-disease
#15
Eric M Pietras
Hematopoietic stem cells (HSCs) are responsible for lifelong production of blood cells. At the same time, they must respond rapidly to acute needs such as infection or injury. Significant interest has emerged in how inflammation regulates HSC fate, and how it impacts the long-term functionality of HSCs and the blood system as a whole. Here we detail recent advances and unanswered questions at the intersection between inflammation and HSC biology in the contexts of development, aging and hematological malignancy...
September 5, 2017: Blood
https://www.readbyqxmd.com/read/28864815/eltrombopag-a-powerful-chelator-of-cellular-or-extracellular-iron-iii-alone-or-combined-with-a-second-chelator
#16
Evangelia Vlachodimitropoulou, Yu-Lin Chen, Maciej Garbowski, Pimpisid Koonyosying, Bethan Psaila, Martha Sola-Visner, Nichola Cooper, Robert Hider, John Porter
Eltrombopag (ELT) is a thrombopoietin receptor agonist, also reported to decrease labile iron in leukemia cells. Here we examine the previously undescribed iron(III)-coordinating and cellular iron-mobilizing properties of ELT. We find a high binding constant for iron(III) (log β2=35). Clinically achievable concentrations (1μM) progressively mobilised cellular iron from hepatocyte, cardiomyocyte and pancreatic cell lines, rapidly decreasing intracellular ROS and also restoring insulin secretion in pancreatic cells...
September 1, 2017: Blood
https://www.readbyqxmd.com/read/28864814/rituximab-based-first-line-treatment-for-chronic-gvhd-after-allogeneic-sct-results-of-a-phase-2-study
#17
Florent Malard, Myriam Labopin, Ibrahim Yakoub-Agha, Sylvain Chantepie, Thierry Guillaume, Didier Blaise, Reza Tabrizi, Leonardo Magro, Bernard Vanhove, Gilles Blancho, Philippe Moreau, Béatrice Gaugler, Patrice Chevallier, Mohamad Mohty
Chronic graft-versus-host disease (cGVHD) is the main cause of late non-relapse mortality and morbidity after allogeneic stem-cell transplantation (allo-SCT). In order to improve such patients' outcome, we conducted a phase 2, prospective, multicenter trial to test the efficacy of addition of rituximab to corticosteroid and cyclosporine A as first line therapy for newly diagnosed cGVHD after allo-SCT. Twenty-four patients (median age, 47 years) with mild (n=2), moderate (n=7) or severe (n=15) cGVHD were included...
September 1, 2017: Blood
https://www.readbyqxmd.com/read/28864813/the-immunophilin-fkbp12-inhibits-hepcidin-expression-by-binding-the-bmp-type-i-receptor-alk2-in-hepatocytes
#18
Silvia Colucci, Alessia Pagani, Mariateresa Pettinato, Irene Artuso, Antonella Nai, Clara Camaschella, Laura Silvestri
The expression of the key regulator of iron homeostasis hepcidin is activated by the BMP-SMAD pathway in response to iron and inflammation and among drugs, by rapamycin, which inhibits mTOR in complex with the immunophilin FKBP12. FKBP12 interacts with BMP type I receptors to avoid uncontrolled signaling. By pharmacologic and genetic studies we identify FKBP12 as a novel hepcidin regulator. Sequestration of FKBP12 by rapamycin or tacrolimus activates hepcidin both in vitro and in murine hepatocytes. Acute tacrolimus treatment transiently increases hepcidin in wild type mice...
September 1, 2017: Blood
https://www.readbyqxmd.com/read/28860210/safety-and-persistence-of-wt1-specific-t-cell-receptor-gene-transduced-lymphocytes-in-patients-with-aml-and-mds
#19
Isao Tawara, Shinichi Kageyama, Yoshihiro Miyahara, Hiroshi Fujiwara, Tetsuya Nishida, Yoshiki Akatsuka, Hiroaki Ikeda, Kazushi Tanimoto, Seitaro Terakura, Makoto Murata, Yoko Inaguma, Masahiro Masuya, Naoki Inoue, Tomohide Kidokoro, Sachiko Okamoto, Daisuke Tomura, Hideto Chono, Ikuei Nukaya, Junichi Mineno, Tomoki Naoe, Nobuhiko Emi, Masaki Yasukawa, Naoyuki Katayama, Hiroshi Shiku
WT1 is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in human trial of TCR-gene transduced T cell (TCR-T cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells. The WT1-specific TCR-gene was transduced to T cells using a retroviral vector encoding siRNAs for endogenous TCR genes...
August 31, 2017: Blood
https://www.readbyqxmd.com/read/28855157/h3-k27m-i-mutations-promote-context-dependent-transformation-in-acute-myeloid-leukemia-with-runx1-alterations
#20
Bernhard Lehnertz, Yu Wei Zhang, Isabel Boivin, Nadine Mayotte, Elisa Tomellini, Jalila Chagraoui, Vincent-Philippe Lavallée, Josée Hébert, Guy Sauvageau
Neomorphic missense mutations affecting crucial lysine residues in histone H3 genes significantly contribute to a variety of solid cancers. Despite the high prevalence of H3(K27M) mutations in pediatric glioblastoma and their well-established impact on global histone H3 lysine 27 di and trimethylation (H3K27me2/3), the relevance of these mutations has not been studied in acute myeloid leukemia (AML). Here, we report the first identification of H3(K27M) and H3(K27I) mutations in AML patients. We find that these lesions are major determinants of reduced H3K27me2/3 in these patients and that they associate with common aberrations in the RUNX1 gene...
August 30, 2017: Blood
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