Brian Custer, Claire A Quiner, Richard Haaland, Amy Martin, Mars Stone, Rita Fitzpatrick Reik, Whitney R Steele, Debra Kessler, Phillip Carl Williamson, Steven A Anderson, Alan E Williams, Henry F Raymond, Willi McFarland, William T Robinson, Sara Nelson Glick, Kwa Sey, C David Melton, Simone A Glynn, Susan L Stramer, Michael P Busch
CONTEXT: Antiretroviral therapy (ART) to treat and pre-exposure prophylaxis (PrEP) to prevent HIV infection are effective tools to help end the HIV epidemic. However, their use could affect HIV transfusion-transmission risk. OBJECTIVES: Three different ART/PrEP prevalence analyses in blood donors were conducted. METHODS: First, blood samples from HIV-positive and a comparison group of infection-nonreactive donors were tested under blind using liquid chromatography-tandem mass spectrometry for ART...
July 9, 2020: Blood
Ellen-Sofie Hansen, Kristian Hindberg, Nadezhda Latysheva, Pål Aukrust, Thor Ueland, John-Bjarne Hansen, Sigrid K Braekkan, Vânia Maris Morelli
Growth differentiation factor 15 (GDF-15), a marker of inflammation and oxidative stress, has emerged as a biomarker for arterial cardiovascular disease. However, the association between GDF-15 and venous thromboembolism (VTE) remains uncertain. We therefore investigated the association between plasma GDF-15 levels and future risk of incident VTE, and explored the potential of a causal association using Mendelian randomization (MR). We conducted a population-based nested case-control study comprising 416 VTE patients and 848 age- and sex-matched controls derived from the Tromsø Study...
July 9, 2020: Blood
Kyohei Nakamura, Mark J Smyth, Ludovic Martinet
Avoiding immune destruction is a hallmark of cancer. Over the past few years, significant advances have been made in understanding immune dysfunction and immunosuppression in multiple myeloma (MM), and various immunotherapeutic approaches have delivered improved clinical responses. However, it is still challenging to completely eliminate malignant plasma cells (PCs) and achieve complete cure. The interplay between the immune system and malignant PCs is implicated throughout all stages of plasma cell dyscrasias including asymptomatic states called monoclonal gammopathy of undetermined significance and smoldering myeloma...
July 9, 2020: Blood
Özgün Babur, Alexander Melrose, Jennifer Cunliffe, John Klimek, Jiaqing Pang, Anna-Liisa Sepp, Jevgenia Zilberman-Rudenko, Samuel Tassi Yunga, Tony Zheng, Iván Parra-Izquierdo, Jessica Minnier, Owen McCarty, Emek Demir, Ashok Reddy, Phillip Wilmarth, Larry L David, Joseph E Aslan
Platelets engage cues of pending vascular injury through coordinated adhesion, secretion and aggregation responses. These rapid, progressive changes in platelet form and function are orchestrated downstream of specific receptors on the platelet cell surface, and through intracellular signaling mechanisms that remain systematically undefined. This study brings together cell physiological and phosphoproteomics methods incorporating peptide tandem mass tag (TMT) labeling, sample multiplexing, synchronous precursor selection (SPS) and triple stage tandem mass spectrometry (MS3) to profile signaling mechanisms downstream of the immunotyrosine activation motif (ITAM) platelet collagen receptor GPVI...
July 8, 2020: Blood
Justin Taylor, Xiaoli Mi, Khrystyna Dilai North, Moritz Binder, Alexander Penson, Terra L Lasho, Katherine Knorr, Michael Haddadin, Bo Liu, Joseph Pangallo, Salima Benbarche, Daniel Howard Wiseman, Ayalew Tefferi, Stephanie Halene, Yang Liang, Mrinal M Patnaik, Robert K Bradley, Omar Abdel-Wahab
Large-scale sequencing studies of hematologic malignancies have revealed notable epistasis among high-frequency mutations. One of the most striking examples of epistasis occurs for mutations in RNA splicing factors. These lesions are amongst the most common alterations in myeloid neoplasms and generally occur in a mutually exclusive manner, a finding attributed to their synthetic lethal interactions and/or convergent effects. Curiously, however, patients with multiple concomitant splicing factor mutations have been observed, challenging our understanding of one of the most common examples of epistasis in hematologic malignancies...
July 8, 2020: Blood
Zhi Wen, Adhithi Rajagopalan, Evan Flietner, Grant Yun, Marta Chesi, Quinlan Furumo, Robert Thomas Burns, Athanasios Papadas, Erik A Ranheim, Adam Charles Pagenkopf, Zachary Taylor Morrow, Remington Finn, Yun Zhou, Shuyi Li, Xiaona You, Jeffrey Lee Jensen, Mei Yu, Alexander Cicala, James Menting, Constantine S Mitsiades, Natalie S Callander, P Leif Bergsagel, Demin Wang, Fotis Asimakopoulos, Jing Zhang
NRAS Q61 mutations are prevalent in advanced/relapsed multiple myeloma (MM) and correlate with poor patient outcomes. Thus, we generated a novel MM model by conditionally activating expression of endogenous NrasQ61R and a MYC transgene in germinal center B cells (VQ mice). VQ mice developed a highly malignant MM characterized by high proliferation index, hyperactivation of ERK and AKT signaling, impaired hematopoiesis, widespread extramedullary disease, bone lesions, kidney abnormalities, preserved PD1 and TIGIT immune checkpoint pathways, and expression of human high-risk MM gene signatures...
July 8, 2020: Blood
Blake J Rust, Leslie S Kean, Lucrezia Colonna, Katherine Brandenstein, Nikhita Hegde Poole, Willimark Obenza, Mark R Enstrom, Colby R Maldini, Gavin I Ellis, Christine M Fennessey, Meei-Li Huang, Brandon F Keele, Keith Jerome, James L Riley, Hans-Peter Kiem, Christopher William Peterson
CAR T cells targeting CD19+ hematologic malignancies have rapidly emerged as a promising, novel therapy. In contrast, results from the few CAR T-cell studies for infectious diseases such as HIV-1 have been less convincing. These challenges are likely due to the low level of antigen present in ART-suppressed patients in contrast to those with hematologic malignancies. Here we tested in our well-established nonhuman primate model of ART-suppressed HIV-1 infection strategies to overcome these limitations and challenges...
July 2, 2020: Blood
Robert Chiesa, Junfeng Wang, Henric-Jan Blok, Sheree Hazelaar, Benedicte Neven, Despina Moshous, Ansgar S Schulz, Manfred Hoenig, Fabian Hauck, Amal Al Seraihy, Jolanta Gozdzik, Per T Ljungman, Caroline Lindemans, Juliana Fernandes, Krzysztof Kalwak, Brigitte Strahm, Urs Schanz, Petr Sedlacek, Karl-Walter Sykora, Serap Aksoylar, Franco Locatelli, Polina Stepensky, Robert F Wynn, Su Han Lum, Marco Zecca, Fulvio Porta, Mervi H Taskinen, Brenda Es Gibson, Susanne Matthes-Martin, Musa Karakukcu, Mathias M Hauri-Hohl, Paul Veys, Andrew R Gennery, Giovanna Lucchini, Matthias Felber, Michael H Albert, Dmitry Balashov, Arjan C Lankester, Tayfun Güngör, Mary Slatter
Chronic Granulomatous Disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure patients, but indication to transplant remains controversial. We performed a retrospective multicentre study on 712 patients with CGD undergoing allo-HCT transplanted in EBMT centres between 1993 and 2018. We studied 635 children (aged < 18 years) and 77 adults. Median follow-up was 45 months. Median age at transplant was 7 years (range: 0...
July 2, 2020: Blood
Margery Gang, Nancy D Marin, Pamela Wong, Carly C Neal, Lynne Marsala, Mark Foster, Timothy Schappe, Wei Meng, Jennifer Tran, Maximilian Schaettler, Marco L Davila, Feng Gao, Amanda F Cashen, Nancy L Bartlett, Neha Mehta-Shah, Brad Kahl, Miriam Kim, Matthew L Cooper, John F DiPersio, Melissa M Berrien-Elliott, Todd A Fehniger
NK cells are a promising cellular immunotherapy for cancer. Cytokine-induced memory-like (ML) NK cells differentiate after activation with IL-12, IL-15, and IL-18, exhibit potent anti-tumor responses, and safely induce complete remissions in patients with leukemia. However, many cancers are not fully recognized via NK cell receptors. Chimeric antigen receptors (CAR) have been utilized to enhance tumor-specific recognition by effector lymphocytes. We hypothesized that memory-like differentiation and CAR-engineering would result in complementary improvements in NK cell responses against NK-resistant cancers...
July 2, 2020: Blood
Anish Vaibhav Sharda, Alexandra M Barr, Joshua A Harrison, Adrian R Wilkie, Chao Fang, Lourdes M Mendez, Ionita C Ghiran, Joseph E Italiano, Robert Flaumenhaft
von Willebrand factor (vWF) is an essential hemostatic protein that is synthesized in endothelial cells and stored in Weibel-Palade bodies (WPBs). Understanding the mechanisms underlying WPB biogenesis and exocytosis could enable therapeutic modulation of endogenous vWF, yet optimal targets for modulating vWF release have not been established. Since biogenesis of lysosomal related organelle-2 (BLOC-2) functions in the biogenesis of platelet dense granules and melanosomes, which like WPBs are lysosome-related organelles (LROs), we hypothesized that BLOC-2-dependent endolysosomal trafficking is essential for WPB biogenesis and sought to identify BLOC-2 interacting proteins...
July 2, 2020: Blood
Antonella Fidanza, Patrick Simon Stumpf, Prakash Ramachandran, Sara Tamagno, Ann Babtie, Martha Lopez-Yrigoyen, Alice Helen Taylor, Jennifer Easterbrook, Beth Henderson, Richard Axton, Neil Cowan Henderson, Alexander Medvinsky, Katrin Ottersbach, Nicola Romanò, Lesley M Forrester
Haematopoietic stem and progenitor cells (HSPCs) develop through distinct waves at various anatomical sites during embryonic development. The in vitro differentiation of human pluripotent stem cells (hPSCs) is able to recapitulate some of these processes, however, it has proven difficult to generate functional haematopoietic stem cells (HSCs). To define the dynamics and heterogeneity of HSPCs that can be generated in vitro from hPSCs, we exploited single cell RNA sequencing (scRNAseq) in combination with single cell protein expression analysis...
July 2, 2020: Blood
Laura Oberholzer, Carsten Lundby, Emeric Stauffer, Mathilde Ulliel-Roche, Ivan Hancco, Aurélien Pichon, Anne-Kristine Lundby, Francisco C Villafuerte, Samuel Verges, Paul Robach
No abstract text is available yet for this article.
July 2, 2020: Blood
Clara Bueno, Paola Ballerini, Ignacio Varela, Pablo Menendez, Rachael Bashford-Rogers
No abstract text is available yet for this article.
July 1, 2020: Blood
Brunangelo Falini, Lorenzo Brunetti, Paolo Sportoletti, Maria Paola Martelli
The nucleophosmin (NPM1) gene encodes for a multifunctional protein with prominent nucleolar localization that shuttles between nucleus and cytoplasm. NPM1 mutations represent the most common genetic lesion in adult AML (about one-third of cases) and act deterministically to cause the aberrant cytoplasmic delocalization of NPM1 mutants. Because of its unique features, NPM1-mutated AML is recognized as a distinct entity in the 2016 World Health Organization classification of hematopoietic neoplasms. Here, we focus on recently identified functions of wild-type NPM1 in the nucleolus and address new biological and clinical issues on NPM1-mutated AML...
July 1, 2020: Blood
Kathryn Lurain, Thomas S Uldrick, Ramya Ramaswami, Mark Polizzotto, Priscila Goncalves, Anaida Widell, Seth M Steinberg, Elaine S Jaffe, Stefania Pittaluga, Hao-Wei Wang, Constance Yuan, Mary Anne Tamula, Staci Martin, Pamela L Wolters, Jomy George, Richard F Little, Robert Yarchoan
No abstract text is available yet for this article.
July 1, 2020: Blood
Valerie Novakovic, Gary E Gilbert
Recent reports indicate that suspended skeletal and cardiac myosin, such as might be released during injury, can act as procoagulants by providing membrane-like support for factors Xa and Va in the prothrombinase complex. Further, skeletal myosin provides membrane-like support for activated protein C. This raises the question of whether purified muscle myosins retain procoagulant phospholipid through purification. We found that lactadherin, a phosphatidyl-L-serine-binding protein, blocked >99% of prothrombinase activity supported by rabbit skeletal and by bovine cardiac myosin...
June 30, 2020: Blood
Sujal Ghosh, Sevgi Köstel Bal, Emily S J Edwards, Bethany Pillay, Raúl Jimenez-Heredia, Geetha Rao, Funda Erol Cipe, Elisabeth Salzer, Samaneh Zoghi, Hassan Abolhassani, Tooba Momen, Emma Gostick, David A Price, Yu Zhang, Andrew J Oler, Claudia Gonzaga-Jauregui, Baran Erman, Ayse Metin, Inci Ilhan, Sule Haskologlu, Candan Islamoglu, Kubra Baskin, Serdar Ceylaner, Ebru Yilmaz, Ekrem Unal, Musa Karakukcu, Dagmar Berghuis, Theresa Cole, Aditya Kumar Gupta, Fabian Hauck, Andy Hoepelman, Safa Baris, Elif Karakoc-Aydiner, Ahmet Ozen, Leo Kager, Dirk Holzinger, Michael Paulussen, Renate Krüger, Roland Meisel, Prasad Thomas Oommen, Emma C Morris, Benedicte Neven, Austen J J Worth, Joris M van Montfrans, Pieter Fraaij, Sharon Choo, Figen Dogu, E Graham Davies, Siobhan Burns, Gregor Dueckers, Ruy Perez Becker, Horst von Bernuth, Sylvain Latour, Maura Faraci, Marco Gattorno, Helen Su, Qiang Pan-Hammarström, Lennart Hammarström, Michael J Lenardo, Cindy S Ma, Tim Niehues, Asghar Aghamohammadi, Nima Rezaei, Aydan Ikinciogullari, Stuart G Tangye, Arjan C Lankester, Kaan Boztug
Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity characterized predominantly by EBV-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and malignancy. A comprehensive understanding of the natural history, immune characteristics and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected clinical information of 49 patients from 29 families (CD27 n=33, CD70 n=16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively...
June 30, 2020: Blood
Brian Kornblit, Barry E Storer, Niels Smedegaard Andersen, Michael B Maris, Thomas R Chauncey, Effie W Petersdorf, Ann E Woolfrey, Mary Ed Flowers, Rainer Storb, David Maloney, Brenda M Sandmaier
This trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine and mycophenolate mofetil for GVHD prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched Hematopoietic cell transplantation (HCT). Eligible patients had hematological malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2-3 Gy total body irradiation. GVHD prophylaxis was with cyclosporine, mycophenolate mofetil and sirolimus. The primary objective was to determine whether the cumulative incidence of grade II-IV acute GVHD could be reduced to less than 70%, in HLA class I or II mismatched HCT...
June 30, 2020: Blood
Anna Hayden, Petter Tonseth, Derrick G Lee, Diego Villa, Alina S Gerrie, David W Scott, Ciara L Freeman, Graham W Slack, Pedro Farinha, Brian Skinnider, Paul Richard Yenson, Francois Benard, Andrea Lo, Tom Pickles, Donald Wilson, Joseph Connors, Laurie H Sehn, Kerry J Savage
Cure rates for primary mediastinal large B-cell lymphoma (PMBCL) have improved with the integration of rituximab. However, the type of primary therapy and role of radiotherapy (RT) remains ill-defined. Herein, we evaluated the outcome of PMBCL primarily treated with R-CHOP and the impact of an end-of-treatment (EOT) FDG-PET scan to guide consolidative RT. Patients ≥18 years of age with PMBCL treated with curative intent R-chemotherapy were identified. Prior to 2005, patients were recommended to receive R-CHOP +RT (RT era)...
June 30, 2020: Blood
Marco Vincent Haselager, Karoline Kielbassa, Johanna Ter Burg, Danique Johanna Cornelia Bax, Stacey Marie Fernandes, Jannie Borst, Constantine Tam, Francesco Forconi, Giorgia Chiodin, Jennifer R Brown, Julie Dubois, Arnon P Kater, Eric Eldering
Chronic lymphocytic leukemia (CLL) cells cycle between lymph node (LN) and peripheral blood (PB) and display major shifts in Bcl-2 family members between those compartments. Specifically, Bcl-XL and Mcl-1, which are not targeted by the Bcl-2 inhibitor venetoclax, are increased in the LN. Since ibrutinib forces CLL cells out of the LN, we hypothesized that ibrutinib may thereby affect expression of Bcl-XL and Mcl-1 and sensitize CLL cells to venetoclax. We investigated expression of Bcl-2 family members in patients under ibrutinib or venetoclax treatment combined with dissecting functional interactions of Bcl-2 family members in an in vitro model for venetoclax resistance...
June 30, 2020: Blood
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