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https://www.readbyqxmd.com/read/28637667/thrombocytopenia-in-pregnancy
#1
Douglas B Cines, Lisa D Levine
Thrombocytopenia develops in 5-10% of women during pregnancy or in the immediate post-partum period. A low platelet count is often an incidental feature, but it can also provide a biomarker of a coexisting systemic or gestational disorder and a potential reason for a maternal intervention or treatment that might pose harm to the fetus. This chapter reflects our approach to these issues with an emphasis on advances in understanding and managing the more common causes of thrombocytopenia in pregnancy made over the past 5-10 years...
June 21, 2017: Blood
https://www.readbyqxmd.com/read/28637666/nr4a-orphan-nuclear-receptor-family-members-nr4a2-and-nr4a3-regulate-neutrophil-number-and-survival
#2
Lynne R Prince, Svenja Dannewitz Prosseda, Kathryn Higgins, Jennifer Carlring, Elizabeth C Prestwich, Nikolay V Ogryzko, Atiqur Rahman, Alexander Basran, Francesco Falciani, Philip Taylor, Stephen A Renshaw, Moira K B Whyte, Ian Sabroe
Neutrophil lifespan is plastic and highly responsive to factors that regulate cellular survival. Defects in neutrophil number and survival are common to both hematologic disorders and chronic inflammatory diseases. At sites of inflammation, neutrophils respond to multiple signals that activate protein kinase A (PKA) signaling, which positively regulates neutrophil survival. The aim of this study was to define transcriptional responses to PKA activation and to delineate the roles of these factors in neutrophil function and survival...
June 21, 2017: Blood
https://www.readbyqxmd.com/read/28637665/hmga2-promotes-the-development-of-myelofibrosis-in-jak2v617f-knock-in-mice-by-enhancing-tgf-%C3%AE-1-and-cxcl12-pathways
#3
Avik Dutta, Robert E Hutchison, Golam Mohi
Myelofibrosis (MF) is a devastating blood disorder. The JAK2V617F mutation has been detected in ~50% cases of MF. Elevated expression of high mobility group AT hook 2 (HMGA2) also has been frequently observed in patients with MF. Interestingly, upregulation of HMGA2 expression has been found in association with the JAK2V617F mutation in significant cases of MF. However, the contribution of HMGA2 in the pathogenesis of MF remains elusive. To determine the effects of concurrent expression of HMGA2 and JAK2V617F mutation in hematopoiesis, we transduced bone marrow cells from Jak2V617F knock-in mice with lentivirus expressing Hmga2 and performed bone marrow transplantation...
June 21, 2017: Blood
https://www.readbyqxmd.com/read/28637664/expanded-repertoire-of-rasgrp2-variants-responsible-for-platelet-dysfunction-and-severe-bleeding
#4
Sarah K Westbury, Matthias Canault, Daniel Greene, Emilse Bermejo, Katharine Hanlon, Michele P Lambert, Carolyn M Millar, Paquita Nurden, Samya G Obaji, Shoshana Revel-Vilk, Chris Van Geet, Kate Downes, Sofia Papadia, Salih Tuna, Christopher Watt, Nihr BioResource-Rare Diseases Consortium, Kathleen Freson, Michael A Laffan, Willem H Ouwehand, Marie-Christine Alessi, Ernest Turro, Andrew D Mumford
Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterised. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in three pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2,042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5,422 controls...
June 21, 2017: Blood
https://www.readbyqxmd.com/read/28637663/ny-eso-1-tcr-single-edited-central-memory-and-memory-stem-t-cells-to-treat-multiple-myeloma-without-inducing-gvhd
#5
Sara Mastaglio, Pietro Genovese, Zulma Magnani, Eliana Ruggiero, Elisa Landoni, Barbara Camisa, Giulia Schiroli, Elena Provasi, Angelo Lombardo, Andreas Reik, Nicoletta Cieri, Martina Rocchi, Giacomo Oliveira, Giulia Escobar, Monica Casucci, Bernhard Gentner, Antonello Spinelli, Anna Mondino, Attilio Bondanza, Luca Vago, Maurilio Ponzoni, Fabio Ciceri, Michael C Holmes, Luigi Naldini, Chiara Bonini
Transfer of T cell receptors (TCR) specific for tumor-associated antigens is a promising approach for cancer immunotherapy. We developed the TCR gene editing technology, that is based on the knockout of the endogenous TCR α and β genes, followed by the introduction of tumor-specific TCR genes, and that proved safer and more effective than conventional TCR gene transfer. While successful, complete editing requires extensive cell manipulation and four transduction procedures. Here we propose a novel and clinically feasible 'single TCR editing' (SE) approach, based on the disruption of the endogenous TCR α chain only, followed by the transfer of genes encoding for a tumor specific TCR...
June 21, 2017: Blood
https://www.readbyqxmd.com/read/28637662/daratumumab-plus-pomalidomide-and-dexamethasone-in-relapsed-and-or-refractory-multiple-myeloma
#6
Ajai Chari, Attaya Suvannasankha, Joseph W Fay, Bertrand Arnulf, Jonathan L Kaufman, Jainulabdeen J Ifthikharuddin, Brendan M Weiss, Amrita Krishnan, Suzanne Lentzsch, Raymond Comenzo, Jianping Wang, Kerri Nottage, Christopher Chiu, Nushmia Z Khokhar, Tahamtan Ahmadi, Sagar Lonial
Daratumumab plus pomalidomide/dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with ≥2 prior lines of therapy, and who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary endpoint. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary endpoints...
June 21, 2017: Blood
https://www.readbyqxmd.com/read/28637661/the-full-transforming-capacity-of-mll-af4-is-interlinked-with-lymphoid-lineage-commitment
#7
Shan Lin, Roger T Luo, Mahesh Shrestha, Michael J Thirman, James C Mulloy
Chromosome rearrangements involving mixed-lineage leukemia gene (MLL) create MLL-fusion proteins, which could drive both acute lymphoblastic and myeloid leukemia (ALL and AML). The lineage decision of MLL-fusion leukemia is influenced by the fusion partner and microenvironment. To investigate the interplay of fusion proteins and microenvironment in lineage choice, we transplanted human hematopoietic stem and progenitor cells (HSPC) expressing MLL-AF9 or MLL-Af4 into immunodeficient NSGS mice, which strongly promote myeloid development...
June 21, 2017: Blood
https://www.readbyqxmd.com/read/28634183/syk-inhibitors-interfere-with-erythrocyte-membrane-modification-during-p-falciparum-growth-and-suppress-parasite-egress
#8
Antonella Pantaleo, Kristina R Kesely, Maria Carmina Pau, Ioannis Tsamesidis, Evelin Schwarzer, Oleksii A Skorokhod, Huynh D Chien, Marta Ponzi, Lucia Bertuccini, Philip S Low, Francesco M Turrini
Band 3 (a.k.a. the anion exchanger, SLCA1, AE1) constitutes the major attachment site of the spectrin-based cytoskeleton to the erythrocyte's lipid bilayer and thereby contributes critically to the stability of the red cell membrane. During the intra-erythrocytic stage of Plasmodium falciparum's life cycle, band 3 becomes tyrosine phosphorylated in response to oxidative stress, leading to a decrease in its affinity for the spectrin/actin cytoskeleton and causing global membrane destabilization. Because this membrane weakening is hypothesized to facilitate parasite egress and the consequent dissemination of released merozoites throughout the bloodstream, we decided to explore which tyrosine kinase inhibitors might block the kinase-induced membrane destabilization...
June 20, 2017: Blood
https://www.readbyqxmd.com/read/28634182/sf3b1-initiating-mutations-in-mds-with-ring-sideroblasts-target-lymphomyeloid-hematopoietic-stem-cells
#9
Teresa Mortera-Blanco, Marios Dimitriou, Petter S Woll, Mohsen Karimi, Edda Elvarsdottir, Simona Conte, Magnus Tobiasson, Monika Jansson, Iyadh Douagi, Matahi Moarii, Leonie Saft, Elli Papaemmanuil, Sten Eirik W Jacobsen, Eva Hellström-Lindberg
Mutations in the RNA splicing gene SF3B1 are found in more than 80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of SF3B1 mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in SF3B1 in 39 of 40 cases (97.5%), combined with TET2 and DNMT3A in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients, and were also present in downstream myeloid and erythroid progenitor cells...
June 20, 2017: Blood
https://www.readbyqxmd.com/read/28630122/eculizumab-blocks-vaccine-induced-opsonophagocytic-killing-of-meningococci-by-whole-blood-from-immunized-adults
#10
Monica Konar, Dan M Granoff
Eculizumab, a humanized anti-complement C5 monoclonal antibody for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome, blocks the terminal complement pathway required for serum bactericidal activity (SBA). Because treated patients are at >1000-fold increased risk of meningococcal disease, vaccination is recommended, but whether vaccination can protect by opsonophagocytic activity in the absence of SBA is not known. Meningococci were added to anticoagulated blood from 12 healthy adults vaccinated with meningococcal serogroup B and serogroup A,C,W,Y vaccines...
June 19, 2017: Blood
https://www.readbyqxmd.com/read/28630121/a-novel-recombinant-human-thrombopoietin-therapy-for-the-management-of-immune-thrombocytopenia-in-pregnancy
#11
Zhangyuan Kong, Ping Qin, Shan Xiao, Hai Zhou, Hong Li, Renchi Yang, Xiaofan Liu, Jianmin Luo, Zhichun Li, Guochao Ji, Zhongguang Cui, Yusheng Bai, Yuxia Wu, Linlin Shao, Jun Peng, Jun Ma, Ming Hou
The aim of this study was to determine the safety and efficacy of recombinant human thrombopoietin (rhTPO) for the management of immune thrombocytopenia (ITP) during pregnancy. Pregnant ITP patients were enrolled in the study if they had a platelet count of < 30 × 10(9)/L, were experiencing bleeding manifestations, had failed to respond to corticosteroids and/or intravenous immunoglobulin (IVIG), and had developed refractoriness to platelet transfusion. Thirty-one patients received rhTPO at an initial dose of 300U/kg once daily for 14 days...
June 19, 2017: Blood
https://www.readbyqxmd.com/read/28630120/selinexor-induced-thrombocytopenia-results-from-inhibition-of-thrombopoietin-signaling-in-early-megakaryopoiesis
#12
Kellie R Machlus, Stephen K Wu, Prakrith Vijey, Thomas S Soussou, Zhi-Jian Liu, Eran Shacham, T J Unger, Trinayan Kashyap, Boris Klebanov, Martha Sola-Visner, Marsha Crochiere, Joseph E Italiano, Yosef Landesman
Selinexor is the first oral Selective Inhibitor of Nuclear Export compound tested for cancer treatment. Selinexor has demonstrated a safety therapy profile with broad antitumor activity against solid and hematological malignancies in phases 2 and 3 clinical trials (NCT03071276, NCT02343042, NCT02227251, NCT03110562, NCT02606461). While selinexor shows promising efficacy, its primary adverse effect is high-grade thrombocytopenia. Therefore, we aimed to identify the mechanism of selinexor-induced thrombocytopenia to relieve it and improve its clinical management...
June 19, 2017: Blood
https://www.readbyqxmd.com/read/28630119/gata2-haploinsufficiency-accelerates-evi1-driven-leukemogenesis
#13
Saori Katayama, Mikiko Suzuki, Ayaka Yamaoka, Nadine Keleku-Lukwete, Fumiki Katsuoka, Akihito Otsuki, Shigeo Kure, James Douglas Engel, Masayuki Yamamoto
Chromosomal rearrangements between 3q21 and 3q26 induce inappropriate EVI1 expression by recruiting a GATA2-distal hematopoietic enhancer (G2DHE) to the proximity of the EVI1 gene, leading to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The acquisition of G2DHE by the EVI1 gene reciprocally deprives this enhancer of one of the two GATA2 alleles, resulting in a loss of function genetic reduction in GATA2 abundance. As GATA2 haploinsufficiency is strongly associated with MDS and AML, here we asked whether EVI1 misexpression and GATA2 haploinsufficiency both contributed to the observed leukemogenesis by using a 3q21q26 mouse model that recapitulates the G2DHE-driven EVI1 misexpression but in this case coupled to a Gata2 heterozygous germ-line deletion...
June 19, 2017: Blood
https://www.readbyqxmd.com/read/28619983/failure-to-replicate-thrombomodulin-genetic-variant-predictors-of-venous-thromboembolism-in-african-americans
#14
Aaron R Folsom, Nicholas S Roetker, Spencer T Kelley, Weihong Tang, Nathan Pankratz
No abstract text is available yet for this article.
June 15, 2017: Blood
https://www.readbyqxmd.com/read/28619982/jak1-2-and-bcl2-inhibitors-synergize-to-counteract-bone-marrow-stromal-cell-induced-protection-of-aml
#15
Riikka Karjalainen, Tea Pemovska, Mihaela Popa, Minxia Liu, Komal K Javarappa, Muntasir M Majumder, Bhagwan Yadav, David Tamborero, Jing Tang, Dmitrii Bychkov, Mika Kontro, Alun Parsons, Minna Suvela, Mireia Mayoral Safont, Kimmo Porkka, Tero Aittokallio, Olli Kallioniemi, Emmet McCormack, Bjørn T Gjertsen, Krister Wennerberg, Jonathan Knowles, Caroline A Heckman
The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be due to the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the impact of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions...
June 15, 2017: Blood
https://www.readbyqxmd.com/read/28615223/daratumumab-yields-rapid-and-deep-hematologic-responses-in-patients-with-heavily-pretreated-al-amyloidosis
#16
Gregory P Kaufman, Stanley L Schrier, Richard A Lafayette, Sally Arai, Ronald M Witteles, Michaela Liedtke
The majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement; additional well tolerated treatment options are therefore needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma...
June 14, 2017: Blood
https://www.readbyqxmd.com/read/28615222/exploring-the-global-landscape-of-genetic-variation-in-coagulation-factor-xi-deficiency
#17
Rosanna Asselta, Elvezia Maria Paraboschi, Valeria Rimoldi, Marzia Menegatti, Flora Peyvandi, Ophira Salomon, Stefano Duga
Factor XI (FXI) deficiency is an autosomal bleeding disorder, usually post trauma or surgery, characterized by reduced levels of coagulation FXI in plasma. The disease is highly prevalent in Ashkenazi Jews (heterozygote frequency ~9%), whereas it is considered a rare condition in most populations (prevalence of the severe deficiency: 1:10(6) in Caucasians). So far, >190 causative mutations have been identified throughout the F11 gene. To have a global landscape of genetic variation of F11, we explored publicly-available exome-based data obtained from >60,000 individuals belonging to different ethnicities (Exome Aggregation Consortium resource)...
June 14, 2017: Blood
https://www.readbyqxmd.com/read/28615221/coronin-1a-a-novel-player-in-integrin-biology-controls-neutrophil-trafficking-in-innate-immunity
#18
Robert Pick, Daniela Begandt, Thomas J Stocker, Melanie Salvermoser, Sarah Thome, Ralph T Böttcher, Eloi Montanez, Ute Harrison, Ignasi Forné, Alexander G Khandoga, Raffaele Coletti, Ludwig T Weckbach, Doris Brechtefeld, Rainer Haas, Axel Imhof, Steffen Massberg, Markus Sperandio, Barbara Walzog
Trafficking of polymorphonuclear neutrophils (PMNs) during inflammation critically depends on the β2 integrins LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18). Here, we identify Coronin 1A (Coro1A) as a novel regulator of β2 integrins that interacts with the cytoplasmic tail of CD18 and is crucial for induction of PMN adhesion and post-adhesion events, including adhesion strengthening, spreading, and migration under flow conditions. Transition of PMN rolling to firm adhesion critically depends on Coro1A by regulating the accumulation of high affinity LFA-1 in focal zones of adherent cells...
June 14, 2017: Blood
https://www.readbyqxmd.com/read/28615220/confounding-in-ex-vivo-models-of-diamond-blackfan-anemia
#19
Jacob C Ulirsch, Caleb Lareau, Leif S Ludwig, Narla Mohandas, David G Nathan, Vijay G Sankaran
No abstract text is available yet for this article.
June 14, 2017: Blood
https://www.readbyqxmd.com/read/28615219/zfp521-regulates-murine-hematopoietic-stem-cell-function-and-facilitates-mll-af9-leukemogenesis-in-mouse-and-human-cells
#20
Brian S Garrison, Adrian P Rybak, Isabel Beerman, Balthasar Heesters, Francois E Mercier, David T Scadden, David Bryder, Roland Baron, Derrick J Rossi
The concept that tumor-initiating cells can co-opt the self-renewal program of endogenous stem cells as a means of enforcing their unlimited proliferative potential is widely accepted, yet identification of specific factors that regulate self-renewal of normal and cancer stem cells remains limited. Using a comparative transcriptomic approach, we identify ZNF521/Zfp521 as a conserved hematopoietic stem cell (HSC)-enriched transcription factor in human and murine hematopoiesis, whose function in HSC biology remains elusive...
June 14, 2017: Blood
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