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Ioulia Vardaki, Claire Sanchez, Pedro Fonseca, Magnus Olsson, Dimitrios Chioureas, George Rassidakis, Anders Ullén, Boris Zhivotovsky, Magnus Björkholm, Theocharis Panaretakis
The intercellular crosstalk between hematological malignancies and the tumor microenvironment is mediated by cell to cell interactions and soluble factors. One component of the secretome that is gaining increasing attention are the extracellular vesicles and in particular the exosomes. Apart from the role as vectors of molecular information, exosomes have been shown to possess intrinsic biological activity. In this study we have found that caspase-3 is activated in L88 bone marrow stroma cell-derived exosomes and identified one of the substrates to be the anti-apoptotic protein Bcl-xL...
October 14, 2016: Blood
S Vincent Rajkumar, Jean Luc Harousseau
Advances in the diagnosis and treatment of multiple myeloma have come at a rapid pace, especially with several new drugs entering the market in the last few years. However access and affordability to new treatments poses a major challenge, both in the United States and around the world. High costs of life-saving drugs are detrimental to both the personal finances of the individual patient, as well as society which must bear the increasing costs in terms of increased health insurance premiums, taxes, or both...
October 14, 2016: Blood
Francesca Lupo, Elena Tibaldi, Alessandro Matte, Alok K Sharma, Anna Maria Brunati, Seth L Alper, Carlo Zancanaro, Donatella Benati, Angela Siciliano, Mariarita Bertoldi, Francesca Zonti, Alexander Storch, Ruth H Walker, Adrian Danek, Benedikt Bader, Andreas Hermann, Lucia De Franceschi
Chorea-acanthocytosis is one of the hereditary neurodegenerative disorders known as the neuroacanthocytoses. Chorea-acanthocytosis is characterized by circulating acanthocytes deficient in chorein, a protein of unknown function. We report here for the first time that chorea-acanthocytosis red-cells are characterized by impaired autophagy, with cytoplasmic accumulation of active Lyn and of autophagy-related proteins Ulk1, Atg7. In chorea-acanthocytosis erythrocytes, active Lyn is sequestered by HSP90-70 to form high-molecular-weight complexes that stabilize and protect Lyn from its proteasomal degradation, contributing to toxic Lyn accumulation...
October 14, 2016: Blood
Maria Bruzelius, Maria Jesus Iglesias, Mun-Gwan Hong, Laura Sanchez-Rivera, Beata Gyorgy, Juan Carlos Souto, Mattias Frånberg, Claudia Fredolini, Rona J Strawbridge, Margareta Holmström, Anders Hamsten, Mathias Uhlén, Angela Silveira, Jose Manuel Soria, David M Smadja, Lynn M Butler, Jochen M Schwenk, Pierre-Emmanuel Morange, David-Alexandre Trégouët, Jacob Odeberg
There is a clear clinical need for high specificity plasma biomarkers for predicting risk of venous thromboembolism (VTE), but thus far such markers have remained elusive. Utilising affinity reagents from the human protein atlas (HPA) project and multiplexed immuoassays we extensively analysed plasma samples from two individual cohorts to identify candidate protein markers associated with VTE risk. We screened plasma samples from 88 VTE cases and 85 matched controls, collected as part of the Swedish 'Venous Thromboembolism Biomarker Study' (VEBIOS), using suspension bead arrays composed of 755 antibodies targeting 408 candidate proteins...
October 14, 2016: Blood
Caron Jacobson, Nadja Kopp, Jacob V Layer, Robert A Redd, Sebastian Tschuri, Sarah Haebe, Diederik van Bodegom, Liat Bird, Amanda L Christie, Alexandra Christodoulou, Amy Saur, Trevor Tivey, Stefanie Zapf, Deepak Bararia, Ursula Zimber-Strobl, Scott J Rodig, Oliver Weigert, David M Weinstock
The BTK inhibitor ibrutinib induces responses in 70% of patients with relapsed and refractory mantle cell lymphoma. Intrinsic resistance can occur through activation of the non-classical NFκB pathway and acquired resistance may involve the BTK C481S mutation. Outcomes after ibrutinib failure are dismal, indicating an unmet medical need. We reasoned that newer HSP90 inhibitors could overcome ibrutinib resistance by targeting multiple oncogenic pathways in MCL. HSP90 inhibition induced the complete degradation of both BTK and IKKα in MCL lines and CD40-dependent B cells, with downstream loss of MAP kinase and non-classical NFκB signaling...
October 14, 2016: Blood
Anita Roy, Larissa Lordier, Stefania Mazzi, Yunhua Chang, Valérie Lapierre, Jérome Larghero, Najet Debili, Hana Raslova, William Vainchenker
Megakaryocyte polyploidy is characterized by cytokinesis failure due to defects in contractile forces at the cleavage furrow. Although immature megakaryocytes express two nonmuscle myosin II isoforms (NMIIA and NMIIB); only NMIIB localizes at the cleavage furrow and its subsequent absence contributes to polyploidy. In this study, we tried to understand why the abundant NMIIA does not localize at the furrow by focusing on RhoA/ROCK pathway that has a low activity in polyploid megakaryocytes. We observed that under low RhoA activity, NMII isoforms presented different activity that determined their localization...
October 13, 2016: Blood
Ashley A Basiorka, Kathy L McGraw, Erika A Eksioglu, Xianghong Chen, Joseph Johnson, Ling Zhang, Qing Zhang, Brittany A Irvine, Thomas Cluzeau, David A Sallman, Eric Padron, Rami Komrokji, Lubomir Sokol, Rebecca C Coll, Avril A B Robertson, Matthew A Cooper, John L Cleveland, Luke A O'Neill, Sheng Wei, Alan F List
Despite genetic heterogeneity, myelodysplastic syndromes (MDS) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDS is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem/progenitor cells (HSPC) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of IL-1β and IL-18 and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPC and bone marrow plasma...
October 13, 2016: Blood
Madhav V Dhodapkar
All cases of multiple myeloma (MM) are preceded by precursor states termed as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). Genetic analyses of MGUS cells have provided evidence that it is a genetically advanced lesion wherein tumor cells carry many of the genetic changes found in MM cells. Intraclonal heterogeneity is also established early during the MGUS phase. While the genetic features of MGUS or SMM cells at baseline may predict disease risk, transition to MM involves altered growth of pre-existing clones...
October 13, 2016: Blood
Yun Mai, J Jessica Yu, Boris Bartholdy, Zijun Y Xu-Monette, Esther E Knapp, Fei Yuan, Hongshan Chen, B Belinda Ding, Zhihua Yao, Bhaskar Das, Yiyu Zou, Ken He Young, Samir Parekh, B Hilda Ye
Diffuse large B cell lymphomas (DLBCL) contain two major molecular subtypes, namely, the germinal center B cell-like (GCB) and the activated B cell-like (ABC) DLBCLs. It is well documented that ABC-DLBCL cases have a significantly poorer survival response than GCB-DLBCLs in both the CHOP and the R-CHOP eras. However, the underlying cause of this subtype disparity is poorly understood. Nevertheless, these clinical observations raise the possibility for an ABC-DLBCL-specific resistance mechanism that is directed towards one of the CHOP components and inadequately addressed by rituximab...
October 13, 2016: Blood
Raffaella Origa, Fabrice Danjou, Valeria Orecchia, Antonietta Zappu, Carlo Dessì, Maria Loreta Foschini, Giovan Battista Leoni, Paolo Moi, Maddalena Morittu, Anna Demurtas, Sandro Loche
No abstract text is available yet for this article.
October 13, 2016: Blood
Jing Du, Martin Neuenschwander, Yong Yu, J Henry M Däbritz, Nina-Rosa Neuendorff, Kolja Schleich, Aitomi Bittner, Maja Milanovic, Gregor Beuster, Silke Radetzki, Edgar Specker, Maurice Reimann, Frank Rosenbauer, Stephan Mathas, Philipp Lohneis, Michael Hummel, Bernd Dörken, Jens Peter von Kries, Soyoung Lee, Clemens A Schmitt
Classical Hodgkin's lymphoma (cHL), although originating from B-cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling...
October 12, 2016: Blood
TaeHyung Kim, Marc S Tyndel, Hyeoung Joon Kim, Jae-Sook Ahn, Seung Hyun Choi, Hee Jeong Park, Yeo-Kyeoung Kim, Soo Young Kim, Jeffrey H Lipton, Zhaolei Zhang, Dennis Dong Hwan Kim
Somatic mutations commonly detected in a variety of myeloid neoplasms have not been systematically investigated in chronic myeloid leukemia (CML). We performed targeted deep sequencing on a total of 300 serial samples from 100 CML patients; thirty-seven patients carried mutations. Sixteen of these had evidence of mutations originating from preleukemic clones. Using unsupervised hierarchical clustering, we identified five distinct patterns of mutation dynamics arising following tyrosine kinase inhibitor (TKI) therapy...
October 12, 2016: Blood
Antonella Antonelli, Willy A Noort, Jenny Jaques, Bauke de Boer, Regina de Jong-Korlaar, Annet Z Brouwers-Vos, Linda Lubbers-Aalders, Jeroen F van Velzen, Andries C Bloem, Huipin Yuan, Joost D de Bruijn, Gert J Ossenkoppele, Anton C M Martens, Edo Vellenga, Richard W J Groen, Jan Jacob Schuringa
In order to begin to understand mechanisms that regulate self-renewal, differentiation and transformation of human hematopoietic stem cells, or to evaluate the efficacy of novel treatment modalities, stem cells need to be studied in their own species-specific microenvironment. By implanting ceramic scaffolds coated with human mesenchymal stromal cells (MSCs) into immune deficient mice we mimic the human bone marrow niche. Thus, we have established a human leukemia xenograft mouse model in which a large cohort of patient samples successfully engrafted covering all important genetic and risk subgroups...
October 12, 2016: Blood
Rikhia Chakraborty, Thomas M Burke, Oliver A Hampton, Daniel J Zinn, Karen Phaik Har Lim, Harshal Abhyankar, Brooks Scull, Vijetha Kumar, Nipun Kakkar, David A Wheeler, Angshumoy Roy, Poulikos I Poulikakos, Miriam Merad, Kenneth L McClain, D Williams Parsons, Carl E Allen
Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing pathologic CD207+ dendritic cells with constitutively activated ERK. Mutually exclusive somatic mutations in MAPK pathway genes have been identified in approximately 75% of LCH cases, including recurrent BRAF-V600E and MAP2K1 mutations. In order to elucidate mechanisms of ERK activation in the remaining 25% of patients, we performed whole exome sequencing (WES, n=6), targeted BRAF sequencing (n=19) and/or whole transcriptome sequencing (RNA-seq, n=6) on 24 LCH patient samples lacking BRAF-V600E or MAP2K1 mutations...
October 11, 2016: Blood
Thomas Dejoie, Jill Corre, Helene Caillon, Cyrille Hulin, Aurore Perrot, Denis Caillot, Eileen Boyle, Marie-Lorraine Chretien, Jean Fontan, Karim Belhadj, Sabine Brechignac, Olivier Decaux, Laurent Voillat, Philippe Rodon, Olivier Fitoussi, Carla Araujo, Lotfi Benboubker, Charlotte Fontan, Mourad Tiab, Pascal Godmer, Odile Luycx, Olivier Allangba, Jean-Michel Pignon, Jean-Gabriel Fuzibet, Laurence Legros, Anne-Marie Stoppa, Mamoun Dib, Brigitte Pegourie, Frederique Orsini-Piocelle, Lionel Karlin, Bertrand Arnulf, Murielle Roussel, Laurent Garderet, Mohamad Mohty, Nathalie Meuleman, Chantal Doyen, Pascal Lenain, Margaret Macro, Xavier Leleu, Thierry Facon, Philippe Moreau, Michel Attal, Herve Avet-Loiseau
Guidelines for monitoring multiple myeloma patients expressing light chains only (light chain multiple myeloma; LCMM) rely on measurements of the monoclonal protein in urine. Alternatively serum free light chain (sFLC) measurements have better sensitivity over urine methods, however, demonstration that improved sensitivity provides any clinical benefit is lacking. Here we compared the performance of serum and urine measurements in 113 (72κ, 41λ) newly diagnosed LCMM patients enrolled onto the IFM-2009 trial...
October 11, 2016: Blood
Eli Muchtar, Dragan Jevremovic, Angela Dispenzieri, David Dingli, Francis K Buadi, Martha Q Lacy, Wilson Gonsalves, Suzanne R Hayman, Prashant Kapoor, Nelson Leung, Stephen Russell, John A Lust, Yi Lin, Ronald S Go, Rajshekhar Chakraborty, Steven Zeldenrust, Shaji K Kumar, Robert A Kyle, S Vincent Rajkumar, Morie A Gertz
Multiparametric flow cytometry (MFC) in AL amyloidosis has not been widely adopted and consequently there is little information on its clinical relevance. We studied 173 AL amyloidosis patients who underwent MFC immunophenotyping of bone marrow sample at diagnosis and 82 patients at the end of the first line of treatment (EOT). The number of monotypic plasma cells (PCs) and the polytypic PCs/bone marrow PCs (pPCs/BMPCs) ratio were analyzed. At diagnosis, ≥2.5% monotypic PCs was associated with a shorter progression-free survival (PFS) and overall survival (OS) compared to patients with <2...
October 11, 2016: Blood
Elenoe C Smith, Sidinh Luc, Donyell M Croney, Mollie B Woodworth, Luciano C Greig, Yuko Fujiwara, Minh Nguyen, Falak Sher, Jeffrey D Macklis, Daniel E Bauer, Stuart H Orkin
BCL11A, a repressor of human fetal (γ-)globin expression, is required for immune and hematopoietic stem cell functions and brain development. Regulatory sequences within the gene, which are subject to genetic variation affecting fetal globin expression, display hallmarks of an erythroid enhancer in cell lines and transgenic mice. As such this enhancer is a novel, attractive target for therapeutic gene editing. To explore the roles of such sequences in vivo, we generated mice in which the orthologous 10 kb intronic sequences were removed...
October 5, 2016: Blood
Markus Ball, Alan F List, Eric Padron
Exome sequencing studies in Chronic Myelomonocytic Leukemia (CMML) illustrate a mutational landscape characterized by few somatic mutations involving a subset of recurrent gene mutations in ASXL1, SRSF2, and TET2, each approaching 40% in incidence. This has led to the clinical implementation of next generation sequencing panels that effectively identify clonal monocytosis and complement clinical prognostic scoring systems in most patients. However, most murine models based on single gene mutations fail to recapitulate the CMML phenotype and many gene mutations are loss-of-function making the identification of traditional therapeutic vulnerabilities challenging...
October 5, 2016: Blood
Adam Ceroi, David Masson, Anne Roggy, Christophe Roumier, Cécile Chagué, Thierry Gauthier, Laure Philippe, Baptiste Lamarthée, Fanny Angelot-Delettre, Francis Bonnefoy, Sylvain Perruche, Sabeha Biichle, Claude Preudhomme, Elisabeth Macintyre, Laurent Lagrost, Francine Garnache-Ottou, Philippe Saas
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from plasmacytoid dendritic cells (PDC). No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared to those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDC. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes...
October 4, 2016: Blood
Rick Admiraal, Caroline A Lindemans, Charlotte van Kesteren, Marc B Bierings, A Birgitta Versluys, Stefan Nierkens, Jaap Jan Boelens
Successful immune reconstitution (IR) is associated with improved outcomes following pediatric cord blood transplantation (CBT). Usage and timing of anti-thymocyte globulin (ATG), introduced to the conditioning to prevent graft-versus-host-disease and graft failure, negatively influences T-cell IR. We studied the relation between ATG exposure, IR and clinical outcomes. All pediatric patients receiving a first CBT between 2004-2015 at the University Medical Center Utrecht were included. ATG-exposure measures were determined with a validated PK-model...
October 4, 2016: Blood
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