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Jean-Paul Fermand, Frank Bridoux, Angela Dispenzieri, Arnaud Jaccard, Robert A Kyle, Nelson Leung, Giampaolo Merlini
Monoclonal gammopathy is a frequent condition, particularly in the elderly. It can indicate a symptomatic multiple myeloma or another overt malignant lymphoid disorder requiring immediate chemotherapy. More frequently, it results from a small and/or quiescent secreting B-cell clone, is completely asymptomatic and requires regular monitoring only, defining a monoclonal gammopathy of unknown significance (MGUS). Sometimes, although quiescent and not requiring any treatment per se, the clone is associated with potentially severe organ damage, due to the toxicity of the monoclonal immunoglobulin or to other mechanisms...
July 16, 2018: Blood
Rebecca Valentin, Stephanie Grabow, Matthew S Davids
Dysregulation of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins of the intrinsic apoptotic pathway is fundamental to the pathophysiology of many hematologic malignancies. The BCL-2 family consists of regulatory proteins that either induce apoptosis (pro-apoptotic) or inhibit it (pro-survival). BCL-2, MCL-1 (myeloid cell leukemia-1) and BCL-xL (B cell lymphoma-extra large) are pro-survival proteins that are prime targets for anti-cancer therapy, and molecules targeting each are in various stages of preclinical and clinical development...
July 16, 2018: Blood
Camila Masias, Spero R Cataland
ADAMTS13 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motif, 13) is a metalloprotease responsible for cleavage of ultra large Von Willebrand factor (ULVWF) multimers. Severely deficient activity of the protease can trigger an acute episode of thrombotic thrombocytopenic purpura (TTP). Our understanding of the pathophysiology of TTP, has allowed us to grasp the important role of ADAMTS13 in other thrombotic microangiopathies (TMA) and thrombotic disorders, such as ischemic stroke and coronary artery disease...
July 13, 2018: Blood
Vittorio Pengo, Gentian Denas, Giacomo Zoppellaro, Seena Padayattil Jose, Ariela Hoxha, Amelia Ruffatti, Laura Andreoli, Angela Tincani, Caterina Cenci, Domenico Prisco, Tiziana Fierro, Paolo Gresele, Arturo Cafolla, Valeria De Micheli, Angelo Ghirarduzzi, Alberto Tosetto, Anna Falanga, Ida Martinelli, Sophie Testa, Doris Barcellona, Maria Gerosa, Alessandra Banzato
Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban as compared to warfarin in high-risk patients with thrombotic Antiphospholipid Syndrome. This is a randomized, open-label, multicenter, non-inferiority study with blinded end-point adjudication. Rivaroxaban 20 mg once daily (15 mg once daily based on kidney function) was compared to warfarin (INR target 2.5), for the prevention of thromboembolic events, major bleeding and vascular death in patients with Antiphospholipid Syndrome...
July 12, 2018: Blood
Dana Hoser, Christian Schön, Christoph Loddenkemper, Philipp Lohneis, Anja A Kühl, Thomas Sommermann, Thomas Blankenstein, Gerald Willimsky
To date, little is known about the interaction between (pre-)malignant B cells and T cells. We generated transgenic mice that allow B cell-specific induction of the oncogene SV40 large T-antigen (TAg) to analyze the role of oncogene-specific T cells during sporadic B cell lymphoma development. Constitutive TAg expression in CD19-Cre x LoxP Tag mice resulted in TAg-tolerant CD8+ T cells and development of B cell lymphomas. In contrast, CD19 CreERT2 x LoxP Tag mice retained TAg-competent CD8+ T cells at time of oncogene induction and TAg expression in few B cells of adult mice resulted in exceptionally rare lymphoma formation late in life...
July 12, 2018: Blood
Kathryn G Roberts, Shalini C Reshmi, Richard C Harvey, I-Ming Chen, Kinnari Patel, Eileen Stonerock, Heather Jenkins, Yunfeng Dai, Marc Valentine, Zhaohui Gu, Yaqi Zhao, Jinghui Zhang, Debbie Payne-Turner, Meenakshi Devidas, Nyla A Heerema, Andrew J Carroll, Elizabeth A Raetz, Michael J Borowitz, Brent L Wood, Leonard A Mattano, Kelly W Maloney, William L Carroll, Mignon L Loh, Cheryl L Willman, Julie M Gastier-Foster, Charles G Mullighan, Stephen P Hunger
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; BCR-ABL1 -like ALL) in children with NCI high-risk (HR) ALL as defined by age and initial white blood cell count, or intermediate risk as defined by minimal residual disease response, is associated with poor outcome. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor and kinase signaling and may be amenable to treatment with tyrosine kinase inhibitors (TKIs). The prevalence, outcome and potential for targeted therapy of Ph-like ALL in NCI standard-risk (SR) ALL is less clear...
July 11, 2018: Blood
Eugenio Morelli, Lavinia Biamonte, Cinzia Federico, Nicola Amodio, Maria Teresa Di Martino, Maria Eugenia Gallo Cantafio, Martina Manzoni, Francesca Scionti, Mehmet Kemal Samur, Annamaria Gullà, Maria Angelica Stamato, Maria Rita Pitari, Daniele Caracciolo, Settimio Sesti, Niels M Frandsen, Marco Rossi, Antonino Neri, Mariateresa Fulciniti, Nikhil C Munshi, Pierosandro Tagliaferri, Pierfrancesco Tassone
The microRNA cluster miR-17-92 is oncogenic and represents a valuable therapeutic target in c-MYC (MYC)-driven malignancies. Here, we developed novel LNA gapmeR antisense oligonucleotides (ASOs) to induce RNase H-mediated degradation of MIR17HG primary transcripts and, consequently, to prevent biogenesis of miR-17-92 microRNAs (miR-17-92s). The leading LNA-ASO, named MIR17PTi, impaired proliferation of several cancer cell lines (n=48) established from both solid and hematologic tumors by on-target antisense activity, and more effectively as compared to miR-17-92s inhibitors...
July 11, 2018: Blood
Carl Allen, Rebecca Marsh, Peter Dawson, Catherine M Bollard, Shalini Shenoy, Philip Roehrs, Rabi Hanna, Lauri Burroughs, Leslie Kean, Julie-An Talano, Kirk R Schultz, Sung-Yun Pai, K Scott Baker, Jeffrey R Andolina, Elizabeth O Stenger, James Connelly, Alyssa Ramirez, Christopher Bryant, Mary Eapen, Michael A Pulsipher
Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced intensity conditioning with melphalan, fludarabine and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA-locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone...
July 11, 2018: Blood
Peter Dreger, Paolo Ghia, Johannes Schetelig, Michel van Gelder, Eva Kimby, Mauricette Michallet, Carol Moreno, Tadeusz Robak, Stephan Stilgenbauer, Emili Montserrat
High-risk chronic lymphocytic leukemia (CLL) has been defined by clinical and/or genetic resistance ( TP53 abnormalities) to treatment with chemoimmunotherapy (CIT). With the availability of pathway inhibitors (PI), such as kinase inhibitors and BCL2 antagonists, the outlook of CIT-resistant patients has dramatically improved. Here, we propose a revision of the concept of high-risk CLL, driven by TP53 abnormalities and response to treatment with PI. CLL high-risk-I, CIT-resistant is defined by clinically CIT-resistant disease with TP53 aberrations, but fully responsive to PI...
July 11, 2018: Blood
Amit Sud, Subhayan Chattopadhyay, Hauke Thomsen, Kristina Sundquist, Jan Sundquist, Richard S Houlston, Kari Hemminki
No abstract text is available yet for this article.
July 10, 2018: Blood
Joseph S Burch, Jason R Marcero, John Alan Maschek, James E Cox, Laurie K Jackson, Amy E Medlock, John D Phillips, Harry A Dailey
During erythroid differentiation the erythron must remodel its protein constituents so that the mature red cell contains hemoglobin as the chief cytoplasmic protein component. For this approximately 109 molecules of heme must be synthesized, consuming 1010 molecules of succinyl-CoA. It has long been assumed that the source of succinyl-CoA for heme synthesis in all cell types is the tricarboxylic acid (TCA) cycle. Based upon the observation that one subunit of succinyl-CoA synthetase (SCS) physically interacts with the first enzyme of heme synthesis (5-aminolevulinate synthase 2, ALAS2) in erythroid cells, it has been posited that succinyl-CoA for ALA synthesis is provided by the ATP-dependent reverse SCS reaction...
July 10, 2018: Blood
Mairi S Shepherd, Juan Li, Nicola K Wilson, Caroline A Oedekoven, Jiangbing Li, Miriam Belmonte, Juergen Fink, Janine C M Prick, Dean C Pask, Tina L Hamilton, Dirk Löffler, Anjana Rao, Timm Schroeder, Berthold Göttgens, Anthony R Green, David G Kent
Recent advances in single cell technologies have permitted the investigation of heterogeneous cell populations at previously unattainable resolution. Here we apply such approaches to resolve the molecular mechanisms driving disease in mouse hematopoietic stem cells (HSCs), using JAK2V617F mutant myeloproliferative neoplasms (MPNs) as a model. Single cell gene expression and functional assays identified a subset of JAK2V617F mutant HSCs that display defective self-renewal. This defect is rescued at the single HSC level by crossing JAK2V617F mice with mice lacking TET2, the most commonly co-mutated gene in MPN patients...
July 10, 2018: Blood
Camille Guillerey, Heidi Harjunpää, Nadège Carrié, Sahar Kassem, Tricia Teo, Kim Miles, Sophie Krumeich, Marianne Weulersse, Marine Cuisinier, Kimberley Stannard, Yuan Yu, Simone A Minnie, Geoffrey R Hill, William C Dougall, Hervé Avet-Loiseau, Michele W L Teng, Kyohei Nakamura, Ludovic Martinet, Mark J Smyth
Immune-based therapies hold promise for the treatment of multiple myeloma (MM), but so far immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) has not proven effective as single agent in this disease. T cell immunoglobulin and ITIM domains (TIGIT) is another immune checkpoint receptor known to negatively regulate T cell functions. In this study, we investigated the therapeutic potential of TIGIT blockade to unleash immune responses against MM. We observed that, in both mice and humans, MM progression was associated with high levels of TIGIT expression on CD8+ T cells...
July 9, 2018: Blood
Gerald Illerhaus, Elisabeth Schorb, Benjamin Kasenda
Primary central nervous system lymphoma (PCNSL) is a rare aggressive extranodal Non- Hodgkin Lymphoma. Despite high remission rates can be achieved with high-dose methotrexate based immunochemotherapy, risk of relapse and associated death is still substantial in at least a third of patients. Novel agents for treating lymphoid malignancies have substantially enriched treatment options for PCNSL. We herein systematically review the existing clinical evidence of novel agents in treatment of PCNSL, summarize ongoing studies, and discuss perspectives...
July 9, 2018: Blood
Hervé Decousus, Aurélie Bourmaud, Pierre Fournel, Laurent Bertoletti, Carine Labruyère, Emilie Presles, Adel Merah, Silvy Laporte, Laetitia Stefani, Francesco Del Piano, Jean-Philippe Jacquin, Guy Meyer, Franck Chauvin
The need to accurately identify cancer outpatients at high risk of thrombotic complications is still unmet. In a prospective, multicenter cohort study, consecutive adult patients with a solid tumor and implanted port underwent 12-month follow-up. Our primary objective was to identify risk factors for (1) catheter-related thrombosis, defined as ipsilateral symptomatic upper-limb deep-vein thrombosis with or without pulmonary embolism, and (2) venous thromboembolism other than catheter-related, defined as any symptomatic superficial- or deep-vein thrombosis (other than catheter-related) or pulmonary embolism, and incidental pulmonary embolism...
July 6, 2018: Blood
Lisa Giulino-Roth
The WHO now recognizes primary mediastinal B-cell lymphoma (PMBCL) as a unique clinical and biologic entity. PMBCL is distinct from other B-cell non-Hodgkin lymphoma subtypes and has features that overlap with classical Hodgkin lymphoma including a peak incidence in the adolescent and young adult population; mediastinal presentation of disease, and molecular alterations in JAK2 and programmed death ligands. Since PMBCL is rare, there are few prospective clinical trials to guide therapy, resulting in no single standard of care...
July 5, 2018: Blood
Sara Gandolfi, Claudia Paba Prada, Paul Richardson
The treatment landscape for multiple myeloma has been transformed by the introduction of novel agents, including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. These have been shown to be more effective and generally better tolerated than conventional chemotherapy, with their introduction into clinical practice leading to improved survival. Furthermore, a better understanding of disease biology, improved diagnostic criteria, as well as the development of sensitive and specific tools for disease prognostication have contributed to better outcome...
July 2, 2018: Blood
Susan Branford, Paul Wang, David T Yeung, Daniel Thomson, Adrian Purins, Carol Wadham, Nur Hezrin Shahrin, Justine E Marum, Nathalie Nataren, Wendy T Parker, Joel Geoghegan, Jinghua Feng, Naranie Shanmuganathan, Martin C Mueller, Christian Dietz, Doris Stangl, Zoe Donaldson, Haley Altamura, Jasmina Georgievski, Jodi Braley, Anna Brown, Christopher Hahn, Ieuan Walker, Soo-Hyun Kim, Soo-Young Choi, Sa-Hee Park, Dong-Wook Kim, Deborah L White, Agnes S M Yong, David M Ross, Hamish S Scott, Andreas W Schreiber, Timothy P Hughes
Genomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole exome sequencing, copy number variation and/or RNA-Seq for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six chronic phase patients with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15/27 patients (56%) with subsequent BC or poor outcome and in 3/19 optimal responders (16%), P=.007. Frequently mutated genes at diagnosis were ASXL1 , IKZF1 and RUNX1 The methyltransferase SETD1B was a novel recurrently mutated gene...
July 2, 2018: Blood
Sarah C Rutherford, Angela A Fachel, Sheng Li, Seema Sawh, Ashlesha Muley, Jennifer Ishii, Ashish Saxena, Pilar M Dominguez, Eloisi Caldas Lopes, Xabier Agirre, Nyasha Chambwe, Fabian Correa, Yanwen Jiang, Kristy L Richards, Doron Betel, Rita Shaknovich
The biological role of extracellular vesicles (EVs) in diffuse large B-cell lymphoma (DLBCL) initiation and progression remains largely unknown. We characterized EVs secreted by five DLBCL cell lines, a primary DLBCL tumor and a normal control B cell sample, optimized their purification and analyzed their content. We found that DLBCLs secreted large quantities of CD63, Alix, TSG101 and CD81 EVs, which can be extracted using an ultracentrifugation-based method and traced by their cell of origin surface markers...
July 2, 2018: Blood
Mengjia Hu, Hao Zeng, Shilei Chen, Yang Xu, Song Wang, Yong Tang, Xinmiao Wang, Changhong Du, Mingqiang Shen, Fang Chen, Mo Chen, Cheng Wang, Jining Gao, Fengchao Wang, Yongping Su, Junping Wang
Quiescence maintenance is an important property of hematopoietic stem cells (HSCs), while the regulatory factors and underlying mechanisms involved in HSC quiescence maintenance are not fully uncovered. Here, we show that steroid receptor coactivator 3 (SRC-3) is highly expressed in HSCs, and SRC-3-deficient HSCs are less quiescent and more proliferative, resulting in increased sensitivity to chemotherapy and irradiation. Moreover, the long-term reconstituting ability of HSCs is markedly impaired in the absence of SRC-3, and SRC-3 knockout (SRC-3-/-) mice exhibit a significant disruption of hematopoietic stem and progenitor cell homeostasis...
June 29, 2018: Blood
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