journal
https://read.qxmd.com/read/33280030/cost-effectiveness-of-caplacizumab-in-acquired-thrombotic-thrombocytopenic-purpura
#1
George Goshua, Pranay Sinha, Jeanne Elise Hendrickson, Christopher A Tormey, Pavan Bendapudi, Alfred Ian Lee
Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by thrombotic microangiopathy leading to end-organ damage. The standard of care (SOC) treatment is therapeutic plasma exchange (TPE) alongside immunomodulation with steroids, with increasing use of rituximab +/- other immunomodulatory agents. The addition of caplacizumab, a nanobody targeting von Willebrand factor, was shown to accelerate platelet count recovery and reduce TPE treatments and hospital length of stay in TTP patients treated in the TITAN and HERCULES trials...
December 6, 2020: Blood
https://read.qxmd.com/read/33275657/partial-f8-gene-duplication-factor-viii-padua-associated-with-high-factor-viii-levels-and-familial-thrombophilia
#2
Paolo Simioni, Stefano Cagnin, Francesca Sartorello, Gabriele Sales, Luca Pagani, Cristiana Bulato, Sabrina Gavasso, Francesca Nuzzo, Francesco Chemello, Claudia Maria Radu, Daniela Tormene, Luca Spiezia, Tilman M Hackeng, Elena Campello, Elisabetta Castoldi
High coagulation factor VIII (FVIII) levels are a common risk factor for venous thromboembolism (VTE), but the underlying genetic determinants are largely unknown. We investigated the molecular bases of high FVIII levels in two Italian families with severe thrombophilia. The proband of the first family had a history of recurrent VTE before the age of 50, with extremely and persistently elevated FVIII antigen and activity levels (>400%) as the only thrombophilic defect. Genetic analysis revealed a 23.4-kb tandem duplication of the proximal portion of the F8 gene (promoter, exon 1 and a large part of intron 1), which co-segregated with high FVIII levels in the family and was absent in 103 normal controls...
December 4, 2020: Blood
https://read.qxmd.com/read/33275656/preleukemic-and-leukemic-evolution-at-the-stem-cell-level
#3
Jacob Stauber, John Greally, Ulrich Steidl
Hematological malignancies are an aggregate of diverse populations of cells that arise following a complex process of clonal evolution and selection. Recent approaches have facilitated the study of clonal populations and their evolution over time across multiple phenotypic cell populations. In this review, we present current concepts on the role of clonal evolution in leukemic initiation, disease progression, and relapse. We highlight recent advances and unanswered questions on the contribution of the hemopoietic stem cell population on these processes...
December 4, 2020: Blood
https://read.qxmd.com/read/33275650/rapid-single-molecule-digital-detection-of-protein-biomarkers-for-continuous-monitoring-of-systemic-immune-disorders
#4
Yujing Song, Erin Sandford, Yuzi Tian, Qingtian Yin, Andrew G Kozminski, Shiuan-Haur Su, Tao Cai, Yuxuan Ye, Meng Ting Chung, Ryan Lindstrom, Annika Goicochea, Jenny Barabas, Mary Olesnavich, Michelle Rozwadowski, Yongqing Li, Hasan B Alam, Benjamin H Singer, Monalisa Ghosh, Sung Won Choi, Muneesh Tewari, Katsuo Kurabayashi
Digital protein assays have great potential to advance immunodiagnostics because of their single-molecule sensitivity, high precision, and robust measurements. However, translating digital protein assays to acute clinical care has been challenging because it requires their deployment with a rapid turnaround. Herein, we present a technology platform for ultra-fast digital protein biomarker detection by employing single-molecule counting of immune-complex formation events at an early, pre-equilibrium state. This method, which we term "pre-equilibrium digital enzyme-linked immunosorbent assay" (PEdELISA), can quantify a multiplexed panel of protein biomarkers in 10 µL of serum within an unprecedented assay incubation time of 15-300 sec over a 104 dynamic range...
December 4, 2020: Blood
https://read.qxmd.com/read/33270841/crispr-screen-identifies-genes-that-sensitize-aml-cells-to-double-negative-t-cell-therapy
#5
Fraser Soares, Branson Chen, Jong Bok Lee, Musaddeque Ahmed, Dalam Ly, Enoch Tin, Hyeonjeong Kang, Yong Zeng, Nayeema Akhtar, Mark D Minden, Housheng He, Li Zhang
Acute myeloid leukemia (AML) remains a devastating disease in need of new therapies to improve patient survival. Targeted, adoptive T cell therapies have achieved impressive clinical outcomes in some B-cell leukemias and lymphomas but not in AML. Double negative T cells (DNTs) effectively kill blast cells from the majority of AML patients and are now being tested in clinical trials. However, AML blasts obtained from ~30% of patients show resistance to DNT cell-mediated cytotoxicity; the markers or mechanisms underlying this resistance have not been elucidated...
December 3, 2020: Blood
https://read.qxmd.com/read/33270832/eculizumab-discontinuation-in-children-and-adults-with-atypical-haemolytic-uremic-syndrome-a-prospective-multicentric-study
#6
Fadi Fakhouri, Marc Fila, Aurelie Hummel, David Ribes, Anne-Laure Sellier-Leclerc, Simon Ville, Claire Pouteil-Noble, Jean-Philippe Coindre, Moglie Le Quintrec, Eric Rondeau, Olivia Boyer, François Provôt, Djamal Djeddi, W Hanf, Yahsou Delmas, Ferielle Louillet, Annie Lahoche, Guillaume Favre, Valérie Chatelet, Emma Allain-Launay, Claire Presne, Ariane Zaloszyc, Sophie Caillard, Stéphane Bally, Quentin Raimbourg, Leila Tricot, Christiane Mousson, Aurélie Le Thuaut, Chantal Loirat, Veronique Fremeaux-Bacchi
The optimal duration of eculizumab treatment in patients with atypical haemolytic uremic syndrome (aHUS) remains poorly defined. We conducted a prospective national multicentric open-label study in order to assess eculizumab discontinuation in children and adults with aHUS. Fifty-five patients (including 19 children) discontinued eculizumab (mean duration of treatment, 16.5 months). Twenty-eight (51%) patients had complement gene rare variants, mostly in MCP (n= 12, 22%), CFH (n= 6, 11%) and CFI (n=6, 10%) genes...
December 3, 2020: Blood
https://read.qxmd.com/read/33270827/genomic-profiling-identifies-somatic-mutations-predicting-thromboembolic-risk-in-patients-with-solid-tumors
#7
Andrew Dunbar, Kelly L Bolton, Sean M Devlin, Francisco Sanchez-Vega, Jianjiong Gao, Jodi V Mones, Jonathan Wills, Daniel Kelly, Mirko Farina, Keith Bryan Cordner, Young C Park, Sirish Kishore, Krishna Juluru, Neil M Iyengar, Ross L Levine, Ahmet Zehir, Wungki Park, Alok A Khorana, Gerald A Soff, Simon Mantha
Cancer-associated venous thromboembolism (CAT) is a well-described complication of cancer and a leading cause of death in cancer patients. The purpose of this study was to assess potential associations of molecular signatures with CAT, including tumor-specific mutations and the presence of clonal hematopoiesis. We analyzed deep-coverage targeted DNA-sequencing data of >14,000 solid tumor samples using the MSK-IMPACT™ platform to identify somatic alterations associated with VTE. Endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis...
December 3, 2020: Blood
https://read.qxmd.com/read/33270819/local-blood-coagulation-drives-cancer-cell-arrest-and-brain-metastasis-in-a-mouse-model
#8
Manuel J Feinauer, Stefan W Schneider, Anna Sophie Berghoff, Jose Ramon Robador, Cedric Tehranian, Matthia A Karreman, Varun Venkataramani, Gergely Solecki, Julia Katharina Grosch, Katharina Gunkel, Bogdana Kovalchuk, Frank Thomas Mayer, Manuel Fischer, Michael O Breckwoldt, Maik Brune, Yannik Schwab, Wolfgang Wick, Alexander Thomas Bauer, Frank Winkler
Clinically relevant brain metastases (BM) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors are not well understood. Here, in vivo multiphoton laser-scanning microscopy (MPLSM) of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice...
December 3, 2020: Blood
https://read.qxmd.com/read/33270816/clinical-effects-of-administering-leukemia-specific-donor-t-cells-to-patients-with-aml-mds-post-allogeneic-transplant
#9
Premal Lulla, Swati Naik, Spyridoula Vasileiou, Ifigeneia Tzannou, Ayumi Watanabe, Manik Kuvalekar, Suhasini Lulla, George Carrum, Carlos Almeida Ramos, Rammurti Kamble, LaQuisa C Hill, Jasleen K Randhawa, Stephen Gottschalk, Robert Krance, Wang Tao, Mengfen Wu, Catherine Robertson, Adrian P Gee, Betty Mi-Yung Chung, Bambi Grilley, Malcolm Brenner, Helen Heslop, Juan F Vera, Ann M Leen
Relapse after allogeneic hematopoietic stem-cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusions of unselected donor lymphocytes (DLIs) are used to enhance the graft-versus-leukemia (GVL) effect, as treatment for relapsed disease. However, as the infused lymphocytes are not selected for leukemia-specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease(GVHD) due to the concurrent transfer of allo-reactive lymphocytes...
December 3, 2020: Blood
https://read.qxmd.com/read/33259596/effect-of-bruton-tyrosine-kinase-inhibitor-on-efficacy-of-adjuvanted-recombinant-hepatitis-b-and-zoster-vaccines
#10
Christopher Pleyer, Mir A Ali, Jeffrey I Cohen, Xin Tian, Susan J Soto, Inhye E Ahn, Erika M Gaglione, Pia K Nierman, Gerald E Marti, Charles Hesdorffer, Jennifer Lotter, Jeanine Superata, Adrian Wiestner, Clare Sun
Vaccinations are effective in preventing infections; however, it is unknown if patients with chronic lymphocytic leukemia (CLL) who are treatment naïve (TN) or receiving Bruton tyrosine kinase inhibitors (BTKis) respond to novel adjuvanted vaccines. Understanding the effect of BTKis on humoral immunity is timely because BTKis are widely used and vaccination against COVID-19 is urgently needed. In two open-label, single-arm clinical trials, we measured the effect of BTKis on de novo immune response against recombinant hepatitis B vaccine (HepB-CpG) and recall response against recombinant zoster vaccine (RZV) in CLL patients who were TN or on BTKi...
December 1, 2020: Blood
https://read.qxmd.com/read/33259592/targeting-bfl-1-via-acute-cdk9-inhibition-overcomes-intrinsic-bh3-mimetic-resistance-in-lymphomas
#11
Scott Boiko, Theresa A Proia, Maryann San Martin, Gareth Gregory, Michelle Min Wu, Neeraj Kumar Aryal, Maureen M Hattersley, Wenlin Shao, Jamal C Saeh, Stephen Fawell, Ricky W Johnstone, Lisa Drew, Justin Cidado
BH3 mimetics like Venetoclax target pro-survival Bcl-2 family proteins and are important therapeutics in the treatment of hematological malignancies. We demonstrate endogenous Bfl-1 expression can render preclinical lymphoma tumor models insensitive to Mcl-1 and Bcl-2-inhibitors. However, suppression of Bfl-1 alone was insufficient to fully induce apoptosis in Bfl-1-expressing lymphomas, highlighting the need for targeting additional pro-survival proteins in this context. Importantly, we demonstrated that CDK9 inhibitors rapidly downregulate both Bfl-1 and Mcl-1, inducing apoptosis in BH3 mimetic resistant lymphoma cell lines in vitro and driving in vivo tumor regressions in DLBCL PDX models expressing Bfl-1...
December 1, 2020: Blood
https://read.qxmd.com/read/33259589/phase-2-study-of-the-safety-and-efficacy-of-umbralisib-in-patients-with-cll-who-are-intolerant-to-btk-or-pi3k%C3%AE-inhibitor-therapy
#12
Anthony R Mato, Nilanjan Ghosh, Stephen J Schuster, Nicole Lamanna, John M Pagel, Ian W Flinn, Jacqueline Barrientos, Kanti R Rai, James A Reeves, Bruce D Cheson, Paul M Barr, Suman Kambhampati, Frederick Lansigan, Jeffrey J Pu, Alan P Skarbnik, Lindsey Elizabeth Roeker, Gustavo Fonseca, Andrea Sitlinger, Issam S Hamadeh, Colleen Dorsey, Nicole LaRatta, Hanna Weissbrot, Eline T Luning Prak, Patricia Y Tsao, Dana Paskalis, Peter Sportelli, Hari P Miskin, Michael S Weiss, Jakub Svoboda, Danielle M Brander
PURPOSE: Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in CLL. Umbralisib a novel, highly selective PI3Kδ/CK1ε inhibitor, is active and well tolerated in CLL patients. This phase 2 trial evaluated umbralisib in CLL patients who are intolerant to prior BTK or PI3K inhibitor therapy. PATIENTS AND METHODS: In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg oral daily in CLL patients requiring therapy per investigator discretion who were intolerant to prior BTK or PI3K inhibitor therapy, until progression or toxicity...
December 1, 2020: Blood
https://read.qxmd.com/read/33259585/hydroxyurea-does-not-affect-the-spermatogonial-pool-in-prepubertal-patients-with-sickle-cell-disease
#13
Anne-Sophie Gille, Corinne Pondarre, Jean-Hugues Dalle, Françoise Bernaudin, Celine Chalas, Mony Fahd, Camille Jean, Harry Lezeau, Lydia Riou, Véronique Drouineaud, Annabel Paye-Jaouen, Annie Kamdem, Benedicte Neven, Cecile Arnaud, Saba Azarnoush, Karima Yakouben, Sabine Sarnacki, Mariane De Montalembert, Eva Maria Comperat, Gilles Lenaour, Mathilde Sibony, Nathalie Dhedin, Daniel Vaiman, Jean-Philippe Wolf, Catherine Patrat, Pierre Fouchet, Catherine Poirot, Virginie Barraud-Lange
No abstract text is available yet for this article.
December 1, 2020: Blood
https://read.qxmd.com/read/33254233/idh1-mutation-contributes-to-myeloid-dysplasia-in-mice-by-disturbing-heme-biosynthesis-and-erythropoiesis
#14
Yu Gu, Risheng Yang, Ying Yang, Yuanlin Zhao, Andrew Wakeham, Wanda Y Li, Alan Tseng, Julie Leca, Thorsten Berger, Mary Saunders, Jerome Fortin, Xing Gao, Yuan Yuan, Liming Xiao, Feng Zhang, Lijun Zhang, Guangxun Gao, Wenjing Zhou, Zhe Wang, Tak W Mak, Jing Ye
Isocitrate dehydrogenase (IDH) mutations are common genetic alterations in myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Epigenetic changes, including abnormal histone and DNA methylation, have been implicated in the pathogenic build-up of hematopoietic progenitors, but it is still unclear whether and how IDH mutations themselves affect hematopoiesis. Here, we show that IDH1-mutant mice develop myeloid dysplasia in that these animals exhibit anemia, ineffective erythropoiesis, increased immature progenitor and erythroblast...
November 30, 2020: Blood
https://read.qxmd.com/read/33238000/increased-%C3%AE-4galt1-expression-associates-with-platelet-surface-galactosylation-and-thrombopoietin-plasma-levels-in-mpns
#15
Christian Andrea Di Buduo, Silvia Giannini, Vittorio Abbonante, Vittorio Rosti, Karin Hoffmeister, Alessandra Balduini
Aberrant megakaryopoiesis is a hallmark of the myeloproliferative neoplasms (MPNs), a group of clonal haematological malignancies originating from haematopoietic stem cells, leading to an increase in mature blood cells in the peripheral blood. Sialylated derivatives of the glycan structure β4-N-acetyllactosamine (Galβ1,4GlcNAc or type-2 LacNAc, thereafter referred to as LacNAc) regulate platelet lifespan, hepatic Thrombopoietin production, and thrombopoiesis. We found increased Thrombopoietin plasma levels in MPNs with high allele burden of the mutated clones...
November 25, 2020: Blood
https://read.qxmd.com/read/33237986/clinical-insights-into-the-origins-of-thrombosis-in-myeloproliferative-neoplasms
#16
Alison R Moliterno, Yelena Z Ginzburg, Ronald Hoffman
The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are hematopoietic stem cell disorders that are defined by activating mutations in signal transduction pathways and are characterized clinically by the overproduction of platelets, red blood cells and neutrophils, significant burden of disease-specific symptoms, and high rates of vascular events. The focus of this review is to critically re-evaluate the clinical burden of thrombosis in the MPNs, to review the clinical associations between clonal hematopoiesis, JAK2V617F burden, inflammation and thrombosis, and to provide insights into novel primary and secondary thrombosis prevention strategies...
November 25, 2020: Blood
https://read.qxmd.com/read/33236046/persistent-challenges-with-treating-multiple-myeloma-early
#17
Aaron Michael Goodman, Myung S Kim, Vinay Prasad
Over the last decade, two strategies have advanced the treatment of patients with multiple myeloma and precursor diseases. First, the definition has changed to include patients without end organ damage, who previously would not be treated. Second, there is widespread enthusiasm to treat high risk smoldering myeloma. In this commentary, we explore the evidence supporting these therapeutic expansions. While treating early adds cost and therapeutic burden, it remains unknown whether survival or health related quality of life is improved from early treatment...
November 24, 2020: Blood
https://read.qxmd.com/read/33232975/procoagulant-activities-of-skeletal-muscle-and-cardiac-myosins-require-both-myosin-protein-and-myosin-associated-anionic-phospholipids
#18
Shravan Morla, Hiroshi Deguchi, José A Fernández, Wolfram Ruf, Rolf Andrew Brekken, John H Griffin
No abstract text is available yet for this article.
November 24, 2020: Blood
https://read.qxmd.com/read/33232973/platelet-extracellular-vesicles-mediate-transfusion-related-acute-lung-injury-by-imbalancing-the-sphingolipid-rheostat
#19
Mark J McVey, Sarah Weidenfeld, Mazharul Maishan, Chris Spring, Michael Kim, Arata Tabuchi, Victoria Srbely, Alisa Takabe-French, Szandor Simmons, Christoph Arenz, John W Semple, Wolfgang Kuebler
Transfusion-related acute lung injury (TRALI) is a hazardous transfusion complication with an associated mortality of 5-15%. We previously showed that stored (5 days; D5) but not fresh platelets (1 day; D1) cause TRALI via ceramide mediated endothelial barrier dysfunction. As biological ceramides are hydrophobic, extracellular vesicles (EVs) may be required to shuttle these sphingolipids from platelets to endothelial cells. Adding to complexity, EV formation in turn requires ceramide. We hypothesized that ceramide-dependent EV formation from stored platelets and EV-dependent sphingolipid shuttling induce TRALI...
November 24, 2020: Blood
https://read.qxmd.com/read/33232972/adaptive-t-cell-immunity-controls-senescence-prone-myd88-or-card11-mutant-b-cell-lymphomas
#20
Maurice Reimann, Jens F Schrezenmeier, Paulina Richter-Pechanska, Anna Dolnik, Timon Pablo Hick, Kolja Schleich, Xiurong Cai, Dorothy N Y Fan, Philipp Lohneis, Sven Masswig, Sophy Denker, Antonia Busse, Gero Knittel, Ruth Flümann, Dorothee Childs, Liam Childs, Ana Maria Gätjens-Sanchez, Lars Bullinger, Andreas Rosenwald, Hans Christian Reinhardt, Clemens A Schmitt
Aberrant B-cell receptor (BCR)/NF-kB signaling is a hallmark feature of B-cell non-Hodgkin lymphomas (B-NHL), especially in diffuse large B-cell lymphoma (DLBCL). Recurrent mutations in this cascade, e.g. in CD79B, CARD11, or NFKBIZ, and also in the Toll-like receptor pathway transducer MyD88, all deregulate NF-kB, but their differential impact on lymphoma development and biology remains to be determined. We functionally investigate here primary mouse lymphomas that formed in recipient mice of Eµ-myc transgenic hematopoietic stem cells (HSC) stably transduced with naturally occurring NF-kB mutants...
November 24, 2020: Blood
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