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Blood Advances

Xiaoli Wang, Cing Siang Hu, Bruce Petersen, Jiajing Qiu, Fei Ye, Jane Houldsworth, Kevin Eng, Fei Huang, Ronald Hoffman
Clinical trials of imetelstat therapy have indicated that this telomerase inhibitor might have disease-modifying effects in a subset of patients with myelofibrosis (MF). The mechanism by which imetelstat induces such clinical responses has not been clearly elucidated. Using in vitro hematopoietic progenitor cell (HPC) assays and in vivo hematopoietic stem cell (HSC) assays, we examined the effects of imetelstat on primary normal and MF HSCs/HPCs. Treatment of CD34+ cells with imetelstat reduced the numbers of MF but not cord blood HPCs (colony-forming unit-granulocyte/macrophage, burst-forming unit-erythroid, and colony-forming unit-granulocyte/erythroid/macrophage/megakaryocyte) as well as MF but not normal CD34+ ALDH+ cells irrespective of the patient's mutational status...
September 25, 2018: Blood Advances
Tao Wu, Yong Yang, Su-Yu Zhu, Mei Shi, Hang Su, Ying Wang, Xia He, Li-Ming Xu, Zhi-Yong Yuan, Li-Ling Zhang, Gang Wu, Bao-Lin Qu, Li-Ting Qian, Xiao-Rong Hou, Fu-Quan Zhang, Yu-Jing Zhang, Yuan Zhu, Jian-Zhong Cao, Sheng-Min Lan, Jun-Xin Wu, Chen Hu, Shu-Nan Qi, Bo Chen, Ye-Xiong Li
This study evaluated the survival benefit of intensity-modulated radiation therapy (IMRT) compared with 3-dimension conformal radiation therapy (3D-CRT) in a large national cohort of patients with early-stage extranodal nasal-type natural killer/T-cell lymphoma (NKTCL). This retrospective study reviewed patients with early-stage NKTCL treated with high-dose radiation therapy (RT; ≥45 Gy) at 16 Chinese institutions. Patients were stratified into 1 of 4 risk groups based on the number of risk factors: low risk (no factors), intermediate-low risk (1 factor), intermediate-high risk (2 factors), and high-risk (3-5 factors)...
September 25, 2018: Blood Advances
Frederic Lagarrigue, Alexandre R Gingras, David S Paul, Andrew J Valadez, Monica N Cuevas, Hao Sun, Miguel A Lopez-Ramirez, Benjamin T Goult, Sanford J Shattil, Wolfgang Bergmeier, Mark H Ginsberg
Activation of platelet glycoprotein IIb-IIIa (GPIIb-IIIa; integrin αIIbβ3) leads to high-affinity fibrinogen binding and platelet aggregation during hemostasis. Whereas GTP-bound Rap1 GTPase promotes talin 1 binding to the β3 cytoplasmic domain to activate platelet GPIIb-IIIa, the Rap1 effector that regulates talin association with β3 in platelets is unknown. Rap1 binding to the talin 1 F0 subdomain was proposed to forge the talin 1-Rap1 link in platelets. Here, we report a talin 1 point mutant (R35E) that significantly reduces Rap1 affinity without a significant effect on its structure or expression...
September 25, 2018: Blood Advances
Thejaswi Kalagara, Tracy Moutsis, Yi Yang, Karin I Pappelbaum, Anne Farken, Lucia Cladder-Micus, Sabine Vidal-Y-Sy, Axel John, Alexander T Bauer, Bruno M Moerschbacher, Stefan W Schneider, Christian Gorzelanny
The dynamic change from a globular conformation to an elongated fiber determines the ability of von Willebrand factor (VWF) to trap platelets. Fiber formation is favored by the anchorage of VWF to the endothelial cell surface, and VWF-platelet aggregates on the endothelium contribute to inflammation, infection, and tumor progression. Although P-selectin and ανβ3-integrins may bind VWF, their precise role is unclear, and additional binding partners have been proposed. In the present study, we evaluated whether the endothelial glycocalyx anchors VWF fibers to the endothelium...
September 25, 2018: Blood Advances
Sarah K Westbury, Kate Downes, Claire Burney, Maria L Lozano, Samya G Obaji, Cheng Hock Toh, Teresa Sevivas, Neil V Morgan, Wendy N Erber, Carly Kempster, Samantha F Moore, Chantal Thys, Sofia Papadia, Willem H Ouwehand, Michael A Laffan, Keith Gomez, Kathleen Freson, Jose Rivera, Andrew D Mumford
No abstract text is available yet for this article.
September 25, 2018: Blood Advances
Kalpana Parvathaneni, David W Scott
Hemophilia A is an X-linked bleeding disorder caused by mutations in the factor VIII (FVIII) gene ( F8 ). Treatment with recombinant or plasma-derived FVIII replacement therapy is standard therapy. A major problem in treating hemophilia A patients with therapeutic FVIII is that 20% to 30% of these patients produce neutralizing anti-FVIII antibodies (inhibitors) because they are not immunologically tolerant to this human protein. Hence, there is a need to establish tolerogenic protocols to FVIII epitopes. To specifically target FVIII-specific B cells, we engineered immunodominant FVIII domains (A2 and C2) as a chimeric antigen receptor expressed by both human and murine cytotoxic T cells...
September 25, 2018: Blood Advances
Constance C F M J Baaten, Frauke Swieringa, Tomasz Misztal, Tom G Mastenbroek, Marion A H Feijge, Paul E Bock, Marjo M P C Donners, Peter W Collins, Renhao Li, Paola E J van der Meijden, Johan W M Heemskerk
The platelet receptors glycoprotein Ibα (GPIbα) and GPVI are known to be cleaved by members of a disintegrin and metalloprotease (ADAM) family (ADAM10 and ADAM17), but the mechanisms and consequences of this shedding are not well understood. Our results revealed that (1) glycoprotein shedding is confined to distinct platelet populations showing near-complete shedding, (2) the heterogeneity between (non)shed platelets is independent of agonist type but coincides with exposure of phosphatidylserine (PS), and (3) distinct pathways of shedding are induced by elevated Ca2+ , low Ca2+ protein kinase C (PKC), or apoptotic activation...
September 25, 2018: Blood Advances
Oleg V Kolupaev, Trisha A Dant, Hemamalini Bommiasamy, Danny W Bruce, Kenneth A Fowler, Stephen L Tilley, Karen P McKinnon, Stefanie Sarantopoulos, Bruce R Blazar, James M Coghill, Jonathan S Serody
Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients after allogeneic bone marrow (BM) or stem cell transplantation (allo-SCT). Recent work has indicated that both T and B lymphocytes play an important role in the pathophysiology of cGVHD. Previously, our group showed a critical role for the germinal center response in the function of B cells using a bronchiolitis obliterans (BO) model of cGVHD. Here, we demonstrated for the first time that cGVHD is associated with severe defects in the generation of BM B lymphoid and uncommitted common lymphoid progenitor cells...
September 25, 2018: Blood Advances
Ruqayyah J Almizraq, Philip J Norris, Heather Inglis, Somaang Menocha, Mathijs R Wirtz, Nicole Juffermans, Suchitra Pandey, Philip C Spinella, Jason P Acker, Jennifer A Muszynski
Transfusion of red cell concentrates (RCCs) is associated with increased risk of adverse outcomes that may be affected by different blood manufacturing methods and the presence of extracellular vesicles (EVs). We investigated the effect of different manufacturing methods on hemolysis, residual cells, cell-derived EVs, and immunomodulatory effects on monocyte activity. Thirty-two RCC units produced using whole blood filtration (WBF), red cell filtration (RCF), apheresis-derived (AD), and whole blood-derived (WBD) methods were examined (n = 8 per method)...
September 25, 2018: Blood Advances
Hiroshi Arima, Momoko Nishikori, Yasuyuki Otsuka, Wataru Kishimoto, Kiyotaka Izumi, Koubun Yasuda, Tomohiro Yoshimoto, Akifumi Takaori-Kondo
The Notch-signaling pathway in a variety of mature B-cell neoplasms is often activated by gene alterations, but its role remains unclear. Here, we show that B cells harboring dysregulated activation of Notch1 signaling have an immunomodulatory effect on T cells by amplifying regulatory T (Treg) and T helper 2 (Th2) cell responses in an interleukin-33 (IL-33)-dependent manner. A conditional mouse model, in which constitutive expression of an active form of Notch1 is induced in B cells by Aicda gene promoter-driven Cre recombinase, revealed no obvious phenotypic changes in B cells; however, mice demonstrated an expansion of Treg and Th2 cell subsets and a decrease in cytokine production by Th1 and CD8+ T cells...
September 25, 2018: Blood Advances
Jennine Grootens, Johanna S Ungerstedt, Gunnar Nilsson, Joakim S Dahlin
Hematopoietic stem cells differentiate into all types of blood cells, including peripheral tissue-resident mast cells. The early mast cell differentiation takes place in the bone marrow, after which the progenitor cells enter the circulation and mature once reaching their target organ. Early results from single-cell culture experiments and colony-forming assays have produced the classic hierarchical tree model of hematopoiesis. The introduction of high-throughput, single-cell RNA sequencing is now revolutionizing our understanding of the differentiation process, questioning the classic tree-based models...
September 11, 2018: Blood Advances
Hideya Seo, Si Jing Chen, Kazuya Hashimoto, Hiroshi Endo, Yohei Nishi, Akira Ohta, Takuya Yamamoto, Akitsu Hotta, Akira Sawaguchi, Hideki Hayashi, Noritaka Koseki, George J Murphy, Kazuhiko Fukuda, Naoshi Sugimoto, Koji Eto
During maturation, megakaryocytes (MKs) express β1-tubulin (TUBB1) and rearrange their microtubule components to enlarge, form proplatelets, and eventually release platelets. The development of a platform to identify in vitro conditions that would efficiently promote MK development could potentially enable large-scale platelet production. Here, we show that an immortalized MK cell line (imMKCL) genetically modified to express the β1-tubulin-Venus reporter provides a practical system to efficiently monitor the in vitro production of platelet-like particles (PLPs)...
September 11, 2018: Blood Advances
Stefan O Ciurea, Maria Cecilia Borges Bittencourt, Denái R Milton, Kai Cao, Piyanuch Kongtim, Gabriela Rondon, Julianne Chen, Marina Konopleva, Jorge M Ramos Perez, Mohammed F El Shazly, Majdi Aljadayeh, Michele Alvarez, Jin Im, Gheath Al-Atrash, Rohtesh Mehta, Uday Popat, Qaiser Bashir, Betul Oran, Chitra M Hosing, Issa F Khouri, Partow Kebriaei, Richard E Champlin
Donor availability for allogeneic transplantation remains an important factor in determining outcomes of a successful transplant. We examined outcomes of 242 patients treated over 3 years who had a matched unrelated donor (MUD) search at our institution. One hundred sixty patients (66%) had a 10 of 10 MUD identified, and 85 (53%) proceeded to MUD transplantation. White patients and those with common haplotypes were more likely to have a MUD identified (odds ratio [OR], 7.4 [ P < .0001]; OR, 41.6 [ P < ...
September 11, 2018: Blood Advances
Takeshi Sugio, Kohta Miyawaki, Koji Kato, Kensuke Sasaki, Kyohei Yamada, Javeed Iqbal, Toshihiro Miyamoto, Koichi Ohshima, Takahiro Maeda, Hiroaki Miyoshi, Koichi Akashi
Peripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts...
September 11, 2018: Blood Advances
Adrienne Sallets, Sophie Robinson, Adel Kardosh, Ronald Levy
Direct activation of tumor infiltrating antigen-presenting cells (APCs) by intratumoral injection of STING agonists (STINGa) leads to regression of the treated lymphoma tumor. Because STING activation induces apoptosis in lymphoma cells in vitro, we distinguished between the direct therapeutic vs the indirect immunotherapeutic properties of STINGa in vivo. Employing wild-type or STING knockout hosts bearing either wild-type or STING knockout tumor cells, we demonstrated that local tumor regression is totally dependent on STING expression by the host and is therefore immune mediated...
September 11, 2018: Blood Advances
Laura K Schoch, Kenneth R Cooke, Nina D Wagner-Johnston, Ivana Gojo, Lode J Swinnen, Philip Imus, Ephraim J Fuchs, Mark Levis, Richard F Ambinder, Richard J Jones, Douglas E Gladstone
Published reports suggest that immune checkpoint inhibitors (ICIs) before allogeneic blood or marrow transplantation (alloBMT) may increase the incidence of graft-versus-host disease (GvHD), immune-related adverse events, and nonrelapse mortality (NRM); this led to the US Food and Drug Administration issuing a "Warning and Precaution" regarding the potential for life-threatening immune-mediated complications associated with alloBMT after nivolumab and pembrolizumab. We retrospectively reviewed the outcomes of 14 consecutive patients who received ICIs as their final salvage therapy before T-cell-replete alloBMT using reduced-intensity conditioning...
September 11, 2018: Blood Advances
Nagaharu Tsukiji, Makoto Osada, Tomoyuki Sasaki, Toshiaki Shirai, Kaneo Satoh, Osamu Inoue, Norihiko Umetani, Chihiro Mochizuki, Tamio Saito, Soichi Kojima, Hideyuki Shinmori, Yukio Ozaki, Katsue Suzuki-Inoue
The platelet activation receptor C-type lectin-like receptor 2 (CLEC-2) interacts with podoplanin on the surface of certain types of tumor cells, and this interaction facilitates tumor metastasis. CLEC-2 is also involved in thrombus formation and its stabilization. Because CLEC-2-depleted mice are protected from experimental lung metastasis and thrombus formation and do not show increased bleeding time, CLEC-2 may serve as a good target for antimetastatic or antithrombotic drugs. We screened 6770 compounds for their capability to inhibit CLEC-2-podoplanin binding using an enzyme-linked immunosorbent assay...
September 11, 2018: Blood Advances
Daniel Ribeiro, Alice Melão, Ruben van Boxtel, Cristina I Santos, Ana Silva, Milene C Silva, Bruno A Cardoso, Paul J Coffer, João T Barata
T-cell acute lymphoblastic leukemia (T-ALL) constitutes an aggressive subset of ALL, the most frequent childhood malignancy. Whereas interleukin-7 (IL-7) is essential for normal T-cell development, it can also accelerate T-ALL development in vivo and leukemia cell survival and proliferation by activating phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling. Here, we investigated whether STAT5 could also mediate IL-7 T-ALL-promoting effects. We show that IL-7 induces STAT pathway activation in T-ALL cells and that STAT5 inactivation prevents IL-7-mediated T-ALL cell viability, growth, and proliferation...
September 11, 2018: Blood Advances
Smita Joshi, Meenakshi Banerjee, Jinchao Zhang, Akhil Kesaraju, Irina D Pokrovskaya, Brian Storrie, Sidney W Whiteheart
We genetically manipulated the major platelet vesicle-associated membrane proteins (VAMP2, VAMP3, and VAMP8) to create mice with varying degrees of disrupted platelet secretion. As previously shown, loss of VAMP8 reduced granule secretion, and this defect was exacerbated by further deletion of VAMP2 and VAMP3. VAMP2Δ 3Δ 8-/- platelets also had reduced VAMP7. Loss of VAMP2 and VAMP3 (VAMP2Δ 3Δ ) had a minimal impact on secretion when VAMP7 and VAMP8 were present. Integrin αIIbβ3 activation and aggregation were not affected, although spreading was reduced in VAMP2Δ 3Δ 8-/- platelets...
September 11, 2018: Blood Advances
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