journal
https://read.qxmd.com/read/38603637/what-clinicians-should-know-about-surrogate-endpoints-in-hematologic-malignancies
#1
JOURNAL ARTICLE
Côme Bommier, Matthew John Maurer, Jerome Lambert
Use of surrogates as primary endpoints is commonplace in hematology/oncology clinical trials. As opposed to prognostic markers, surrogates are endpoints that can be measured early and yet can still capture the full effect of treatment, as it would be captured by the true outcome (e.g., overall survival). We discuss the level of evidence of the most commonly used endpoints in hematology and share recommendations on how to apply and evaluate surrogate endpoints in research and clinical practice. Based on the statistical literature, this clinician-friendly review intends to build a bridge between clinicians and surrogacy specialists...
April 11, 2024: Blood
https://read.qxmd.com/read/38603633/gm-csf-receptor-expression-determines-opposing-innate-memory-phenotypes-at-different-stages-of-myelopoiesis
#2
JOURNAL ARTICLE
Paula Guerrero, Cristina Bono, María Sobén, Andrea Guiu, Quen J Cheng, M Luisa Gil, Alberto Yáñez
Inflammatory responses must be tightly coordinated with the activation of emergency myelopoiesis to produce potent myeloid cells that fight infection without causing excessive host damage. Here, we show that GM-CSF programs myeloid committed progenitors to produce trained macrophages (increased cytokine response), but programs the upstream non-committed LKS+ progenitors to produce tolerized macrophages (decreased cytokine response). In myeloid progenitors, GM-CSF strongly activates STAT5, ERK and Akt-mTOR signaling pathways, which are essential to establish a training program, whereas in LKS+ progenitors GM-CSF induces NF-κB translocation to the nucleus to establish a tolerization program...
April 11, 2024: Blood
https://read.qxmd.com/read/38603632/notch1-regulates-hepatic-thrombopoietin-production
#3
JOURNAL ARTICLE
Yueyue Sun, Huan Tong, Xiang Chu, Yingying Li, Jie Zhang, Yangyang Ding, Sixuan Zhang, Xiang Gui, Chong Chen, Mengdi Xu, Zhenyu Li, Elizabeth E Gardiner, Robert K Andrews, Lingyu Zeng, Kailin Xu, Jianlin Qiao
Notch signaling regulates cell-fate decisions in several developmental processes and cell functions. However, a role for Notch in hepatic thrombopoietin (TPO) production remains unclear. We noted thrombocytopenia in mice with hepatic Notch1 deficiency, and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control mice and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO mRNA levels, concomitant with lower numbers of platelets and impaired megakaryocyte differentiation and maturation, which were rescued by addition of exogenous TPO...
April 11, 2024: Blood
https://read.qxmd.com/read/38598841/variation-in-mesenchymal-kitl-scf-and-igf1-expression-at-middle-age-underlies-steady-state-hematopoietic-stem-cell-aging
#4
JOURNAL ARTICLE
Kira A Young, Maria A Telpoukhovskaia, Johanna Hofmann, Jayna J Mistry, Konstantinos Kokkaliaris, Jennifer J Trowbridge
Intrinsic molecular programs and extrinsic factors including pro-inflammatory molecules are understood to regulate hematopoietic aging. This is based on foundational studies using genetic perturbation to evaluate causality. However, individual organisms exhibit natural variation in hematopoietic aging phenotypes and the molecular basis of this heterogeneity is poorly understood. Here, we generated individual single cell transcriptomic profiles of hematopoietic and non-hematopoietic cell types in five young adult and nine middle-aged C57BL/6J female mice, providing a web-accessible transcriptomic resource for the field...
April 10, 2024: Blood
https://read.qxmd.com/read/38598835/nsd2-drives-t-4-14-myeloma-cell-dependence-on-adenylate-kinase-2-by-diverting-one-carbon-metabolism-to-the-epigenome
#5
JOURNAL ARTICLE
Amin Sobh, Elena Encinas, Alisha M Patel, Greeshma Surapaneni, Emilie Bonilla, Charlotte Leonie Kaestner, Janai Poullard, Monica Clerio, Karthik Vasan, Tzipporah Freeman, Dongwen Lv, Daphné Dupéré-Richer, Alberto Riva, Benjamin G Barwick, Daohong Zhou, Lawrence H Boise, Constantine S Mitsiades, Baek Kim, Richard L Bennett, Navdeep S Chandel, Jonathan D Licht
Chromosomal translocation (4;14), an adverse prognostic factor in multiple myeloma (MM), drives overexpression of the histone methyltransferase NSD2. A genome-wide CRISPR screen in MM cells identified adenylate kinase 2 (AK2), an enzyme critical for high energy phosphate transfer from the mitochondria, as an NSD2-driven vulnerability. AK2 suppression in t(4;14) MM cells decreased NADP(H) critical for conversion of ribonucleotides to deoxyribonucleosides, leading to replication stress, DNA damage and apoptosis...
April 10, 2024: Blood
https://read.qxmd.com/read/38588489/mutational-and-transcriptional-landscape-of-pediatric-b-cell-precursor-lymphoblastic-lymphoma
#6
JOURNAL ARTICLE
Emma Kroeze, Ingram Iaccarino, Michelle M Kleisman, Mayukh Mondal, Thomas Beder, Mouhamad Khouja, Marc P Höppner, Marijn A Scheijde-Vermeulen, Lennart A Kester, Monika Brüggemann, Claudia D Baldus, Gunnar Cario, Reno S Bladergroen, Nathalie Garnier, Andishe Attarbaschi, Jaime Verdu-Amorós, Rosemary Sutton, Elizabeth A Macintyre, Kenneth Scholten, Laura Arias Padilla, Birgit Burkhardt, Auke Beishuizen, Monique L den Boer, Roland P Kuiper, Jan L C Loeffen, Judith M Boer, Wolfram Klapper
Pediatric B-cell precursor (BCP) lymphoblastic malignancies are neoplasms with manifestation either in bone marrow/blood (BCP acute lymphoblastic leukemia, BCP-ALL) or less common in extramedullary tissue (BCP lymphoblastic lymphoma, BCP-LBL). Although both presentations are similar in morphology and immunophenotype, molecular studies are virtually restricted to BCP-ALL so far. The lack of molecular studies on BCP-LBL is due to its rarity and the restriction to small, mostly formalin-fixed paraffin embedded (FFPE) tissues...
April 8, 2024: Blood
https://read.qxmd.com/read/38598839/mortality-cardiac-and-cerebral-damages-reduction-by-il-1-inhibition-in-a-murine-model-of-ttp
#7
JOURNAL ARTICLE
Romain Muller, Raphael Cauchois, Marie Lagarde, Sandrine Roffino, Cecile Genovesio, Samantha Fernandez, Guillaume Hache, Benjamin Guillet, Yeter Kara, Marion Marlinge, Peter J Lenting, Pascale Poullin, Françoise Dignat-George, Edwige Tellier, Gilles Kaplanski
Thrombotic thrombocytopenic purpura (TTP), a rare but fatal disease if untreated, is due to alteration in Von Willebrand factor cleavage resulting in capillary microthrombi formation and ischemic organ damage. Interleukin-1 (IL-1), has been shown to drive sterile inflammation following ischemia and could play an essential contribution to post-ischemic organ damage in TTP. Our objectives were to evaluate IL-1 involvement during TTP and to test the efficacy of the recombinant IL-1 receptor antagonist, anakinra, in a murine TTP model...
April 5, 2024: Blood
https://read.qxmd.com/read/38579288/il-18-secreting-multi-antigen-targeting-car-t-cells-eliminate-antigen-low-myeloma-in-an-immunocompetent-mouse-model
#8
JOURNAL ARTICLE
Brandon D Ng, Adhithi Rajagopalan, Anastasia I Kousa, Jacob S Fischman, Sophia Chen, Alyssa Rae Massa, Harold K Elias, Dylan Manuele, Michael Galiano, Andri L Lemarquis, Alexander P Boardman, Susan DeWolf, Jonah Addison Pierce, Bjarne Bogen, Scott E James, Marcel R M van den Brink
Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T-cells in leukemia and lymphoma, CAR T-cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to low expression of BCMA on myeloma cells, suggesting that novel approaches to better address antigen-low disease may improve patient outcomes...
April 5, 2024: Blood
https://read.qxmd.com/read/38579286/loss-of-stress-sensor-gadd45a-promotes-stem-cell-activity-and-ferroptosis-resistance-in-lgr4-hoxa9-dependent-aml
#9
JOURNAL ARTICLE
Nunki Hassan, Hangyu Yi, Bilal Malik, Lucie Charlotte Gaspard-Boulinc, Saumya E E Samaraweera, Debora A Casolari, Janith A Seneviratne, Anushree Balachandran, Tracy Chew, Alastair Duly, Daniel R R Carter, Belamy Cheung, Murray Norris, Michelle Haber, Maria Kavallaris, Glenn M Marshall, Xu Dong Zhang, Tao Liu, Jianlong Wang, Dan A Liebermann, Richard J J D'Andrea, Jenny Y Wang
The overall prognosis of acute myeloid leukemia (AML) remains dismal, largely due to the inability of current therapies to kill leukemia stem cells (LSCs) with intrinsic resistance. Loss of the stress sensor GADD45A is implicated in poor clinical outcomes but its role in LSCs and AML pathogenesis is unknown. Here we define GADD45A as a key downstream target of LGR4 oncogenic signaling and discover a regulatory role for GADD45A loss in promoting leukemia-initiating activity and oxidative resistance in LGR4/HOXA9-dependent AML, a poor prognosis subset of leukemia...
April 5, 2024: Blood
https://read.qxmd.com/read/38579285/bone-marrow-niches-for-hematopoietic-stem-cells-lifespan-dynamics-and-adaptation-to-acute-stress
#10
JOURNAL ARTICLE
Johanna Hofmann, Konstantinos Kokkaliaris
Hematopoietic stem cells (HSCs) are instrumental for organismal survival as they are responsible for lifelong production of mature blood lineages in homeostasis and response to external stress. To fulfill their function, HSCs rely on reciprocal interactions with specialized tissue microenvironments, termed HSC niches. From embryonic development to advanced aging, HSCs transition through several hematopoietic organs where they are supported by distinct extrinsic cues. Here, we describe recent discoveries on how HSC niches collectively adapt to ensure robust hematopoietic function during biological aging and following exposure to acute stress...
April 5, 2024: Blood
https://read.qxmd.com/read/38579284/wiskott-aldrich-syndrome-a-study-on-577-patients-defining-the-genotype-as-a-predictive-biomarker-for-disease-severity
#11
JOURNAL ARTICLE
Tanja C Vallée, Jannik S Glasmacher, Hannes Buchner, Peter D Arkwright, Uta Behrends, Anastasia Bondarenko, Michael J Browning, David K Buchbinder, Alessandro Cattoni, Liudmyla Chernyshova, Peter Ciznar, Theresa Cole, Wojciech Czogala, Gregor Dueckers, John David M Edgar, Fatih Erbey, Anders Fasth, Francesca Ferrua, Renata Formankova, Eleonora Gambineri, Andrew R Gennery, Frederick D Goldman, Luis Ignacio Gonzalez-Granado, Carsten Heilmann, Tarja Heiskanen-Kosma, Hanna Juntti, Leena Kainulainen, Hirokazu Kanegane, Neslihan E Karaca, Sara Sebnem Kilic, Christoph Klein, Sylwia Koltan, Irina Kondratenko, Isabelle Meyts, Gulnara M Nasrullayeva, Lucia Dora Notarangelo, Srdjan Pasic, Isabelle Pellier, Claudio Pignata, Siraj Ahmed Misbah, Ansgar S Schulz, Gesmar Rs Segundo, Anna Shcherbina, Mary A Slatter, Robert Sokolic, Pere Soler-Palacin, Polina Stepensky, Joris M van Montfrans, Samppa Ryhänen, Beata Wolska-Kuśnierz, John B Ziegler, Xiaodong Zhao, Alessandro Aiuti, Hans D Ochs, Michael H Albert
WAS is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study...
April 5, 2024: Blood
https://read.qxmd.com/read/38574321/platelet-derived-tgf-%C3%AE-1-induces-functional-reprogramming-of-myeloid-derived-suppressor-cells-in-immune-thrombocytopenia
#12
JOURNAL ARTICLE
Lingjun Wang, Haoyi Wang, Mingfang Zhu, Xiaofei Ni, Lu Sun, Wanru Wang, Jie Xie, Yubin Li, Yitong Xu, Ruting Wang, Shouqing Han, Ping Zhang, Jun Peng, Ming Hou, Yu Hou
Platelet α-granules are rich in TGF-β1 which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and re-balancing T cell subsets...
April 4, 2024: Blood
https://read.qxmd.com/read/38558106/b-cell-directed-car-t-cell-therapy-activates-cd8-cytotoxic-carneg-bystander-t-cells-in-non-human-primates-and-patients
#13
JOURNAL ARTICLE
James Kaminski, Ryan A Fleming, Francesca Alvarez-Calderon, Marlana B Winschel, Connor McGuckin, Emily Elizabeth Ho, Fay Eng, Xianliang Rui, Paula Keskula, Lorenzo Cagnin, Joanne Charles, Jillian M Zavistaski, Steven P Margossian, Malika Kapadia, James B Rottman, Jennifer Lane, Susanne H C Baumeister, Victor Tkachev, Alex Shalek, Leslie S Kean, Ulrike Gerdemann
CAR-T cells hold promise as a therapy for B-cell-derived malignancies, yet despite their impressive initial response rates, a significant proportion of patients ultimately experience relapse. While recent studies have explored the mechanisms of in vivo CAR-T cell function, little is understood about the activation of surrounding CARneg bystander T-cells and their potential to enhance tumor responses. We performed single-cell RNA-Seq (scRNA-Seq) on non-human primate (NHP) and patient-derived T-cells to identify the phenotypic and transcriptomic hallmarks of bystander activation of CARneg T-cells following B-cell targeted CAR-T cell therapy...
April 1, 2024: Blood
https://read.qxmd.com/read/38557775/axicabtagene-ciloleucel-versus-standard-of-care-in-second-line-large-b-cell-lymphoma-outcomes-by-metabolic-tumor-volume
#14
JOURNAL ARTICLE
Frederick L Locke, Olalekan O Oluwole, John Kuruvilla, Catherine Thieblemont, Franck Morschhauser, Gilles A Salles, Steven P Rowe, Saran Vardhanabhuti, Joshua Winters, Simone Filosto, Christina To, Paul Cheng, Marco Schupp, Ronald Korn, Marie José Kersten
Metabolic tumor volume (MTV) assessed using 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography, a measure of tumor burden, is a promising prognostic indicator in large B-cell lymphoma (LBCL). This exploratory analysis evaluated relationships between baseline MTV (categorized as low [≤median] vs high [>median]) and clinical outcomes in the phase 3 ZUMA-7 study (NCT03391466). Patients with LBCL relapsed within 12 months of or refractory to first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel (axi-cel; autologous anti-CD19 chimeric antigen receptor [CAR] T-cell therapy) or standard care (2-3 cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response)...
April 1, 2024: Blood
https://read.qxmd.com/read/38551812/loss-of-gabarap-mediates-resistance-to-immunogenic-chemotherapy-in-multiple-myeloma
#15
JOURNAL ARTICLE
Annamaria Gulla, Eugenio Morelli, Megan Johnstone, Marcello Turi, Mehmet K Samur, Cirino Botta, Selma Cifric, Pietro Folino, Delaney Vinaixa, Francesca Barello, Cole Clericuzio, Vanessa Katia Favasuli, Domenico Maisano, Srikanth Talluri, Rao H Prabhala, Giada Bianchi, Mariateresa Fulciniti, Kenneth Wen, Keiji Kurata, Jiye Liu, Johany Penailillo, Alberto Bragoni, Anna Sapino, Paul G Richardson, Dharminder Chauhan, Ruben D Carrasco, Teru Hideshima, Nikhil C Munshi, Kenneth C Anderson
Immunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant anti-tumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABARAP is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment...
March 29, 2024: Blood
https://read.qxmd.com/read/38551811/unraveling-mcl-biology-to-understand-resistance-and-identify-vulnerabilities
#16
JOURNAL ARTICLE
Clémentine Sarkozy, Benoit Tessoulin, David Chiron
Mantle cell lymphoma (MCL) is a rare (5-7%), aggressive B-cell non-Hodgkin's lymphoma with well-defined hallmarks (e.g. Cyclin D1, SOX11), and whose expansion is highly dependent on the tumor microenvironment (TME). Parallel drastic progresses in the understanding of the lymphomagenesis and improved treatments led to paradigm shift in this B-cell malignancy with now prolonged disease-free survival after intensive chemotherapy and anti-CD20 based maintenance. However, this toxic strategy is not applicable in frail or elderly patients and a small but significant part of the cases will present a refractory disease representing unmet medical needs...
March 29, 2024: Blood
https://read.qxmd.com/read/38551807/genomic-determinants-of-response-and-resistance-to-inotuzumab-ozogamicin-in-b-cell-all
#17
JOURNAL ARTICLE
Yaqi Zhao, Nicholas J Short, Hagop M Kantarjian, Ti-Cheng Chang, Pankaj S Ghate, Chunxu Qu, Walid Macaron, Nitin Jain, Beenu Thakral, Aaron Phillips, Joseph D Khoury, Guillermo Garcia-Manero, Wenchao Zhang, Yiping Fan, Hui Yang, Rebecca Garris, Lewis Fady Nasr, Richard Kriwacki, Kathryn G Roberts, Marina Y Konopleva, Elias J Jabbour, Charles G Mullighan
Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of response and resistance to InO. Pre- and post-InO patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed tumor samples, but not in refractory samples (0/16)...
March 29, 2024: Blood
https://read.qxmd.com/read/38527216/excess-of-circulating-apo-transferrin-enhances-dietary-iron-absorption
#18
JOURNAL ARTICLE
Sofiya Tsyplenkova, Edouard Charlebois, Carine Fillebeen, Kostas Pantopoulos
Intravenous injection of excess apo-transferrin enhances dietary iron absorption in mice, and triggers accumulation of plasma non-transferrin bound iron (NTBI). Injected fluorescent-labeled transferrin colocalizes with lamina propria macrophages, consistent with the recently proposed iron absorption checkpoint involving macrophage-mediated transferrin degradation.
March 25, 2024: Blood
https://read.qxmd.com/read/38518106/an-oral-carbon-monoxide-releasing-molecule-protects-against-acute-hyper-hemolysis-in-sickle-cell-disease
#19
JOURNAL ARTICLE
Kim Anh Nguyen, Alessandro Matte, Roberta Foresti, Enrica Federti, Laurent Kiger, Cecile Lefebvre, Hakim Hocini, Yanis Pelinski, Hiroaki Kitagishi, Laura Bencheikh, France Pirenne, Lucia De Franceschi, Roberto Motterlini, Pablo Bartolucci
Acute hyper-hemolysis is a severe life-threatening complication in patients with sickle cell disease (SCD) that may occur during delayed hemolytic transfusion reaction (DHTR), or vaso-occlusive crises associated with multi-organ failure. Here, we developed in vitro and in vivo animal models to mimic endothelial damage during the early phase of hyper-hemolysis in SCD. We then used the carbon monoxide (CO)-releasing molecule CORM-401 and examined its effects against endothelial activation, damage, and inflammation inflicted by hemolysates containing red blood cell membrane-derived particles...
March 22, 2024: Blood
https://read.qxmd.com/read/38518105/the-il-7r-antagonist-lusvertikimab-reduces-leukemic-burden-in-xenograft-all-via-antibody-dependent-cellular-phagocytosis
#20
JOURNAL ARTICLE
Lennart Lenk, Irène Baccelli, Anna Laqua, Julia Heymann, Claas Reimer, Anna Dietterle, Dorothee Winterberg, Caroline Mary, Frédérique Corallo, Julien Taurelle, Emma Narbeburu, Stéphanie Lara Neyton, Mylène Déramé, Sabrina Pengam, Fotini Vogiatzi, Beat Bornhauser, Jean-Pierre Bourquin, Simon Raffel, Vladyslava Dovhan, Thomas Schüler, Gabriele Escherich, Monique L den Boer, Judith M Boer, Wiebke Wessels, Matthias Peipp, Julia Alten, Željko Antić, Anke Katharina Bergmann, Martin Schrappe, Gunnar Cario, Monika Brüggemann, Nicolas Poirier, Denis M Schewe
Acute lymphoblastic leukemia (ALL) arises from the uncontrolled proliferation of precursor B or T cells (BCP- or T-ALL). Current treatment protocols obtain high cure rates in children but are based on toxic polychemotherapy. Novel therapies are urgently needed, especially in relapsed/refractory (r/r) disease, high-risk leukemias and T-ALL, where immunotherapy approaches remain scarce. While the Interleukin-7 receptor (IL-7R) plays a pivotal role in ALL development, no IL-7R-targeting immunotherapy has yet reached clinical application in ALL...
March 22, 2024: Blood
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