Institution
St. Jude Children's Research Hospital
Healthcare•Memphis, Tennessee, United States•
About: St. Jude Children's Research Hospital is a healthcare organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Virus. The organization has 9344 authors who have published 19233 publications receiving 1233399 citations. The organization is also known as: St. Jude Children's Hospital & St. Jude Hospital.
Topics: Population, Virus, Cancer, Influenza A virus, Leukemia
Papers published on a yearly basis
Papers
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TL;DR: In isolation and characterization of an antibody called C05, which neutralizes strains from multiple subtypes of influenza A virus, including H1, H2 and H3, it is shown that C05 recognizes conserved elements of the receptor-binding site on the haemagglutinin surface glycoprotein.
Abstract: Immune recognition of protein antigens relies on the combined interaction of multiple antibody loops, which provide a fairly large footprint and constrain the size and shape of protein surfaces that can be targeted. Single protein loops can mediate extremely high-affinity binding, but it is unclear whether such a mechanism is available to antibodies. Here we report the isolation and characterization of an antibody called C05, which neutralizes strains from multiple subtypes of influenza A virus, including H1, H2 and H3. X-ray and electron microscopy structures show that C05 recognizes conserved elements of the receptor-binding site on the haemagglutinin surface glycoprotein. Recognition of the haemagglutinin receptor-binding site is dominated by a single heavy-chain complementarity-determining region 3 loop, with minor contacts from heavy-chain complementarity-determining region 1, and is sufficient to achieve nanomolar binding with a minimal footprint. Thus, binding predominantly with a single loop can allow antibodies to target small, conserved functional sites on otherwise hypervariable antigens.
418 citations
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Harvard University1, Beth Israel Deaconess Medical Center2, Centro de Investigación y Docencia Económicas3, Pontifícia Universidade Católica do Rio Grande do Sul4, Universidade Federal do Rio Grande do Sul5, University of the Republic6, Union for International Cancer Control7, National Autonomous University of Mexico8, King's College London9, Pan American Health Organization10, Federal University of São Paulo11, University of Virginia12, University of Chicago13, Massachusetts Institute of Technology14, Johns Hopkins University15, Johns Hopkins University School of Medicine16, East Jefferson General Hospital17, Hoffmann-La Roche18, PATH19, University of Milan20, Hospital Maciel21, University of Tennessee Health Science Center22, St. Jude Children's Research Hospital23, International Atomic Energy Agency24, University of Buenos Aires25, University of São Paulo26, Universidad de La Sabana27, University of Houston28, University of Texas MD Anderson Cancer Center29, GlaxoSmithKline30, American Cancer Society31
TL;DR: In this article, the authors present the findings of their Cancer Commission and their recommendations to encourage Latin American stakeholders to redouble their efforts to address this increasing cancer burden and to prevent it from worsening and threatening their societies.
Abstract: Non-communicable diseases, including cancer, are overtaking infectious disease as the leading health-care threat in middle-income and low-income countries. Latin American and Caribbean countries are struggling to respond to increasing morbidity and death from advanced disease. Health ministries and health-care systems in these countries face many challenges caring for patients with advanced cancer: inadequate funding; inequitable distribution of resources and services; inadequate numbers, training, and distribution of health-care personnel and equipment; lack of adequate care for many populations based on socioeconomic, geographic, ethnic, and other factors; and current systems geared toward the needs of wealthy, urban minorities at a cost to the entire population. This burgeoning cancer problem threatens to cause widespread suffering and economic peril to the countries of Latin America. Prompt and deliberate actions must be taken to avoid this scenario. Increasing efforts towards prevention of cancer and avoidance of advanced, stage IV disease will reduce suffering and mortality and will make overall cancer care more affordable. We hope the findings of our Commission and our recommendations will inspire Latin American stakeholders to redouble their efforts to address this increasing cancer burden and to prevent it from worsening and threatening their societies.
418 citations
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TL;DR: It is shown that mice lacking both IL-1β and IL-18 are normally susceptible to LPS-induced splenocyte apoptosis and endotoxic shock, and the existence of another caspase 1-dependent mediator of endotoxemia is indicated.
Abstract: Endotoxin administration recapitulates many of the host responses to sepsis. Inhibitors of the cysteine protease caspase 1 have long been sought as a therapeutic because mice lacking caspase 1 are resistant to LPS-induced endotoxic shock. According to current thinking, caspase 1-mediated shock requires the proinflammatory caspase 1 substrates IL-1β and IL-18. We show, however, that mice lacking both IL-1β and IL-18 are normally susceptible to LPS-induced splenocyte apoptosis and endotoxic shock. This finding indicates the existence of another caspase 1-dependent mediator of endotoxemia. Reduced serum high mobility group box 1 (HMGB1) levels in caspase 1-deficient mice correlated with their resistance to LPS. A critical role for HMGB1 in endotoxemia was confirmed when mice deficient for IL-1β and IL-18 were protected from a lethal dose of LPS by pretreatment with HMGB1-neutralizing Abs. We found that HMGB1 secretion from LPS-primed macrophages required the inflammasome components apoptotic speck protein containing a caspase activation and recruitment domain (ASC), caspase 1 and Nalp3, whereas HMGB1 secretion from macrophages infected in vitro with Salmonella typhimurium was dependent on caspase 1 and Ipaf. Thus, HMGB1 secretion, which is critical for endotoxemia, occurs downstream of inflammasome assembly and caspase 1 activation.
418 citations
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Fred Hutchinson Cancer Research Center1, University of Arkansas for Medical Sciences2, University of Southern California3, BC Cancer Agency4, Children's Oncology Group5, St. Jude Children's Research Hospital6, Boston Children's Hospital7, University of Utah8, Brigham Young University9, Alfred I. duPont Hospital for Children10, Children's Mercy Hospital11, National Institutes of Health12
TL;DR: The results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.
Abstract: We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.
417 citations
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TL;DR: It is found that the risk of relapse in pediatric patients with hematologic malignancies was best predicted by a model taking into consideration the presence of inhibitory killer cell Ig-like receptors on the donor's NK cells and the absence of corresponding KIR ligand in the recipient’s HLA repertoire (a receptor-ligand model).
Abstract: In HLA-nonidentical bone marrow transplantation, we studied the characteristics of donor NK cells, recipient leukemia cells, and the cytokine environment that predict the antileukemia effects of allogeneic NK cells. We found that the risk of relapse in pediatric patients with hematologic malignancies was best predicted by a model taking into consideration the presence of inhibitory killer cell Ig-like receptors (KIRs) on the donor's NK cells and the absence of corresponding KIR ligand in the recipient's HLA repertoire (a receptor-ligand model). The risk of relapse was prognosticated less precisely by the Perugia donor-recipient KIR ligand-ligand mismatch model or by a natural cytotoxicity model. In contrast to the ligand-ligand model, we found that the new receptor-ligand model was accurate when analysis was applied to patients with lymphoid malignancy. These findings corroborate our observations that the recipient's KIR repertoire, which was derived from highly purified, HLA-disparate CD34+ cells, resumed a donor-specific pattern within 3 mo of transplantation, but did not correlate evidently with the donor or recipient ligand repertoire. In an in vitro assay and an in vivo mouse model, human NK cell cytotoxicity toward human leukemia cells with 11q23 chromosomal rearrangement increased with the number of receptor-ligand mismatch pairs or prestimulation with IL-12 and IL-18. These findings provide new insights into the determinants of antileukemia effects of allogeneic NK cells and therapeutic strategies.
416 citations
Authors
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Name | H-index | Papers | Citations |
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Richard A. Flavell | 231 | 1328 | 205119 |
David Baltimore | 203 | 876 | 162955 |
John C. Reed | 190 | 891 | 164382 |
Joan Massagué | 189 | 408 | 149951 |
Stuart H. Orkin | 186 | 715 | 112182 |
Douglas R. Green | 182 | 661 | 145944 |
Richard K. Wilson | 173 | 463 | 260000 |
Todd R. Golub | 164 | 422 | 201457 |
Robert G. Webster | 158 | 843 | 90776 |
Elaine R. Mardis | 156 | 485 | 226700 |
David Cella | 156 | 1258 | 106402 |
Rafi Ahmed | 146 | 633 | 93190 |
Ching-Hon Pui | 145 | 805 | 72146 |
Yoshihiro Kawaoka | 139 | 883 | 75087 |
Seth M. Steinberg | 137 | 936 | 80148 |