bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence and Predictors Of Venous Thromboembolism Among Lymphoma Patients In Denmark: A Nationwide Population-Based Cohort Study
Authors: Lund Jennifer L , Ostgard Lene Sofie Granfeldt , Prandoni Paolo , Sorensen Henrik Toft , Brown Peter de Nully 
Published: October 2019

Abstract

Background
Prior studies examining the incidence of venous thromboembolism (VTE) in lymphoma patients have been limited by small sample size and restriction to specific lymphoma subtypes, leading to a wide range of estimates (1.5%-59.5%). Incidence of VTE in lymphoma patients may be influenced by a variety of patient, clinical, and treatment-related factors. These factors also can influence risk of death, a nuance ignored in prior work. We examined the incidence and predictors of VTE among lymphoma patients in Denmark, considering death as a competing risk.

Methods
Our nationwide cohort study identified all newly diagnosed lymphoma patients in Denmark from 2000-2010 using a population-based lymphoma registry (n=10,759), which prospectively collects clinical, pathological, treatment, and relapse and progression data. These data were linked to the Danish National Registry of Patients to identify selected comorbid conditions, treatments, incident VTE (excluding patients with a VTE registered before the year preceding lymphoma diagnosis, n=256), and vital status. VTE incidence rates per 1,000 person-years and 95% confidence intervals (CIs) were computed for pre-specified time intervals from 1 year before through 2 years following lymphoma diagnosis. After excluding patients diagnosed with a VTE during the year before lymphoma diagnosis (n=128), we estimated the 2-year cumulative incidence of VTE overall and by lymphoma subtype, accounting for death as a competing risk. Using the Fine and Gray model, we estimated subdistribution hazard ratios (sHRs) and 95% CIs to identify patient, clinical, and time-dependent treatment predictors of VTE.

Results
The VTE incidence rate varied over time (Figure 1), with a peak immediately following diagnosis.
Excluding patients with a VTE prior to lymphoma diagnosis, the 2-year cumulative incidence was 3.5% and was highest among peripheral T-cell (5.2%) and diffuse large B-cell (4.5%) lymphoma patients. The overall 2-year cumulative incidence of death was 24.7%.
CNS involvement, elevated lactate dehydrogenase count, central venous catheter placement, and chemotherapy were the strongest predictors of VTE, after accounting for risk of death. Patients with low-risk or mantle cell lymphomas were at decreased risk of VTE compared with diffuse large B-cell lymphoma patients. Risks were similar for all other lymphoma subtypes.

Conclusions
Although the incidence of VTE was high among lymphoma patients in Denmark, this risk was substantially lower than the risk of death. In order to mitigate VTE risk while continuing to treat patients with lymphoma, prophylactic approaches should be targeted towards patient subgroups at highest risk.

Disclosures:
No relevant conflicts of interest to declare.
From B-Cell Tolerance to Autoimmunity
Authors: Marshak-Rothstein Ann 
Published: October 2019

Abstract
Despite numerous mechanisms that exist to purge the B-cell repertoire of potentially dangerous autoreactive cells, it is now clear that numerous cells with the capability of binding self determinants survive negative selection and persist peripherally as anergic or ignorant cells. Exactly how these B cells are normally constrained, and then aberrantly activated in the context of autoimmunity, are two major questions in B-cell biology. A better understanding of the mechanisms involved in these processes could provide important insights to the regulation of alloreactivity. One clue to our understanding of autoimmunity comes from the nature of the autoantigens commonly targeted in systemic autoimmune diseases. Autoantigens often consist of macromolecular complexes that incorporate self-nucleic acids, and numerous in vitro studies have now shown that many of these canonical autoantigens are essentially potent endogenous autoadjuvants. Mice expressing a low affinity BCR specific for autologous IgG2a can be potently activated by DNA or RNA-associated immune complexes through a mechanism dependent on both the BCR and either TLR9 or TLR7, and serve as a useful prototype for autoreactive B cells in general. A number of groups have now tested this BCR/TLR paradigm in vivo. As expected, Tlr9-/- autoimmune-prone mice fail to produce autoantibodies directed against chromatin, while Tlr7-/- mice fail to produce autoantibodies directed against numerous RNA-associated proteins. However, the Tlr9-/- mice develop accelerated clinical disease, while the Tlr7-/- mice exhibit remarkably prolonged survival. We have now shown that BCR/TLR9 and BCR/TLR7 induce inherently different functional outcomes in B cells. Quite remarkably, both in vitro and in vivo, BCR/TLR7-dependent activation of autoreactive B cells leads to a more prolonged response and increased numbers of antibody producing cells. This response can be defined by a unique gene-expression profile and associated with proteins known to promote plasmablast differentiation. By contrast, BCR/TLR9 activation appears to initially limit autoreactive B-cell expansion; although in the context of systemic autoimmunity TLR9 is required for the production of DNA-reactive autoantibodies. Together these data indicate that the outcome BCR/TLR9 engagement of autoreactive B cells is highly dependent on environmental cues, and suggest that BCR/TLR7 B-cell activation is a key factor in the initiation of systemic lupus erythematosus and other systemic disorders.

Disclosures:
Marshak-Rothstein: Idera Pharmaceuticals: Consultancy; Abbvie: Consultancy; Genentech: Honoraria.
Gene Regulation: A Genomic Perspective
Authors: Stamatoyannopoulos John 
Published: October 2019

Abstract
Regulatory elements control the anatomic and cellular contexts, timing, and magnitude of gene expression patterns. Under the ENCODE and Roadmap Epigenomics Projects, human regulatory DNA has been mapped using a variety of approaches in over 300 cell and tissue types and developmental states. Collectively, the human genome encodes several million regulatory elements, most of which are located at some distance from promoters. The vast majority of these elements exhibit exquisite cell-and lineage-selective activation patterns, providing novel insights into the coordination of gene expression patterns. Genomic footprinting is a new and powerful technology that enables simultaneous profiling of the occupancy of hundreds of sequence-specific transcription factors within regulatory regions. These profiles in turn enable construction of transcription factor regulatory networks that are providing new insights into how cell-and lineage-specific gene expression programs arise. Hundreds of genetic variants associated with a wide range of hematological traits and disorders localize within regulatory regions. Many such variants disrupt specific transcription factor-DNA interactions, exposing pathophysiologically relevant transcriptional regulatory pathways.

Disclosures:
No relevant conflicts of interest to declare.
Genomic Evolution and Clinical Correlates
Authors: Campbell Peter J. 
Published: October 2019

Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. It is classically subdivided into a subtype with rearrangements involving the IGH locus and the hyperdiploid subtype, which harbors multiple trisomies involving odd-numbered chromosomes. These chromosomal abnormalities are nevertheless insufficient for malignant transformation because they are also observed in monoclonal gammopathy of unknown significance, a pre-malignant syndrome that precedes MM. Malignant progression is associated with additional events such as somatic mutations, aberrant methylation, and chromosomal copy-number changes. This implies that the genetic landscape of MM changes over time, driving its symptomatic emergence and progression. Furthermore, evidence suggests that the molecular events necessary for myeloma progression are not attained in a linear fashion but rather through branching, nonlinear pathways. Through whole exome and genome sequencing, copy number profiling and cytogenetics, it has been possible to identify new candidate genes, define diverse mutational processes contributing to the genomic landscape, and study patterns of disease evolution. In particular, the overwhelming majority of MM patients have at least one cluster of subclonal variants, including subclonal driver mutations, implying ongoing tumor evolution. Serial samples reveal diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. These new findings reveal the myeloma genome to be heterogeneous across patients and within individual patients and that it can exhibit diversity in clonal admixture and dynamics in response to therapy. As modern genomics technologies will increasingly become available in routine diagnostic laboratories, it will be critical to develop an understanding of myeloma as a restless and dynamic disease, with multiple subclones exploring the genomic landscape seeking fitter states. This understanding should, in turn, be used to shape our therapeutic approach to the disease.

Disclosures:
No relevant conflicts of interest to declare.
Targeting Iron/Heme in Infectious Disease
Authors: Soares Miguel 
Published: October 2019

Abstract
Inflammation and immunity can be associated with varying degrees of hemolysis and as such with heme release from cell-free hemoglobin (Hb), i.e. free heme. Accumulation of free heme in plasma can lead, eventually, to tissue iron (Fe) overload, oxidative stress, and tissue damage. Presumably, these deleterious effects contribute critically to the pathogenesis of systemic infections, as illustrated for severe sepsis (1) as well as for severe forms of malaria (2). Free heme sensitizes parenchyma cells to undergo programmed cell death in response to pro-inflammatory agonists (1). This cytotoxic effect is driven by the intracellular accumulation of free radicals, which sustain the activation of the c-Jun N-terminal Kinase (JNK) signaling transduction pathway. While heme catabolism by heme oxygenase1 (HO-1) prevents heme driven programmed cell death, this cytoprotective effect requires the co-expression of ferritin H chain (FTH), which controls the pro-oxidant labile Fe released from the protoporphyrin IX ring of heme (3). The antioxidant effect of FTH restrains JNK activation, while JNK activation inhibits FTH expression, a crosstalk that controls metabolic adaptation to cellular Fe overload during systemic infections (4).
1. Larsen, R. et al., Sci Transl Med 2 (51), 51ra71 (2010).
2. Pamplona, A. et al., Nat Med 13 (6), 703 (2007); Ferreira, A. et al., J Mol Med 86 (10), 1097 (2008); Ferreira, A. et al., Cell 145 (April 29), 398 (2011).
3. Gozzelino, R. et al., Cell Host Microbe 12 (5), 693 (2012)
4.Medzhitov, R, Schneider, DS, and Soares. Science 335, 936 (2012).

Disclosures:
No relevant conflicts of interest to declare.
Targeting Metabolic Inputs into Epigenetic Regulations of Acute Leukemia
Authors: Thompson Craig B. 
Published: October 2019

Abstract
An essential feature of acute myeloid leukemia (AML) is the profound block to differentiation exhibited by leukemic cells. This AML-associated arrest in the normal process of cellular differentiation is not observed in more chronic forms of leukemia. Chronic forms of leukemia and lymphoma are marked by the increased propensity to enter the cell cycle as the malignant cells move to more mature states of differentiation and the increased resistance to apoptosis these cells exhibit. Considerable recent evidence has suggested that profound epigenetic remodeling occurs as either a result or a cause of cellular differentiation. Altered DNA methylation has now been established as a hallmark of acute leukemia and yet very little is known concerning the mechanisms through which this occurs. In 2010, in collaboration with others, we found that neomorphic mutations of the citrate metabolism genes IDH1 and IDH2 induce DNA hypermethylation and impair differentiation in hematopoietic cells. IDH mutations create a block to DNA and histone demethylation as a result of the production of 2-hydroxyglutarate (2HG). 2HG acts as a competitive inhibitor of α-ketoglutarate-dependent enzymes. The epigenetic effects of 2HG are caused in part though inhibition of TET2, a DNA demethylase enzyme also mutated in leukemia. IDH 1/2- and TET2-mutant primary AML cells displayed a similar defect in epigenetic programming consisting of global hypermethylation and a gene-specific methylation signature. This work identifies IDH1/2- and TET2-mutant leukemias as a biologically distinct disease subtype, and links cancer metabolism with epigenetic control of gene expression. The implications of this work and the identification of additional metabolic genes involved in epigenetic deregulation in leukemia will be discussed.

Disclosures:
Thompson: NIH: Research Funding; Keystone Symposia: Consultancy; NCI: Research Funding; Damon Runyon : Research Funding; Ludwig: Membership on an entity’s Board of Directors or advisory committees; HHMI: Membership on an entity’s Board of Directors or advisory committees; Merck: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; Agios: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; MSKCC: Employment; Pfizer: Patents & Royalties; BMS: Patents & Royalties; Repligen: Patents & Royalties.
Lessons from the Mouse Model
Authors: Rommens Johanna M. , Tourlakis Marina E. , Liu Holly , Gandhi Rikesh , Durie Peter R. 
Published: October 2019

Abstract
Shwachman-Diamond syndrome (SDS) is a member of the growing list of inherited diseases that result from mutations in genes that encode components of the protein synthesis machinery. Collectively referred to as ribosomopathies, these diseases have selective organ involvement and serious hematological issues with increased susceptibility to malignancy. SDS is caused by mutations in the highly conserved SBDS gene. Recent studies have implicated SBDS in facilitating ribosomal subunit joining for translation initiation. We study mouse models with disease-associated alleles to determine the consequences of loss of Sbds and gain insight into ribosomopathy phenotypes. Mice that are homozygous for a disease-associated allele (SbdsR126T/R126T) die at birth. Growth issues and developmental delay are evident in mid-to-late-stage embryos, and analysis of ribosome profiles indicate disturbed protein synthesis in all tissues examined. SDS-related pathologies in the fetal liver, bone, and brain are also observed. For example, flow cytometry analyses and culturing of fetal liver cells show growth impairment of myeloid lineage progenitors. Ossification is delayed in the developing phalanges. Poor proliferation is evident in early neurons and death due to apoptosis occurs in differentiating neurons, as early as E14.5. As with the brain, the fetal spleen also shows disproportionate growth restriction. These responses reflect varying underlying molecular pathways that hinge on p53 activation. Breeding to Trp53 (p53) deficient mice attenuates the SDS phenotypes but does not rescue the overall growth impairment or the perinatal death. Loss of Sbds leads to a range of organ responses, with engagement of stress pathways at different times and stages. As the severity of the organ pathology does not correlate directly with alteration of 80S or polysome component peak levels in ribosome profiles, we conclude that the organ phenotype reflects limitations in gene expression and timing of expression, or results from disturbed regulation that is specific to cell type and respective protein synthesis demand.

Disclosures:
No relevant conflicts of interest to declare.
Linking Defective Ribosome Maturation to Shwachman-Diamond Syndrome
Authors: Warren Alan John 
Published: October 2019

Abstract
Ribosomes are RNA-protein machines that translate the genetic information encoded by the mRNA template in all living cells. Recent high-resolution structures of the ribosome have revolutionized our understanding of protein translation. However, the mechanisms of ribosome assembly and the surveillance mechanisms that monitor this process and couple it to growth are poorly understood. Causative mutations and deletions of genes involved in ribosome biogenesis define an emerging group of disorders known as the ribosomopathies. Recent work from my laboratory strongly supports the hypothesis that Shwachman-Diamond syndrome (SDS) is a ribosomopathy caused by defective maturation of the large ribosomal subunit. Elucidation of the specific function of the SBDS protein that is deficient in SDS is revealing unexpected new insights that extend our understanding of the mechanisms underlying the late cytoplasmic steps of ribosome assembly and the quality control surveillance pathways that monitor 60S maturation. Genetic dissection of this pathway may inform novel therapeutic strategies for SDS.
1. Wong C.C., Traynor D., Basse N., Kay R.R., Warren A.J. Defective ribosome assembly in Shwachman-Diamond syndrome. Plenary Paper, Blood. 2011 Oct 20;118(16):4305-12.
2. Finch A.J., Hilcenko C., Basse N., Drynan L.F., Goyenechea B., Menne T.F., González Fernández Á., Simpson P., D’Santos C.S., Arends M.J., Donadieu J., Bellanné-Chantelot C., Costanzo M., Boone C., McKenzie A.N., Freund S.M., Warren A.J. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes and Development (2011) 25: 917-929.
3. Menne T.M., Goyenechea B., Sánchez-Puig N., Wong C.C., Tonkin L.M., Ancliff P., Brost R.L., Costanzo M., Boone C. and Warren A.J. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genetics (2007) 39: 486-95.

Disclosures:
No relevant conflicts of interest to declare.
Ontogeny of Hematopoiesis
Authors: Dzierzak Elaine 
Published: October 2019

Abstract
The current challenge in hematopoietic transplantation and regeneration therapies is acquiring and/or producing a reliable and plentiful source of hematopoietic stem cells (HSCs). Given that HSCs from bone marrow, peripheral, or umbilical cord blood undergo only limited/no expansion ex vivo, there is a high interest in understanding how the adult cohort of multipotent self-renewing HSCs are generated and expanded during embryonic development. The development of HSCs in vertebrate embryos begins in the major vasculature. HSCs are generated in a short window of developmental time starting at embryonic day E10.5 until E12 in the mouse embryo, and from gestational weeks four to six in the human embryo. The first HSCs, which are as potent as bone marrow HSCs in transplantation procedures, are generated in the aorta-gonad-mesonephros (AGM) region. HSCs are found in the major vasculature – aorta, vitelline artery, and umbilical artery – subsequent to the appearance of hematopoietic cell clusters closely associated with the lumenal walls of these vessels. The relationship of HSCs to these clusters and the identification of the precursors to HSCs have been recently established through genetic, phenotypic, and real-time imaging studies. Remarkably, HSCs and hematopoietic progenitors arise directly from a subset of endothelial cells (hemogenic endothelial cells) in a natural transdifferentiation event. They are made through a process called endothelial to hematopoietic cell transition (EHT). EHT and HSC generation is in part regulated through ventral-derived developmental signals and a group of pivotal (core) transcription factors, including Runx1 and Gata2. Conditional knockout strategies show that these transcription factors are required for the generation of vascular hematopoietic clusters and HSCs, suggesting a role in hematopoietic fate induction and/or cell expansion. Interestingly, whereas both Runx1 and Gata2 are required for HSC generation, only Gata2 remains essential in HSCs after their production. We are profiling hemogenic endothelial and HSCs by RNA sequencing so as to understand the complete genetic program that leads to generation of HSCs. These results will be discussed in the context of developmental signaling pathways (BMP4, Hedgehog, etc.) that appear to impact HSC generation and expansion, and the localized dynamic expression and function of Gata2 and Runx1 in vascular endothelial and hematopoietic cluster cells.

Disclosures:
No relevant conflicts of interest to declare.
Role of Bcl-2 Family in Lymphoid Malignancies
Authors: Strasser Andreas , Kelly G. , Glaser S. , Grabow S. , Delbridge A. , Adams J.M. , Herold M. 
Published: October 2019

Abstract
Impaired apoptosis is considered one of the prerequisites for the development of most, if not all, cancers, but the mechanisms that guarantee the sustained survival of most cancer cells remain unknown. Members of the Bcl-2 family are key regulators of apoptosis and include proteins essential for cell survival and those required to initiate cell death. Studies with transgenic mice have shown that over-expression of Bcl-2 or related pro-survival family proteins, such as Bcl-xL or Mcl-1, can promote tumorigenesis, particularly in conjunction with mutations that deregulate cell cycle control, such as deregulated c-myc expression. It is, however, not known whether expression of pro-survival Bcl-2 family members under endogenous control is required to maintain the survival of cells undergoing neoplastic transformation. Using Eµ-myc transgenic mice, a well-characterized model of human Burkitt’s lymphoma, we investigated the role of endogenous Bcl-2 in lymphoma development. Bcl-2 was found to be dispensable for the development of Eµ-myc pre-B/B lymphoma. In contrast, loss of Bcl-xL and even, more remarkable, loss of a single allele of Mcl1 greatly impaired lymphoma development. Experiments with inducible knockout mice demonstrated that Mcl-1 but not Bcl-xL is essential for the sustained survival and expansion of Myc-driven malignant pore-B/B lymphoma. Remarkably, even loss of one Mcl1allele greatly impaired lymphoma growth. These findings were translated into using lymphoid malignancies by using inducible expression of selective antagonists of distinct pro-survival Bcl-2 family members. Such studies showed that Mcl-1 is also critical for the sustained survival and expansion of Burkitt Lymphoma, a Myc-driven malignancy. These observations indicate that (even relatively weak) targeting of Mcl-1 may be an attractive strategy for the treatment of Myc-driven hematological malignancies.

Disclosures:
Strasser: Genentech Inc: Consultancy.
Control of the Stem Cell Gene Expression Program
Authors: Young Richard A. 
Published: October 2019

Abstract
The gene expression programs that establish and maintain specific cell states in humans are controlled by thousands of transcription factors, cofactors, and chromatin regulators. Our understanding of the DNA elements and regulators that control gene expression programs has advanced considerably in the last year. I will describe new insights into the roles that these elements and regulators play in global gene control during normal development and in various diseases. These insights provide opportunities for the development of novel diagnostics and therapeutics.

Disclosures:
Young: Syros Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; Enzon Pharmaceuticals: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.