The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. ...Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.
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•EZH2 and BCL6 mediate combinatorial tethering of non-canonical PRC1-BCOR complex•CBX8 binding to bivalent promoters enables GC B cell-specific PRC1-BCOR recruitment•BCOR tethering by EZH2 activity and BCL6 is required for GC and drives GC hyperplasia•Combinatorial targeting of EZH2 and BCL6 yields enhanced anti-lymphoma effect
Béguelin et al. show that EZH2 and BCL6 cooperate to recruit a non-canonical PRC1/BCOR complex containing CBX8 to repress differentiation gene expression in germinal center B cells and promote lymphomagenesis. Targeting both BCL6 and EZH2 elicits strong anti-lymphoma activity in diffuse large B cell lymphoma.
The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic ...inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell (ABC)-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.
•EZH2 is required for germinal center formation and immunoglobulin affinity maturation•Conditional expression of an EZH2 mutant lymphoma allele drives GC hyperplasia in vivo•Mutant EZH2 functions in part through aberrant repression of GC-specific bivalent promoters•EZH2 cooperates with BCL2 to initiate and maintain diffuse large B cell lymphomas
Biotic resistance describes the ability of resident species in a community to reduce the success of exotic invasions. Although resistance is a well‐accepted phenomenon, less clear are the processes ...that contribute most to it, and whether those processes are strong enough to completely repel invaders. Current perceptions of strong, competition‐driven biotic resistance stem from classic ecological theory, Elton's formulation of ecological resistance, and the general acceptance of the enemies‐release hypothesis. We conducted a meta‐analysis of the plant invasions literature to quantify the contribution of resident competitors, diversity, herbivores and soil fungal communities to biotic resistance. Results indicated large negative effects of all factors except fungal communities on invader establishment and performance. Contrary to predictions derived from the natural enemies hypothesis, resident herbivores reduced invasion success as effectively as resident competitors. Although biotic resistance significantly reduced the establishment of individual invaders, we found little evidence that species interactions completely repelled invasions. We conclude that ecological interactions rarely enable communities to resist invasion, but instead constrain the abundance of invasive species once they have successfully established.
The Society of Radiologists in Ultrasound convened a panel of specialists from radiology, hepatology, pathology, and basic science and physics to arrive at a consensus regarding the use of ...elastography in the assessment of liver fibrosis in chronic liver disease. The panel met in Denver, Colo, on October 21-22, 2014, and drafted this consensus statement. The recommendations in this statement are based on analysis of current literature and common practice strategies and are thought to represent a reasonable approach to the noninvasive assessment of diffuse liver fibrosis.
This paper compares the results of four recent engineering-economic studies
of the potential for energy technologies to reduce greenhouse gas emissions.
The review includes a sector-by-sector ...assessment of specific technology
opportunities and their costs, as estimated by (
a
) five National
Laboratories, (
b
) the Tellus Institute, (
c
) the National Academy
of Sciences, and (
d
) the Office of Technology Assessment. These studies
document that numerous cost-effective, energy-efficient technologies remain
underutilized in each end-use sector of the economy. Supply-side options, on
the other hand, are generally found to involve some net costs. Demand- and
supply-side options benefit from being pursued concurrently because of various
interaction effects. In combination, large carbon reductions are possible at
incremental costs that are less than the value of the energy saved. An
aggressive national commitment involving some combination of targeted tax
incentives, emissions trading, and non-price policies is needed to exploit
these carbon reduction opportunities.
Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM ...hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.
•Short-term fasting improves anticancer chemotherapy•Treatment with caloric restriction mimetics (CRMs) inhibits tumor growth in vivo•CRMs trigger an autophagy-dependent anticancer immune response•CRMs deplete regulatory T Cells from tumor bed
Pietrocola et al. show that short-term fasting or autophagy-inducing caloric restriction mimetics, such as hydroxycitrate and spermidine, improves the antitumor efficacy of chemotherapy in vivo. The effect is specific for autophagy-competent tumors and depends on regulatory T cell depletion from the tumor bed.
In young febrile infants, serious bacterial infections (SBIs), including urinary tract infections, bacteremia, and meningitis, may lead to dangerous complications. However, lumbar punctures and ...hospitalizations involve risks and costs. Clinical prediction rules using biomarkers beyond the white blood cell count (WBC) may accurately identify febrile infants at low risk for SBIs.
To derive and validate a prediction rule to identify febrile infants 60 days and younger at low risk for SBIs.
Prospective, observational study between March 2011 and May 2013 at 26 emergency departments. Convenience sample of previously healthy febrile infants 60 days and younger who were evaluated for SBIs. Data were analyzed between April 2014 and April 2018.
Clinical and laboratory data (blood and urine) including patient demographics, fever height and duration, clinical appearance, WBC, absolute neutrophil count (ANC), serum procalcitonin, and urinalysis. We derived and validated a prediction rule based on these variables using binary recursive partitioning analysis.
Serious bacterial infection, defined as urinary tract infection, bacteremia, or bacterial meningitis.
We derived the prediction rule on a random sample of 908 infants and validated it on 913 infants (mean age was 36 days, 765 were girls 42%, 781 were white and non-Hispanic 43%, 366 were black 20%, and 535 were Hispanic 29%). Serious bacterial infections were present in 170 of 1821 infants (9.3%), including 26 (1.4%) with bacteremia, 151 (8.3%) with urinary tract infections, and 10 (0.5%) with bacterial meningitis; 16 (0.9%) had concurrent SBIs. The prediction rule identified infants at low risk of SBI using a negative urinalysis result, an ANC of 4090/µL or less (to convert to ×109 per liter, multiply by 0.001), and serum procalcitonin of 1.71 ng/mL or less. In the validation cohort, the rule sensitivity was 97.7% (95% CI, 91.3-99.6), specificity was 60.0% (95% CI, 56.6-63.3), negative predictive value was 99.6% (95% CI, 98.4-99.9), and negative likelihood ratio was 0.04 (95% CI, 0.01-0.15). One infant with bacteremia and 2 infants with urinary tract infections were misclassified. No patients with bacterial meningitis were missed by the rule. The rule performance was nearly identical when the outcome was restricted to bacteremia and/or bacterial meningitis, missing the same infant with bacteremia.
We derived and validated an accurate prediction rule to identify febrile infants 60 days and younger at low risk for SBIs using the urinalysis, ANC, and procalcitonin levels. Once further validated on an independent cohort, clinical application of the rule has the potential to decrease unnecessary lumbar punctures, antibiotic administration, and hospitalizations.
Abstract
Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can be detected indirectly by measuring the host immune response. For some viruses, antibody concentrations ...correlate with host protection and viral neutralization, but in rare cases, antiviral antibodies can promote disease progression. Elucidation of the kinetics and magnitude of the SARS-CoV-2 antibody response is essential to understand the pathogenesis of coronavirus disease 2019 (COVID-19) and identify potential therapeutic targets.
Methods
Sera (n = 533) from patients with real-time polymerase chain reaction–confirmed COVID-19 (n = 94 with acute infections and n = 59 convalescent patients) were tested using a high-throughput quantitative immunoglobulin M (IgM) and immunoglobulin G (IgG) assay that detects antibodies to the spike protein receptor binding domain and nucleocapsid protein. Individual and serial samples covered the time of initial diagnosis, during the disease course, and following recovery. We evaluated antibody kinetics and correlation between magnitude of the response and disease severity.
Results
Patterns of SARS-CoV-2 antibody production varied considerably. Among 52 patients with 3 or more serial specimens, 44 (84.6%) and 42 (80.8%) had observed IgM and IgG seroconversion at a median of 8 and 10 days, respectively. Compared to those with milder disease, peak measurements were significantly higher for patients admitted to the intensive care unit for all time intervals between 6 and 20 days for IgM, and all intervals after 5 days for IgG.
Conclusions
High-sensitivity assays with a robust dynamic range provide a comprehensive picture of host antibody response to SARS-CoV-2. IgM and IgG responses were significantly higher in patients with severe than mild disease. These differences may affect strategies for seroprevalence studies, therapeutics, and vaccine development.
In sera (n = 533) from patients with COVID-19 (n = 153), immunoglobulin M and immunoglobulin G responses, as measured by a quantitative immunoassay, were significantly higher in patients with severe than mild disease. These differences may affect strategies for seroprevalence studies, therapeutics, and vaccine development.
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