Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.

Data from a nationally representative probability-based online survey sample of US adults conducted in 2015 (n = 3949, response rate 55%) were used to assess self-reported gun storage practices among gun owners with children. The presence of firearms and children in the home, along with other household and individual level characteristics, was ascertained from all respondents. Questions pertaining to household firearms (how guns are stored, number, type, etc.) were asked only of those respondents who reported that they personally owned a gun. We found that approximately one in three US households contains at least one firearm, regardless of whether children lived in the home (0.34 [0.29-0.39]) or not (0.35 [0.32-0.38]). Among gun-owning households with children, approximately two in ten gun owners store at least one gun in the least safe manner, i.e., loaded and unlocked (0.21 [0.17-0.26]); three in ten store all guns in the safest manner, i.e., unloaded and locked (0.29, [0.24-0.34]; and the remaining half (0.50 [0.45-0.55]) store firearms in some other way. Although firearm storage practices do not appear to vary across some demographic characteristics, including age, sex, and race, gun owners are more likely to store at least one gun loaded and unlocked if they are female (0.31 [0.23-0.41]) vs. male (0.17 [0.13-0.22]); own at least one handgun (0.27 [0.22-0.32] vs. no handguns (0.05 [0.02-0.15]); or own firearms for protection (0.29 [0.24-0.35]) vs. do not own for protection (0.03 [0.01-0.08]). Approximately 7% of US children (4.6 million) live in homes in which at least one firearm is stored loaded and unlocked, an estimate that is more than twice as high as estimates reported in 2002, the last time a nationally representative survey assessed this outcome. To the extent that the high prevalence of children exposed to unsafe storage that we observe reflects a secular change in public opinion towards the belief that having a gun in the home makes the home safer, rather than less safe, interventions that aim to make homes safer for children should address this misconception. Guidance alone, such as that offered by the American Academy of Pediatrics, has fallen short. Our findings underscore the need for more active and creative efforts to reduce children's exposure to unsafely stored firearms.

Synthetic cannabinoids are relatively novel substances of abuse. The use of these compounds among adolescents and young adults has been increasing, making it important for pediatric providers to be familiar with the presenting signs and symptoms of intoxication. We describe three case presentations of reported synthetic cannabinoid intoxication and provide a brief discussion of these compounds.

This is a prepublication version of an article that has undergone peer review and been accepted for publication but is not the final version of record. This paper may be cited using the DOI and date of access. This paper may contain information that has errors in facts, figures, and statements, and will be corrected in the final published version. The journal is providing an early version of this article to expedite access to this information. The American Academy of Pediatrics, the editors, and authors are not responsible for inaccurate information and data described in this version.

Rationale: Sepsis-related mortality results in part from immunodeficiency secondary to profound lymphoid apoptosis. The biological mechanisms responsible are not understood.Objectives: Because recent evidence shows that platelets are involved in microvascular inflammation and that they accumulate in lymphoid microvasculature in sepsis, we hypothesized a direct role for platelets in sepsis-related lymphoid apoptosis. Methods: We studied megakaryocytes and platelets from a murineinduced sepsis model, with validation in septic children, which showed induction of the cytotoxic serine protease granzyme B. Measurements and Main Results: Platelets from septic mice induced marked apoptosis of healthy splenocytes ex vivo. Platelets from septic granzyme B null (2/2) mice showed no lymphotoxicity. Conclusions: Our findings establish a conceptual advance in sepsis: Septic megakaryocytes produce platelets with acutely altered mRNA profiles, and these platelets mediate lymphotoxicity via granzyme B. Given the contribution of lymphoid apoptosis to sepsis-related mortality, modulation of platelet granzyme B becomes an important new target for investigation and therapy.