Citations

ABSTRACT Background: High density lipoprotein (HDL) can be readily oxidized in inflammatory conditions and exhibit pro-inflammatory and dysfunctional (Dys-HDL) characteristics. We hypothesize that Dys-HDL may predict adverse outcomes and correlate with inflammatory cytokines in sepsis. Methods: Emergency department (ED) patients with sepsis were enrolled. Blood was drawn at enrollment and after 48 h. Dys-HDL, expressed as HDL inflammatory index (HII), and cytokines were measured. Multivariable logistic regression was used to determine the predictive ability of Dys-HDL for adverse outcomes (death, discharge to hospice, or nursing home). Results: Thirty-five patients were included in the study. HII was not significantly different at baseline or 48 h between patients with adverse outcomes versus those without. However, there was a significant difference in change in HII over the first 48 h between those with adverse outcomes (+0.21, 95% CI −0.13 to 0.31) versus those without (−0.11, 95% CI −1 to 0.11) (P = 0.025). Logistic regression revealed increasing HII to be an independent predictor of adverse outcomes (OR 5.2, 95% CI 1.1–25.1 P = 0.040). Of the 24 patents with cytokine measurements at both time points, significant inverse correlations between change in HII and change in GRO (rs = −0.52, P = 0.0088) and monocyte chemotactic protein-1 (rs = −0.61, P = 0.0014) concentrations over 48 h were observed. Conclusion: Increasing Dys-HDL concentrations in the first 48 h of sepsis are associated with an ongoing inflammatory response and adverse clinical outcomes. Early changes in HII may be a potential biomarker in ED patients admitted with sepsis.

Single-cell diversity in the brain The cells that make up an organism may all start from one genome, but somatic mutations mean that somewhere along the line of development, an organism's individual cellular genomes diverge. McConnell et al. review the implications and causes of single-cell genomic diversity for brain function. Somatic mutations caused by mobile genetic elements or errors in DNA repair may underlie certain neuropsychiatric disorders. Science , this issue p. eaal1641

ABSTRACT Serologic evaluation for Zika virus (ZIKV) infection currently includes an initial screen using an anti-ZIKV IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) followed by supplemental testing of specimens with nonnegative results by a plaque reduction neutralization test (PRNT). We compared the performance characteristics of three ELISAs for the detection of IgM class antibodies to ZIKV, including the Centers for Disease Control and Prevention (CDC) Zika MAC-ELISA, the InBios ZIKV Detect MAC-ELISA, and the Euroimmun anti-Zika Virus IgM ELISA. Additionally, we present our initial experiences with ZIKV serologic testing from a national reference laboratory perspective. Using both retrospectively and prospectively collected specimens from patients with possible ZIKV infection, we show that the CDC and InBios MAC-ELISAs perform comparably to each other, with positive agreement, negative agreement, and interrater kappa values ranging from 87.5% to 93.1%, 95.7% to 98.5%, and 0.52 to 0.83, respectively. In contrast, comparison of the Euroimmun ZIKV ELISA to either the CDC or InBios MAC-ELISAs resulted in positive agreement, negative agreement, and interrater kappa values ranging from 17.9% to 42.9%, 91.7% to 98.6%, and 0.10 to 0.39, respectively. Among the 19 prospective samples submitted for PRNT, nine were negative, eight specimens had neutralizing antibodies to a flavivirus (unable to be identified), and one sample each was confirmed for ZIKV or dengue virus infection. This study highlights the ongoing challenges associated with serologic diagnosis of ZIKV infection. Although the availability of a commercial serologic test for ZIKV has greatly expanded the national capacity for such testing, the need to further characterize and improve these assays, particularly with regard to specificity, remains.

Abstract The current integrative pathobiologic hypothesis states that pancreatic cancer (PDAC) develops and progresses in response to an interaction between known oncogenes and downstream epigenomic regulators. Congruently, this study tests a new combinatorial therapy based on the inhibition of the Aurora kinase A (AURKA) oncogene and one of its targets, the H3K9 methylation–based epigenetic pathway. This therapeutic combination is effective at inhibiting the in vitro growth of PDAC cells both, in monolayer culture systems, and in three-dimensional spheroids and organoids. The combination also reduces the growth of PDAC xenografts in vivo. Mechanistically, it was found that inhibiting methyltransferases of the H3K9 pathway in cells, which are arrested in G2–M after targeting AURKA, decreases H3K9 methylation at centromeres, induces mitotic aberrations, triggers an aberrant mitotic check point response, and ultimately leads to mitotic catastrophe. Combined, these data describe for the first time a hypothesis-driven design of an efficient combinatorial treatment that targets a dual oncogenic–epigenomic pathway to inhibit PDAC cell growth via a cytotoxic mechanism that involves perturbation of normal mitotic progression to end in mitotic catastrophe. Therefore, this new knowledge has significant mechanistic value as it relates to the development of new therapies as well as biomedical relevance. Implications: These results outline a model for the combined inhibition of a genetic-to-epigenetic pathway to inhibit cell growth and suggest an important and provocative consideration for harnessing the capacity of cell-cycle inhibitors to enhance the future use of epigenetic inhibitors. Mol Cancer Res; 15(8); 984–97. ©2017 AACR.

The prevalence of childhood obesity has increased over the past 3 decades. This study was designed to understand how childhood body mass index (BMI) influences later risk of obesity. We calculated BMIs for children residing in Olmsted County, Minnesota, between January 1, 2005 and December 31, 2012 using medical records data. We defined homogenous BMI trajectory clusters using a nonparametric hill-climbing algorithm. Overall, 16,538 (47%) children had >3 weight assessments at least 1 year apart and were included in the analyses. Within the 8-year follow-up period, children who were younger than 2 years and overweight had a 3- fold increase of obesity (adjusted hazard ratio [HR] = 3.24; 95% confidence interval [CI] = 2.69-3.89) and those aged 5 years and overweight had a 10-fold increased risk of obesity (adjusted HR = 9.97, 95% CI = 8.55-11.62). Three distinct BMI trajectories could be distinguished prior to 5 years of age. The risk of developing obesity in those who are overweight increased dramatically with increasing age. Interventions to prevent obesity need to occur prior to school age to prevent children from entering unhealthy BMI trajectories.

Abstract Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10−5 to 10−6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980–93. ©2017 AACR.

Key Points Pembrolizumab was first shown to be clinically active in CLL patients with RT. PD-1 and PD-L1 expression in tumor microenvironment are promising biomarkers to select RT patients for PD-1 blockade.