Presenter: Emma Yi Lu

Paper: Exposure to Secondhand Smoke and Arrhythmogenic Cardiac Alternans in a Mouse Model

Authors:  Zhen Wang, Lianguo Wang, Srinivas Tapa, Kent E. Pinkerton, Chao-Yin Chen, and Crystal M. Ripplinger

Abstract:

BACKGROUND: Epidemiological evidence suggests that a majority of deaths attributed to secondhand smoke (SHS) exposure are cardiovascular related. However, to our knowledge, the impact of SHS on cardiac electrophysiology, Ca2þ handling, and arrhythmia risk has not been studied.

OBJECTIVES: The purpose of this study was to investigate the impact of an environmentally relevant concentration of SHS on cardiac electrophysiology and indicators of arrhythmia.

METHODS: Male C57BL/6 mice were exposed to SHS . Hearts were excised and Langendorff perfused for dual optical mapping with voltage- and Ca2þ-sensitive dyes.

RESULTS:At slow pacing rates, SHS exposure did not alter baseline electrophysiological parameters. With increasing pacing frequency, action potential duration (APD), and intracellular Ca2þ alternans magnitude progressively increased in all groups. At 4 and 8 wk, there were no statistical differences in APD or Ca2þ alternans magnitude between SHS and FA groups. At 12 wk, both APD and Ca2þ alternans magnitude were significantly increased in the SHS compared to FA group (p<0 :05). SHS exposure did not impact the time constant of Ca2þ transient decay (s) at any exposure time point. At 12 wk exposure, the recovery of Ca2þ transient amplitude with premature stimuli was slightly (but nonsignificantly) delayed in SHS compared to FA hearts, suggesting that Ca2þ release via ryanodine receptors may be impaired.

CONCLUSIONS: In male mice, chronic exposure to SHS at levels relevant to social situations in humans increased their susceptibility to cardiac alternans, a known precursor to ventricular arrhythmia

Presenter: Heng Bai

Paper: Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

Authors:  Miroslav Balaz, Anton S. Becker, Lucia Balazova, ..., Matthias Johannes Betz, Irene A. Burger, Christian Wolfrum

Abstract:

Through genetic and pharmacological in vivo and in vitro approaches, Balaz et al. show that the mevalonate pathway is important for adipocyte browning. The importance of this pathway is supported by a retrospective clinical study and a small volunteer trial with fluvastatin. The authors identify geranylgeranyl pyrophosphate as the key mevalonate intermediate driving adipocyte browning.

Presenter: Pattra Chun-On

Paper: Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma

Authors:  Hanjie Li, Anne M. van der Leun, Ido Yofe, Yaniv Lubling, ..., Ton N. Schumacher, Amos Tanay, Ido Amit

Abstract:
Single-cell analysis of melanoma tumor immune infiltrates reveals a separation between bystander cytotoxic T cells and a population that displays a continuous progression from a transitional toward a dysfunctional state that is associated with active proliferation and tumor reactivity.

Presenter: Nicole Shuangjia Xue

Paper: Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications

Authors: Susanne Jahreis, PhD, Saskia Trump, PhD, Mario Bauer, MD, Tobias Bauer, PhD,c Loreen Th€urmann, MSc, Ralph Feltens, PhD, Qi Wang, PhD, Lei Gu, PhD, Konrad Gr€utzmann, PhD, Stefan R€oder, PhD, Marco Averbeck, MD, Dieter Weichenhan, PhD, Christoph Plass, PhD, Ulrich Sack, MD, Michael Borte, MD, Virginie Dubourg, MSc, Gerrit Sch€u€urmann, PhD, Jan C. Simon, MD, Martin von Bergen, PhD, J€org Hackerm€uller, PhD,h Roland Eils, PhD, Irina Lehmann, PhD, and Tobias Polte, PhD

Abstract:
Background: Prenatal and early postnatal exposures to environmental factors are considered responsible for the increasing prevalence of allergic diseases. Although there is some evidence for allergy-promoting effects in children because of exposure to plasticizers, such as phthalates, findings of previous studies are inconsistent and lack mechaistic information.

Objective: We investigated the effect of maternal phthalate exposure on asthma development in subsequent generations and their underlying mechanisms, including epigenetic alterations.

Methods: Phthalate metabolites were measured within the prospective mother-child cohort Lifestyle and Environmental Factors and Their Influence on Newborns Allergy Risk (LINA) and correlated with asthma development in the children. A murine transgenerational asthma model was used to identify involved pathways.

Results: In LINA maternal urinary concentrations of mono-nbutyl phthalate, a metabolite of butyl benzyl phthalate (BBP), were associated with an increased asthma risk in the children. Using a murine transgenerational asthma model, we demonstrate a direct effect of BBP on asthma severity in the offspring with a persistently increased airway inflammation up to the F2 generation. This disease-promoting effect was mediated by BBP-induced global DNA hypermethylation in CD41 T cells of the offspring because treatment with a DNA-demethylating agent alleviated exacerbation of allergic
airway inflammation. Thirteen transcriptionally downregulated genes linked to promoter or enhancer hypermethylation were identified. Among these, the GATA-3 repressor zinc finger protein 1 (Zfpm1) emerged as a potential mediator of the enhanced susceptibility for TH2-driven allergic asthma.

Conclusion: These data provide strong evidence that maternal BBP exposure increases the risk for allergic airway inflammation in the offspring by modulating the expression of genes involved in TH2 differentiation through epigenetic alterations. (J Allergy Clin Immunol 2018;141:741-53.)

Presenter: Grace Tengziyi Ge

Paper: Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer

Authors: JoAnn E. Manson, M.D., Dr.P.H., Nancy R. Cook, Sc.D., I‑Min Lee, M.B., B.S., Sc.D., William Christen, Sc.D., Shari S. Bassuk, Sc.D., Samia Mora, M.D., M.H.S.,Heike Gibson, Ph.D., Christine M. Albert, M.D.,M.P.H., David Gordon, M.A.T.,Trisha Copeland, M.S., R.D., Denise D’Agostino, B.S., Georgina Friedenberg, M.P.H., Claire Ridge, M.P.H., Vadim Bubes, Ph.D., Edward L. Giovannucci, M.D., Sc.D., Walter C. Willet, M.D., Dr.P.H., and Julie E. Buring, Sc.D.,

Abstract:
BACKGROUND
Higher intake of marine n−3 (also called omega-3) fatty acids has been associated with reduced risks of cardiovascular disease and cancer in several observational studies. Whether supplementation with n−3 fatty acids has such effects in general populations at usual risk for these end points is unclear.

METHODS
We conducted a randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (at a dose of 2000 IU per day) and marine n−3 fatty acids (at a dose of 1 g per day) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of the composite cardiovascular end point, the composite end point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from cancer. Safety was also assessed. This article reports the results of the comparison of n−3 fatty acids with placebo.

RESULTS

A total of 25,871 participants, including 5106 black participants, underwent randomization. During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n−3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P = 0.24). Invasive cancer was diagnosed in 820 participants in the n−3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P = 0.56). In the analyses of key secondary end points, the hazard ratios were as follows: for the expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); for total stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascular causes, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths from cancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any
cause (978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). No excess risks of bleeding or other serious adverse events were observed.

CONCLUSIONS
Supplementation with n−3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259.)