Cancer cells recruit monocytes, macrophages and other inflammatory cells by producing abundant chemoattractants and growth factors, such as macrophage colony-stimulating factor (M-CSF/CSF-1) and monocyte chemoattractant protein-1 (MCP-1/CCL2), to promote tumor growth and dissemination. An understanding of the mechanisms that target cancer cells and regulate tumor microenvironment is essential in designing anticancer therapies. Here, we showed that serum amyloid-A (SAA) and cathelicidin (LL-37) stimulated M-CSF and MCP-1 expression with or without lipopolysaccharide (LPS) administration; conversely, lipoxin-A 4 (LXA 4 ) and annexin-A1 (ANXA1) inhibited LPS-induced M-CSF and MCP-1 production by human (HepG2) and mouse (H22) hepatocellular carcinoma cells (HCCs). The effects of LXA 4 , ANXA1, SAA and LL-37 were dependent on the activation of their mutual cell-surface receptor formyl peptide receptor-2 (FPR2) and subsequent ROS-MAPK-NF-kB signalings. Furthermore, our results indicated that LPS switched macrophages into an IL-10 low IL-12 high M1 profile, whereas M-CSF þ MCP-1 and FPR2 agonists skewed them into M2 (IL-10 high IL-12 low ). In that respect, through modulating the phosphorylation of signal transducer and activator of transcription-3 (STAT3), LXA 4 and ANXA1 induced monocyte differentiation into M2a þ M2c-like cells and showed antitumorigenetic activities, whereas SAA, LL-37 and M-CSF þ MCP-1 led to M2b-or M2d-like polarization, which exacerbated HCC invasion in vitro and in vivo, respectively. Our results suggest that FPR2 has an appreciable pleiotropic regulator role in tumor immunoediting.

102Sleep is an essential homeostatically-regulated state of decreased activity and alertness 103 conserved across animal species, and both short and long sleep duration associate with 104 chronic disease and all-cause mortality 1,2 . Defining genetic contributions to sleep 105 duration could point to regulatory mechanisms and clarify causal disease relationships. 106Through genome-wide association analyses in 446,118 participants of European 107 ancestry from the UK Biobank, we discover 78 loci for self-reported sleep duration that 108 further impact accelerometer-derived measures of sleep duration, daytime inactivity 109 duration, sleep efficiency and number of sleep bouts in a subgroup (n=85,499) with up 110 to 7-day accelerometry. Associations are enriched for genes expressed in several brain 111 regions, and for pathways including striatum and subpallium development, 112 mechanosensory response, dopamine binding, synaptic neurotransmission, 113 catecholamine production, synaptic plasticity, and unsaturated fatty acid 114 metabolism. Genetic correlation analysis indicates shared biological links between sleep 115 duration and psychiatric, cognitive, anthropometric and metabolic traits and Mendelian 116 randomization highlights a causal link of longer sleep with schizophrenia. 117 118 Research in model organisms (reviewed in 3,4 ) has delineated aspects of the neural-119 circuitry of sleep-wake regulation 5 and molecular components including specific 120 neurotransmitter and neuropeptide systems, intracellular signaling molecules, ion 121 channels, circadian clock genes and metabolic and immune factors 4 , but their specific 122 roles and relevance to human sleep regulation are largely unknown. Prospective 123 epidemiologic studies suggest that both short (<6,7 hours per night) and long (>8,9 124 hours per night) habitual self-reported sleep duration associate with cognitive and 125 psychiatric, metabolic, cardiovascular, and immunological dysfunction as well as all-126 cause mortality compared to sleeping 7-8 hours per night 6-12 . Furthermore, chronic 127 sleep deprivation in modern society may lead to increased errors and accidents 13 . Yet, 128 whether short or long habitual sleep duration causally contributes to disease initiation or 129 progression remains to be established. 130 131 Habitual self-reported sleep duration is a complex trait with an established genetic 132 component (twin-and family-based heritability (h 2 ) estimates =9-45% 14-20 ). Candidate 133 gene sequencing in pedigrees and functional validation of rare, missense variants 134 established BHLHE41 (previously DEC2), a repressor of CLOCK/ARNTL activity, as a 135 causal gene 21,22 , supporting the role of the circadian clock in sleep regulation. Previous 136 genome-wide association studies (GWAS) in up to 128,286 individuals identified 137 association of common variants at or near the PAX8 and VRK2 genes 20,23,24 . 138 139Here, we extend GWAS of self-reported sleep duration in UK Biobank to discover 78 140 loci, test for consistency of eff...

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes, but underlying pathophysiological processes and causal relationships with disease are poorly understood. Here we identify 57 loci for self-reported insomnia symptoms in the UK Biobank (n=453,379) and confirm their impact on self-reported insomnia symptoms in the HUNT study (n=14,923 cases, 47,610 controls), physician diagnosed insomnia in Partners Biobank (n=2,217 cases, 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n=83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis, phototransduction and muscle development pathways and of genes expressed in multiple brain regions, skeletal muscle and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, aging, cardio-metabolic, behavioral, psychiatric and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary heart disease, depressive symptoms and subjective well-being.One Sentence Summary: We identify 57 genomic regions associated with insomnia pointing to the involvement of phototransduction and ubiquitination and potential causal links to CAD and depression.

Excessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with substantial functional deficits. We identified 42 loci for self-reported EDS in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirmed the aggregate effect of a genetic risk score of 42 SNPs on EDS in independent Scandinavian cohorts and on other sleep disorders (restless leg syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). Strong genetic correlations were also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing. EDS variants clustered into two predominant composite phenotypes -sleep propensity and sleepfragmentation -with the former showing stronger evidence for enriched expression in central nervous system tissues, suggesting two unique mechanistic pathways. Mendelian randomization analysis indicated that higher BMI is causally associated with EDS risk, but EDS does not appear to causally influence BMI.

Dietary intake, a major contributor to the global obesity epidemic 1-5 , is a complex phenotype partially affected by innate physiological processes. [6][7][8][9][10][11] However, previous genome-wide association studies (GWAS) have only implicated a few loci in variability of dietary composition. 12-14 Here, we present a multi-trait genome-wide association meta-analysis of inter-individual variation in dietary intake in 283,119 European-ancestry participants from UK Biobank and CHARGE consortium, and identify 96 genome-wide significant loci. Dietary intake signals map to different brain tissues and are enriched for genes expressed in b1tanycytes and serotonergic and GABAergic neurons. We also find enrichment of biological pathways related to neurogenesis. Integration of cell-line and brainspecific epigenomic annotations identify 15 additional loci. Clustering of genomewide significant variants yields three main genetic clusters with distinct associations with obesity and type 2 diabetes (T2D). Overall, these results enhance biological understanding of dietary composition, highlight neural mechanisms, and support functional follow-up experiments.As dietary components are strongly correlated, we conducted a multi-trait genomewide association meta-analysis of overall variation in dietary intake among 283,119European-ancestry participants from the UK Biobank 15 and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium 14 (Methods; Supplementary Table 1). First, we conducted single-trait GWAS for the proportion of total energy intake from carbohydrate, fat, and protein in UK Biobank (n=192,005).Next, single-trait GWAS from the UK Biobank and CHARGE Consortium (n=91,114) were meta-analyzed and combined into a multi-trait genome-wide association metaanalysis (Methods). An analysis overview is presented in Supplementary Fig. 1.We evaluated dietary intake using 24-hour web-based diet recall in the UK Biobank 16,17 and validated food frequency questionnaires, diet history and diet records in the CHARGE Consortium. 14 We observed strong genome-wide genetic correlations for nutrient estimates between the UK Biobank and CHARGE datasets (r g >0.6 for all; P <0.001; Supplementary Table 2). The quantile-quantile plots of single-trait and multi-trait meta-analyses showed moderate inflation (l GC ranging from 1.12 to 1.17) with a linkage disequilibrium (LD) score intercept 18 of ~1 (standard error (s.e.) = 0.01), indicating that most inflation could be explained by polygenic signal ( Supplementary Fig. 2, Supplementary Table 3). In single-trait meta-analyses, genome-wide SNP-based heritability 19 was estimated at 3.9% (s.e.=0.01), 2.8% (s.e.=0.01), and 3.0% (s.e.=0.01) for carbohydrate, fat, and protein, respectively ( Supplementary Table 3), in line with previous GWAS findings 12,14 and other behavioral phenotypes such as tobacco or alcohol use. 20

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Introduction: A large and growing body of evidence shows that sleep loss has profound deleterious effects on health and has been specifically linked to the development of several cancers. Despite this obvious health cost, there is almost no current understanding of how sleep loss increases the risk for tumor development. The purpose of the present study was to identify epigenetic mechanisms through which total sleep deprivation (TSD) altered expression of known cancer-related genes (suppressors and promoters). To that end, we tested the effects of TSD on the expression of miRNAs that are associated with tumor development. Methods: Twenty-three participants (14 males, mean age = 20) underwent actigraphy-verified TSD for 24 hours in a controlled environment. miRNA preparations were extracted from participants' plasma and processed for cDNA synthesis. The resulting cDNA pools were used as templates in qPCR reactions in an effort to estimate differential miRNA expression. Results: Results indicated that sleep deprivation caused significant differential expression of several specific miRNA tumor-related genes, including miR-15a, miR-96, and miR-296-5p. Accordingly, further tests were focused on these two miRNA species on a subset of participants. Results showed that, there was a significant upregulation of miR-15a (p < 0.05), miR-96 (p < 0.05), and miR-22 (p < 0.05), but not miR-296-5p (p=0.12). Conclusion: Overall, these findings show how even short-term sleep loss can alter cancer-associated pathways. Increased expression of miR-15a and miR-22 have known tumor suppression properties. It is possible that miR-15a and miR-22 exert protective effects in response the TSD-induced disruption to homeostasis. Although miR-96 is a known oncogene, it is also part a complex clock gene signaling pathway with diurnal expression. Accordingly, TSD potentially disrupts the normal diurnal expression pattern miR-96. We are currently following up on these results in a study of people who regularly experience sleep loss (i.e. chronic sleep restriction). Support (If Any): This work is supported by the Department of Education. Number P120A1400. INTERMITTENT HYPOXIA PARTIALLY IMPAIRS INSULIN-SIGNALING VIA INCREASES IN CAVEOLIN-1 EXPRESSION: VASCULAR IMPLICATIONS Singh P, Sharma P, Peterson TE, Zhang Y, Somers VK Mayo Clinic, Rochester, MNIntroduction: Insulin resistance and endothelial dysfunction are associated with obstructive sleep apnea (OSA), which is characterized by frequent episodes of nocturnal intermittent hypoxia (IH). However, molecular mechanisms contributing to endothelial dysfunction and insulin resistance in OSA are not completely understood. Caveolin-1 (cav-1) is a membrane protein which negatively regulates endothelial nitric oxide synthase (eNOS) activity and contributes to endothelial dysfunction. The objective of our study was to examine the interactions between IH, cav-1, and eNOS activity in vascular endothelial cells in the context of insulin resistance. Methods: We used an in-vitro approach to examine the effects ...

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