Authors: Ward Y, Lake R, Faraji F, Sperger J, Martin P, Gilliard C, Ku KP, Rodems T, Niles D, Tillman H, Yin J, Hunter K, Sowalsky AG, Lang J, Kelly K
Journal: Cell Rep. 2018 Apr 17;23(3):808-822. doi: 10.1016/j.celrep.2018.03.092.
Tumor cells initiate platelet activation leading to the secretion of bioactive molecules, which promote metastasis. Platelet receptors on tumors have not been well-characterized, resulting in a critical gap in knowledge concerning platelet-promoted metastasis. We identify a direct interaction between platelets and tumor CD97 that stimulates rapid bidirectional signaling. CD97, an adhesion G protein-coupled receptor (GPCR), is an overexpressed tumor antigen in several cancer types. Purified CD97 extracellular domain or tumor cell-associated CD97 stimulated platelet activation. CD97-initiated platelet activation led to granule secretion, including the release of ATP, a mediator of endothelial junction disruption. Lysophosphatidic acid (LPA) derived from platelets induced tumor invasiveness via proximal CD97-LPAR heterodimer signaling, coupling coincident tumor cell migration and vascular permeability to promote transendothelial migration. Consistent with this, CD97 was necessary for tumor cell-induced vascular permeability in vivo and metastasis formation in preclinical models. These findings support targeted blockade of tumor CD97 as an approach to ameliorate metastatic spread.
Authors: Anttila JE, Albert K, Wires ES, Mätlik K, Loram L, Watkins L, Rice KC, Wang Y, Harvey BK, Airavaara M
Journal: eNeuro. 2018 Apr 16;ENEURO.0395-17.2018.
Ischemic stroke is the leading cause of disability, and effective therapeutic strategies are needed to promote incomplete recovery. Neuroinflammation plays a significant role in stroke pathophysiology, and there is limited understanding how it affects recovery. The aim of the study was to characterize the spatiotemporal expression profile of microglial activation and to study whether dampening microglial/macrophage activation post-stroke facilitates the recovery. For dampening microglial/macrophage activation we chose intranasal administration of naloxone, a drug that is already in clinical use for opioid overdose and is known to decrease microglia/macrophage activation. We characterized the temporal progression of microglia/macrophage activation following cortical ischemic injury in rat and found the peak activation in cortex 7 days post-stroke. Unexpectedly, there was a chronic expression of phagocytic cells in the thalamus associated with neuronal loss. (+)-Naloxone, an enantiomer that reduces microglial activation without antagonizing opioid receptors, was administered intranasally starting 1 day post-stroke and continuing for 7 days. (+)-Naloxone treatment decreased microglia/macrophage activation in the striatum and thalamus, promoted behavioral recovery during the 14-day monitoring period, and reduced neuronal death in the lesioned cortex and ipsilateral thalamus. Our results are the first to show that post-stroke intranasal (+)-naloxone administration promotes short-term functional recovery and reduces microglia/macrophage activation. Therefore, (+)-naloxone is a promising drug for the treatment of ischemic stroke and further studies should be conducted.
Authors: Chia CW, Shardell M, Gravenstein KS, Carlson OD, Simonsick EM, Ferrucci L, Egan JM
Journal: Diabetes Obes Metab. 2018 Apr 23. doi: 10.1111/dom.13328. [Epub ahead of print]
Low-calorie sweeteners (LCS) are widely used for weight control despite limited evidence of their effectiveness and studies linking LCS consumption with incident obesity. We tested the hypothesis that regular LCS consumption is associated with higher post-prandial glucose-dependent insulinotropic polypeptide (GIP) secretion, which has been linked to obesity. We used data from Baltimore Longitudinal Study of Aging participants who had completed a diet diary, had at least one visit with an oral glucose tolerance test (OGTT), and had no diabetes. Of 232 participants, 166 contributed one, 39 contributed two, and 27 contributed three visits; and 96 (41%) reported using LCS. Plasma OGTT samples were analyzed for glucose, insulin and GIP. Fasting glucose, insulin or GIP were no different between LCS users and non-users. The association of LCS use with 2-hr OGTT responses after adjustment for covariates were non-significant for glucose (P=0.98) and insulin (P=0.18), but significant for greater increase in GIP in users (P=0.037). Regular consumption of LCS is associated with greater increases in GIP secretion following food intake, which may potentially lead to weight gain through lipogenic properties of GIP.
Authors: Lee NJ, Ha SK, Sati P, Absinta M, Luciano NJ, Lefeuvre JA, Schindler MK, Leibovitch EC, Ryu JK, Petersen MA, Silva AC, Jacobson S, Akassoglou K, Reich DS
Journal: Brain. 2018 Apr 20. doi: 10.1093/brain/awy082. [Epub ahead of print]
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although it has been extensively studied, the proximate trigger of the immune response remains uncertain. Experimental autoimmune encephalomyelitis in the common marmoset recapitulates many radiological and pathological features of focal multiple sclerosis lesions in the cerebral white matter, unlike traditional experimental autoimmune encephalomyelitis in rodents. This provides an opportunity to investigate how lesions form as well as the relative timing of factors involved in lesion pathogenesis, especially during early stages of the disease. We used MRI to track experimental autoimmune encephalomyelitis lesions in vivo to determine their age, stage of development, and location, and we assessed the corresponding histopathology post-mortem. We focused on the plasma protein fibrinogen-a marker for blood-brain barrier leakage that has also been linked to a pathogenic role in inflammatory demyelinating lesion development. We show that fibrinogen has a specific spatiotemporal deposition pattern, apparently deriving from the central vein in early experimental autoimmune encephalomyelitis lesions <6 weeks old, and preceding both demyelination and visible gadolinium enhancement on MRI. Thus, fibrinogen leakage is one of the earliest detectable events in lesion pathogenesis. In slightly older lesions, fibrinogen is found inside microglia/macrophages, suggesting rapid phagocytosis. Quantification demonstrates positive correlation of fibrinogen deposition with accumulation of inflammatory cells, including microglia/macrophages and T cells. The peak of fibrinogen deposition coincides with the onset of demyelination and axonal loss. In samples from chronic multiple sclerosis cases, fibrinogen was found at the edge of chronic active lesions, which have ongoing demyelination and inflammation, but not in inactive lesions, suggesting that fibrinogen may play a role in sustained inflammation even in the chronic setting. In summary, our data support the notion that fibrinogen is a key player in the early pathogenesis, as well as sustained inflammation, of inflammatory demyelinating lesions.
Authors: LeBlanc KH, London TD, Szczot I, Bocarsly ME, Friend DM, Nguyen KP, Mengesha MM, Rubinstein M, Alvarez VA, Kravitz AV
Journal: Mol Psychiatry. 2018 Apr 25. doi: 10.1038/s41380-018-0051-3. [Epub ahead of print]
The dorsal striatum has been linked to decision-making under conflict, but the mechanism by which striatal neurons contribute to approach-avoidance conflicts remains unclear. We hypothesized that striatopallidal dopamine D2 receptor (D2R)-expressing neurons promote avoidance, and tested this hypothesis in two exploratory approach-avoidance conflict paradigms in mice: the elevated zero maze and open field. Genetic elimination of D2Rs on striatopallidal neurons (iMSNs), but not other neural populations, increased avoidance of the open areas in both tasks, in a manner that was dissociable from global changes in movement. Population calcium activity of dorsomedial iMSNs was disrupted in mice lacking D2Rs on iMSNs, suggesting that disrupted output of iMSNs contributes to heightened avoidance behavior. Consistently, artificial disruption of iMSN output with optogenetic stimulation heightened avoidance of open areas of these tasks, while inhibition of iMSN output reduced avoidance. We conclude that dorsomedial striatal iMSNs control approach-avoidance conflicts in exploratory tasks, and highlight this neural population as a potential target for reducing avoidance in anxiety disorders.
Authors: Saint-Maurice PF, Troiano RP, Berrigan D, Kraus WE, Matthews CE
Journal: J Am Heart Assoc. 2018 Apr 2;7(7). pii: e008815. doi: 10.1161/JAHA.118.008815.
BACKGROUND: It is unclear whether the greater benefits of moderate-to-vigorous physical activity (PA) over light PA are attributed to the higher-intensity PA or simply the greater volume of PA accumulated per unit time for moderate-to-vigorous PA. We examined this question using estimates of the volume of light and moderate-to-vigorous PA in relation to all-cause mortality.
METHODS AND RESULTS: We used National Health and Nutrition Examination Survey 2003-2006 accelerometer records in adults (≥40 years; n=4840) and mortality data collected through 2011 (n=700 deaths). We estimated intensity-specific PA volume using activitycounts (AC) accumulated in light (100-759 AC/min), moderate-to-vigorous PA (≥760 AC/min), and total PA (≥100 AC/min). We examined quartiles of each exposure using Cox proportional hazard models (hazard ratios [95% confidence interval) adjusted for demographic and behavioral risk factors, health status, and body mass index. Mortality risk was less across increasing quartiles of light PA volume (AC×1000) when compared with the least quartile (AC ≤61.8); the least risk occurred in the upper quartile of light PA, AC >98.5 (hazard ratios=0.69, 95% confidence interval: 0.47, 1.00, P trend ≤0.05). The benefits for mortality risk were greater across quartiles of moderate-to-vigorous PA and reached a hazard ratio of 0.28 (95% confidence interval: 0.17, 0.46, P trend ≤0.05) for AC >187.9, when compared with the referent group (AC ≤50.8). Results examining various combinations of light and moderate-to-vigorous intensity-specific volumes demonstrated the strong influence of total activity on mortality risk.
CONCLUSIONS: In this population, increasing light PA was associated with less mortality, but at an approximately equal volume of PA, moderate-to-vigorous PA appeared to have greater benefits.
Authors: Jefferson WN, Kinyamu HK, Wang T, Miranda AX, Padilla-Banks E, Suen AA, Williams CJ
Journal: Nucleic Acids Res. 2018 Apr 10. doi: 10.1093/nar/gky260. [Epub ahead of print]
Little is known regarding how steroid hormone exposures impact the epigenetic landscape in a living organism. Here, we took a global approach to understanding how exposure to the estrogenic chemical, diethylstilbestrol (DES), affects the neonatal mouse uterineepigenome. Integration of RNA- and ChIP-sequencing data demonstrated that ∼80% of DES-altered genes had higher H3K4me1/H3K27ac signal in close proximity. Active enhancers, of which ∼3% were super-enhancers, had a high density of estrogen receptor alpha (ERα) binding sites and were correlated with alterations in nearby gene expression. Conditional uterine deletion of ERα, but not the pioneer transcription factors FOXA2 or FOXO1, prevented the majority of DES-mediated changes in gene expression and H3K27ac signal at target enhancers. An ERα dependent super-enhancer was located at the Padi gene locus and a topological connection to the Padi1 TSS was documented using 3C-PCR. Chromosome looping at this site was independent of ERα and DES exposure, indicating that the interaction is established prior to ligand signaling. However, enrichment of H3K27ac and transcriptional activation at this locus was both DES and ERα-dependent. These data suggest that DES alters uterine development and consequently adult reproductive function by modifying the enhancer landscape at ERα binding sites near estrogen-regulated genes.
Authors: Puurunen MK, Hwang SJ, Larson MG, Vasan RS, O'Donnell CJ, Tofler G, Johnson AD.
Journal: J Am Heart Assoc. 2018 Mar 3;7(5). pii: e008522. doi: 10.1161/JAHA.118.008522.
BACKGROUND: Platelet function is associated with adverse events in patients with cardiovascular disease (CVD).
METHODS AND RESULTS: We examined associations of baseline platelet function with incident CVD events in the community-based FHS (Framingham Heart Study). Participants free of prevalent CVD and without recent aspirin treatment with available data in the Framingham Offspring cohort (1991-1995) and Omni cohort (1994-1998) were included. Platelet function was measured with light transmission aggregometry using collagen (1.9 μg/mL), ADP (0.05-15 μmol/L), and epinephrine (0.01-15 μmol/L). We used proportional hazards models to analyze incident outcomes (myocardial infarction/stroke, CVD, and CVD mortality) with respect to platelet measures. The study sample included 2831 participants (average age, 54.3 years; 57% women). During follow-up (median, 20.4 years), we observed 191 composite incident myocardial infarction or stroke events, 432 incident CVD cases, and 117 CVD deaths. Hyperreactivity to ADP and platelet aggregation at ADP concentration of 1.0 μmol/L were significantly associated with incident myocardial infarction/stroke in a multivariable model (hazard ratio, 1.68 [95% confidence interval, 1.13-2.50] [P=0.011] for hyperreactivity across ADP doses; and hazard ratio, 1.16 [95% confidence interval, 1.02-1.33] [P=0.029] for highest quartile of ADP response at 1.0 μmol/L versus others). No association was observed for collagen lag time or any epinephrine measures with incident myocardial infarction or stroke.
CONCLUSIONS: Intrinsic hyperreactivity to low-dose ADP in our community-based sample, who were free of CVD and any antiplatelet therapy, is associated with future arterial thrombosis during a 20-year follow-up. These findings reinforce ADP activation inhibition as a critical treatment paradigm and encourage further study of ADP inhibitor-refractive populations.
Authors: Cook MB, Coburn SB, Lam JR, Taylor PR, Schneider JL, Corley DA
Journal: Gut. 2018 Mar;67(3):418-529. doi: 10.1136/gutjnl-2016-312223. Epub 2017 Jan 4.
OBJECTIVE: Barrett's oesophagus (BE) increases the risk of oesophageal adenocarcinoma by 10-55 times that of the general population, but no community-based cancer-specific incidence and cause-specific mortality risk estimates exist for large cohorts in the USA.
DESIGN: Within Kaiser Permanente Northern California (KPNC), we identified patients with BE diagnosed during 1995-2012. KPNC cancerregistry and mortality files were used to estimate standardised incidence ratios (SIR), standardised mortality ratios (SMR) and excess absolute risks.
RESULTS: There were 8929 patients with BE providing 50 147 person-years of follow-up. Compared with the greater KPNC population, patients with BE had increased risks of any cancer (SIR=1.40, 95% CI 1.31 to 1.49), which slightly decreased after excluding oesophageal cancer. Oesophageal adenocarcinoma risk was increased 24 times, which translated into an excess absolute risk of 24 cases per 10 000 person-years. Although oesophageal adenocarcinoma risk decreased with time since BE diagnosis, oesophageal cancer mortality did not, indicating that the true risk is stable and persistent with time. Relative risks of cardia and stomach cancers were increased, but excess absolute risks were modest. Risks of colorectal, lung and prostate cancers were unaltered. All-cause mortality was slightly increased after excluding oesophageal cancer (SMR=1.24, 95% CI 1.18 to 1.31), but time-stratified analyses indicated that this was likely attributable to diagnostic bias. Cause-specific SMRs were elevated for ischaemic heart disease (SMR=1.39, 95% CI 1.18 to 1.63), respiratory system diseases (SMR=1.51, 95% CI 1.29 to 1.75) and digestive system diseases (SMR=2.20 95% CI 1.75 to 2.75).
CONCLUSIONS: Patients with BE had a persistent excess risk of oesophageal adenocarcinoma over time, although their absolute excess risks for this cancer, any cancer and overall mortality were modest.
Authors: Huang J, Polgár E, Solinski HJ, Mishra SK, Tseng PY, Iwagaki N, Boyle KA, Dickie AC, Kriegbaum MC, Wildner H, Zeilhofer HU, Watanabe M, Riddell JS, Todd AJ, Hoon MA.
Journal: Nat Neurosci. 2018 Mar 19. doi: 10.1038/s41593-018-0119-z. [Epub ahead of print]
Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb+ neurons, and we demonstrate that Nppb+somatostatin+ cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR+neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide.