GPER1 links estrogens to centrosome amplification and chromosomal instability in human colon cells.

The role of the alternate G protein-coupled estrogen receptor 1 (GPER1) in colorectal cancer (CRC) development and progression is unclear, not least because of conflicting clinical and experimental evidence for pro- and anti-tumorigenic activities. Here, we show that low concentrations of the estrogenic GPER1 ligands, 17ß-estradiol, bisphenol A, and diethylstilbestrol cause the generation of lagging chromosomes in normal colon and CRC cell lines, which manifest in whole chromosomal instability and aneuploidy. Mechanistically, (xeno)estrogens triggered centrosome amplification by inducing centriole overduplication that leads to transient multipolar mitotic spindles, chromosome alignment defects, and mitotic laggards. Remarkably, we could demonstrate a significant role of estrogen-activated GPER1 in centrosome amplification and increased karyotype variability. Indeed, both gene-specific knockdown and inhibition of GPER1 effectively restored normal centrosome numbers and karyotype stability in cells exposed to 17ß-estradiol, bisphenol A, or diethylstilbestrol. Thus, our results reveal a novel link between estrogen-activated GPER1 and the induction of key CRC-prone lesions, supporting a pivotal role of the alternate estrogen receptor in colon neoplastic transformation and tumor progression.

Estrogens-Origin of Centrosome Defects in Human Cancer?

Estrogens are associated with a variety of diseases and play important roles in tumor development and progression. Centrosome defects are hallmarks of human cancers and contribute to ongoing chromosome missegragation and aneuploidy that manifest in genomic instability and tumor progression. Although several mechanisms underlie the etiology of centrosome aberrations in human cancer, upstream regulators are hardly known. Accumulating experimental and clinical evidence points to an important role of estrogens in deregulating centrosome homeostasis and promoting karyotype instability. Here, we will summarize existing literature of how natural and synthetic estrogens might contribute to structural and numerical centrosome defects, genomic instability and human carcinogenesis.

Wide awake at bedtime? Effects of caffeine on sleep and circadian timing in male adolescents - A randomized crossover trial.

Adolescents often suffer from short and mistimed sleep. To counteract the resulting daytime sleepiness they frequently consume caffeine. However, caffeine intake may exaggerate sleep problems by disturbing sleep and circadian timing. In a 28-hour double-blind randomized crossover study, we investigated to what extent caffeine disturbs slow-wave sleep (SWS) and delays circadian timing in teenagers. Following a 6-day ambulatory phase of caffeine abstinence and fixed sleep-wake cycles, 18 male teenagers (14-17 years old) ingested 80 mg caffeine vs. placebo in the laboratory four hours prior to an electro-encephalographically (EEG) recorded nighttime sleep episode. Data were analyzed using both frequentist and Bayesian statistics. The analyses suggest that subjective sleepiness is reduced after caffeine compared to placebo. However, we did not observe a strong caffeine-induced reduction in subjective sleep quality or SWS, but rather a high inter-individual variability in caffeine-induced SWS changes. Exploratory analyses suggest that particularly those individuals with a higher level of SWS during placebo reduced SWS in response to caffeine. Regarding salivary melatonin onsets, caffeine-induced delays were not evident at group level, and only observed in participants exposed to a higher caffeine dose relative to individual bodyweight (i.e., a dose > 1.3 mg/kg). Together, the results suggest that 80 mg caffeine are sufficient to induce alertness at a subjective level. However, particularly teenagers with a strong need for deep sleep might pay for these subjective benefits by a loss of SWS during the night. Thus, caffeine-induced sleep-disruptions might change along with the maturation of sleep need.

S100B Serum Level is Independent of Moderate Alcohol Intoxication. / S100B-Serumniveau ist unabhängig von moderatem Alkoholkonsum.

OBJECTIVE: In Germany, among patients with minor head injury (MHI), the incidence of coexisting alcohol intoxication is indicated up to 50%. The neurological symptoms of patients with MHI may be caused or altered by alcohol intoxication, this could mislead to further, potential harmful, diagnostic steps or to misinterpretation of the symptoms and to non-execution of necessary treatments. In order to decide which patients need further diagnostics by CCT, S100B has been proposed as a potential selection criterion. On the other hand, studies have hypothesized that alcohol intoxication may lead to elevated S100B serum levels. Therefore, the present study aims to investigate the relationship between the blood ethyl alcohol concentration and the S100B serum concentration in an experimental setting in young human adult volunteers. METHODS: In a cohort of 58 healthy volunteers, serum S100B concentration and blood ethyl alcohol concentration were measured before and after liberately drinking alcohol. The study was approved by the local Ethics Committee of the Medical Faculty Mannheim (Ethics Committee II, AZ 2012-272 N-MA). Instantaneous analysis of the samples was carried out using state-of-the art automated measuring systems. (Analyzer Cobas e411, Roche and Analyzer Dimension Vista 1500, Siemens). RESULTS: After drinking, alcohol levels ranged from 0,23 to 1,92 g/l. The S100B value ranged from to 0,021 to 0,115 µg/l after alcohol consumption (S100B standard value < 0,11 µg/l). By calculating the Pearson correlation of empirical correlation after drinking alcohol with r = 0.01181, a correlation between serum S100B concentration and ethyl alcohol concentration is not probable. The S100B concentrations were independent on the alcohol intake in low to medium alcohol levels. CONCLUSION: A relevant alcohol blood concentration (~ 1 g/l), in otherwise healthy volunteers, does not affect the serum concentration of S100B. S100B may be a useful brain injury marker in low to moderate drunken patients.