Plasma appearance and correlation between coffee and green tea metabolites in human subjects

Coffee and green tea are two of the most widely consumed hot beverages in the world. Their respective bioavailability has been studied separately, but absorption of their respective bioactive phenolics has not been compared. In a randomised cross-over design, nine healthy subjects drank instant coffee and green tea. Blood samples were collected over 12h and at 24h to assess return to baseline. After green tea consumption, (−)-epigallocatechin (EGC) was the major catechin, appearing rapidly in the plasma; (−)-EGC gallate (EGCg) and (−)-epicatechin (EC) were also present, but (−)-EC gallate and C were not detected. Dihydroferulic acid and dihydrocaffeic acid were the major metabolites that appeared after coffee consumption with a long time needed to reach maximum plasma concentration, suggesting metabolism and absorption in the colon. Other phenolic acid equivalents (caffeic acid (CA), ferulic acid (FA) and isoferulic acid (iFA)) were detected earlier, and they peaked at lower concentrations. Summations of the plasma area under the curves (AUC) for the measured metabolites showed 1·7-fold more coffee-derived phenolic acids than green tea-derived catechins (P=0·0014). Furthermore, we found a significant correlation between coffee metabolites based on AUC. Inter-individual differences were observed, but individuals with a high level of CA also showed a correspondingly high level of FA. However, no such correlation was observed between the tea catechins and coffee phenolic acids. Correlation between AUC and maximum plasma concentration was also significant for CA, FA and iFA and for EGCg. This implies that the mechanisms of absorption for these two classes of compounds are different, and that a high absorber of phenolic acids is not necessarily a high absorber of catechin

Risk algorithm using serial biomarker measurements doubles the number of screen-detected cancers compared with a single-threshold rule in the United Kingdom collaborative trial of ovarian cancer screening

PURPOSE: Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates. PATIENTS AND METHODS: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves. RESULTS: After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869). CONCLUSION: Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded

Exercise and pregnancy in recreational and elite athletes: 2016 evidence summary from the IOC expert group meeting, Lausanne. Part 1-exercise in women planning pregnancy and those who are pregnant

BACKGROUND Guidelines on physical activity or exercise and pregnancy encourage pregnant women to continue or adopt an active lifestyle during and following pregnancy.1-3 Two systematic reviews of pregnancy-related guidelines on physical activity found similarities between recommendations from different countries, but noted that the guidelines differed in focus.4 5 The guidelines provided variable guidance on prenatal exercise, or on how pregnant women might approach continuing or adopting sport activities.6 However, most guidelines did not include important topics such as prevalence and known risk factors for common pregnancy-related diseases and complaints, and the role of exercise in preventing and treating them. Importantly, the focus of most previous guidelines has been on healthy pregnant women in the general population, in whom there is almost always a decline in physical activity during pregnancy.7 8 Indeed, a high proportion of pregnant women follow neither physical activity nor exercise guidelines, 9 putting them at increased risk of obesity, gestational diabetes mellitus (GDM), and other pregnancy-related diseases and complaints.1 On the other hand, there are enthusiastic exercisers and elite athletes who often meet and exceed general exercise recommendations for pregnant women, but there are no exercise guidelines specifically for these women. Important questions for such women are unanswered in current guidelines: Which activities, exercises and sports can they perform, for how long and at what intensity, without risking their own health and the health of the fetus? How soon can they return to highintensity training and competition after childbirth? The IOC and most National Sports Federations encourage women to participate in all Olympic sport disciplines. The IOC promotes high-level performance, and it is also strongly committed to promoting lifelong health among athletes10-not just during their competitive sporting careers. With an increasing number of elite female athletes competing well into their thirties, many may wish to become pregnant, and some also want to continue to compete after childbirth. With this background, the IOC assembled an international expert committee to review the literature on physical activity and exercise (1) during pregnancy and (2) after childbirth, using rigorous systematic review and search criteria.11 For efficiency, where sex is not specified, the reader should assume that this manuscript about pregnancy and childbirth refers to females (ie, \u27the elite athlete who wishes to train at altitude\u27 is used in preference to \u27the elite female athlete...\u27). AIMS The September 2015 IOC meeting of 16 experts in Lausanne had three aims. They were to: 1. Summarise common conditions, illnesses and complaints that may interfere with strenuous exercise and competition, during pregnancy and after childbirth; 2. Provide recommendations for exercise training during pregnancy and after childbirth, for highlevel regular exercisers and elite athletes; and 3. Identify major gaps in the literature that limit the confidence with which recommendations can be made. METHODS For each section of the document, a search strategy was performed using search terms such as \u27pregnancy\u27 OR \u27pregnant\u27 OR \u27postpartum\u27 AND \u27exercise\u27 OR \u27physical activity\u27 OR\u27leisure activity\u27 OR\u27leisure\u27 OR \u27recreation\u27 OR \u27recreational activity\u27 or \u27physical fitness\u27 OR \u27occupational activity\u27 AND terms related to the condition under study (eg, \u27gestational diabetes\u27). Available databases were searched, with an emphasis on PubMed, EMBASE, Cochrane, PEDro, Web of Science and SPORTDiscus. In addition, existing guidelines with reference lists were scanned. The review of each topic followed the general order: prevalence of the condition in the general pregnant or postpartum population, prevalence in high-level exercisers or elite athletes, risk factors in the general population and in relation to exercise and sport, and effect of preventive and treatment interventions. Level of evidence and grade of recommendations are according to the Cochrane handbook (table 1) for prevention and treatment interventions only. Each member of the working group was assigned to be the lead author of one or more topics and 1-3 others were assigned to review each topic. A first full consensus draft was reviewed before and during the 3-day IOC meeting (27-29 September 2015), and a new version of each topic was submitted to the meeting chairs (KB and KMK) shortly after the meeting. Each topic leader made amendments before sending a new version for comments to the working group

Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial

Background: In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy.// Methods: UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50–74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032.// Findings: 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04–13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4–13·0; p=0·042) at 18 years (21% [95% CI 15·6–26·2] vs 14% [95% CI 10·5–17·4]).// Interpretation: To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer

Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial

Background: In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy. Methods: UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50–74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032. Findings: 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04–13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4–13·0; p=0·042) at 18 years (21% [95% CI 15·6–26·2] vs 14% [95% CI 10·5–17·4]). Interpretation: To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer. Funding: National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal

Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity

Here, using methylCIBERSORT, the authors characterize the tumour-immune microenvironment of paediatric central nervous system (CNS) tumours and its association with tumour type and prognosis. These findings suggest that immuno-methylomic profiling may inform immunotherapy approaches in paediatric patients with CNS tumour

BETWEEN BROADCASTING POLITICAL MESSAGES AND INTERACTING WITH VOTERS

Politicians across Western democracies are increasingly adopting and experimenting with Twitter, particularly during election time. The purpose of this article is to investigate how candidates are using it during an election campaign. The aim is to create a typology of the various ways in which candidates behaved on Twitter. Our research, which included a content analysis of tweets (n = 26,282) from all twittering Conservative, Labour and Liberal Democrat candidates (n = 416) during the 2010 UK General Election campaign, focused on four aspects of tweets: type, interaction, function and topic. By examining candidates' twittering behaviour, the authors show that British politicians mainly used Twitter as a unidirectional form of communication. However, there were a group of candidates who used it to interact with voters by, for example, mobilizing, helping and consulting them, thus tapping into the potential Twitter offers for facilitating a closer relationship with citizens

Transplacental Transmission of Bluetongue Virus 8 in Cattle, UK

To determine whether transplacental transmission could explain overwintering of bluetongue virus in the United Kingdom, we studied calves born to dams naturally infected during pregnancy in 2007–08. Approximately 33% were infected transplacentally; some had compromised health. In all infected calves, viral load decreased after birth; no evidence of persistent infection was found

Interplay between Polo kinase, LKB1-activated NUAK1 kinase, PP1β^MYPT1phosphatase complex and the SCF^βTrCP E3 ubiquitin ligase

NUAK1 (NUAK family SnF1-like kinase-1) and NUAK2 protein kinases are activated by the LKB1 tumour suppressor and have been implicated in regulating multiple processes such as cell survival, senescence, adhesion and polarity. In the present paper we present evidence that expression of NUAK1 is controlled by CDK (cyclin-dependent kinase), PLK (Polo kinase) and the SCF(βTrCP) (Skp, Cullin and F-box(βTrCP)) E3 ubiquitin ligase complex. Our data indicate that CDK phosphorylates NUAK1 at Ser(445), triggering binding to PLK, which subsequently phosphorylates NUAK1 at two conserved non-catalytic serine residues (Ser(476) and Ser(480)). This induces binding of NUAK1 to βTrCP, the substrate-recognition subunit of the SCF(βTrCP) E3 ligase, resulting in NUAK1 becoming ubiquitylated and degraded. We also show that NUAK1 and PLK1 are reciprocally controlled in the cell cycle. In G(2)–M-phase, when PLK1 is most active, NUAK1 levels are low and vice versa in S-phase, when PLK1 expression is low, NUAK1 is more highly expressed. Moreover, NUAK1 inhibitors (WZ4003 or HTH-01-015) suppress proliferation by reducing the population of cells in S-phase and mitosis, an effect that can be rescued by overexpression of a NUAK1 mutant in which Ser(476) and Ser(480) are mutated to alanine. Finally, previous work has suggested that NUAK1 phosphorylates and inhibits PP1β(MYPT1) (where PP1 is protein phosphatase 1) and that a major role for the PP1β(MYPT1) complex is to inhibit PLK1 by dephosphorylating its T-loop (Thr(210)). We demonstrate that activation of NUAK1 leads to a striking increase in phosphorylation of PLK1 at Thr(210), an effect that is suppressed by NUAK1 inhibitors. Our data link NUAK1 to important cell-cycle signalling components (CDK, PLK and SCF(βTrCP)) and suggest that NUAK1 plays a role in stimulating S-phase, as well as PLK1 activity via its ability to regulate the PP1β(MYPT1) phosphatase

Conserved nucleotides in an RNA essential for hepatitis B virus replication show distinct mobility patterns

The number of regulatory RNAs with identified non-canonical structures is increasing, and structural transitions often play a role in their biological function. This stimulates interest in internal motions of RNA, which can underlie structural transitions. Heteronuclear NMR relaxation measurements, which are commonly used to study internal motion, only report on local motions of few sites within the molecule. Here we have studied a 27-nt segment of the human hepatitis B virus (HBV) pregenomic RNA, which is essential for viral replication. We combined heteronuclear relaxation with the new off-resonance ROESY technique, which reports on internal motions of H,H contacts. Using off-resonance ROESY, we could for the first time detect motion of through-space H,H contacts, such as in intra-residue base-ribose contacts or inter-nucleotide contacts, both essential for NMR structure determination. Motions in non-canonical structure elements were found primarily on the sub-nanosecond timescale. Different patterns of mobility were observed among several mobile nucleotides. The most mobile nucleotides are highly conserved among different HBV strains, suggesting that their mobility patterns may be necessary for the RNA’s biological function