Metabolic fate, mass spectral fragmentation, detectability, and differentiation in urine of the benzofuran designer drugs 6-APB and 6-MAPB in comparison to their 5-isomers using GC-MS and LC-(HR)-MSn techniques

The number of so-called new psychoactive substances (NPS) is still increasing by modification of the chemical structure of known (scheduled) drugs. As analogues of amphetamines, 2-aminopropyl-benzofurans were sold. They were consumed because of their euphoric and empathogenic effects. After the 5-(2-aminopropyl)benzofurans, the 6-(2-aminopropyl)benzofuran isomers appeared. Thus, the question arose whether the metabolic fate, the mass spectral fragmentation, and the detectability in urine are comparable or different and how an intake can be differentiated. In the present study, 6-(2-aminopropyl)benzofuran (6-APB) and its N-methyl derivative 6-MAPB (N-methyl-6-(2-aminopropyl)benzofuran) were investigated to answer these questions. The metabolites of both drugs were identified in rat urine and human liver preparations using GC-MS and/or liquid chromatography-high resolution-mass spectrometry (LC-HR-MSn). Besides the parent drug, the main metabolite of 6-APB was 4-carboxymethyl-3-hydroxy amphetamine and the main metabolites of 6-MAPB were 6-APB (N-demethyl metabolite) and 4-carboxymethyl-3-hydroxy methamphetamine. The cytochrome P450 (CYP) isoenzymes involved in the 6-MAPB N-demethylation were CYP1A2, CYP2D6, and CYP3A4. An intake of a common users’ dose of 6-APB or 6-MAPB could be confirmed in rat urine using the authors’ GC-MS and the LC-MSn standard urine screening approaches with the corresponding parent drugs as major target allowing their differentiation. Furthermore, a differentiation of 6-APB and 6-MAPB in urine from their positional isomers 5-APB and 5-MAPB was successfully performed after solid phase extraction and heptafluorobutyrylation by GC-MS via their retention times

Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.This research uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD) and JDRF and supported by grant U01 DK062418 from the US National Institutes of Health. Further support was provided by grants from the NIDDK (DK046635 and DK085678) to P.C. and by a joint JDRF and Wellcome Trust grant (WT061858/09115) to the Diabetes and Inflammation Laboratory at Cambridge University, which also received support from the NIHR Cambridge Biomedical Research Centre. ImmunoBase receives support from Eli Lilly and Company. C.W. and H.G. are funded by the Wellcome Trust (089989). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). We gratefully acknowledge the following groups and individuals who provided biological samples or data for this study. We obtained DNA samples from the British 1958 Birth Cohort collection, funded by the UK Medical Research Council and the Wellcome Trust. We acknowledge use of DNA samples from the NIHR Cambridge BioResource. We thank volunteers for their support and participation in the Cambridge BioResource and members of the Cambridge BioResource Scientific Advisory Board (SAB) and Management Committee for their support of our study. We acknowledge the NIHR Cambridge Biomedical Research Centre for funding. Access to Cambridge BioResource volunteers and to their data and samples are governed by the Cambridge BioResource SAB. Documents describing access arrangements and contact details are available at http://www.cambridgebioresource.org.uk/. We thank the Avon Longitudinal Study of Parents and Children laboratory in Bristol, UK, and the British 1958 Birth Cohort team, including S. Ring, R. Jones, M. Pembrey, W. McArdle, D. Strachan and P. Burton, for preparing and providing the control DNA samples. This study makes use of data generated by the Wellcome Trust Case Control Consortium, funded by Wellcome Trust award 076113; a full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/.This is the author accepted manuscript. The final version is available via NPG at http://www.nature.com/ng/journal/v47/n4/full/ng.3245.html

EuReCa ONE—27 Nations, ONE Europe, ONE Registry A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe

AbstractIntroductionThe aim of the EuReCa ONE study was to determine the incidence, process, and outcome for out of hospital cardiac arrest (OHCA) throughout Europe.MethodsThis was an international, prospective, multi-centre one-month study. Patients who suffered an OHCA during October 2014 who were attended and/or treated by an Emergency Medical Service (EMS) were eligible for inclusion in the study. Data were extracted from national, regional or local registries.ResultsData on 10,682 confirmed OHCAs from 248 regions in 27 countries, covering an estimated population of 174 million. In 7146 (66%) cases, CPR was started by a bystander or by the EMS. The incidence of CPR attempts ranged from 19.0 to 104.0 per 100,000 population per year. 1735 had ROSC on arrival at hospital (25.2%), Overall, 662/6414 (10.3%) in all cases with CPR attempted survived for at least 30 days or to hospital discharge.ConclusionThe results of EuReCa ONE highlight that OHCA is still a major public health problem accounting for a substantial number of deaths in Europe.EuReCa ONE very clearly demonstrates marked differences in the processes for data collection and reported outcomes following OHCA all over Europe. Using these data and analyses, different countries, regions, systems, and concepts can benchmark themselves and may learn from each other to further improve survival following one of our major health care events

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Amphetamin-Abkömmlinge der neuen psychoaktiven substanzen : Metabolismus und toxikologische Nachweisbarkeit von Methiopropamin, drei Methyl-Amphetamin Isomeren, Camfetamin, 5-APB, 6-APB, 5-MAPB und 6-MAPB im Urin und humanen Leberpreparationen mittels GC-MS, LC-MSn und LC-HR-MSn Techniken

The number of new psychoactive substances identified each year by the EMCDDA is increasing rapidly, as in 2014, 101 new compounds have been identified. One important structural group of NPS are the phenethylamines. In the presented studies, the metabolic fate and the toxicological detection of different amphetamine-derived compounds belonging to the phenethylamine group of NPS have been investigated. Using GC-MS and/or LC-High-Resolution-MSn, the main phase I metabolic step observed for the compounds containing the methamphetamine backbone, such as 2 MPA, 5-MAPB, and 6-MAPB, was N-demethylation, whereas for the three methyl-amphetamine isomers and CFA aromatic hydroxylation was the predominant step. 5 APB and 6-APB were metabolized only to a minor extent, resulting in the unchanged drug being the main target for urinalysis. The isoenzymes mainly involved in the N demethylation steps were CYP2B6, CYP2C19, CYP2D6, and CYP3A4, whereas the aromatic hydroxylations were catalyzed by CYP2D6 and CYP2C19. The intake of each tested compound could be proved within the established SUSAs, either with the unchanged drugs or the nor metabolites being the main targets in urine, or in the case of CFA and the three MAs, the hydroxy-aryl metabolites. Separation of isomers was successfully accomplished with an additional work-up, including heptafluorobutyrylation. For 5-MAPB, plasma concentrations determined in authentic cases were in the same range as published for MDMA.Die Anzahl neuer psychoaktiver Substanzen, die jedes Jahr von der EMCDDA identifiziert wird, steigt stetig an. Alleine 2014, wurden 101 neue Substanzen identifiziert. Die Phenethylamine stellen dabei eine wichtige Gruppe dar, deshalb wurde im Rahmen dieser Dissertation der Metabolismus und die Nachweisbarkeit von verschiedenen Phenethylamin-Abkömmlingen mittels GC-MS- und LC-(HR)-MSn-Verfahren untersucht. Für Substanzen, mit einer Methamphetamin-verwandten Struktur, wie 2-MPA, 5-MAPB und 6-MAPB, war der nachgewiesene Hauptstoffwechselschritt die N-Demethylierung, während es für die drei Isomere des Methyl-Amphetamins und CFA, die aromatische Hydroxylierung war. 5-APB und 6 APB wurden insgesamt nur wenig verstoffwechselt, was dazu führt, dass hauptsächlich der unveränderte Stoff im Urin nachgewiesen wurde. CYP2B6, CYP2C19, CYP2D6 und CYP3A4 waren an der N-Demethylierung beziehungsweise CYP2D6 und CYP2C19 an der aromatischen Hydroxylierung beteiligt. Eine Einnahme der untersuchten Substanzen konnte im Urin nachgewiesen werden mithilfe der im Labor durchgeführten Standard Urinscreening-Verfahren. Der Fokus für die Nachweisbarkeit lag dabei entweder auf den unveränderten Substanzen, und den Nor-Metaboliten, oder im Fall von CFA und den Methyl-Amphetaminen auf den Hydroxy-Aryl-Metaboliten. Eine Isomeren-Trennung wurde erfolgreich durchgeführt. 5-MAPB-Plasmakonzentrationen, die in authentischen Fällen bestimmt wurden, waren vergleichbar mit bekannten MDMA-Konzentrationen

Jessica Cormier\u27s Research Experience

When Jessica Cormier first came to St. Kate’s, she had an interest in ecology, but was undecided if she wanted to pursue the subject as her future career path. In the spring of 2010, Jill Welter, assistant biology professor, invited Cormier to be a part of her on-going research project studying nutrient uptake and nitrogen fixation in streams and rivers on the Heath and Marjorie Angelo Coast Range Reserve in Angelo, California. Cormier says her attraction to the project stemmed from wanting to apply what she was learning in the classroom to research in a real-life setting. “I wanted to see what it was like to be outside doing field research and collecting data. I can read material from books but it doesn’t apply for me as much if I don’t have that first-hand experience.” Over a two-month period during the summer of 2010, Cormier conducted research with Welter, Angela Rosendahl ’11, in addition to two students from St. Olaf College. “We worked with one another individually and as a big group. This showed me that within research, a sense of community is developed.” She says being away from home and not having the stress of academic classes enabled her “to be fully focused and involved [in the research].” Cormier’s meaningful experience in California helped solidify her career aspirations. “I can now see myself performing ecological research in the future,” she says. “This research project definitely gave me a foundation I can use in the future. From my experience I have a better sense of what research is like – self-driven and self-motivated.”https://sophia.stkate.edu/orsp_studentresexp/1002/thumbnail.jp

Jill Welter, Ph.D., Biology

https://sophia.stkate.edu/orsp_faculty/1007/thumbnail.jp

Angela Rosendahl\u27s Research Experience

If there’s one word to describe how Angela Rosendahl ‘11 felt prior to embarking on her first research collaboration, it would be: terrified. “I thought I wouldn’t be able to contribute anything,” says Rosendahl, an elementary education major with a STEM certificate. “I didn’t have any background knowledge on [analyzing and collecting data].” Her fear quickly dissipated, however, as she realized how much she could learn. “Most of my concerns came from not knowing the answers,” she says. “But in research you don’t know the answers at the onset. That’s why you do research. You’re setting out to prove or disprove something, and it’s a process of discovery throughout.” Rosendahl and another St. Kate’s student researcher, Jessica Cormier, collaborated with biology Associate Professor Jill Welter during the summer of 2010. Their research is part of an on-going study that focuses on nutrient uptake and nitrogen fixation in streams and rivers. The project takes place on the Heath and Marjorie Angelo Coast Range Reserve in northern California. As part of a grant funded by the National Science Foundation, Welter brings St. Kate’s students to the reserve during the summer to gain hands-on experience in ecology. Rosendahl, who’s enrolled in St. Kate’s Weekend Program, says her interest in this student-faculty collaborative research project at St. Kate’s was piqued after taking “Environmental Biology.” Welter co-teaches the course with Tony Murphy, executive director for the National STEM Center at St. Kate’s. “I loved the class, and I approached [Jill] to see what my options were for furthering my knowledge in that area,” she says. Professor Welter told her about the research opportunity and asked if she wanted to join her ongoing project at the Angelo Reserve. Rosendahl jumped at the chance. “I had no idea what a collaborative research project was, but I really wanted to see how research was done and what was involved,” she says. A year after the summer project, Rosendahl still feels the transformative effects of the collaboration with Welter on her professional growth. “I came from a place where science just didn’t really co-exist with girls,” she says. “I have more confidence to go into a classroom full of children now and teach them science-related things without being scared. I’m really comfortable with what it takes to do research and complete an experiment.” The research experience has also had a profound personal effect on her as well. “It helped me see what my strong points were in a research setting,” she says. “And when I’m looking for a job later, I can tell [future employers] specifically what I know about myself.” “I never dreamed going into this research opportunity I would learn as much about myself as I did. I thought there was everything to know about me and I was very wrong.” According to Rosendahl, her experience has been enriching because of Welter’s support and the personal relationship the two were able to establish. “There is no way I could pick a better mentor,” says Rosendahl. “She knew my apprehension about even admitting I liked science, but then she pushed me to try things and strive for more.” Rosendahl’s advice for other St. Kate’s students: step outside your comfort zone. “Whether research related or not, don’t be scared to ask questions, don’t be scared to jump in and do something, and don’t be scared to say what you think – even if it’s wrong,” she says.https://sophia.stkate.edu/orsp_studentresexp/1000/thumbnail.jp