Metabolomic Profiling of Extracellular Vesicles and Alternative Normalization Methods Reveal Enriched Metabolites and Strategies to Study Prostate Cancer-Related Changes

Body fluids are a rich source of extracellular vesicles (EVs), which carry cargo derived from the secreting cells. So far, biomarkers for pathological conditions have been mainly searched from their protein, (mi) RNA, DNA and lipid cargo. Here, we explored the small molecule metabolites from urinary and platelet EVs relative to their matched source samples. As a proof-of-concept study of intra-EV metabolites, we compared alternative normalization methods to profile urinary EVs from prostate cancer patients before and after prostatectomy and from healthy controls. Methods: We employed targeted ultra-performance liquid chromatography-tandem mass spectrometry to profile over 100 metabolites in the isolated EVs, original urine samples and platelets. We determined the enrichment of the metabolites in the EVs and analyzed their subcellular origin, pathways and relevant enzymes or transporters through data base searches. EV-and urine-derived factors and ratios between metabolites were tested for normalization of the metabolomics data. Results: Approximately 1 x 10(10) EVs were sufficient for detection of metabolite profiles from EVs. The profiles of the urinary and platelet EVs overlapped with each other and with those of the source materials, but they also contained unique metabolites. The EVs enriched a selection of cytosolic metabolites including members from the nucleotide and spermidine pathways, which linked to a number of EV-resident enzymes or transporters. Analysis of the urinary EVs from the patients indicated that the levels of glucuronate, D-ribose 5-phosphate and isobutyryl-L-carnitine were 2-26-fold lower in all pre-prostatectomy samples compared to the healthy control and post-prostatectomy samples (p <0.05). These changes were only detected from EVs by normalization to EV-derived factors or with metabolite ratios, and not from the original urine samples. Conclusions: Our results suggest that metabolite analysis of EVs from different samples is feasible using a high-throughput platform and relatively small amount of sample material. With the knowledge about the specific enrichment of metabolites and normalization methods, EV metabolomics could be used to gain novel biomarker data not revealed by the analysis of the original EV source materials.Peer reviewe

First Administration of the Fc-Attenuated Anti-beta Amyloid Antibody GSK933776 to Patients with Mild Alzheimer's Disease: A Randomized, Placebo-Controlled Study

Objectiv

Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans

Background: Despite the good prognosis of erythema migrans (EM), some patients have persisting symptoms of various character and duration post-treatment. Several factors may affect the clinical outcome of EM, e. g. the early interaction between Borrelia (B.) burgdorferi and the host immune response, the B. burgdorferi genotype, antibiotic treatment as well as other clinical circumstances. Our study was designed to determine whether early cytokine expression in the skin and in peripheral blood in patients with EM is associated with the clinical outcome. Methods: A prospective follow-up study of 109 patients with EM was conducted at the A land Islands, Finland. Symptoms were evaluated at 3, 6, 12 and 24 months post-treatment. Skin biopsies from the EM and healthy skin were immunohistochemically analysed for expression of interleukin (IL)-4, IL-10, IL-12p70 and interferon (IFN)-gamma, as well as for B. burgdorferi DNA. Blood samples were analysed for B. burgdorferi antibodies, allergic predisposition and levels of systemic cytokines. Findings: None of the patients developed late manifestations of Lyme borreliosis. However, at the 6-month follow-up, 7 of 88 patients reported persisting symptoms of diverse character. Compared to asymptomatic patients, these 7 patients showed decreased expression of the Th1-associated cytokine IFN-gamma in the EM biopsies (p = 0.003). B. afzelii DNA was found in 48%, B. garinii in 15% and B. burgdorferi sensu stricto in 1% of the EM biopsies, and species distribution was the same in patients with and without post-treatment symptoms. The two groups did not differ regarding baseline patient characteristics, B. burgdorferi antibodies, allergic predisposition or systemic cytokine levels. Conclusion: Patients with persisting symptoms following an EM show a decreased Th1-type inflammatory response in infected skin early during the infection, which might reflect a dysregulation of the early immune response. This finding supports the importance of an early, local Th1-type response for optimal resolution of LB.Original Publication: Johanna Sjöwall, Linda Fryland, Marika Nordberg, Florence Sjögren, Ulf Garpmo, Christian Jansson, Sten-Anders Carlsson, Sven Bergstrom, Jan Ernerudh, Dag Nyman, Pia Forsberg and Christina Ekerfelt, Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans, 2011, PLOS ONE, (6), 3, 0018220. http://dx.doi.org/10.1371/journal.pone.0018220 Copyright: Public Library of Science (PLoS) http://www.plos.org

Russia of Challenges

In 2007 the Ministry of Defence conducted the research project Stable Russia – an evaluation of the security situation in Finland’s neighbourhood. The goal of the project was to paint an all-round picture of the factors affecting stability in Russia as well as possible destabilizing developments which could alter the security situation close to the Finnish borders. The project comprehensively tapped into Finnish Russia-expertise. This publication is based on the reports written for that project

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

Morgondagens skärgårdskvinnor

Under en längre tid har en negativ befolkningstrend pågått i skärgården. Det blir allt svårare att bo på öar utan fast vägförbindelse och statistiken visar att det främst är kvinnor som flyttar bort. För att kunna hålla skärgården levande måste inflyttningen öka och könsfördelningen behöver bli jämnare. Det här är ett arbete inom projektet ”Morgondagens skärgårdskvinnor”. Syftet med arbetet är tvådimensionellt. Dels är syftet att utreda in- och utflyttningsorsaker bland kvinnor och dels att bidra med kunskap som kan användas för att utveckla fortsatt datainsamling inom projektet hösten 2017. Målgruppen har begränsats till kvinnor i åldern 20 till 65 som bor på eller flyttat från en ö utan fast vägförbindelse i Åbolands, Ålands och Stockholms skärgård. Arbetet baseras på en litteraturgenomgång, i vilken det har tagits upp viktiga villkor för livet i skärgården. Datainsamlingen har gjorts både ur ett kvantitativt och kvalitativt perspektiv genom en pilotenkät, fokusgruppintervjuer och individuella intervjuer. Sammanlagt har 160 kvinnor deltagit i undersökningarna. I resultaten kan ses att miljön och de sociala relationerna är viktiga vid valet av boningsort. Likväl bör trafikförbindelserna, serviceutbudet och social- och hälsovårdstjänsterna utvecklas och förbättras. För att skapa förutsättningar för ett aktivt liv i skärgården behövs förändring och nytänk.Saaristossa on tapahtunut negatiivinen väestömuutos pidemmällä ajanjaksolla. On yhä vaikeampaa asua saarilla ilman kiinteää tieyhteyttä ja tilastoiden mukaan naiset ennen kaikkea ovat he, jotka muuttavat pois. Jotta voitaisiin pitää saaristo elävänä, on muuttaminen saaristosta saatava kääntymään muuttamiseksi saaristoon sekä saada sukupuolten välinen jakauma tasapainoon. Tämä työ kuuluu projektiin ”Huomispäivän saaristolaisnaiset”. Työn tarkoitus on kaksiulotteinen. Osittain on tavoitteena ollut selvittää syitä naisten muuttoon saaristoon ja saaristosta pois sekä osittain tuoda tietoa, jota voitaisiin käyttää hyväksi kehiteltäessä tiedonkeruuta projektin jatkuessa syksyllä 2017. Kohderyhmä on rajattu 20-vuotiaista 65- vuotiaisiin naisiin, jotka asuvat Turunmaan, Ahvenanmaan ja Tukholman saaristoissa ilman kiinteää tieyhteyttä tai ovat muuttaneet pois mainituilta alueilta. Työ perustuu kirjallisuuskatsaukseen, jossa tarkastellaan tärkeitä elämisen edellytyksiä saaristossa. Tiedonkeruu pohjautuu sekä määrälliseen näkökulmaan pilottikyselylomakkeella että laadulliseen näkökulmaan kohderyhmä- että yksilöhaastatteluissa. Tutkimuksiin osallistui kaiken kaikkeaan 160 naista. Tuloksesta selviää, että ympäristö ja sosiaaliset suhteet ovat tärkeitä asuinpaikan valinnassa. Liikenneyhteyksiä, palvelutarjontaa sekä sosiaali- ja terveydenhoitopalveluja on kehitettävä ja parannettava. Jotta voitaisiin saada aikaan edellytykset aktiiviseen elämään saaristossa, tarvitaan muutoksia ja uusajattelua.The Finnish archipelago has endured a reduction of its population during a longer period of time. It is exceedingly difficult to live on islands without permanent road links to the mainland and statistics show that it is mainly women who move away from these islands and settle elsewhere. Improvement in immigration and a better gender balance amongst the population is necessary to keep the archipelago alive. This is a thesis of the project “The Archipelagic Women of Tomorrow”. The purpose of the assignment is two-dimensional. A part of the study is to investigate the reasons behind immigration and emigration amongst women in the archipelago, while another part is to contribute with knowledge for developing the collecting of data in the project during the autumn of 2017. The target group is limited to women between 20-65 years of age that live on or have moved away from an island without permanent road links to the mainland in the archipelago of Turku, Åland or Stockholm. The purpose of the study is to give the project a solid basis on which to build future studies on. The thesis is built on a review of literature that brings attention to crucial terms and conditions of life in the archipelago. The collecting of data has been done from a quantitative and qualitative perspective through a pilot survey, group interviews as well as individual ones. A total of 160 women have taken part in the study and made their voices heard in the interviews or questionnaire. The results show that the environment and social relations helps tip the scale when the women have been faced with the decision on where to live. Other important issues such as traffic connections between mainland and islands, the range of services and the development of social- and health care services were brought to the surface as important factors in the decision making. A change and new ways of thinking are prerequisites for active life in the archipelago

Guided internet-delivered cognitive behavior therapy for post-traumatic stress disorder: A randomized controlled trial

The aim of this randomized controlled trial was to investigate the effects of guided internet-based cognitive behavior therapy (ICBT) for posttraumatic stress disorder (PTSD). Sixty-two participants with chronic PTSD, as assessed by the Clinician-administered PTSD Scale, were recruited via nationwide advertising and randomized to either treatment (n= 31) or delayed treatment attention control (n= 31). The ICBT treatment consisted of 8 weekly text-based modules containing psychoeducation, breathing retraining, imaginal and in vivo exposure, cognitive restructuring, and relapse prevention. Therapist support and feedback on homework assignment were given weekly via an online contact handling system. Assessments were made at baseline, post-treatment, and at 1-year follow-up. Main outcome measures were the Impact of Events Scale - Revised (IES-R) and the Posttraumatic Stress Diagnostic Scale (PDS). Results showed significant reductions of PTSD symptoms (between group effect on the IES-R Cohens d= 1.25, and d= 1.24 for the PDS) compared to the control group. There were also effects on depression symptoms, anxiety symptoms, and quality of life. The results at one-year follow-up showed that treatment gains were maintained. In sum, these results suggest that ICBT with therapist support can reduce PTSD symptoms significantly. © 2014 The Authors