Acyclovir inhibition of IDO to decrease Tregs as a glioblastoma treatment adjunct

Regulatory T cells, Tregs, are a subset of lymphocytes that have immunosuppressive attributes. They are elevated in blood of glioblastoma patients and within this tumor's tissue itself. Indoleamine 2,3-dioxygenase, IDO, converts tryptophan to kynurenine. IDO activity enhances Treg formation by pathways that are unknown. Experimentally, inhibition of IDO decreases Treg function and number in rodents. The common anti-viral agent acyclovir inhibits IDO. Acyclovir may thereby decrease Treg function in glioblastoma. If it can be confirmed that Treg counts are elevated in glioblastoma patients' tumor tissue, and if we can document acyclovir's lowering of tissue Treg counts by a small trial of acyclovir in pre-operative glioblastoma patients, a trial of acyclovir effect on survival should be done given the current poor prognosis of glioblastoma and the well-established safety and low side effect burden of acyclovir

Risk factors and dynamics of verotoxigenic Escherichia coli O157:H7 on cattle farms: An observational study combining information from questionnaires, spatial data and molecular analyses

The increasing number of human cases infected with a highly virulent type of verotoxigenic Escherichia coli (VTEC) O157:H7 in Sweden is the result of domestic transmission originating in regional clusters of infected cattle farms. To control the spread of the bacteria a comprehensive picture of infection dynamics, routes of transmission between farms and risk factors for persistence is urgently needed. The aim of the study was to investigate different aspects of the epidemiology of VTEC O157:H7 on the Swedish island of Öland by combining information from environmental sampling of VTEC O157:H7 from 80 farms with information from farmer questionnaires, spatial and molecular analyses. The farms were sampled in the spring and fall of 2014 and on four of them additional samples were collected during summer and winter. The results show a high prevalence of VTEC O157:H7 and a high proportion of strains belonging to the virulent clade 8. Farms that became infected between samplings were all located in an area with high cattle density. The most important risk factors identified are generally associated with biosecurity and indicate that visitors travelling between farms may be important for transmission. In addition, whole genome sequencing of a subset of isolates from the four farms where additional sampling was performed revealed ongoing local transmission that cannot be observed with a lower resolution typing method. Our observations also show that VTEC O157:H7 may persist in the farm environment for extended periods of time, suggesting that specific on-farm measures to reduce environmental prevalence and spread between groups of animals may be required in these cases

Long-term tolerability and efficacy after initial PegIFN-alpha addition to dasatinib in CML-CP : Five-year follow-up of the NordCML007 study

Objectives Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-alpha in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-alpha (PegIFN-alpha) in combination with dasatinib (DAS) in CML-CP. Methods Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 mu g/wk of PegIFN-alpha was added and increased to 25 mu g/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. Results After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion Initial addition of PegIFN-alpha to DAS shows good long-term efficacy without increased toxicity.Peer reviewe

IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia

In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-alpha is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-alpha in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCR beta sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8(+) recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-alpha reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-alpha had costimulatory effects on TCR signaling. Our work supports the combination of IFN-alpha with TKI therapy, as IFN-alpha broadens the immune repertoire and restores immunological function.Peer reviewe

Association Testing of Previously Reported Variants in a Large Case-Control Meta-analysis of Diabetic Nephropathy

We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10−9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated

The Burden of Inflammatory Bowel Disease in Europe.

AbstractInflammatory bowel diseases (IBD) are chronic disabling gastrointestinal disorders impacting every aspect of the affected individual's life and account for substantial costs to the health care system and society. New epidemiological data suggest that the incidence and prevalence of the diseases are increasing and medical therapy and disease management have changed significantly in the last decade. An estimated 2.5–3million people in Europe are affected by IBD, with a direct healthcare cost of 4.6–5.6bn Euros/year. Therefore, the aim of this review is to describe the burden of IBD in Europe by discussing the latest epidemiological data, the disease course and risk for surgery and hospitalization, mortality and cancer risks, as well as the economic aspects, patients' disability and work impairment

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

En praktisk introduktion till webbutveckling med Drupal och WordPress

Examensarbetet fungerar som en introduktion till webbutveckling med hjälp av innehållshanteringssystemen Drupal och WordPress. Inom ramen för detta examensarbete har vi skapat två identiska webbplatser med Drupal respektive WordPress. I arbetet jämför vi funktionaliteten och utvecklarvänligheten på dessa webbplatser. För att det skall vara så nybörjarvänligt som möjligt beskrivs arbetsprocessen mycket ingående. Webbplatsen skall fungera responsivt eftersom det är en grundläggande funktion i webbutveckling i dagens läge. Vi går noggrant in på hur det här fungerar i praktiken. Eftersom vi jobbade med de båda CMS-systemen Drupal och WordPress gjorde vi en jämförelse av de båda systemen. Detta gör vi genom slutsatser vi drar från det praktiska arbetet och från intervjuer med experter. Vi har intervjuat en Drupalexpert och en WordPress expert. Resultatet av arbetet är att vi skapat en responsiv webbplats där arbetsprocessen fungerar som en introduktion till webbutveckling och CMS-systemen Drupal och WordPress. Vi har också gjort en klar och tydlig jämförelse av de här två systemen.Opinnäytetyö toimii johdantona web-kehitykseen sisällönhallintajärjestelmien Drupalin ja WordPressin avulla. Tämä tarkoitta käytännössä sitä että luomme kaksi samanlaista sivustoja Drupalin ja WordPressin avulla jossa vertaamme toiminnallisuutta ja käytettävyyttä. Jotta opinnäytetyö olisi niin aloittelijaystävällinen kuin mahdollista kuvaamme työprosessia hyvin yksityiskohtaisesti. Sivusto toimii Responsive web design periaatteella koska se on olennainen osa web-kehittelyä tällä hetkellä. Selitämme mitä tämä tarkoittaa ja miten se käytännösa toimii perusteellisesti. Työskenneltyämme CMS-järjestelmien Drupalin ja WordPressin kanssa teimme vertailun järjestelmien kesken. Tämän teimme vetäämällä johtopäätöksiä työprosessista ja haastatteluista asiantuntijoiden kanssa. Olemme haastattelleet Drupal asiantuntijan ja WordPress asiantuntijan. Työn tulos on responsiivinen sivusto jossa työprosessi toimii johdantona web-kehitykseen ja CMS-järjestelmiin Drupal ja WordPress. Olemme myös tehneet selvän vertailun näiden kahden järjestelmien kesken.The thesis functions as an introduction to web development by using the Content Management Systems Drupal and WordPress. In practice we have created two identical websites using Drupal and WordPress in which we compare the functionality and how user-friendly the systems are. To be as beginner-friendly as possible we describe the work-process very thoroughly. The website will be responsive because that is a basic function today in web development. We describe how to make the website responsive in practice. As we worked with the two CMS systems Drupal and WordPress we did a comparison of the two systems. We did this by drawing conclusions from the practical work we did and by interviewing experts. We have interviewed an expert on Drupal and an expert on WordPress. The result of the thesis is that we have created a responsive website where the work process serves as an introduction to web development and the CMS systems Drupal and WordPress. We also made a clear and concise comparison between these two systems

Implicit användarmodellering

ntranät har medfört många nya möjligheter för företag och organisationer. Samtidigt har det också orsakat problem kring hur de nya flödena med kommunikation och information skall hanteras. Utbudet av information ökar samtidigt som vårt begränsade fält av uppmärksamhet är ändligt. Informationsstress har blivit ett begrepp som används i detta sammanhang. För att möta upp mot detta problem förser vi oss med tekniker och hjälpmedel som är tänkta att reducera överflödet av information. Användarmodellering är en teknik som är avsedd för att avhjälpa denna problematik. Genom att specificera användarens intressen kan andelen relevant information ökas. Vid implicit användarmodellering analyseras användarens handhavande då denne tar del av information, för att på så sätt bilda en uppfattning om individens intressen. Tekniken är inte fulländad varför projektet har undersökt hur tekniken kan utvecklas och vilka beteenden som har bäst förmåga att ge ledning till den upplevda relevansen. Projektet har identifierat ett flertal potentiella utvecklingsmöjligheter och fyra beteenden som har särskild god förmåga att ge ledning till den upplevda relevansen