Comparison of naltrexone and quaternary naltrexone after systemic and intracerebroventricular administration in pigeons

The behavioral effects of naltrexone and quaternary naltrexone were evaluated in two groups of pigeons. One group responded under a fixed-ratio schedule of food reinforcement and was trained to discriminate between 3.2 mg/kg morphine (i.m.) and saline. Drug-appropriate responding occurred in a dose-related manner to morphine, given intramuscularly and intraventricularly. When administered intraventricularly morphine was 50 times more potent as a discriminative stimulus and 50-100 times more potent at suppressing responding. Naltrexone, given intraventricularly and intramuscularly, attenuated the discriminative stimulus effects of morphine. Quaternary naltrexone was more potent at suppressing responding when administered intraventricularly but it failed to attenuate the discriminative stimulus effects of morphine. A second group of pigeons, responding under a variable-interval schedule of food reinforcement, was treated with 100.0 mg/kg/day of morphine. Naltrexone and quaternary naltrexone suppressed responding by both routes of administration. Naltrexone was approximately equipotent when given intramuscularly or intraventricularly, and the doses that suppressed responding were 50-500 times smaller than doses required to suppress responding in untreated pigeons. Although quaternary naltrexone was 1800 times more potent when given intraventricularly, the doses necessary to suppress responding by each route were the same as doses required in untreated pigeons. These results extend the conditions under which a quaternary derivative of naltrexone failed to display antagonist activity in the pigeon. The utility of this compound for characterizing central and peripheral mechanisms of action has not been established in different species and testing conditions and, therefore, appears to be appropriate only under conditions in which it is evaluated after systemic, as well as central, administration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26698/1/0000246.pd

Intracerebroventricular drug administration in pigeons

For many procedures used in behavioral pharmacology, the intracerebroventricular (ICV) route of drug administration is infrequently used due, in part, to the lack of a reliable technique for determining cannula patency in vivo. This study describes an in vivo technique for assessing ICV cannula patency in pigeons. The technique was applied in an experiment designed to evaluate several drugs, which are presumed to differ in the extent to which they enter the central nervous system, for their rate-suppressing effects in pigeons trained to peck a key on a fixed-ratio 20 schedule of food reinforcement. The opioid agonist morphine and antagonist quaternary naltrexone were 100 and 280 times more potent, respectively, in suppressing responding when administered ICV, as compared to systemic administration. Tertiary naltrexone was approximately equipotent as an antagonist of morphine's rate-suppressing effects when administered ICV or systemically. Quaternary naltrexone did not antagonize morphine by either route of administration. The utility of this in vivo cannula verification technique is discussed, as well as the limitations of comparisons between systemically-administered tertiary and quaternary derivatives.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25518/1/0000059.pd

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

WSES guidelines for management of Clostridium difficile infection in surgical patients

In the last two decades there have been dramatic changes in the epidemiology of Clostridium difficile infection (CDI), with increases in incidence and severity of disease in many countries worldwide. The incidence of CDI has also increased in surgical patients. Optimization of management of C difficile, has therefore become increasingly urgent. An international multidisciplinary panel of experts prepared evidenced-based World Society of Emergency Surgery (WSES) guidelines for management of CDI in surgical patients.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The habitats, distribution, and taxonomic problems of Potentilla fruticosa.

http://deepblue.lib.umich.edu/bitstream/2027.42/53639/1/2074.pdfDescription of 2074.pdf : Access restricted to on-site users at the U-M Biological Station