A Cost-Consequences Analysis of a Primary Care Librarian Question and Answering Service

Background - Cost consequences analysis was completed from randomized controlled trial (RCT) data for the Just-in-time (JIT) librarian consultation service in primary care that ran from October 2005 to April 2006. The service was aimed at providing answers to clinical questions arising during the clinical encounter while the patient waits. Cost saving and cost avoidance were also analyzed. The data comes from eighty-eight primary care providers in the Ottawa area working in Family Health Networks (FHNs) and Family Health Groups (FHGs). // Methods - We conducted a cost consequences analysis based on data from the JIT project. We also estimated the potential economic benefit of JIT librarian consultation service to the health care system. // Results - The results show that the cost per question for the JIT service was $38.20. The cost could be as low as$5.70 per question for a regular service. Nationally, if this service was implemented and if family physicians saw additional patients when the JIT service saved them time, up to 61,100 extra patients could be seen annually. A conservative estimate of the cost savings and cost avoidance per question for JIT was $11.55. // Conclusions - The cost per question, if the librarian service was used at full capacity, is quite low. Financial savings to the health care system might exceed the cost of the service. Saving physician's time during their day could potentially lead to better access to family physicians by patients. Implementing a librarian consultation service can happen quickly as the time required to train professional librarians to do this service is short

Mesenchymal Migration as a Therapeutic Target in Glioblastoma

Extensive infiltration of the surrounding healthy brain tissue is a cardinal feature of glioblastomas, highly lethal brain tumors. Deep infiltration by the glioblastoma cells renders complete surgical excision difficult and contemporary adjuvant therapies have had little impact on long-term survival. Thus, deep infiltration and resistance to irradiation and chemotherapy remain a major cause of patient mortality. Modern therapies specifically targeted to this unique aspect of glioblastoma cell biology hold significant promise to substantially improve survival rates for glioblastoma patients. In the present paper, we focus on the role of adhesion signaling molecules and the actin cytoskeleton in the mesenchymal mode of motility that characterizes invading glioblastoma cells. We then review current approaches to targeting these elements of the glioblastoma cell migration machinery and discuss other aspects of cell migration that may improve the treatment of infiltrating glioblastoma

NEDD9 regulates 3D migratory activity independent of the Rac1 morphology switch in glioma and neuroblastoma.

Metastasizing tumor cells must transmigrate the dense extracellular matrix that surrounds most organs. The use of three-dimensional (3D) collagen gels has revealed that many cancer cells can switch between different modes of invasion that are characterized by distinct morphologies (e.g., rounded vs. elongated). The adhesion protein NEDD9 has the potential to regulate the switch between elongated and rounded morphologies; therefore, its role was interrogated in the invasion switch of glioblastoma and neuroblastoma tumors that similarly derive from populations of neural crest cells. Interestingly, siRNA-mediated depletion of NEDD9 failed to induce cell rounding in glioma or neuroblastoma cells, contrasting the effects that have been described in other tumor model systems. Given that Rac1 GTPase has been suggested to mediate the switch between elongated and rounded invasion, the functionality of the Rac1 morphology switch was evaluated in the glioma and neuroblastoma cells. Using both dominant-negative Rac1 and Rac1-specific siRNA, the presence of this morphologic switch was confirmed in the neuroblastoma, but not in the glioma cells. However, in the absence of a morphologic change following NEDD9 depletion, a significant decrease in the cellular migration rate was observed. Thus, the data reveal that NEDD9 can regulate 3D migration speed independent of the Rac1 morphology switch. IMPLICATIONS: NEDD9 targeting is therapeutically viable as it does not stimulate adaptive changes in glioma and neuroblastoma invasion.National Health and Medical Research Council (NHMRC) grant 63251

NEDD9 Stabilizes Focal Adhesions, Increases Binding to the Extra-Cellular Matrix and Differentially Effects 2D versus 3D Cell Migration

The speed of cell migration on 2-dimensional (2D) surfaces is determined by the rate of assembly and disassembly of clustered integrin receptors known as focal adhesions. Different modes of cell migration that have been described in 3D environments are distinguished by their dependence on integrin-mediated interactions with the extra-cellular matrix. In particular, the mesenchymal invasion mode is the most dependent on focal adhesion dynamics. The focal adhesion protein NEDD9 is a key signalling intermediary in mesenchymal cell migration, however whether NEDD9 plays a role in regulating focal adhesion dynamics has not previously been reported. As NEDD9 effects on 2D migration speed appear to depend on the cell type examined, in the present study we have used mouse embryo fibroblasts (MEFs) from mice in which the NEDD9 gene has been depleted (NEDD9 −/− MEFs). This allows comparison with effects of other focal adhesion proteins that have previously been demonstrated using MEFs. We show that focal adhesion disassembly rates are increased in the absence of NEDD9 expression and this is correlated with increased paxillin phosphorylation at focal adhesions. NEDD9−/− MEFs have increased rates of migration on 2D surfaces, but conversely, migration of these cells is significantly reduced in 3D collagen gels. Importantly we show that myosin light chain kinase is activated in 3D in the absence of NEDD9 and is conversely inhibited in 2D cultures. Measurement of adhesion strength reveals that NEDD9−/− MEFs have decreased adhesion to fibronectin, despite upregulated α5β1 fibronectin receptor expression. We find that β1 integrin activation is significantly suppressed in the NEDD9−/−, suggesting that in the absence of NEDD9 there is decreased integrin receptor activation. Collectively our data suggest that NEDD9 may promote 3D cell migration by slowing focal adhesion disassembly, promoting integrin receptor activation and increasing adhesion force to the ECM

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years

The controlled delivery of hydrogen sulfide for the preservation of heart tissue

Gemstone Team Organ Storage and HibernationThere are over 100,000 patients on organ transplant waiting lists, creating a significant need to expand the donor pool. The heart is the most difficult organ to preserve ex vivo, with a short viable storage time of 4-6 hours, because damage to mitochondria during preservation can impair the heart's contractile function. By extending the viability time, the geographical range of donors can be extended. Hydrogen sulfide (H2S) has been shown to reduce metabolism, increase preservation times, and enhance graft viability. We have developed gelatin microspheres under 10 microns able to slowly release H2S and investigated different crosslinking concentrations to understand the time release profiles. These microspheres were then used to maintain H2S levels in cardiomyocyte cell cultures without decreasing cell viability. Histological samples from 20 cold-stored rat hearts in various experimental treatments show H2S-releasing microspheres offer protection against preservation injury comparable to the current clinical standard, University of Wisconsin solution

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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

The migration signalling molecule NEDD9 and glioblastoma

Glioblastoma is a malignant brain tumour characterised by diffuse and extensive invasion of normal brain parenchyma. Despite technological advances in treatment, overall survival still averages 12-15 months. The docking protein NEDD9 promotes cell migration, invasion and metastasis in multiple cancers and is suggested to be a specific regulator of Rac-dependent mesenchymal, elongated phenotype. NEDD9 knockdown did not induce cell rounding, but suppressed both cell migration in collagen matrices and spheroid invasion in brain slices. To assess clinical relevance of NEDD9, glioblastoma tumours were examined and NEDD9, absent in normal adult brain, was found to be highly-expressed in 30% of glioblastomas. Although NEDD9 was co-expressed with Proneural subtype marker DLL3, and high DLL3 expression was associated with improved survival, NEDD9 expression did not correlate with survival and therefore, was not predictive of patient outcome. Following identification and investigation of novel binding partner CIN85 (a regulator of EGFR uptake and endosomal sorting), NEDD9 was observed to downregulate total EGFR levels and reduce downstream signalling, without effecting EGFR trafficking. Collectively, data presented in this thesis confirmed that NEDD9 promotes invasion of malignant glioma and revealed a novel function of NEDD9 in regulating the stability of EGFR protein and its downstream signalling networks