Alterations of the extracellular matrix in ovarian cancer studied by Second Harmonic Generation imaging microscopy

<p>Abstract</p> <p>Background</p> <p>Remodeling of the extracellular matrix (ECM) has been implicated in ovarian cancer, and we hypothesize that these alterations may provide a better optical marker of early disease than currently available imaging/screening methods and that understanding their physical manifestations will provide insight into invasion.</p> <p>Methods</p> <p>For this investigation we use Second Harmonic Generation (SHG) imaging microcopy to study changes in the structure of the ovarian ECM in human normal and malignant ex vivo biopsies. This method directly visualizes the type I collagen in the ECM and provides quantitative metrics of the fibrillar assembly. To quantify these changes in collagen morphology we utilized an integrated approach combining 3D SHG imaging measurements and bulk optical parameter measurements in conjunction with Monte Carlo simulations of the experimental data to extract tissue structural properties.</p> <p>Results</p> <p>We find the SHG emission attributes (directionality and relative intensity) and bulk optical parameters, both of which are related to the tissue structure, are significantly different in the tumors in a manner that is consistent with the change in collagen assembly. The normal and malignant tissues have highly different collagen fiber assemblies, where collectively, our findings show that the malignant ovaries are characterized by lower cell density, denser collagen, as well as higher regularity at both the fibril and fiber levels. This further suggests that the assembly in cancer may be comprised of newly synthesized collagen as opposed to modification of existing collagen.</p> <p>Conclusions</p> <p>Due to the large structural changes in tissue assembly and the SHG sensitivity to these collagen alterations, quantitative discrimination is achieved using small patient data sets. Ultimately these measurements may be developed as intrinsic biomarkers for use in clinical applications.</p

The Campbells: lordship, literature and liminality

The Campbells have the potential to offer much to the theme of literature and borders, given that the kindred’s astonishing political success in the late medieval and early modern period depended heavily upon the ability to negotiate multiple frontiers: between Highlands and Lowlands; between Gaelic Scotland and Ireland, and, especially after the Reformation, with England and the matter of Britain. This paper will explore the literary dimension to Campbell expansionism, from the Book of the Dean of Lismore in the earlier sixteenth century, to poetry addressed to dukes of Argyll in the earlier eighteenth century. Particular attention will be paid to the literary proclivities of the household of the Campbells of Glenorchy on either side of what appears to be a major watershed in 1550; and to the agenda of the Campbell protégé John Carswell, first post-Reformation bishop of the Isles, and author of the first printed book in Gaelic in either Scotland or Ireland, Foirm na n-Urrnuidheadh (‘The Form of Prayers’), published at Edinburgh in 1567

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

Marji̇nali̇zm ve Marki̇sm

Tercüme edilen künye bilgisi: Ronald L. Meek, Marginalism and Marxism, History of Political Economy, Fall 1972, s. 500-511. (Ronald L. Meek, Marjinalizm ve Marksizm, Politik Ekonomi Tarihi, Güz 1972, s. 500-511.)Marjinalizm ve marksizm ilk bakışta tartışmak için çok bayat, sadece antika meraklıları ve çağ kutlayıcılarının ilgisini çeken konular olarak görünmektedir. Denebilir ki bir asır kadar önce ileri sürülen ve önemli birtakım koşullarla geçerlilikleri kabul edilen iki kuramsal sistem hakkında ne düşünülebilir? Bugün tek metalizme karşı ikili metalizm tartışmaları hakkında kendimizi sıkmayız; Öyleyse niçin >? Konuya girmeden önce iki nokta üzerinde durmakta yarar vardır