NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Hepatocellular carcinoma (HCC) can have viral or non-viral causes(1-5). Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need(6,7). Here we report the progressive accumulation of exhausted, unconventionally activated CD8(+)PD1(+) T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8(+)PD1(+) T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8(+)PD1(+)CXCR6(+), TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8(+) T cells or TNF neutralization, suggesting that CD8(+) T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8(+)PD1(+) T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment

Jus post bellum and Christian perspectives on the ethical use of force : reframing the traditional debate.

This dissertation examines the potential effect of the jus post bellum (post-war justice and peace) debate on the larger just war framework in order to argue that this category has the potential to reframe the traditional debate between various Christian responses to the ethical use of force. In addition to the traditional debates between Christian realism, pacifism, and the just war tradition, there has arisen in recent decades a debate within just war circles regarding the presumption against war thesis. While the debates between these various responses to the ethical use of force have produced some beneficial effects, the contemporary debates have become increasingly partisan and stymied in a state of gridlock. I utilize the developing jus post bellum discussions as a lens through which to view anew the traditional debates and move beyond the impasse. The emphasis on the relationship of the phases of war (in bello, ad bellum, and now post bellum) that emerged from jus post bellum discussions challenges recent trends in the use of just war reasoning by both presumption against war advocates and classic just war supporters. What is more, jus post bellum discussions have given us a new way to speak meaningfully about the ethically complex notion of humanitarian intervention in the form of The Responsibility to Protect (R2P). The three pillars of R2P, the responsibility to prevent, react, and rebuild, correspond to the traditional just war categories of in bello, ad bellum, and post bellum respectively, and once again emphasize the importance of the relationship of the phases of war and a holistic just war approach. While disagreement concerning the ethical use of force persists at the ad bellum level between the just war tradition, Christian realism, and pacifism, this reality does not rule out post bellum cooperation. This project concludes with a practical application of a robust jus post bellum strategy, arguing that care for the moral injury of returning warriors provides one area of common cause for collaboration between Christian realists, pacifists, and just war supporters.Ph.D

Soil Survey Report for Saucelito Canyon Vineyard Proposed Vineyard Site

The Saucelito Canyon Vineyard ranch future vineyard site was investigated using eighteen (18) soil pits to document soil morphological properties including soil structure, color, depth, presence of carbonates, and soil chemical characteristics. Pits were also used to obtain soil samples that were delivered to A & L Western Agriculture Laboratories for further soil chemical analysis and to classify the soils. This collective information was used to classify the soils into five (5) different soil series using Soil Taxonomy. The surface soil textures and slope phases for these soil series were then used to group similar soil types located throughout the vineyards into five (5) different soil map units. The map units were then mapped and delineated on aerial photographic base maps. Digital soil maps were produced using ESRI software and computer hardware. The aerial photograph, used as a raster image for the digitizing and vector data for the series of maps created, was obtained from the San Luis Obispo County aerial files and the Digital Elevation Model (DEM) was obtained from the city of San Luis Obispo’s county files. Soil map unit boundaries were digitized onto the aerial photograph by creating a polygon shapefile and using the editor tool to draw in the map units