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Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the RORγt/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric RORγt inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenance in vitro and Th17-dependent inflammation and associated gene expression in vivo , in a dose-dependent manner. Finally, RORγt inhibitors were assessed for efficacy against tumor formation. While, RORγt inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids in vitro and modulate RORγt target genes in vivo , this activity was not sufficient to delay tumor volume in a KP/C human tumor mouse model of pancreatic cancer.

Retinoic acid receptor-related orphan nuclear receptor (ROR) [gamma]t is a member of the RORC nuclear hormone receptor family of transcription factors. ROR[gamma]t functions as a critical regulator of thymopoiesis and immune responses. ROR[gamma]t is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the ROR[gamma]t/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric ROR[gamma]t inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenance in vitro and Th17-dependent inflammation and associated gene expression in vivo, in a dose-dependent manner. Finally, ROR[gamma]t inhibitors were assessed for efficacy against tumor formation. While, ROR[gamma]t inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids in vitro and modulate ROR[gamma]t target genes in vivo, this activity was not sufficient to delay tumor volume in a KP/C human tumor mouse model of pancreatic cancer.

Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the RORγt/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric RORγt inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenance in vitro and Th17-dependent inflammation and associated gene expression in vivo, in a dose-dependent manner. Finally, RORγt inhibitors were assessed for efficacy against tumor formation. While, RORγt inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids in vitro and modulate RORγt target genes in vivo, this activity was not sufficient to delay tumor volume in a KP/C human tumor mouse model of pancreatic cancer.

Ownership of mass media companies in recent years has grown increasingly concentrated in many areas of the world. Consolidation of ownership has raised fears among some industry observers that declining media pluralism could affect the political functions performed by the mass media for democratic societies. This study uses longitudinal analysis to assess claims that declining media pluralism impairs democratic institutions, the observance of human rights, and the control of corruption. I first explain the economic logic behind steady consolidation of media ownership, and the rationale for concerns about declining media pluralism. I then examine the European media market, which confronts both issues of media ownership consolidation and commercialization of former state broadcasting systems. In Chapter Five, I use a dataset with information from former communist countries to analyze the effects of media pluralism on observance of human rights and corruption. Using logistic and ordinary least square regression, I find mixed results. Lower levels of media pluralism are associated with poorer records with some human rights, but not with all of the human rights surveyed. Also, lower levels of media pluralism do not show statistically significant effects on levels of corruption. I follow this quantitative analysis with a case study that examines one of the countries included in the dataset. I draw upon my first hand experience in Azerbaijan as a journalism instructor to examine how the media and the political environment in that country have changed since its independence 20 years ago. Media pluralism has become increasingly constricted in Azerbaijan, as levels of corruption and human rights abuses have increased. Finally, I revisit the media environment within the United States, presenting data on the current state of media ownership. I discuss technological trends in media leading to growing partisanship of both the news media and the media audience. I conclude overall that effects of lower levels of media pluralism are deleterious and conditional on the existing institutions of a country. Where democratic institutions are stronger, the effects of lower media pluralism can be mitigated, but when democratic institutions are weak, the effects of lower media pluralism can be severe.