Defining the role of Notch Signalling in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with a dismal prognosis. Few patients present with disease amenable to resection and chemotherapy is not curative. The incidence of ICC is rising worldwide and new therapeutic approaches are urgently required. Notch signalling is critical for the embryological development and regeneration of the biliary tree in the mammalian liver. Dysregulation of Notch is known to drive tumorigenesis in a range of solid and haematological malignancies and the aim of this work was to define its contribution to the pathogenesis of ICC. Transgenic overexpression of Notch1 has been described to result in the formation of biliary lineage tumours in the liver. I have used resected human tissue, a chemically-induced model of ICC in rat and a novel transgenic murine model in which the tumour suppressor p53 is conditionally deleted from biliary epithelia, to demonstrate that endogenous Notch signalling is acting via the Notch3 receptor to drive tumorigenesis. I use multiple independent methods of Notch3 blockade to establish that Notch3 promotes epithelial cell survival and self-renewal in ICC and demonstrate that Notch3 inhibition significantly attenuates tumour growth in vivo. My data suggest that Notch3 promotes activity through the PI3K/AKT cell survival cascade via a mechanism independent of the effector of canonical Notch, RBPJκ. Given the significant toxicity associated with gamma-secretase inhibitors these findings offer a novel and specific target for further investigation and future therapeutic development in ICC

Illinois State University Wind Symphony, April 6, 2022

Center for the Performing Arts April 6, 2022 Wednesday Evening 8:00 p.m

Familiarity and strangeness: seeing everyday practices of punishment and resistance in Holloway Prison

London’s Holloway Prison, the largest women’s prison in western Europe, closed in 2016. The impact of the closure on the women incarcerated in Holloway, and the prison’s place in the local community, is the focus of a project led by Islington Museum. Here, we develop an innovative, emotion-led methodology to explore photographs of the decommissioned Holloway, asking what they communicate about experiences of imprisonment and practices of punishment. The images illustrate the strategies of control, mechanisms of punishment and tactics of resistance that operate through the carceral space. From a feminist, anti-carceral perspective, we emphasise the importance of seeing prison spaces and attending to the emotional responses generated. We offer a creative intervention into dominant government and media narratives of Holloway’s closure and suggest that considering what it is that feels familiar and strange about carceral spaces has the potential to operate as a form of anti-carceral work

Symphonic Winds

Center for the Perfonning Arts March 22, 2019 Friday Evening 8:00p.m

Meta-analysis and Meta-regression of Survival After Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma

Objective: To systematically review studies reporting survival data following neoadjuvant chemoradiation and orthotopic liver transplantation (NCR-OLT) for unresectable perihilar cholangiocarcinoma (pCC). Background: Despite survival improvements for other cancers, the prognosis of pCC remains dismal. Since publication of the Mayo protocol in 2000, increasing numbers of series globally are reporting outcomes after NCR-OLT. Methods: MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from January 2000 to February 2019. A meta-analysis of proportions was conducted, pooling 1, 3-, and 5-year overall survival and recurrence rates following NCR-OLT across centers. Per protocol and intention to treat data were interrogated. Meta-regression was used to evaluate PSC as a confounder affecting survival. Results: Twenty studies comprising 428 patients were eligible for analysis. No RCTs were retrieved; the majority of studies were noncomparative cohort studies. The pooled 1, 3-, and 5-year overall survival rates following OLT without neoadjuvant therapy were 71.2% (95% CI 62.2%–79.4%), 48.0% (95% CI 35.0%–60.9%), and 31.6% (95% CI 23.1%–40.7%). These improved to 82.8% (95% CI 73.0%–90.8%), 65.5% (95% CI 48.7%–80.5%), and 65.1% (95% CI 55.1%–74.5%) if neoadjuvant chemoradiation was completed. Pooled recurrence after 3 years was 24.1% (95% CI 17.9%–30.9%) with neoadjuvant chemoradiation, 51.7% (95% CI 33.8%–69.4%) without. Conclusions: In unresectable pCC, NCR-OLT confers long-term survival in highly selected patients able to complete neoadjuvant chemoradiation followed by transplantation. PSC patients appear to have the most favorable outcomes. A high recurrence rate is of concern when considering extending national graft selection policy to pCC.publishedVersio

Notch-IGF1 signalling in biliary epithelial cells drives their expansion and inhibits hepatocyte differentiation

[no abstract available

In vivo modeling of patient genetic heterogeneity identifies new ways to target cholangiocarcinoma.

L. Boulter was funded by The Wellcome Trust (207793/Z/17/Z), AMMF (2016/108, 2017/115), and Cancer Research UK (C52499/A27948). L. Boulter is also supported by an MRC university grant to the MRC Human Genetics Unit

If I Had My Way, I'd Have Been a Killer: Songwriting and its Motivations for Leisure and Work

This paper builds on our earlier work (Henderson and Spracklen, 2014) which looked at folk musicians exercising agency in careers that can develop from casual leisure through serious leisure to work. In looking specifically at songwriting, it synthesises theories on the underlying motivations refelecting the view of Born (2010, p.171) who suggests that the ‘theory of cultural production requires reinvention’ citing key themes of ’aesthetics and the cultural object; agency and subjectivity; the place of institutions; history, temporality and change; and problems of value and judgement.’ It examines in a phenomenological way, through songwriter interviews, the cultural production of songs and the motivational factors within the songwriting process. Highlighting that this form of cultural production challenges the hierarchical view of Maslow’s needs and suggests the career arc proposed by Stebbins (1992, p. 68) is not a case of work simply following sequentially from serious and casual leisure