MERTK receptor tyrosine kinase is a therapeutic target in melanoma

Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. Although recent therapeutic advances have prolonged patient survival, the prognosis remains dismal. C-MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that MERTK expression correlates with disease progression. MERTK expression was highest in metastatic melanomas, followed by primary melanomas, while the lowest expression was observed in nevi. Additionally, over half of melanoma cell lines overexpressed MERTK compared with normal human melanocytes; however, overexpression did not correlate with mutations in BRAF or RAS. Stimulation of melanoma cells with the MERTK ligand GAS6 resulted in the activation of several downstream signaling pathways including MAPK/ERK, PI3K/AKT, and JAK/STAT. MERTK inhibition via shRNA reduced MERTK-mediated downstream signaling, reduced colony formation by up to 59%, and diminished tumor volume by 60% in a human melanoma murine xenograft model. Treatment of melanoma cells with UNC1062, a novel MERTK-selective small-molecule tyrosine kinase inhibitor, reduced activation of MERTK-mediated downstream signaling, induced apoptosis in culture, reduced colony formation in soft agar, and inhibited invasion of melanoma cells. This work establishes MERTK as a therapeutic target in melanoma and provides a rationale for the continued development of MERTK-targeted therapies

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Improving public deliberative practice : a comparative analysis of two Italian citizens' jury projects in 2006

Recently the author was invited to Italy, by the Regional Government of Tuscany, the University of Bologna and the University of Turin. The three institutions asked the author to speak about random sampling as a means to include missing voices in political decision making, i.e. the voices of those who usually remain unheard (see Carson & Martin 1999). Their interest was with the author’s work in the field of deliberative democracy and its practical expression, democratic deliberative processes, best exemplified by citizens’ juries (see, for example, Carson & Martin 1999, Carson & Hart 2005, Carson & Hartz-Karp 2005, Carson 2004, Carson 2003, Carson et al. 2002, Crosby 2003). Inevitably the author was drawn into deep discussions about the two recent attempts to convene citizens’ juries (CJs) in Bologna and Turin (both in 2006). It became apparent, as it had already to the convenors from the Universities of Bologna and Torino (Turin), that both attempts were ambitious and well executed but still fell short of the convenors’ ideals. This paper draws together the author’s reflections about the concerns that were heard during these discussions. Advice was sought, and that advice is repeated here. These observations may be helpful for those embarking on similar experiments for the first time

Designing a public conversation using the World Café method

Leaders talk about holding large-scale public conversations, but they won\u27t succeed if the methods are unsatisfying for participants, if an authentic conversation occurs at all. In this paper, Lyn Carson presents the World Café method, a viable way of involving large numbers of people in a meaningful, conversational exchange. She describes how a particular World Café event was designed, and then explore the value of the World Café method as a means to achieve social change. Report image: The Hon. Fred Chaney AO chaired the panel for theWorld Café at the Festival of Dangerous Ideas, Sydney 2010

Deliberative public participation and hexachlorobenzene stockpiles

This paper is concerned with the quality of citizen involvement in relation to the governance of industrial risks. Specifically, it explores the hexachlorobenzene (HCB) case relative to best practice public participation, which is consistent with deliberative democratic theory. The case could be judged a public participation failure given that the community committee in combination with the corporate sponsor was unable to agree on a mutually acceptable technological pathway. This stalemate might have been attributable in part to the time spent on thetask of review. A diligent participation working party could have created a much more effective public participation plan, grounded in the core values of professional public participation practice

Creating democratic surplus through citizens' assemblies

This paper, originally a presentation to the Sydney Democracy Forum, discusses how the current democratic deficit could be converted to a democratic surplus. In particular, attention is focused on an ambitious project which has recently commenced in Australia which will culminate in a grassroots citizens' assembly. One hundred and fifty Australians will be randomly selected from each electorate and will participate in a range of deliberative environments (online and face-to-face), culminating in a four-day citizens' parliament in Sydney. The project is jointly funded by an Australian Research Council-Linkage grant and a not-for-profit organisation, newDemocracy. During the entire process, typical Australians will consider ways in which Australia's political system could be strengthened to better represent the will of the people

Deliberative public participation and hexachlorobenzene stockpiles

a b s t r a c t This paper is concerned with the quality of citizen involvement in relation to the governance of industrial risks. Specifically, it explores the hexachlorobenzene (HCB) case relative to best practice public participation, which is consistent with deliberative democratic theory. The case could be judged a public participation failure given that the community committee in combination with the corporate sponsor was unable to agree on a mutually acceptable technological pathway. This stalemate might have been attributable in part to the time spent on the task of review. A diligent participation working party could have created a much more effective public participation plan, grounded in the core values of professional public participation practice

Improving Public Deliberative Practice: A Comparative Analysis of Two Italian Citizens’ Jury Projects in 2006

Recently the author was invited to Italy, by the Regional Government of Tuscany, the University of Bologna and the University of Turin. The three institutions asked the author to speak about random sampling as a means to include missing voices in political decision making, i.e. the voices of those who usually remain unheard (see Carson & Martin 1999). Their interest was with the author’s work in the field of deliberative democracy and its practical expression, democratic deliberative processes, best exemplified by citizens’ juries (see, for example, Carson & Martin 1999, Carson & Hart 2005, Carson & Hartz-Karp 2005, Carson 2004, Carson 2003, Carson et al. 2002, Crosby 2003). Inevitably the author was drawn into deep discussions about the two recent attempts to convene citizens’ juries (CJs) in Bologna and Turin (both in 2006). It became apparent, as it had already to the convenors from the Universities of Bologna and Torino (Turin), that both attempts were ambitious and well executed but still fell short of the convenors’ ideals. This paper draws together the author’s reflections about the concerns that were heard during these discussions. Advice was sought, and that advice is repeated here. These observations may be helpful for those embarking on similar experiments for the first time