IDH1-mutated Crohn's disease-associated small bowel adenocarcinomas: Distinctive pathological features and association with MGMT methylation and serrated-type dysplasia

Aims: Patients with Crohn's disease (CrD) have an elevated risk for the development of small bowel adenocarcinomas (SBAs). Actionable isocitrate dehydrogenase 1 (IDH1) mutations have been reported to be more frequent in CrD-SBAs than in sporadic SBAs. The present study aimed to investigate the clinicopathological and immunophenotypical features, as well as methylation profiles, of IDH1-mutated CrD-SBAs. Methods and results: An international multicentre series of surgically resected CrD-SBAs was tested for IDH1 mutation. Clinicopathological features, immunophenotypical marker expression and O6-methylguanine-DNA methyltransferase (MGMT) and long interspersed nuclear element-1 (LINE-1) methylation were compared between IDH1-mutated and IDH1 wild-type CrD-SBAs. Ten (20%) of the 49 CrD-SBAs examined harboured an IDH1 mutation and all the mutated cancers harboured the R132C variant. Compared to IDH1 wild-type cases, IDH1-mutated CrD-SBAs showed significantly lower rates of cytokeratin 7 expression (P = 0.005) and higher rates of p53 overexpression (P = 0.012) and MGMT methylation (P = 0.012). All three dysplastic growths associated with IDH1-mutated SBAs harboured the same IDH1 variant (R132C) of the corresponding invasive cancer, and all were of non-conventional subtype (two serrated dysplastic lesions and one goblet cell-deficient dysplasia). In particular, non-conventional serrated dysplasia was significantly associated with IDH1-mutated CrD-SBAs (P = 0.029). No significant cancer-specific survival difference between IDH1-mutated CrD-SBA patients and IDH1 wild-type CrD-SBA patients was found (hazard ratio = 0.55, 95% confidence interval = 0.16–1.89; P = 0.313). Conclusions: IDH1-mutated CrD-SBAs, which represent approximately one-fifth of total cases, are characterised by distinctive immunophenotypical features and methylation profiles, with potential therapeutic implications. Moreover, IDH1-mutated non-conventional, serrated dysplasia is likely to represent a precursor lesion to such CrD-SBAs

Prognostic relevance and putative histogenetic role of cytokeratin 7 and MUC5AC expression in Crohn\u2019s disease-associated small bowel carcinoma

Most Crohn\u2019s disease-associated small bowel carcinomas (CrD-SBCs) are diagnosed in advanced stage and have poor prognosis. To improve diagnosis and therapy, a better knowledge of tumour precancerous lesions, histotypes and prognostic factors is needed. We investigated histologically and immunohistochemically 52 CrD-SBCs and 51 small bowel carcinomas unrelated to inflammatory disease, together with their tumour-associated mucosa, looking for Crohn-selective changes. Histologic patterns and phenotypic markers potentially predictive of CrD-SBC histogenesis and prognosis were analysed. Cytokeratin 7 or MUC5AC-positive metaplastic changes were found in about half of investigated CrD-SBCs, significantly more frequently than in CrD-unrelated SBCs. They correlated with metaplastic changes of their associated mucosa, while being absent in normal ileal mucosa. Histologic patterns suggestive for progression of some cytokeratin 7 and/or MUC5AC-positive metaplastic lesions into cancer of the same phenotype were also observed. Patient survival analyses showed that tumour cytokeratin 7 or MUC5AC expression and non-cohesive histotype were adverse prognostic factors at univariable analysis, while cytokeratin 7 and non-cohesive histotype were also found to predict worse survival in stage- and age-inclusive multivariable analyses. Besides conventional dysplasia, hyperplasia-like non-conventional lesions were observed in CrD-SBC-associated mucosa, with patterns suggestive for a histogenetic link with adjacent cancer. In conclusion the cytokeratin 7 and/or MUC5AC-positive metaplastic foci and the non-conventional growths may have a role in cancer histogenesis, while tumour cytokeratin 7 and non-cohesive histotype may also predict poor patient survival. Present findings are worth being considered in future prospective histogenetic and clinical studies

Towards sustainable agriculture: fossil-free ammonia

Citation: Pfromm, P. H. (2017). Towards sustainable agriculture: Fossil-free ammonia. Journal of Renewable and Sustainable Energy, 9(3), 034702. https://doi.org/10.1063/1.4985090About 40% of our food would not exist without synthetic ammonia (NH3) for fertilization. Yet, NH3 production is energy intensive. About 2% of the world's commercial energy is consumed as fossil fuels for NH3 synthesis based on the century-old Haber-Bosch (H.-B.) process. The state of the art and the opportunities for reducing the fossil energy footprint of industrial H.-B. NH3 synthesis are discussed. It is shown that even a hypothetical utterly revolutionary H.-B. catalyst could not significantly reduce the energy demand of H.-B. NH3 as this is governed by hydrogen production. Renewable energy-enabled, fossil-free NH3 synthesis is then evaluated based on the exceptional and continuing cost decline of renewable electricity. H.-B. syngas (H2, N2) is assumed to be produced by electrolysis and cryogenic air separation, and then supplied to an existing H.-B. synthesis loop. Fossil-free NH3 could be produced for energy costs of about $232 per tonne NH3 without claiming any economic benefits for the avoidance of about 1.5 tonnes of CO2 released per tonne NH3 compared to the most efficient H.-B. implementations. Research into alternatives to the H.-B. process might be best targeted at emerging markets with currently little NH3 synthesis capacity but significant future population growth such as Africa. Reduced capital intensity, good scale-down economics, tolerance for process upsets and contamination, and intermittent operability are some desirable characteristics of NH3 synthesis in less developed markets, and for stranded resources. Processes that are fundamentally different from H.-B. may come to the fore under these specific boundary conditions

Public financing of innovation: new questions

Economic theory justifies policy when there are concrete market failures. The article shows how in the case of innovation, successful policies that have led to radical innovations have been more about market shaping and creating through direct and pervasive public financing, rather than market fixing. The paper reviews and discusses evidence for this in three key areas: (i) the presence of finance from public sources across the entire innovation chain; (ii) the concept of ‘mission-oriented’ policies that have created new technological and industrial landscapes; and (iii) the entrepreneurial and lead investor role of public actors, willing and able to take on extreme risks, independent of the business cycle. We further illustrate these three characteristics for the case of clean technology, and discuss how a market-creating and -shaping perspective may be useful for understanding the financing of transformative innovation needed for confronting contemporary societal challenges

Gender and recovery pathways in the UK

Recovery is now the defining feature of UK drug and alcohol policy. Despite this policy emphasis, little attention has been paid to the lived experience of those in recovery. Instead, research has typically concentrated on treatment populations, which are predominantly male. Consequently, we have little insight into recovery experiences in general, and specifically how they might differ for females and males. This article makes an important contribution through offering a unique insight into the addiction/recovery pathways of 342 female and 410 male participants using data gathered via the UK Life in Recovery survey. Participants were recruited via social media and recovery groups. Bivariate analyses were used to explore gender differences in relation to personal characteristics, addiction and recovery (self-defined), well-being, and family life. These data suggest that a greater proportion of females in recovery report having specific needs in relation to mental health and relationships with children or partners whilst a greater proportion of males disclosed having specific needs in relation to physical health. Whilst the findings reflect the importance of ongoing support for everyone in recovery, they also suggest the need to provide gender-responsive recovery support