The narrative paradox of the BRCA gene: An ethnographic study in the clinical encounters of ovarian cancer patients

In this era of personalisation a patient’s molecular profile plays an increasingly central role in development and delivery of personalised medicine. This paper sets out to explore the sociocultural implications of mainstreaming BRCA genetic testing in the treatment of advanced ovarian cancer patients, who carry a BRCA1 or BRCA2 gene mutation. It draws on ethnographic research conducted by between April-June 2016 in a large tertiary London hospital. Participant observation was conducted across two sites. For the first two weeks participant observation was conducted in the traditional genetic testing setting in two separate clinics. From thereon, participant observation was conducted in the clinical encounters of treating patients in the ovarian cancer clinic. In addition, face-to-face interviews were conducted with medical oncologists who worked in the clinic. Contributing to the fields of cancer genetics, personalised medicine and medical material culture studies in medical anthropology the paper seeks to further discussions about the interactions and relationships unfolding between medical objects and subjects across the landscape of cancer care. It highlights the importance of clinic-based ethnography to examine the complexities of identities and technologies as they intersect with the themes of suffering and hope in new and contradictory ways for BRCA-positive patients with late-stage disease. The paper argues that a BRCA mutation is not only central to the political economy of hope but takes on a more materialist nature as it becomes an embodied practice that moves in and beyond the clinic

Integrating agri-environmental indicators, ecosystem services assessment, life cycle assessment and yield gap analysis to assess the environmental sustainability of agriculture

Agriculture's primary function is the production of food, feed, fibre and fuel for the fast-growing world population. However, it also affects human health and ecosystem integrity. Policymakers make policies in order to avoid harmful impacts. How to assess such policies is a challenge. In this paper, we propose a conceptual framework to help evaluate the impacts of agricultural policies on the environment. Our framework represents the global system as four subsystems and their interactions. These four components are the cells of a 2 by 2 matrix [Agriculture, Rest of the word]; [Socio-eco system, Ecological system]. We then developed a set of indicators for environmental issues and positioned these issues in the framework. To assess these issues, we used four well-known existing approaches: Life Cycle Assessment, Ecosystem Services Analysis, Yield Gap Analysis and Agro-Environmental Indicators. Using these four approaches together provided a more holistic view of the impacts of a given policy on the system. We then applied our framework on existing cover crop policies using an extensive literature survey and analysing the different environmental issues mobilised by the four assessment approaches. This demonstration case shows that our framework may be of help for a full systemic assessment. Despite their differences (aims, scales, standardization, data requirements, etc.), it is possible and profitable to use the four approaches together. This is a significant step forward, though more work is needed to produce a genuinely operational tool. © 2022 The Author

Point Mutations in GLI3 Lead to Misregulation of its Subcellular Localization

Background Mutations in the transcription factor GLI3, a downstream target of Sonic Hedgehog (SHH) signaling, are responsible for the development of malformation syndromes such as Greig-cephalopolysyndactyly-syndrome (GCPS), or Pallister-Hall-syndrome (PHS). Mutations that lead to loss of function of the protein and to haploinsufficiency cause GCPS, while truncating mutations that result in constitutive repressor function of GLI3 lead to PHS. As an exception, some point mutations in the C-terminal part of GLI3 observed in GCPS patients have so far not been linked to loss of function. We have shown recently that protein phosphatase 2A (PP2A) regulates the nuclear localization and transcriptional activity a of GLI3 function. Principal Findings We have shown recently that protein phosphatase 2A (PP2A) and the ubiquitin ligase MID1 regulate the nuclear localization and transcriptional activity of GLI3. Here we show mapping of the functional interaction between the MID1-α4-PP2A complex and GLI3 to a region between amino acid 568-1100 of GLI3. Furthermore we demonstrate that GCPS-associated point mutations, that are located in that region, lead to misregulation of the nuclear GLI3-localization and transcriptional activity. GLI3 phosphorylation itself however appears independent of its localization and remains untouched by either of the point mutations and by PP2A-activity, which suggests involvement of an as yet unknown GLI3 interaction partner, the phosphorylation status of which is regulated by PP2A activity, in the control of GLI3 subcellular localization and activity. Conclusions The present findings provide an explanation for the pathogenesis of GCPS in patients carrying C-terminal point mutations, and close the gap in our understanding of how GLI3-genotypes give rise to particular phenotypes. Furthermore, they provide a molecular explanation for the phenotypic overlap between Opitz syndrome patients with dysregulated PP2A-activity and syndromes caused by GLI3-mutations

The Effect of Sugar-Free Versus Sugar-Sweetened Beverages on Satiety, Liking and Wanting: An 18 Month Randomized Double-Blind Trial in Children

BACKGROUND: Substituting sugar-free for sugar-sweetened beverages reduces weight gain. A possible explanation is that sugar-containing and sugar-free beverages cause the same degree of satiety. However, this has not been tested in long-term trials. METHODS: We randomized 203 children aged 7-11 years to receive 250 mL per day of an artificially sweetened sugar-free beverage or a similarly looking and tasting sugar-sweetened beverage. We measured satiety on a 5-point scale by questionnaire at 0, 6, 12 and 18 months. We calculated the change in satiety from before intake to 1 minute after intake and 15 minutes after intake. We then calculated the odds ratio that satiety increased by 1 point in the sugar-group versus the sugar-free group. We also investigated how much the children liked and wanted the beverages. RESULTS: 146 children or 72% completed the study. We found no statistically significant difference in satiety between the sugar-free and sugar-sweetened group; the adjusted odds ratio for a 1 point increase in satiety in the sugar group versus the sugar-free group was 0.77 at 1 minute (95% confidence interval, 0.46 to 1.29), and 1.44 at 15 minutes after intake (95% CI, 0.86 to 2.40). The sugar-group liked and wanted their beverage slightly more than the sugar-free group, adjusted odds ratio 1.63 (95% CI 1.05 to 2.54) and 1.65 (95% CI 1.07 to 2.55), respectively. CONCLUSIONS: Sugar-sweetened and sugar-free beverages produced similar satiety. Therefore when children are given sugar-free instead of sugar-containing drinks they might not make up the missing calories from other sources. This may explain our previous observation that children in the sugar-free group accumulated less body fat than those in the sugar group.<br /

A Genome-Wide RNAi Screen Identifies Regulators of Cholesterol-Modified Hedgehog Secretion in Drosophila

Hedgehog (Hh) proteins are secreted molecules that function as organizers in animal development. In addition to being palmitoylated, Hh is the only metazoan protein known to possess a covalently-linked cholesterol moiety. The absence of either modification severely disrupts the organization of numerous tissues during development. It is currently not known how lipid-modified Hh is secreted and released from producing cells. We have performed a genome-wide RNAi screen in Drosophila melanogaster cells to identify regulators of Hh secretion. We found that cholesterol-modified Hh secretion is strongly dependent on coat protein complex I (COPI) but not COPII vesicles, suggesting that cholesterol modification alters the movement of Hh through the early secretory pathway. We provide evidence that both proteolysis and cholesterol modification are necessary for the efficient trafficking of Hh through the ER and Golgi. Finally, we identified several putative regulators of protein secretion and demonstrate a role for some of these genes in Hh and Wingless (Wg) morphogen secretion in vivo. These data open new perspectives for studying how morphogen secretion is regulated, as well as provide insight into regulation of lipid-modified protein secretion